16 - PART 9 Disorders of the Kidney and Urinary Tract

02 - 320 Cell Biology and Physiology of the Kidney

320 Cell Biology and Physiology of the Kidney

palpable mass best felt with the patient supine, usually in a thin patient but occasionally due to a very large protruding mass. Very large masses or multiple masses that are easily palpable may represent cystic diseases of the kidney, including PCKD or even a single cyst, versus a congenital ureteral pelvic obstruction. Other times, a renal cell carcinoma can present as anemia, possibly caused by hematuria, or as back pain asso­ ciated with metastatic lytic vertebral lesions. Metastases may involve the lungs and bone marrow as well. ■ ■IMAGING AND RENAL BIOPSY INDICATIONS For hematuric syndromes, imaging may provide valuable information, particularly in a patient who has heavy bleeding or blood clots in the urine. Renal pathology may be detected as an abdominal mass, as in the set­ ting of renal cell carcinoma, chronic UTO, or cystic diseases of the kidney including PCKD and simple cyst. If the patient has a known his­ tory of tubular sclerosis or the finding of skin fibroadenoma, one might identify a renal mass found on CT imaging as an angiomyolipoma. The renal ultrasound is efficacious in determining the size and sym­ metry of the kidneys and in excluding urinary obstruction. It is useful in detecting renal cysts or masses but less effective in kidney stone disease. Ultrasound is not as accurate a tool as a computed tomography (CT) scan for angiomyolipomas. The renal-limited noncontrast CT scan is the standard test for nephrolithiasis but carries the risk of accu­ mulative radiation. Magnetic resonance imaging (MRI) is often useful in evaluating and following renal masses, including renal cell carci­ noma. The patient with renal disease may develop a toxic complication of systemic sclerosis after receiving multiple gadolinium studies for MRI enhancement; new contrast agents to replace it are emerging. CT scans with high-osmolality iodinated contrast media, administered in large volumes, remain an important cause of AKI (contrast nephropa­ thy) in elderly male patients with vascular disease of the kidney, mul­ tiple myeloma, hepatic disease, extracellular fluid depletion, DM, or concurrent use of NSAIDs. The accompanied radiation is a concern for radiation exposure. Radioisotope scanning is useful in demonstrating the percentage of renal function coming from each kidney. Finally, in many of the diseases discussed above, diagnosis ultimately depends on renal biopsy and pathologic evaluation. ■ ■FURTHER READING Bhosale SJ, Kulkarni AP: Biomarkers in acute kidney injury. Indian J Crit Care Med 24:S90, 2020. Canki E et al: Urinary biomarkers in kidney disease. Clin Chim Acta 55:117798, 2024. Glassock RJ: Kidney biopsy is required for nephrotic syndrome with PLA2R+ and normal kidney function: Commentary. Kidney 360:894, 2020. Levey AS et al: Nomenclature for kidney function and disease: Report of Kidney Disease: Improving Global Outcomes (KDIGO) Consen­ sus Conference. Kidney Int 97:1117, 2020. Liang Y et al: Serum anti-phospholipase A2 receptor (PLA2R) anti­ body detected at diagnosis as a predictor for clinical remission in patients with primary membranous nephropathy: A meta-analysis. BMC Nephrol 20:360, 2019. Pollak MR, Friedman DJ: APOL1 and APOL1-associated kidney disease: A common disease, an unusual disease gene—Proceedings of the Henry Shavelle Professorship. Glomerular Dis 3:75, 2023. Ponticelli C et al: C3 glomerulopathies: Dense deposit disease and C3 glomerulonephritis. Front Med (Lausanne) 24:1289812, 2023. Romagnani P et al: The five types of glomerulonephritis classified by pathogenesis, activity and chronicity (GN-AC). Nephrol Dial Trans­ plant 38:ii3, 2023. Rysz J et al: Novel biomarkers in the diagnosis of chronic kidney dis­ ease and the prediction of its outcome. Int J Mol Sci 18:1702, 2017. Vijay P et al: Cystatin C: Best biomarker for acute kidney injury and estimation of glomerular filtration rate in childhood cirrhosis. Eur J Pediatr 180:3287, 2021. Vink CH et al: Antibody-guided therapy in phospholipase A-2 recep­ tor associated membranous nephropathy. Clin Res 8:432, 2023.

Alfred L. George, Jr., Eric G. Neilson

Cell Biology and

Physiology of the Kidney The kidney is one of the most highly differentiated organs in the body. At the conclusion of embryologic development, nearly 30 different cell types form a multitude of filtering capillaries and segmented nephrons enveloped by a dynamic interstitium. This cellular diversity modulates a variety of complex physiologic processes. Endocrine functions, the regulation of blood pressure and intraglomerular hemodynamics, solute and water transport, acid-base balance, and removal of drug metabolites are all accomplished by intricate mechanisms of renal response. This breadth of physiology hinges on the clever ingenuity of nephron architecture that evolved as complex organisms came out of water to live on land. EMBRYOLOGIC DEVELOPMENT Kidneys develop from intermediate mesoderm under the timed or sequential control of a growing number of genes, described in Fig. 320-1. The transcription of these genes are determined or guided by morphogenic cues, the orientation of cilia-derived planar cell polar­ ity, and the generational legacy of epigenetic marks that invite two ureteric buds to each penetrate bilateral metanephric blastema, where they induce primary mesenchymal cells to form early nephrons. The two ureteric buds emerge from posterior nephric ducts and mature into separate collecting systems that eventually form a renal pelvis and ureter. Induced mesenchyme undergoes mesenchymal epithelial transitions to form comma-shaped bodies at the proximal end of each ureteric bud leading to the formation of S-shaped nephrons that cleft and enjoin with penetrating endothelial cells derived from sprouting angioblasts. Under the influence of vascular endothelial growth factor A (VEGF-A), these penetrating cells form capillaries with surrounding mesangial cells that differentiate into a glomerular filter for plasma water and solute. The ureteric buds branch, and each branch produces a new set of nephrons. The number of branching events ultimately determines the total number of nephrons in each kidney. There are ~900,000 glomeruli in each kidney in normal-birth-weight adults and as few as 225,000 in low-birth-weight adults, with the latter producing numerous comorbid risks. CHAPTER 320 Cell Biology and Physiology of the Kidney Glomeruli evolve as complex capillary filters with fenestrated endo­ thelia under the guiding influence of VEGF-A and angiopoietin-1 secreted by adjacently developing podocytes. Epithelial podocytes facing the urinary space envelop the exterior basement membrane sup­ porting these emerging endothelial capillaries. Podocytes are partially polarized and periodically slough into the urinary space by epithelialmesenchymal transition and, to a lesser extent, apoptosis, only to be replenished by migrating parietal epithelia from Bowman capsule. Impaired replenishment results in heavy proteinuria. Podocytes attach to the basement membrane by special foot processes and share a slitpore membrane with their neighbor. The slit-pore membrane forms a filter for plasma water and solute by the synthetic interaction of nephrin, annexin-4, CD2AP, FAT, ZO-1, P-cadherin, podocin, TRPC6, PLCE1, and Neph 1-3 proteins. Mutations in many of these proteins also result in heavy proteinuria. The glomerular capillaries are embed­ ded in a mesangial matrix shrouded by parietal and proximal tubular epithelia forming Bowman capsule. Mesangial cells have an embryonic lineage consistent with arteriolar or juxtaglomerular cells and contain contractile actin-myosin fibers. These mesangial cells make contact with glomerular capillary loops, and their local matrix holds them in condensed arrangement. Between nephrons lies the renal interstitium. This region forms a functional space surrounding glomeruli and their downstream tubules, which are home to resident and trafficking cells such as fibroblasts, dendritic cells, occasional lymphocytes, and lipid-laden macrophages. The cortical and medullary peritubular capillaries, which siphon off

Brn1 DII1 Jag1 Lhx1 Wnt4 Emx2 Fgf8 Notch2 Notch1 Lgr5 S-shape Comma-shape Pax2 Gdnf/Ret Lhx1 Cited1 Six1 Itga8/Itgb1 Fgfr2 Hoxa11/Hoxd11 Foxd1 Slit2/Robo2 Wt1 Pretubular aggregation Ureteric bud induction and condensation Nephrogenesis FIGURE 320-1  Genes controlling renal nephrogenesis. A growing number of genes have been identified at various stages of glomerulotubular development in the mammalian kidney. The genes listed have been tested in various genetically modified mice, and their location corresponds to the classical stages of kidney development postulated by Saxen in 1987. solute and water following tubular reclamation of glomerular filtrate, are also part of the interstitial fabric as well as a web of connective tissue that supports the kidney’s emblematic architecture of folding tubules. The relational precision of these structures determines the unique physiology of the kidney. PART 9 Disorders of the Kidney and Urinary Tract Each nephron is partitioned during embryologic development into a proximal tubule, descending and ascending limbs of the loop of Henle, distal tubule, and the collecting duct. These classic tubular segments build from subsegments lined by highly unique epithelia serving regional physiology. All nephrons have the same structural components, but there are two types whose structures depend on their location within the kidney. The majority of nephrons are cortical, with glomeruli located in the mid-to-outer cortex. Fewer nephrons are juxtamedullary, with glomeruli at the boundary of the cortex and outer medulla. Cortical nephrons have short loops of Henle, whereas juxtamedullary nephrons have long loops of Henle. There are critical differences in blood supply as well. The peritubular capillaries surrounding cortical nephrons are shared among adjacent nephrons. By contrast, juxtamedullary nephrons depend on indi­ vidual capillaries called vasa recta that run alongside the long loops of Henle. Cortical nephrons perform most of the glomerular filtration because there are more of them and because their afferent arterioles are larger than their respective efferent arterioles. The juxtamedul­ lary nephrons, with longer loops of Henle, create an osmotic gradient for concentrating urine. How developmental instructions specify the differentiation of all these unique epithelia among various tubular segments is still unknown. DETERMINANTS AND REGULATION OF GLOMERULAR FILTRATION Renal blood flow normally drains ~20% of the cardiac output, or 1000 mL/min. Blood reaches each nephron through the afferent arte­ riole leading into a glomerular capillary where ultrafiltration forms the tubular fluid. The distal ends of the glomerular capillaries coalesce to form an efferent arteriole leading to the first segment of a second capillary network (cortical peritubular capillaries or medullary vasa recta) surrounding the tubules (Fig. 320-2A). Thus, nephrons have two capillary beds arranged in a series separated by the efferent arteriole that regulates the hydrostatic pressure in both capillary beds. The distal capillaries empty into small venous branches that coalesce into larger veins to eventually form the renal vein. The hydrostatic pressure gradient across the glomerular capillary wall is the primary driving force for glomerular filtration. Oncotic pressure within the capillary lumen, determined by the concentration of unfiltered plasma proteins, partially offsets the hydrostatic pressure gradient and opposes filtration. As the oncotic pressure rises along the length of the glomerular capillary, the driving force for filtration

Hnf1b VEGF-A/Kdr (Flk-1) Tcf21 Foxc2 Lmx1b Itga3/Itgb1 Pdgfb/Pdgfbr Cxcr4/Cxcl12 Nphs1 Nck1/Nck2 Cd36 CD2AP
Neph1 Nphs2 Lamb2 Capillary loop Mature glomerulus falls to zero en route to the efferent arteriole. Approximately 20% of the renal plasma flow is filtered into Bowman space, and the ratio of glomerular filtration rate (GFR) to renal plasma flow determines the filtration fraction. Several factors, mostly hemodynamic, contribute to the regulation of filtration under physiologic conditions. Although glomerular filtration is affected by renal artery pressure, this relationship is not linear across the range of physiologic blood pressures due to autoregulation of GFR. Autoregulation of glomeru­ lar filtration is the result of three major factors that modulate either afferent or efferent arteriolar tone; these include an autonomous vaso­ reactive (myogenic) reflex in the afferent arteriole, tubuloglomerular feedback (TGF), and angiotensin II–mediated vasoconstriction of the efferent arteriole. The myogenic reflex is a first line of defense against fluctuations in renal blood flow. Acute changes in renal perfusion pres­ sure evoke reflex constriction or dilatation of the afferent arteriole in response to rising or falling pressure, respectively. This phenomenon helps protect the glomerular capillary from sudden changes in systolic pressure. TGF changes the rate of filtration and tubular flow by reflex vaso­ constriction or dilatation of the afferent arteriole. TGF is mediated by specialized cells in the thick ascending limb of the loop of Henle called the macula densa that act as sensors of solute concentration and tubular fluid flow rate. With high tubular flow rates, a proxy for an inappropriately high filtration rate, greater solute delivery to the macula densa (Fig. 320-2B) evokes vasoconstriction of the afferent arteriole, causing GFR to return toward normal. One component of the soluble signal from the macula densa is adenosine triphosphate (ATP) released by the cells during increased NaCl reabsorption. ATP is metabolized in the extracellular space to generate adenosine, a potent vasoconstrictor of the afferent arteriole. During conditions associated with a fall in filtration rate, a lower rate of solute delivery to the macula densa attenuates TGF, allowing afferent arteriolar dilatation and restor­ ing GFR to normal levels. Angiotensin II and reactive oxygen species enhance TGF, whereas nitric oxide (NO) blunts TGF. A distinct feed­ back mechanism may exist between the connecting tubule and GFR in which high Na+ delivery evokes afferent arteriolar dilation possibly mediated by prostaglandins. The third component underlying autoregulation of GFR involves angiotensin II. During states of reduced renal blood flow, renin is released from granular cells within the wall of the afferent arteriole near the macula densa in a region called the juxtaglomerular apparatus (Fig. 320-2B). Renin, a proteolytic enzyme, catalyzes the conversion of angiotensinogen to angiotensin I, which is subsequently converted to angiotensin II by angiotensin-converting enzyme (ACE) (Fig. 320-2C). Angiotensin II evokes vasoconstriction of the efferent arteriole, and the resulting increased glomerular hydrostatic pressure elevates GFR to normal levels.

Peritubular Proximal convoluted tubule capillaries Efferent arteriole Efferent arteriole Distal convoluted tubule Bowman capsule Glomerulus Afferent arteriole Thick ascending limb Proximal tubule Collecting duct B Peritubular venules A Angiotensinogen Asp-Arg-Val-Tyr-IIe-His-Pro-Phe-His-Leu - Val-IIe-His Angiotensin I Asp-Arg-Val-Tyr-IIe-His-Pro-Phe - His-Leu Angiotensin II Asp-Arg-Val-Tyr-IIe-His-Pro-Phe Angiotensin (I-VII) Asp-Arg-Val-Tyr-IIe-His-Pro C FIGURE 320-2  Renal microcirculation and the renin-angiotensin system. A. Diagram illustrating relationships of the nephron with glomerular and peritubular capillaries. B. Expanded view of the glomerulus with its juxtaglomerular apparatus including the macula densa and adjacent afferent arteriole. C. Proteolytic processing steps in the generation of angiotensins. MECHANISMS OF RENAL

TUBULAR TRANSPORT The renal tubules are composed of highly differentiated epithelia that vary in morphology and function along the nephron (Fig. 320-3). The cells lining the various tubular segments form monolayers connected to one another by a specialized region of the adjacent lateral membranes called the tight junction. Tight junctions form an occlusive barrier that separates the lumen of the tubule from the interstitial spaces surrounding the tubule and also apportions the cell membrane into discrete domains: the apical membrane facing the tubular lumen and the basolateral membrane facing the interstitium. This regionalization allows cells to allocate membrane proteins and lipids asymmetrically. Owing to this feature, renal epithelial cells are said to be polarized. The asymmetric assignment of membrane proteins, especially proteins mediating transport pro­ cesses, provides the machinery for directional movement of fluid and solutes by the nephron. ■ ■EPITHELIAL SOLUTE TRANSPORT There are two types of epithelial transport. Movement of fluid and solutes sequentially across the apical and basolateral cell membranes

Extraglomerular mesangial cells Glomerulus Macula densa Afferent arteriole Renin-secreting granular cells Proximal tubule Thick ascending limb CHAPTER 320 Renin Cell Biology and Physiology of the Kidney ACE ACE2 (or vice versa) mediated by transporters, channels, or pumps is called cellular transport. By contrast, movement of fluid and solutes through the narrow passageway between adjacent cells is called paracellular transport. Paracellular transport occurs through tight junctions, indi­ cating that they are not completely “tight” or occlusive. Indeed, some epithelial cell layers allow rather robust paracellular transport to occur (leaky epithelia), whereas other epithelia have more restrictive tight junctions (tight epithelia). In addition, because the ability of ions to flow through the paracellular pathway determines the electrical resistance across the epithelial monolayer, leaky and tight epithelia are also referred to as low- or high-resistance epithelia, respectively. The proximal tubule contains leaky epithelia, whereas distal nephron segments, such as the collecting duct, contain tight epithelia. Leaky epithelia are most well suited for bulk fluid reabsorption, whereas tight epithelia allow for more refined control and regulation of transport. ■ ■MEMBRANE TRANSPORT Cell membranes are composed of hydrophobic lipids that repel water and aqueous solutes. The movement of solutes and water across cell membranes is made possible by discrete classes of integral membrane

proteins, including channels, pumps, and transporters. These different mechanisms mediate specific types of transport activities, including active transport (pumps), passive transport (channels), facilitated diffusion (transporters), and secondary active transport (cotransporters). Active transport requires metabolic energy generated by the hydrolysis of ATP. Active transport pumps are ion-translocating ATPases, including the ubiquitous Na+/K+-ATPase, the H+-ATPases, and Ca2+-ATPases. Active transport creates asymmetric ion concentrations across a cell membrane and can move ions against a chemical gradient. The poten­ tial energy stored in a concentration gradient of an ion such as Na+ can be used to drive transport through other mechanisms (secondary active transport). The movement of solutes through a membrane protein by simple diffusion is called passive transport. This activity is mediated by channels created by selectively permeable membrane proteins, and it allows solute or water to move across a membrane driven by favorable concentration gradients or electrochemical potential. Facilitated diffu­ sion is a specialized type of passive transport mediated by simple trans­ porters called carriers or uniporters. For example, hexose transporters such as GLUT2 mediate glucose transport by tubular cells. These transporters are driven by the concentration gradient for glucose that is highest in extracellular fluids and lowest in the cytoplasm due to rapid metabolism. Many other transporters operate by translocating two or more ions/solutes in concert either in the same direction (symporters or cotransporters) or in opposite directions (antiporters or exchangers) across the cell membrane. The movement of two or more ions/solutes may produce no net change in the balance of electrostatic charges across the membrane (electroneutral), or a transport event may alter the balance of charges (electrogenic). Several inherited disorders of renal tubular solute and water transport occur as a consequence of mutations

PART 9 Disorders of the Kidney and Urinary Tract CORTEX Macula densa Cortical collecting duct Distal convoluted tubule Proximal tubule Bowman capsule Vein Artery Connecting tubule SGLT2 inhibitors MEDULLA Loop of Henle: Thin descending limb Thick ascending limb Thin ascending limb Inner medullary collecting duct A FIGURE 320-3  Transport activities of the major nephron segments. Representative cells from five major tubular segments are illustrated with the lumen side (apical membrane) facing left and interstitial side (basolateral membrane) facing right. A. Overview of entire nephron. B. Proximal tubular cells. C. Typical cell in the thick ascending limb of the loop of Henle. D. Distal convoluted tubular cell. E. Cortical collecting duct principal cell. F. Cortical collecting duct type A and type B intercalated cells. G. Typical cell in the inner medullary collecting duct. The major membrane transporters, channels, and pumps are drawn with arrows indicating the direction of solute or water movement. For some events, the stoichiometry of transport is indicated by numerals preceding the solute. Targets for major diuretic agents are labeled. The actions of hormones are illustrated by arrows with plus signs for stimulatory effects and lines with perpendicular ends for inhibitory events. The dashed line indicates water impermeability of cell membranes in the thick ascending limb and distal convoluted tubule.

in genes encoding a variety of channels, transporter proteins, and their regulators (Table 320-1). The rate of tubular fluid flow through the nephron is highly variable, for which reason ion transport needs to be adjusted accordingly. Renal epithelial cells have the ability to monitor tubular fluid flow by mecha­ nisms involving cellular structures (apical microvilli, primary cilium) or mechanosensing ion channels. Tubular transport is regulated in response to changes in fluid flow through changes in intracellular Ca2+ or by purinergic receptor-mediated signal transduction. SEGMENTAL NEPHRON FUNCTIONS Each anatomic segment of the nephron has unique characteristics and specialized functions enabling selective transport of solutes and water (Fig. 320-3A). Through sequential events of reabsorption and secretion along the nephron, tubular fluid is progressively conditioned into urine. Knowledge of the major tubular mechanisms responsible for solute and water transport is critical for understanding hormonal regulation of kidney function and the pharmacologic manipulation of renal excretion. PROXIMAL TUBULE The proximal tubule is responsible for reabsorbing ~60% of filtered NaCl and water, as well as ~90% of filtered bicarbonate and most critical nutrients such as glucose and amino acids. The proximal tubule uses both cellular and paracellular transport mechanisms. The apical membrane of proximal tubular cells has an expanded surface area available for reabsorption created by a dense array of microvilli called the brush border, and leaky tight junctions enable high-capacity fluid reabsorption. PROXIMAL TUBULE Lumen Interstitium Apical Basolateral HPO4 + H Na H 3Na 2K H2O H2PO4 Na Phosphate Na Glucose Glucose Na Amino acids Amino acids H2O, solutes Na H 3Na 2K NH4 Formic acid NH3 Cl K HCO3 + H
H Cl Formate Na 3HCO3 H2CO3 H2CO3 carbonic anhydrase carbonic anhydrase H2O + CO2 CO2 B

THICK ASCENDING LIMB Lumen Interstitium Loop diuretics 3Na Na K 2Cl 2K Cl K Ca H2O + – Ca, Mg C DISTAL CONVOLUTED TUBULE Lumen Interstitium Thiazides 3Na Na Cl 2K Cl Mg Ca 3Na Ca H2O D CORTICAL COLLECTING DUCT Lumen Interstitium Amiloride Principal cell Na 3Na 2K + + Spironolactone Eplerenone K Aldosterone + + Vasopressin + + H2O H2O E FIGURE 320-3  (Continued) Solute and water pass through these tight junctions to enter the lateral intercellular space where absorption by the peritubular capil­ laries occurs. Bulk fluid reabsorption by the proximal tubule is driven by high oncotic pressure and low hydrostatic pressure within the peri­ tubular capillaries. Cellular transport of most solutes by the proximal tubule is coupled to the Na+ concentration gradient established by the activity of a basolateral Na+/K+-ATPase (Fig. 320-3B). This active transport mechanism maintains a steep Na+ gradient by keep­ ing intracellular Na+ concentrations low. Solute reabsorption from

CORTICAL COLLECTING DUCT Type A intercalated cell Lumen Interstitium 3Na 2K H carbonic anhydrase H K HCO3 Cl Type B intercalated cell 3Na 2K carbonic anhydrase CHAPTER 320 HCO3 Cl H F Cell Biology and Physiology of the Kidney INNER MEDULLARY COLLECTING DUCT Lumen Interstitium ANP Na 3Na K 2K Vasopressin Urea + + H2O H2O G the tubular lumen is coupled to the Na+ gradient by Na+-dependent transporters such as Na+-glucose and Na+-phosphate cotransporters present in apical membranes. In addition to the paracellular route, water reabsorption also occurs through the cellular pathway enabled by constitutively active water channels (aquaporin-1) present on both apical and basolateral membranes. Proximal tubular cells reclaim nearly all filtered bicarbonate by a mechanism dependent on carbonic anhydrases. Filtered bicarbonate is first titrated by protons delivered to the lumen mainly by apical

TABLE 320-1  Inherited Disorders Affecting Renal Tubular Ion and Solute Transport DISEASE OR SYNDROME PROTEIN (GENE) OMIMa Disorders Involving the Proximal Tubule Proximal renal tubular acidosis Sodium bicarbonate cotransporter (SLC4A4, 4q21)

Fanconi-Bickel syndrome Glucose transporter, GLUT2 (SLC2A2, 3q26.2)

Isolated renal glycosuria Sodium glucose cotransporter (SLC5A2, 16p11.2)

Cystinuria   Type I Cystine, dibasic and neutral amino acid transporter (SLC3A1, 2p16.3)

  Non-type I Amino acid transporter, light subunit (SLC7A9, 19q13.1)

Lysinuric protein intolerance Amino acid transporter (SLC7A7, 4q11.2)

Dicarboxylic aminoaciduria Glutamate transporter (SLC1A1, 9q24.2)

Hartnup disorder Neutral amino acid transporter (SLC6A19, 5p15.33)

Hypophosphatemic nephrolithiasis/osteoporosis 1 Sodium phosphate cotransporter (SLC34A1, 5q35.3)

Hereditary hypophosphatemic rickets with hypercalcemia Sodium phosphate cotransporter (SLC34A3, 9q34)

Renal hypouricemia   Type 1 Urate-anion exchanger (SLC22A12, 11q13)

  Type 2 Urate transporter, GLUT9 (SLC2A9, 4p16.1)

Dent’s disease Chloride channel, ClC-5 (CLCN5, Xp11.22)

X-linked recessive nephrolithiasis with renal failure Chloride channel, ClC-5 (CLCN5, Xp11.22)

PART 9 Disorders of the Kidney and Urinary Tract X-linked recessive hypophosphatemic rickets Chloride channel, ClC-5 (CLCN5, Xp11.22)

Disorders Involving the Loop of Henle Bartter’s syndrome   Type 1 Sodium, potassium chloride cotransporter (SLC12A1, 15q21.1)

  Type 2 Potassium channel, ROMK (KCNJ1, 11q24)

  Type 3 Chloride channel, ClC-Kb (CLCNKB, 1p36)

  with sensorineural deafness Chloride channel accessory subunit, Barttin (BSND, 1p31)

Autosomal dominant hypocalcemia with Bartter-like syndrome Calcium-sensing receptor (CASR, 3q13.33)

Familial hypocalciuric hypercalcemia Calcium-sensing receptor (CASR, 3q13.33)

Familial hypomagnesemia type 3 Claudin-16 (CLDN16, 3q27)

Familial hypomagnesemia type 5 Claudin-19 (CLDN19, 1p34.2)

Isolated renal magnesium loss Sodium potassium ATPase, γ1-subunit (ATP1G1, 11q23)

Disorders Involving the Distal Tubule and Collecting Duct Gitelman syndrome Sodium chloride cotransporter (SLC12A3, 16q13)

Primary hypomagnesemia with secondary hypocalcemia Melastatin-related transient receptor potential cation channel 6 (TRPM6, 9q22)

Pseudoaldosteronism (Liddle’s syndrome) Epithelial sodium channel β and γ subunits (SCNN1B, SCNN1G, 16p12.1)

Recessive pseudohypoaldosteronism type 1 Epithelial sodium channel, α, β, and γ subunits (SCNN1A, 12p13; SCNN1B, SCNN1G, 16pp12.1)

Pseudohypoaldosteronism type 2 (Gordon’s hyperkalemia-hypertension syndrome) Kinases WNK-1, WNK-4 (WNK1, 12p13; WNK4, 17q21.31)

X-linked nephrogenic diabetes insipidus Vasopressin V2 receptor (AVPR2, Xq28)

EAST/SeSAME syndrome Potassium channel Kir4.1 (KCNJ10, 1q23.2)

Nephrogenic diabetes insipidus (autosomal) Water channel, aquaporin-2 (AQP2, 12q13)

Distal renal tubular acidosis   autosomal dominant Anion exchanger-1 (SLC4A1, 17q21.31)

  autosomal recessive Anion exchanger-1 (SLC4A1, 17q21.31)

  with neural deafness Proton ATPase, β1 subunit (ATP6V1B1, 2p13.3)

  with normal hearing Proton ATPase, 116-kD subunit (ATP6V0A4, 7q34)

aOnline Mendelian Inheritance in Man database (https://www.ncbi.nlm.nih.gov/omim). membrane Na+/H+ exchange. The resulting carbonic acid (H2CO3) is metabolized by brush border carbonic anhydrase to water and carbon dioxide. Dissolved carbon dioxide then diffuses into the cell, where it is enzymatically hydrated by cytoplasmic carbonic anhydrase to re-form carbonic acid. Finally, intracellular carbonic acid dissociates into free protons and bicarbonate anions, and bicarbonate exits the cell through a basolateral Na+/HCO3 − cotransporter. This process is saturable, which can result in renal bicarbonate excretion when plasma levels exceed the physiologically normal range (24–26 meq/L). Carbonic anhydrase

inhibitors such as acetazolamide block proximal tubule bicarbonate reabsorption and are useful for alkalinizing the urine. The proximal tubule contributes to acid secretion by two mechanisms involving the titration of the urinary buffers ammonia (NH3) and phos­ phate. Renal NH3 is produced by glutamine metabolism in the proximal tubule. Subsequent diffusion of NH3 out of the proximal tubular cell enables trapping of H+, which is secreted by apical Na+/H+ exchange, in the lumen as ammonium ion (NH4 +). Cellular K+ levels inversely modu­ late proximal tubular ammoniagenesis, and in the setting of high serum

K+ from hypoaldosteronism, reduced ammoniagenesis promotes type IV renal tubular acidosis. Filtered hydrogen phosphate ion (HPO4 2−) is also titrated in the proximal tubule by secreted H+ to form H2PO4 −, and this reaction constitutes a major component of the urinary buffer referred to as titratable acid. Most filtered phosphate ion is reabsorbed by the proximal tubule through a sodium-coupled cotransport process that is regulated by parathyroid hormone (PTH). Chloride is poorly reabsorbed throughout the first segment of the proximal tubule, and a rise in Cl− concentration counterbalances the removal of bicarbonate anion from tubular fluid. In later proxi­ mal tubular segments, cellular Cl− reabsorption is initiated by apical exchange of cellular formate for higher luminal concentrations of Cl−. Once in the lumen, formate anions are titrated by H+ (provided by Na+/H+ exchange) to generate neutral formic acid, which can diffuse passively across the apical membrane back into the cell where it dis­ sociates a proton and is recycled. Basolateral Cl− exit is mediated by a K+/Cl− cotransporter. Reabsorption of glucose is nearly complete by the end of the proxi­ mal tubule. Cellular transport of glucose is mediated by apical Na+- glucose cotransport coupled with basolateral, facilitated diffusion by a glucose transporter. This process is also saturable, leading to glycosuria when plasma levels exceed 180–200 mg/dL, as seen in untreated dia­ betes mellitus. Inhibitors of the Na+-glucose cotransporter SLGT2 in proximal tubules block glucose reabsorption and lower blood glucose, which has therapeutic benefits in diabetes mellitus and chronic dia­ betic kidney disease. The proximal tubule possesses specific transporters capable of secret­ ing a variety of organic acids (carboxylate anions) and bases (mostly primary amine cations). Organic anions transported by these systems include several protein-bound drugs not filtered at the glomerulus (penicillins, cephalosporins, salicylates, and others). Organic cations secreted by the proximal tubule include various biogenic amine neu­ rotransmitters (dopamine, acetylcholine, epinephrine, norepinephrine, and histamine) and creatinine. The ATP-dependent transporter P-gly­ coprotein encoded by ABCB1 is expressed in brush border membranes and secretes several medically important drugs, including cyclosporine, digoxin, tacrolimus, and various cancer chemotherapeutic agents. Certain drugs such as cimetidine and trimethoprim compete with endogenous compounds for transport by the organic cation pathways. Although these drugs elevate serum creatinine levels, there is no actual change in GFR in this setting. Calcium and phosphorus homeostasis depends on normal function­ ing of the proximal tubule. Approximately 60–70% of filtered calcium and ~85% of filtered phosphorus (in the form of inorganic phosphate) are reabsorbed by the proximal tubule. Whereas calcium reabsorp­ tion is mostly by passive diffusion through the paracellular route, phosphate reabsorption is mediated by sodium-coupled cotransport. In addition to direct reabsorption, the proximal tubule contributes to systemic mineral balance by participating in specific endocrine path­ ways. Circulating 25-hydroxy vitamin D (calcidiol) is bioactivated by proximal tubular 1α-hydroxylase to produce 1,25-di-hydroxy vitamin D (calcitriol), the most active form of the hormone, which acts on the small intestine to promote calcium absorption. Phosphate balance is affected by circulating fibroblast growth hormone 23 (FGF23), a bone-derived hormone that interacts with its receptor (FGFR1) and co-receptor (Klotho) on proximal tubular cells to suppress sodiumphosphate cotransport and promote renal phosphate excretion. PTH stimulates proximal tubular 1α-hydroxylation of vitamin D, whereas it suppresses sodium-phosphate cotransport. Derangements in PTH and FGF23 account for abnormal calcium and phosphate balance in chronic kidney disease. The proximal tubule, through distinct classes of Na+-dependent and Na+-independent transport systems, reabsorbs amino acids efficiently. These transporters are specific for different groups of amino acids. For example, cystine, lysine, arginine, and ornithine are transported by a system comprising two proteins encoded by the SLC3A1 and SLC7A9 genes. Mutations in either SLC3A1 or SLC7A9 impair reabsorption of these amino acids and cause the disease cystinuria. Peptide hormones, such as insulin and growth hormone, β2-microglobulin, and other

small proteins, are taken up by the proximal tubule through a process of absorptive endocytosis and are degraded in acidified endocytic lysosomes. Acidification of these vesicles depends on a multi-subunit vacuolar H+-ATPase and a separate Cl−/H+ exchanger encoded by CLCN5. Impaired acidification of endocytic vesicles because of CLCN5 patho­ genic variants causes low-molecular-weight proteinuria in Dent’s disease.

LOOP OF HENLE The loop of Henle consists of three major segments: descending thin limb, ascending thin limb, and ascending thick limb. Approximately 15–25% of filtered NaCl is reabsorbed in the loop of Henle, mainly by the thick ascending limb. The loop of Henle has an important role in urinary concentration by contributing to the generation of a hyper­ tonic medullary interstitium in a process called countercurrent multipli­ cation. The loop of Henle is the site of action for the most potent class of diuretic agents (loop diuretics) and also contributes to reabsorption of calcium and magnesium ions. The descending thin limb is highly water permeable owing to dense expression of constitutively active aquaporin-1 water channels. By contrast, water permeability is negligible in the ascending thin and thick limbs. In the thick ascending limb, there is a high level of secondary active NaCl transport enabled by the Na+/K+/2Cl− cotrans­ porter on the apical membrane in series with basolateral Cl− channels and Na+/K+-ATPase (Fig. 320-3C). The Na+/K+/2Cl− cotransporter is the molecular target for loop diuretics. Tubular fluid K+ is the limit­ ing substrate for this cotransporter (tubular concentration of K+ is similar to plasma, ~4 meq/L), but transporter activity is maintained by K+ recycling through an apical potassium channel. The cotrans­ porter also enables reabsorption of NH4 CHAPTER 320 Cell Biology and Physiology of the Kidney

DISTAL CONVOLUTED TUBULE The distal convoluted tubule reabsorbs ~5% of filtered NaCl. This seg­ ment is composed of a tight epithelium with little water permeability. The major NaCl-transporting pathway uses an apical membrane, electroneutral thiazide-sensitive Na+/Cl− cotransporter in tandem with basolateral Na+/K+-ATPase and Cl− channels (Fig. 320-3D). Apical Ca2+-selective channels (TRPV5) and basolateral Na+/Ca2+ exchange mediate calcium reabsorption in the distal convoluted tubule. Ca2+ reabsorption is inversely related to Na+ reabsorption and is stimulated by PTH. Blocking apical Na+/Cl− cotransport will reduce intracellular Na+, favoring increased basolateral Na+/Ca2+ exchange and passive api­ cal Ca2+ entry. Loss-of-function mutations of SLC12A3 encoding the apical Na+/Cl− cotransporter cause Gitelman syndrome, a salt-wasting disorder associated with hypokalemic alkalosis and hypocalciuria. Mutations in TRPM6 encoding Mg2+ permeable ion channels also cause familial hypomagnesemia with hypocalcemia. A molecular com­ plex of TRPM6 and TRPM7 proteins is critical for Mg2+ reabsorption in the distal convoluted tubule. Basolateral Mg2+ exit from these cells is postulated to involve Na+/Mg2+ exchange.

COLLECTING DUCT The collecting duct modulates the final composition of urine. The two major divisions, the cortical collecting duct and inner medullary collecting duct, contribute to reabsorbing ~4–5% of filtered Na+ and are important for hormonal regulation of salt and water balance. Cells in both segments of the collecting duct express vasopressin-regulated water channels (aquaporin-2 on the apical membrane, aquaporin-3 and -4 on the basolateral membrane). The antidiuretic hormone vaso­ pressin binds to the V2 receptor on the basolateral membrane and triggers an intracellular signaling cascade through G protein–mediated activation of adenylyl cyclase, which raises intracellular levels of cyclic AMP. This signaling cascade stimulates the insertion of water channels into the apical membrane of collecting duct cells to promote water per­ meability, water reabsorption, and production of concentrated urine. In the absence of vasopressin, collecting duct cells are water imper­ meable, and urine remains dilute. Nonpeptide V2 receptor blockers (vaptans) antagonize the antidiuretic effect of vasopressin and produce a water diuresis to treat symptomatic hyponatremia and can slow the progression of polycystic kidney disease. PART 9 Disorders of the Kidney and Urinary Tract The cortical collecting duct contains high-resistance epithelia with two cell types. Principal cells are the main water-reabsorbing, Na+-reabsorbing, and K+-secreting cells, and the site of action of aldosterone, K+-sparing diuretics, and mineralocorticoid receptor antagonists such as spironolactone and eplerenone. The other cells are type A and B intercalated cells. Type A intercalated cells mediate acid secretion and bicarbonate reabsorption also under the influence of aldosterone. Type B intercalated cells mediate bicarbonate secretion and acid reabsorption. Virtually all transport is mediated through the cellular pathway for both principal cells and intercalated cells. In principal cells, passive apical Na+ entry occurs through an amiloride-sensitive, epithelial Na+ channel (ENaC) with basolateral exit mediated by the Na+/ K+-ATPase (Fig. 320-3E). This Na+ reabsorptive process is tightly regulated by aldosterone and is physiologically activated by a variety of proteolytic enzymes that cleave extracellular domains of ENaC; plasmin in the tubular fluid of individuals affected by nephrotic syndrome, for example, activates ENaC, leading to Na+ retention. Aldosterone enters the cell across the basolateral membrane, binds to a cytoplasmic mineralocorticoid receptor, and then translocates into the nucleus, where it modulates gene transcription, which potentiates Na+ reabsorption and K+ secretion. Activating mutations in ENaC increase Na+ reclamation and produce hypokalemia, hypertension, and metabolic alkalosis (Liddle’s syndrome). The potassium-sparing diuretics amiloride and triamterene block ENaC, resulting in lower Na+ reabsorption. Principal cells secrete K+ through an apical membrane potassium channel. Several forces govern the secretion of K+. Most importantly, the high intracellular K+ concentration generated by Na+/K+-ATPase creates a favorable concentration gradient for K+ secretion into tubular

fluid. With reabsorption of Na+ without an accompanying anion, the tubular lumen becomes negative relative to the cell interior, creating a favorable electrical gradient for secretion of potassium. When Na+ reabsorption is blocked, the electrical component of the driving force for K+ secretion is blunted, and this explains lack of excess urinary K+ loss during treatment with potassium-sparing diuretics or min­ eralocorticoid receptor antagonists. K+ secretion is also promoted by aldosterone actions that potentiate regional Na+ transport, which favor more lumen electronegativity, and by increasing the number and activity of potassium channels. Fast tubular fluid flow rates that occur during volume expansion or diuretics acting “upstream” of the cortical collecting duct also promote K+ secretion, as does the presence of relatively nonreabsorbable anions (including bicarbonate and semi­ synthetic penicillins) that contribute to the lumen-negative potential. Off-target effects of certain antibiotics, such as trimethoprim and pentamidine, block ENaCs and predispose to hyperkalemia, especially when renal K+ handling is impaired for other reasons. Principal cells, as described below, also participate in water reabsorption in response to vasopressin. Intercalated cells do not participate in Na+ reabsorption but instead mediate acid-base balance. These cells perform two types of transport: active H+ transport mediated by H+-ATPase (proton pump) and Cl−/ HCO3 − exchange. Intercalated cells arrange the two transport mecha­ nisms on opposite membranes to enable either acid or base secretion. Type A intercalated cells have an apical proton pump that mediates acid secretion and a basolateral Cl−/HCO3 − anion exchanger for bicar­ bonate reabsorption (Fig. 320-3E). Aldosterone increases the number of H+-ATPase pumps, sometimes contributing to the development of metabolic alkalosis. Secreted H+ is buffered by NH3 that has diffused into the collecting duct lumen from the surrounding interstitium. By contrast, type B intercalated cells have the Cl−/HCO3 − exchanger on the apical membrane to mediate bicarbonate secretion while the proton pump resides on the basolateral membrane to enable H+ reabsorption. Under conditions of acidemia, the kidney preferentially uses type A intercalated cells to secrete the excess H+ and generate more HCO3 −. The opposite is true in states of bicarbonate excess with alkalemia where the type B intercalated cells predominate. An extracellular pro­ tein called hensin mediates this adaptation. Inner medullary collecting duct cells share many similarities with principal cells of the cortical collecting duct. They have apical Na+ and K+ channels that mediate Na+ reabsorption and K+ secretion, respectively (Fig. 320-3F). Sodium reabsorption by inner medullary collecting duct cells is also inhibited by the natriuretic peptides atrial natriuretic peptide or renal natriuretic peptide (urodilatin); the same gene encodes both peptides but uses different posttranslational pro­ cessing of a common preprohormone to generate different proteins. Atrial natriuretic peptides are secreted by atrial myocytes in response to volume expansion, whereas urodilatin is secreted by renal tubular epithelia. Natriuretic peptides interact with either apical (urodilatin) or basolateral (atrial natriuretic peptides) receptors on inner medul­ lary collecting duct cells to stimulate guanylyl cyclase and raise levels of cytoplasmic cGMP. This effect in turn reduces the activity of the apical Na+ channel in these cells and attenuates net Na+ reabsorption, producing natriuresis. The inner medullary collecting duct transports urea out of the lumen, returning urea to the interstitium, where it contributes to the hypertonicity of the medullary interstitium. Urea is recycled by diffus­ ing from the interstitium into the descending and ascending limbs of the loop of Henle. HORMONAL REGULATION OF SODIUM AND WATER BALANCE The balance of solute and water in the body is determined by the amounts ingested, distributed to various fluid compartments, and excreted by skin, bowel, and kidneys. Tonicity, the osmolar state deter­ mining the volume behavior of cells in a solution, is regulated by water balance (Fig. 320-4A), and extracellular blood volume is regulated by Na+ balance (Fig. 320-4B). The kidney is a critical modulator of both physiologic processes.

Cell volume Cell membrane TB H2O Net water balance

Determinants Water intake Clinical result Thirst Osmoreception Custom/habit Hyponatremia Hypotonicity Water intoxication – TB H2O Hypernatremia Hypertonicity Dehydration Renal regulation ADH levels V2-receptor/AP2 water flow Medullary gradient Free water clearance Determinants Na+ intake Clinical result Taste Baroreception Custom/habit CHAPTER 320 Edema – TB Na+ Volume depletion Cell Biology and Physiology of the Kidney Renal regulation Na+ reabsorption Tubuloglomerular feedback Macula densa Atrial natriuretic peptides Fractional Na+ excretion vasculosum of the lamina terminalis are osmoreceptive. Only these cells, because of their neural connectivity and adjacency to a minimal blood-brain barrier, modulate the downstream release of vasopressin by the posterior lobe of the pituitary gland. Secretion is stimulated primarily by changing tonicity and secondarily by other nonosmotic signals such as variable blood volume, stress, pain, nausea, and some drugs. The release of vasopressin by the posterior pituitary increases linearly as plasma tonicity rises above normal, although this var­ ies, depending on the perception of extracellular volume (one form of cross-talk between mechanisms that regulate blood volume and osmolality). Changing the intake or excretion of water provides a means for adjusting plasma tonicity; thus, osmoregulation governs water balance. The kidneys contribute to maintaining water balance through the regulation of renal water excretion. The ability to concentrate urine to an osmolality exceeding that of plasma enables water conservation, whereas the ability to produce urine more dilute than plasma promotes excretion of excess water. For water to enter or exit a cell, the cell mem­ brane must express aquaporins. In the kidney, aquaporin-1 is consti­ tutively active in all water-permeable segments (e.g., proximal tubule, descending thin limb of the loop of Henle), whereas aquaporin-2, -3, and -4 in the collecting duct promote vasopressin-regulated water perme­ ability. Net water reabsorption is ultimately driven by the osmotic gradient between dilute tubular fluid and a hypertonic medullary interstitium.

03 - 321 Acute Kidney Injury

321 Acute Kidney Injury

■ ■SODIUM BALANCE The perception of extracellular blood volume is determined, in part, by the integration of arterial tone, cardiac stroke volume, heart rate, and the water and solute content of extracellular fluid. Na+ and accompanying anions are the most abundant extracellular effective osmoles and together support a blood volume around which pres­ sure is generated. Under normal conditions, this volume is regulated by sodium balance (Fig. 320-4B), and the balance between daily Na+ intake and excretion is under the influence of baroreceptors in regional blood vessels and vascular hormone sensors modulated by atrial natriuretic peptides, the renin-angiotensin-aldosterone sys­ tem, Ca2+ signaling, adenosine, vasopressin, and the neural adrener­ gic axis. If Na+ intake exceeds Na+ excretion (positive Na+ balance), then a rising blood volume will trigger a proportional increase in urinary Na+ excretion. Conversely, when Na+ intake is less than urinary excretion (negative Na+ balance), blood volume will fall and trigger enhanced renal Na+ reabsorption, leading to decreased urinary Na+ excretion.

The renin-angiotensin-aldosterone system is the best-understood hormonal system modulating renal Na+ excretion. Renin is syn­ thesized and secreted by granular cells in the wall of the afferent arteriole. Its secretion is controlled by several factors, including β1-adrenergic stimulation to the afferent arteriole, input from the macula densa, and prostaglandins. Renin and ACE activity eventually produce angiotensin II that directly and indirectly promotes renal Na+ and water reabsorption. Stimulation of proximal tubular Na+/ H+ exchange by angiotensin II directly increases Na+ reabsorption. Angiotensin II also promotes Na+ reabsorption along the collect­ ing duct by stimulating aldosterone secretion by the adrenal cortex. Constriction of the efferent glomerular arteriole by angiotensin II indirectly boosts the filtration fraction and raises peritubular capil­ lary oncotic pressure to promote tubular Na+ reabsorption. Finally, angiotensin II inhibits renin secretion through a negative feedback loop. Alternative metabolism of angiotensin by ACE2 generates the vasodilatory peptide angiotensin 1-7 that acts through Mas receptors to counterbalance several actions of angiotensin II on blood pressure and renal function (Fig. 320-2C). PART 9 Disorders of the Kidney and Urinary Tract Aldosterone is synthesized and secreted by granulosa cells in the adrenal cortex. It binds to cytoplasmic mineralocorticoid receptors in the collecting duct principal cells and boosts the activ­ ity of ENaC, apical membrane K+ channel, and basolateral Na+/ K+-ATPase. These effects are mediated in part by aldosteronestimulated transcription of the gene encoding serum/glucocorti­ coid-induced kinase 1 (SGK1). The activity of ENaC is increased by SGK1-mediated phosphorylation of the ubiquitin-protein ligase Nedd4-2 that promotes ubiquitination and recycling of the Na+ channel from the plasma membrane. Phosphorylated Nedd4-2 has impaired interactions with ENaC, leading to higher channel density at the plasma membrane and greater capacity for Na+ reabsorption by the collecting duct. Chronic exposure to aldosterone is associated with lower urinary Na+ excretion lasting only a few days, after which Na+ excretion returns to previous levels. This phenomenon, called aldosterone escape, is explained by lower proximal tubular Na+ reabsorption following blood volume expansion. Excess Na+ that is not reabsorbed by the proximal tubule overwhelms the reabsorptive capacity of more distal nephron segments. This escape may be facilitated by atrial natriuretic peptides that lose their effectiveness in the clinical settings of heart failure, nephrotic syndrome, and cirrhosis, leading to severe Na+ retention and volume overload. ■ ■FURTHER READING Avraham S: The mesangial cell: The glomerular stromal cell. Nature Rev Nephrol 17:855, 2021. Carrisoza-Gaytan R: PIEZO1 is a distal nephron mechanosen­ sory and is required for flow-induced K+ secretion. J Clin Invest 134:E174806, 2024. De Baaij JHF: Magnesium reabsorption in the kidney. Am J Physiol Renal Physiol 324:F227, 2023.

Downie ML et al: Inherited tubulopathies of the kidney. Clin J Am Soc Nephrol 16:620, 2021. Polidoro JZ et al: Paracrine and endocrine regulation of renal K+ secretion. Am J Physiol Renal Physiol 322:F360, 2022. Schnell J: Principles of human and mouse nephron development. Nature Rev Nephrol 18:628, 2022. Verschuren EHJ et al: Sensing of tubular flow and renal electrolyte transport. Nature Rev Nephrol 16:337, 2020. Sushrut S. Waikar, Joseph V. Bonventre

Acute Kidney Injury Acute kidney injury (AKI) is defined by the impairment of kidney filtration and excretory function over days to weeks (generally known or expected to have occurred within 7 days), resulting in the reten­ tion of nitrogenous and other waste products normally cleared by the kidneys. The generally accepted Kidney Disease: Improving Global Outcomes (KDIGO) definition of AKI is an increase in serum creatinine (SCr) of ≥0.3 mg/dL within 48 h or an increase in SCr ≥1.5 times from baseline over 7 days or urine output <0.5 mL/kg per h for >6 h. AKI is not a single disease but rather a designation for a heterogeneous group of conditions that share common diagnostic features: specifically, an increase in filtration markers (SCr or cystatin C) often associated with a reduction in urine volume. It is important to recognize that AKI is a clinical diagnosis and not a structural one. A patient may have AKI with or without injury to the kidney parenchyma making the term a misnomer. AKI can range in severity from asymptomatic and transient changes in laboratory parameters of glomerular filtration rate (GFR), to overwhelming and rapidly fatal derangements in the ability of the kidney to maintain effective circulating volume regulation, excrete nitrogenous wastes and metabolic toxins, and maintain electrolyte and acid-base composition of the plasma. EPIDEMIOLOGY AKI complicates 5–7% of acute-care hospital admissions and up to 30% of admissions to the intensive care unit (ICU). AKI severity is staged based on the magnitude of the rise in SCr and severity and duration of oliguria (Table 321-1). The incidence of AKI has grown by more than fourfold in the United States since 1988 and is estimated to have a yearly incidence of 500 per 100,000 population, higher than the yearly incidence of stroke. Morbidity of AKI in those admitted to the ICU exceeds 50% in many studies. AKI also has longer term implications even if the patient survives the hospitalization. AKI increases the risk TABLE 321-1  Staging of Acute Kidney Injury Severity STAGE SERUM CREATININE URINE OUTPUT

1.5–1.9 times baseline OR ≥0.3 mg/dL (≥26.5 μmol/L) increase <0.5 mL/kg per h for 6–12 h

2.0–2.9 times baseline <0.5 mL/kg per h for ≥12 h

3.0 times baseline OR increase in serum creatinine to ≥4.0 mg/dL (≥353.6 μmol/L) OR initiation of renal replacement therapy OR, in patients <18 years of age, decrease in eGFR to <35 mL/min per 1.73 m2 <0.3 mL/kg per h for ≥24 h OR Anuria for ≥12 h Abbreviation: eGFR, estimated glomerular filtration rate.

for the development or worsening of chronic kidney disease (CKD) and also increases the risk of future cardiovascular disease. AKI may also occur in the community. Common causes of community-acquired AKI include volume depletion, heart failure, adverse effects of medi­ cations, obstruction of the urinary tract, or malignancy. The most common clinical settings for hospital-acquired AKI are sepsis, major surgical procedures, critical illness involving heart or liver failure, and nephrotoxic medication administration. Clinically, AKI more com­ monly develops when ischemia or other insults occur in the context of limited renal functional reserve. The healthy kidney has the ability to increase its regional or overall function in response to damage to a sub­ set of nephrons or in response to a perceived need to enhance excre­ tion, such as in response to a protein load. With normal aging, there is reduction in this capacity, which is also reduced in individuals with CKD or coexisting insults such as sepsis, vasoactive or nephrotoxic drugs, rhabdomyolysis, or the systemic inflammatory states associated with burns and pancreatitis. When there is reduced renal reserve, any additional impairment in GFR is likely to be reflected by a change in SCr or cystatin C and hence a more likely diagnosis of AKI. ■ ■AKI IN THE DEVELOPING WORLD AKI is also a major medical complication in the developing world, where the epidemiology differs from that in developed countries due to differences in demographics, economics, environmental factors, and comorbid disease burden. While certain features of AKI are common in developed and developing countries—particularly because urban centers of some developing countries increasingly resemble those in the developed world—many etiologies for AKI are region-specific, such as envenomations from snakes, spiders, caterpillars, and bees; infectious causes such as malaria and leptospirosis; and crush injuries and resultant rhabdomyolysis from earthquakes. In developing coun­ tries, resources to diagnose and manage AKI are often limited. ETIOLOGY AND PATHOPHYSIOLOGY The causes of AKI have traditionally been divided into three broad categories: prerenal azotemia, intrinsic renal parenchymal disease, and postrenal obstruction (Fig. 321-1). ■ ■PRERENAL AZOTEMIA Prerenal azotemia (from “azo,” meaning nitrogen, and “-emia,” meaning in the blood), the most common form of AKI, results from inadequate Prerenal Postrenal Intrinsic Glomerular • Acute glomerulo- nephritis Hypovolemia Decreased cardiac output Decreased effective circulating volume • Congestive heart failure • Liver failure Impaired renal autoregulation • NSAIDs • ACE-I/ARB • Cyclosporine Ischemia FIGURE 321-1  Classification of the major causes of acute kidney injury. ACE-I, angiotensin-converting enzyme inhibitor-I; ARB, angiotensin receptor blocker; NSAIDs, nonsteroidal anti-inflammatory drugs; PPI, proton pump inhibitors; TTP-HUS, thrombotic thrombocytopenic purpura–hemolytic-uremic syndrome.

renal plasma flow and intraglomerular hydrostatic pressure to support normal glomerular filtration. The most common clinical conditions associated with prerenal azotemia are hypovolemia, decreased cardiac output, and medications that interfere with renal autoregulatory vascu­ lar responses such as nonsteroidal anti-inflammatory drugs (NSAIDs) and inhibitors of the renin-angiotensin system (Fig. 321-2). Sodiumglucose cotransporter 2 (SGLT-2) inhibitors used for the treatment of diabetes mellitus and related complications do not appear to increase the risk of AKI despite their effects on lowering intraglomerular pres­ sure and inducing natriuresis; in fact, recent studies have suggested a protective effect of these agents in preventing AKI.

By definition, prerenal azotemia involves no parenchymal damage to the kidney and is rapidly reversible once parenchymal blood flow and intraglomerular hemodynamics are restored. In many cases, how­ ever, prerenal azotemia may coexist with other forms of intrinsic AKI associated with processes acting directly on the renal parenchyma. Pro­ longed periods of prerenal azotemia may lead to ischemic injury to the tubular cells with necrosis, hence termed acute tubular necrosis (ATN). Normal GFR is maintained in part by renal blood flow and the relative resistances of the afferent and efferent renal arterioles, which determine the glomerular plasma flow rate and the transcapillary hydraulic pressure gradient that drive glomerular ultrafiltration. Mild degrees of hypovolemia and reductions in cardiac output elicit com­ pensatory renal vasoconstriction and enhanced reabsorption of salt and water to maintain blood pressure and increase intravascular volume to sustain perfusion to the cerebral and coronary vessels. Mediators of this response include angiotensin II, norepinephrine, and vasopressin (also termed antidiuretic hormone). Glomerular filtration can be maintained despite reduced renal blood flow by angiotensin II–mediated renal efferent arteriolar vasoconstriction. In addition, a myogenic reflex within the afferent arteriole leads to dilation in the setting of low perfusion pressure, thereby maintaining glomerular perfusion. Intrarenal biosynthesis of vasodilator prostaglandins (pros­ tacyclin, prostaglandin E2), kallikrein and kinins, and possibly nitric oxide (NO) also increases in response to low renal perfusion pressure. Autoregulation is also accomplished by tubuloglomerular feedback, in which decreases in solute delivery to the macula densa (specialized cells within the distal tubule) elicit dilation of the juxtaposed afferent arteriole in order to maintain glomerular perfusion, a mechanism mediated, in part, by NO. There is a limit, however, to the ability of CHAPTER 321 Acute Kidney Injury Acute kidney injury Tubules and interstitium Vascular • Vasculitis • Malignant hypertension • TTP-HUS Bladder outlet obstruction Bilateral pelvoureteral obstruction (or unilateral obstruction of a solitary functioning kidney) Sepsis/ Infection Nephrotoxins Exogenous: Iodinated contrast, aminoglycosides, cisplatin, amphotericin B, PPIs, NSAIDs, immune checkpoint inhibitors Endogenous: Hemolysis, rhabdomyolysis, myeloma, intratubular crystals

Normal perfusion pressure Arteriolar resistances Afferent arteriole Efferent arteriole Increased vasodilatory prostaglandins Increased angiotensin II Glomerulus Tubule A B Normal GFR Normal GFR maintained PART 9 Disorders of the Kidney and Urinary Tract Decreased perfusion pressure in the presence of NSAIDs Decreased vasodilatory prostaglandins Increased angiotensin II C D Low GFR FIGURE 321-2  Intrarenal mechanisms for autoregulation of the glomerular filtration rate (GFR) under decreased perfusion pressure and reduction of the GFR by drugs. A. Normal conditions and a normal GFR. B. Reduced perfusion pressure within the autoregulatory range. Normal glomerular capillary pressure is maintained by afferent vasodilatation and efferent vasoconstriction. Angiotensin constricts afferent (preglomerular) and efferent (postglomerular) arterioles but preferentially increases efferent arteriolar resistance. C. Reduced perfusion pressure with a nonsteroidal anti-inflammatory drug (NSAID). Loss of vasodilatory prostaglandins increases afferent resistance; this causes the glomerular capillary pressure to drop below normal values and the GFR to decrease. D. Reduced perfusion pressure with an angiotensin-converting enzyme inhibitor (ACE-I) or an angiotensin receptor blocker (ARB). Loss of angiotensin II action reduces efferent resistance; this causes the glomerular capillary pressure to drop below normal values and the GFR to decrease. (From JG Abuelo: Normotensive ischemic acute renal failure. N Engl J Med 357:797, 2007. Copyright © 2007, Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.) these counterregulatory mechanisms to maintain GFR in the face of systemic hypotension. Even in healthy adults, renal autoregulation usu­ ally fails once the systolic blood pressure falls below 80 mmHg. A number of factors determine the robustness of the autoregula­ tory response and the risk of prerenal azotemia. Atherosclerosis, long-standing hypertension, and older age can lead to hyalinosis and myointimal hyperplasia, causing structural narrowing of the intrare­ nal arterioles and impaired capacity for renal afferent vasodilation. In CKD, renal afferent vasodilation may be operating at maximal capac­ ity in order to maximize GFR in response to reduced functional renal mass. Drugs can affect the compensatory changes evoked to maintain GFR. NSAIDs inhibit renal prostaglandin production, limiting renal afferent vasodilation. Angiotensin-converting enzyme (ACE) inhibi­ tors and angiotensin receptor blockers (ARBs) limit renal efferent vasoconstriction; this effect is particularly pronounced in patients

Decreased perfusion pressure Decreased perfusion pressure in the presence of ACE-I or ARB Slightly increased vasodilatory prostaglandins Decreased angiotensin II Low GFR with bilateral renal artery stenosis or unilateral renal artery stenosis (in the case of a solitary functioning kidney) because, as indicated above, efferent arteriolar vasoconstriction is needed to maintain GFR due to low renal perfusion. The combined use of NSAIDs with ACE inhibitors or ARBs poses a particularly high risk for developing prerenal azotemia. Hepatorenal syndrome is a cause of AKI in individuals with multi­ organ pathobiology affecting kidney and liver. Many individuals with advanced liver disease exhibit a hemodynamic profile that resembles prerenal azotemia in the setting of total-body volume overload. Sys­ temic vascular resistance is markedly reduced due to primary arte­ rial vasodilation in the splanchnic circulation, resulting ultimately in activation of vasoconstrictor responses similar to those seen in hypo­ volemia. AKI is a common complication in this setting, and it can be triggered by volume depletion and spontaneous bacterial peritonitis.

The hepatorenal syndrome, which represents the advanced stage of impaired perfusion to the kidneys secondary to advanced liver disease, is difficult to distinguish from prerenal azotemia and is a diagnosis of exclusion. A particularly poor prognosis is seen in the case of type 1 hepatorenal syndrome, in which AKI persists despite volume adminis­ tration and withholding of diuretics. Type 2 hepatorenal syndrome is a less severe form characterized mainly by refractory ascites. ■ ■INTRINSIC AKI The most common causes of intrinsic AKI are sepsis, ischemia, and nephrotoxins, both endogenous and exogenous (Fig. 321-3). As mentioned previously, in many cases, prerenal azotemia advances to tubular injury. Although often the AKI is attributed to “acute tubular necrosis,” human biopsy confirmation of tubular necrosis is, in general, often lacking in cases of sepsis and ischemia; indeed, processes such as inflammation, apoptosis, and altered regional perfusion may be impor­ tant contributors pathophysiologically without frank necrosis. There are other potential causes of AKI in settings such as sepsis, including drug-induced interstitial nephritis or glomerulonephritis. These and other causes of intrinsic AKI can be catalogued anatomically according to the major site of renal parenchymal damage: glomeruli, tubuloin­ terstitium, and vessels, although there is frequently overlap in tissue Intrinsic Renal Failure Small vessels • Glomerulonephritis • Vasculitis • TTP/HUS • DIC • Atheroemboli • Malignant HTN • Calcineurin inhibitors • Sepsis Juxtamedullary glomerulus Distal convoluted tubule Cortex Medulla Proximal convoluted tubule Outer Inner Pars recta Loop of Henle Thick ascending limb Loop of Henle Collecting duct Thin descending limb FIGURE 321-3  Major causes of intrinsic acute kidney injury. ATN, acute tubular necrosis; DIC, disseminated intravascular coagulation; HTN, hypertension; PCN, penicillin; PPI, proton pump inhibitors; TINU, tubulointerstitial nephritis-uveitis; TTP/HUS, thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome.

compartment involvement. For example, glomerulonephritis can alter efferent arteriolar blood flow, which then reduces capillary perfusion to a region of the nephron leading to cell death, obstruction of the lumen with cellular debris, and impaired tubular function.

■ ■SEPSIS-ASSOCIATED AKI In the United States, >1 million cases of sepsis occur each year. AKI complicates >50% of cases of severe sepsis and greatly increases the risk of death. Sepsis is also a very important cause of AKI in the developing world. AKI also predisposes to sepsis. Decreases in GFR with sepsis can occur even in the absence of overt hypotension, although many cases of severe AKI typically occur in the setting of hemodynamic compromise requiring vasopressor support. Reduced urine output is common in sepsis-induced AKI. While there can be tubular injury associated with AKI in sepsis as manifest by the presence of tubular debris and casts in the urine, postmortem examinations of kidneys from individuals with severe sepsis suggest that other factors, perhaps related to inflamma­ tion, mitochondrial dysfunction, and interstitial edema, contribute to the pathophysiology of sepsis-induced AKI. The hemodynamic effects of sepsis—arising from generalized arte­ rial vasodilation, mediated in part by cytokines that upregulate the expression of inducible NO synthase in the vasculature—can lead to a CHAPTER 321 Tubules • Toxic ATN • Endogenous (rhabdomyolysis, hemolysis) • Exogenous (contrast, cisplatin, gentamicin) • Ischemic ATN • Sepsis Intratubular • Endogenous • Myeloma proteins • Uric acid (tumor lysis syndrome) • Cellular debris • Exogenous • Acyclovir, methotrexate

Acute Kidney Injury Proximal convoluted tubule Outer cortical glomerulus Distal convoluted tubule Thick ascending limb Pars recta Interstitium • Allergic (PCN, PPIs, NSAIDs, rifampin, etc.) • Infection (severe pyelonephritis, Legionella, sepsis) • Infiltration (lymphoma, leukemia) • Inflammatory (Sjogren’s, tubulointerstitial nephritis uveitis), sepsis Large vessels • Renal artery embolus, dissection, vasculitis • Renal vein thrombosis • Abdominal compartment syndrome

reduction in GFR. The operative mechanisms may be excessive efferent arteriole vasodilation, particularly early in the course of sepsis, or renal vasoconstriction from activation of the sympathetic nervous system, the renin-angiotensin-aldosterone system, or increased levels of vaso­ pressin or endothelin. Sepsis may lead to endothelial damage, which results in increased microvascular leukocyte adhesion and migration, thrombosis, permeability, increased interstitial pressure, reduction in local flow to tubules, and activation of reactive oxygen species, all of which may injure renal tubular cells.

AKI can be an important complication of viral infections, such as hantavirus, dengue virus, or SARS-CoV-2. The pathophysiology of AKI due to viral infections remains incompletely understood. As an example, some have reported infection of the kidney with SARSCoV-2, whereas others have found less direct involvement. SARSCoV-2 is associated with a large release of cytokines into the circulation (“cytokine storm”), which may cause diffuse intrarenal vasoconstric­ tion. Finally, there is a generalized hypercoagulable state associated with SARS-CoV-2 that may contribute to the impairment of intrarenal blood flow. ■ ■ISCHEMIA-ASSOCIATED AKI Healthy kidneys receive 20% of the cardiac output and account for 10% of resting oxygen consumption, despite constituting only 0.5% of the human body mass. The kidneys are also the site of one of the most hypoxic regions in the body, the renal medulla. The outer medulla is particularly vulnerable to ischemic damage because of the architecture of the blood vessels that supply oxygen and nutrients to the tubules. In the outer medulla, enhanced leukocyte-endothelial interactions in the small vessels lead to inflammation and reduced local blood flow to the metabolically very active S3 segment of the proximal tubule, which depends on oxidative metabolism for survival. Mitochondrial dysfunction leads to impaired oxidative phosphorylation with less efficient adenosine triphosphate (ATP) generation and mitochondrial release of reactive oxygen species, both of which play a role in renal tubular injury. Transient ischemia alone in a normal kidney is usually not sufficient to cause severe AKI, as evidenced by the relatively low risk of severe AKI even after total interruption of renal blood flow dur­ ing suprarenal aortic clamping or cardiac arrest. Prerenal azotemia and ischemia-associated AKI represent a continuum of the manifestations of renal hypoperfusion leading to ATN. Persistent preglomerular vaso­ constriction may be a common underlying cause of the reduction in GFR seen in AKI; implicated factors for vasoconstriction include acti­ vation of tubuloglomerular feedback from enhanced delivery of solute to the macula densa following proximal tubule injury and reduced reabsorption, increased basal vascular tone and reactivity to vasocon­ strictive agents, and decreased vasodila­ tor responsiveness. Other contributors to low GFR include backleak of filtrate across damaged and denuded tubular epithelium and mechanical obstruction of tubules from necrotic debris (Fig. 321-4). Postoperative AKI  Ischemia-asso­ ciated AKI is a serious complication in the postoperative period, especially after major operations involving significant blood loss and intraoperative hypoten­ sion. The procedures most commonly associated with AKI are cardiac surgery with cardiopulmonary bypass (particu­ larly for combined valve and bypass pro­ cedures), vascular procedures with aortic cross clamping, and intraperitoneal pro­ cedures. Severe AKI requiring dialysis occurs in ~1% of cardiac and vascular surgery procedures. The risk of severe AKI has been less well studied for major intraperitoneal procedures but appears to be of comparable magnitude. Common risk factors for postoperative AKI include PART 9 Disorders of the Kidney and Urinary Tract Pathophysiology of Ischemic Acute Kidney Injury MICROVASCULAR Glomerular Medullary Vasoconstriction in response to: endothelin, adenosine, angiotensin II, thromboxane A2, leukotrienes, sympathetic nerve activity Vasodilation in response to: nitric oxide, PGE2, acetylcholine,
bradykinin Endothelial and vascular smooth muscle cell structural damage Leukocyte-endothelial adhesion, vascular obstruction, leukocyte activation, and inflammation FIGURE 321-4  Interacting microvascular and tubular events contributing to the pathophysiology of ischemic acute kidney injury. PGE2, prostaglandin E2. (Reproduced with permission from JV Bonventre, JM Weinberg. J Am Soc Nephrol. 14:2199, 2003.)

underlying CKD, older age, diabetes mellitus, congestive heart failure, and emergency procedures. The pathophysiology of AKI following cardiac surgery is multifactorial. Major AKI risk factors are common in the population undergoing cardiac or vascular surgery. Over time, more of these surgical procedures are performed on older patients with comorbidities that predispose them to AKI and hasten progression of end-stage kidney disease (ESKD) if they develop AKI. Longer dura­ tion of cardiopulmonary bypass is a risk factor for AKI. In addition to ischemic injury from sustained hypoperfusion, cardiopulmonary bypass may cause AKI through a number of mechanisms including extracorporeal circuit activation of leukocytes and inflammatory pro­ cesses, hemolysis with resultant pigment nephropathy (see below), and aortic injury with resultant atheroemboli. AKI from atheroembolic disease, which can also occur following percutaneous catheterization of the aorta, or spontaneously, is due to cholesterol crystal emboliza­ tion resulting in partial or total occlusion of multiple small arteries within the kidney. Over time, a foreign body reaction can result in intimal proliferation, giant cell formation, and further narrowing of the vascular lumen, accounting for the generally subacute (over a period of weeks rather than days) decline in renal function. Burns and Acute Pancreatitis  Extensive fluid losses into the extravascular compartments of the body frequently accompany severe burns and acute pancreatitis. AKI is an ominous complication of burns, affecting 25% of individuals with >10% total body surface area involve­ ment. In addition to severe hypovolemia resulting in decreased cardiac output and increased neurohormonal activation, burns and acute pan­ creatitis both lead to dysregulated inflammation and an increased risk of sepsis and acute lung injury, all of which may facilitate the develop­ ment and progression of AKI. Individuals undergoing massive fluid resuscitation for trauma, burns, and acute pancreatitis can also develop abdominal compartment syndrome, where markedly elevated intraab­ dominal pressures, usually >20 mmHg, lead to renal vein compression and reduced GFR. Drug nephrotoxicity is also an important contribu­ tor to AKI. Mortality is much higher in patients who develop AKI. Diseases of the Vasculature Leading to Ischemia  These dis­ eases can compromise oxygen and metabolic substrate delivery to the tubules and glomeruli. Microvascular causes of AKI include the throm­ botic microangiopathies (due to cocaine, certain chemotherapeutic agents, antiphospholipid antibody syndrome, radiation nephritis, malignant hypertensive nephrosclerosis, thrombotic thrombocytope­ nic purpura/hemolytic-uremic syndrome [TTP-HUS]), scleroderma, some chemotherapeutic agents, and atheroembolic disease. Largevessel diseases associated with AKI include renal artery dissection, O2 TUBULAR Cytoskeletal breakdown Mitochondrial injury Loss of polarity Apoptosis and necrosis Inflammatory and vasoactive mediators Desquamation of viable and necrotic cells Tubular obstruction Backleak

thromboembolism, or thrombosis, and renal vein compression or thrombosis. ■ ■NEPHROTOXIN-ASSOCIATED AKI The kidney has very high susceptibility to nephrotoxic agents due to extremely high blood perfusion and concentration of filtered substances along the nephron where filtrate water is reabsorbed. Nephrotoxic injury occurs in response to a number of pharmacologic compounds with diverse structures, endogenous substances, and environmental exposures. All structures of the kidney are vulnerable to toxic injury, including the tubules, interstitium, vasculature, and collecting system. As with other forms of AKI, risk factors for nephro­ toxicity include older age, CKD, and prerenal azotemia. Hypoalbumin­ emia may increase the risk of some forms of nephrotoxin-associated AKI due to increased free circulating drug concentrations. Contrast Agents  Iodinated contrast agents used for cardiovascular and computed tomography (CT) imaging have been implicated as a cause of AKI. Many question whether AKI in response to contrast agents represents an important consequence of contrast studies. It is likely to have been diagnosed too frequently in the past, particularly in individuals who had many risk factors for AKI, making the cause difficult to identify. The terminology has changed so that the former “contrast nephropathy” has been replaced by “contrast-associated AKI” or “contrast-induced AKI” (CI-AKI), with the latter representing a smaller subgroup of the former. The occurrence of CI-AKI is negligible in those with normal renal function but increases in the setting of CKD, particularly in individuals with diabetic kidney disease. The most com­ mon clinical course of contrast nephropathy is characterized by a rise in SCr beginning 24–48 h following exposure, peaking within 3–5 days, and resolving within 1 week. More severe, dialysis-requiring AKI is uncommon except in the setting of significant preexisting CKD, often in association with congestive heart failure or other coexisting causes for ischemia-associated AKI. Patients with multiple myeloma and/or renal disease are particularly susceptible. Other diagnostic agents implicated as a cause of AKI are high-dose gadolinium used for magnetic resonance imaging (MRI) and oral sodium phosphate solu­ tions used as bowel purgatives. Gadolinium has been associated with development of nephrogenic systemic fibrosis (NSF) in subjects with advanced kidney disease or AKI, but the majority of these cases were associated with group I gadolinium-based contrast media, which are rarely used now in the United States and have been withdrawn from the market in many other countries. The risk of AKI associated with stan­ dard doses of group II gadolinium-based contrast media is very low. Antibiotics  Several antimicrobial agents are commonly associated with AKI. Vancomycin may be associated with AKI from tubular injury, particularly when trough levels are high and when used in combina­ tion with other nephrotoxic antibiotics. Vancomycin can also crystalize in tubules and cause intratubular obstruction. Aminoglycosides and amphotericin B both cause tubular necrosis. Nonoliguric AKI (i.e., with a urine volume >400 mL/d) accompanies 10–30% of courses of aminoglycoside antibiotics, even when plasma levels are in the thera­ peutic range. Aminoglycosides are freely filtered across the glomerulus and then accumulate within the renal cortex, where concentrations can greatly exceed those of the plasma. AKI typically manifests after 5–7 days of therapy and can present even after the drug has been discontinued. Hypomagnesemia is a common finding. Amphotericin B causes renal vasoconstriction from an increase in tubuloglomerular feedback as well as direct tubular toxicity mediated by reactive oxygen species. Nephrotoxicity from amphotericin B is dose and duration dependent. This drug binds to tubular membrane cholesterol and introduces pores. Clinical features of amphotericin B nephrotoxicity include polyuria, hypomagnesemia, hypocalcemia, and nongap metabolic acidosis. Acyclovir can precipitate in tubules and cause AKI by tubular obstruction, particularly when given as an intravenous bolus at high doses (500 mg/m2) or in the setting of hypovolemia. Foscarnet, pentam­ idine, tenofovir, and cidofovir are also frequently associated with AKI due to tubular toxicity. AKI secondary to acute interstitial nephritis

can occur as a consequence of exposure to many antibiotics, including penicillins, cephalosporins, quinolones, sulfonamides, and rifampin.

Chemotherapeutic Agents  Cisplatin and carboplatin are accu­ mulated by proximal tubular cells and cause necrosis and apoptosis. Intensive hydration regimens have reduced the incidence of cisplatin nephrotoxicity, but it remains a dose-limiting toxicity. Ifosfamide may cause hemorrhagic cystitis and tubular toxicity, manifested as type II renal tubular acidosis (Fanconi syndrome), polyuria, hypoka­ lemia, and a modest decline in GFR. Antiangiogenesis agents, such as bevacizumab, can cause proteinuria and hypertension via injury to the glomerular microvasculature (thrombotic microangiopathy). Other antineoplastic agents such as mitomycin C and gemcitabine may cause thrombotic microangiopathy with resultant AKI. Immune checkpoint inhibitors, such as ipilimumab, tremelimumab, nivolumab, and pembro­ lizumab can cause immune-related adverse events, often manifesting in the kidney as acute interstitial nephritis. Lower GFR, proton pump inhibitor use, and extrarenal immune-related adverse events are pre­ disposing risk factors for AKI secondary to immune checkpoint inhibi­ tors. The checkpoint inhibitors result in hyperactivity of the immune system triggered by these agents. Toxic Ingestions  Ethylene glycol, present in automobile antifreeze, is metabolized to oxalic acid, glycolaldehyde, and glyoxylate, which may cause AKI through direct tubular injury and tubular obstruction. Diethylene glycol is an industrial agent that has caused outbreaks of severe AKI around the world due to adulteration of pharmaceutical preparations. The metabolite 2-hydroxyethoxyacetic acid (HEAA) is thought to be responsible for tubular injury. Melamine contamination of foodstuffs has led to nephrolithiasis and AKI, either through intra­ tubular obstruction or possibly direct tubular toxicity. Aristolochic acid was found to be the cause of “Chinese herb nephropathy” and “Balkan nephropathy” due to its contamination of medicinal herbs or farming. The list of environmental toxins is likely to grow and contribute to a better understanding of previously catalogued “idiopathic” chronic tubular interstitial disease, a common diagnosis in both the developed and developing world. CHAPTER 321 Acute Kidney Injury Endogenous Toxins  AKI may be caused by a number of endog­ enous compounds, including myoglobin, hemoglobin, uric acid, and myeloma light chains. Myoglobin can be released by injured muscle cells, and hemoglobin can be released during massive hemolysis leading to pigment nephropathy. Rhabdomyolysis may result from traumatic crush injuries, muscle ischemia during vascular or orthopedic surgery, compression during coma or immobilization, prolonged seizure activity, excessive exercise, heat stroke or malignant hyperthermia, infections, metabolic disorders (e.g., hypophosphatemia, severe hypothyroidism), and myopathies (drug-induced, metabolic, or inflammatory). Patho­ genic factors contributing to AKI upon exposure to endogenous toxins include intrarenal vasoconstriction, direct proximal tubular toxicity, and mechanical obstruction of the distal nephron lumen when myoglobin or hemoglobin precipitates with Tamm-Horsfall protein (uromodulin, the most common protein in urine and produced in the thick ascend­ ing limb of the loop of Henle), a process favored by acidic urine. Tumor lysis syndrome may follow initiation of cytotoxic therapy in patients with high-grade lymphomas and acute lymphoblastic leukemia; massive release of uric acid (with serum levels often exceeding 15 mg/dL) leads to precipitation of uric acid in the renal tubules and AKI (Chap. 75). Other features of tumor lysis syndrome include hyperkalemia and hyper­ phosphatemia. The tumor lysis syndrome can also occasionally occur spontaneously or with treatment for solid tumors or multiple myeloma. Myeloma light chains can also cause AKI by glomerular damage and/or direct tubular toxicity and by binding to Tamm-Horsfall protein to form obstructing intratubular casts. Hypercalcemia, which can also be seen in multiple myeloma, may cause AKI by intense renal vasoconstriction and inhibition of sodium and water reabsorption in the nephron with resultant volume depletion. Other Causes of Acute Tubulointerstitial Disease Leading to AKI 

While many drugs result in toxin-induced injury to the nephron with

subsequent inflammation, drugs can also lead to the development of an allergic response characterized by an inflammatory infiltrate, sometimes associated with blood and urinary eosinophilia. Proton pump inhibi­ tors and NSAIDs are commonly used drugs that have been associated with acute tubulointerstitial nephritis. AKI may be also caused by severe infections and infiltrative malignant or nonmalignant (e.g., sarcoidosis) diseases with tubulointerstitial disease.

Anticoagulant-Related Nephropathy  Excessive anticoagula­ tion with warfarin or other classes of anticoagulants has been reported to cause AKI through glomerular hemorrhage resulting in the forma­ tion of obstructing red blood cell casts within the kidney tubule and tubular injury. Glomerulonephritis  Diseases involving the glomerular podo­ cytes, mesangial, and/or endothelial cells can lead to AKI by com­ promising the filtration barrier and blood flow within the renal circulation. Although glomerulonephritis is a less common (~5%) cause of AKI, early recognition is particularly important because the diseases can respond to timely treatment with immunosuppressive agents or therapeutic plasma exchange, and the treatment may reverse the AKI and decrease subsequent longer term injury. ■ ■POSTRENAL AKI (See also Chap. 331.) Postrenal AKI occurs when the normally uni­ directional flow of urine is acutely blocked either partially or totally, leading to increased retrograde hydrostatic pressure and interference with glomerular filtration. Obstruction to urinary flow may be caused by functional or structural derangements anywhere from the renal pelvis to the tip of the urethra (Fig. 321-5). Normal urinary flow rate does not rule out the presence of partial obstruction, because the GFR is normally two orders of magnitude higher than the urinary flow rate and hence a preservation of urine output may be misleading in hiding the postrenal partial obstruction. For moderate to severe AKI to occur in individuals with two healthy functional kidneys, obstruction must affect both kidneys in order to observe large increases in SCr, unless there is asymmetric kidney function with one chronically diseased. Unilateral obstruction may cause AKI in the setting of significant underlying CKD with loss of renal reserve or, in rare cases, from reflex vasospasm of the contralateral kidney. Bladder neck obstruction is a PART 9 Disorders of the Kidney and Urinary Tract Postrenal Kidney Ureter Bladder Sphincter Urethra FIGURE 321-5  Anatomic sites and causes of obstruction leading to postrenal acute kidney injury.

common cause of postrenal AKI. This can be due to prostate disease (benign prostatic hypertrophy or prostate cancer), neurogenic bladder, or therapy with anticholinergic drugs. Obstructed bladder catheters can cause postrenal AKI if not recognized. Other causes of lower tract obstruction are blood clots, calculi, and urethral strictures. Ureteric obstruction can occur from intraluminal obstruction (e.g., calculi, blood clots, sloughed renal papillae), infiltration of the ureteric wall (e.g., neoplasia), or external compression (e.g., retroperitoneal fibrosis, neoplasia, abscess, or inadvertent surgical damage). The pathophysi­ ology of postrenal AKI involves hemodynamic alterations triggered by an abrupt increase in intratubular pressures. An initial period of hyperemia from afferent arteriolar dilation is followed by intrarenal vasoconstriction from the generation of angiotensin II, thromboxane A2, and vasopressin, and a reduction in NO production. Secondary reductions in glomerular function are due to underperfusion of glom­ eruli and, possibly, changes in the glomerular ultrafiltration coefficient. DIAGNOSTIC EVALUATION (TABLE 321-2) As described previously, AKI is defined by an elevation in the SCr concentration from baseline of at least 0.3 mg/dL within 48 h or at least 50% within 1 week, or a reduction in urine output to <0.5 mL/kg per h for longer than 6 h. Serum cystatin C is increasingly being used to estimate GFR and may have a role in AKI diagnosis; both SCr and cystatin C have distinct non-GFR determinants that can influence their sensitivity and specificity. As indicated previously, some patients with AKI will not have tubular or glomerular damage (e.g., prerenal azote­ mia). The distinction between AKI and CKD is important for proper diagnosis and treatment. CKD is defined by an estimated GFR <60 mL/ min per 1.73 m2 or an albumin-to-creatinine ratio (ACR) of >30 mg/g for a period of at least 3 months. If the diagnosis of AKI is made and renal dysfunction persists for more than a week but not yet 3 months, then some refer to this renal dysfunction as acute kidney disease. The distinction between AKI and CKD is straightforward when a recent baseline SCr concentration is available, but more difficult in the many instances in which the baseline is unknown. In such cases, clues sug­ gestive of CKD can come from radiologic studies (e.g., small, shrunken kidneys with cortical thinning on renal ultrasound) or laboratory tests such as normocytic anemia in the absence of blood loss or secondary hyperparathyroidism with hyperphosphatemia and hypocalcemia, consistent with CKD. No set of tests, however, can rule out AKI super­ imposed on CKD because AKI is a frequent complication in patients with CKD, further complicating the distinc­ tion. Serial blood tests showing a con­ tinued substantial rise of SCr represent clear evidence of AKI. Once the diag­ nosis of AKI is established, its cause needs to be determined because the elevation of SCr or reduction in urine output can be due to a large number of physiologic and pathophysiologic pro­ cesses, as described previously. Increas­ ingly, the electronic medical record is being utilized for automated alerts to identify AKI and artificial intelligence approaches for AKI prediction. The role of automated alerts and artificial intelligence to predict and/or identify AKI is an area of active investigation. Stones, blood clots, external compression, tumor, retroperitoneal fibrosis, cancer ■ ■HISTORY AND PHYSICAL EXAMINATION The clinical context, careful history taking, and physical examination often narrow the differential diagnosis for the cause of AKI. Prerenal azotemia should be suspected in the setting of vomiting, diarrhea, glycosuria caus­ ing polyuria, and several medications Prostatic enlargement, blood clots, cancer Strictures Obstructed Foley catheter

TABLE 321-2  Major Causes, Clinical Features, and Diagnostic Studies for Prerenal and Intrinsic Acute Kidney Injury ETIOLOGY CLINICAL FEATURES LABORATORY FEATURES COMMENTS Prerenal azotemia History of poor fluid intake or fluid loss (hemorrhage, diarrhea, vomiting, sequestration into extravascular space); NSAID/ ACE-I/ARB; heart failure; evidence of volume depletion (tachycardia, absolute or postural hypotension, low jugular venous pressure, dry mucous membranes), decreased effective circulatory volume (cirrhosis, heart failure) Sepsis, sepsis syndrome, or septic shock; overt hypotension not always seen in mild to moderate AKI Sepsis-associated AKI Systemic hypotension, often superimposed upon sepsis and/or reasons for limited renal reserve such as older age, CKD Ischemiaassociated AKI Nephrotoxin-Associated AKI: Endogenous Rhabdomyolysis Traumatic crush injuries, seizures, immobilization Elevated myoglobin, creatine kinase; urine heme positive with few red blood cells Hemolysis Recent blood transfusion with transfusion reaction Anemia, elevated LDH, low haptoglobin Tumor lysis Recent chemotherapy Hyperphosphatemia, hypocalcemia, hyperuricemia Multiple myeloma Age >60 years, constitutional symptoms, bone pain Monoclonal spike in urine or serum electrophoresis; elevated serum free light chains, low anion gap; anemia Nephrotoxin-Associated AKI: Exogenous Contrast nephropathy Exposure to iodinated contrast Characteristic course is rise in SCr within 1–2 d, peak within 3–5 d, recovery within 7 d Tubular injury Aminoglycoside antibiotics, cisplatin, tenofovir, vancomycin, zoledronate, ethylene glycol, aristolochic acid, and melamine (to name a few) Other Causes of Intrinsic AKI Glomerulonephritis/ vasculitis Variable (Chap. 326) features include skin rash, arthralgias, sinusitis (AGBM disease), lung hemorrhage (AGBM, ANCA, lupus), recent skin infection or pharyngitis (poststreptococcal), thrombotic microangiopathies including those related to drugs, such as cocaine, anti-VEGF agents, genetic abnormalities of the complement pathways Tubulointerstitial nephritis Drugs are responsible for about 75% of the biopsy-proven acute interstitial nephritis, which involves tubules in most cases. Examples of causes include antibiotics, PPIs, immune checkpoint inhibitors. Non-drug-related causes include tubulointerstitial nephritis-uveitis (TINU) syndrome, lupus, viral infection (e.g., COVID, HIV, hantavirus), and Legionella infection. TTP/HUS Neurologic abnormalities and/or AKI; recent diarrheal illness; use of calcineurin inhibitors; pregnancy or postpartum; spontaneous Atheroembolic disease Recent manipulation of the aorta or other large vessels; may occur spontaneously or after anticoagulation; retinal plaques, palpable purpura, livedo reticularis, GI bleed Postrenal AKI History of kidney stones, prostate disease, obstructed bladder catheter, retroperitoneal or pelvic neoplasm Abbreviations: ACE-I, angiotensin-converting enzyme inhibitor-I; AGBM, antiglomerular basement membrane; AKI, acute kidney injury; ANA, antinuclear antibody; ANCA, antineutrophilic cytoplasmic antibody; ARB, angiotensin receptor blocker; ASO, antistreptolysin O; BUN, blood urea nitrogen; CKD, chronic kidney disease; FeNa, fractional excretion of sodium; GI, gastrointestinal; LDH, lactate dehydrogenase; NSAID, nonsteroidal anti-inflammatory drug; PPI, proton pump inhibitors; TTP/HUS, thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome.

BUN/creatinine ratio above 20, FeNa <1%, hyaline casts in urine sediment, urine specific gravity >1.018, urine osmolality >500 mOsm/kg Low FeNa, high specific gravity and osmolality may not be seen in the setting of CKD, diuretic use; BUN elevation out of proportion to creatinine may alternatively indicate upper GI bleed or increased catabolism. Response to restoration of hemodynamics is most diagnostic. Positive culture from normally sterile body fluid or other test confirming infection; urine sediment often contains granular casts, renal tubular epithelial cell casts FeNa may be low (<1%), particularly early in the course, but is usually >1% with osmolality <500 mOsm/kg Urine sediment often contains granular casts, renal tubular epithelial cell casts; FeNa typically >1% FeNa may be low (<1%) FeNa may be low (<1%); evaluation for transfusion reaction CHAPTER 321 Bone marrow or renal biopsy can be diagnostic Acute Kidney Injury FeNa may be low (<1%) Urine sediment often contains granular casts, renal tubular epithelial cell casts. FeNa typically >1%. Can be oliguric or nonoliguric ANA, ANCA, Anti-GBM antibody, hepatitis serologies, cryoglobulins, blood culture, complement abnormalities, ASO titer (abnormalities of these tests depending on etiology) Kidney biopsy may be necessary Eosinophilia, sterile pyuria; often nonoliguric Urine eosinophils have limited diagnostic accuracy; kidney biopsy may be necessary Schistocytes on peripheral blood smear, elevated LDH, anemia, thrombocytopenia “Typical HUS” refers to AKI with a diarrheal prodrome, often due to Shiga toxin released from Escherichia coli or other bacteria; “atypical HUS” is due to inherited or acquired complement dysregulation. Diagnosis may involve screening for ADAMTS13 activity, Shiga toxin–producing E. coli, genetic evaluation of complement regulatory proteins, and kidney biopsy. Hypocomplementemia, eosinophiluria (variable), variable amounts of proteinuria Skin or kidney biopsy can be diagnostic No specific findings other than AKI; may have pyuria or hematuria Imaging with computed tomography or ultrasound

including diuretics, NSAIDs, ACE inhibitors, and ARBs. Physical signs of orthostatic hypotension, tachycardia, reduced jugular venous pres­ sure, decreased skin turgor, and dry mucous membranes are often pres­ ent in prerenal azotemia. Congestive heart failure, liver disease, and nephrotic syndrome can be associated with reductions in renal blood flow and/or alterations in intrarenal hemodynamics leading to reduced GFR. Extensive vascular disease raises the possibility of renal artery disease, especially if kidneys are known to be asymmetric in size. Ath­ eroembolic disease can be associated with livedo reticularis and other signs of emboli to the legs. The presence of sepsis is an important clue to causation, although, as described above, the detailed pathophysiol­ ogy may be multifactorial.

A history of prostatic disease, nephrolithiasis, or pelvic or paraaortic malignancy would suggest the possibility of postrenal AKI. Whether or not symptoms are present early during obstruction of the urinary tract depends on the location of obstruction. Colicky flank pain radiating to the groin suggests acute ureteric obstruction. Nocturia and urinary frequency or hesitancy can be seen in prostatic disease. Abdominal fullness and suprapubic pain can accompany bladder enlargement. Definitive diagnosis of obstruction requires radiologic investigations. A careful review of all medications is imperative in the evalua­ tion of an individual with AKI. Not only are medications frequently a nephrotoxic cause of AKI, but doses of administered medications must be adjusted for reductions in kidney function. In this regard, it is important to recognize that reductions in true GFR are not reflected by equations that estimate GFR because those equations are dependent on SCr and the patient being in a steady state. With AKI, changes in SCr will lag behind changes in filtration rate. Allergic interstitial nephritis may be accompanied by fever, arthralgias, and a pruritic erythematous rash. The absence of systemic features of hypersensitivity, however, does not exclude the diagnosis of interstitial nephritis, and a kidney biopsy should be considered for definitive diagnosis when the cause of AKI is not apparent from the clinical presentation. PART 9 Disorders of the Kidney and Urinary Tract AKI accompanied by palpable purpura, pulmonary hemorrhage, or sinusitis raises the possibility of systemic vasculitis with glomeru­ lonephritis. A history of autoimmune disease, such as systemic lupus erythematosus, should lead to consideration of the possibility that the AKI is related to worsening of this underlying disease. Pregnancy should lead to the consideration of preeclampsia as a pathophysiologic contributor to the AKI. A tense abdomen should prompt consideration Urinary sediment in AKI Normal or few RBCs or WBCs or hyaline casts RBCs RBC casts WBCs WBC casts GN Interstitial nephritis ATN Prerenal Vasculitis Tubulointerstitial nephritis Postrenal GN Malignant hypertension Arterial thrombosis or embolism Pyelonephritis Acute cellular allograft rejection Thrombotic microangiopathy Allograft rejection Preglomerular vasculitis Myoglobinuria Malignant infiltration of the kidney Hemoglobinuria HUS or TTP Scleroderma crisis FIGURE 321-6  Interpretation of urinary sediment findings in acute kidney injury (AKI). ATN, acute tubular necrosis; GN, glomerulonephritis; HUS, hemolytic-uremic syndrome; RBCs, red blood cells; RTE, renal tubular epithelial; TTP, thrombotic thrombocytopenic purpura; WBCs, white blood cells. (Adapted from L Yang, JV Bonventre: Diagnosis and clinical evaluation of acute kidney injury. In Comprehensive Nephrology, 4th ed. J Floege et al [eds]. Philadelphia, Elsevier, 2010.)

of acute abdominal compartment syndrome, a diagnosis facilitated by measurement of bladder pressure. Signs and/or symptoms of limb ischemia may be clues to the diagnosis of rhabdomyolysis. ■ ■URINE FINDINGS Complete anuria early in the course of AKI is uncommon except in the following situations: complete urinary tract obstruction, renal artery occlusion, overwhelming septic shock, severe ischemia (often with cortical necrosis), or severe proliferative glomerulonephritis or vascu­ litis. A reduction in urine output (oliguria, defined as <400 mL/24 h) usually denotes more severe AKI (i.e., lower GFR) than when urine output is preserved. Oliguria is associated with worse clinical outcomes in AKI. Preserved urine output can be seen in nephrogenic diabetes insipidus characteristic of long-standing urinary tract obstruction, tubulointerstitial disease, or nephrotoxicity from cisplatin or amino­ glycosides, among other causes. Red or brown urine may be seen with or without gross hematuria; if the color persists in the supernatant after centrifugation, then pigment nephropathy from rhabdomyolysis or hemolysis should be suspected. The urinalysis and urine sediment examination are invaluable tools, but they require clinical correlation because of generally limited sen­ sitivity and specificity (see Fig. 321-6 and Chap. A4). In the absence of preexisting proteinuria from CKD, AKI secondary to ischemia or nephrotoxins leads to mild proteinuria (<1 g/d). Greater proteinuria in AKI suggests damage to the glomerular ultrafiltration barrier or excre­ tion of small molecular weight proteins such as myeloma light chains; the latter are not detected with conventional urine dipsticks (which detect albumin) and require the sulfosalicylic acid test or immunoelec­ trophoresis. Atheroemboli can cause a variable degree of proteinuria. Heavy proteinuria (“nephrotic range,” >3.5 g/d) can occasionally be seen in glomerulonephritis, vasculitis, or toxins/medications that can affect the glomerulus as well as the tubulointerstitium (e.g., NSAIDs). AKI can also complicate cases of minimal change disease, a cause of the nephrotic syndrome often associated with low serum albumin concentrations (Chap. 320). Prerenal azotemia may present with hyaline casts or an unremark­ able urine sediment examination. Postrenal AKI may also be associated with an unremarkable sediment, but hematuria and pyuria may be seen depending on the cause of obstruction. AKI from ATN due to ischemic injury, sepsis, or certain nephrotoxins has characteristic urine sediment Abnormal Renal tubular epithelial (RTE) cells RTE casts Pigmented casts Granular casts Eosinophiluria Crystalluria ATN Allergic interstitial nephritis Acute uric acid nephropathy GN Calcium oxalate (ethylene glycol intoxication) Vasculitis Atheroembolic disease Tubulo- interstitial nephritis Pyelonephritis Cystitis Glomerulo- nephritis Drugs or toxins (acyclovir, indinavir, sulfadiazine, amoxicillin)

findings: pigmented “muddy brown” granular casts and tubular epithe­ lial cell casts. These findings may be absent in >20% of cases, however. Glomerulonephritis may lead to dysmorphic red blood cells or red blood cell casts. Interstitial nephritis may lead to white blood cell casts. The urine sediment findings overlap somewhat in glomerulonephritis and interstitial nephritis, and a diagnosis is not always possible on the basis of the urine sediment alone. Urine eosinophils have a limited role in differential diagnosis; they can be seen in interstitial nephritis, pyelonephritis, cystitis, atheroembolic disease, or glomerulonephritis. Crystalluria may be important diagnostically. The finding of oxalate crystals in AKI should prompt an evaluation for ethylene glycol toxic­ ity. Abundant uric acid crystals may be seen in tumor lysis syndrome. ■ ■BLOOD LABORATORY FINDINGS Certain forms of AKI are associated with characteristic patterns in the rise and fall of SCr. Prerenal azotemia typically leads to modest rises in SCr that return to baseline with improvement in hemodynamic status. In comparison, atheroembolic disease usually manifests with more subacute rises in SCr, although severe AKI with rapid increases in SCr can occur in this setting. With many of the epithelial cell toxins such as aminoglycoside antibiotics and cisplatin, the rise in SCr is characteris­ tically delayed for 3–5 days to 2 weeks after initial exposure. A complete blood count may provide diagnostic clues. Anemia is common in AKI and is usually multifactorial in origin. It is not related to an effect of AKI solely on production of red blood cells because this effect in isolation takes longer to manifest. Myeloma can be diagnosed with serum immunoelectrophoresis or free light chain assay, and it can often be suspected if the blood anion gap is low due to unmeasured cationic proteins. Peripheral eosinophilia can accompany interstitial nephritis, atheroembolic disease, polyarteritis nodosa, and ChurgStrauss vasculitis. Severe anemia in the absence of bleeding may reflect hemolysis, multiple myeloma, or thrombotic microangiopathy (e.g., HUS or TTP). Other laboratory findings of thrombotic microangi­ opathy include thrombocytopenia, schistocytes on peripheral blood smear, elevated lactate dehydrogenase level, and low haptoglobin con­ tent. Evaluation of patients suspected of having TTP or HUS includes measurement of levels of the von Willebrand factor cleaving protease (ADAMTS13) and testing for Shiga toxin–producing Escherichia coli. “Atypical HUS” constitutes the majority of adult cases of HUS; genetic testing is important because it is estimated that 60–70% of atypical HUS patients have mutations in genes encoding proteins that regulate the alternative complement pathway. AKI often leads to hyperkalemia, hyperphosphatemia, and hypocal­ cemia. Marked hyperphosphatemia with accompanying hypocalcemia may suggest rhabdomyolysis or tumor lysis syndrome. Serum creatine kinase and uric acid levels are often elevated in rhabdomyolysis, while tumor lysis syndrome can be associated with normal or marginally ele­ vated creatine kinase and markedly elevated serum uric acid. The anion gap may be increased with any cause of uremia due to retention of anions such as phosphate, hippurate, sulfate, and urate. The co-occurrence of an increased anion gap and an osmolal gap may suggest ethylene glycol poi­ soning, which may also cause oxalate crystalluria and oxalate deposition in kidney tissue. As discussed previously, low anion gap may provide a clue to the diagnosis of multiple myeloma due to the presence of unmea­ sured cationic proteins. Laboratory blood tests helpful for the diagnosis of glomerulonephritis and vasculitis include depressed complement levels and high titers of antinuclear antibodies (ANAs), antineutrophil cytoplasmic antibodies (ANCAs), antiglomerular basement membrane (anti-GBM) antibodies, and cryoglobulins. It is important to diagnose glomerulonephritis or myeloma early in the course of AKI since effective therapies (e.g., immunosuppression or chemotherapy) are now available for some of the causes. In general, however, the therapies are less effec­ tive when severe kidney injury has progressed. ■ ■RENAL FAILURE INDICES Several indices have been used to help differentiate prerenal azotemia from intrinsic AKI when the tubules are malfunctioning. The low tubular flow rate and increased renal medullary recycling of urea seen in prerenal azotemia may cause a disproportionate elevation of

the blood urea nitrogen (BUN) compared to creatinine. Other causes of disproportionate BUN elevation need to be kept in mind, how­ ever, including upper gastrointestinal bleeding, hyperalimentation, increased tissue catabolism, and glucocorticoid use.

The FeNa is the fraction of the filtered sodium load that is not reab­ sorbed by the tubules and is a measure of both the kidney’s ability to reabsorb sodium as well as endogenously and exogenously administered factors that affect tubular reabsorption. As such, it depends on sodium intake, effective intravascular volume, GFR, diuretic intake, and intact tubular reabsorptive mechanisms. With prerenal azotemia, the FeNa may be <1%, suggesting avid tubular sodium reabsorption. In patients with CKD, a FeNa significantly >1% can be present due to tubular dys­ function in the reabsorption of sodium, despite a superimposed prerenal state. The FeNa may also be >1% despite hypovolemia due to treatment with diuretics. Low FeNa is often seen early in glomerulonephritis and other disorders and, hence, should not be taken as prima facie evidence of prerenal azotemia. Low FeNa is therefore suggestive of, but not syn­ onymous with, effective intravascular volume depletion, and should not be used as the sole guide for volume management. The response of urine output to crystalloid or colloid fluid administration may be both diagnostic and therapeutic in prerenal azotemia. In ischemic AKI, the FeNa is frequently >1% because of tubular injury and resultant impaired ability to reabsorb sodium. Several causes of ischemia-associated and nephrotoxin-associated AKI can present with FeNa <1%, however, including sepsis (often early in the course), rhabdomyolysis, and contrast nephropathy. FeNa has the most utility in oliguric patients who are not given diuretics and do not have CKD. CHAPTER 321 The ability of the kidney to produce a concentrated urine is dependent upon many factors and relies on good blood flow and tubular function in multiple regions of the kidney. In the patient not taking diuretics and with good baseline kidney function, urine osmolality may be >500 mOsm/kg in prerenal azotemia, consistent with an intact medullary concentration gradient and elevated serum vasopressin levels causing water reabsorp­ tion by passive diffusion from the collecting duct into a concentrated medullary interstitium, resulting in concentrated urine. In elderly patients and those with CKD, however, baseline concentrating defects may exist, making urinary osmolality unreliable in many instances. Concentrating ability may also be maintained early in the course of glomerular disease when the tubules are not yet affected. Loss of concentrating ability (<350 mOsm/kg) is common in most forms of AKI that affect the tubules and interstitium, but this finding is not specific. Acute Kidney Injury ■ ■RADIOLOGIC EVALUATION Postrenal AKI should always be considered in the differential diagnosis of AKI because treatment is usually successful if instituted early. Simple bladder catheterization can rule out urethral obstruction. Imaging of the urinary tract with renal ultrasound or CT scan should be under­ taken to investigate obstruction in individuals with AKI unless an alternate diagnosis is apparent. Findings of obstruction include dilation of the collecting system and hydroureteronephrosis. Obstruction can be present without radiologic abnormalities in the setting of volume depletion, retroperitoneal fibrosis, encasement with tumor, and also early in the course of obstruction. If a high clinical index of suspicion for obstruction persists despite normal imaging, antegrade or retro­ grade pyelography should be performed. Imaging may also provide additional helpful information about kidney size and echogenicity to assist in the distinction between AKI versus CKD. In CKD, kidneys are usually smaller unless the patient has diabetic nephropathy, HIVassociated nephropathy, or infiltrative diseases. Normal-sized kidneys are expected in AKI. Enlarged kidneys in a patient with AKI suggest the possibility of acute interstitial nephritis or infiltrative diseases. Vascular imaging may be useful if venous or arterial obstruction is suspected. ■ ■KIDNEY BIOPSY If the cause of AKI is not apparent based on the clinical context, physi­ cal examination, laboratory studies, and radiologic evaluation, kidney biopsy should be considered. The kidney biopsy can provide definitive diagnostic and prognostic information about acute kidney disease and CKD. The procedure is most often used in AKI when prerenal azotemia,

postrenal AKI, and ischemic or nephrotoxic AKI have been deemed unlikely and other possible diagnoses are being considered such as glo­ merulonephritis, vasculitis, interstitial nephritis, myeloma kidney, HUS and TTP, and allograft dysfunction. Kidney biopsy is associated with a risk of bleeding, which can be severe and organ- or life-threatening in patients with thrombocytopenia or coagulopathy, but the diagnostic and prognostic information obtained can be invaluable.

■ ■NOVEL BIOMARKERS BUN, SCr, and cystatin C are functional biomarkers of glomerular filtration rather than tissue injury biomarkers and, therefore, may be suboptimal for the diagnosis of actual parenchymal kidney damage. Filtration markers are also relatively slow to rise after kidney injury. Several urine and blood biomarkers have been investigated and show promise for earlier and accurate diagnosis of AKI and for predict­ ing AKI prognosis. In cases of oliguric AKI, the urinary flow rate in response to bolus intravenous furosemide 1.0–1.5 mg/kg can be used as a prognostic test: urine output <200 mL over 2 h after intravenous furosemide may identify patients at higher risk of progression to more severe AKI and the need for renal replacement therapy. The severity or risk of progressive AKI may also be reflected in findings on urine microscopy. In one study involving review of fresh urine sediments by board-certified nephrologists, a greater number of renal tubular epi­ thelial cells and/or granular casts in the urine sediment was associated with both the severity and worsening of AKI. Protein biomarkers of kidney injury have also been identified in animal models of AKI and have been used in humans and found to be particularly useful in toxic­ ity identification. Kidney injury molecule-1 (KIM-1) is a type 1 trans­ membrane protein that is abundantly expressed in proximal tubular cells injured by ischemia or multiple, distinct nephrotoxins, such as cis­ platin. KIM-1 is not expressed in appreciable quantities in the absence of tubular injury or in extrarenal tissues. KIM-1 can be detected after ischemic or nephrotoxic injury in the urine and plasma. Neutrophil gelatinase associated lipocalin (NGAL, also known as lipocalin-2 or siderocalin) is another biomarker of AKI. NGAL was first discovered as a protein in granules of human neutrophils. NGAL can bind to iron siderophore complexes and may have tissue-protective effects in the proximal tubule. NGAL is highly upregulated after inflammation and kidney injury and can be detected in the plasma and urine within 2 h of cardiopulmonary bypass–associated AKI. Soluble urokinase plasmino­ gen activator receptor (suPAR) is a signaling glycoprotein expressed in multiple cell types and thought to be involved in the pathogenesis of certain kidney diseases; suPAR has been measured in the plasma and found to predict the subsequent development of AKI. In 2014, the U.S. Food and Drug Administration (FDA) approved the marketing of a test based on the combination of the urinary concentrations of two cellcycle arrest biomarkers, insulin-like growth factor binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinase-2 (TIMP-2) as pre­ dictive biomarkers for higher risk of the development of moderate to severe AKI in critically ill patients. In 2023, the FDA also approved the use of NGAL for the early identification of AKI in pediatric patients. Biomarkers may also be helpful in distinguishing tubulointerstitial nephritis where interstitial inflammation plays a dominant role from other causes of AKI that primarily affect the glomeruli or the tubule where inflammation also exists but may be less dominant. One such marker, CXCL9, has recently been reported. The optimal use of AKI biomarkers in clinical settings is an area of ongoing investigation. PART 9 Disorders of the Kidney and Urinary Tract COMPLICATIONS OF AKI The kidney plays a central role in homeostatic control of volume status, blood pressure, plasma electrolyte composition, acid-base balance, and the excretion of nitrogenous and other waste products. Complications associated with AKI are, therefore, protean, and depend on the severity of AKI and other associated conditions. Mild to moderate AKI may be entirely asymptomatic, particularly early in the course. ■ ■UREMIA Buildup of nitrogenous waste products, manifested as an elevated BUN concentration, is a hallmark of AKI. BUN itself poses little direct

toxicity at levels <100 mg/dL. In more severe AKI or when, as is often the case, AKI is on the backdrop of CKD, mental status changes and bleeding complications can arise. Other toxins normally cleared by the kidney may be responsible for the symptom complex known as uremia, which literally means “urine in the blood.” Urea has direct and indirect toxic effects. There are increased blood levels of parathyroid hormone, advanced glycosylation end products, and many other “middle mole­ cules” that contribute to the uremic syndrome. Few of the many possible uremic toxins have been definitively identified. The correlation of filtra­ tion markers or BUN concentrations with uremic symptoms is extremely variable, due in part to differences in generation rates across individuals. ■ ■HYPERVOLEMIA AND HYPOVOLEMIA Expansion of extracellular fluid volume is a major complication of oliguric and anuric AKI, due to impaired salt and water excretion. The result can be weight gain, dependent edema, increased jugular venous pressure, and pulmonary edema. AKI may also induce or exacerbate acute lung injury characterized by increased vascular permeability and inflammatory cell infiltration in lung parenchyma. Recovery from AKI is often heralded by an increase in urine output. This “polyuric” phase of recovery may be due to an osmotic diuresis from retained urea and other waste products as well as delayed recovery of tubular reabsorptive functions. ■ ■HYPONATREMIA Abnormalities in plasma electrolyte composition can be mild or lifethreatening. The dysfunctional kidney has limited ability to regulate electrolyte balance. Administration of excessive hypotonic crystal­ loid or isotonic dextrose solutions can result in hypoosmolality and hyponatremia, which, if severe, can cause neurologic abnormalities, including seizures. ■ ■HYPERKALEMIA An important complication of AKI is hyperkalemia. Marked hyper­ kalemia is particularly common in rhabdomyolysis, hemolysis, and tumor lysis syndrome due to release of intracellular potassium from damaged cells. Muscle weakness may be a symptom of hyperkalemia. Potassium affects the cellular membrane potential of cardiac and neu­ romuscular tissues. The more serious complication of hyperkalemia is due to effects on cardiac conduction, leading to potentially fatal arrhythmias. ■ ■ACIDOSIS Metabolic acidosis, usually accompanied by an elevation in the anion gap, is common in AKI, and can further complicate acid-base and potassium balance in individuals with other causes of acidosis, includ­ ing sepsis, diabetic ketoacidosis, or respiratory acidosis. ■ ■HYPERPHOSPHATEMIA AND HYPOCALCEMIA AKI can lead to hyperphosphatemia, particularly in highly catabolic patients or those with AKI from rhabdomyolysis, hemolysis, and tumor lysis syndrome. Metastatic deposition of calcium phosphate can lead to hypocalcemia. AKI-associated hypocalcemia may also arise from derangements in the vitamin D–parathyroid hormone– fibroblast growth factor-23 axis. Hypocalcemia is often asymptom­ atic but can lead to perioral paresthesias, muscle cramps, seizures, carpopedal spasms, and prolongation of the QT interval on electro­ cardiography. Calcium levels should be corrected for the degree of hypoalbuminemia, if present, or ionized calcium levels should be fol­ lowed. Mild, asymptomatic hypocalcemia does not require treatment. ■ ■BLEEDING Hematologic complications of AKI include anemia and bleeding, both of which are exacerbated by coexisting disease processes such as sepsis, liver disease, and disseminated intravascular coagulation. Direct hema­ tologic effects from AKI-related uremia include decreased erythropoi­ esis and platelet dysfunction. ■ ■INFECTIONS Infections are a common precipitant of AKI and also a dreaded com­ plication of AKI. Impaired host immunity has been described in ESKD and may be operative in severe AKI.

■ ■CARDIAC COMPLICATIONS The major cardiac complications of AKI are arrhythmias, pericarditis, and pericardial effusion. In addition, volume overload and uremia may lead to cardiac injury and impaired cardiac function. In animal studies, cellular apoptosis and capillary vascular congestion as well as mitochondrial dysfunction have been described in the heart after renal ischemia reperfusion. ■ ■MALNUTRITION AKI is often a severely hypercatabolic state, and therefore, malnutrition is a major complication. ■ ■PREVENTION AND TREATMENT OF AKI The management of individuals with and at risk for AKI varies according to the underlying cause (Table 321-3). Common to all are several principles. Optimization of hemodynamics, correction of fluid and electrolyte imbalances, discontinuation of nephrotoxic medications, and dose adjustment of administered medications are all critical. Common causes of AKI such as sepsis and ischemic ATN do not yet have specific therapies once injury is established, but meticulous clinical attention is needed to support the patient until (if) AKI resolves. The kidney possesses remarkable capacity to repair itself after even severe, dialysis-requiring AKI, when baseline renal function was previously intact. However, many patients with AKI, particularly when superimposed on preexisting CKD, undergo mal­ adaptive repair processes and do not recover fully and may remain dialysis dependent. It has become increasingly apparent that AKI pre­ disposes to accelerated progression of CKD, and CKD is an important risk factor for AKI. Prerenal Azotemia  Prevention and treatment of prerenal azote­ mia require optimization of renal perfusion. In AKI, oliguria alone is not an indication for fluid administration. Intravascular hypovole­ mia should be the only indication. The composition of replacement fluids should be targeted to the type of fluid lost. Severe acute blood loss should be treated with packed red blood cells. Crystalloids are in general favored over colloid-containing solutions (e.g., hyperoncotic albumin-containing solutions, which are still commonly used for volume resuscitation in liver failure). The colloidal solution hydroxy­ ethyl starch is no longer available for hospitalized patients, due in part to concerns over increased risk of AKI. The most commonly used crystalloid solution is 0.9% saline. Other options are buffered crystalloid solutions (e.g., Ringer’s lactate, Hartmann’s solution, Plasma-Lyte). The choice between 0.9% saline or buffered crystal­ loid solutions can be based on serum electrolyte (e.g., some buffered crystalloid solutions are slightly hypotonic to plasma water and may be preferred for patients with hypernatremia; 0.9% saline can cause or exacerbate hyperchloremic metabolic acidosis and can be used in those with metabolic alkalosis; bicarbonate-containing solutions like dextrose water with 150 mEq sodium bicarbonate can be used in those with metabolic acidosis). Optimization of cardiac function in AKI may require use of ino­ tropic agents, preload- and afterload-reducing agents, antiarrhythmic drugs, and mechanical aids such as ventricular assist devices. Invasive hemodynamic monitoring to guide therapy may be necessary. Cirrhosis and Hepatorenal Syndrome  Fluid management in individuals with cirrhosis, ascites, and AKI is challenging because of the frequent difficulty in ascertaining intravascular volume status. Administration of intravenous fluids as a volume challenge may be required diagnostically as well as therapeutically. Excessive volume administration may, however, result in worsening ascites and pulmo­ nary compromise in the setting of hepatorenal syndrome or AKI due to superimposed spontaneous bacterial peritonitis. Peritonitis should be ruled out by inflammatory cell count and culture of ascitic fluid. Albumin may prevent AKI in those treated with antibiotics for sponta­ neous bacterial peritonitis. The definitive treatment of the hepatorenal syndrome is orthotopic liver transplantation. Bridge therapies that have shown promise include norepinephrine, terlipressin (a vasopres­ sin analogue), or combination therapy with octreotide (a somatostatin

TABLE 321-3  Management of Acute Kidney Injury General Issues

  1. Optimization of systemic and renal hemodynamics through volume resuscitation and judicious use of vasopressors
  2. Maintain mean arterial pressure >65 mmHg
  3. Elimination of nephrotoxic agents (e.g., ACE inhibitors, ARBs, NSAIDs, aminoglycosides, chemotherapeutic agents, checkpoint inhibitors, antibiotics) if possible
  4. Sufficient protein and calorie intake (20–30 kcal/kg per day) to avoid negative nitrogen balance. Nutrition should be provided by the enteral route if oral intake is not possible.
  5. Initiation of renal replacement therapy when indicated Specific Issues
  6. Nephrotoxin-specific a. Rhabdomyolysis: aggressive intravenous fluids; consider forced alkaline diuresis b. Tumor lysis syndrome: aggressive intravenous fluids and allopurinol or rasburicase
  7. Volume overload a. Salt and water restriction b. Diuretics c. Ultrafiltration
  8. Hyponatremia CHAPTER 321 a. Restriction of enteral free water intake, minimization of hypotonic intravenous solutions including those containing dextrose b. Hypertonic saline is rarely necessary in AKI. Vasopressin antagonists are generally not needed.
  9. Hyperkalemia Acute Kidney Injury a. Restriction of dietary potassium intake b. Discontinuation of potassium-sparing diuretics, ACE inhibitors, ARBs, NSAIDs c. Loop diuretics to promote urinary potassium loss d. Potassium-binding molecules (sodium zirconium cyclosilicate) or ionexchange resins (patiromer, sodium or calcium polystyrene sulfonate) e. Insulin and glucose to promote entry of potassium intracellularly f. Inhaled beta-agonist therapy to promote entry of potassium intracellularly g. Calcium gluconate or calcium chloride (1 g) to stabilize the myocardium
  10. Metabolic acidosis a. Sodium bicarbonate (if pH <7.2 to keep serum bicarbonate >15 mmol/L) b. Renal replacement therapy
  11. Hyperphosphatemia a. Restriction of dietary phosphate intake b. Phosphate binding agents (calcium acetate, sevelamer hydrochloride, aluminum hydroxide—taken with meals)
  12. Hypocalcemia a. Calcium carbonate or calcium gluconate if symptomatic
  13. Hypermagnesemia a. Discontinue Mg2+-containing antacids
  14. Hyperuricemia a. Acute treatment is usually not required except in the setting of tumor lysis syndrome (see above)
  15. Drug dosing a. Careful attention to dosages and frequency of administration of drugs, adjustment for degree of renal failure b. Note that serum creatinine concentration may overestimate renal function in the non-steady-state characteristic of patients with AKI Abbreviations: ACE, angiotensin-converting enzyme; AKI, acute kidney infection; ARBs, angiotensin receptor blockers; NSAIDs, nonsteroidal anti-inflammatory drugs. analogue) and midodrine (an α1-adrenergic agonist), in combination with intravenous albumin (25–50 g, maximum 100 g/d). Intrinsic AKI  Several agents have been tested and have failed to show benefit in the treatment of acute tubular injury. These include atrial natriuretic peptide, low-dose dopamine, endothelin antagonists, erythropoietin, prostaglandin analogues, antioxidants, antibodies against leukocyte adhesion molecules, growth factors,

intra-aortic mesenchymal stem cells, and small interfering RNAs to inhibit p53-mediated cell death, among many others. Most studies have used changes in SCr to identify AKI; kidney injury biomarkers described previously may provide an opportunity to test agents with greater sensitivity.

AKI due to acute glomerulonephritis or vasculitis may respond to immunosuppressive agents, anticomplement therapies, and/or plasmapheresis (Chap. 320). Allergic interstitial nephritis due to medications requires discontinuation of the offending agent. Glu­ cocorticoids have been used but not tested in randomized trials, in cases where AKI persists or worsens despite discontinuation of the suspected medication. AKI due to scleroderma (scleroderma renal crisis) should be treated with ACE inhibitors. Idiopathic TTP is a medical emergency and should be treated promptly with plasma exchange. Pharmacologic blockade of complement activation may be effective in atypical HUS. Early and aggressive volume repletion is mandatory in patients with rhabdomyolysis, who may initially require 10 L of fluid per day. Alka­ line fluids (e.g., 75 mmol/L sodium bicarbonate added to 0.45% saline) may be beneficial in preventing tubular injury and cast formation but carry the risk of worsening hypocalcemia. Diuretics may be used if fluid repletion is adequate but unsuccessful in achieving urinary flow rates of 200–300 mL/h. There is no specific therapy for established AKI in rhab­ domyolysis, other than dialysis in severe cases or general supportive care to maintain fluid and electrolyte balance and tissue perfusion. Careful attention must be focused on calcium and phosphate status because of precipitation in damaged tissue and release when the tissue heals. PART 9 Disorders of the Kidney and Urinary Tract Postrenal AKI  Prompt recognition and relief of urinary tract obstruction can forestall the development of permanent structural damage induced by urinary stasis. The site of obstruction defines the treatment approach. Transurethral or suprapubic bladder cath­ eterization may be all that is needed initially for urethral strictures or functional bladder impairment. Ureteric obstruction may be treated by percutaneous nephrostomy tube placement or ureteral stent place­ ment. Relief of obstruction is usually followed by an appropriate diure­ sis for several days. In rare cases, severe polyuria persists due to tubular dysfunction and may require continued administration of intravenous fluids and electrolytes for a period of time. ■ ■SUPPORTIVE MEASURES FOR AKI Volume Management  Hypervolemia in oliguric or anuric AKI may be life threatening due to acute pulmonary edema, especially because many patients have coexisting pulmonary disease, and AKI likely increases pulmonary vascular permeability. Fluid and sodium should be restricted, and diuretics may be used to increase the uri­ nary flow rate. There is no evidence that increasing urine output itself improves the natural history of AKI, but diuretics may help to avoid the need for dialysis in some cases. In severe cases of volume overload, furosemide may be given as a bolus (200 mg) followed by an intravenous drip (10–40 mg/h), with or without a thiazide diuretic. In decompensated heart failure, stepped diuretic therapy was found to be superior to ultrafiltration in preserving renal function. Dopamine in low doses may transiently increase salt and water excretion by the kid­ ney in prerenal states, but clinical trials have failed to show any benefit in patients with intrinsic AKI. Because of the risk of arrhythmias and potential bowel ischemia, the risks of dopamine outweigh the benefits if used specifically for the treatment or prevention of AKI. Electrolyte and Acid-Base Abnormalities  The treatment of dysnatremias and hyperkalemia is described in Chap. 56. Metabolic acidosis associated with AKI is generally not treated unless severe (pH <7.20 and serum bicarbonate <15 mmol/L). Acidosis can be treated with oral or intravenous sodium bicarbonate (Chap. 58), but overcorrec­ tion should be avoided because of the possibility of metabolic alkalosis, hypocalcemia, hypokalemia, and volume overload. Hyperphosphatemia is common in AKI and can usually be treated by limiting intestinal absorption of phosphate using phosphate binders (calcium carbon­ ate, calcium acetate, lanthanum, sevelamer, or aluminum hydroxide).

Symptomatic hypocalcemia should be treated with calcium gluconate or calcium chloride. Ionized calcium should be monitored rather than total calcium when hypoalbuminemia is present. Malnutrition  Increased catabolism with protein energy wasting is common in severe AKI, particularly in the setting of multisystem organ failure. Inadequate nutrition may lead to starvation ketoacidosis and protein catabolism. Excessive nutrition may increase the generation of nitrogenous waste and lead to worsening azotemia. Total parenteral nutrition requires large volumes of fluid administration and may com­ plicate efforts at volume control. According to the KDIGO guidelines, patients with AKI should achieve a total energy intake of 20–30 kcal/ kg per day. Protein intake should vary depending on the severity of AKI: 0.8–1.0 g/kg per day in noncatabolic AKI without the need for dialysis; 1.0–1.5 g/kg per day in patients on dialysis; and up to a maxi­ mum of 1.7 g/kg per day if hypercatabolic and receiving continuous renal replacement therapy. Trace elements and water-soluble vitamins should also be supplemented in AKI patients treated with dialysis and continuous renal replacement therapy. Anemia  The anemia seen in AKI is usually multifactorial and is not improved by erythropoiesis-stimulating agents, due to their delayed onset of action and the presence of bone marrow resistance in critically ill patients. Uremic bleeding may respond to desmopressin or estrogens but may require dialysis for treatment in the case of long-standing or severe uremia. Gastrointestinal prophylaxis with proton pump inhibi­ tors or histamine (H2) receptor blockers is required. It is important to recognize, however, that proton pump inhibitors have been associated with AKI due to interstitial nephritis, a relationship that is increasingly being recognized. Venous thromboembolism prophylaxis is important and should be tailored to the clinical setting; low-molecular-weight heparins and factor Xa inhibitors have unpredictable pharmacokinetics in severe AKI and should generally be avoided if possible. Dialysis Indications and Modalities (See also Chap. 323.) 

Dialysis is indicated when medical management fails to control volume overload, hyperkalemia, or acidosis; in some toxic ingestions; and when there are severe complications of uremia (asterixis, pericardial rub or effusion, encephalopathy, uremic bleeding). Late initiation of dialysis carries the risk of avoidable volume, electrolyte, and metabolic complications of AKI. On the other hand, initiating dialysis too early may unnecessarily expose individuals to intravenous lines and invasive procedures, with the attendant risks of infection, bleeding, procedural complications, and hypotension. In randomized controlled trials, earlier versus later initiation of dialysis has not been demonstrated to improve survival and may increase the risk of adverse events. The initiation of dialysis should not, however, await the development of a life-threatening complication of renal failure. Many nephrologists initi­ ate dialysis for AKI empirically when the BUN exceeds a certain value (e.g., 100 mg/dL) in patients without clinical signs of recovery of kidney function. The available modes for renal replacement therapy in AKI require either access to the peritoneal cavity (for peritoneal dialysis) or the large blood vessels (for hemodialysis, hemofiltration, and other hybrid procedures). Small solutes are removed across a semiperme­ able membrane down their concentration gradient (“diffusive” clear­ ance) and/or along with the movement of plasma water (“convective” clearance). Hemodialysis can be used intermittently or continuously and can be done through convective clearance, diffusive clearance, or a combination of the two. Vascular access is through the femoral, internal jugular, or subclavian veins. Hemodialysis is an intermittent procedure that removes solutes through diffusive and convective clear­ ance. Hemodialysis is typically performed 3–4 h per day, three to four times per week, and is the most common form of renal replacement therapy for AKI. One of the major complications of hemodialysis is hypotension, particularly in the critically ill, which can perpetuate AKI by causing ischemic injury to the recovering organ. Continuous intravascular procedures were developed in the early 1980s to treat hemodynamically unstable patients without inducing the rapid shifts of volume, osmolarity, and electrolytes characteristic of inter­ mittent hemodialysis. Continuous renal replacement therapy (CRRT)

04 - 322 Chronic Kidney Disease

322 Chronic Kidney Disease

can be performed by convective clearance (continuous venovenous hemofiltration [CVVH]), in which large volumes of plasma water (and accompanying solutes) are forced across the semipermeable membrane by means of hydrostatic pressure; the plasma water is then replaced by a physiologic crystalloid solution. CRRT can also be performed by dif­ fusive clearance (continuous venovenous hemodialysis [CVVHD]), a technology similar to hemodialysis except at lower blood flow and dialy­ sate flow rates. A hybrid therapy combines both diffusive and convective clearance (continuous venovenous hemodiafiltration [CVVHDF]). To achieve some of the advantages of CRRT without the need for 24-h staffing of the procedure, some physicians favor slow low-efficiency dialysis (SLED) or extended daily dialysis (EDD). In this therapy, blood flow and dialysate flow are higher than in CVVHD, but the treatment time is reduced to ≤12 h. The choice of modality is often dictated by the immediate availability of technology and the expertise of medical staff. The optimal dose of dialysis for AKI for any particular patient is not clear. Daily intermittent hemodialysis and high-dose CRRT do not confer a demonstrable survival or renal recovery advantage, but care should be taken to avoid undertreatment. Studies have failed to show that continuous therapies are superior to intermittent therapies when measuring survival rates. If available, CRRT is often preferred in patients with severe hemodynamic instability, cerebral edema, or significant volume overload. Peritoneal dialysis can be performed through a temporary intra­ peritoneal catheter. It is rarely used in the United States for AKI in adults (although it was “rediscovered” during the COVID-19 pandemic owing to inadequate numbers of continuous and intermittent hemo­ dialysis machines). Peritoneal dialysis has enjoyed widespread use internationally, particularly when hemodialysis technology is not as readily available. Dialysate solution is instilled into and removed from the peritoneal cavity at regular intervals in order to achieve diffusive and convective clearance of solutes across the peritoneal membrane; ultrafiltration of water is achieved by the presence of an osmotic gradi­ ent across the peritoneal membrane achieved by high concentrations of dextrose in the dialysate solution. Because of its continuous nature, it is often better tolerated than intermittent procedures like hemodialysis in hypotensive patients. Peritoneal dialysis may not be sufficient for hypercatabolic patients due to inherent limitations in dialysis efficacy. OUTCOME AND PROGNOSIS The development of AKI is associated with a significantly increased risk of in-hospital and long-term mortality, longer length of stay, and increased costs. AKI is also associated with an increased risk of later cardiovascular disease events, though the mechanisms are not well understood. Prerenal azotemia, with the exception of the cardiorenal and hepatorenal syndromes, and postrenal azotemia carry a better prognosis than most cases of intrinsic AKI. The kidneys may recover even after severe, dialysis-requiring AKI. Survivors of an episode of AKI requiring temporary dialysis, however, are at extremely high risk for progressive CKD, and up to 10% may develop ESKD requiring dialysis or transplantation. AKI and CKD are increasingly seen as interrelated syndromes: CKD is a major risk factor for the development of AKI, and AKI is a risk factor for the future development of CKD. Measurement of albuminuria after an AKI episode can help predict the risk of kidney disease progression and can serve as a valuable risk-stratification tool. Postdischarge care after AKI under the supervision of a nephrologist for aggressive secondary prevention of kidney disease is prudent. ■ ■FURTHER READING Chawla LS et al: Acute kidney injury and chronic kidney disease as interconnected syndromes. N Engl J Med 371:58, 2014. Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group: KDIGO Clinical Practice Guidelines for Acute Kidney Injury. Kidney Int Supp 2:1, 2012. Lake BB et al: An atlas of healthy and injured cell states and niches in the human kidney. Nature 610:585, 2023. Molitoris BA: Low-flow acute kidney injury: The pathophysiology of prerenal azotemia, abdominal compartment syndrome, and obstruc­ tive uropathy. Clin J Am Soc Nephrol 17:1039, 2022.

Ronco C et al: Acute kidney injury. Lancet 394: 1949, 2019. STARRT-AKI Investigators for the Canadian Critical Care

Trials Group: Timing of initiation of renal-replacement therapy in acute kidney injury. N Engl J Med 383:240, 2020. Tomasev N et al: A clinically applicable approach to continuous pre­ diction of future acute kidney injury. Nature 572:116, 2019. Yu SM, Bonventre JV: Acute kidney injury and maladaptive tubular repair leading to renal fibrosis. Curr Opin Nephrol Hypertens 29:310, 2020. Wilson FP et al: A randomized clinical trial assessing the effect of automated medication-targeted alerts on acute kidney injury out­ comes. Nat Commun 14:2826, 2023. Joanne M. Bargman, Karl L. Skorecki

Chronic Kidney Disease CHAPTER 322 Chronic kidney disease (CKD) encompasses a spectrum of pathophysi­ ologic processes associated with abnormal kidney function, often with a progressive decline in glomerular filtration rate (GFR). The risk of worsening CKD is closely linked to the GFR, its trajectory over time, and the quantity of urinary albumin excretion (albuminuria). Figure 322-1 provides a staging of CKD stratified by the estimated risk for further progressive decline of GFR based on these parameters. Chronic Kidney Disease The dispiriting term end-stage renal disease represents a stage of CKD where the accumulation of toxins, fluid, and electrolytes nor­ mally excreted by the kidneys leads to death unless the toxins are removed by renal replacement therapy by means of dialysis or kidney transplantation. These interventions are discussed in Chaps. 323 and 325. End-stage renal disease will be supplanted in this chapter by the term stage 5 CKD. ■ ■PATHOPHYSIOLOGY OF CKD The pathophysiology of CKD involves two broad mechanisms of dam­ age: (1) specific initiating mechanisms particular to the underlying etiology (e.g., genetic abnormalities in development, immune complex deposition, inflammation, metabolic, microvascular perturbation, or toxin exposure affecting vascular, glomerular, or tubulointerstitial compartments of the kidney), and (2) nonspecific mechanisms involv­ ing hyperfiltration and hypertrophy of the remaining viable nephrons, which are common consequences of long-term reduction of renal mass, irrespective of underlying etiology. The responses to reduction in nephron number are mediated by vasoactive hormones, cytokines, and growth factors. Eventually, the short-term adaptations of hyper­ filtration and hypertrophy to maintain GFR become maladaptive as the increased pressure and flow within the nephron predisposes to distortion of glomerular architecture, abnormal podocyte function, and disruption of the filtration barrier, leading to sclerosis and dropout of the remaining nephrons. Increased intrarenal activity of the reninangiotensin system (RAS) together with reduced tubuloglomerular feedback appears to contribute both to the initial compensatory hyper­ filtration and to the subsequent maladaptive hypertrophy and sclerosis (Fig. 322-2). This process explains why a reduction in functioning nephron number from initial injuries may lead to a progressive decline in kidney function over many years. ■ ■IDENTIFICATION OF RISK FACTORS AND STAGING OF CKD There has been significant progress in the identification of risk factors that increase the risk for CKD, even in individuals with normal GFR and often years prior to the development of overt kidney impairment (Table 322-1).

PART 9 Disorders of the Kidney and Urinary Tract <10 urine alb/cr (mg/g) 10–29 urine alb/cr (mg/g) 30–299 urine alb/cr (mg/g) 300–999 urine alb/cr (mg/g)

1000 urine alb/cr (mg/g)

Relative Risk (RR) All-Cause Mortality by GFR and Proteinuria

105 90–104 60–89 45–59 30–44 15–29 <15 Glomerular Filtration Rate (mL/min/1.73 m2) A

Relative Risk (RR) Cardiovascular Mortality by GFR and Proteinuria

105 90–104 60–89 45–59 30–44 15–29 <15 B Kidney Failure with Replacement Therapy by GFR and Proteinuria 105 90–104 60–89 45–59 30–44 15–29 <15 C FIGURE 322-1  Kidney Disease Improving Global Outcome (KDIGO) classification of chronic kidney disease (CKD). Glomerular filtration rate (GFR) and Increasing albuminuria correspond to increasing risk of All-Cause Mortality (A), Cardiovascular Mortality (B) and Progression of CKD (C). (Figure created using data from ME Grams et al: JAMA 330:1266, 2023.) Adults with such risk factors should be monitored yearly for urinary albumin excretion level, decline in estimated GFR (eGFR), and blood pressure, so that a clinical reno-protective management pathway can be planned. More recently, identified risk factors for which there is now a consensus include tobacco use, increased body mass index (BMI) and sedentary lifestyle, a past episode of clinically recovered acute kidney injury (AKI), and many forms of apparently recovered childhood and adolescent kidney disease. There is also an increasing awareness of the role of genetic risk fac­ tors, which may account for up to 20% of adult-onset CKD, depending on the clinical phenotype, family background, demographic history, and population ancestry. Many rare inherited forms of CKD follow a Mendelian inheritance pattern, sometimes as part of a systemic syndrome, with the most common in this category being autosomal dominant polycystic kidney disease (ADPKD). In addition, it is now appreciated that many unique, kindred-specific, site-specific copy number variants and microdeletions, as well as functional single nucleotide variants at >300 genetic loci known to harbor systemic and kidney-only disease pathogenic mutations with high penetrance, also contribute to pleiotropic presentations of CKD (Table 322-2). Many of the genes with identified CKD-causing mutations are expressed in the podocytes of the glomeruli or in the glomerular basement membrane, but others are expressed in tubule segments associated with a primary tubulointerstitial process and secondary glomerular injury. In addition to these high penetrance mutations, DNA sequence variants with partial penetrance for causation or progression of CKD have been identified and often require an acquired second hit for emer­ gence of disease. A striking example is the finding of allelic versions of the APOL1 gene, of sub-Saharan African population ancestry, which contributes to the several-fold higher frequency of certain common

Distal tubule Distal tubule Afferent arteriole Efferent arteriole Normal kidney Glomerulus Tubule Tubule A B FIGURE 322-2  Schematic representation of the effect of intraglomerular hypertension on nephron survival. etiologies of nondiabetic CKD (e.g., focal segmental glomeruloscle­ rosis, HIV- and SARS-CoV-2–associated nephropathy, CKD with hypertension, lupus nephritis) observed among African and Hispanic Americans in major regions of continental Africa and the global African diaspora. The prevalence in West African populations seems to have arisen as an evolutionary adaptation conferring protection from tropi­ cal pathogens. As in other common diseases with a heritable compo­ nent, acquired triggers (e.g., increased levels of interferon-γ and other cytokines) can transform genetic risk into disease. In addition to these single-gene loci, recent studies have identified genome-wide patterns of DNA sequence variants that confer increased risk for CKD. These include risk alleles associated with idiopathic IgA and idiopathic mem­ branous glomerulopathy. Staging of CKD (Fig. 322-1) is based on both GFR and on urinary albumin excretion rate and is key to understanding the emergence of symptoms, for determining the risk and rate of CKD progression and complications, and for determining indications for medical interven­ tion. GFR is estimated (eGFR) rather than directly measured, using equations that include serum creatinine concentration and various other individual patient parameters, in place of timed urine collections, which have proven cumbersome and unreliable. U.S.-based national professional societies have recommended utilizing the equations shown in Table 322-3. eGFR determination in CKD is valid only if the patient is in steady state, that is, the serum creatinine is neither rising nor falling over days. The newly recommended equations no longer include a parameter that adjusts for differences in creatinine produc­ tion based on continental ancestry (race-free eGFR estimation equa­ tions). However, in some situations where precise estimation of GFR might affect medication dosing or other individual clinical decisions, it is reasonable to include an estimated adjustment based on various parameters that could modify creatinine production downward (e.g., loss of a limb) or upward (increased muscle mass) or, in some cases, revert to measure timed creatinine production rates or use of the more costly and less widely available marker cystatin-C, which is not affected by variables that influence creatinine production. The normal annual mean decline in GFR with age from the peak GFR (~120 mL/min per 1.73 m2) attained during the third decade of

Urinary protein Efferent arteriolar constricted Afferent arteriole Ang II Ang II Increased intraglomerular pressure CHAPTER 322 Chronic Kidney Disease life is ~1 mL/min per year per 1.73 m2, reaching a mean value of 70 mL/ min per 1.73 m2 at age 70, with considerable interindividual variability. Although reduced GFR is expected with aging, the lower GFR signifies a true loss of kidney function with attendant consequences in terms of risk of CKD complications and requirement for dose adjustment of medications. The mean GFR is lower in women than in men, though men are at greater risk for CKD than women. A woman in her eight­ ies with a laboratory report of serum creatinine in the normal range may have a GFR of <50 mL/min per 1.73 m2. Relatedly, even a mild elevation in serum creatinine concentration often signifies a substantial reduction in GFR in older individuals. It is not entirely clear as yet as to whether advancing age as a risk factor for progressive CKD is indepen­ dent of such age-related reduction in the measure of eGFR. Measurement of albuminuria is also helpful for monitoring nephron injury and the response to therapy in many forms of CKD, especially chronic glomerular diseases. The cumbersome 24-h urine collection has been replaced by measurement of urinary albumin-to-creatinine ratio (UACR) in one and preferably several spot first-morning urine samples as a measure pointing to glomerular injury. Even in patients with negative conventional urinary dipstick tests for protein, persis­ tent UACR >2.5 mg/mmol (male) or >3.5 mg/mmol (female) on two to three occasions serves as a marker not only for early detection of primary kidney disease but for systemic microvascular disease as well. A Kidney Failure Risk (KFR) equation has been devised to predict the risk of progression to stage 5 dialysis-dependent kidney disease. The equa­ tion is available on many sites online (for example, www.kidneyfailurerisk. com) and uses age, sex, region (North American or non–North American), GFR, and UACR. It has been validated in several cohorts around the world, although the risk for progression appears to be greater in North America, accounting for the regional adjustment in the equation. Stages 1 and 2 CKD are usually asymptomatic, such that the recog­ nition of CKD occurs more often as a result of laboratory testing in clinical settings other than suspicion of kidney disease. Moreover, in the absence of the risk factors noted above, population-wide screening is not recommended. With progression to CKD stages 3 and 4, clinical and laboratory complications become more prominent. Virtually all organ systems are affected, but the most evident complications include

TABLE 322-1  Risk Factors for Chronic Kidney Disease (CKD)a Noncommunicable Diseases   Diabetes   Increased BMI   Autoinflammatory disease (e.g., lupus, vasculitis, cancer immunotherapy)   Nephrotoxic exposure (including many antineoplastic therapies)   Hypertension (risk, cause, or consequence) Communicable Diseases   Streptococcal infection   Mycobacterial infection   HIV infection (HIVAN)   SARS-CoV-2   HBV, HCV Demographic, Anthropomorphic, Ancestry, Geographic   Age   Male sex   Population ancestry   Region-specific CKD risk of uncertain etiology (e.g., Central America,   Sri Lanka, and indigenous peoples of Australia and New Zealand)   Family history of kidney disease Genetic   Monogenic inheritance with (1) high penetrance or (2) low to medium PART 9 Disorders of the Kidney and Urinary Tract penetrance   Polygenic risk factors Childhood-Related Risk Factors   Premature and SGA birth   Persistent asymptomatic microscopic hematuria   Childhood kidney disease (even resolved)   Treated childhood cancer Lifestyle   Tobacco use   Sedentary lifestyle Other   Prior acute kidney injury   Preeclampsia   Kidney donation (or other acquired nephrectomy) aNot biomarkers. Abbreviations: BMI, body mass index; HBV, hepatitis B virus; HCV, hepatitis C virus; HIVAN, HIV-associated nephropathy; SGA, small for gestational age. anemia with easy fatigability; decreased appetite with progressive malnutrition; abnormalities in calcium, phosphorus, and mineralregulating hormones, such as 1,25(OH)2D3 (calcitriol), parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF-23); and abnor­ malities in sodium, potassium, water, and acid-base homeostasis. Many patients, especially older individuals, will have eGFR values compatible with stage 2 or 3 CKD. However, the majority of these patients will show no further deterioration of kidney function. In this setting, it is advised to recheck kidney function, and if it is stable and not associ­ ated with proteinuria, the patient can usually be followed with interval repeat testing without referral to a nephrologist. If repeat testing shows declining GFR, albuminuria, or uncontrolled hypertension, referral to a nephrologist is appropriate. If the patient progresses to stage 5 CKD (GFR <15 mL/min), toxins accumulate such that patients usually experience a disturbance in their activities of daily living, well-being, nutritional status, and water and electrolyte homeostasis, eventuating in the uremic syndrome. ■ ■ETIOLOGY AND EPIDEMIOLOGY It has been estimated from population data that at least 6% of the adult population in the United States has CKD at stages 1 and 2. An additional 4.5% of the U.S. population is estimated to have stages 3 and 4 CKD. Table 322-4 lists the five most frequent clinical catego­ ries of CKD, cumulatively accounting for >90% of the CKD disease burden worldwide. The relative contribution of each category varies among different geographic regions. The most frequent cause of CKD

TABLE 322-2  Monogenic Risk Loci for Chronic Kidney Disease (CKD) Copy Number Variants Causative of Congenital Renal Anomalies   1q21   4p16.1-p16.3   16p11.2   16p13.11   17q12   22q11.2 Five Most Predominant Causes of CKD with Mendelian Inheritance Genes for autosomal dominant polycystic kidney disease   ADPKD1   ADPKD2   IFT140   GANAB   DNAJB2   ALG9 Genes for type IV collagen-associated nephropathy   COL4A3   COL4A4   COL4A5 Genes for autosomal dominant tubulointerstitial kidney disease   UMOD   MUC1   HNF1B Genes for nephronophthisis   NPHP genes   Other Genes with known common variants that confer increased risk with odds ratio exceeding 2 with non-Mendelian inheritance patterns   APOL1 in North America and Europe is diabetic nephropathy, most often secondary to type 2 diabetes mellitus. Patients with newly diagnosed CKD often have hypertension. When no overt evidence for a primary glomerular or tubulointerstitial kidney disease process is present, CKD is frequently attributed to hypertension. However, it is now appreciated that some of these patients may have a subclinical primary glomeru­ lopathy, such as focal segmental or global glomerulosclerosis, and the elevated blood pressure is a consequence of the kidney disease. In other patients, progressive nephrosclerosis and hypertension are the renal correlates of a systemic vascular disease, often also involving large and small vessels elsewhere, such as the heart and brain. This latter combi­ nation is especially common in older patients, among whom chronic kidney ischemia as a cause of CKD may be underdiagnosed. ■ ■PATHOPHYSIOLOGY AND BIOCHEMISTRY

OF UREMIA Uremia is the syndrome with symptoms, signs, and accompanying dis­ turbances in laboratory measurements that result from reduced kidney TABLE 322-3  Recommended Equations for Estimation of Glomerular Filtration Rate (GFR) Using Serum Creatinine Concentration (SCr), Age, Sex, Race, and Body Weight

  1. Equation from the Modification of Diet in Renal Disease Study Estimated GFR (mL/min per 1.73 m2) = 1.86 × (SCr)−1.154 × (age)−0.203 Multiply by 0.742 for women Multiply by 1.21 for African ancestry (currently under review)
  2. CKD-EPI Equation GFR = 141 × min(SCr/kappa, 1)α × max(SCr/kappa, 1)–1.209 × 0.993Age Multiply by 1.018 for women Multiply by 1.159 for African ancestry (currently under review) where SCr is serum creatinine in mg/dL, kappa is 0.7 for females and 0.9 for males, α is –0.329 for females and –0.411 for males, min indicates the minimum of SCr/kappa or 1, and max indicates the maximum of SCr/kappa or 1. Abbreviation: CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration.

TABLE 322-4  Leading Categories of Etiologies of Chronic Kidney Disease (CKD)a • Diabetic nephropathy • Glomerulonephritis • Hypertension-associated CKD (includes vascular and ischemic kidney disease and primary glomerular disease with associated hypertension) • Autosomal dominant polycystic kidney disease • Other cystic and tubulointerstitial nephropathy aRelative contribution of each category varies with geographic region and race. function. Although serum urea and creatinine concentrations rise with reduced excretory capacity of the kidneys, accumulation of these two molecules themselves does not account for the symptoms and signs that characterize the uremic syndrome. Large numbers of solutes that accumulate when GFR declines have been implicated. These include water-soluble, hydrophobic, protein-bound, charged, and uncharged nitrogen-containing nonvolatile products of metabolism. It is thus evident that the serum concentrations of urea and creatinine should be viewed as being readily measured but very incomplete surrogate markers for retained toxins, and monitoring the levels of urea and cre­ atinine in the patient with impaired kidney function represents a vast oversimplification of the uremic state. The uremic syndrome involves more than renal excretory failure. A host of metabolic and endocrine functions normally performed by the kidneys are also impaired and can result in anemia, malnutrition, and abnormal metabolism of carbohydrates, fats, and proteins. Fur­ thermore, plasma levels of many hormones, including PTH, FGF-23, insulin, glucagon, steroid hormones including vitamin D and sex hormones, and prolactin change with CKD as a result of reduced excre­ tion, decreased degradation, or abnormal regulation. Finally, CKD is associated with increased systemic inflammation. Elevated levels of C-reactive protein are detected along with other acute-phase reactants, whereas levels of so-called negative acute-phase reactants, such as albu­ min and fetuin, decline. Thus, the inflammation associated with CKD is important in the malnutrition-inflammation-atherosclerosis/calcifi­ cation syndrome, which contributes in turn to the acceleration of vas­ cular disease and morbidity associated with advanced kidney disease. In summary, the pathophysiology of the uremic syndrome can be divided into manifestations in three spheres of dysfunction: (1) those consequent to the accumulation of toxins that normally undergo renal excretion; (2) those consequent to the loss of other kidney functions, such as fluid and electrolyte homeostasis and hormone regulation; and (3) progressive systemic inflammation and its vascular and nutritional consequences. CLINICAL AND LABORATORY MANIFESTATIONS OF CKD AND UREMIA ■ ■FLUID, ELECTROLYTE, AND ACID-BASE DISORDERS Sodium and Water Homeostasis  With normal kidney function, excretion of filtered sodium and water matches intake. Many forms of kidney disease disrupt this balance such that dietary intake of sodium exceeds its excretion, leading to sodium retention and attendant extra­ cellular fluid volume (ECFV) expansion. This expansion may contrib­ ute to hypertension, which itself can accelerate nephron hyperfiltration and injury. As long as water intake does not exceed the capacity for renal water clearance, the ECFV expansion will be isonatric and the patient will have a normal plasma sodium concentration. Hyponatre­ mia is not commonly seen in CKD patients, but when present, often responds to water restriction. The patient with ECFV expansion should be counseled regarding salt restriction. While the thiazide diuretic chlorthalidone alone has been shown to reduce elevated blood pressure in some patients even with stage 4 CKD, administration of loop diuret­ ics, including furosemide, bumetanide, or torsemide, may be needed to manage sodium accumulation. Resistance to loop diuretics in CKD often mandates use of higher doses than those used in patients with

normal GFR. The combination of loop diuretics with metolazone may be helpful. Diuretic resistance with intractable edema and hypertension in advanced CKD may serve as an indication to initiate dialysis.

Rarely, patients with CKD may have impaired renal conservation of sodium and water. When an extrarenal cause for fluid loss, such as gastrointestinal (GI) loss, is present, these patients may be prone to ECFV depletion because of the inability of the failing kidney to reclaim filtered sodium adequately. Any depletion of ECFV, whether due to GI losses, renal sodium loss, or overzealous diuretic therapy, can further compromise kidney function through hypoperfusion, or a “prerenal” state, leading to acute-on-chronic kidney failure. In this setting, holding or adjusting the diuretic dose or rarely even cautious volume repletion with normal saline may return the ECFV to normal and restore renal function to baseline. Many patients are given a “sick day” warning, wherein should they experience volume depletion, for example from vomiting or diarrhea, they are told to not take their diuretics or other antihypertensive medications until they resume eat­ ing and drinking normally. Potassium Homeostasis  In CKD, the decline in GFR is not necessarily accompanied by a parallel decline in urinary potassium excretion, which is predominantly mediated by aldosterone-dependent secretion in the distal nephron. Another defense against potassium retention in these patients is augmented potassium excretion in the GI tract. Notwithstanding these two homeostatic responses, hyperkalemia may be precipitated in certain settings. These include increased dietary potassium intake, hemolysis, transfusion of stored red blood cells, and metabolic acidosis. Importantly, a host of medications can inhibit renal potassium excretion and lead to hyperkalemia. The most important medications in this respect include the RAS inhibitors and spirono­ lactone and other potassium-sparing diuretics such as amiloride, eplerenone, and triamterene, as well as the new nonsteroidal miner­ alocorticoid receptor antagonists. As will be outlined below, several of these are major agents in the medical management armamentarium to slow or prevent progression of CKD. The benefits of the RAS inhibitors in ameliorating hyperfiltration and progression of CKD and mitigating cardiovascular complications very often favor their cautious and judi­ cious use with very close monitoring of plasma potassium concentra­ tion. Coadministration of potassium-lowering agents may allow for the use of RAS inhibitors with reduced risk of hyperkalemia. Gratifyingly, the gliflozin diuretics, administrated even in advanced stages of CKD, seem to have counterbalancing effects on kidney potassium handling that result in net preservation of potassium homeostasis. CHAPTER 322 Chronic Kidney Disease Certain causes of CKD can be associated with earlier and more severe disruption of potassium secretory mechanisms in the distal nephron, out of proportion to the decline in GFR. These include con­ ditions associated with hyporeninemic hypoaldosteronism, such as diabetes, and renal diseases that preferentially affect the distal nephron, such as obstructive uropathy and sickle cell nephropathy. Hypokalemia is not common in CKD and usually reflects markedly reduced dietary potassium intake, especially in association with exces­ sive diuretic therapy or concurrent GI losses. The use of potassium supplements and potassium-sparing diuretics may be risky in patients with impaired renal function and needs to be monitored closely. Metabolic Acidosis  Metabolic acidosis is a common disturbance in CKD. The majority of patients can still acidify the urine, but they produce less ammonia and, therefore, cannot excrete the quantity of protons required to maintain acid-base balance in most diets. Hyperkalemia, if present, further depresses ammonia production. The combination of hyperkalemia and hyperchloremic metabolic acidosis is often present, even at earlier stages of CKD, in patients with diabetic nephropathy or in those with predominant tubulointerstitial disease including obstructive uropathy. With further declining GFR, the total urinary net daily acid excretion may be severely limited to <30–40 mmol, and the accumulation of anions of retained organic acids can then lead to an anion-gap metabolic acidosis. Thus, the non-anion-gap metabolic acidosis seen in earlier stages of CKD may be complicated by the addition of an anion-gap metabolic acidosis as CKD progresses. In most patients, the metabolic acidosis is mild; the pH is rarely <7.32

and can usually be corrected with oral sodium bicarbonate supplemen­ tation. Studies have suggested that even modest degrees of metabolic acidosis may be associated with the development of protein catabolism and progression of CKD.

TREATMENT Fluid, Electrolyte, and Acid-Base Disorders Dietary salt restriction and the use of loop diuretics, occasion­ ally in combination with metolazone, may be needed to main­ tain euvolemia. Water restriction is indicated only if there is hyponatremia. Hyperkalemia often responds to dietary restriction of potassium, the use of kaliuretic diuretics, and both avoidance of potassium supplements (including occult sources, such as dietary salt substi­ tutes) and monitoring with dose adjustment, or at times avoidance of potassium-retaining medications, which are often prescribed to slow CKD progression or afford cardioprotection (RAS inhibitors, steroidal or nonsteroidal mineralocorticoid antagonists). Kaliuretic diuretics promote urinary potassium excretion, whereas potassiumbinding resins, such as calcium resonium, sodium polystyrene, or the newer agents patiromer and calcium zirconium cyclosilicate, promote potassium loss through the GI tract and may reduce the incidence of hyperkalemia. Intractable hyperkalemia is an indica­ tion (although uncommon) to consider institution of dialysis in a CKD patient. The renal tubular acidosis and subsequent anion-gap metabolic acidosis in progressive CKD will respond to alkali sup­ plementation. Recent studies suggest that this replacement should be considered when the serum bicarbonate concentration falls below 20–23 mmol/L to avoid the protein catabolic state seen with even mild degrees of metabolic acidosis. Relatedly, a recent study suggested that bicarbonate supplementation in stages 3–5 CKD was also associated with slower progression to dialysis. The sodium load in sodium bicarbonate supplementation needs to be taken into account when ECFV expansion is present. PART 9 Disorders of the Kidney and Urinary Tract ■ ■DISORDERS OF CALCIUM AND PHOSPHATE METABOLISM The principal complications of abnormalities of calcium and phosphate metabolism in CKD occur in the skeleton and the vascular bed, with occasional involvement of soft tissues. It is likely that disorders of bone turnover and disorders of vascular and soft tissue calcification are related to each other. Bone Manifestations of CKD  The major disorders of bone disease can be classified into those associated with high bone turn­ over with increased PTH levels (including osteitis fibrosa cystica, the classic lesion of secondary hyperparathyroidism), osteomalacia due to reduced vitamin D effect, and low bone turnover with low or normal PTH levels (adynamic bone disease) or often some combination of the foregoing. The pathophysiology of secondary hyperparathyroidism and the consequent high-turnover bone disease is related to abnormal mineral metabolism through the following series of interrelated mechanisms: (1) declining GFR leads to reduced excretion of phosphate and, thus, phosphate retention; (2) the retained phosphate stimulates increased synthesis of both FGF-23 by osteocytes and of PTH and also stimulates growth of parathyroid gland mass; and (3) decreased levels of ionized calcium, which results from decreased levels of renal calcitriol produc­ tion due to phosphate retention and elevated levels of FGF-23, which also increases degradation of calcitriol. Low calcitriol levels contribute to hyperparathyroidism, both by leading to hypocalcemia and also by a direct effect on PTH gene transcription. In addition, the normal inhibi­ tory effect of FGF-23 on PTH production, which is Klotho-dependent, is also attenuated in CKD. These changes start to occur when the GFR falls below 60 mL/min, though some studies point to retention of phos­ phate as an event antedating measurable reduction in GFR, together with early elevation of FGF-23 as well. FGF-23 is part of a family of

phosphatonins that promotes phosphate excretion, and high levels of FGF-23 are an independent risk factor for left ventricular hypertrophy and are associated with increased mortality in CKD, dialysis, and kid­ ney transplant patients. Hyperparathyroidism stimulates bone turnover and leads to oste­ itis fibrosa cystica. Bone histology shows abnormal osteoid, bone and bone marrow fibrosis, and, in advanced stages, the formation of bone cysts, sometimes with hemorrhagic elements so that they appear brown in color; hence, the term brown tumor. Clinical manifestations of severe hyperparathyroidism include bone pain and fragility, brown tumors with compression syndromes, and resistance to erythropoiesisstimulating agents (ESA) in part related to the bone marrow fibrosis. Furthermore, PTH itself is considered a uremic toxin, and high levels are associated with muscle weakness, fibrosis of cardiac muscle, and constitutional symptoms. Adynamic bone disease is increasing in prevalence, especially among diabetics and older patients. It is characterized by reduced bone volume and mineralization and may result from excessive suppression of PTH production, chronic inflammation, or both. Suppression of PTH can result from the use of vitamin D preparations or from exces­ sive calcium exposure in the form of calcium-containing phosphate binders or high-calcium dialysis solutions. Complications of adynamic bone disease include an increased incidence of fracture and bone pain and an association with increased vascular and cardiac calcification. Occasionally, the calcium will precipitate in the soft tissues into large concretions termed tumoral calcinosis (Fig. 322-3). Patients with adynamic bone disease often experience the most severe symptoms of musculoskeletal pain, owing to the inability to repair the microfractures that occur normally as a part of healthy skeletal homeostasis with regular physical activity. Patients with advanced CKD experience more frequent fractures than their age-matched controls. Osteomalacia is a distinct process, conse­ quent to reduced production and action of 1,25(OH)2D3, leading to accumulation of nonmineralized osteoid. Calcium, Phosphorus, and the Cardiovascular System  There is a strong association between hyperphosphatemia and increased car­ diovascular mortality in patients with CKD. Hyperphosphatemia and hypercalcemia are associated with increased vascular calcification, but it is unclear whether the excessive mortality is mediated by this mecha­ nism. Studies using computed tomography (CT) and electron-beam CT scanning show that CKD patients have calcification in the media of coronary arteries and heart valves that appears to be orders of magni­ tude greater than that in patients without kidney disease. The magni­ tude of the calcification is proportional to age and hyperphosphatemia and is also associated with low PTH levels and low bone turnover. It is possible, that in CKD patients, ingested calcium cannot be incor­ porated into bones with low turnover, and therefore, is deposited at FIGURE 322-3  Tumoral calcinosis. This patient was on hemodialysis for many years and was nonadherent to dietary phosphorus restriction or the use of phosphate binders. He was chronically severely hyperphosphatemic. He developed an enlarging painful mass on his arm that was extensively calcified.

FIGURE 322-4  Calciphylaxis. This peritoneal dialysis patient was on chronic warfarin therapy for atrial fibrillation. She noticed a small painful nodule on the abdomen that was followed by progressive skin necrosis and ulceration of the anterior abdominal wall. She was treated with hyperbaric oxygen, intravenous thiosulfate, and discontinuation of warfarin, with slow resolution of the ulceration. extraosseous sites, such as the vascular bed and soft tissues. There is a similar association between osteoporosis and vascular calcification in the general population. Finally, hyperphosphatemia can induce a change in gene expression in vascular cells to an osteoblast-like profile, leading to vascular calcification and even ossification. Other Complications of Abnormal Mineral Metabolism  Cal­ ciphylaxis is a devastating condition seen almost exclusively in patients with advanced CKD. It is heralded by painful livedo reticularis and subcutaneous nodules that advance to patches of ischemic necrosis, especially on the legs, thighs, abdomen, and breasts (Fig. 322-4). Pathologically, there is evidence of vascular occlusion in association with extensive vascular and soft tissue calcification. It appears that this condition is increasing in incidence. Originally it was ascribed to severe abnormalities in calcium and phosphorus control in dialysis patients, usually associated with advanced hyperparathyroidism. How­ ever, more recently, calciphylaxis has been seen with increasing fre­ quency in the absence of severe hyperparathyroidism. Warfarin is still used in some CKD patients in whom several members of the direct oral anticoagulant (DOAC) family of drugs are contraindicated, and one of the effects of warfarin therapy is to decrease the vitamin K–dependent activation of matrix GLA protein. This latter protein is important in preventing vascular calcification. Thus, warfarin treatment is con­ sidered a risk factor for calciphylaxis, and if a patient develops this syndrome, this medication should be discontinued and alternative means of anticoagulation should be chosen, depending on the specific underlying indication for anticoagulation. TREATMENT Disorders of Calcium and Phosphate Metabolism The optimal management of secondary hyperparathyroidism and osteitis fibrosa is prevention. Once the parathyroid gland mass is very large, it is difficult to control the disease. Careful attention should be paid to the plasma phosphate concentration in CKD patients, who should be counseled on a low-phosphate diet as well as the appropriate use of phosphate-binding agents, which are taken with meals and complex dietary phosphate to limit its GI absorption. Examples of phosphate binders are calcium acetate and calcium carbonate. A major side effect of calcium-based phosphate binders is calcium accumulation and hypercalcemia, especially in patients with low-turnover bone disease. Sevelamer and lanthanum are non-calcium-containing polymers that also function as phos­ phate binders; they do not predispose CKD patients to hypercal­ cemia and may attenuate calcium deposition in the vascular bed.

Tenapanor is a sodium-proton inhibitor that decreases GI phos­ phate absorption and may be useful to manage hyperphosphatemia in CKD and dialysis patients.

Calcitriol exerts a direct suppressive effect on PTH secretion and also indirectly suppresses PTH secretion by raising the concentra­ tion of ionized calcium. However, calcitriol therapy may result in hypercalcemia and/or hyperphosphatemia through increased GI absorption of these minerals. Certain analogues of calcitriol are available (e.g., paricalcitol) that suppress PTH secretion with less attendant hypercalcemia. Recognition of the role of the extracellular calcium-sensing receptor has led to the development of calcimimetic agents that enhance the sensitivity of parathyroid cells to the suppressive effect of calcium. This class of drug, which includes cinacalcet and etelcal­ cetide, produces a dose-dependent reduction in PTH and plasma calcium concentration in some patients. Current National Kidney Foundation Kidney Disease Outcomes Quality Initiative guidelines recommend a target PTH level between 2 and 9 times the upper limit of normal, recognizing that very low PTH levels are associated with adynamic bone disease and possible consequences of fracture and ectopic calcification. For CKD patients requiring anticoagulation, careful assessment of the indication and choice and dosing of medication appropriate for reduced renal clearance, with avoidance of warfarin, should be considered to reduce the risk of calciphylaxis. CHAPTER 322 ■ ■CARDIOVASCULAR ABNORMALITIES Cardiovascular disease is the leading cause of morbidity and mortality in patients at every stage of CKD. The incremental risk of cardiovascu­ lar disease in those with CKD compared to the age- and sex-matched general population ranges from 10- to 200-fold, depending on the stage of CKD. As a result, most patients with CKD succumb to cardiovascu­ lar disease before ever reaching stage 5 CKD. Between 30 and 45% of those patients who do reach stage 5 CKD have advanced significant cardiovascular complications. Chronic Kidney Disease Vascular Disease  The increased prevalence of vascular disease in CKD patients derives from both traditional (“classic”) and nontra­ ditional (CKD-related) risk factors. Traditional risk factors include hypertension, diabetes mellitus, hypervolemia, dyslipidemia, sym­ pathetic overactivity, and hyperhomocysteinemia. The CKD-related risk factors comprise anemia, hyperphosphatemia, hyperparathyroid­ ism, increased FGF-23, sleep apnea, and systemic inflammation. The inflammatory state appears to accelerate vascular occlusive disease, and low levels of fetuin may permit more rapid vascular calcification, especially in the face of hyperphosphatemia. Other abnormalities seen in CKD may augment myocardial ischemia, including left ventricular hypertrophy and microvascular disease. It is noteworthy that both high and low ejection fraction congestive heart failure, left ventricular hypertrophy, systemic hypertension, and pulmonary hypertension are no less prominent than coronary ischemia as causes of cardiovascular mortality in patients with advanced stages of CKD. Cardiac troponin levels are frequently elevated in CKD without evidence of acute ischemia. The elevation complicates the diagnosis of acute myocardial infarction in this population. Serial measurements may be needed. Therefore, the trend in levels over the hours after presentation may be more informative than a single, elevated level. Interestingly, consistently elevated levels are an independent prognos­ tic factor for adverse cardiovascular events. Heart Failure  Abnormal cardiac function secondary to myocar­ dial ischemia, left ventricular hypertrophy, diastolic dysfunction, and frank cardiomyopathy, in combination with salt and water retention, often results in heart failure or even pulmonary edema. Heart failure can occur with preserved (diastolic dysfunction) or reduced (systolic dysfunction) ejection fraction. A form of “low-pressure” pulmonary edema can also occur in advanced CKD, manifesting as shortness of breath and a “bat wing” distribution of alveolar edema fluid on chest x-ray. This finding can occur even in the absence of ECFV overload

and is associated with normal or mildly elevated pulmonary venous pressure. This process has been ascribed to increased permeability of alveolar capillary membranes as a manifestation of the uremic state, and it responds to dialysis. Other CKD-related risk factors, including anemia and sleep apnea, may contribute to the risk of heart failure.

Hypertension and left ventricular hypertrophy are common com­ plications of CKD. Hypertension usually develops early during the course of CKD and is associated with adverse outcomes, including the development of ventricular hypertrophy and a more rapid loss of renal function. Left ventricular hypertrophy and dilated cardiomyopathy are among the strongest risk factors for cardiovascular morbidity and mortality in patients with CKD and are thought to be related primar­ ily, but not exclusively, to prolonged hypertension and ECFV overload. In addition, anemia and the placement of an arteriovenous fistula for hemodialysis can generate a high cardiac output state and consequent high-output heart failure. It is important to note that in advanced stages of CKD, the presence of an advanced malnutrition-inflammation state can actually reverse the elevation of classic cardiovascular risk factors such as hypertension and hyperlipidemia and is associated in such patients with reduced left ventricular function, loss of body weight, and a poor prognosis. The use of exogenous ESAs can increase blood pressure and the requirement for antihypertensive drugs. Chronic ECFV overload is also a contributor to hypertension, and improvement in blood pressure can often be seen with the use of dietary sodium restriction and diuret­ ics, and when refractory, hypertension can serve as an indication of ini­ tiating renal replacement therapy. Nevertheless, because of activation of the RAS and other disturbances in the balance of vasoconstrictors and vasodilators, some patients remain hypertensive, despite careful attention to ECFV status. PART 9 Disorders of the Kidney and Urinary Tract TREATMENT Cardiovascular Abnormalities MANAGEMENT OF HYPERTENSION The overarching goal of hypertension therapy in CKD is to prevent the extrarenal complications of high blood pressure, such as cardio­ vascular disease and stroke. National guideline panels recommend that in CKD patients with diabetes or proteinuria >1 g per 24 h, blood pressure should be reduced to <130/80 mmHg, if achiev­ able without prohibitive adverse effects. Salt restriction should be the first line of therapy. When volume management alone is not sufficient, the choice of antihypertensive agent is similar to that in the general population. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) appear to slow the rate of decline of kidney function in a manner that extends beyond reduction of systemic arterial pressure and that involves reduction in the intraglomerular hyperfiltration and hyperten­ sion by disproportionately reducing glomerular efferent arteriolar vasoconstriction. Occasionally, introduction of ACE inhibitors and ARBs can actually precipitate an episode of AKI, especially when used in combination in patients with ischemic renovascular disease. More commonly, a slight reduction of GFR (<30% of baseline) may actually signify a salutary reduction in intraglomerular hypertension and hyperfiltration and, if stable over time, can be tolerated with continued monitoring. With progressive CKD, RAS inhibitors can be continued with careful monitoring. Careful clinical studies have shown that even in patients with an eGFR <30 mL/min, continuation of these agents was not associated with any signal for harm compared to those in whom the drugs were stopped and that discontinuing RAS inhibitors in CKD was associated with an increased risk of death or cardiovascular events but a lower incidence of starting kidney replace­ ment therapy. Since the use of ACE inhibitors and ARBs may also be complicated by the development of hyperkalemia, the concomitant use of kaliuretic diuretics (e.g., furosemide with metolazone) or a potassium-lowering GI tract binder, such as patiromer, can improve potassium excretion in addition to improving blood pressure control. Likewise, if gliflozins are implemented in renoprotection, then these

may also assist in potassium homeostasis. Potassium-sparing diuret­ ics, such as amiloride and triamterene, should be avoided in most patients, and steroidal (e.g., spironolactone) or nonsteroidal (finere­ none) mineralocorticoid receptor blockers should be accompanied by careful monitoring of serum potassium concentration, weighing potential cardiovascular and renoprotective benefits against risk for lethal hyperkalemia. The recent movement to even lower blood pressure targets in the general population may not be applicable to patients with CKD, who often lack autoregulation to maintain GFR in the face of low perfusion pressure. If a patient experiences sudden decline in kidney function with intensification of antihypertensive therapy, consideration should be given to reducing therapy. MANAGEMENT OF CARDIOVASCULAR DISEASE There are many strategies available to treat the traditional and nontraditional risk factors in CKD patients. Although these have proved effective in the general population, there is little evidence for their benefit in patients with the most advanced stages of CKD. Certainly, hypertension and dyslipidemia promote atherosclerotic disease and are treatable complications of CKD. Renal disease complicated by nephrotic syndrome is associated with a very ath­ erogenic lipid profile and hypercoagulability, which increases the risk of occlusive vascular disease. Because diabetes mellitus and hypertension are frequently associated with advanced CKD, it is not surprising that cardiovascular disease is the most frequent cause of death in dialysis patients. The use of the gliflozins (sodium-glucose cotransporter 2 [SGLT2] inhibitors) in patients with and without diabetes mellitus is quickly becoming a mainstay for both kidney protection, with marked amelioration of GFR reduction, and a reduction in cardiovascular events, including heart failure, even in advanced stages of CKD (including stage 4). Pericardial Disease  Chest pain with respiratory accentuation, accompanied by a friction rub, is diagnostic of pericarditis. Classic electrocardiographic abnormalities include PR-interval depression and diffuse ST-segment elevation. Pericarditis can be accompanied by peri­ cardial effusion that is seen on echocardiography and can rarely lead to tamponade. However, the pericardial effusion can be asymptomatic, and pericarditis can be seen without significant effusion. Pericarditis is observed in advanced uremia and, with the advent of timely initiation of dialysis, is not as common as it once was. It is now more often observed in underdialyzed, nonadherent patients than in those starting dialysis. TREATMENT Pericardial Disease Uremic pericarditis is an absolute indication for the urgent initiation of dialysis or for intensification of the dialysis prescription in those already receiving dialysis. Because of the propensity to hemorrhage in pericardial fluid, hemodialysis should be performed without heparin. A pericardial drainage procedure should be considered in patients with recurrent pericardial effusion, especially with echo­ cardiographic signs of impending tamponade. Nonuremic causes of pericarditis and effusion include viral, malignant, tuberculous, and autoimmune etiologies. It may also be seen after myocardial infarction and as a complication of treatment with the antihyper­ tensive drug minoxidil. Consideration could be given to the use of colchicine or nonsteroidal anti-inflammatory drugs, although the latter agents could adversely affect renal function. ■ ■HEMATOLOGIC ABNORMALITIES Anemia  A normocytic, normochromic anemia is observed as early as stage 3 CKD and is almost universal by stage 4. The primary cause is insufficient production of erythropoietin (EPO) by the diseased kidneys, together with reduced erythrocyte lifespan and other factors. (See Table 322-5.)

TABLE 322-5  Causes of Anemia in Chronic Kidney Disease Relative deficiency of erythropoietin Diminished red blood cell survival Bleeding diathesis Iron deficiency due to poor dietary absorption and gastrointestinal blood loss Hyperparathyroidism/bone marrow fibrosis Chronic inflammation Folate or vitamin B12 deficiency Hemoglobinopathy Comorbid conditions: hypo-/hyperthyroidism, pregnancy, HIV-associated disease, autoimmune disease, immunosuppressive drugs Causes of Anemia in Chronic Kidney Disease  The anemia of CKD is associated with a number of adverse pathophysiologic conse­ quences, including decreased tissue oxygen delivery and utilization, increased cardiac output, ventricular dilation, and ventricular hyper­ trophy. Clinical manifestations include fatigue and diminished exercise tolerance, angina, heart failure, decreased cognition and mental acuity, and impaired host defense against infection. In addition, anemia may play a role in growth restriction in children with CKD. Although many studies in CKD patients have found that anemia and resistance to exogenous ESAs are associated with a poor prognosis, the relative con­ tribution to a poor outcome of the low hematocrit itself, versus inflam­ mation as a cause of the anemia and ESA resistance, remains unclear. TREATMENT Anemia The availability of recombinant human ESA has been one of the most significant advances in the care of renal patients since the introduction of dialysis and renal transplantation. Its routine use has obviated the need for regular blood transfusions in severely anemic CKD patients, thus dramatically reducing the incidence of transfusion-associated infections, iron overload, and the develop­ ment of alloantibodies that can sensitize patients to donor kidney antigens and render kidney transplantation more problematic. Adequate bone marrow iron stores should be available before treatment with ESA is initiated. Iron supplementation is usually essential to ensure an optimal response to ESA in patients with CKD because the demand for iron by the marrow frequently exceeds the amount of iron that is immediately available for erythropoiesis (measured by percent transferrin saturation), as well as the amount in iron stores (measured by serum ferritin). For the CKD patient not yet on dialysis or the patient treated with peritoneal dialysis, oral iron supplementation should be attempted. If there is GI intoler­ ance or poor GI absorption, the patient may have to undergo IV iron infusion, keeping in mind that parenteral iron therapy can increase the susceptibility to bacterial infections and that the adverse effects of free serum iron are still under investigation. In addition to iron, an adequate supply of other major substrates and cofactors for red cell production must be ensured, including vitamin B12 and folate. Anemia resistant to recommended doses of ESA in the face of adequate iron stores may be due to some combination of the fol­ lowing: acute or chronic inflammation, inadequate dialysis, severe hyperparathyroidism, chronic blood loss or hemolysis, chronic infection, or malignancy. A new class of agents to treat the anemia of CKD are the prolylhydroxylase inhibitors of endogenous hypoxia-inducible factors (HIFs). This inhibition leads to an increase in both endogenous production of EPO and an increase in GI absorption of iron. While studies comparing HIF inhibitors to ESAs have demonstrated simi­ lar effectiveness, some safety considerations remain to be clarified in the realms of cardiovascular, retinal vessel, and possibly tumor vasculogenesis. Randomized, controlled trials of ESAs in CKD have failed to show an improvement in cardiovascular outcomes with this

therapy. Indeed, there has been an indication that the use of ESAs in CKD may be associated with an increased risk of stroke in those with type 2 diabetes or an increase in thromboembolic events and perhaps a faster progression of renal decline.

Therefore, any benefit in terms of improvement of anemic symp­ toms needs to be balanced against such potential cardiovascular risk. Since normalization of the hemoglobin concentration has not been demonstrated to be of benefit to CKD patients, current prac­ tice is to target a hemoglobin concentration of 100–115 g/L. Abnormal Hemostasis  Patients with later stages of CKD may have a prolonged bleeding time, decreased activity of platelet factor III, abnormal platelet aggregation and adhesiveness, and impaired pro­ thrombin consumption. Clinical manifestations include an increased tendency to bleeding and bruising, prolonged bleeding from surgical incisions, menorrhagia, and GI bleeding. Interestingly, CKD patients also have a greater susceptibility to thromboembolism, especially if they have renal disease that includes nephrotic-range proteinuria. The latter condition results in hypoalbuminemia and renal loss of antico­ agulant factors, which can lead to a thrombophilic state. TREATMENT Abnormal Hemostasis CHAPTER 322 Abnormal bleeding time and coagulopathy in patients with renal failure may be reversed temporarily with desmopressin (DDAVP), cryoprecipitate, IV conjugated estrogens, blood transfusions, and ESA therapy. Rarely with refractory and life-threatening bleeding, tranexamic acid and epsilon aminocaproic acid have also been used for hemostasis control. Optimal dialysis will usually correct a pro­ longed bleeding time. Chronic Kidney Disease Given the coexistence of bleeding disorders and a propensity to thrombosis that is unique in the CKD patient, decisions about anticoagulation that have a favorable risk-benefit profile in the gen­ eral population may not be applicable to the patient with advanced CKD. One example is warfarin anticoagulation for atrial fibrillation; the decision to anticoagulate should be made on an individual basis in the CKD patient because there appears to be a greater risk of bleeding complications, as well as the consideration of precipitating calciphylaxis. Certain anticoagulants, such as fractionated low-molecularweight heparin, may need to be avoided or dose-adjusted in these patients, with monitoring of factor Xa activity where available. It is often more prudent to use conventional unfractionated heparin, titrated to the measured partial thromboplastin time, in hospital­ ized patients requiring an alternative to warfarin anticoagulation. Most of the new classes of oral anticoagulants are eliminated by the kidneys, although apixaban in either full or reduced dose is being used more often in CKD and dialysis patients (Chap. 123). ■ ■NEUROMUSCULAR ABNORMALITIES Central nervous system (CNS), peripheral, and autonomic neuropathy, as well as abnormalities in muscle structure and function, are all wellrecognized complications of CKD. Subtle clinical manifestations of uremic neuromuscular disease usually become evident at stage 3 CKD. Early manifestations of CNS complications include mild distur­ bances in memory and disturbances in concentration and sleep. Neuromuscular irritability, including hiccups, cramps, and twitching, becomes evident at later stages. In advanced untreated kidney failure, asterixis, myoclonus, seizures, and coma can be seen. Peripheral neuropathy usually becomes clinically evident after the patient reaches stage 4 CKD, although electrophysiologic and histo­ logic evidence occurs earlier. Initially, sensory nerves are involved more than motor, lower extremities more than upper, and distal parts of the extremities more than proximal. The “restless leg syndrome” is characterized by ill-defined sensations of sometimes debilitating discomfort in the legs and feet relieved by frequent leg movement. Evi­ dence of peripheral neuropathy without another cause (e.g., diabetes

mellitus or iron deficiency) is an indication for starting renal replace­ ment therapy. Many of the complications described above will resolve with dialysis, although some may persist.

■ ■GASTROINTESTINAL AND NUTRITIONAL ABNORMALITIES Uremic fetor, a urine-like odor on the breath, derives from the break­ down of urea to ammonia in saliva and is often associated with an unpleasant metallic taste (dysgeusia). Gastritis, peptic disease, and mucosal ulcerations at any level of the GI tract occur in uremic patients and can lead to abdominal pain, nausea, vomiting, and GI bleeding. These patients are also prone to constipation, which can be worsened by the administration of calcium and iron supplements. The retention of uremic toxins also leads to anorexia, nausea, and vomiting. Protein restriction may be useful to decrease nausea and vomiting; however, it may put the patient at risk for malnutrition and should be carried out, if possible, in consultation with a registered dietitian specializing in the management of CKD patients. Weight loss and protein-energy malnutrition, consequences of low protein and caloric intake, are common in advanced CKD and are often an indication for initiation of renal replacement therapy. Metabolic acidosis and the activation of inflammatory cytokines can promote protein catabolism. A number of indices are useful in nutritional assessment and include dietary history, including food diary, and subjective global assessment; edema-free body weight; and measurement of urinary protein nitrogen appearance. Dual-energy x-ray absorptiometry bioimpedance analysis is now widely used to estimate lean body mass versus fluid weight. Nutritional guidelines for patients with CKD are summarized in the “Treatment” section. PART 9 Disorders of the Kidney and Urinary Tract ■ ■ENDOCRINE-METABOLIC DISTURBANCES Glucose metabolism is impaired in CKD. However, fasting blood glucose is usually normal or only slightly elevated, and mild glucose intolerance does not require specific therapy. Because the kidney contributes to insulin removal from the circulation, plasma levels of insulin are slightly to moderately elevated in most uremic patients, both in the fasting and postprandial states. Because of this diminished renal degradation of insulin, patients on insulin therapy may need progressive reduction in dose as their renal function worsens. Many antihyperglycemic agents, including the gliptins, require dose reduc­ tion in renal failure, and some, such as metformin and sulfonylureas, are contraindicated when the GFR is less than half of normal. The gliflozins, discussed above, that inhibit sodium-glucose transport in the proximal tubule result in glucose lowering, accompanied by strik­ ing reductions in kidney function decline and in cardiovascular events. The stabilization of GFR in many patients with this therapeutic inter­ vention represents a major, important added beneficial effect of these drugs. Their long-term stabilizing effect on GFR and urine albumin excretion appears to result from correction of hyperfiltration early in type 2 diabetes mellitus via reactivation of the tubuloglomerular feed­ back loop. This represents a fortunate convergence of pathophysiology of glomerular hyperfiltration in diabetes with drug discovery. A similar effect on hyperfiltration by residual nephrons in certain nondiabetic forms of CKD may explain the salutary role of this class of medications more broadly in CKD. Other studies have also pointed to a more direct effect on proximal tubule metabolic pathways that alleviate cell injury. In women with CKD, estrogen levels are low, and menstrual abnor­ malities, infertility, and inability to carry pregnancies to term are common. When the GFR has declined to ~40 mL/min, pregnancy is associated with a high rate of spontaneous abortion, with only ~20% of pregnancies leading to live births, and pregnancy may hasten the progression of the kidney disease itself. Women with CKD who are contemplating pregnancy should consult first with a nephrologist in conjunction with an obstetrician specializing in high-risk pregnancy. Men with CKD have reduced plasma testosterone levels, and sexual dysfunction and oligospermia may supervene. Sexual maturation may be delayed or impaired in adolescent children with CKD, even among those treated with dialysis. Many of these abnormalities improve or reverse with intensive dialysis or with successful renal transplantation.

■ ■DERMATOLOGIC ABNORMALITIES Abnormalities of the skin are prevalent in progressive CKD. Pruritus is quite common and one of the most vexing manifestations of the uremic state. In advanced CKD, even on dialysis, patients may become more pigmented, and this is felt to reflect the deposition of retained pigmented metabolites, or urochromes. Although many of the cutane­ ous abnormalities improve with dialysis, pruritus is often tenacious. The first lines of management are to rule out unrelated skin disorders, such as scabies, and to treat hyperphosphatemia, which can cause itch. Local moisturizers, mild topical glucocorticoids, oral antihistamines, and ultraviolet radiation have been reported to be helpful. Agonists of kappa opioid receptors can reduce pruritus intensity and improve quality of life. A skin condition unique to CKD patients called nephrogenic fibros­ ing dermopathy consists of progressive subcutaneous induration, especially on the arms and legs. The condition is seen very rarely in patients with CKD who have been exposed to the magnetic resonance contrast agent gadolinium. Current recommendations are that patients with CKD stage 3 (GFR 30–59 mL/min) should minimize exposure to gadolinium and those with CKD stages 4–5 (GFR <30 mL/min) should avoid the use of gadolinium agents unless it is medically necessary. However, no patient should be denied an imaging investigation that is critical to management, and under such circumstances, rapid removal of gadolinium by hemodialysis (even in patients not yet receiving renal replacement therapy) shortly after the procedure may mitigate this sometimes devastating complication. Newer forms of gadolinium are not associated with this complication, and it remains to be seen if cau­ tion about their use will remain relevant. EVALUATION AND MANAGEMENT OF PATIENTS WITH CKD ■ ■INITIAL APPROACH History and Physical Examination  Symptoms and overt signs of kidney disease are often subtle or absent until renal failure super­ venes. Thus, the diagnosis of kidney disease often surprises patients and may lead to denial, especially given that pain in the region of the kidneys and decrease in urinary volume are not clinical features. Par­ ticular aspects of the history that are germane to renal disease include a history of hypertension (which can cause CKD or more commonly be a consequence of CKD), diabetes mellitus, abnormal urinalyses, and preeclampsia or early pregnancy loss. A careful drug history should be elicited. Drugs to consider include nonsteroidal anti-inflammatory agents, cyclooxygenase-2 (COX2) inhibitors, antimicrobials, che­ motherapeutic agents, antiretroviral agents, proton pump inhibitors, phosphate-containing bowel cathartics, and lithium. In evaluating the uremic syndrome, questions about appetite, weight loss, nausea, hic­ cups, peripheral edema, muscle cramps, pruritus, and restless legs are especially helpful. A family history of kidney disease, together with assessment of manifestations in other organ systems such as auditory, visual, and integumentary, may lead to the diagnosis of a heritable form of CKD (e.g., Alport’s or Fabry’s disease, cystinosis) or shared environ­ mental exposure to nephrotoxic agents (e.g., heavy metals, aristolochic acid). It should be noted that clustering of CKD, sometimes of different etiologies, is often observed within families. The physical examination should focus on blood pressure and target organ damage from hypertension. Fundoscopy is especially important in the diabetic patient, because it may show evidence of diabetic reti­ nopathy, which is associated with diabetic nephropathy. Other mani­ festations of CKD include edema and sensory polyneuropathy. The finding of asterixis or a pericardial friction rub not attributable to other causes signifies the presence of the uremic syndrome. Laboratory Investigation  Laboratory studies should focus on a search for clues to an underlying causative or aggravating disease pro­ cess and on the degree of renal damage and its consequences. Serum and urine protein electrophoresis, looking for multiple myeloma, should be obtained in all patients >35 years old with unexplained CKD, especially if there is associated anemia and elevated, or even

inappropriately normal, serum calcium concentration in the face of renal insufficiency. In the presence of hematuria or proteinuria, auto­ immune diseases such as lupus and underlying infectious etiologies such as hepatitis B and C and HIV should be tested. Serial measure­ ments of renal function should be obtained to determine the pace of deterioration and ensure that the disease is truly chronic, rather than acute or subacute and hence potentially reversible. Serum concentra­ tions of calcium, phosphorus, and PTH should be measured to evaluate metabolic bone disease. Hemoglobin concentration, iron, vitamin B12, and folate should also be evaluated. A 24-h urine collection may be helpful, because protein excretion >300 mg may be an indication for therapy with ACE inhibitors, ARBs, and SGLT2 inhibitors and also is associated with a higher risk of progression. If the patient has diffi­ culty in carrying out a 24-h urine collection, a random urine albumin/ creatinine or protein/creatinine is less accurate than a well-done 24-h collection but less cumbersome. Imaging Studies  The most useful imaging study is a renal ultra­ sound, which can verify the presence of two kidneys, determine if they are symmetric, provide an estimate of kidney size, and rule out renal masses and evidence of obstruction. Because it takes time for kidneys to shrink as a result of chronic disease, the finding of bilaterally small kidneys supports the diagnosis of CKD of long-standing duration. If the kidney size is normal, it is possible that the kidney disease is acute or subacute. The exceptions are diabetic nephropathy (where kidney size is increased at the onset of diabetic nephropathy before CKD supervenes), amyloidosis, and HIV nephropathy, where kidney size may be normal in the face of CKD. Polycystic kidney disease that has reached some degree of renal failure will almost always present with enlarged kidneys with multiple cysts (Chap. 327). A discrepancy >1 cm in kidney length suggests either a unilateral developmental abnormality or a disease process or renovascular disease with arterial insufficiency affecting one kidney more than the other. The diagnosis of renovas­ cular disease can be undertaken with different techniques, including Doppler sonography, nuclear medicine studies, or CT or magnetic resonance imaging (MRI) studies. If there is a suspicion of reflux nephropathy (recurrent childhood urinary tract infection, asymmetric renal size with scars on the renal poles), a voiding cystogram may be indicated. However, in most cases, by the time the patient has CKD, the reflux has resolved, and even if still present, repair does not improve renal function. Radiographic contrast imaging studies are not particu­ larly helpful in the investigation of CKD. Intravenous or intraarterial dye should be avoided where possible in the CKD patient, especially with diabetic nephropathy, because of the risk of radiographic contrast dye–induced renal failure. When unavoidable, appropriate precaution­ ary measures include avoidance of hypovolemia at the time of contrast exposure, minimization of the dye load, and choice of radiographic contrast preparations with the least nephrotoxic potential. Additional measures thought to attenuate contrast-induced worsening of renal function include judicious administration of sodium bicarbonate–con­ taining solutions and N-acetylcysteine, although these agents may not be as effective as previously thought. Kidney Biopsy  In the patient with bilaterally small kidneys, renal biopsy is not advised because (1) it is technically difficult and has a greater likelihood of causing bleeding and other adverse con­ sequences, (2) there is usually so much scarring that the underlying disease may not be apparent, and (3) the window of opportunity to render disease-specific therapy has passed. Other contraindications to renal biopsy include uncontrolled hypertension, active urinary tract infection, bleeding diathesis (including ongoing anticoagulation), and severe obesity. Ultrasound-guided percutaneous biopsy is the favored approach, but a surgical or laparoscopic approach can be considered, especially in the patient with a single kidney where direct visualization and control of bleeding are crucial. In the CKD patient in whom a kidney biopsy is indicated (e.g., suspicion of a concomitant or super­ imposed active process or in the face of accelerated loss of GFR), the bleeding time should be measured, and if increased, desmopressin should be administered immediately prior to the procedure.

A brief run of hemodialysis (without heparin) may also be consid­ ered prior to renal biopsy to normalize the bleeding time.

■ ■ESTABLISHING THE DIAGNOSIS AND ETIOLOGY OF CKD The most important initial diagnostic step is to distinguish newly diagnosed CKD from acute or subacute renal failure, because the latter two conditions may respond to targeted therapy. Previous measure­ ments of serum creatinine concentration are particularly helpful in this regard. Normal values from recent months or even years suggest that the current extent of renal dysfunction could be more acute, and hence reversible, than might otherwise be appreciated. In contrast, elevated serum creatinine concentration in the past suggests that the renal disease represents a chronic process. Even if there is evidence of chronicity, there is the possibility of a superimposed acute process (e.g., ECFV depletion, urinary infection or obstruction, or nephrotoxin exposure) supervening on the chronic condition. If the history suggests multiple systemic manifestations of recent onset (e.g., fever, polyar­ thritis, rash), it should be assumed that renal insufficiency is part of an acute systemic illness. Although kidney biopsy can usually be performed in early CKD (stages 1–3), it is not always indicated. For example, in a patient with a history of type 1 diabetes mellitus for 15–20 years with retinopathy, nephrotic-range proteinuria, and absence of hematuria, the diagno­ sis of diabetic nephropathy is very likely and biopsy is usually not necessary. However, if there is another finding not typical of diabetic nephropathy, such as hematuria or white blood cell casts, or absence of diabetic retinopathy, some other disease may be present and a biopsy may be indicated. CHAPTER 322 Chronic Kidney Disease In the absence of a clinical diagnosis, kidney biopsy may be the only recourse to establish an etiology in early-stage CKD. However, as noted above, once the CKD is advanced and the kidneys are small and scarred, there is little utility and significant risk in attempting to arrive at a specific diagnosis. Genetic testing is increasingly entering the repertoire of diagnostic tests since the patterns of injury and kidney morphologic abnormalities often reflect overlapping causal mechanisms, whose origins can some­ times be attributed to a genetic predisposition or cause (Table 322-2). The increased application of genetic testing has often yielded surprising diagnoses that deviate from the cause of CKD suggested by clinical or even kidney pathology alone. Given this realization and the cumulative significant contribution of monogenic disease etiologies, consideration is now given to large CKD gene panels, chromosomal microarrays, whole exome or even whole genome sequencing, and other advanced genetic analysis technologies in the evaluation and management of CKD. Suggested indications for such genetic evaluation in patients without a clinically evident etiology and course include family history (family member[s] with unexplained kidney failure, dialysis, or kidney transplant recipient; family member affected with maturity-onset dia­ betes of the young, kidney disease together with psychiatric morbidity, hearing or vision loss, autism spectrum disorder, developmental delay, and/or intellectual disability; multiple family members affected with similar phenotype); parental consanguinity; extrarenal involvement (dysmorphic facial features, autism spectrum disorder, developmental delay, and/or intellectual disability); multiple congenital structural kidney anomalies; steroid-resistant nephrotic syndrome; persistent active clinical or laboratory manifestations of glomerulonephritis or glomerular endotheliopathy; imaging consistent with cystic kidney dis­ eases/ciliopathies; young adult onset of unexplained progressive CKD; consideration of APOL1-mediated kidney disease; and unexplained kidney failure prior to kidney transplantation. TREATMENT Chronic Kidney Disease Therapy for CKD can be divided into interventions that are directed at the specific etiology and those that attenuate progression related to the common pathway of glomerular hyperfiltration, which

perpetuates kidney injury following reduced nephron mass, as discussed below. Treatments aimed at causes of CKD related to systemic diseases are discussed in the respective chapters. Recent developments in the etiology-directed therapy of CKD include the emergence of genome-specific therapies for certain patients with ADPKD (Chap. 327), siRNA therapy (lumasiran) for type 1 hyperoxaluria, and highly specific inhibitors for APOL1-mediated kidney disease (AMKD). Inaxaplin, a specific inhibitor of APOL1 channel function, has been shown to decrease urine protein excre­ tion in patients with focal segmental glomerulosclerosis caused by the high-risk genotypes at the APOL1 gene. In the absence of validated and specific biomarkers of imminent or ongoing kidney injury, the optimal timing for such specific therapies is usually well before there has been a measurable decline in GFR and certainly before CKD is established. It is helpful to measure sequentially and plot the rate of decline of GFR in all patients. Any acceleration in the rate of decline should prompt a search for superimposed acute or subacute processes that may be reversible. These include ECFV depletion, uncontrolled hypertension, urinary tract infection, new obstructive uropathy, exposure to nephrotoxic agents (e.g., nonsteroidal antiinflammatory drugs [NSAIDs] or radiographic dye), and reactiva­ tion or flare of the original disease, such as lupus or vasculitis. SLOWING THE PROGRESSION OF CKD There is variation in the rate of decline of GFR among patients with CKD. However, the several established and newer available interventions should be strongly considered in an effort to stabilize or slow the decline of renal function in most patients with reduced nephron mass at risk for progression from increased intraglomeru­ lar pressure and hyperfiltration as described above. Fortunately, these very same interventions also reduce cardiovascular compli­ cations of CKD and are therefore expected to greatly alleviate the global burden of CKD in the coming years to decades.

PART 9 Disorders of the Kidney and Urinary Tract Reducing Intraglomerular Hypertension and Proteinuria  Increased intraglomerular filtration pressures and glomerular hypertrophy develop as a response to loss of nephron number. This response is maladaptive as it promotes the ongoing decline of kidney func­ tion even if the inciting process has been treated or spontaneously resolved. Control of glomerular hypertension is important in slow­ ing the progression of CKD. Moreover, elevated blood pressure increases proteinuria by increasing its flux across the glomerular capillaries. Conversely, the renoprotective effect of antihypertensive medications is gauged through the consequent reduction of pro­ teinuria. Thus, the more effective a given treatment is in lowering Normal TGF Impaired TGF Restored TGF Appropriate afferent arteriole tone Macula densa Afferent arteriole vasodilation

Normal GFR Increased Na+/glucose reabsorption Na+/glucose reabsorption SGLT-2 SGLT-2 SGLT-2 inhibition in proximal tubule Normal physiology Hyperfiltration in early stages of diabetic nephropathy SGLT-2 inhibition reduces hyperfiltration via TGF A B FIGURE 322-5  The postulated role of the gliflozins in generating tubuloglomerular feedback (TGF) to reduce intraglomerular hypertension. (Reproduced with permission from DZ Cherney et al: Cherney et al: Circulation 129:587, 2014.)

protein excretion, the greater is the subsequent impact on protec­ tion from decline in GFR. This observation is the basis for the treatment guideline establishing 130/80 mmHg as a target blood pressure in proteinuric CKD patients. Several controlled studies have shown that ACE inhibitors and ARBs are effective in slowing the progression of renal failure in patients with advanced stages of both diabetic and nondiabetic CKD, in large part through effects on efferent vasodilatation and the subsequent decline in glomerular hypertension. The combina­ tion of these two classes should be avoided, due to a demonstrated greater incidence of AKI and adverse cardiac events from such combination therapy. While a nonprogressive decrease in eGFR of up to 30% may be a tolerable reflection of effective unloading of glomerular hyperfiltration, a progressive increase in serum creati­ nine concentration with these agents may suggest the presence of renovascular disease within the large or small arteries. Together with efferent arteriolar vasodilation, afferent vasocon­ striction should reduce intraglomerular pressure. Indeed, gliflozins, which are a family of inhibitors of SGLT2 transporters in the proxi­ mal tubule, result in precisely this glomerular response by activat­ ing tubuloglomerular feedback (Fig. 322-5) and are indicated in slowing the decline of GFR in both diabetic and nondiabetic kidney disease. Other more direct cellular protective mechanisms of the gliflozins have been invoked in kidney and other tissues. This class of agents also has been demonstrated to reduce major cardiovascu­ lar events in CKD patients. Recent studies have also shown that the glucagon-like peptide receptor agonists reduce major cardiovascu­ lar events and CKD in at-risk patients. Among the calcium channel blockers, diltiazem and verapamil may exhibit superior antiproteinuric and renoprotective effects com­ pared to the dihydropyridines. At least two different categories of response can be considered: one in which progression is strongly associated with systemic and intraglomerular hypertension and pro­ teinuria (e.g., diabetic nephropathy, glomerular diseases) and in which ACE inhibitors and ARBs are recommended choices, and another in which proteinuria is mild or absent initially (e.g., ADPKD and other tubulointerstitial diseases), where the contribution of intraglomerular hypertension is less prominent and other antihy­ pertensive agents can be useful for control of systemic hypertension. MANAGING OTHER COMPLICATIONS OF CKD Medication Dose Adjustment  Although the loading dose of most drugs is not affected by CKD because renal elimination is not used in the calculation, the maintenance doses of many drugs will need to

Normalization of GFR Decreased Na+ delivery to macula densa Elevated GFR Increased Na+ delivery to macula densa Afferent arteriole constriction

Na+

Glucosuria C

be adjusted. For those agents in which >70% excretion is by a non­ renal route, such as hepatic elimination, dose adjustment may not be needed. Some drugs that should be avoided include metformin, meperidine, and oral antihyperglycemics that are eliminated by the kidney. NSAIDs including COX2 inhibitors should be avoided because of the risk of further worsening of kidney function. Many antibiotics, antihypertensives, and antiarrhythmics may require a reduction in dosage or change in the dose interval. Several online Web-based databases for dose adjustment of medications according to stage of CKD or estimated GFR are available (e.g., http://www. globalrph.com/index_renal.htm). Nephrotoxic radiocontrast agents and gadolinium should be used according to strict guidelines when medically necessary, as discussed above. PREPARATION FOR RENAL REPLACEMENT THERAPY (See also Chap. 325.) Temporary relief of symptoms and signs of impending uremia, such as anorexia, nausea, vomiting, lassitude, and pruritus, may sometimes be achieved with dietary protein restriction. However, this diet carries a risk of malnutrition; thus, plans for more long-term management should be in place. Maintenance dialysis and kidney transplantation have extended the lives of hundreds of thousands of patients with CKD world­ wide. Clear indications for initiation of renal replacement therapy for patients with CKD include anorexia and nausea not attribut­ able to reversible causes such as peptic ulcer disease, evidence of malnutrition, and fluid and electrolyte abnormalities, principally hyperkalemia or ECFV overload, that are refractory to other mea­ sures. Encephalopathy and pericarditis are very late complications, so it is now rare that they serve as indications for initiation of renal replacement therapy. Recommendations for the Optimal Time for Initiation of Renal Replacement Therapy  Because of the individual variability in the severity of uremic symptoms and renal function, it is ill-advised to assign an arbitrary urea nitrogen or creatinine level to the need to start dialysis. Moreover, patients may become accustomed to chronic uremia and deny symptoms, only to find that they feel better with dialysis and realize in retrospect how poorly they were feeling before its initiation. Previous studies suggested that starting dialysis before the onset of severe symptoms and signs of uremia was associated with pro­ longation of survival. This led to the concept of “healthy” start and is congruent with the philosophy that it is better to keep patients feeling well rather than allowing them to become ill with uremia and then attempting to return them to better health with dialysis or transplantation. Although recent studies have not confirmed an association of early-start dialysis with improved patient survival, there may be merit in this approach for some patients. At a practi­ cal level, advanced preparation may help to avoid problems with the dialysis process itself (e.g., a poorly functioning fistula for hemo­ dialysis or malfunctioning peritoneal dialysis catheter) and, thus, preempt the morbidity associated with resorting to the insertion of temporary hemodialysis access with its attendant risks of sepsis, bleeding, thrombosis, and association with accelerated mortality. Patient Education  Social, psychological, and physical preparation for the transition to renal replacement therapy and the choice of the optimal initial modality are best accomplished with a gradual approach involving a multidisciplinary team. Along with conserva­ tive measures discussed in the sections above, it is important to prepare patients with an intensive educational program, explain­ ing the likelihood and timing of initiation of renal replacement therapy and the various forms of therapy available and the option of nondialytic conservative care. The more knowledgeable that patients are about hemodialysis (both in-center and home-based), peritoneal dialysis, and kidney transplantation, the easier and more appropriate will be their decisions. Patients who are provided with education are more likely to choose home-based dialysis therapy. This approach is of societal benefit because home-based therapy is less expensive in most jurisdictions and is associated with improved

quality of life. The educational programs should be commenced no later than stage 4 CKD so that the patient has sufficient time and cognitive function to learn the important concepts, make informed choices, and implement preparatory measures for renal replace­ ment therapy.

Exploration of social support is also important. Early education of family members for selection and preparation of a home dialy­ sis helper or a biologically or emotionally related potential living kidney donor should occur long before the onset of symptomatic renal failure. Kidney transplantation (Chap. 325) offers the best potential for complete rehabilitation because dialysis replaces only a small fraction of the kidneys’ filtration function and none of the other renal functions, including endocrine and anti-inflammatory effects. Generally, kidney transplantation follows a period of dialysis treat­ ment, although preemptive kidney transplantation (usually from a living donor) can be carried out if it is certain that the renal failure is irreversible and, under such circumstances, is preferred to trans­ planting after a period of dialysis. ■ ■IMPLICATIONS FOR GLOBAL HEALTH In contrast to the natural decline and successful eradication of many devastating infectious diseases, there is rapid growth in the prevalence of metabolic and vascular disease in developing countries. Diabetes mellitus is becoming increasingly prevalent in these countries, perhaps due in part to change in dietary habits, diminished physical activity, and weight gain. Therefore, it follows that there will be a proportionate increase in vascular and renal disease. According to a recent analysis, in the absence of effective implementation of significant preventive and therapeutic inroads, a forecasting analysis for the U.S. popula­ tion suggests that the number of global years of life lost (YLLs) due to CKD is expected to rise from a prior value of ~26 million in 2016 to 52.5 million in 2040, accompanied by a rise in mortality from 1.2 million in 2016 to 3.1 million in 2040. These increases are predicted to move CKD in the YLL rankings from 16th in 2016 to 5th in 2040. This rise will be disproportionately large in many other regions of the world where CKD prevalence is already rising at alarming rates due to population aging and the rapid increase in diabetes, hypertension, and obesity. CHAPTER 322 Chronic Kidney Disease Health care agencies must plan for improved screening of high-risk individuals for early detection, prevention, and treatment plans in these nations and must start considering options for improved avail­ ability of renal replacement therapies. There is also increasing recognition of endemic nephropathies in developing countries that particularly target young males working in agriculture. The extent of morbidity and mortality associated with these nephropathies is only starting to be appreciated. It is unclear what the cause is, but population genetic risk, endemic nephrotoxins, expo­ sure to pesticides, NSAID use, and chronic volume depletion have all been suggested to contribute. Global warming and air pollution have also been implicated in the development of kidney diseases. ■ ■FURTHER READING Bhandari S et al: Renin-angiotensin system inhibition in advanced chronic kidney disease. N Engl J Med 387:2021, 2022. Chertow G et al: Effects of dapagliflozin in stage 4 chronic kidney disease. J Am Soc Nephrol 32:2352, 2021. Dahl NK et al: The clinical utility of genetic testing in the diagnosis and management of adults with chronic kidney disease. J Am Soc Nephrol 34:2039, 2023. Egbuna OL et al: Inaxaplin for proteinruic kidney disease in persons with two APOL1 variants. N Engl J Med 388:969, 2023. Kovesdy CP: Epidemiology of chronic kidney disease: An update 2022. Kidney Int Suppl (2011) 12:7, 2021. Vivante A: Genetics of chronic kidney disease. N Engl J Med 391:627, 2024. Yu JH et al: GLP-1 receptor agonists in diabetic kidney disease: Current evidence and future directions. Kidney Res Clin Pract 41:136, 2022.

05 - 323 Dialysis in the Treatment of Kidney Failure

323 Dialysis in the Treatment of Kidney Failure

Kathleen D. Liu, Glenn M. Chertow

Dialysis in the Treatment

of Kidney Failure Dialysis may be required for the treatment of either acute or chronic kidney disease (CKD). The use of continuous renal replacement thera­ pies (CRRTs) and prolonged intermittent renal replacement therapy (PIRRT)/slow low-efficiency dialysis (SLED) is specific to the manage­ ment of acute kidney injury/acute kidney disease and is discussed in Chap. 321. These modalities are performed continuously (CRRT) or over 6–12 h per session (PIRRT/SLED), in contrast to the 3–4 h of an intermittent hemodialysis session. Advantages and disadvantages of CRRT and PIRRT/SLED are discussed in Chap. 321. Peritoneal dialysis is rarely used in developed countries for the treatment of acute kidney injury/acute kidney disease because of the increased risk of infection and (as will be discussed in more detail below) less efficient clearance per unit of time. The focus of this chap­ ter will be on the use of peritoneal and hemodialysis for end-stage kidney disease (ESKD). PART 9 Disorders of the Kidney and Urinary Tract With the widespread availability of dialysis, the lives of hundreds of thousands of patients with ESKD have been prolonged. In the United States alone, there are now >800,000 patients with treated ESKD (kidney failure requiring dialysis or transplantation), the vast majority of whom require dialysis. Since 2000, the prevalence of treated ESKD has increased 65%, which predominantly reflects enhanced survival of patients receiving dialysis. The crude incidence rate for treated ESKD in the United States is 363 cases per million population per year; this incidence has slowly fallen over time. ESKD is disproportionately higher in African Americans as compared with white Americans. In the United States, the leading cause of ESKD is diabetes mellitus, currently accounting for ~45% of newly diagnosed cases of ESKD. Approximately 30% of patients have ESKD that has been attributed to hypertension, although it is unclear whether in these cases hypertension is the cause or a consequence of vascular disease or other unknown causes of kidney failure. Other prevalent causes of ESKD include glomerulonephritis, polycystic kidney disease, and obstructive uropathy. A fraction of the excess incidence of ESKD in African Americans is likely related to trans­ mission of high-risk alleles for the APOL1 gene. Globally, mortality rates for patients with ESKD are lowest in Europe and Japan but very high in the developing world because of the limited availability of dialysis. In the United States, the mortality rate of patients on dialysis had decreased somewhat but remained extremely high prior to the COVID-19 pandemic. During the pandemic, there was a signifi­ cant increase in the mortality of patients receiving hemodialysis or peri­ toneal dialysis, but we remove the point estimates. Deaths are due mainly to cardiovascular diseases and infections. Older age, male sex, nonblack race, diabetes mellitus, malnutrition, and underlying heart disease are important predictors of death. TREATMENT OPTIONS FOR PATIENTS WITH ESKD Commonly accepted criteria for initiating patients on maintenance dialysis include the presence of uremic symptoms, the presence of hyperkalemia unresponsive to conservative measures, persistent extra­ cellular volume expansion despite diuretic therapy, acidosis refractory to medical therapy, a bleeding diathesis, and a creatinine clearance or estimated glomerular filtration rate (GFR) <10 mL/min per 1.73 m2, although we should emphasize that there is no absolute level of serum creatinine, cystatin C, blood urea nitrogen (BUN), or estimated GFR that should be considered an absolute indication (see Chap. 322 for estimating equations). Timely referral to a nephrologist for advanced planning and creation of a dialysis access, education about ESKD treat­ ment options, and management of the complications of advanced CKD, including hypertension, anemia, metabolic acidosis, and disorders of

bone and mineral metabolism, including secondary hyperparathyroid­ ism, is advisable. Recent data have suggested that a sizable fraction of ESKD cases result following episodes of acute kidney injury, particu­ larly among persons with underlying CKD. Furthermore, there is no benefit to initiating dialysis preemptively at a GFR of 10–14 mL/min per 1.73 m2 compared to initiating dialysis for symptoms of uremia. In ESKD, treatment options include hemodialysis (in a center or at home); peritoneal dialysis, as either continuous ambulatory peritoneal dialysis (CAPD) or continuous cyclic peritoneal dialysis (CCPD); or transplantation (Chap. 325). Although there are significant geographic variations and differences in practice patterns, in-center hemodialysis remains the most common therapeutic modality for ESKD (>80% of patients) in the United States. In contrast to hemodialysis, peritoneal dialysis is continuous, but much less efficient in terms of solute clear­ ance. While no large-scale clinical trials have been completed compar­ ing outcomes among patients randomized to either hemodialysis or peritoneal dialysis, outcomes associated with both therapies are similar in most reports, and the decision of which modality to select is often based on personal preferences and quality-of-life considerations. HEMODIALYSIS Hemodialysis relies on the principles of solute diffusion across a semi­ permeable membrane. Movement of by-products of metabolism (often referred to as “waste products” or “toxins”—terms that may under­ standably create anxiety in patients) takes place down a concentration gradient from the circulation into the dialysate. The rate of diffusive transport increases in response to several factors, including the mag­ nitude of the concentration gradient, the membrane surface area, and the mass transfer coefficient of the membrane. The latter is a function of the porosity and thickness of the membrane, the size of the solute molecule, and the conditions of flow on the two sides of the membrane. According to laws of diffusion, the larger the molecule, the slower is its rate of transfer across the membrane. A small molecule, such as urea (60 Da), undergoes substantial clearance, whereas a larger molecule, such as creatinine (113 Da), is cleared less efficiently. In addition to dif­ fusive clearance, movement of waste products from the circulation into the dialysate may occur as a result of ultrafiltration. Convective clear­ ance occurs because of solvent drag, with solutes being swept along with water across the semipermeable dialysis membrane. ■ ■THE DIALYZER There are three essential components to hemodialysis: the dialyzer, the composition and delivery of the dialysate, and the blood delivery system (Fig. 323-1). The dialyzer is a plastic chamber with the ability to perfuse blood and dialysate compartments simultaneously at very high flow rates. The hollow-fiber dialyzer is the most common in use in the United States. These dialyzers are composed of bundles of capil­ lary tubes through which blood circulates while dialysate travels on the outside of the fiber bundle. Virtually all dialyzers now manufactured in the United States are “biocompatible” synthetic membranes derived from polysulfone or related compounds (versus older cellulose “bioin­ compatible” membranes that activated the complement cascade). The frequency of reprocessing and reuse of hemodialyzers and blood lines varies across the world. In general, as the cost of disposable supplies has decreased, the use of single-use dialyzers has increased. In the United States, reprocessing of dialyzers is now extremely rare. Formal­ dehyde, peracetic acid–hydrogen peroxide, glutaraldehyde, and bleach have all been used as reprocessing agents. ■ ■DIALYSATE The potassium concentration of dialysate may be varied from 0–4 mmol/L depending on the predialysis serum potassium concentration. The use of 0- or 1-mmol/L potassium dialysate is becoming much less common owing to data suggesting that patients who undergo treatments with very low potassium dialysate have an increased risk of sudden death, perhaps due to arrhythmias in the setting of potassium shifts. The usual dialysate calcium concentration is 1.25 mmol/L (2.5 mEq/L), although modification may be required in selected settings (e.g., higher dialysate calcium concentrations may be used in patients with hypocalcemia

Venous Arterial Dialysate V Arteriovenous fistula A Venous line Hollow fiber dialyzer Arterial line FIGURE 323-1  Schema for hemodialysis. associated with secondary hyperparathyroidism or with “hungry bone syndrome” following parathyroidectomy). The usual dialysate sodium concentration is 135–140 mmol/L. In patients who frequently develop hypotension during their dialysis run, “sodium modeling” to coun­ terbalance urea-related osmolar gradients may be employed. With sodium modeling, the dialysate sodium concentration is gradually lowered from the range of 145–155 mmol/L to isotonic concentrations (135–140 mmol/L) near the end of the dialysis treatment, typically declining either in steps or in a linear or exponential fashion. However, higher dialysate sodium concentrations and sodium modeling may predispose patients to positive sodium balance and increased thirst; thus, these strategies to ameliorate intradialytic hypotension may be undesirable in patients with hypertension or in patients with large interdialytic weight gains. Because patients are exposed to ~120 L of water during each dialysis treatment, water used for the dialysate is subjected to filtration, softening, deionization, and, ultimately, reverse osmosis to remove microbiologic contaminants and dissolved ions. ■ ■BLOOD DELIVERY SYSTEM The blood delivery system is composed of the extracorporeal circuit and the dialysis access. The dialysis machine consists of a blood pump, dialysis solution delivery system, and various safety monitors. The blood pump moves blood from the access site, through the dialyzer, and back to the patient. The blood flow rate typically ranges from 250– 450 mL/min, depending on the type and integrity of the vascular access and needle gauge. Negative hydrostatic pressure on the dialysate side can be manipulated to achieve desirable fluid removal or ultrafiltration. Dialysis membranes have different ultrafiltration coefficients (i.e., mL removed/min per mmHg) so that along with hydrostatic changes, fluid removal can be varied. The dialysis solution delivery system dilutes the concentrated dialysate with water and monitors the temperature, conductivity, and flow of dialysate. ■ ■DIALYSIS ACCESS The fistula, graft, or catheter through which blood is obtained for hemodialysis is often referred to as a hemodialysis (or vascular) access. A native fistula created by the anastomosis of an artery to a vein (e.g., the Brescia-Cimino fistula, in which the cephalic vein at the wrist is anas­ tomosed end-to-side to the radial artery) results in arterialization of the

Acid concentrate Water treatment (deionization and reverse osmosis) Na+ Cl– K+ Acetate– Ca2+ Mg2+ NaBicarb NaCl Dialysate Dialysate flow rate Dialysate pressure Dialysate conductivity Blood (leak) detection CHAPTER 323 Arterial pressure Venous pressure Blood flow rate Air (leak) detection “Delivery” system Dialysate drain Dialysis in the Treatment of Kidney Failure vein. This facilitates its subsequent use in the placement of large needles (typically 15 or 16 gauge) to access the circulation. Fistulas have the highest long-term patency rate of all hemodialysis access options. For patients in whom fistulas fail to mature or in patients whose vasculature does not allow creation of a successful fistula (i.e., poor arterial inflow or recipient veins of inadequate caliber), patients undergo placement of an arteriovenous graft (i.e., the interposition of prosthetic material, usually polytetrafluoroethylene, between an artery and a vein) or a tunneled hemodialysis catheter. Nephrologists, vascular surgeons, and health care policymakers in the United States have encouraged creation of arteriovenous fistulas in a larger fraction of patients (the “fistula first” initiative). Unfortunately, even when created, arteriovenous fistulas may not mature sufficiently to provide reliable access to the circulation, or they may thrombose early in their development. The most important complication of arteriovenous grafts is throm­ bosis of the graft and graft failure, due principally to intimal hyper­ plasia at the anastomosis between the graft and recipient vein. When grafts (or fistulas) fail, catheter-guided angioplasty can be used to dilate stenoses; monitoring of venous pressures on dialysis and of access flow, although not universally performed, may assist in the early recognition of impending vascular access failure. In addition to increased rates of access failure, grafts and (in particular) catheters are associated with much higher rates of infection than fistulas. Intravenous large-bore catheters are often used in patients with acute renal failure and CKD. For persons on maintenance hemodialy­ sis, tunneled catheters (either two separate catheters or a single catheter with two lumens) are often used when arteriovenous fistulas and grafts have failed or are not feasible due to anatomic considerations. These catheters are tunneled under the skin; the tunnel reduces bacterial translocation from the skin, resulting in a lower infection rate than with nontunneled temporary catheters. Most tunneled catheters are placed in the internal jugular veins; the external jugular, femoral, and subclavian veins may also be used. Infection, venous thrombosis, and venous stenosis resulting in swelling of the extremity or superior vena cava syndrome are complications best avoided by limiting the time during which catheters are employed. Nephrologists, interventional radiologists, and vascular surgeons generally prefer to avoid placement of catheters into the subclavian

veins; while flow rates are usually excellent, subclavian stenosis is a frequent complication and, if present, will likely prohibit permanent vascular access (i.e., a fistula or graft) in the ipsilateral extremity. Infec­ tion rates may be higher with femoral catheters. For patients with mul­ tiple vascular access complications and no other options for permanent vascular access, tunneled catheters may be the last “lifeline” for hemo­ dialysis. Translumbar or transhepatic approaches into the inferior vena cava may be required if the superior vena cava or other central veins draining the upper extremities are stenosed or thrombosed.

■ ■GOALS OF DIALYSIS The hemodialysis procedure consists of pumping heparinized blood through the dialyzer at a flow rate of 250–450 mL/min, while dialysate flows in an opposite counter-current direction at 500–800 mL/min. The efficiency of dialysis is determined by blood and dialysate flow through the dialyzer as well as dialyzer characteristics (i.e., its efficiency in removing solute). The dose of dialysis, which is currently defined as a derivation of the fractional urea clearance during a single treatment, is further governed by patient size (in particular, the total body water or urea volume of distribution, which resides to large extent in the skeletal muscle), residual kidney function, dietary protein intake, the degree of anabolism or catabolism, and the presence of comorbid conditions, including, in particular, heart failure. Since the landmark studies of Sargent and Gotch relating the mea­ surement of the dose of dialysis using urea concentrations with mor­ bidity in the National Cooperative Dialysis Study, the delivered dose of dialysis has been measured and considered as a quality assurance and improvement tool. While the fractional removal of urea nitrogen and derivations thereof are considered to be the standard methods by which “adequacy of dialysis” is measured, a large multicenter random­ ized clinical trial (the HEMO study) failed to show a difference in mor­ tality associated with a large difference in per-session urea clearance. Current targets include a urea reduction ratio (the fractional reduction in blood urea nitrogen per hemodialysis session) of >65–70% and a total body water–indexed clearance × time product (Kt/V) >1.2 or 1.05, depending on whether urea concentrations are “equilibrated.” For the majority of patients with ESKD, 9–12 h of dialysis are required each week, usually divided into three equal sessions. Several studies have suggested that longer hemodialysis session lengths may be ben­ eficial (independent of urea clearance), although these studies are con­ founded by a variety of patient characteristics, including body size and nutritional status. Hemodialysis “dose” should be individualized, and factors other than the urea nitrogen should be considered, including the adequacy of ultrafiltration or fluid removal and control of hyper­ kalemia, hyperphosphatemia, and metabolic acidosis. A randomized clinical trial comparing hemodialysis performed 6 versus 3 times per week (the Frequent Hemodialysis Network Daily Trial) demonstrated improved control of hypertension and hyperphosphatemia, reduced left ventricular mass, and improved self-reported physical health with more frequent hemodialysis. Secondary analyses also demonstrated improvements in other metrics of health-related quality of life, includ­ ing improved self-reported general health and a reduced “time to recovery” (time until usual activities can be resumed) among patients randomized to more frequent hemodialysis. A companion trial in which frequent nocturnal hemodialysis was compared to conventional hemodialysis at home showed no significant effect on left ventricular mass or self-reported physical health. Finally, an evaluation of the U.S. Renal Data System registry showed a significant increase in mortality and hospitalization for heart failure after the longer interdialytic inter­ val that occurs over the dialysis “weekend.” PART 9 Disorders of the Kidney and Urinary Tract ■ ■COMPLICATIONS DURING HEMODIALYSIS Hypotension is the most common acute complication of hemodialysis, particularly among patients with diabetes mellitus. Numerous fac­ tors appear to increase the risk of hypotension, including excessive ultrafiltration with inadequate compensatory vascular filling, impaired vasoactive or autonomic responses, osmolar shifts, overzealous use of antihypertensive agents, and reduced cardiac reserve. Patients with arteriovenous fistulas and grafts may develop high-output cardiac failure due to shunting of blood through the dialysis access; on rare occasions,

this may necessitate ligation of the fistula or graft. The management of hypotension during dialysis consists of discontinuing ultrafiltration, the administration of 100–250 mL of isotonic saline, or administration of salt-poor albumin, although the latter is generally unavailable in outpa­ tient settings. Hypotension during dialysis can frequently be prevented by careful evaluation of the dry weight and by ultrafiltration modeling, such that more fluid is removed at the beginning rather than the end of the dialysis procedure. Excessively rapid fluid removal (>13 mL/kg per h) should be avoided, as rapid fluid removal has been associated with adverse outcomes, including cardiovascular deaths. Additional maneuvers to prevent intradialytic hypotension include the performance of sequential ultrafiltration followed by dialysis, cooling of the dialysate during dialysis treatment, and avoiding heavy meals during dialysis. Midodrine, an oral selective α1 adrenergic agent, has been advocated by some practitioners, although there is insufficient evidence of its safety and efficacy to support its routine use. Muscle cramps during dialysis are also a common complication. The etiology of dialysis-associated cramps remains obscure. Changes in muscle perfusion because of excessively rapid volume removal or targeted removal below the patient’s estimated dry weight often precip­ itate dialysis-associated cramps. Strategies that may be used to prevent cramps include reducing volume removal during dialysis, ultrafiltra­ tion profiling, and the use of sodium modeling (see above). Anaphylactoid reactions to the dialyzer, particularly on its first use, have been reported, most frequently with the bioincompatible cellulosic-containing membranes, which are rarely used today. Dialyzer reactions can be divided into two types, A and B. Type A reactions are attributed to an IgE-mediated intermediate hypersensitivity reaction to ethylene oxide used in the sterilization of new dialyzers. This reaction typically occurs soon after the initiation of a treatment (within the first few minutes) and can progress to full-blown anaphylaxis. The type B reaction consists of a symptom complex of nonspecific chest and back pain, which appears to result from complement activation and cytokine release. These symptoms typically occur several minutes into the dialy­ sis run and typically resolve over time with continued dialysis. PERITONEAL DIALYSIS In peritoneal dialysis, 1.5–3 L of a dextrose-containing solution is infused into the peritoneal cavity and allowed to dwell for a set period of time, usually 2–4 h. As with hemodialysis, metabolic by-products are removed through a combination of convective clearance generated through ultrafiltration and diffusive clearance down a concentration gradient. The clearance of solutes and water during a peritoneal dialysis exchange depends on the balance between the movement of solute and water into the peritoneal cavity versus absorption from the peritoneal cavity. The rate of diffusion diminishes with time and eventually stops when equilibration between plasma and dialysate is reached. Absorp­ tion of solutes and water from the peritoneal cavity occurs across the peritoneal membrane into the peritoneal capillary circulation and via peritoneal lymphatics into the lymphatic circulation. The rate of perito­ neal solute transport varies from patient to patient and may be altered by the presence of infection (peritonitis), drugs, and physical factors such as position and exercise. ■ ■FORMS OF PERITONEAL DIALYSIS Peritoneal dialysis may be carried out as CAPD, CCPD, or a combination of both. In CAPD, dialysate is manually infused into the peritoneal cav­ ity and exchanged three to five times during the day. A nighttime dwell is frequently instilled at bedtime and remains in the peritoneal cavity through the night. In CCPD, exchanges are performed in an automated fashion, usually at night; the patient is connected to an automated cycler that performs a series of exchange cycles while the patient sleeps. The number of exchange cycles required to optimize peritoneal solute clear­ ance varies by the peritoneal membrane characteristics; as with hemodi­ alysis, solute clearance should be tracked to ensure dialysis “adequacy.” Peritoneal dialysis solutions are available in volumes typically rang­ ing from 1.5–3 L. The major difference between the dialysate used for peritoneal dialysis rather than hemodialysis is that the hypertonicity of peritoneal dialysis solutions drives solute and fluid removal, whereas

solute removal in hemodialysis depends on concentration gradients, and fluid removal requires transmembrane pressure. Typically, dex­ trose at varying concentrations contributes to the hypertonicity of peritoneal dialysate. In some cases in which patients have developed severe protein-energy malnutrition or have struggled with insufficient ultrafiltration, amino acid–containing peritoneal dialysis solutions have been added to the CAPD or CCPD regimen. Icodextrin is a nonabsorbable carbohydrate that is frequently used in place of dex­ trose during a single daily exchange. Studies have demonstrated more efficient ultrafiltration with icodextrin than with dextrose-containing solutions. Icodextrin is typically used as the “last fill” for patients on CCPD or for the longest dwell in patients on CAPD. The most com­ mon additives to peritoneal dialysis solutions are heparin to prevent obstruction of the dialysis catheter lumen with fibrin and antibiotics during an episode of acute peritonitis. Insulin may also be added in patients with diabetes mellitus. ■ ■ACCESS TO THE PERITONEAL CAVITY Access to the peritoneal cavity is obtained through a peritoneal cath­ eter. Catheters used for maintenance peritoneal dialysis are flexible, being made of silicone rubber with numerous side holes at the distal end. These catheters usually have two Dacron cuffs. The scarring that occurs around the cuffs anchors the catheter and seals it from bacteria tracking from the skin surface into the peritoneal cavity; it also pre­ vents the external leakage of fluid from the peritoneal cavity. The cuffs are placed in the preperitoneal plane and ~2 cm from the skin surface. The peritoneal equilibrium test is a formal evaluation of peritoneal membrane characteristics that measures the transfer rates of creatinine and glucose across the peritoneal membrane. Patients are classified as low, low–average, high–average, and high transporters. Patients with rapid equilibration (i.e., high transporters) tend to absorb more glucose and lose efficiency of ultrafiltration with long daytime dwells. High transport­ ers also tend to lose larger quantities of albumin and other proteins across the peritoneal membrane. In general, patients with rapid transporting characteristics require more frequent, shorter dwell-time exchanges, nearly always obligating use of a cycler. Slower (low and low–average) transporters tend to do well with fewer exchanges. The efficiency of solute clearance also depends on the volume of dialysate infused. Larger volumes allow for greater solute clearance, particularly with CAPD in patients with low and low–average transport characteristics. As with hemodialysis, the optimal dose of peritoneal dialysis is unknown. Several observational studies have suggested that higher rates of urea and creatinine clearance (the latter generally measured in L/week) are associated with lower mortality rates and fewer uremic complications. However, a randomized clinical trial (Adequacy of Peritoneal Dialysis in Mexico [ADEMEX]) failed to show a significant reduction in mortality or complications with a relatively large incre­ ment in urea clearance. In general, patients on peritoneal dialysis do well when they retain residual kidney function. Rates of technique fail­ ure increase with years on dialysis and have been correlated with loss of residual function to a greater extent than loss of peritoneal membrane capacity. For some patients in whom CCPD does not provide suffi­ cient solute clearance, a hybrid approach can be adopted where one or more daytime exchanges are added to the CCPD regimen. While this approach can enhance solute clearance and prolong a patient’s capacity to remain on peritoneal dialysis, the burden of the hybrid approach can be overwhelming. ■ ■COMPLICATIONS DURING PERITONEAL DIALYSIS The major complications of peritoneal dialysis are peritonitis, catheterassociated nonperitonitis infections, weight gain and other metabolic disturbances, and residual uremia (especially among patients with little or no residual kidney function). Peritonitis typically develops when there has been a break in sterile technique during one or more of the exchange procedures. Peritonitis is usually defined by an elevated peritoneal fluid leukocyte count (100/mm3, of which at least 50% are polymorphonuclear neutrophils); these cutoffs are lower than in spontaneous bacterial peritonitis because of the presence of dextrose in peritoneal dialysis solutions and rapid bacterial proliferation in this environment without antibiotic

therapy. The clinical presentation typically consists of pain and cloudy dialysate, often with fever and other constitutional symptoms. The most common culprit organisms are gram-positive cocci, including Staphylococcus, reflecting the origin from the skin. Gram-negative rod infections are less common; fungal and mycobacterial infections can be seen in selected patients, particularly after antibacterial therapy. Most cases of peritonitis can be managed either with intraperitoneal or oral antibiotics, depending on the organism; many patients with peri­ tonitis do not require hospitalization. In cases where peritonitis is due to hydrophilic gram-negative rods (e.g., Pseudomonas spp.) or yeast, antimicrobial therapy is usually not sufficient, and catheter removal is required to ensure complete eradication of infection. Nonperitonitis catheter-associated infections (often termed tunnel infections) vary widely in severity. Some cases can be managed with local antibiotic or silver nitrate administration, while others are severe enough to require parenteral antibiotic therapy and catheter removal.

Peritoneal dialysis is associated with a variety of metabolic compli­ cations. Albumin and other proteins can be lost across the peritoneal membrane in concert with the loss of metabolic wastes. Hypoprotein­ emia obligates a higher dietary protein intake in order to maintain nitrogen balance. Hyperglycemia and weight gain are also common complications of peritoneal dialysis. Several hundred calories in the form of dextrose are absorbed each day, depending on the concentra­ tion of dextrose employed. Patients receiving peritoneal dialysis, par­ ticularly those with diabetes mellitus, are prone to other complications of insulin resistance, including hypertriglyceridemia. On the positive side, the continuous nature of peritoneal dialysis usually allows for a more liberal diet due to continuous removal of potassium and phos­ phorus—two major dietary components whose accumulation can be hazardous in ESKD. CHAPTER 323 Dialysis in the Treatment of Kidney Failure LONG-TERM OUTCOMES IN ESKD Cardiovascular disease constitutes the major cause of death in patients with ESKD. Cardiovascular mortality and event rates are higher in patients receiving dialysis than in patients posttransplantation, although rates are extraordinarily high in both populations. The underlying cause of cardiovascular disease is unclear but may be related to shared risk factors (e.g., diabetes mellitus, hypertension, atherosclerotic and arteriosclerotic vascular disease), chronic inflam­ mation, massive changes in extracellular volume (especially with high interdialytic weight gains), inadequate treatment of hypertension, dyslipidemia, anemia, dystrophic (vascular) calcification, and, perhaps, alterations in cardiovascular dynamics during the dialysis treatment. Few studies have targeted cardiovascular risk reduction in patients with ESKD; none has demonstrated consistent benefit. Two clinical trials of statin agents in ESKD demonstrated significant reductions in low-density lipoprotein (LDL) cholesterol concentrations but no significant reductions in death or cardiovascular events (Die Deutsche Diabetes Dialyse Studie [4D] and AURORA studies). The Study of Heart and Renal Protection (SHARP), which included patients on dialysis and others with non-dialysis-requiring CKD, showed a 17% reduction in the rate of major cardiovascular events or cardiovascular death with simvastatin-ezetimibe treatment. Most experts recommend conventional cardioprotective strategies (e.g., lipid-lowering agents, aspirin, inhibitors of the renin-angiotensin-aldosterone system, and β-adrenergic antagonists) in patients receiving dialysis based on the patients’ cardiovascular risk profile, which appears to be increased by more than an order of magnitude relative to persons unaffected by kidney disease. To date, sodium-glucose cotransporter 2 (SGLT-2) inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists have not been formally studied in the context of ESKD for cardiovascular risk reduction. Other complications of ESKD include a high incidence of infection, progressive debility and frailty, protein-energy malnutri­ tion, and impaired cognitive function. GLOBAL PERSPECTIVE The incidence of ESKD is increasing worldwide with longer life expectancies and improved care of infectious and cardiovascular dis­ eases. The management of ESKD varies widely by country and within

06 - 324 Interventional Nephrology

324 Interventional Nephrology

country by region, and it is influenced by economic and other major factors. In general, peritoneal dialysis is more commonly performed in poorer countries owing to its lower expense and the high cost of establishing in-center hemodialysis units.

■ ■FURTHER READING Cooper BA et al: A randomized, controlled trial of early versus late initiation of dialysis. N Engl J Med 363:609, 2010. Correa-Rotter R et al: Peritoneal dialysis, in Brenner and Rector’s The Kidney, 11th ed, MW Taal et al (eds). Philadelphia, Elsevier, 2020. Fellstrom BC et al: Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N Engl J Med 360:1395, 2009. Flythe JE et al: Rapid fluid removal during dialysis is associated with cardiovascular morbidity and mortality. Kidney Int 79:250, 2011. Foley RN et al: Long interdialytic interval and mortality among patients receiving hemodialysis. N Engl J Med 365:1099, 2011. Frequent Hemodialysis Network Trial Group: In-center hemodi­ alysis six times per week versus three times per week. N Engl J Med 363:2287, 2010. National Kidney Foundation: Kidney disease quality initiative clinical practice guidelines: Hemodialysis and peritoneal dialysis adequacy, 2006. Available at http://www.kidney.org/professionals/ kdoqi/guidelines.cfm. Rocco MV et al: The effects of frequent nocturnal home hemodialysis: PART 9 Disorders of the Kidney and Urinary Tract The frequent hemodialysis network nocturnal trial. Kidney Int 80:1080, 2011. U.S. Renal Data System: USRDS 2021 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. Bethesda, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Disease, 2021. Dirk M. Hentschel

Interventional

Nephrology Interventional nephrology is a procedure-oriented subspecialty with a focus on dialysis access for peritoneal and hemodialysis, typically performed under fluoroscopy. Ultrasound (US) evaluation of dialysis access is common, and some practitioners perform renal and renal artery US evaluation as well as renal biopsies. Endovascular creation of arteriovenous fistulas (AVFs) is a recent addition to the procedural spectrum; (open) surgical access creation by nephrologists is limited to very few centers in the United States, while common in China, Germany, India, and Italy. Interventional nephrologists (INs) usually provide patient care in multidisciplinary teams that include clinical nephrologists; access sur­ geons with vascular, transplant, or general surgery background; other interventionalists (with radiology or cardiology training); and dialysis unit access coordinators, nurses, and technicians involved in needle placement. Long-term preservation of venous and arterial vascular access options is one tenet of chronic kidney disease (CKD) care, lead­ ing INs to advocate for specific vascular access options (tunneled smalldiameter catheters over peripherally inserted central catheters [PICCs]) and cardiac devices (epicardial rather than endovascular lead passage). ■ ■HISTORY The history of vascular access for hemodialysis is closely tied to the history of dialysis. The first hemodialysis treatments in humans were performed in 1924 using glass needles to access the radial artery and return blood into the cubital vein. In 1943, a “rotating drum kidney” was used to dialyze a 29-year-old housemaid with CKD by surgical

exposure of different arteries until she ran out of access sites after 12 treatments. The challenge of repetitive vascular access prevented dialy­ sis from becoming a routine method for the treatment of CKD until the development of an arteriovenous Teflon shunt and then the develop­ ment of an autogenous arterial-venous access (arteriovenous fistula, AVF) by side-to-side-anastomoses between the radial artery and the cephalic vein at the wrist (Cimino fistula). Catheter-based approaches for chronic renal replacement therapy (RRT) were designed initially in 1961 for hemodialysis and in 1968 for peritoneal dialysis, both using Dacron felt cuffs to protect against infection. Material sciences have continued to evolve the development of grafts for use in hemodialysis. A modified bovine carotid artery biological graft was introduced in 1972, followed by the use of expanded polytet­ rafluoroethylene (ePTFE) grafts in 1976, and most recently in 2016, tissue-engineered blood vessels from human fibroblasts and endothe­ lial cells. Some ePTFE grafts are modified with a silicone layer to allow for early cannulation within days of insertion. Ultra-high-pressure (up to 40 atm) angioplasty balloons are a mainstay of peripheral and central venous therapy, and Nitinol self-expanding stents and stent grafts serve as rescue tools for unsuccessful angioplasty as well as vessel rupture with extravasation. The role of drug-coated balloons in dialysis access care continues to be assessed, although greater cost and, to date, mixed clinical trial results have limited widespread use. ■ ■PHYSIOLOGY AND PATHOPHYSIOLOGY OF DIALYSIS ACCESS Peritoneal Dialysis  Peritoneal dialysis (PD) catheters can be placed fluoroscopically, peritoneoscopically, laparoscopically, and open surgi­ cally. Procedural success is typically linked to provider experience and procedural planning to optimize positioning of the PD catheter coil as this improves function and decreases drain pain and other complica­ tions. The internal cuff is placed within the rectus sheath just laterally to the linea alba, while the external PD catheter cuff should be located 2–4 cm from the skin exit site. Ingrowth of both cuffs ensures secure positioning of the catheter and allows water emersion. Over time, the peritoneal catheter can become encased in a fibrinous sheath, which, if limiting fluid flow during exchanges, can be disrupted by guidewire manipulation. Omental entrapment of the catheter often requires lapa­ roscopic intervention; omentopexy at the time of PD catheter placement can prevent later entrapment. Repeated infections affect the permeability of the peritoneal membrane, as does long-term exposure to glucose-con­ taining exchange solutions. Encapsulating peritoneal sclerosis is a latestage complication of PD thought to be triggered by repeated peritonitis. Hemodialysis Catheters  Dialysis catheters are typically made of polyurethane that softens at body temperature but is sufficiently strong to allow for blood flow rates of 400–500 mL/min in each of two chan­ nels inside a 14.5–16 French design without collapse of the catheter lumen. Tunneled catheters have a cuff that creates a barrier between skin flora at the exit site and the sterile catheter tunnel leading into the fibrinous sheath covering the catheter from the vessel insertion point to its tip. The fibrinous sheath can extend too far, impeding catheter flow and necessitating exchange of the catheter with disruption of the sheath by balloon angioplasty. Catheter-related bacteremia is best treated with exchange of the catheter and disruption of any fibrinous sheath, although removal of the catheter and delayed reinsertion after several days is also successful. Catheter infection-related sepsis unre­ sponsive to antibiotics requires removal of the catheter. Thrombotic occlusion and later sclerotic scarring of the vein at catheter insertion sites is common, however, and removal of a catheter may lead to loss of this access site. Catheter vessel wall contact points are thought to lead to central vein stenosis, which is more commonly observed in patients with catheter contact times of longer duration (>3 months). Catheter tip position in the large central veins instead of the right atrium causes additional injury from dynamic blood movement during dialysis treatments and should be corrected. A thrombus is commonly found attached to the catheter, often tethering the catheter to the vessel wall and right atrium. While some thrombi are mobile and dissolve with anticoagulation, a wall-tethered thrombus is often well organized

with cellular components and quite resistant to pharmacologic lysis. Clinically significant pulmonary embolism from catheter-associated thrombus is rare, and it may be that only intra-atrial thrombus >2 cm in diameter deserves active intervention. Arteriovenous Graft and Fistulas  During the first decades of hemodialysis for loss of renal function, U.S. patients were relatively young and without long-term systemic vascular disease. Creation of forearm Cimino AVFs was common, and access failure usually led to creation of a second AVF slightly higher up on the arm. As diabetes and hypertension with associated systemic arterial and venous vascular disease became more prevalent in the CKD population, placement of nonautogenous accesses (arteriovenous grafts [AVGs]) increased. In the mid-1990s, 65% of prevalent dialysis patients used an AVG for access. The United States was an international outlier in this regard, and studies associated increased mortality in U.S. dialysis patients with lower AVF prevalence. In the context of “Fistula First” and then “Fistula First, Catheter Last” campaigns, AVG prevalence decreased to its current value of <20%, while AVFs increased to near 65% preva­ lence. However, most centers still struggle with the challenging condi­ tions of arteries and veins in these patients requiring that 75% of AVFs are now created in the upper arm, where the veins a priori are larger in diameter, and arteries can deliver higher blood flow rates due to large vessel diameter (see Fig. 324-1). To provide successful dialysis, an AVF or AVG has to provide at least the desired blood pump speed (Chap. 323) plus 100–200 mL/min to minimize recirculation and prevent collapse of the access. In the United States, this usually means flow in the 600–800 mL/min range. A fistula created using an artery with ≥2 mm diameter and a vein ≥3 mm will typically have flow volumes >500 mL/min when the systolic blood pressure is >100 mmHg. After creation of the arterial-venous anasto­ mosis (or insertion of the AVG), blood flow increases significantly: brachial artery flow at rest is typically <50 mL/min, but after access creation, flow volume in AVFs increases within weeks to 800 mL/min, while flow volume in AVGs increases within minutes to 1000 mL/min. The increased flow changes the arterial shear stress profile and leads to enlargement of the artery over time. In AVGs, this process is limited by the graft itself, which typically is 6 mm in diameter and 35–40 cm long, and access flows remain in the 1200–1800 mL/min range. The access vein in AVFs in the right shear stress environment enlarges over time, often to >10 mm in diameter in the upper arm such that the artery A C B D FIGURE 324-1  Dialysis access health depends on intra-access pressures and needle insertions. A. A right upper arm brachial-cephalic arteriovenous fistula (AVF) with two recurrences of clinically relevant inflow stenosis in 4 years has low-normal intra-access pressure before and after angioplasty; there is only minimal needle insertion site enlargement. B. In contrast, a right upper arm brachial-cephalic AVF with seven recurrences of cephalic arch outflow stenosis in 4-year cycles between states of highnormal to high intra-access pressures with notable needle insertion site enlargement. C. Focal needle insertions despite available graft segments led to penetrating skin ulcers over 3 years. D. Segmental needle rotation preserves skin integrity even after 7 years of arteriovenous graft (AVG) use.

continues to enlarge until a narrow segment in the venous conduit becomes flow limiting. Flow volumes in these mature upper arm AVFs are usually 1400–1800 mL/min, but after a few years can be as high as 2000–4000 mL/min. Forearm AVFs usually have lower flow volumes (500–700 mL/min) as the feeding radial artery is of smaller diameter and, in the context of systemic vascular disease in the United States, only increases in diameter over many years.

Increased flows and pressure in the venous segment of the access circuit combine to lead to “chronic dialysis access disease” that mani­ fests differently for each type of the common long-term accesses in predetermined segments particularly prone to shear stress and needle insertion–related injury. AVGs develop venous anastomotic stenoses that recur with very short periodicity in the 3- to 4-month range. Stent grafts can effectively be deployed to extend patency for usually 1 year at the site, after which the buildup of pauci-cellular fibrous depositions at the stent edges requires re-angioplasty one to three times per year. Forearm radial-cephalic autogenous accesses of the Cimino type at the wrist are most prone to low flow due to juxta-anastomotic stenoses. Over time, these stenoses can stabilize, and with enlargement of the inflow artery, they effectively provide protection against excessive flows and their sequelae. “Snuff box” radial-cephalic fistulas require mini­ mal mobilization of the cephalic vein with fewer juxta-anastomotic stenoses. However, the additional side branches and associated venous valves may present as stenosis and require ligation to allow cannulation (see below discussion of augmentation). Upper arm brachial-cephalic autogenous accesses typically develop stenoses in the cephalic arch, which recur in accelerated fashion after each angioplasty. Flexible stent grafts in the cephalic arch extend intraprocedural intervals usually to 9–12 months. Upper arm transposed brachial-basilic autogenous accesses develop stenoses in the swing point where the basilic vein is curved during a mobilization procedure to provide a location more lateral and closer to the skin to facilitate needle cannulation. Angio­ plasty and stent graft placement approaches extend patency. In both types of upper arm accesses, there are often prolonged periods with increased intra-access pressures due to outflow stenoses, which lead to enlargement of needle insertion site aneurysm as the skin heals in a pressurized, stretched state. Continued use of pressurized accesses leads to enlargement of needle sites, then thinning of the skin, scab formation, and, finally, full-thickness ulceration with often significant bleeding events. Recognizing the occurrence of outflow stenoses early CHAPTER 324 Interventional Nephrology

is an important skill for nurses and technologists working in dialysis units to acquire in order to avoid irreversible loss of skin coverage and possible loss of the access.

High-access flow (>1500 mL/min) can lead to systemic complica­ tions, such as heart failure and pulmonary hypertension. Fistula inflow higher than outflow capacity leads to accelerated aneurysm formation and breakdown of skin coverage as intra-access pressures are increased over the ideal pressure of 20–35 mmHg. High-access flows are also associated with steal syndrome, typically ischemia of the hand. A variety of procedures have been described to reduce access flows, the most common being “banding,” where typically a 2-0 Prolene suture is guided around the inflow and a 3- or 4-mm spacer and is tied snugly over the spacer to create an inflow stenosis. APPROACH TO THE PATIENT Physical Examination of Dialysis Access The 2019 Kidney Disease Outcomes Quality Initiative (KDOQI) vascular access guidelines were developed under the tenet, “[t]he right access for the right patient at the right time.” Progression of CKD is highly variable, many patients die from other causes before reaching end-stage renal disease (ESRD), and some AVFs require 6–12 months to mature to usability in patients with hypertension and diabetes, leading to uncertainty as to when to create AVFs. The more common need of upper arm accesses for interventions to maintain patency favors the creation of forearm accesses during the pre-ESRD period. The processes of care from vein mapping, sur­ gery, follow-up visits after access creation, to availability and tim­ ing of open surgical or endovascular interventions have profound effects on the overall success rate needed to achieve mature and usable accesses and appear to be key factor in the highly variable outcomes across the United States. PART 9 Disorders of the Kidney and Urinary Tract A central skill in dialysis access evaluation is the physical exami­ nation. Five steps in the access examination capture all aspects of possible pathology: Pulsatility reflects the force of access expan­ sion during systole and the degree of softening during diastole. Very high blood pressures will suggest increased pulsatility, but the access softens remarkably during diastole. An outflow stenosis will lead to increased pulsatility and reduced softening during diastole. An inflow stenosis will blunt the systolic component and create the impression of an “empty” access during diastole unless there is a coexisting outflow stenosis. The audible flow murmur can be char­ acterized by pitch and continuity (Video 324-1). A change in pitch toward higher frequency is typical at the site of a stenosis due to accelerated flow velocity at this site. A discontinuous flow murmur indicates that during diastole flow is so low that no audible shear force is created; this is the sign of a severe inflow or outflow steno­ sis. Typically, the stenotic inflow murmur is faint (like a whistle), whereas the stenotic outflow murmur can be coarse and loud (akin to a handsaw) (Video 324-2). A thrill is palpable through the skin when the vessel is close enough to the surface and the flow high enough in relation to the diameter of the vessel to create vibration of the vessel wall. A continuous thrill can be a sign of a well-developed access, usually in the inflow segment, dissipating as the access ves­ sel branches and takes a deeper course. In contrast, a discontinuous thrill is found with severe stenosis. An isolated thrill is also found focally immediately after a stenosis. The differentiation from a “healthy” thrill can be made by documenting a change in pulsatil­ ity at the site of the focal thrill, increased retrograde (inflow) and decreased antegrade (outflow). Augmentation is the engorgement of the body of the access (where needles are inserted) with occlusion of the outflow necessary for safe and successful needle insertions. An inflow stenosis will impair augmentation, as will side branches and collaterals between the occluding finger/tourniquet and the inflow. The location of side branches can be elucidated by moving the occluding finger closer toward the anastomosis until augmenta­ tion is achieved. With several collaterals, this may be a staged phe­ nomenon. Collapse of the access with arm elevation (against gravity)

is a measure of inflow and outflow capacity match or mismatch. A forearm access typically displays complete collapse, while upper arm accesses typically show only partial collapse. An outflow steno­ sis or very high inflow will decrease the degree of collapse; banding of an upper arm access or a natural flow-limiting stenosis may lead to complete collapse of an upper arm access. Enlarged needle insertion sites (and any sites of suspected skin thinning) are best examined while occluding inflow: the completely empty access allows palpation of a firm, layered thrombus inside aneurysms as well as a better appreciation of the thickness of the overlying skin by rolling it between thumb and index finger. The chest wall and neck should be inspected for the presence of skin veins and venous distention, which are associated with central venous stenosis or occlusion, as is ipsilateral arm edema. PRESERVATION OF VENOUS “REAL ESTATE” Preserving access is a key care component for the patient with advancing CKD. Approximately 8–10% of this population has the need for cardiac rhythm management devices (CRMDs) that can lead to loss of the upper arm cephalic vein as well as central venous stenoses and occlusions around device leads. Planning for which side a future autogenous access is to be placed and where a CRMD is located is recommended in all cases. CKD patients also have an increased frequency of hospitalizations, some of which require intravenous access beyond the hospital stay for antibiotics, nutri­ tional support, or hydration. Avoiding PICCs in a patient with CKD stage 3 or 3b and higher and, instead, using internal (or external) jugular vein tunneled small-diameter catheters preserves arm veins for long-term access creation. Arterial access points for cardiac pro­ cedures should be chosen with AVF creation in mind. Approach to the dialysis access of patients with a kidney trans­ plant depends on the function of the transplanted kidney, the risk of recurrence of kidney disease in the transplant, the ability to limit access flow over time while maintaining patency, and the potential benefit of the AVF for blood pressure control. ■ ■FURTHER READING DePietro DM, Trerotola SO: Choosing the right treatment for the right lesion, Part II: A narrative review of drug-coated balloon angio­ plasty and its evolving role in dialysis access maintenance. Cardiovasc Diagn Ther 13:233, 2023. Haskal ZJ, Dolmatch BL: Hemodialysis access stent graft trials: Past, present, and future. Cardiovasc Intervent Radiol 46:1154, 2023. Hentschel DM: Hemodialysis access maintenance and salvage, in Mastery of Surgery: Vascular Surgery: Hybrid, Venous, Dialysis Access, Thoracic Outlet, and Lower Extremity Procedures, Philadelphia, Wolters Kluwer, 2015, pp 191–205. Hentschel DM et al: Hemodialysis access interventions, in Vascular Imaging and Intervention, 2nd ed. D Kim et al (eds). India, Jaypee Brothers Medical Publishers, 2020, pp 1655–1686. Hoggard J et al: Guidelines for venous access in patients with chronic kidney disease. Semin Dial 21:186, 2008. Lok CK et al: KDOQI clinical practice guideline for vascular access: 2019 update. Am J Kidney Dis 75:S1, 2020. Ozaki CK et al: Non-maturing autogenous arteriovenous fistula, in Vascular Decision Making. Philadelphia, Wolters Kluwer, 2020. VIDEO 324-1  Flow murmur of an upper arm brachial-cephalic autogenous access (arteriovenous fistula [AVF]) with a juxta-anastomotic stenosis. The sound is discontinuous as the stenosis is severe enough that only during systole is the flow volume high enough to create audible turbulence. There also is a high-pitch component of the murmur due to the high flow velocity during the peak of the flow cycle. VIDEO 324-2  Flow murmur of an upper arm brachial-cephalic autogenous access (arteriovenous fistula [AVF]) with a juxta-anastomotic stenosis after angioplasty. The sound is now continuous with systolic-diastolic modulation. There is an even pitch, overall lower than the pitch associated with peak flow in the setting of an untreated stenosis.

07 - 325 Kidney Transplantation

325 Kidney Transplantation

Jamil R. Azzi, Naoka Murakami,

Anil K. Chandraker

Kidney Transplantation Kidney transplantation is the treatment of choice for patients with end-stage kidney disease (ESKD). Worldwide, tens of thousands of kidney transplants have been performed, and >220,000 patients are living with a functioning kidney transplant in the United States today. The first successful kidney transplant was performed in Boston in 1954 between identical twins. The introduction of immunosuppressive therapies such as azathioprine and prednisone in the 1960s established kidney transplantation across nonidentical individuals (allografts). During the 1970s and 1980s, the success rate at the 1-year mark for deceased-donor allografts markedly improved after the introduction of calcineurin inhibitors. Currently, 1-year survival rates for living-donor and deceased-donor allografts are 98 and 93%, respectively, in the United States. However, long-term survival has not improved as much over time, and the average allograft survival time is 19 and 12 years for living-donor and deceased-donor grafts, respectively. Age-related mortality rates after transplantation are highest in the first year due to the surgical risks: 2% for ages 18–34 years, 3% for ages 35–49 years, and 6.8% for ages ≥50–60 years. Despite this, the actual survival benefit of transplantation compared to chronic dialysis becomes apparent within days to months following transplantation, even after risk adjustments for age, diabetes, and cardiovascular status. While the loss of kidney transplant due to acute rejection is now a rare event, most allografts eventually succumb at varying rates to a chronic process consisting of interstitial fibrosis, tubular atrophy, vasculopathy, and glomerulopathy, the pathogenesis of which in varying degrees is likely a combination of an alloimmune response, drug toxicity, and the result of a variety of other insults. Overall, transplantation results in an improved life expectancy with a higher quality of life compared to patients who remain on dialysis. RECENT ACTIVITY AND RESULTS In 2022, >19,000 deceased-donor kidney transplants and approxi­ mately 6000 living-donor transplants were performed in the United States, with the ratio of deceased-donor to living-donor transplants remaining stable over the past few years. As the number of patients with ESKD increases, the number of patients on the transplant waitlist also increases. The donor shortage remains a critical challenge; as of 2022, there were nearly 139,000 adult kidney transplant candidates on the waiting list, with 25,000 patients being transplanted yearly. This imbalance is set to worsen over the coming years with the predicted increased rates of kidney failure associated with obesity and diabetes worldwide. In an attempt to increase utilization of marginal kidneys and allocate organs equitably, a new allocation system within the United States was implemented in 2014. The guiding principles of the changes were to offer an opportunity for transplantation to patients who were highly sensitized and, thus, less likely to find a suitable donor, while at the same time allowing patients expected to survive the longest to receive the best-quality deceased donor organs. The Kidney Donor Profile Index (KDPI) score, which ranges from 0 to 100%, was introduced to estimate the potential risk of graft failure after kidney transplant based on 10 donor factors. The lower KDPI values are associated with higher expected posttransplant survival. Hence, the kidneys with a KDPI <20% are allocated to the 20% of the potential recipients with the highest expected posttransplant survival. Kidneys with a KDPI >85% (previously called expanded criteria donor [ECD] kidneys) are directed toward patients who are expected to fare less well on dialysis and would benefit from being transplanted earlier even if it means accepting a lower-quality organ. In 2021, a new distance-based kidney allocation policy was intro­ duced. Under this policy, deceased-donor kidneys are to be offered first to candidates listed at transplant hospitals within 250 nautical miles of

the donor hospitals. While intended to reduce geographic disparities in access to kidney transplantation, this program has resulted in more complex organ sharing, unintended higher kidney discard rates, and increased cold ischemia time. A variety of other means to increase the donor pool and equity have also become more popular. Kidneys from donors after cardiac death (DCD) are now commonly used to overcome the demand for organs, consisting of 30% of total deceased kidney transplants (Table 325-1). Furthermore, with the advance­ ment of the direct-acting antiviral therapies for hepatitis C virus (HCV), transplantation from HCV-positive donors to HCV-positive or -negative recipients has been performed since 2017 in order to increase the donor pool. Now this practice is becoming more common, consisting of 9% of deceased kidney transplants. Recently, the HOPE (Human Immunodeficiency Virus [HIV] Organ Policy Equity) Act authorized organ donation from HIV-positive candidates, and >100 transplants have been performed. As patients with blood group B wait longer for deceased donor offers, eligible B blood type candidates who have low anti-A titer are eligible for an allograft from A blood type donors. This helps improve access and reduce disparities in wait time for minorities, especially for the African-American ESKD population, in whom blood type B is more common than in other ethnicities. Finally, with recent advances in gene editing technology, xenotrans­ plantation is becoming a more realistic endeavor. Using kidneys from genetically engineered pigs, three experimental kidney transplanta­ tions into brain-dead recipients were performed in 2022. There are still multiple issues to overcome, including xenoimmunity, transmission of zoonosis, and ethical challenges, but xenotransplantation has the potential to provide an unlimited source of organs.

CHAPTER 325 Kidney Transplantation The overall results of transplantation are presented in Table 325-2. At the 1-year mark, allograft survival is higher for living-donor recipi­ ents. This is most likely related to less ischemic injury of the transplant organ. The introduction of more effective immunosuppression and more accurate matching between recipients and donors has almost equalized the risk of graft rejection in the majority of patients within the first year. At 5- and 10-year follow-up, however, there remains a steeper decline in survival of those with deceased-donor kidneys. RECIPIENT EVALUATION Virtually all patients with ESKD benefit from transplantation with a longer life expectancy and a better quality of life. While the mortality rate after transplantation is highest in the first year due to perioperative complications, recipient evaluation is critical in identifying patients at risk. It involves a multidisciplinary approach that requires thorough medical, surgical, social, and psychosocial evaluations to identify the risk factors that prohibit transplantation or mandate treatment before proceeding, as well as ensuring the appropriate use of limited organs. There are a few absolute contraindications to kidney transplanta­ tion: chronic illness that limits predicted survival for <2 years, active malignancy, active infection, psychosocial issues affecting adherence to the medical care, and active substance abuse. Cardiovascular risk assessment is crucial during both the perioperative and postoperative periods. Patients with ESKD are at higher cardiovascular mortality risk, TABLE 325-1  Definition of a Non-Heart-Beating Donor (Donation After Cardiac Deatha [DCD])   I: Brought in dead II: Unsuccessful resuscitation III: Awaiting cardiac arrest IV: Cardiac arrest after brainstem death V: Cardiac arrest in a hospital patient aKidneys can be used for transplantation from categories II–V but are commonly only used from categories III and IV. The survival of these kidneys has not been shown to be inferior to that of deceased-donor kidneys. Note: Kidneys can both have a Kidney Donor Profile Index (KDPI) score >85% and be DCD. High KDPI kidneys have been shown to have a poorer survival, and there is a separate shorter waiting list for those kidneys. They are generally utilized for patients for whom the benefits of being transplanted earlier outweigh the associated risks of using a lower-quality kidney.

TABLE 325-2  Mean Rates of Graft and Patient Survival for Kidneys Transplanted in the United States from 1999 to 2018a 1-YEAR FOLLOW-UP 5-YEAR FOLLOW-UP 10-YEAR FOLLOW-UP   GRAFTS, % PATIENTS, % GRAFTS, % PATIENTS, % GRAFTS, % PATIENTS, % Deceased donor

Living donor

aAll patients transplanted are included, and the follow-up unadjusted survival data from the 1-, 5-, and 10-year periods are presented to show the attrition rates over time within the two types of organ donors. Source: Data from Summary Tables, 2021 Annual Reports, Scientific Registry of Transplant Recipients. and thorough cardiovascular evaluation for coronary artery diseases, valvular diseases, and heart failure is critical. At most centers, there is no official age limit for transplantation, with >20% of waitlisted candidates currently being older than 65. However, overall physical and cognitive function of the candidates needs to be fully assessed. While history of malignancy itself is not a contraindication for kidney transplantation, potential recipients should be treated to ensure cancer-free wait time of 2–5 years depending on the type and stages of malignancy to decrease the risk of cancer recur­ rence. Latent or indolent infection (HIV, hepatitis B or C, tuberculosis) should be a routine part of the candidate workup. While historically transplant centers considered overt AIDS and active hepatitis absolute contraindications to transplantation because of the high risk of oppor­ tunistic infection, with the introduction of potent antiviral regimens, many centers are now transplanting individuals with hepatitis and HIV infection under strict protocols. PART 9 Disorders of the Kidney and Urinary Tract One of the few “immunologic” contraindications to transplantation is the presence of preformed antibodies against the donor kidney at the time of the anticipated transplant that can cause hyperacute rejection. Those harmful antibodies include natural antibodies against the ABO blood group antigens and antibodies against human leukocyte antigen (HLA) class I (A, B, C) or class II (DR, DQ, DP) antigens. These antibodies are routinely excluded by proper screening of the candidate’s ABO compatibility and direct cytotoxic cross-matching of candidate serum with lymphocytes of the donor. Removal of these antibodies directed at donor tissue through a variety of strategies (desensitization) is now routinely performed with varying levels of success. TISSUE TYPING AND CLINICAL IMMUNOGENETICS Matching of HLA major histocompatibility complex antigens (Chap. 361) is an important criterion for the selection of donors. Each mammalian species has a single chromosomal region that encodes the major histocompatibility antigens, and this region on the human chromosome 6 codes the HLA genes. HLA is highly polymorphic; therefore, it can be an immunologic target of organ rejection when mismatched between the donor and the recipient. Historically, HLA antigens have been defined by serologic techniques by adding sera of a recipient (potentially containing anti-HLA anti­ bodies) with a “library” of leukocytes with known serotypes. How­ ever, currently, molecular typing of HLA by genomic sequencing is almost universally used. Other “minor,” non-HLA antigens may also elicit an alloimmune response in addition to the ABH(O) antigens and endothelial antigens that are not expressed on lymphocytes. The number of HLA antigen mismatches in A, B, and DR loci correlates with allograft survival; the more mismatches, the higher is the risk of allograft rejection. Nevertheless, some HLA-identical renal allografts are rejected, often within the first few weeks after transplantation. These observations may represent prior sensitization to non-HLA antigens. Non-HLA minor antigens are relatively weak when initially encountered and are, therefore, suppressible by conventional immu­ nosuppressive therapy. If prior exposure to the antigen and priming of the recipient immune system have occurred, secondary exposure at the time of transplantation may lead to an immune response refrac­ tory to treatment. More recently, a genetics study of donor-recipient pairs revealed that non-HLA antigen polymorphisms in the LIMS-1 locus can contribute to the risk of acute rejection; more of these nonHLA antigens are likely to be discovered.

DONOR EVALUATION ■ ■LIVING-DONOR EVALUATION Living kidney donors experience the immediate risk of surgery and the long-term potential risk of developing kidney dysfunction pre­ maturely; thus, the basic principle of “first, do no harm” (Chap. 12) is important. Therefore, donor evaluation must take every effort to exclude any medical conditions that may cause morbidity and mor­ tality after kidney donation, such as hypertension, diabetes, and/or proteinuria. Although studies have shown that the risk of ESKD after kidney donation is not greater than that of the general population, donation is associated with a small but significant potential lifetime risk of ESKD (0.3–0.4%; absolute risk increased by 0.2–0.3% compared to that of healthy nondonors). The mechanism of premature renal failure is thought to be due to increased blood flow and hyperfiltration injury in the remaining kidney. There are a few reports of the develop­ ment of hypertension, proteinuria, and even lesions of focal segmental sclerosis in donors over long-term follow-up. In family members of type 1 diabetics, anti-insulin and anti-islet cell antibodies should be measured, and a glucose tolerance test should be performed. AfricanAmerican donors have a higher risk of ESKD after donation (in line with their higher risk of kidney failure in general), and the genetic screening for APOL1 risk alleles may be appropriate (Chap. 326). Additionally, as more robust genetic testing becomes available, predo­ nation genetic testing per protocol is being introduced to stratify the risks of kidney donors. From the surgical perspective, selective renal arteriography is essential to reveal any anatomic anomaly and to assess the size imbalance and laterality of donor kidneys. In most cases, donor nephrectomy is performed laparoscopically to minimize the surgical scar and to enhance a faster postsurgical recovery. Lastly, although financial and nonfinancial conflicts of interest between kidney donors and recipients are strictly prohibited, removing financial disincentives is increasingly accepted to reduce barriers toward living donation, and legislative efforts to protect kidney donors are ongoing (Chap. 12). ■ ■DECEASED-DONOR EVALUATION Deceased donors should be free of malignant neoplastic disease, hepa­ titis, and HIV owing to possible transmission to the recipient, although under certain circumstances, HCV- and HIV-positive organs may be used. Increased risk of graft failure exists when the donor is elderly or has acute kidney injury or when the kidney experiences a prolonged period of ischemia. In the United States, there is a national system of regulations, alloca­ tion support, and outcomes analysis for kidney transplantation called the Organ Procurement Transplant Network. Studies have shown that deceased-donor kidneys can be maintained for up to 48 h on cold pulsatile perfusion or on ice before being used for transplantation. Normothermic perfusion of donated organs has been studied, but it has not been part of clinical care as of yet. Generally, an ischemic time of <24 h is preferred; this approach permits adequate time for typing, cross-matching, transportation, and selection issues to be resolved. ■ ■PRESENSITIZATION The presence of antibodies against donor antigens, either HLA or nonHLA, can be a potential cause of allograft injury after transplantation, and, hence, it is important to perform crossmatching prior to trans­ plantation. For the purposes of crossmatching, donor T lymphocytes, which express class I but not class II HLA, are used as a surrogate target for detection of circulating anti–class I (HLA-A and -B) antibodies

in the recipient. Note that T cells are used as surrogate cells to detect class I HLA as a matter of convenience and this is unrelated to the risk of “T cell–mediated” rejection. A positive cytotoxic crossmatch of recipient serum with donor T lymphocytes indicates the presence of preformed donor-specific anti-HLA class I antibodies and is usually predictive of an acute vasculitic event termed hyperacute rejection. This finding represents the only widely accepted absolute immunologic contrain­ dication for kidney transplantation. Recently, an increasing number of tissue-typing laboratories have shifted to a more sensitive flow cyto­ metric crossmatch assay, which detects the presence of anti-HLA IgG antibodies that are not necessarily detected on a cytotoxic crossmatch assay and may not be an absolute contraindication to transplantation. The known sources of sensitization are blood transfusion, a prior transplant, pregnancy, and less commonly, vaccination or infection. Preformed anti–class II (HLA-DR and -DQ) antibodies against the donor also carry a higher risk of graft loss, particularly in recipients who have suffered early loss of a prior kidney transplant. B lympho­ cytes (again, used for convenience), which express both class I and class II HLA, are used as a surrogate target in these assays. Some nonHLA antigens restricted in expression to endothelium and monocytes have been described, but their clinical relevance is not well established. A series of minor histocompatibility antigens do not elicit antibodies, and sensitization to these antigens is detectable only by cytotoxic T cells, an assay too cumbersome for routine use. Recent studies revealed the importance of “eplet” matching in antigen recognition. Eplets are short sequences of polymorphic amino acids on the surface of HLA antigens, recognized by HLA antibodies, and can be shared among different HLA antigens. Especially in class II HLA DQ loci, eplet mismatches are shown to be important risk factors for acute rejection. Desensitization prior to transplantation by reducing the level of anti­ donor antibodies utilizing plasmapheresis and/or the administration of pooled immunoglobulin (IV immunoglobulin [IVIG]) has been useful in reducing the risk of hyperacute rejection following transplantation. In addition, kidney paired donation programs where living donor kidneys are swapped so each recipient receives a compatible transplant organ are increasingly popular to transplant presensitized candidates safely. IMMUNOLOGY OF REJECTION Both T cell–mediated and antibody-mediated effector mechanisms can play roles in kidney transplant rejection. T cell–mediated rejection is caused by recipient T lymphocytes that respond to donor HLA antigens expressed within the transplanted TCR Indirect Pathway Direct Pathway MHC II Tfh CD4 T Cell Allogeneic peptide Th1 Plasma Cell Self APC Th2 CD4 T Cell Th17 CD4 MHC I CD8 T Cell Allogeneic APC CD8 FIGURE 325-1  Recognition pathways for major histocompatibility complex (MHC) antigens. Graft rejection is initiated by CD4 helper T lymphocytes (TH) having antigen receptors that bind to specific complexes of peptides and MHC class II molecules on antigen-presenting cells (APC). In transplantation, in contrast to other immunologic responses, there are two sets of T-cell clones involved in rejection. In the direct pathway, the class II MHC of donor allogeneic APCs is recognized by CD4 TH cells that bind to the intact MHC molecule, and class I MHC allogeneic cells are recognized by CD8 T cells. The latter generally proliferate into cytotoxic cells (TC). In the indirect pathway, the incompatible MHC molecules are processed into peptides that are presented by the self-APCs of the recipient. The indirect, but not the direct, pathway is the normal physiologic process in T-cell recognition of foreign antigens. Once TH cells are activated, they proliferate and, by secretion of cytokines and direct contact, exert strong helper effects on macrophages, TC, and B cells. (Courtesy of Andrew Badoui and Nadim Al Rahy.)

organ. CD4+ lymphocytes respond to class II (HLA-DR) incompatibility by proliferating and releasing proinflammatory cytokines that augment the proliferative response of the immune system. CD8+ cytotoxic lym­ phocytes respond primarily to class I (HLA-A, -B) antigens and mature into cytotoxic effector cells that cause organ damage through direct con­ tact and lysis of donor target cells. Full T-cell activation requires not only T-cell receptor binding to the alloantigens presented by self or donor HLA molecules (known as indirect and direct presentation, respectively) but also engagement of costimulatory molecules such as CD28 on T cells and CD80 and CD86 ligands on antigen-presenting cells (Fig. 325-1). Signaling through both of these pathways induces activation of the kinase activity of calcineurin, which, in turn, activates transcription factors leading to upregulation of multiple genes, includ­ ing interleukin (IL) 2 and interferon γ. IL-2 signals through the target of rapamycin (TOR) to induce cell proliferation in an autocrine fashion.

Antibody-mediated rejection is caused by circulating antibodies against donor antigens. After transplantation, donor-derived antigens are delivered to the recipient’s draining lymph nodes and activate an alloimmune response. A subset of CD4+ T cells called follicular helper T cells (Tfh) are activated and promote differentiation of B cells into antibody-secreting plasma cells. Plasma cells produce donor-targeting antibodies against HLA and non-HLA antigens, which can deposit in allograft kidney and cause injury via complement-dependent and independent mechanisms. C4d deposition in peritubular capillaries and glomerular basement membrane is a footprint of complement acti­ vation and is one of the diagnostic criteria of antibody-mediated rejec­ tion, together with the presence of circulating donor-specific antibody. CHAPTER 325 Kidney Transplantation IMMUNOSUPPRESSIVE TREATMENT Kidney transplant recipients need to take immunosuppressive drugs for life, except identical twins or simultaneous bone marrow–kidney transplant recipients. Currently clinically available immunosuppres­ sive therapies suppress all immune responses nonspecifically, includ­ ing those to exogenous pathogens (bacteria, viruses, and fungi) and even malignant tumors, and tend to spare memory immune responses. Immunosuppressive agents are divided into induction and mainte­ nance agents. Those currently in clinical use are listed in Table 325-3. ■ ■INDUCTION THERAPY Induction therapy is given to most kidney transplant recipients in the United States at the time of transplant to reduce the risk of early acute rejection and to minimize or eliminate the use of either steroids or B Cell Activation Naïve B Cell Cytokine Production Antibody Mediated Rejection GzmB Cellular Rejection and Organ Damage CD8 Activation Cytotoxic CD8 T Cell Perforin Attack on Target Cells

TABLE 325-3  Maintenance Immunosuppressive Drugs AGENT PHARMACOLOGY MECHANISMS SIDE EFFECTS Glucocorticoids Increased bioavailability with hypoalbuminemia and liver disease; prednisone/prednisolone generally used Binds cytosolic receptors and heat shock proteins. Blocks transcription of IL-1, -2, -3, -6, TNF-α, and IFN-γ Cyclosporine (CsA) Lipid-soluble polypeptide, variable absorption, microemulsion more predictable Trimolecular complex with cyclophilin and

calcineurin → block in cytokine (e.g., IL-2) production; however, stimulates TGF-β production Tacrolimus Macrolide, well absorbed Trimolecular complex with FKBP-12 and

calcineurin → block in cytokine (e.g., IL-2) production; may stimulate TGF-β production Azathioprine Mercaptopurine prodrug Hepatic metabolites inhibit purine synthesis Marrow suppression (WBC > RBC > platelets) Mycophenolate mofetil/sodium Metabolized to mycophenolic acid Inhibits purine synthesis via inosine monophosphate dehydrogenase Sirolimus/everolimus Macrolide, poor oral bioavailability Complexes with FKBP-12 and then blocks p70 S6 kinase in the IL-2 receptor pathway for proliferation Belatacept Fusion protein, intravenous injections Binds CD80 and CD86, prevents CD28 binding and T-cell activation Abbreviations: FKBP-12, FK506 binding protein 12; IFN, interferon; IL, interleukin; RBC, red blood cells; TGF, transforming growth factor; TNF, tumor necrosis factor; WBC, white blood cells. PART 9 Disorders of the Kidney and Urinary Tract calcineurin inhibitors and their associated toxicities. Induction therapy consists of antibodies that could be depleting or nondepleting. Depleting Agents  Antithymocyte globulin (ATG) is a lympho­ cyte-depleting agent. Peripheral human lymphocytes, thymocytes, or lymphocytes from spleens or thoracic duct fistulas are injected into horses or rabbits to produce antilymphocyte serum, from which the immunoglobulin fraction is then separated. Those polyclonal antibod­ ies induce lymphocyte depletion, and the immune system may take several months, if not years, to fully recover. Monoclonal antibodies against defined lymphocyte subsets offer a more precise and standardized form of therapy. Alemtuzumab is directed against CD52, widely expressed on immune cells such as B and T cells, natural killer cells, macrophages, and some granulocytes. Nondepleting Agents  Another more selective approach is to target the 55-kDa alpha chain of the IL-2 receptor, which is expressed only on activated T cells. This approach is used as prophylaxis for (but not treat­ ment of) acute rejection in the immediate posttransplant period and is effective at decreasing the early acute rejection rate with few adverse side effects. ■ ■MAINTENANCE THERAPY The most frequently used combination is a calcineurin inhibitor (CNI), usually tacrolimus, and an antimetabolite, usually mycophenolic acid, with or without early steroid withdrawal. Belatacept is a co-stimulatory bocking antibody, used as an alternative to long-term toxic CNI therapy. The mammalian TOR (mTOR) inhibitors sirolimus and everolimus are infrequently used as first-line maintenance immunosuppression. Antimetabolites  Azathioprine is a prodrug that must first be acti­ vated to form thioguanine nucleotides. Thiopurine S-methyltransferase (TPMT) inactivates azathioprine. Patients with two nonfunctional TPMT alleles experience life-threatening myelosuppression when treated with azathioprine, and those who carry one nonfunctional TPMT allele may also have significant side effects; therefore, the U.S. Food and Drug Administration (FDA) recommends TPMT genotyping or phenotyping before starting treatment with azathioprine. Azathioprine, which inhibits synthesis of DNA and RNA and thereby inhibits T-cell proliferation, was the keystone of immunosuppressive therapy in kidney transplant recipients until the 1990s but has been replaced by more effective agents. Concomitant use of allopurinol is best avoided and, if used, very care­ fully monitored, owing to inhibition of xanthine oxidase. Mycophenolate mofetil and mycophenolate sodium, both of which are metabolized to mycophenolic acid, are now used in place of azathioprine based on superior efficacy. Mycophenolic acid has a similar mode of action as azathioprine and is associated with a mild degree of gastrointestinal toxicity but less bone marrow suppression.

Hypertension, glucose intolerance, dyslipidemia, osteoporosis Nephrotoxicity, hypertension, dyslipidemia, glucose intolerance, hirsutism/hyperplasia of gums Similar to CsA, but hirsutism/hyperplasia of gums unusual, and diabetes more likely Diarrhea/cramps; dose-related liver and marrow suppression is uncommon Hyperlipidemia, thrombocytopenia Posttransplant lymphoproliferative disease (PTLD) Steroids  Glucocorticoids are important adjuncts to immunosup­ pressive therapy and used as both induction and maintenance ther­ apy. In general, methylprednisolone 250–500 mg is given immediately before or at the time of transplantation, and the dose is tapered to 20 mg

within a week. The side effects of the glucocorticoids, particularly impairment of wound healing and predisposition to infection, make it desirable to taper the dose as rapidly as possible in the immediate postoperative period. Early discontinuation or avoidance of steroids is common to avoid long-term adverse effects on bone, skin, and glu­ cose metabolism. Most patients whose renal function is stable after 6 months or a year do not require large doses of prednisone; mainte­ nance doses of 5–10 mg per day are the rule. A major effect of steroids is preventing the release of IL-6 and IL-1 by monocytes-macrophages. Calcineurin Inhibitors  Cyclosporine is a fungal peptide with potent immunosuppressive activity. It acts on the calcineurin pathway to inhibit transcription of IL-2 and other proinflammatory cytokines, thereby inhib­ iting T-cell proliferation. It works synergistically with glucocorticoids and mycophenolate. Among its toxic effects (nephrotoxicity, hepatotoxicity, hirsutism, tremor, gingival hyperplasia, and diabetes), nephrotoxicity presents a serious management problem and is further discussed below. Tacrolimus (FK506) is a fungal macrolide that has the same mode of action as cyclosporine as well as a similar side effect profile; it does not, however, produce hirsutism or gingival hyperplasia; in contrast, it can be associated with hair loss. Posttransplant diabetes mellitus more com­ monly occurs with tacrolimus. An extended-release formulation of tacro­ limus is now available and is given once daily. Owing to its nephrotoxicity and narrow therapeutic window, the drug level of CNIs should be moni­ tored, and drug–drug interactions should be carefully examined. Antibi­ otics and antifungals (e.g., erythromycin, ketoconazole, fluconazole) and nondihydropyridine calcium channel blockers (e.g., diltiazem, verapamil) inhibit the activity of cytochrome P450 C3A enzyme and cause elevated levels of CNIs. On the other hand, antiepileptics, such as phenytoin and carbamazepine, increase metabolism, resulting in lower levels. mTOR Inhibitors  Sirolimus (previously called rapamycin) is another fungal macrolide but has a different mode of action from tacrolimus; i.e., it inhibits T-cell growth factor signaling pathways, pre­ venting the response to IL-2 and other cytokines. Sirolimus can be used in conjunction with cyclosporine or tacrolimus, or with mycophenolic acid, to avoid the use of CNIs. Everolimus is another mTOR inhibitor with similar mechanism of action as sirolimus but with better bioavailability. mTOR inhibitors are modestly tolerated and are associated with gastrointestinal disturbance, stomatitis, mucositis, and pneumonitis. Poor wound healing associ­ ated with mTOR inhibitors makes them less preferable agents during the perisurgical period. While the PI3K-mTOR is the most commonly

mutated cellular pathway in malignant cells, mTOR inhibitors have been used more frequently in transplant patients who develop cancers, in particular recurrent skin cancers. Belatacept  Belatacept is a fusion protein composed of the Fc frag­ ment of human IgG1 immunoglobulin and the extracellular domain of cytotoxic T-lymphocyte associated protein 4 (CTLA-4). It binds to its costimulatory ligands (CD80 and CD86) on antigen-presenting cells, interrupting their binding to CD28 on T cells. This inhibition leads to T-cell anergy and apoptosis. Belatacept is FDA approved for kidney transplant recipients and is given monthly as an intravenous infusion. The 7-year follow-up of the Belatacept Evaluation of Nephroprotec­ tion and Efficacy as First-Line Immunosuppression Trial (BENEFIT) showed improved patient and graft survival for the belatacept-treated group compared to patients treated with cyclosporine, despite shortterm risks of higher rates of acute rejection. CLINICAL COURSE AND MANAGEMENT OF THE RECIPIENT Adequate hemodialysis should be performed within 48 h prior to the surgery as needed to control serum potassium to prevent cardiac arrhythmias. During the transplantation surgery, the kidney allograft is usually placed in the recipient’s iliac fossa using a retroperitoneal approach. An anastomosis is made between donor renal artery and recipient external iliac artery and donor renal vein to recipient external Recipient high %PRA (sensitized) Recipient with prior transplant Recipient with autoimmune GN Donor cold ischemia time >24 h or Donor age >60 years or Donor with high KDPI High risk Low risk Antithymocyte globulin induction Steroids, mycophenolic acid Calcineurin inhibitor (a few days after) Persistent allograft dysfunction Delayed graft function/HD support Good urine output Improvement in Cr Allograft biopsy Acute rejection No rejection Adjust CNI dose. Supportive care (BP control, fluid) Outpatient follow-up FIGURE 325-2  A typical algorithm for early posttransplant care of a kidney recipient. If any of the recipient or donor “high-risk” factors exist, more aggressive management is called for. Low-risk patients can be treated with a standard immunosuppressive regimen with no or less-potent induction therapy (e.g., basiliximab). Patients at higher risk of rejection or early ischemic transplant dysfunction are often induced with an antithymocyte globulin to provide more potent early immunosuppression or to spare calcineurin use in the immediate posttransplant period. When there is early transplant dysfunction, prerenal, obstructive, and vascular causes must be ruled out by ultrasonographic examination. The panel reactive antibody (PRA) is a quantitation of how much antibody is present in a candidate against a panel of cells representing the distribution of antigens in the donor pool. BP, blood pressure; CNI, calcineurin inhibitor; Cr, creatinine; DM2, type 2 diabetes; GN, glomerulonephritis; HD, hemodialysis; HTN, hypertension; KDPI, Kidney Donor Profile Index.

iliac vein. The donor ureter is anastomosed to the recipient bladder mucosa. Native kidney nephrectomy is rarely performed except in the case of an extremely enlarged polycystic kidney or chronic pyelone­ phritis. In many cases, especially after living kidney transplantation, the allograft starts to produce urine immediately after anastomosis. The allograft often has some degree of acute tubular injury due to ischemia, which accounts for postoperative diuresis. Large amounts of sodium, potassium, and water may be lost postoperatively, which requires close monitoring and replacement. The recipient’s serum creatinine should start to fall as the allograft starts to function, and recovery usually occurs within 2 weeks, although periods as long as 6 weeks have been reported. Slow recovery or oliguria should prompt an allograft biopsy because superimposition of rejection on acute tubular injury is common and difficult to distinguish without an allograft biopsy. Induction immunosuppression therapy and maintenance steroids and antimetabolites start on the day of surgery, and it is usually safe to delay introduction of a CNI for a few days if a lymphocyte-depleting induc­ tion agent is used. Figure 325-2 illustrates a typical algorithm followed by transplant centers for early posttransplant management of recipients at high or low risk of early renal dysfunction.

■ ■MANAGEMENT OF REJECTION Early diagnosis of rejection allows prompt institution of therapy to preserve allograft function and prevent irreversible damage. Clinical CHAPTER 325 Recipient PRA <10% (unsensitized) Recipient first transplant, or >65 years old Original disease non-immune related (DM2, HTN) Kidney Transplantation Living donor Donor cold ischemia time <12 h or Donor age 15–35 years old Basiliximab induction Steroids, mycophenolic acid Calcineurin inhibitor (day 1–2) Good urine output Improvement in Cr --> Outpatient follow-up Adjust CNI dose. If kidney function remains inadequate or low. IV steroid (methylprednisolone, 0.5–1 g/d × 3 days), or antithymocyte globulin

evidence of rejection is rarely characterized by fever, swelling, and tenderness over the allograft. Rejection may present only with a rise in serum creatinine, with or without a reduction in urine volume. The focus should be on ruling out other causes of functional deterioration, such as acute tubular injury, calcineurin toxicity, BK nephropathy, and recurrent glomerular diseases.

Doppler ultrasonography is useful in ascertaining changes in the allograft vasculature and in blood flow. Thrombosis of the renal vein occurs rarely; it may be reversible if it is caused by technical factors and intervention is prompt. Diagnostic ultrasound is also helpful in identifying urinary obstruction or the presence of perirenal collections of urine (urinoma), blood (hematoma), or lymph (lymphocele). Allograft biopsy is the gold standard for diagnosis of acute T cell– mediated and antibody-mediated rejection. Acute T cell–mediated rejection is diagnosed by the presence of immune cell infiltration in the interstitial, tubular, or vascular compartments, according to the Banff classification. Treatment of T cell–mediated rejection involves a high-dose steroid, e.g., IV administration of methylprednisolone, 500–1000 mg daily for 3 days. Failure to respond is an indication for antibody therapy, usually with ATG. Evidence of antibody-mediated rejection is present when endothe­ lial injury and deposition of complement component C4d is detected in peritubular capillaries. This is usually accompanied by detection of the circulating donor-specific antibody in the recipient’s blood. Treatment of antibody-mediated rejection remains a challenge, and aggressive use of plasmapheresis, IVIG, anti-CD20 monoclonal antibody (rituximab) to target B lymphocytes, and bortezomib to target antibody-producing plasma cells is indicated. Recently, noninvasive biomarkers such as cir­ culating donor-derived cell-free DNA, urine chemokine markers (e.g., CXCL9), and characterization of the urine exosome have been used as adjunct diagnostic markers for rejection. Future studies to identify prognostic, noninvasive biomarkers that predict response to therapy, that risk stratify, and that provide personalized immunosuppression strategies will be needed. PART 9 Disorders of the Kidney and Urinary Tract ■ ■MANAGEMENT OF CHRONIC COMPLICATIONS Cardiovascular events (29%), infection (18%), and malignancy (17%) are the major causes of death in kidney transplant recipients. Typi­ cal time courses of opportunistic infections after transplantation are shown in Table 325-4. The signs and symptoms of infection may be atypical due to immu­ nosuppression, which makes diagnosis challenging. In addition to commensal infections, opportunistic infections should be considered based on the clinical presentation. Diagnostic measures such as culture (blood, urine, drain fluids), viral load in plasma, and imaging (allograft ultrasound and computed tomography [CT]) should be obtained. Overall therapy involves adequate source control, anti-microorganism therapy, and reduction of immunosuppression. Pneumocystis jirovecii is a rare but critical opportunistic infec­ tion (Chap. 227). Aggressive diagnostic procedures, includ­ ing transbronchial and open-lung biopsy, are frequently indicated. TABLE 325-4  The Most Common Opportunistic Infections in Renal Transplant Recipients Peritransplant (<1 month) Late (>6 months)   Wound infections   Aspergillus   Herpesvirus   Nocardia   Oral candidiasis   BK virus (polyoma)   Urinary tract infection   Herpes zoster Early (1–6 months)   Hepatitis B   Pneumocystis carinii   Hepatitis C   Cytomegalovirus     Legionella     Listeria     Hepatitis B     Hepatitis C  

Trimethoprim-sulfamethoxazole (TMP-SMX) is the treatment of choice; amphotericin B has been used effectively in systemic fungal infections. Prophylaxis against P. jirovecii with daily low-dose TMPSMX for 6 months is effective. Involvement of the oropharynx with Candida (Chap. 222) may be treated with local nystatin. Tissueinvasive fungal infections require treatment with systemic agents such as fluconazole or one of the newer antifungal agents. Aspergillus (Chap. 223), Nocardia (Chap. 179), and especially cytomegalovirus (CMV) (Chap. 200) infections also occur. CMV infection is a serious complication after kidney transplanta­ tion associated with increased morbidity and mortality. While the seronegative recipients of seropositive donors are at the highest risk, presentation varies from asymptomatic CMV viremia to a systemic syndrome (fever, leukopenia) and tissue-specific manifestation (hepa­ titis, gastroenteritis, and retinopathy). Plasma viral load and a rise in IgM antibodies to CMV are diagnostic. Valganciclovir has proved effective in both prophylaxis and treatment of CMV disease. Acyclovir is an effective therapy for herpes simplex virus infections. BK virus is a latent polyomavirus that lies dormant in the kidney and urothelial tract and can be activated in the setting of immunosup­ pression. Reactivation of BK, if left untreated, will lead to progressive fibrosis and loss of the graft within 1 year in most cases. However, as risk of reactivation of BK infection is associated with the overall degree of immunosuppression, in most cases, BK infection can be managed by regular testing of BK viral load and judicious reduction of mainte­ nance immunosuppression. Renal biopsy can be useful in examining for the presence of interstitial nephritis, tubular cytopathic changes of BK nephropathy, and viral antigens in the allograft. In difficult to treat cases beyond reduction in immunosuppression, a variety of therapies including leflunomide, cidofovir, and quinolone antibiotics (which are effective against polyoma helicase) and IVIG have been tried but with inconsistent results. ■ ■CHRONIC LESIONS OF THE TRANSPLANTED KIDNEY Although current 1-year transplant survival is excellent, most recipi­ ents experience a progressive decline in kidney function over time thereafter. Chronic renal transplant dysfunction can be caused by chronic active antibody-mediated rejection, recurrent glomerular disease, hypertension, CNI nephrotoxicity, secondary focal glomeru­ losclerosis, or a combination of these pathophysiologies. Chronic vascular changes with intimal proliferation and medial hypertrophy are commonly found. Control of systemic and intrarenal hypertension with calcium channel blockers is thought to have a beneficial influence on the rate of progression of chronic allograft dysfunction. Kidney allograft biopsy can distinguish subacute cellular rejection from recur­ rent disease or secondary focal sclerosis. MALIGNANCY The incidence of tumors in patients on immunosuppressive therapy is 5–6%, or ~100 times greater than that in the general population in the same age range. The most common lesions are cancer of the skin and lips. Hence, surveillance for skin cancers and protection from ultra­ violet radiation are necessary. Solid organ transplant recipients are at higher risk to develop posttransplant lymphoproliferative disease, most frequently seen early (<1 year) or late (7–10 years) after transplanta­ tion. Most cases are associated with Epstein-Barr virus infection, and the prognosis is poor. The overall malignancy risks are increased in proportion to the total immunosuppressive load administered and the time elapsed since transplantation. Treatment of cancer after transplant involves the reduction of immunosuppression, surgery, conventional cytotoxic chemotherapy, and radiotherapy. Cancer immunotherapy is associated with a high risk of allograft rejection (30–40%), and the multidisciplinary risk-benefit discussion should be made before the initiation of therapy. ■ ■OTHER COMPLICATIONS Both chronic dialysis and renal transplant patients have a higher incidence of death from myocardial infarction and stroke than the

08 - 326 Glomerular Diseases

326 Glomerular Diseases

population at large, and this is particularly true of diabetic patients. Contributing factors are the use of glucocorticoids and sirolimus, as well as hypertension. Recipients of renal transplants have a high prevalence of coronary artery and peripheral vascular diseases. The percentage of deaths from these causes has been slowly rising as the numbers of transplanted diabetic patients and the average age of recipi­ ents increase. More than 30% of kidney transplant recipient mortality is attributable to cardiovascular disease. Strict control of blood pressure and blood sugar and lipid levels is essential in this population. Hypertension may be caused by (1) native kidney disease, (2) rejec­ tion activity in the transplant, (3) renal artery stenosis if an end-to-end anastomosis was constructed with an iliac artery branch, and (4) renal CNI toxicity, which may improve with reduction in dose. Calcium channel blockers are shown to improve long-term mortality. Ameliora­ tion of hypertension to the range of 120–130/70–80 mmHg should be the goal in all patients. Hypercalcemia after transplantation may indicate failure of hyper­ plastic parathyroid glands to regress. Aseptic necrosis of the head of the femur when it occurs is probably due to preexisting hyperparathy­ roidism, with aggravation by glucocorticoid treatment. With improved management of calcium and phosphorus metabolism during chronic dialysis, the incidence of parathyroid-related complications has fallen dramatically. Persistent hyperparathyroid activity may require subtotal parathyroidectomy. Although most transplant patients have robust production of eryth­ ropoietin and normalization of hemoglobin, anemia is commonly seen in the posttransplant period. Often the anemia is attributable to bone marrow–suppressant immunosuppressive medications such as azathioprine, mycophenolic acid, and mTOR inhibitors. Gastroin­ testinal bleeding is a common side effect of high-dose and long-term steroid administration. Many transplant patients have creatinine clearances of 30–50 mL/min and can be considered to have chronic renal insufficiency for anemia management, including supplemental erythropoietin. Chronic hepatitis, particularly when due to hepatitis B virus, can be a progressive, fatal disease over a decade or so. Patients who are persis­ tently hepatitis B surface antigen–positive are at higher risk, according to some studies, but the presence of HCV is also a concern when one embarks on a course of immunosuppression in a transplant recipient. However, the introduction of the new highly effective, direct-acting HCV antiviral medications reduced this risk significantly. In conclusion, while kidney transplantation has progressed sig­ nificantly toward the goals of longer patient survival and better qual­ ity of life, the field still has significant challenges and unmet needs. Advanced immunologic and genetic studies have led and will continue to lead us to detailed understanding of alloimmunity at the molecular level. Noninvasive biomarkers for monitoring and diagnosing rejection and novel therapeutic targets will continue to evolve. Further effort is needed to achieve equity and improve personalized care of kidney transplant recipients. ■ ■FURTHER READING Allen PJ et al: Recurrent glomerulonephritis after kidney transplanta­ tion: Risk factors and allograft outcomes. Kidney Int 92:461, 2017. Chadban SJ et al: Summary of the Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guideline on the evaluation and management of candidates for kidney transplantation. Transplanta­ tion 104:708, 2020. Chapman JR et al: Cancer in the transplant recipient. Cold Spring Harb Perspect Med 3:pii:a015677, 2013. Euvrard S et al: Sirolimus and secondary skin-cancer prevention in kidney transplantation. N Engl J Med 367:329, 2012. Grams ME et al: Kidney-failure risk projection for the living kidneydonor candidate. N Engl J Med 374:411, 2016. Hariharan S et al: Long-term survival after kidney transplantation. N Eng J Med 385:729, 2021. Hirsh HH et al: BK polyomavirus in solid organ transplantation: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant 33:e13528, 2019.

Kotton CN et al: The third international consensus guidelines on

the management of cytomegalovirus in solid-organ transplantation. Transplantation 102:900, 2018. Lentine KL et al: OPTN/SRTR 2021 Annual data report: Kidney. Am J Transplant 23:21, 2023. Loupy A et al: Complement-binding anti-HLA antibodies and kidneyallograft survival. N Engl J Med 369:1215, 2013. Orandi BJ et al: Survival benefit with kidney transplants from HLAincompatible live donors. N Engl J Med 374:940, 2016. Julia B. Lewis, Eric G. Neilson

Glomerular Diseases Two human kidneys harbor nearly 1.8 million glomerular capillary tufts. Each glomerular tuft resides within Bowman’s space. The cap­ sule circumscribing this space is lined by parietal epithelial cells that transition into tubular epithelia forming the proximal nephron or migrate into the tuft to replenish podocytes. The glomerular capillary tuft derives from an afferent arteriole that forms a branching capil­ lary bed embedded in mesangial matrix (Fig. 326-1). This capillary network funnels into an efferent arteriole, which passes filtered blood into cortical peritubular capillaries or medullary vasa recta that supply and exchange with a folded tubular architecture. Hence, the glomerular capillary tuft, fed and drained by arterioles, represents an arteriolar portal system. Fenestrated endothelial cells resting on a glomerular basement membrane (GBM) line glomerular capillaries. Delicate foot processes extending from epithelial podocytes shroud the outer surface of these capillaries, and adjacent podocytes interconnect to each other by slit-pore membranes forming a selective filtration barrier. CHAPTER 326 Glomerular Diseases The glomerular capillaries filter 120–180 L/d of plasma water con­ taining various solutes for reclamation or discharge by downstream tubules. Most large proteins and all cells are excluded from filtration by a physicochemical barrier governed by pore size and negative elec­ trostatic charge. The mechanics of filtration and reclamation are quite complicated for many solutes (Chap. 320). For example, in the case of serum albumin, the glomerulus is an imperfect barrier. Although albu­ min has a negative charge, which would tend to repel the negatively charged GBM, it only has a physical radius of 3.6 nm, while pores in the GBM and slit-pore membranes have a radius of 4 nm. Consequently, variable amounts of albumin inevitably cross the filtration barrier to be reclaimed by megalin and cubilin receptors along the proximal tubule. Remarkably, humans with normal nephrons excrete on average 8–10 mg of albumin in daily voided urine, ~20–60% of total excreted protein. This amount of albumin, and other proteins, can rise to gram quantities following glomerular injury. The breadth of diseases affecting the glomerulus is expansive because the microenvironment supporting the glomerular capillaries can be injured in a variety of ways, producing many different lesions. Some order to this vast subject is brought by grouping all of these dis­ eases into a smaller number of clinical syndromes. PATHOGENESIS OF GLOMERULAR DISEASE There are many forms of glomerular disease with pathogenesis variably linked to the presence of genetic mutations, infection, toxin exposure, autoimmunity, atherosclerosis, hypertension, emboli, thrombosis, or diabetes mellitus. Even after careful study, however, the cause often remains unknown, and the lesion is called idiopathic. Specific or unique features of pathogenesis are mentioned with the description of each of the glomerular diseases later in this chapter. Some glomerular diseases result from genetic mutations producing familial disease or a founder effect: congenital nephrotic syndrome from mutations in NPHS1 (nephrin) and NPHS2 (podocin) affects the slit-pore membrane at birth, and TRPC6 cation channel muta­ tions produce focal segmental glomerulosclerosis (FSGS) in adulthood;

A B C PART 9 Disorders of the Kidney and Urinary Tract D FIGURE 326-1  Glomerular architecture. A. The glomerular capillaries form from a branching network of renal arteries, arterioles leading to an afferent arteriole, glomerular capillary bed (tuft), and a draining efferent arteriole. (From VH Gattone II et al: Hypertension 5:8, 1983.) B. Scanning electron micrograph of podocytes that line the outer surface of the glomerular capillaries (arrow shows foot process). C. Scanning electron micrograph of the fenestrated endothelia lining the glomerular capillary. D. The various normal regions of the glomerulus on light microscopy. (A–C: Courtesy of Dr. Vincent Gattone, Indiana University; with permission.) polymorphisms in the gene encoding apolipoprotein L1, APOL1, are a major risk for nearly 70% of African Americans with nondiabetic end-stage kidney disease (ESKD), particularly FSGS; monogenetic causes of FSGS are increasingly linked to early age of onset and to genes encoding type IV collagen in older adults, suggesting that much of FSGS may be hereditary; mutations in control of the complement pathway increasingly associate with various forms of membranoprolif­ erative glomerulonephritis (MPGN) and C3 glomerulopathies including dense deposit disease, or atypical hemolytic-uremic syndrome (aHUS); type II partial lipodystrophy from mutations in genes encoding lamin A/C or PPARγ causes a metabolic syndrome associated with MPGN; IgG3 subclass antibodies to antigens expressed on podocytes encoded by PLAR2gc indicate a poor prognosis in membranous nephropathy; Alport’s syndrome, from mutations in the genes encoding for the α3, α4, or α5 chains of type IV collagen, produces split basement membranes with glomerulosclerosis; and lysosomal storage diseases, such as α-galactosidase A deficiency causing Fabry’s disease and N-acetylneuraminic acid hydrolase deficiency causing nephrosialido­ sis, produce FSGS. Systemic hypertension and atherosclerosis can produce pressure stress, ischemia, or lipid oxidants that lead to chronic glomerulosclerosis. Malignant hypertension can quickly complicate glomerulosclerosis with fibrinoid necrosis of arterioles and glomeruli, thrombotic microangi­ opathy, and acute kidney failure. Diabetic nephropathy is an acquired sclerotic injury associated with thickening of the GBM secondary to the long-standing effects of hyperglycemia, advanced glycosylation end products, and reactive oxygen species. Inflammation of the glomerular capillaries is called glomerulone­ phritis. Most glomerular or mesangial antigens involved in immunemediated glomerulonephritis are unknown (Fig. 326-2). Glomerular epithelial or mesangial cells may shed or express epitopes that mimic other immunogenic proteins made elsewhere in the body. Bacteria, fungi, and viruses can directly infect the kidney, producing their own antigens. Autoimmune diseases such as idiopathic membranous glomerulonephritis (MGN) or MPGN are confined to the kidney, whereas systemic inflammatory diseases such as lupus nephritis or

granulomatosis with polyangiitis spread to the kidney, causing second­ ary glomerular injury. Antiglomerular basement membrane disease producing Goodpasture’s syndrome primarily injures both the lung and kidney because of the narrow distribution of the α3 NC1 domain of type IV collagen that is the target antigen. Local activation of Toll-like receptors on glomerular cells, deposi­ tion of immune complexes, or complement injury to glomerular struc­ tures induces mononuclear cell infiltration, which subsequently leads to an adaptive immune response attracted to the kidney by local release of chemokines. Neutrophils, macrophages, and T cells are drawn by chemokines into the glomerular tuft, where they react with antigens and epitopes on or near somatic cells or their structures, producing more cytokines and proteases that damage the mesangium, capillaries, and/or the GBM. While the adaptive immune response is similar to that of other tissues, early T-cell activation plays an important role in the mechanism of glomerulonephritis. Antigens presented by class II major histocompatibility complex (MHC) molecules on macrophages and dendritic cells in conjunction with associative recognition mol­ ecules engage the CD4/8 T-cell repertoire. Mononuclear cells by themselves can injure the kidney, but auto­ immune events that damage glomeruli classically produce a humoral immune response. Poststreptococcal glomerulonephritis, lupus nephritis, and idiopathic membranous nephritis typically are associated with immune deposits along the GBM, while anti-GBM antibodies pro­ duce the linear binding of anti-GBM disease. Preformed circulating immune complexes can precipitate along the subendothelial side of the GBM, while other immune deposits form in situ on the subepithelial side. These latter deposits accumulate when circulating autoantibodies find their antigen trapped along the subepithelial edge of the GBM. Immune deposits in the glomerular mesangium may result from the deposition of preformed circulating complexes or in situ antigenantibody interactions. Immune deposits stimulate the release of local proteases and activate the complement cascade, producing C5–9 attack complexes. In addition, local oxidants damage glomerular structures, producing proteinuria and effacement of the podocytes. Overlap­ ping etiologies or pathophysiologic mechanisms can produce similar

Basement membrane Subepithelial deposit Endothelia Podocytes Subendothelial deposit Linear IgG staining IgG Lumpy-bumpy staining C B A TH1/2 Immune deposits Cytokines Chemokines Basement membrane damage Extracapillary proliferation Endocapillary proliferation Oxidants Proteases C3/C5-9MAC D FIGURE 326-2  The glomerulus is injured by a variety of mechanisms. A. Preformed immune deposits can precipitate from the circulation and collect along the glomerular basement membrane (GBM) in the subendothelial space or can form in situ along the subepithelial space. B. Immunofluorescent staining of glomeruli with labeled antiIgG demonstrating linear staining from a patient with anti-GBM disease or immune deposits from a patient with membranous glomerulonephritis. C. The mechanisms of glomerular injury have a complicated pathogenesis. Immune deposits and complement deposition classically draw macrophages and neutrophils into the glomerulus.

T lymphocytes may follow to participate in the injury pattern as well. D. Amplification mediators as locally derived oxidants and proteases expand this inflammation, and depending on the location of the target antigen and the genetic polymorphisms of the host, basement membranes are damaged with either endocapillary or extracapillary proliferation. glomerular lesions, suggesting that downstream molecular and cellular responses often converge toward common patterns of injury. PROGRESSION OF GLOMERULAR DISEASE Persistent glomerulonephritis that worsens kidney function is always accompanied by interstitial nephritis, renal fibrosis, and tubular atrophy. What is not so obvious, however, is that kidney failure in glomerulonephritis best correlates histologically with the appearance of tubulointerstitial nephritis rather than with the type of inciting glomerular injury. Loss of kidney function due to interstitial damage is explained hypothetically by several mechanisms. The simplest explanation is that urine flow is impeded by tubular obstruction as a result of interstitial inflammation and fibrosis. Thus, obstruction of the tubules with debris or by extrinsic compression functionally results in aglomerular neph­ rons. A second mechanism suggests that interstitial changes, including interstitial edema or fibrosis, alter tubular and vascular architecture

Mθ N Cytokines Chemokines CHAPTER 326 Glomerular Diseases and thereby compromise the normal tubular transport of solutes and water from tubular lumen to vascular space. This failure increases the solute and water content of the tubule fluid, resulting in isosthenu­ ria and polyuria. Adaptive mechanisms related to tubuloglomerular feedback also fail, resulting in a reduction of renin output from the juxtaglomerular apparatus trapped by interstitial inflammation. Con­ sequently, the local vasoconstrictive influence of angiotensin II on the glomerular arterioles decreases, and filtration drops owing to a generalized decrease in arteriolar tone. A third mechanism involves changes in vascular resistance due to damage of peritubular capillar­ ies. The cross-sectional volume of these capillaries is decreased by interstitial inflammation, edema, or fibrosis. These structural altera­ tions in vascular resistance affect kidney function through two mecha­ nisms. First, tubular cells are very metabolically active, and as a result, decreased perfusion leads to tubular ischemic injury. Second, impair­ ment of glomerular arteriolar outflow leads to increased intravascular hypertension in less-involved glomeruli; this selective intraglomerular

hypertension aggravates and extends mesangial sclerosis and glomerulo­ sclerosis to less-involved glomeruli. Regardless of the exact mechanism, early acute tubulointerstitial nephritis (see Fig. A4-31) suggests poten­ tially recoverable kidney function, whereas the development of chronic interstitial fibrosis prognosticates permanent loss (see Fig. A4-25).

Persistent damage to glomerular capillaries spreads to the tubu­ lointerstitium in association with proteinuria. There is a hypothesis that efferent arterioles leading from inflamed glomeruli carry for­ ward inflammatory mediators, which induces downstream interstitial nephritis, resulting in fibrosis. Glomerular filtrate from injured glo­ merular capillaries adherent to Bowman’s capsule may also be misdi­ rected to the periglomerular interstitium. Most nephrologists believe, however, that proteinuric glomerular filtrate forming tubular fluid is the primary route to downstream tubulointerstitial injury, although none of these hypotheses are mutually exclusive. The simplest explanation for the effect of proteinuria on the devel­ opment of interstitial nephritis is that increasingly severe proteinuria, carrying activated cytokines and lipoproteins producing reactive oxygen species, triggers a downstream inflammatory cascade in and around epithelial cells lining the tubular nephron. These effects induce T lymphocyte and macrophage infiltrates in the interstitial spaces along with fibrosis and tubular atrophy. Tubules disaggregate following direct damage to their basement membranes, leading to more interstitial fibroblasts and fibrosis at the site of injury; recent comprehensive evidence suggests that renal fibro­ blasts increase through several mechanisms: epithelial or endothelialmesenchymal transitions (15%), bone marrow–derived fibrocytes (35%), and the proliferation of resident fibroblasts (50%). Most renal myofibroblasts are formed from bone marrow fibrocytes or prolifer­ ating fibroblasts. Transforming growth factor β (TGF-β), fibroblast growth factor 2 (FGF-2), hypoxemia-inducible factor 1α (HIF-1α), and platelet-derived growth factor (PDGF) are particularly active in this transition. With persistent nephritis, fibroblasts multiply and lay down tenascin and a fibronectin scaffold for the polymerization of new interstitial collagen types I/III. These events form scar tissue through a process called fibrogenesis. In experimental studies, bone morphogenetic protein 7 and hepatocyte growth factor can reverse early fibrogenesis and preserve tubular architecture. When fibroblasts outdistance their survival factors, apoptosis occurs, and the permanent renal scar becomes acellular, leading to irreversible kidney failure. PART 9 Disorders of the Kidney and Urinary Tract APPROACH TO THE PATIENT Glomerular Disease HEMATURIA, PROTEINURIA, AND PYURIA Patients with glomerular disease usually have some hematuria with varying degrees of proteinuria. Hematuria is typically asymptomatic. As few as 3–5 red blood cells in the spun sediment from first-voided morning urine is suspicious. The diagnosis of glomerular injury can be delayed because patients will not realize they have microscopic hematuria, and only rarely with the exception of IgA nephropathy and sickle cell disease is gross hematuria present. When work­ ing up microscopic hematuria, perhaps accompanied by minimal proteinuria (<500 mg/24 h), it is important to exclude anatomic lesions, such as malignancy of the urinary tract, particularly in older men. Microscopic hematuria may also appear with the onset of benign prostatic hypertrophy, interstitial nephritis, papillary necro­ sis, hypercalciuria, kidney stones, cystic kidney diseases, or renal vascular injury. However, when red blood cell casts (see Fig. A4-38) TABLE 326-1  Urine Assays for Albuminuria/Proteinuria   24-h ALBUMINa (mg/24 h) ALBUMINa/CREATININE RATIO (mg/g) DIPSTICK PROTEINURIA 24-h URINE PROTEINb (mg/24 h) Normal 8–10 <30 – <150 Microalbuminuria 30–300 30–300 –/Trace/1+ –/>150 Proteinuria

300 300 Trace–3+ 150 aAlbumin detected by radioimmunoassay. bAlbumin represents 20–60% of the total protein excreted in the urine.

or dysmorphic red blood cells are found in the sediment, glomerulo­ nephritis is likely. A mean of 8–10 mg/24 h of albumin appears in the urine in the absence of kidney disease. In early nephropathy, such as in diabetic nephropathy, proteinuria increases to 30–300 mg/24 h and is called microalbuminuria and represents the presence of kid­ ney disease. Screening spot urine albumin/creatinine ratio (UACR) of >30 mg/g suggests a need for further investigation. Greater than 300 mg/24 h of albuminuria represents frank proteinuria and more advanced kidney disease (Table 326-1). Sustained proteinuria >1–2 g/24 h is also commonly associated with glomerular disease. Patients often will not know they have proteinuria unless they become edematous or notice foaming urine on voiding. Sustained proteinuria has to be distinguished from lesser amounts of so-called benign proteinuria in the normal popu­ lation. (Table 326-1). This latter class of proteinuria is nonsustained, generally <1 g/24 h, and is sometimes called functional or transient proteinuria. Fever, exercise, obesity, sleep apnea, emotional stress, and congestive heart failure can explain transient proteinuria. Proteinuria only seen with upright posture is called orthostatic pro­ teinuria and has a benign prognosis. Isolated proteinuria sustained over multiple clinic visits is found in many glomerular lesions. Proteinuria in most adults with glomerular disease is nonselective, containing albumin and a mixture of other serum proteins, whereas in children with minimal change disease (MCD), the proteinuria is selective and composed largely of albumin. Some patients with inflammatory glomerular disease, such as acute poststreptococcal glomerulonephritis or MPGN, have pyuria characterized by the presence of considerable numbers of leuko­ cytes. This latter finding has to be distinguished from urine infected with bacteria. CLINICAL SYNDROMES Various forms of glomerular injury can also be parsed into sev­ eral distinct syndromes on clinical grounds (Table 326-2). These syndromes, however, are not always mutually exclusive. There is an acute nephritic syndrome producing 1–2 g/24 h of proteinuria, hematuria with red blood cell casts, pyuria, hypertension, fluid retention, and a rise in serum creatinine associated with a reduc­ tion in glomerular filtration. If glomerular inflammation devel­ ops slowly, the serum creatinine will rise gradually over many weeks, but if the serum creatinine rises quickly, particularly over a few days, acute nephritis is sometimes called rapidly progres­ sive glomerulonephritis (RPGN); the histopathologic term crescen­ tic glomerulonephritis is the pathologic equivalent of the clinical presentation of RPGN. When patients with RPGN present with lung hemorrhage from Goodpasture’s syndrome, antineutrophil cytoplasmic antibody (ANCA)–associated small-vessel vasculitis, lupus erythematosus, or cryoglobulinemia, they are often diag­ nosed as having a pulmonary-renal syndrome. Nephrotic syndrome describes the onset of heavy proteinuria (>3.0 g/24 h), hyperten­ sion, hypercholesterolemia, hypoalbuminemia, edema/anasarca, and microscopic hematuria; if only large amounts of proteinuria are present without clinical manifestations, the condition is sometimes called nephrotic-range proteinuria. The glomerular filtration rate (GFR) in these patients may initially be normal or, rarely, higher than normal, but with persistent hyperfiltration and continued nephron loss, it typically declines over months to years. Patients with a basement membrane syndrome either have genetically abnor­ mal basement membranes (Alport’s syndrome) or an autoimmune

TABLE 326-2  Patterns of Clinical Glomerulonephritis GLOMERULAR SYNDROMES PROTEINURIA HEMATURIA VASCULAR INJURY Acute Nephritic Syndromes Poststreptococcal glomerulonephritisa +/++ ++/+++ – Subacute bacterial endocarditisa +/++ ++ – Lupus nephritisa +/++ ++/+++ + Antiglomerular basement membrane diseasea ++ ++/+++ – IgA nephropathya +/++ +++c – ANCA small-vessel vasculitisa   Granulomatosis with polyangiitis (Wegener’s) +/++ ++/+++ ++++   Microscopic polyangiitis +/++ ++/+++ ++++   Churg-Strauss syndrome +/++ ++/+++ ++++ Henoch-Schönlein purpuraa +/++ ++/+++c ++++ Cryoglobulinemiaa +/++ ++/+++ ++++ Membranoproliferative glomerulonephritisa ++ ++/+++ – C3 glomerulopathies ++ ++/+++ – Mesangioproliferative glomerulonephritis + +/++ – Pulmonary-Renal Syndromes Goodpasture’s syndromea ++ ++/+++ – ANCA small-vessel vasculitisa   Granulomatosis with polyangiitis (Wegener’s) +/++ ++/+++ ++++   Microscopic polyangiitis +/++ ++/+++ ++++   Churg-Strauss syndrome +/++ ++/+++ ++++ Henoch-Schönlein purpuraa +/++ ++/+++c ++++ Cryoglobulinemiaa +/++ ++/+++ ++++ Nephrotic Syndromes Minimal change disease ++++ – – Focal segmental glomerulosclerosis +++/++++ + – Membranous glomerulonephritis ++++ + – Diabetic nephropathy ++/++++ –/+ – AL and AA amyloidosis +++/++++ + +/++ Light chain deposition disease +++ + – Fibrillary-immunotactoid disease +++/++++ + + Fabry’s disease + + – Basement Membrane Syndromes Anti-GBM diseasea ++ ++/+++ – Alport’s syndrome ++ ++ – Thin basement membrane disease + ++ – Nail-patella syndrome ++/+++ ++ – Glomerular Vascular Syndromes Atherosclerotic nephropathy + + +++ Hypertensive nephropathyb +/++ +/++ ++ Cholesterol emboli +/++ ++ +++ Sickle cell disease +/++ +++c +++ Thrombotic microangiopathies ++ ++ +++ Antiphospholipid syndrome ++ ++ +++ ANCA small-vessel vasculitisa   Granulomatosis with polyangiitis (Wegener’s) +/++ ++/+++ ++++   Microscopic polyangiitis +/++ ++/+++ ++++   Churg-Strauss syndrome +++ ++/+++ ++++ Henoch-Schönlein purpuraa +/++ ++/+++c ++++ Cryoglobulinemiaa +/++ ++/+++ ++++ AL and AA amyloidosis +++/++++ + +/++ Infectious Disease–Associated Syndromes Poststreptococcal glomerulonephritisa +/++ ++/+++ – Subacute bacterial endocarditisa +/++ ++ – HIV +++ +/++ –

CHAPTER 326 Glomerular Diseases (Continued)

TABLE 326-2  Patterns of Clinical Glomerulonephritis (Continued) GLOMERULAR SYNDROMES PROTEINURIA HEMATURIA VASCULAR INJURY Hepatitis B and C +++ +/++ – Syphilis +++ + – Leprosy +++ + – Malaria +++ +/++ – Schistosomiasis +++ +/++ – aCan present as rapidly progressive glomerulonephritis (RPGN); sometimes called crescentic glomerulonephritis. bCan present as a malignant hypertensive crisis producing an aggressive fibrinoid necrosis in arterioles and small arteries with microangiopathic hemolytic anemia. cCan present with gross hematuria. Abbreviations: AA, amyloid A; AL, amyloid L; ANCA, antineutrophil cytoplasmic antibodies; GBM, glomerular basement membrane. response to basement membrane collagen IV (Goodpasture’s syn­ drome) associated with microscopic hematuria, mild to heavy proteinuria, and hypertension with variable elevations in serum creatinine. Glomerular-vascular syndrome describes patients with vascular injury producing hematuria and moderate proteinuria. Affected individuals can have vasculitis, thrombotic microangi­ opathy, antiphospholipid syndrome, or, more commonly, a systemic disease such as atherosclerosis, cholesterol emboli, hypertension, sickle cell anemia, and autoimmunity. Infectious disease–associated syndrome is most important if one has a global perspective. Save for subacute bacterial endocarditis (SBE) in the Western Hemisphere, malaria and schistosomiasis may be the most common causes of glomerulonephritis throughout the world, closely followed by HIV and chronic hepatitis B and C. These infectious diseases produce a variety of inflammatory reactions in glomerular capillaries, ranging from nephrotic syndrome to acute nephritic injury, and urinalyses that demonstrate a combination of hematuria and proteinuria. PART 9 Disorders of the Kidney and Urinary Tract These six general categories of syndromes are usually determined at the bedside with the help of a history and physical examination, blood chemistries, kidney ultrasound, and urinalysis. These initial studies help frame further diagnostic workup that typically involves testing of the serum for the presence of various proteins (HIV and hepatitis B and C antigens) or antibodies (anti-GBM, antiphospho­ lipid, antistreptolysin O [ASO], PLA2R, THSD7A, anti-DNAse, antihyaluronidase, ANCA, anti-DNA, cryoglobulins, anti-HIV, and anti-hepatitis B and C antibodies) or depletion of complement com­ ponents (C3 and C4). The bedside history and physical examination can also help determine whether the glomerulonephritis is isolated to the kidney (primary glomerulonephritis) or is part of a systemic disease (secondary glomerulonephritis). When confronted with an abnormal urinalysis and elevated serum creatinine, with or without edema or congestive heart fail­ ure, one must consider whether the glomerulonephritis is acute or chronic. This assessment is best made by careful history (last known urinalysis or serum creatinine during pregnancy or insurance physical, evidence of infection, or use of medication or recreational drugs), the size of the kidneys on ultrasound examination, and how the patient feels at presentation. Chronic glomerular disease often presents with decreased kidney size. Patients who quickly develop kidney failure are fatigued and weak and often have uremic symptoms associated with nausea, vomiting, fluid retention, and somnolence. Primary glomerulonephritis presenting with kidney failure that has progressed slowly, however, can be remarkably asymptomatic, as are patients with acute glomerulonephritis with­ out much loss in kidney function. Once this initial information is collected, selected patients who are clinically stable, have adequate blood clotting parameters, and are willing and able to receive treat­ ment are encouraged to have a kidney biopsy. ■ ■KIDNEY PATHOLOGY A kidney biopsy in the setting of glomerulonephritis quickly identifies the type of glomerular injury and often suggests a course of treatment. The biopsy is processed for light microscopy using stains for hematoxy­ lin and eosin (H&E) to assess cellularity and architecture, periodic acid– Schiff (PAS) to stain carbohydrate moieties in the membranes of the

glomerular tuft and tubules, Jones-methenamine silver to enhance base­ ment membrane structure, Congo red for amyloid deposits, and Mas­ son’s trichrome to identify collagen deposition and assess the degree of glomerulosclerosis and interstitial fibrosis. Biopsies are also processed for direct immunofluorescence using conjugated antibodies against IgG, IgM, and IgA to detect the presence of “lumpy-bumpy” immune deposits or “linear” IgG or IgA antibodies bound to GBM, antibodies against trapped complement proteins (C3 and C4), or specific antibod­ ies against a relevant antigen (PLA2R, THSD7A, and DNAJB9). Highresolution electron microscopy can clarify the principal location of immune deposits and the status of the basement membrane. Each region of a kidney biopsy is assessed separately. By light microscopy, glomeruli (ideally 20) are reviewed individually for dis­ crete lesions; <50% involvement is considered focal, and >50% is diffuse. Injury in each glomerular tuft can be segmental, involving a portion of the tuft, or global, involving most of the glomerulus. Glomeruli having proliferative characteristics show increased cellularity. When cells in the capillary tuft proliferate, it is called endocapillary, and when cellular proliferation extends into Bowman’s space, it is called extracapillary. Synechiae are formed when epithelial podocytes attach to Bowman’s capsule in the setting of glomerular injury; crescents, which in some cases may be the extension of synechiae, develop when fibrocellular/ fibrin collections fill all or part of Bowman’s space; and sclerotic glom­ eruli show acellular, amorphous accumulations of proteinaceous mate­ rial throughout the tuft with loss of functional capillaries and normal mesangium. Since age-related glomerulosclerosis is common in adults, one can estimate the background percentage of sclerosis by dividing the patient’s age in half and subtracting 10. Immunofluorescent and electron microscopy can detect the presence and location of subepithe­ lial, subendothelial, or mesangial immune deposits, or reduplication or splitting of the basement membrane. In the other regions of the biopsy, the vasculature surrounding glomeruli and tubules can show angiopa­ thy, vasculitis, the presence of fibrils, or thrombi. The tubules can be assessed for adjacency to one another; separation can be the result of edema, tubular dropout, or collagen deposition resulting from intersti­ tial fibrosis. Interstitial fibrosis is an ominous sign of irreversibility and progression to kidney failure. ACUTE NEPHRITIC SYNDROMES Acute nephritic syndromes classically present with hypertension, hema­ turia, red blood cell casts, pyuria, and mild to moderate proteinuria. Extensive inflammatory damage to glomeruli causes a fall in GFR and eventually produces uremic symptoms with salt and water retention, leading to edema and hypertension. ■ ■POSTSTREPTOCOCCAL GLOMERULONEPHRITIS Poststreptococcal glomerulonephritis is prototypical for acute endo­ capillary proliferative glomerulonephritis. The incidence of poststrep­ tococcal glomerulonephritis has dramatically decreased in developed countries, and in these locations is typically sporadic. Acute nephritis in developing countries is epidemic and usually affects children between the ages of 2 and 14 years. In developed countries, it is more typical in the elderly, especially in association with debilitating conditions. It is more common in males, and the familial or cohabitant incidence is as high as 40%. Skin and more commonly throat infections with particu­ lar M types of streptococci (nephritogenic strains) antedate glomerular

disease. Antibiotic therapy does not reduce the occurrence of nephritis. Poststreptococcal glomerulonephritis due to pharyngitis develops 1–3 weeks after infection and 2–6 weeks after skin infection. The kidney biopsy in poststreptococcal glomerulonephritis demon­ strates hypercellularity of mesangial and endothelial cells; glomerular infiltrates of polymorphonuclear leukocytes; granular subendothelial immune deposits of IgG, IgM, C3, C4, and C5–9; and subepithelial deposits, which appear as “humps” (see Fig. A4-6). (See Glomerular Schematic 1.) Poststreptococcal glomerulonephritis is an immunemediated disease involving putative streptococcal antigens, circulating immune complexes, and activation of the alternate complement path­ way in association with cell-mediated injury. Leading candidate anti­ gens from nephritogenic streptococci are a cationic cysteine proteinase known as streptococcal pyrogenic exotoxin B (SPEB) and NAPlr, the nephritis-associated plasmin receptor. The nephritogenic antigen SPEB has been demonstrated inside the subepithelial deposits. The classic presentation is an acute nephritic picture with hema­ turia, pyuria, red blood cell casts, edema, hypertension, and oliguric acute kidney injury (AKI), which may be severe enough to appear as RPGN. Systemic symptoms of headache, malaise, anorexia, and flank pain (due to swelling of the renal capsule) are reported in as many as 50% of cases. Five percent of children and 20% of adults have proteinuria in the nephrotic range. In the first week of symptoms, 90% of patients will have a depressed CH50 and decreased levels of C3 with normal levels of C4. Positive rheumatoid factor (30–40%), cryoglobulins, circulating immune complexes (60–70%), and ANCA against myeloperoxidase (10%) are also reported. Positive cultures for streptococcal infection are inconsistently present (~25%) but the strep­ tozyme test is positive in 80–95% of patients and includes antibodies to ASO, anti-DNAse, Altase, ASKase, and anti-NAD. Consequently, the diagnosis of poststreptococcal glomerulonephritis rarely requires a kidney biopsy. A subclinical disease is reported in some series to be 4–5 times as common as clinical nephritis, and these latter cases are characterized by asymptomatic microscopic hematuria with low serum C3 complement levels. Treatment is supportive, with control of hypertension, edema, and dialysis as needed. Antibiotic treatment for active streptococcal infec­ tion should be given to patients and their cohabitants. There is no role for immunosuppressive therapy, even in the setting of crescents. Recur­ rent poststreptococcal glomerulonephritis is rare despite repeated streptococcal infections. Early death is rare in children but does occur in the elderly. Complete resolution of the azotemia, hematuria, and proteinuria in the majority of children occurs within 3–6 weeks of the onset of nephritis, but 3–10% of children may have persistent microscopic hematuria, non-nephrotic proteinuria, or hypertension. Overall, the prognosis is good, with ESKD being very uncommon in Glomerular schematic 1 Hump Poly Subendothelial deposits Mesangial deposits POSTSTREPTOCOCCAL GLOMERULONEPHRITIS

children and adults. The prognosis in elderly patients is worse, with a high incidence of azotemia (up to 60%), nephrotic-range proteinuria, and ESKD.

■ ■SUBACUTE BACTERIAL ENDOCARDITIS Endocarditis-associated glomerulonephritis is typically a complication of SBE, particularly in patients who remain untreated for a long time, have negative blood cultures, or have right-sided endocarditis. Com­ mon comorbidities are valvular heart disease, intravenous drug use, hepatitis C, and diabetes mellitus. Glomerulonephritis is unusual in acute bacterial endocarditis because it takes 10–14 days to develop immune complex–mediated injury, by which time the patient has been treated, often with emergent surgery. Grossly, the kidneys in SBE have subcapsular hemorrhages with a “flea-bitten” appearance, and kidney biopsy reveals focal or diffuse proliferation with C3 (94%), IgG, and IgA staining, as well as mesangial, subendothelial, and subepithelial immune deposits. Commonly patients present with a clinical picture of RPGN and have crescents on biopsy. Embolic infarcts or septic abscesses may also be present. The pathogenesis hinges on the deposi­ tion of circulating immune complexes in the kidney with complement activation. Patients present with gross or microscopic hematuria, pyuria, and mild proteinuria, acute kidney injury, or RPGN with rapid loss of kidney function. A normocytic anemia, elevated erythrocyte sedimentation rate, hypocomplementemia, high titers of rheumatoid factor, type III cryoglobulins, circulating immune complexes, and ANCAs may be present. Levels of serum creatinine may be elevated at diagnosis, but with modern therapy, there is little progression to chronic kidney disease. Primary treatment is eradication of the infec­ tion with 4–6 weeks of antibiotics, and if accomplished expeditiously, the prognosis for kidney recovery is good. ANCA-associated vasculitis sometimes accompanies or is confused with SBE and should be ruled out, as the treatment is different. CHAPTER 326 Glomerular Diseases As variants of persistent bacterial infection in blood-associated glomerulonephritis, infection-associated glomerulonephritis can occur in patients with ventriculoatrial and ventriculoperitoneal shunts; pul­ monary, intraabdominal, pelvic, or cutaneous infections; and infected vascular prostheses. In developed countries, a significant proportion of cases afflict adults, especially the immunocompromised, and the pre­ dominant organism is Staphylococcus. The clinical presentation of these conditions is variable and includes proteinuria, microscopic hematuria, acute kidney injury, and hypertension. Serum complement levels are low, and there may be elevated levels of C-reactive proteins, rheuma­ toid factor, antinuclear antibodies, and cryoglobulins. Biopsy findings include membranoproliferative glomerulonephritis (MPGN), diffuse proliferative and exudative glomerulonephritis (DPGN), or mesangio­ proliferative glomerulonephritis, sometimes leading to RPGN. Treat­ ment focuses on eradicating the infection, with most patients treated as if they have endocarditis. The prognosis is guarded. ■ ■LUPUS NEPHRITIS Lupus nephritis is a common and serious complication of systemic lupus erythematosus (SLE). Clinical manifestations of kidney disease are present in 30% of patients at the time of diagnosis, and the major­ ity will develop kidney abnormalities in the course of their disease. Lupus nephritis results from the deposition of circulating immune complexes composed of primarily DNA and anti-DNA, which activate the complement cascade, leading to complement-mediated damage, leukocyte infiltration, activation of procoagulant factors, and release of various cytokines. In situ immune complex formation also plays a role in kidney injury. These immune deposits may occur in the mesangial, subendothelial, and/or subepithelial spaces. The clinical manifestations, course of disease, and treatment of lupus nephritis are closely linked to kidney pathology. The most common clinical sign of kidney disease is proteinuria, but hematu­ ria, hypertension, varying degrees of kidney injury, and active urine sediment with red blood cell casts can all be present. Anti-dsDNA antibodies that fix complement correlate best with the presence of kidney disease. Hypocomplementemia is common in patients with acute lupus nephritis (70–90%), and declining complement levels may

TABLE 326-3  Classification for Lupus Nephritis Class I Minimal mesangial Normal histology with mesangial deposits Class II Mesangial proliferation Mesangial hypercellularity with expansion of the mesangial matrix Class III Focal nephritis Focal endocapillary ± extracapillary hypercellularity with focal subendothelial immune deposits and mild mesangial

expansion ± fibrinoid necrosis Class IV Diffuse nephritis Diffuse endocapillary ± extracapillary hypercellularity with diffuse subendothelial immune deposits and mesangial alterations ± crescents ± fibrinoid necrosis Class V Membranous nephritis Thickened basement membranes with diffuse subepithelial immune deposits; may occur with class III or IV lesions and is sometimes called mixed membranous and proliferative nephritis Class VI Sclerotic nephritis Global sclerosis of nearly all glomerular capillaries Note: Revised in 2004 by the International Society of Nephrology-Renal Pathology Society Study Group. Recommendation for revision 2018. herald a flare. A kidney biopsy should be performed in most patients with kidney involvement to establish the histologic subtype, which guides therapy. PART 9 Disorders of the Kidney and Urinary Tract The World Health Organization (WHO) workshop in 1974 first outlined several distinct patterns of lupus-related glomerular injury, and this classification was modified in 2004. This version with ongoing refinement (Table 326-3) forms the basis for treatment recommen­ dations. Class I nephritis describes normal glomerular histology by normal light microscopy with minimal mesangial deposits on immu­ nofluorescent or electron microscopy. Class II designates mesangial immune complexes with mesangial proliferation. Both class I and II lesions are typically associated with minimal kidney manifestation and normal kidney function; nephrotic syndrome is rare. Patients with lesions limited to the renal mesangium have an excellent prognosis and need little or no therapy for their lupus nephritis. The subject of lupus nephritis is presented under acute nephritic syndromes because of the aggressive and important proliferative lesions seen in class III–V kidney diseases (see Figs. A4-14 and A4-15). Class III describes focal lesions involving <50% of the glomeruli with proliferation or scarring, often involving only a segment of the glomerulus. Class III

lesions have the most varied course. Hematuria and proteinuria are present, and some patients also have an active urinary sediment, nephrotic syndrome, hypertension, and a decreased GFR. Patients with mild proliferation involving a small percentage of glomeruli respond well to therapy with steroids alone, and <5% progress to kidney failure over 5 years. Patients with more severe proliferation involving a greater percentage of glomeruli or include fibrinoid necrosis have a far worse prognosis and lower remission rates. Treatment of those patients is the same as that for class IV lesions. Class IV describes diffuse lesions with

50% of the glomeruli involved and proliferative endocapillary lesions with or without extracapillary lesions that may be segmental (IV-S), involving <50% of the glomerular tuft, or global (IV-G), involving >50%. Patients with class IV lesions commonly have high anti-DNA antibody titers, low serum complement, hematuria, red blood cell casts, protein­ uria, hypertension, and decreased kidney function; 50% of patients have nephrotic-range proteinuria. Patients with crescents on biopsy often have a rapidly progressive decline in kidney function. Without treatment, this aggressive lesion has the worst kidney prognosis, with class IV-S worse than class IV-G. However, if a remission—defined as a return to near-normal kidney function and proteinuria ≤330 mg/dL per day—is achieved with treatment, kidney outcomes are excellent. Inducing a remission with administration of high-dose steroids and either cyclophosphamide or mycophenolate mofetil for 2–6 months, followed by maintenance therapy with lower doses of steroids and mycophenolate mofetil or azathioprine, best balances the likelihood of successful remission with the side effects of therapy. Voclosporin may also be used in combination with steroids and mycophenolate mofetil

in patients with focal or diffuse lupus nephritis. Belimumab can also be added to standard maintenance therapy. There is no consensus on use of high-dose intravenous methylprednisolone versus oral prednisone, monthly intravenous cyclophosphamide versus daily oral cyclophos­ phamide, or other immunosuppressants such as cyclosporine, tacroli­ mus, or rituximab. Prolonged use of cyclophosphamide is avoided in patients of childbearing age. The class V lesion describes subepithelial immune deposits produc­ ing a membranous pattern; a subcategory of class V lesions is associated with proliferative lesions and is sometimes called mixed membranous and proliferative disease (see Fig. A4-14); this category of injury is treated like class IV glomerulonephritis. Sixty percent of patients pres­ ent with nephrotic syndrome or lesser amounts of proteinuria. Patients with lupus nephritis class V, like patients with primary membranous nephropathy, are predisposed to renal vein thrombosis and other thrombotic complications. A minority of patients with class V will present with hypertension and kidney dysfunction. There are conflict­ ing data on the clinical course, prognosis, and appropriate therapy for patients with class V disease, which may reflect the heterogeneity of this group of patients. Patients with severe nephrotic syndrome, elevated serum creatinine, and a progressive course will probably benefit from therapy with steroids in combination with other immu­ nosuppressive agents. Therapy with inhibitors of the renin-angiotensin system also may attenuate the proteinuria. Antiphospholipid antibod­ ies present in lupus may result in glomerular microthromboses and a thrombotic microangiopathy. The kidney prognosis is worse despite anticoagulant therapy. Patients with any of the above lesions also can transform to another lesion; hence, patients often require reevaluation, including repeat kidney biopsy. Lupus patients with class VI lesions have >90% sclerotic glomeruli and ESKD with interstitial fibrosis. Up to 20% of patients with lupus nephritis will reach end-stage disease, requiring dialysis or transplantation. Patients with lupus nephritis have a markedly increased mortality compared with the general population. Kidney transplantation usually performed after ~6 months of inactive disease results in allograft survival rates comparable to patients transplanted for other reasons. ■ ■ANTIGLOMERULAR BASEMENT

MEMBRANE DISEASE Patients who develop autoantibodies directed against glomerular basement antigens frequently develop a glomerulonephritis termed anti-glomerular basement membrane (anti-GBM) disease. When they present with lung hemorrhage and glomerulonephritis, they have a pulmonary-renal syndrome called Goodpasture’s syndrome. The target epitopes for this autoimmune disease lie in the quaternary structure of α3 NC1 domain of collagen IV. Indeed, anti-GBM disease may be considered an autoimmune “conformeropathy” that involves the perturbation of quaternary structure of the α 345NC1 hexamer. MHCrestricted T cells initiate the autoantibody response because humans are not tolerant to the epitopes created by this quaternary structure. The epitopes are normally sequestered in the collagen IV hexamer and can be exposed by infection, smoking, oxidants, or solvents. Good­ pasture’s syndrome is rare and appears in two age groups: in young men in their late twenties and in men and women in their sixties and seventies. Younger patients are more likely to present with the full Goodpasture’s syndrome, with hemoptysis, a sudden fall in hemoglo­ bin, fever, dyspnea, and hematuria, and older patients are more likely to present with isolated glomerulonephritis. Those who present with lung hemorrhage as a group do better than older populations who have prolonged, asymptomatic kidney injury; presentation with oliguria is often associated with a particularly bad outcome. The performance of an urgent kidney biopsy is important in suspected cases of Goodpas­ ture’s syndrome to confirm the diagnosis and assess prognosis. Kidney biopsies typically show focal or segmental necrosis that later, with aggressive destruction of the capillaries by cellular proliferation, leads to crescent formation in Bowman’s space (see Fig. A4-17). As these lesions progress, there is concomitant interstitial nephritis with fibrosis and tubular atrophy.

The presence of anti-GBM antibodies and complement is recognized on biopsy by linear immunofluorescent staining for IgG (rarely IgA). In testing serum for anti-GBM antibodies, it is particularly important that the α3 NC1 domain of collagen IV alone be used as the target. This is because non-nephritic antibodies against the α1 NC1 domain are seen in paraneoplastic syndromes and cannot be discerned from assays that use whole basement membrane fragments as the binding target. Between 10 and 15% of sera from patients with Goodpasture’s syndrome also contain ANCA antibodies against myeloperoxidase. Prognosis at presentation is worse if there are >50% crescents on kid­ ney biopsy with advanced fibrosis, if serum creatinine is >5–6 mg/dL, if oliguria is present, or if there is a need for acute dialysis. Patients who present with hemoptysis should be treated for their lung hem­ orrhage, as it responds to plasmapheresis. Treated patients with less severe disease typically respond to 8–10 treatments of plasmapheresis accompanied by oral prednisone and cyclophosphamide. Maintenance therapy with low-dose immunosuppressants should be considered until antibody titers are negative. There are scarce data alternatively using rituximab or mycophenolate mofetil. Kidney transplantation should wait for 6 months and until serum antibodies are undetectable. ■ ■IgA NEPHROPATHY Berger first described the glomerulonephritis now termed IgA nephrop­ athy. It is classically characterized by episodic hematuria associated with the deposition of IgA in the mesangium. IgA nephropathy is one of the most common forms of glomerulonephritis worldwide. There is a male preponderance, a peak incidence in the second and third decades of life, and rare familial clustering. There are geographic differences in the prevalence of IgA nephropathy, with 30-45% prevalence along the Asian and Pacific Rim and 20% in southern Europe, compared to 10% in northern Europe and North America. This may reflect variation in detection or a true variation among racial and ethnic groups. IgA nephropathy is predominantly a sporadic disease, but suscepti­ bility to it has been shown uncommonly to have a genetic component depending on geography and the existence of “founder effects.” No single causal gene has been identified. Clinical and laboratory evidence sug­ gests close similarities between IgA vasculitis (formerly called HenochSchonlein purpura) and IgA nephropathy. IgA vasculitis is distinguished clinically from IgA nephropathy by prominent systemic symptoms, a younger age (<20 years old), preceding infection, and abdominal com­ plaints. Deposits of IgA are also found in the glomerular mesangium in a variety of systemic diseases, including chronic liver disease, Crohn’s disease, celiac disease, chronic bronchiectasis, idiopathic interstitial pneumonia, dermatitis herpetiformis, mycosis fungoides, ankylosing spondylitis, HIV infection, and Sjögren’s syndrome. IgA deposition in these entities is not usually associated with clinically significant kidney disease. IgA-dominant Staphylococcus-associated infectious glomerulo­ nephritis is associated with clinically significant kidney disease. The pathognomonic finding on kidney biopsy is dominant or codominant mesangial IgA deposits, either alone or with IgG, IgM, or complement. (See Glomerular Schematic 2.) IgA deposits are typically J-chain containing polymeric IgA1. Abnormalities in the O-glycosylation of the hinge region of primarily polymeric IgA1 seem to best account for the pathogenesis. Synthesis of poorly galactosyl­ ated IgA1 results in exposure of N-acetyl-galactosamine in truncated IgA1 hinge regions, which is recognized by IgG or IgA1 antibodies leading to formation of immune complexes in the circulation or in situ after glomerular deposition of galactose-deficient IgA1 activating the complement system through the alternative and lectin pathways. Viral or other antigen exposure, or hereditary defects in alternative comple­ ment pathway proteins may affect the manifestation of disease. Despite the presence of elevated serum IgA levels in 20–50% of patients and IgA deposition in skin biopsies in 15–55% of patients, a kidney biopsy is necessary to confirm the diagnosis. Although the immunofluores­ cent pattern of IgA on kidney biopsy defines IgA nephropathy in the proper clinical context, a variety of histologic lesions may be seen on light microscopy (see Fig. A4-8), including DPGN; segmental sclerosis; and, rarely, segmental necrosis with cellular crescent formation, which typically presents as RPGN.

Glomerular schematic 2 Mesangial deposits plus more mesangial cells IgA NEPHROPATHY CHAPTER 326 The two most common presentations of IgA nephropathy are per­ sistent asymptomatic microscopic hematuria and recurrent episodes of macroscopic hematuria during or immediately following an upper respiratory infection, often accompanied by proteinuria. Nephrotic syndrome is uncommon. Proteinuria can also first appear late in the course of the disease. Rarely, patients present with acute kidney failure and a rapidly progressive clinical picture. IgA nephropathy can be a benign disease with some patients going into complete remis­ sion while others may have ongoing hematuria but well-preserved kidney function. Slow progression to ESKD is seen in only 25–30% of patients over 20–25 years. This risk varies considerably among populations. Cumulatively, risk factors for the loss of kidney func­ tion identified thus far account for <50% of the variation in observed outcome but include the presence of hypertension or proteinuria, the absence of episodes of macroscopic hematuria, male sex, and older age of onset. Mesangial hypercellularity (M), endocapillary hyper­ cellularity (E), segmental glomerulosclerosis (S), tubular interstitial fibrosis (T), and crescents (C) have predictive value as established by the Oxford Classification and the MEST-C score. Several analyses in large populations of patients found persistent proteinuria for 6 months or longer to have the greatest predictive power for adverse kidney outcomes. Glomerular Diseases There is no agreement on optimal treatment. Both large studies that include patients with multiple glomerular diseases and small studies of patients with IgA nephropathy support the use of angiotensin-converting enzyme (ACE) inhibitors in patients with proteinuria or declining kidney function. Steroid treatment or other immunosuppressives have demonstrated conflicting results. An oral targeted-release formulation of budesonide has been shown to reduce proteinuria and improve preserved kidney function in patients with risk of rapid progression. In preliminary studies the sodium-glucose transport-2 inhibitor (SGLT2i) dapagliflozin and the endothelin antagonist sparsentan have reduced adverse kidney outcomes. Tonsillectomy and fish oil have also been suggested in small studies to benefit select patients. When present­ ing as RPGN, patients typically receive steroids, cytotoxic agents, and plasmapheresis. ■ ■ANCA SMALL-VESSEL VASCULITIS A group of patients with small-vessel vasculitis (arterioles, capillaries, and venules; rarely small arteries) and glomerulonephritis have circu­ lating antineutrophil cytoplasmic autoantibodies (ANCAs); the most common antigen targets are proteinase 3 (PR3) and myeloperoxidase

(MPO) (Chap. 375). ANCA are produced with the help of T cells and activate leukocytes and monocytes, which together damage the walls of small vessels. Endothelial injury also attracts more leukocytes and extends the inflammation. Granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA), and renal-limited vasculitis belong to this group because they are associated with ANCAs and have a pauci-immune glomerulonephritis given the absence or paucity of immune complex deposition. Patients with any of these diseases can have any combi­ nation of the above serum antibodies, but anti-PR3 antibodies are more common in GPA, and anti-MPO antibodies are more common in MPA or EGPA. Although each of these diseases has some unique clinical features, most features do not predict relapse or progression, and as a group, they are generally treated in the same way. Targeted determination of ANCA levels may be useful in monitoring response to therapy or if a relapse is clinically suspected. Since mortality is high without treatment, virtually all patients receive urgent treat­ ment. Induction therapy usually includes glucocorticoids and either cyclophosphamide or rituximab. Plasmapheresis remains controversial but is generally recommended in rapidly progressive kidney failure or pulmonary hemorrhage, or with concomitantly positive anti-GBM antibodies. Remission is induced in 75–90% of patients, but clinical relapse is common (25–50%). There is evidence to support a reduced dose corticosteroid regimen with discontinuation at 16 weeks recom­ mended. Additionally, novel complement antagonists may have a role as steroid sparing agents. Maintenance therapy is recommended for up to 1–2 years following remission and includes cyclophosphamide or rituximab, or in certain circumstances azathioprine or methotrexate.

PART 9 Disorders of the Kidney and Urinary Tract Granulomatosis with Polyangiitis  Patients with this disease classically present with fever, purulent rhinorrhea, nasal ulcers, sinus pain, polyarthralgias/arthritis, cough, hemoptysis, shortness of breath, hematuria, and subnephrotic proteinuria; occasionally, there may be cutaneous purpura and mononeuritis multiplex. Patients may present without kidney involvement, although most of these patients develop kidney injury later. Chest x-ray often reveals nodules and persistent infiltrates, sometimes with cavities. Biopsy of involved tissue will show a small-vessel vasculitis and adjacent noncaseating granulomas. Kidney biopsies during active disease demonstrate segmental necrotizing glo­ merulonephritis without immune deposits and have been classified as focal, mixed, crescentic, or sclerotic (see Fig. A4-16). The disease is more common in patients exposed to silica dust and those with α1-antitrypsin deficiency, which is an inhibitor of PR3. Relapse after achieving remission is common and is more common in patients with GPA than the other ANCA-associated vasculitis, necessitating diligent follow-up care. Although associated with an unacceptable high mortality rate without treatment, the greatest threat to patients is from adverse events often secondary to treatment rather than active vasculitis; this is particularly true in elderly patients in the first year of therapy. Patients should also be monitored long term for malignancy after immunosuppressive therapy. Microscopic Polyangiitis  Clinically, these patients present simi­ larly to GPA, except they rarely have significant lung disease or destructive sinusitis. The distinction is made on biopsy, where the vasculitis in MPA is without granulomas. Some patients will also have injury limited to the capillaries and venules. Eosinophilic Granulomatosis with Polyangiitis  When small-vessel vasculitis is associated with peripheral eosinophilia, cutaneous purpura, mononeuritis, asthma, and allergic rhinitis, a diagnosis of EGPA is considered. Hypergammaglobulinemia, ele­ vated levels of serum IgE, or the presence of rheumatoid factor some­ times accompanies the allergic state. Lung inflammation, including fleeting cough and pulmonary infiltrates, often precedes the systemic manifestations of disease by years; lung manifestations are rarely absent. A third of patients may have exudative pleural effusions asso­ ciated with eosinophils. Small-vessel vasculitis and focal segmental necrotizing glomerulonephritis without immune deposits can be seen on kidney biopsy, usually absent of eosinophils or granulomas. The

cause of is thought to be abnormal immune function, but the inciting factors are unknown. ■ ■C3 GLOMERULOPATHIES C3 glomerulopathy is a recent disease classification that is defined by the glomerular accumulation of C3 with little or no immunoglobulin and encompasses dense deposit disease (DDD), formerly MPGN type II (see below), and C3 glomerulonephritis (C3GN). DDD is defined morphologically by dense deposits forming ribbons in the GBM. In the absence of this specific morphology, the entity is catego­ rized as C3GN. Both are associated with the presence of a complement mutation believed to cause the kidney pathology, including mutations in the complement factor H regulatory (CFHR) protein genes. DDD is primarily a disease of children and young adults, whereas the other C3 glomerulopathies are reported to present in an older age group (mean age 30). By definition, kidneys with C3 glomerulopathy show sole or dominant staining for C3 but can have variable light microscopy, with mesangial proliferative or membranoproliferative patterns seen most commonly. Morphologically, many cases are not distinguishable from recovering postinfectious glomerulonephritis. Low serum C3 and a dense thickening of the GBM containing ribbons of dense despits and C3 characterize DDD (see Fig. A4-10). Patients with DDD present with proteinuria, which may be nephrotic range, and/or hematuria, which may be macroscopic or microscopic. Partial lipodystrophy and Drusen bodies in the retina may also be present. Prognosis is poor, with 50% of patients progressing to ESKD. C3GN patients are clinically less well defined, but approximately two-thirds have hematuria and one-third have proteinuria. C3 levels are low with normal C4, and C3 nephritic factor is present in most patients with DDD and less com­ monly in C3GN. Abnormalities in factor H, soluble C5b-9, paraprotein detection, and specific CFHR genetic mutations should be assessed as well. Screening family members may be indicated. The optimal thera­ pies remain undefined but include inhibition of the renin-angiotensin system, lipid lowering, steroids, and other immunosuppressants. Evi­ dence suggests a benefit of therapy with eculizumab, a monoclonal antibody directed at C5, which is activated by C3. ■ ■MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS MPGN has been previously identified as a disease with the classifica­ tion MPGN types I, II, and III; however, it is now considered a pattern of glomerular injury characterized by mesangial and subendothelial immune complexes, complement deposits and/or monoclonal protein deposits, or chronic endothelial cell injury. In addition to increased mesangial and endocapillary hypercellularity, there are thickened GBM’s with interposition of cellular elements between the endothelial cell and the GBM creating double contours, sometimes call “tramtracking” (see Fig. A4-9). (See Glomerular Schematic 3.) The MPGN pattern of injury can be seen with immune complex mediated diseases Glomerular schematic 3 Subendothelial deposits Widened mesangial Mesangial interposition Macrophage and mesangial cells MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS

including cryoglobulinemia, infection associated GN, and hepatitis C and B; complement mediated diseases including inherited or acquired dysregulation of complement (see C3G Glomerulopathies); and mono­ clonal immunoglobulin mediated diseases including light and heavy chain deposition diseases. The MPGN pattern of injury can be seen with unusual deposits as well including fibrillary glomerulonephritis. Each of these diseases have distinct findings on biopsy, natural history and treatments. ■ ■MESANGIOPROLIFERATIVE GLOMERULONEPHRITIS Mesangioproliferative glomerulonephritis is characterized by expan­ sion of the mesangium, sometimes associated with mesangial hyper­ cellularity; thin, single contoured capillary walls; and mesangial immune deposits. Mesangioproliferative pathology may be seen in IgA nephropathy, Plasmodium falciparum malaria, resolving postinfectious glomerulonephritis, and class II nephritis from lupus, all of which can have a similar histologic appearance. With these secondary entities excluded, the diagnosis of primary mesangioproliferative glomerulone­ phritis is made in <15% of kidney biopsies. NEPHROTIC SYNDROME Nephrotic syndrome classically presents with heavy proteinuria, mini­ mal hematuria, hypoalbuminemia, hypercholesterolemia, edema, and hypertension. If left undiagnosed or untreated, some of these syn­ dromes will progressively damage enough glomeruli to cause a fall in GFR, producing kidney failure. Multiple studies have noted that the higher the 24-h urine protein excretion, the more rapid is the decline in GFR. Therapies for various causes of nephrotic syndrome are noted under individual disease headings below. In general, all patients with hypercholesterolemia secondary to nephrotic syndrome should be treated with lipid-lowering agents because they are at increased risk for cardiovascular disease. Edema secondary to salt and water reten­ tion can be controlled with the use of diuretics, avoiding intravascular volume depletion. Venous complications secondary to the hyperco­ agulable state associated with nephrotic syndrome can be treated with anticoagulants. The losses of various serum binding proteins, such as thyroid-binding globulin, lead to alterations in functional tests. Lastly, proteinuria itself is hypothesized to be nephrotoxic, and treatment of proteinuria with inhibitors of the renin-angiotensin system and SGLT2i can lower urinary protein excretion and preserve kidney func­ tion across a wide range of chonic kidney diseases. ■ ■MINIMAL CHANGE DISEASE MCD, sometimes known as nil lesion, causes 70–90% of nephrotic syn­ drome in childhood but only 10–15% of nephrotic syndrome in adults. MCD usually presents as a primary kidney disease but can be associ­ ated with several conditions, including Hodgkin’s disease, allergies, use of nonsteroidal anti-inflammatory agents or lithium, infections, and other glomerular diseases. MCD on kidney biopsy shows no glomeru­ lar lesion by light microscopy and is negative for deposits by immuno­ fluorescent microscopy or occasionally shows small amounts of IgM in the mesangium (see Fig. A4-1). (See Glomerular Schematic 4.) Elec­ tron microscopy, however, consistently demonstrates an effacement of the foot processes supporting the epithelial podocytes with weakening of slit-pore membranes. The pathogenesis of this lesion is unclear, although immune dysfunction is likely the initiating factor for MCD. Disturbances in T cell response may result in circulating glomerular permeability factors which directly affect the glomerular capillary wall, postulated to be T cell derived cytokines, such as IL13 and IL4. There is also evidence of increased CD80 on podocytes, promoting dysregu­ lated interactions with T cells via T lymphocyte antigen-4 (CLTA-4). Other evidence supporting cell-mediated immunity includes the presence of preceding allergies, altered cell-mediated immunity dur­ ing viral infections, and a high frequency of remissions with steroids. Evidence to suggest that there is a role for B cell dysfunction includes reports of patients with anti-nephrin antibodies and the successful treatment with the anti-CD20 monoclonal antibody, rituximab.

Glomerular schematic 4 MINIMAL CHANGE DISEASE MCD presents clinically with the abrupt onset of edema and nephrotic syndrome accompanied by acellular urinary sediment. Average urine protein excretion reported in 24 h is 10 g with severe hypoalbuminemia. Less common clinical features include hyperten­ sion (30% in children, 20–50% in adults), microscopic hematuria (20% in children, 33% in adults), atopy or allergic symptoms (40% in chil­ dren, 30% in adults), and decreased kidney function (25–40%), which often returns to normal after remission of the nephrotic syndrome. The appearance of acute kidney failure in adults is often seen more commonly in patients with low serum albumin and intrarenal edema (nephrosarca) that is responsive to diuretics. This presentation must be distinguished from acute kidney failure secondary to hypovolemia. Acute tubular necrosis and interstitial inflammation are also reported. In children, the abnormal urine principally contains albumin with minimal amounts of higher-molecular-weight proteins and is some­ times called selective proteinuria. Although up to 30% of children have a spontaneous remission, most children today are treated with steroids; only children who are nonresponders are biopsied. Primary responders are patients who have a complete remission (<0.2 mg/24 h of proteinuria), often abruptly after a single course of prednisone; steroid-dependent patients relapse as their steroid dose is tapered. Frequent relapsers have two or more relapses in the 6 months following taper, and steroidresistant patients fail to respond to steroid therapy. Adults are not considered steroid-resistant until after 4 months of therapy. Ninety to 95% of children will develop a complete remission after 8 weeks of steroid therapy, and 80–90% of adults will achieve complete remission, but the response is more delayed. Patients with steroid resistance may have FSGS on repeat biopsy. If the first kidney biopsy does not have a sample of deeper corticomedullary glomeruli, then the correct diagno­ sis of FSGS may be missed. CHAPTER 326 Glomerular Diseases Relapses occur in 70–75% of children after the first remission, and early relapse predicts multiple subsequent relapses, as do high levels of basal proteinuria. The frequency of relapses decreases after puberty. Relapses are less common in adults but are more resistant to subsequent therapy. Prednisone is first-line therapy. Other immuno­ suppressive drugs, such as cyclophosphamide, mycophenolate mofetil, calcineurin inhibitors (CNIs), and rituximab are reserved for frequent relapsers, steroid-dependent patients, or steroid-resistant patients. CNIs can induce remission, but relapse is also common when with­ drawn. The long-term prognosis in adults is less favorable when acute kidney failure or steroid resistance occurs. ■ ■FOCAL SEGMENTAL GLOMERULOSCLEROSIS FSGS refers to a pattern of kidney injury characterized by segmental glomerular scars that involve some but not all glomeruli (focal); the clinical findings of FSGS largely manifest as proteinuria. When the secondary and genetic causes of FSGS are eliminated (Table 326-4), the remaining patients are considered to have primary FSGS. FSGS

TABLE 326-4  Focal Segmental Glomerulosclerosis Primary focal segmental glomerulosclerosis Yet to be identified circulating permeable factor Secondary focal segmental glomerulosclerosis Adaptive response to hyperfiltration/reduced kidney mass, obesity Viruses: HIV/hepatitis B/parvovirus/SARS-CoV-2 Hypertensive nephropathy Reflux nephropathy Cholesterol emboli Drugs: Heroin/analgesics/bisphosphonates/ecstasy/interferon/anabolic steroids Oligomeganephronia Sickle cell disease Radiation nephritis Familial podocytopathies   NPHS1 mutation/nephrin   NPHS2 mutation/podocin   PLCE1 mutation/phospholipase Cε1   INF2 mutation/inverted formin 2   WT1 mutation/Wilms tumor   TRPC6 mutation/cation channel   ACTN4 mutation/actinin   α-Galactosidase A deficiency/Fabry’s disease   N-Acetylneuraminic acid hydrolase deficiency/nephrosialidosis Uncertain cause PART 9 Disorders of the Kidney and Urinary Tract is now recognized as the most common cause of primary glomerular disease in patients with ESKD in the US. The pathogenesis of FSGS has multiple possible mechanisms including a circulating permeability fac­ tor (primary FSGS), an adaptive response to glomerular hypertrophy or hyperfiltration, and podocyte abnormalities associated with direct Glomerular schematic 5 Detachment of cell from GBM Collapsed capillary and scar Proliferation of subepithelial cells

toxic injury or genetic mutations. Risk polymorphisms at the APOL1 locus expressed in podocytes are thought to predispose patients to FSGS. The pathologic changes of FSGS are most prominent in glomeruli located at the corticomedullary junction (see Fig. A4-2), so if the kidney biopsy specimen is from superficial tissue, the lesions can be missed, which sometimes leads to a misdiagnosis of MCD. The most frequent variant is FSGS not otherwise specified (NOS), previously called classic FSGS, which may occur in primary or secondary FSGS. In addition to focal and segmental scarring, other variants have been described, including cellular lesions with endocapillary hypercellularity and heavy proteinuria; collapsing glomerulopathy (see Fig. A4-3) with segmental or global glomerular collapse and a rapid decline in kidney function; a perihilar lesion (see Fig. A4-4); or the glomerular tip lesion (see Fig. A4-5), which is usually steroid responsive and has a favorable prognosis. (See Glomerular Schematic 5.) FSGS can present with hematuria, hypertension, any level of pro­ teinuria, and kidney injury. Nephrotic-range proteinuria and kidney injury are associated with a poor outcome, with 50% of patients reaching ESKD in 10 years. FSGS rarely remits spontaneously, but treatment-induced remission of proteinuria significantly improves prognosis. Treatment of patients with FSGS should include inhibitors of the renin-angiotensin system and SGLT2i. Patients with primary FSGS with nephrotic-range proteinuria can be treated with steroids but respond far less often and after a longer course of therapy than patients with MCD. Proteinuria remits in only 20–45% of patients receiving a course of steroids over 6–12 months. CNIs have been used in patients requiring a steroid sparing regimen. Limited evidence suggests the use of cyclosporine in steroid-responsive patients helps ensure remissions. Relapse frequently occurs after cessation of cyclosporine therapy, and CNIs themselves can lead to a deterioration of kidney function due to their nephrotoxic effects. A role for other agents that suppress the immune system such as rituximab or mycophenolate mofetil has not FOCAL SCLEROSING GLOMERULONEPHRITIS Efferent arteriole Afferent arteriole

TABLE 326-5  Membranous Glomerulonephritis Primary/antigen-associated membranous glomerulonephritis PLA2R, NELL1, THSD7A, Sema3B, PCDH7, HTRA1, EXT1, EXT2, NCAM1 Secondary membranous glomerulonephritis Infection: Hepatitis B and C, syphilis, malaria, schistosomiasis, leprosy, filariasis Cancer: Breast, colon, lung, stomach, kidney, esophagus, neuroblastoma Drugs: Gold, mercury, penicillamine, nonsteroidal anti-inflammatory agents, probenecid, antitumor necrosis factor agents Autoimmune diseases: Systemic lupus erythematosus, rheumatoid arthritis, primary biliary cirrhosis, dermatitis herpetiformis, bullous pemphigoid, myasthenia gravis, Sjögren’s syndrome, Hashimoto’s thyroiditis, IgG4 disease Other systemic diseases: Fanconi’s syndrome, sickle cell anemia, diabetes, Crohn’s disease, sarcoidosis, Guillain-Barré syndrome, Weber-Christian disease, angiofollicular lymph node hyperplasia Abbreviations: PLA2R, phospholipase A2 receptor; EXT1 and EXT2, exostosin 1 and 2; NCAM1, neural cell adhesion molecule 1; NELL1, neural epidermal growth factorlike 1; PCDH7, protocadherin 7; Sema3B, semaphorin 3B; THSD7A, thrombospondin type-1 domain containing 7A. been established. FSGS recurs in 30% of kidney transplants, more com­ monly in primary FSGS, less commonly in secondary FSGS, and rarely in genetic FSGS. In recurrent posttransplant FSGS from presumed circulating factor, many patients will achieve a full or partial remis­ sion with plasmapheresis. The treatment of secondary FSGS typically involves treating the underlying cause and controlling proteinuria. There is no role for steroids or other immunosuppressive agents in secondary or genetic FSGS. ■ ■MEMBRANOUS GLOMERULONEPHRITIS MGN, or membranous nephropathy as it is sometimes called, accounts for ~25% of cases of nephrotic syndrome in adults, with a peak inci­ dence between the ages of 30 and 50 years and a male-to-female ratio of 2:1. MGN is most often primary in the absence of an identifiable associated disease, but with the identification of novel associated anti­ gens (see Table 326-5), this nomenclature may change particularly in children in whom these antigens are increasingly found. In 20–30% of cases, MGN is secondary and is associated with a malignancy (solid tumors of the breast, lung, colon), infection (hepatitis B, syphilis, malaria, schistosomiasis), rheumatologic disorders such as lupus or rheumatoid arthritis, IgG4 diseases, or drug exposure (see Table 326-5). Uniform thickening of the basement membrane along the periph­ eral capillary loops is seen by light microscopy on kidney biopsy (see Fig. A4-7); this thickening needs to be distinguished from that seen in diabetes and amyloidosis. (See Glomerular Schematic 6.) There may be characteristic “spikes” seen on silver stain due to the glomeru­ lar basement membrane reactivity to deposits. Immunofluorescence demonstrates diffuse granular deposits of IgG and C3, and electron Glomerular schematic 6 Foot process fusion Subepithelial deposits MEMBRANOUS GLOMERULONEPHRITIS

microscopy typically reveals electron-dense subepithelial deposits. While different stages (I–V) of progressive membranous lesions have been described, some published analyses indicate the degree of tubular atrophy or interstitial fibrosis is more predictive of progression than is the stage of glomerular disease. The presence of subendothelial deposits or the presence of tubuloreticular inclusions strongly points to a diagnosis of membranous lupus nephritis, which may precede the extrarenal manifestations of lupus. In 70–80% of cases of primary MGN, IgG4 autoantibodies against the M-type phospholipase A2 receptor circulate and bind to a conformational epitope present in the PLA2R on human podocytes, producing characteristic in situ deposits. The diagnosis of MGN may no longer require a kidney biopsy in the setting of anti-PLA2R antibody positivity, normal creatinine, and no identifiable other causes of MGN. THSD7A is another antigen local­ ized on the podocyte surface that complexes with IgG4, while NELL1 is the most common non-PLA2R antigen accounting for up to 16% of primary MGN cases. These novel antigens (see Table 326-5) along with PLA2R account for over 90% of cases of primary MGN. In most cases of secondary membranous nephropathy, autoantibodies to these anti­ gens are absent, with rare reports of autoantibodies to PLA2R associ­ ated with hepatitis B, cancer, and sarcoidosis. Circulating deposits and glomerular deposits of these autoantibodies have correlated with the likelihood of a spontaneous remission, severity of primary MGN, and the response to therapy.

CHAPTER 326 Eighty percent of patients with MGN present with nephrotic syn­ drome and nonselective proteinuria. Microscopic hematuria is seen but less commonly than in IgA nephropathy or FSGS. Spontaneous remis­ sions occur in 20–33% of patients and often occur late in the course, making treatment decisions difficult. One-third of patients continue to have relapsing nephrotic syndrome but maintain normal kidney function, and approximately another third of patients develop kidney failure or die from the complications of nephrotic syndrome. Male gender, older age, hypertension, and the persistence of nephrotic-range proteinuria are associated with worse prognosis. Although thrombotic complications are a feature of all nephrotic syndromes, MGN has the highest reported incidences of renal vein thrombosis, pulmonary embolism, and deep-vein thrombosis. Prophylactic anticoagulation is controversial but has been recommended in select patients with hypoalbuminemia. Glomerular Diseases The treatment of edema, dyslipidemia, hypertension, and inhibi­ tion of the renin-angiotensin system and the use of SGLT2i is recom­ mended. Therapy with immunosuppressive drugs is recommended for patients with primary MGN and persistent proteinuria. The choice of immunosuppressive drugs for therapy is controversial, however, patient risk stratification based on proteinuria, GFR, and serum albu­ min can help guide therapy choices with steroids and cyclophospha­ mide, CNIs or rituximab. Attaining remission is associated with a good long-term prognosis. ■ ■DIABETIC NEPHROPATHY Diabetic nephropathy is the single most common cause of chronic kidney disease in the United States and worldwide. The dramatic increase in the number of patients with diabetic nephropathy reflects the epidemic increase in obesity and type 2 diabetes mellitus. Approximately 40% of patients with diabetes develop nephropathy; the vast majority of patients with diabetic nephropathy will have type 2 diabetes due to the higher prevalence compared to type 1 diabetes. Within 1–2 years after the onset of clinical diabetes, morphologic changes appear in the kidney. Thickening of the GBM is a sensitive indicator for the presence of diabetes but correlates poorly with the presence of nephropathy. The composition of the GBM is altered notably with a loss of heparan sulfate moieties that form the negatively charged filtration barrier resulting in increased filtration of serum proteins into the urine. The expansion of the mesangium due to the accumulation of extracellular matrix correlates with the clinical manifestations of diabetic nephropathy (see stages in Fig. A4-24). This expansion in mesangial matrix is associated with the development of mesangial sclerosis. Some patients also develop eosinophilic, PAS+ nod­ ules called nodular glomerulosclerosis or Kimmelstiel-Wilson nodules.

Immunofluorescence microscopy often reveals the nonspecific depo­ sition of IgG (at times in a linear pattern) or complement staining without immune deposits on electron microscopy. Prominent vascular changes are frequently seen with hyaline and hypertensive arterioscle­ rosis. This is associated with varying degrees of chronic glomerulo­ sclerosis and tubulointerstitial changes. Kidney biopsies from patients with types 1 and 2 diabetic nephropathies with albuminuria are largely indistinguishable. Patients with type 2 diabetes without albuminuria are classified as having diabetic kidney disease as opposed to diabetic nephropathy and may have myriad pathologic findings.

Multiple lines of evidence support an important role for changes in glomerular hemodynamics including increases in glomerular capillary pressure and glomerular hyperfiltration in these pathologic changes. Hyperglycemia activates the renin-angiotensin-aldosterone system and alters insulin-like growth factor, reactive oxygen species, and endothelin 1. Diabetes upregulates the sodium-glucose cotransporters (SGLT1 and SGLT2) in the proximal tubule, resulting in decreased distal delivery of sodium to the macula densa and further glomerular hyperfiltration. Sustained glomerular hypertension increases matrix production and alterations in the GBM with disruption in the filtration barrier. Other factors that alter matrix production include the accu­ mulation of advanced glycosylation end products, circulating factors including growth hormone, connective tissue growth factor, TGF-β, and dyslipidemia. PART 9 Disorders of the Kidney and Urinary Tract The natural history of diabetic nephropathy has been historically well characterized in the ~40% of diabetics who develop it as a pro­ gression from glomerular hyperfiltration and renal hypertrophy to increasing albuminuria followed by declining GFR and ESKD. How­ ever, since the onset of type 1 diabetes is readily identifiable and the onset of type 2 diabetes is not, a patient newly diagnosed with type 2 diabetes may present with advanced diabetic nephropathy. Albuminuria and decreased GFR are potent risk factors for cardiovascular disease, with some patients dying before they reach ESKD. Furthermore, contemporary studies reveal that up to 24% of patients with type 1 diabetes and 50% with type 2 diabetes and chronic kidney disease may be normoalbuminuric. It is unknown whether this alteration in the natural history reflects contemporary effective interventions or per­ haps other kidney diseases that happen to occur in patients with diabetes. The degree of early glomerular hyperfiltration does correlate with the development of albuminuria and declining GFR. Albuminuria in the range of 30–300 mg/24 h is called microalbuminuria (Table 326-1). Microalbuminuria appears 5–10 years after the onset of diabetes. It is currently recommended to test patients with type 1 disease for micro­ albuminuria 5 years after diagnosis of diabetes and yearly thereafter. Patients with type 2 diabetes should be tested for microalbuminuria at time of diagnosis followed by annual monitoring. Microalbuminuria classically progresses over 5–10 years to proteinuria and declining GFR, but in contemporary studies, greater heterogeneity is reported with regression to normoalbuminuria. Albuminuria remains the single most important predictor of a faster decline in GFR. Regression of albuminuria with a treatment intervention is a good prognostic sign. Proteinuria in diabetic nephropathy can be variable, ranging from 500 mg to 25 g/24 h. More than 90% of patients with type 1 diabetes and nephropathy have diabetic retinopathy, so the absence of retinopa­ thy in type 1 patients with proteinuria should prompt consideration of a diagnosis other than diabetic nephropathy; only 60% of patients with type 2 diabetes with nephropathy have diabetic retinopathy. There is a significant correlation between the presence of retinopathy and the presence of Kimmelstiel-Wilson nodules. Even with advanced chronic kidney disease, patients with diabetic nephropathy will have enlarged kidneys. Using the above data, and in the absence of other clinical or serologic data suggesting another disease, diabetic nephropathy is usually diagnosed without a kidney biopsy. The risk of progression to ESKD is influenced by treatment and other risk factors, and reports vary from a decline of 1.8–14 mL/min per year. Survival on dialysis is worse for patients with diabetes. Kidney transplantation results in better survival. Good evidence supports the benefits of blood sugar and blood pres­ sure control, inhibitors of the renin-angiotensin-aldosterone system

(RAAS), and inhibitors of SGLT2 in slowing the progression of diabetic nephropathy. In patients with type 1 diabetes, intensive control of blood sugar clearly prevents the development or progression of diabetic nephropathy. The evidence for benefit of intensive blood glucose con­ trol in patients with type 2 diabetes is less certain. Controlling systemic blood pressure decreases kidney and cardio­ vascular adverse events in this high-risk population. The vast majority of patients with diabetic nephropathy require three or more antihyper­ tensive drugs to achieve this goal. Drugs that inhibit the RAAS (ACE inhibitors, angiotensin receptor blockers [ARBs]) have been shown in large clinical trials to slow the progression of diabetic nephropa­ thy at early (microalbuminuria) and late (proteinuria with reduced glomerular filtration) stages, independent of their effects on systemic blood pressure. Finerenone, a nonsteroidal mineralocorticoid receptor antagonist, therapy in patients with diabetes and nephropathy on ACEi or ARB improved cardiovascular and kidney outcomes. In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in those receiving SGLT2 inhibitors in addition to ACE inhibitors or ARBs. ■ ■GLOMERULAR DEPOSITION DISEASES Plasma cell dyscrasias producing excess light chain (80%), heavy chain (10%) or both immunoglobulins can lead to the formation of glo­ merular and tubular deposits. The same is true for the accumulation of serum amyloid A protein fragments and monoclonal gammopathy of renal significance (MGRS). This broad group of proteinuric patients has glomerular deposition disease. Light Chain Deposition Disease  The biochemical characteris­ tics of nephrotoxic light chains produced in patients with light chain malignancies confer kidney injury; that of either cast nephropathy (see Fig. A4-21), which causes kidney injury but not heavy proteinuria or amyloidosis, or light chain deposition disease (LCDD) (see Fig. A4-20), which produces proteinuria with kidney injury. These latter patients produce kappa light chains that do not have the biochemical features necessary to form amyloid fibrils. Instead, they self-aggregate and form granular deposits along the glomerular capillary and mesangium or, more prominently, in the tubular basement membrane and Bowman’s capsule. Light chain deposits are not fibrillar and do not stain with Congo red, but they are easily detected with anti–light chain antibody. A combination of the light chain rearrangement, self-aggregating prop­ erties at neutral pH, and abnormal metabolism probably contributes to the deposition. Multiple myeloma, Waldenström’s macroglobulinemia, or lymphoma may be present, as well as heart, liver, and pulmonary involvement. The monoclonal protein may be found with serum electrophoresis or with serum free light chain analysis. Nephrotic syn­ drome may develop, and ~70% of patients progress to dialysis. Treat­ ment for LCDD is treatment of the primary disease. Less commonly, the deposits may be composed of heavy chains only (HCDD) or both ligh and heavy chains (LHCDD); both diseases have similar clinical characteristics to LCDD. Monoclonal Gammopathy of Renal Significance  In MGRS, a monoclonal immunoglobulin secreted by a nonmalignant or prema­ lignant B cell or plasma cell clone results in monoclonal deposits in the kidney which can manifest as proteinuria and ESKD. Treatment is controversial but may include chemotherapy. Renal Amyloidosis  Most renal amyloidosis is either the result of primary fibrillar deposits of immunoglobulin light chains known as amyloid L (AL) or secondary to fibrillar deposits of serum amyloid A (AA) protein fragments (Chap. 117). Hereditary amyloidosis is rare. Even though AA and AL amyloid occur for different reasons, their clinicopathophysiology is quite similar. Amyloid infiltrates the liver, heart, peripheral nerves, carpal tunnel, upper pharynx, and kidney, ultimately producing restrictive cardiomyopathy, hepatomegaly, mac­ roglossia, and heavy proteinuria sometimes associated with renal vein thrombosis. In contrast to LCDD, amyloid kidney deposits are fibrillar, stain with Congo red, and contain predominantly the variable region of lambda chains (see Fig. A4-19). In systemic AL amyloidosis, also

called primary amyloidosis, light chains produced in excess by clonal plasma cell dyscrasias are made into fragments by macrophages that aggregate into amyloid fibrils. Approximately 10% of patients have overt myeloma as defined by CRAB (hypercalcemia, renal insuffi­ ciency, anemia, or lytic bone lesions). Nephrotic syndrome is common and ~20% of patients progress to dialysis. AA amyloidosis is sometimes called secondary amyloidosis and is due to deposition of β-pleated sheets of serum amyloid A protein, an acute phase reactant. Fragments of serum amyloid A protein increase and self-aggregate by attaching to receptors for advanced glycation end products in the extracellular environment. Patients with AA amyloid have associated inflamma­ tory diseases including autoimmune diseases, chronic infections, and genetic autoinflammatory diseases. An increasing proportion of patients have unidentified chronic inflammation; this may reflect bet­ ter treatments for the previously associated diseases or a rise in chronic inflammation due to obesity. Nephrotic syndrome is common, and ~40–60% of patient’s progress to dialysis. Serum-free light chain analy­ sis is useful in the early diagnosis and follow-up of disease progression. Biopsy of involved liver or kidney is diagnostic 90% of the time when the pretest probability is high; abdominal fat pad aspirates are positive ~70% of the time, but apparently less so when looking for AA amyloid. Amyloid deposits are distributed along blood vessels and in the mesan­ gial regions of the kidney. The recommended treatment for primary amyloidosis is melphalan followed by autologous hematopoietic cell transplantation (HCT) which can achieve remission, however relapses are common. Patients who are not candidates for HCT often receive bortezomib-based regimens. Secondary amyloidosis is relentless unless the primary disease can be controlled. Drugs in development that dis­ rupt the formation of fibrils may be available in the future. Fibrillary and Immunotactoid Glomerulopathies  Fibrillary and immunotactoid glomerulopathies are rare (<1.0% of kidney biop­ sies), morphologically defined diseases characterized by glomerular accumulation of nonbranching randomly arranged fibrils that are Congo red negative (see Fig. A4-18). Fibrillary glomerulopathy accounts for 85–90% of cases and is identified by the presence of the protein DnaJ heat shock protein family member B9 (DNAJB9) in the glomeruli, which is absent in the rarer immunotactoid glomerulopa­ thy. In both, glomerular and mesangial deposits contain oligoclonal or oligotypic immunoglobulins and complement, with 12- to 24-nm fibrils randomly arranged in fibrillary glomerulopathy and 16 to 52-nm fibrils organized into microtubules in immunotactoid glomeru­ lopathy. The cause of this “nonamyloid” glomerulopathy is mostly idio­ pathic; reports of fibrillary glomerulonephritis describe associations with malignancy, autoimmune disease, and monoclonal gammopathy. Immunotactoid glomerulopathy has been associated with lymphoma or plasma cell disorders. Both disorders appear in adults aged 40–80 years old, with moderate to heavy proteinuria (100%), hematuria (70%), kidney injury (50%), a wide variety of histologic lesions, and ESKD within 2 to 6 years in 50% of patients. Most patients have disease limited to the kidney. Patients should be screened for associated disor­ ders. There is no consensus on treatment of this uncommon disorder, although rituximab has been reported to remit proteinuria. These diseases can recur in the kidney transplant. ■ ■FABRY’S DISEASE Fabry’s disease is an X-linked inborn error of globotriaosylceramide metabolism secondary to deficient lysosomal α-galactosidase A (alpha-Gal A) activity, resulting in excessive intracellular storage of globotriaosylceramide. Affected organs include the vascular endothe­ lium, heart, brain, and kidneys. Classically, Fabry’s disease presents in childhood in males with acroparesthesias, angiokeratomas commonly in groin and periumbilical areas, abdominal pain, cornea verticillate, and hypohidrosis. Over time, male patients develop cardiac involve­ ment, cerebrovascular disease, and kidney injury, with an average age of death around 50 years of age. Female heterozygotes with unfavor­ able X inactivation present with mild single-organ involvement or rarely severe manifestations including kidney failure but do so later in life than males. Kidney biopsy reveals enlarged glomerular visceral

epithelial cells packed with small clear vacuoles containing globotri­ aosylceramide; vacuoles may also be found in parietal and tubular epithelia (see Fig. A4-22). These vacuoles of electron-dense materials in parallel arrays (zebra bodies) are easily seen on electron microscopy. Ultimately, kidney biopsies reveal FSGS. The nephropathy of Fabry’s disease typically presents in the third decade as mild to moderate proteinuria, sometimes with microscopic hematuria or nephrotic syndrome. Urinalysis may reveal oval fat bodies and birefringent gly­ colipid globules under polarized light (Maltese cross). Measurement of alpha-Gal A activity and mutational analysis of the gene is diagnostic, with kidney biopsies sometimes helpful. Progression to ESKD occurs by the fourth or fifth decade. Treatment with inhibitors of the reninangiotensin system is recommended. Treatment with recombinant agalsidase alpha or beta or migalastat, a chaperone that facilitates traf­ ficking of alpha-Gal A, clears microvascular endothelial deposits of globotriaosylceramide from the kidneys, heart, and skin. In patients with advanced organ involvement including chronic kidney disease, progression of disease occurs despite enzyme replacement therapy. Variable responses to enzyme therapy may be due to the occurrence of neutralizing antibodies or differences in uptake of the enzyme. Graft and patient survival following kidney transplantation in patients with Fabry’s disease are similar to those of other causes of ESKD.

CHAPTER 326 PULMONARY-RENAL SYNDROMES Several diseases can present with catastrophic hemoptysis and glo­ merulonephritis associated with varying degrees of kidney injury. The usual causes include Goodpasture’s syndrome, granulomatosis with polyangiitis, microscopic polyangiitis, Churg-Strauss vasculitis, and, rarely, Henoch-Schönlein purpura or cryoglobulinemia. Each of these diseases can also present without hemoptysis and are discussed in detail earlier in “Acute Nephritic Syndromes.” (See Glomerular Schematic 7.) Pulmonary bleeding in this setting is life-threatening and often results in airway intubation, and acute kidney injury may require dialysis. Diagnosis is difficult initially because biopsies and serologic testing take time. Treatment with plasmapheresis and methyl­ prednisolone is often empirical and temporizing until results of testing are available. Glomerular Diseases BASEMENT MEMBRANE SYNDROMES All kidney epithelia, including podocytes, rest on basement mem­ branes assembled into a planar surface through the interweaving of col­ lagen IV with laminins, nidogen, and sulfated proteoglycans. Structural abnormalities in GBM associated with hematuria are characteristic of several familial disorders related to the expression of collagen IV genes. The extended family of collagen IV contains six chains, which are expressed in different tissues at different stages of embryonic develop­ ment. All epithelial basement membranes early in human development are composed of interconnected triple-helical protomers rich in α1.α1. α2(IV) collagen. Some specialized tissues undergo a developmental switch replacing α1.α1.α2(IV) protomers with an α3.α4.α5(IV) colla­ gen network; this switch occurs in the kidney (glomerular and tubular basement membrane), lung, testis, cochlea, and eye, while an α5.α5. α6(IV) network appears in skin, smooth muscle, and esophagus and along Bowman’s capsule in the kidney. This switch probably occurs because the α3.α4.α5(IV) network is more resistant to proteases and ensures the structural longevity of critical tissues. When basement membranes are the target of glomerular disease, they produce moder­ ate proteinuria, some hematuria, and progressive kidney failure. ■ ■ANTI-GBM DISEASE Autoimmune disease where antibodies are directed against the α3 NC1 domain of collagen IV produces an anti-GBM disease often associated with RPGN and/or a pulmonary-renal syndrome called Goodpas­ ture’s syndrome. Discussion of this disease is covered earlier in “Acute Nephritic Syndromes.” ■ ■ALPORT’S SYNDROME Classically, patients with Alport’s syndrome develop hematuria, and mild proteinuria (<1–2 g/24 h), which appears late in the course,

Glomerular schematic 7 PART 9 Disorders of the Kidney and Urinary Tract followed by chronic glomerulosclerosis leading to kidney failure in association with sensorineural deafness. Some patients develop lentico­ nus of the anterior lens capsule, “dot and fleck” retinopathy, and rarely, leiomyomatosis. Approximately 80–85% of patients with Alport’s syndrome have an X-linked inheritance of mutations at the COL4A5 locus affecting in the α5(IV) collagen chain on chromosome Xq22–24. Female carriers have variable penetrance depending on the type of mutation or the degree of mosaicism created by X inactivation. Muta­ tions on chromosome 2q35-37 at the COL4A3 and COL4A4 loci of the α3(IV) and α4(IV) chains, respectively, are associated with autosomal recessive (AR) disease and less commonly autosomal dominant (AD) disease. With use of next generation sequencing, AD disease is now noted to likely occur more frequently than previously thought. Pedigrees with the X-linked syndrome are quite variable in their rate and frequency of tissue damage leading to organ failure. There is strong correlation between genotype and phenotype regarding risk of disease progression in males; truncating variants, including large dele­ tions and nonsense mutations, are associated with rapidly progressive disease with ESKD by age 30 in up to 90% of males. By contrast, those with missense or splice variants may not deteriorate until after the age of 30 with mild or late deafness. Early severe deafness, lenticonus, or proteinuria suggests a poorer prognosis. Usually females from X-linked pedigrees have only microhematuria, but up to 25% of carrier females have been reported to have more severe kidney manifestations. Pedi­ grees with the AR form of the disease have severe early disease in both females and males with asymptomatic parents. Clinical evaluation should include a careful eye examination and hearing tests. However, the absence of extrarenal symptoms does not rule out the diagnosis. Genetic testing can be used for the diagnosis of Alport’s syndrome and the demonstration of the mode of inheri­ tance. In certain cases with high clinical suspicion or family history of Alport’s, genetic testing alone may be sufficient for diagnosis. Since α5(IV) collagen is expressed in the skin, some X-linked Alport’s patients can be diagnosed with a skin biopsy revealing the lack of the

RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS α5(IV) collagen chain on immunofluorescent analysis. Patients with mutations in α3(IV) or α4(IV) require a kidney biopsy. Early in their disease, Alport’s patients typically have thin basement membranes on kidney biopsy (see Fig. A4-23), which thicken over time into mul­ tilamellations surrounding lucent areas that often contain granules of varying density—the so-called split basement membrane. In any Alport’s kidney, there are areas of thinning mixed with splitting of the GBM. Tubules drop out, glomeruli scar, and the kidney eventually succumbs to interstitial fibrosis. All affected members of a family with X-linked Alport’s syndrome should be identified and followed, includ­ ing mothers of affected males. Primary treatment is control of systemic hypertension and use of ACE inhibitors and possibly SGLT2i to slow kidney disease progression. Although patients who receive kidney allografts usually develop anti-GBM antibodies directed toward the collagen epitopes absent in their native kidney, overt Goodpasture’s syndrome is rare and graft survival is good. ■ ■THIN BASEMENT MEMBRANE DISEASE Thin basement membrane disease (TBMD), a relatively common dis­ order characterized by persistent or intermittent hematuria, which is usually microscopic hematuria and rarely macroscopic hematuria with flank pain. It is not typically associated with proteinuria, hyperten­ sion, or loss of kidney function or extrarenal disease. TBMD is often familial, with pedigrees exhibiting an autosomal dominant pattern. It usually presents in childhood in multiple family members and has also been called benign familial hematuria. Many cases of TBMD have genetic defects in type IV collagen; in contrast to Alport’s syndrome, the disease behaves as an autosomal dominant disorder that in ~40% of families segregates with the COL(IV) α3/COL(IV) α4 loci. Mutations in these loci can result in a spectrum of disease, ranging from TBMD to autosomal dominant or recessive Alport’s. The GBM shows diffuse thinning compared to normal values for the patient’s age in otherwise normal biopsies (see Fig. A4-23). The vast majority of patients have a benign course.

■ ■NAIL-PATELLA SYNDROME Patients with nail-patella syndrome develop iliac horns on the pelvis and dysplasia of the dorsal limbs involving the patella, elbows, and nails, variably associated with neural-sensory hearing impairment, glaucoma, and abnormalities of the GBM and podocytes, leading to hematuria, proteinuria, and FSGS. The syndrome is autosomal domi­ nant, with haploinsufficiency for the LIM homeodomain transcription factor LMX1B; pedigrees are extremely variable in the penetrance for all features of the disease. LMX1B regulates the expression of genes encoding α3 and α4 chains of collagen IV, interstitial type III collagen, podocin, and CD2AP that help form the slit-pore membranes connect­ ing podocytes. Mutations in the LIM domain region of LMX1B associ­ ate with glomerulopathy in 30–40% of patients and rarely progress to ESKD. Proteinuria or isolated hematuria is discovered throughout life but usually by the third decade. Genetic testing can confirm the diag­ nosis. Treatment is nonspecific, but renin-angiotensin system inhibi­ tion is recommended. Patients with ESKD do well with transplantation. ■ ■GLOMERULAR-VASCULAR SYNDROMES A variety of diseases result in classic vascular injury to the glomerular capillaries. Most of these processes also damage blood vessels else­ where in the body. The group of diseases discussed here lead to vascu­ litis, renal endothelial injury, thrombosis, ischemia, and/or lipid-based occlusions. ■ ■ATHEROSCLEROTIC NEPHROPATHY Aging in the developed world is commonly associated with the occlu­ sion of coronary and systemic blood vessels. When the renal arterial circulation is involved, the glomerular microcirculation is damaged, leading to chronic nephrosclerosis. Several aggressive lipid disorders can accelerate this process, but most of the time, atherosclerotic progres­ sion to chronic nephrosclerosis is associated with poorly controlled hypertension. ■ ■HYPERTENSIVE NEPHROSCLEROSIS Systemic hypertension causes permanent damage to the kidneys in ~6% of patients with elevated blood pressure. As many as 27% of patients with ESKD have hypertension as a primary cause, and it is the second most common cause of ESKD after diabetic nephropathy in the US. Risk alleles associated with APOL1, a functional gene for apolipoprotein L1 expressed in podocytes are associated with an increased risk of ESKD. Other associated risk factors for progres­ sion to end-stage kidney disease include increased age, male gender, smoking, hypercholesterolemia, duration of hypertension, low birth weight, and preexisting kidney injury. Kidney biopsies in patients with hypertension, microhematuria, and moderate proteinuria demonstrate arteriolosclerosis, chronic nephrosclerosis, and interstitial fibrosis in the absence of immune deposits (see Fig. A4-25). Based on a careful history, physical examination, urinalysis, and some serologic testing, the diagnosis of chronic nephrosclerosis is usually inferred without a biopsy. Recent studies suggest, in the absence of diabetes, adults with hypertension and cardiovascular risk factors benefit from achieving a systolic blood pressure <120 mmHg, compared to <140 mmHg. In the presence of kidney disease, most patients begin antihypertensive therapy with two drugs, classically a thiazide diuretic and an ACE inhibitor; most will require three drugs. There is strong evidence in a study with self-identified African Americans with hypertensive neph­ rosclerosis that therapy initiated with an ACE inhibitor can slow the rate of decline in kidney function independent of effects on systemic blood pressure. Malignant acceleration of hypertension complicates the course of chronic nephrosclerosis, particularly in the setting of scleroderma or cocaine use (see Fig. A4-28). The hemodynamic stress of malignant hypertension leads to fibrinoid necrosis of small blood vessels, thrombotic microangiography, a nephritic urinalysis, and AKI. In the setting of kidney injury, chest pain, or papilledema, the condi­ tion is treated as a hypertensive emergency. ■ ■CHOLESTEROL EMBOLI Aging patients with clinical complications from atherosclerosis some­ times shower cholesterol crystals into the circulation following an

endovascular procedure with manipulation of the aorta or with use of systemic anticoagulation. Less commonly, spontaneous emboli can occur and may shower acutely or shower subacutely which is somewhat more silently. Irregular emboli trapped in the microcirculation produce ischemic damage that induces an inflammatory reaction. Depending on the location of the atherosclerotic plaques releasing these choles­ terol fragments, one may see cerebral transient ischemic attacks; livedo reticularis in the lower extremities; Hollenhorst plaques in the retina with visual field cuts; necrosis of the toes; and acute glomerular capil­ lary injury leading to FSGS sometimes associated with hematuria, mild proteinuria, and loss of kidney function, which typically progresses over a few years. Occasional patients have fever, eosinophilia, or eosin­ ophiluria. A skin biopsy of an involved area may be diagnostic. Since tissue fixation dissolves the cholesterol, one typically sees only residual, biconvex clefts in involved vessels (see Fig. A4-26). There is no therapy to reverse embolic occlusions, and steroids do not help. Controlling blood pressure and lipids and cessation of smoking are usually recom­ mended for prevention.

■ ■SICKLE CELL DISEASE Sickle cell disease (SCD) is an autosomal recessive disease that occurs due to a mutation in the hemoglobin β-chain (HβS). Clinical dis­ ease occurs in homozygous patients (SS) or heterozygous patients in the presence of an abnormal or missing β-chain (SC, HbSβ). Under certain circumstances (i.e., hypoxia, hypovolemia, acidity, hyperos­ molality), HbS polymerizes which causes the red blood cell shape to distort. These cells attach to endothelia, causing obstruction as well as other changes to the vasculature that produce acute and chronic vasoocclusion disease in many organs, including the kidney. The major site of injury in the kidney is the renal medulla, an area supplied by the vasa recta capillaries that promotes sickling due to the relative hypoxic, acidotic, and hypertonic environment. Repeated injury overtime pro­ duces chronic organ damage leading to sickle cell nephropathy (SCN). Early changes of SCN include glomerular hyperfiltration, albuminuria, and both micro- and macro-hematuria. Nearly all SCD patients have concentrating defects which cause hyposthenuria and can lead to severe dehydration. Later changes include papillary necrosis, renal infarction, interstitial nephritis, proteinuria, and FSGS. Rarely patients may present with MPGN. Several genetic risk factors have been identi­ fied that may increase risk for progression of CKD, including APOL1 gene variants. Treatment is directed at reducing the frequency of vaso-occlusive events and administering ACE inhibitors/ARBs and hydroxyurea in the hope of delaying a progressive decline in kidney function. Management of anemia in SCN patients is complex and may require high doses of erythropoiesis-stimulating agents. A number of patients will develop progressive CKD, and one study found that 20% of SCD patients develop ESKD before the age of 30. SCD patients with ESKD have poor prognosis on kidney replacement therapy (KRT), with a mean time to death of 4 years. Prognosis for ESKD patients improves after kidney transplant with 7 year survival of 67%. CHAPTER 326 Glomerular Diseases Sickle cell trait occurs in patients with one HbS and one normal hemoglobin. Although individuals usually do not experience vasoocclusive symptoms, most will gradually develop hyposthenuria due to subclinical infarction of the renal medulla and a consequent loss of concentrating ability. They may experience hematuria and are at higher risk for renal medullary carcinoma than SCD patients. ■ ■THROMBOTIC MICROANGIOPATHIES Thrombotic microangiopathy (TMA) refers to a pathologic lesion that causes thrombocytopenia and microangiopathic hemolytic anemia with schistocytes. Thrombotic thrombocytopenic purpura (TTP), Shiga toxin–mediated hemolytic-uremic syndrome (HUS), and complementmediated HUS represent a spectrum of primary TMAs that share these features and may have concurrent fever, kidney failure, and neurologic disturbances. HUS is suspected with patients have more severe kidney injury while TTP is suspected in adults with neurologic disease and more severe thrombocytopenia. On examination of kidney tissue, there is evidence of glomerular capillary endotheliosis associated with platelet thrombi, damage to the capillary wall, and formation of fibrin

TABLE 326-6  Thrombotic Microangiopathies Primary thrombotic microangiopathy   TTP   Shiga-toxin HUS   Complement-mediated HUS Secondary thrombotic microangiopathy   Pregnancy related: preeclampsia, HELLP (hemolysis, elevated liver enzymes, and low platelet count syndrome), postpartum (thought to be complement mediated)   Drug induced: oral contraceptives or quinine, calcineurin inhibitors, antiplatelet agents (ticlopidine and clopidogrel), drugs of abuse (cocaine, IV use of oxycodone)   Kidney transplant patients given OKT3 for rejection   Malignant hypertension   Autoimmune: antiphospholipid syndrome, lupus, scleroderma   Infections: HIV, pneumococcal, CMV   Cobalamin deficiency Abbreviations: CMV, cytomegalovirus; HUS, hemolytic-uremic syndrome; TTP, thrombotic thrombocytopenic purpura. material in and around glomeruli (see Fig. A4-27). These tissue find­ ings are similar to what is seen in secondary TMA, which includes a broad group of conditions known to be associated with TMA (see Table 326-6). PART 9 Disorders of the Kidney and Urinary Tract Shiga toxin–mediated HUS is caused by a toxin released by Esch­ erichia coli 0157:H7 and occasionally by Shigella dysenteriae. This Shiga toxin (verotoxin) directly injures endothelia, enterocytes, and kidney cells, causing apoptosis, platelet clumping, and intravascular hemolysis by binding to the glycolipid receptors (Gb3). These receptors are more abundant along endothelia in children compared to adults. Shiga toxin also inhibits the endothelial production of ADAMTS13. In familial cases of adult TTP, there is a genetic deficiency of the ADAMTS13 metalloprotease that cleaves large multimers of von Willebrand’s fac­ tor (VWF). In the absence of ADAMTS13, these large multimers cause platelet clumping and intravascular hemolysis. An antibody to ADAMTS13 is found in many sporadic cases of adult TTP. Patients can be tested for ADAMTS13 activity, and if low, the presence of anti­ bodies to ADAMTS13 distinguishes the deficiency from the immune-

mediated disease. Complement-mediated HUS, previously referred to as atypical HUS, is thought to occur when there is a hereditary defi­ ciency or antibody to a regulatory protein in the alternative comple­ ment pathway leading to overactivation. The treatment of adult TTP with ADAMTS13 antibodies is daily plasmapheresis, which can be lifesaving. Plasmapheresis with fresh frozen plasma is given until the platelet count rises, or longer for relapsing patients. There is an anec­ dotal role in relapsing patients for splenectomy. Refractory or relapsing patients may benefit from steroids, immunosuppressive drugs such as rituximab, or caplacizumab, a monoclonal antibody that blocks interaction between VWF and platelets. In the absence of ADAMTS13 antibodies, patients with a genetic deficiency of ADAMTS13 pro­ duction can be treated with fresh frozen plasma alone. Patients with Shiga toxin–mediated HUS are treated primarily with supportive care because antibiotics are thought to accelerate the release of the toxin and the diarrhea is usually self-limited. Patients with complementmediated HUS are treated with anticomplement therapy, such as ecu­ lizumab or ravulizumab. ■ ■ANTIPHOSPHOLIPID ANTIBODY SYNDROME

(SEE CHAP. 369) GLOBAL CONSIDERATIONS ■ ■INFECTIOUS DISEASE–ASSOCIATED SYNDROMES A number of infectious diseases will injure the glomerular capillaries as part of a systemic reaction producing an immune response or from direct infection of kidney tissue. Evidence of this immune response is collected by glomeruli in the form of immune deposits that damage the kidney, producing moderate proteinuria and hematuria. A high

prevalence of many of these infectious diseases in developing countries results in infection-associated kidney disease being the most common cause of glomerulonephritis in many parts of the world. Poststreptococcal Glomerulonephritis  This form of glomeru­ lonephritis is one of the classic complications of streptococcal infec­ tion. The discussion of this disease can be found earlier, in the section “Acute Nephritic Syndromes.” Subacute Bacterial Endocarditis  Kidney injury from persistent bacteremia absent the continued presence of a foreign body, regardless of cause, is treated presumptively as if the patient has endocarditis. The discussion of this disease can be found earlier, in the section “Acute Nephritic Syndromes.” Human Immunodeficiency Virus  Kidney disease is an impor­ tant complication of HIV disease. About 50% of HIV-infected patients with kidney disease have HIV-associated nephropathy (HIVAN) on biopsy. The lesion in HIVAN is FSGS, characteristically revealing a collapsing glomerulopathy (see Fig. A4-3) with visceral epithelial cell swelling, microcystic dilatation of renal tubules, and tubuloreticular inclusion. Renal epithelial cells express replicating HIV virus, but host immune responses also play a role in the pathogenesis. HIVAN is thought to be linked to APOL1 risk variants. HIV immune complex kidney disease (HIVICK) is a group of immune complex–mediated glomerular lesions seen in HIV patients that, on biopsy, can look like a constellation of other glomerular lesions, including postinfectious glo­ merulonephritis, MGN, MPGN, DPGN, MCD, and IgA nephropathy. The HIVICK effect is a complication of active HIV viremia. HIV patients with FSGS typically present with nephrotic-range pro­ teinuria and hypoalbuminemia, but unlike patients with other etiologies for nephrotic syndrome, they do not commonly have hypertension, edema, or hyperlipidemia. Kidney ultrasound also reveals large, echo­ genic kidneys despite the finding that kidney function in some patients declines rapidly. Treatment with inhibitors of the renin-angiotensin sys­ tem decreases the proteinuria. Effective antiretroviral therapy benefits both the patient and the kidney and improves survival of HIV-infected patients with HIVAN and, in some cases, HIVICK-associated chronic kidney disease or ESKD. In HIV-infected patients not yet on therapy, the presence of HIVAN is an indication to initiate therapy. Following the introduction of antiretroviral therapy, survival on dialysis for the HIVinfected patient has improved dramatically. Kidney transplantations in HIV-infected patients without detectable viral loads or histories of opportunistic infections provide a better survival benefit over dialysis. Following transplantation, patient and graft survival are similar to the general transplant population despite frequent rejections. Hepatitis B and C  Typically, infected patients present with micro­ scopic hematuria, nonnephrotic or nephrotic-range proteinuria, and hypertension. There is a close association between hepatitis B infec­ tion and polyarteritis nodosa, with vasculitis appearing generally in the first 6 months following infection. Kidney manifestations include renal artery aneurysms, renal infarction, and ischemic scars. Alterna­ tively, the hepatitis B carrier state can produce an MGN with predomi­ nant IgG1 deposition that is more common in children than adults or MPGN that is more common in adults than in children. Kidney histology is indistinguishable from idiopathic MGN or MPGN. Viral antigens, most commonly HBeAG, are found in the kidney deposits. Cryoglobulinemic glomerulonephritis has also been reported. Treat­ ment is with antiviral agents. Children have a better prognosis than adults. Up to 30% of patients with chronic hepatitis C infection have some kidney manifestations. Patients often present with type II mixed cryo­ globulinemia, nephrotic syndrome, microscopic hematuria, abnormal liver function tests, depressed C3 levels, anti–hepatitis C virus (HCV) antibodies, and viral RNA in the blood. The lesions most commonly seen, in order of decreasing frequency, are cryoglobulinemic glomeru­ lonephritis, MGN, and MPGN, but polyarteritis nodosa (PAN), IgA nephropathy, and FSGS have been reported. With the availability of direct-acting antivirals, which can achieve a viral remission in >95% of

patients, the prevalence of glomerular disease in HCV patients should decline. These drugs are currently the treatment of choice for patients with HCV-related MPGN or PAN. SARS-CoV-2  The novel coronavirus, SARS-CoV-2, is associ­ ated with several complications related to kidney disease including acute kidney injury, chronic kidney disease, and, rarely, glomerular diseases. The glomerular lesions reported in patients with COVID-19 include FSGS, minimal change disease, membranous nephropathy, ANCA-associated vasculitis, anti-GBM disease, IgA nephropathy and thrombotic microangiopathy. The glomerular disease most commonly associated with COVID-19 is collapsing glomerulopathy, a morpho­ logic variant of FSGS, also referred to as COVID-associated nephrop­ athy (COVAN). Patients may present with new onset nephrotic syndrome or nephrotic range proteinuria with AKI. There have been case reports of de novo glomerular disease and relapse of pre-existing glomerular disease following administration of COVID-19 mRNA vaccines, although evidence for causal link is not well established. The use of immunosuppression therapy may be considered in patients with severe nephrotic syndrome or persistent disease despite resolu­ tion of infection, however there is limited data to guide treatment recommendations. Other Viruses  Other viral infections are occasionally associated with glomerular lesions, but cause and effect are not well estab­ lished. These viral infections and their respective glomerular lesions include cytomegalovirus producing MPGN or FSGS; influenza and anti-GBM disease; measles-associated endocapillary proliferative glo­ merulonephritis, with measles antigen in the capillary loops and mesangium; parvovirus causing mild proliferative or mesangioprolif­ erative glomerulonephritis or FSGS; mumps and mesangioprolifera­ tive glomerulonephritis; Epstein-Barr virus producing MPGN, diffuse proliferative nephritis, or IgA nephropathy; dengue hemorrhagic fever causing endocapillary proliferative glomerulonephritis; Hanta virus and mesangial proliferative glomerulonephritis; and coxsackievirus producing focal glomerulonephritis or DPGN. Syphilis  Secondary syphilis, with rash and constitutional symp­ toms, develops weeks to months after the chancre first appears and occasionally presents with the nephrotic syndrome from MGN caused by subepithelial immune deposits containing treponemal antigens. Neuron-derived neurotrophic factor has also been identified as an anti­ genic target. Other lesions have also rarely been described, including interstitial syphilitic nephritis. The diagnosis is confirmed with non­ treponemal and treponemal tests for Treponema pallidum. The kidney lesion responds to treatment with penicillin or an alternative drug, if allergic. Additional testing for other sexually transmitted diseases is an important part of disease management. Leprosy  Despite aggressive eradication programs, new cases of leprosy appear primarily in developing countries. The diagnosis is best made in patients with multiple skin lesions accompanied by sensory loss in affected areas, using skin smears showing paucibacillary or multibacillary infection (WHO criteria). Leprosy is caused by infec­ tion with Mycobacterium leprae and can be classified by Ridley-Jopling criteria into various types: tuberculoid, borderline tuberculoid, midborderline and borderline lepromatous, and lepromatous. Kidney involvement in leprosy is related to the quantity of bacilli in the body, and the kidney is one of the target organs during splanchnic localiza­ tion. In some series, all cases with borderline lepromatous and lep­ romatous types of leprosy have various forms of kidney involvement including FSGS, mesangioproliferative glomerulonephritis, or renal amyloidosis; much less common are DPGN and MPGN. Treatment of the infection with multidrug therapy can reduce the incidence of kidney disease or produce remission of the kidney disease. Malaria  There are 300–500 million incident cases of malaria each year worldwide, and the kidney is commonly involved. Glomerulo­ nephritis is due to immune complexes containing malarial antigens that are implanted in the glomerulus. In malaria from P. falciparum,

mild proteinuria is associated with subendothelial deposits, mesangial deposits, and mesangioproliferative glomerulonephritis that usually resolve with treatment. In quartan malaria from infection with Plas­ modium malariae, children are more commonly affected and kidney involvement is more severe. Transient proteinuria and microscopic hematuria can resolve with treatment of the infection. However, resis­ tant nephrotic syndrome with progression to ESKD over 3–5 years does happen, as <50% of patients respond to steroid therapy. Affected patients with nephrotic syndrome have thickening of the glomerular capillary walls, with subendothelial deposits of IgG, IgM, and C3 asso­ ciated with a sparse membranoproliferative lesion. The rare mesangio­ proliferative glomerulonephritis reported with Plasmodium vivax or Plasmodium ovale typically has a benign course. Acute kidney injury can often complicate these glomerulopathies.

Schistosomiasis  Schistosomiasis affects >300 million people worldwide and primarily involves the urinary and gastrointestinal tracts. Glomerular involvement varies with the specific strain of schistosomiasis; Schistosoma mansoni is most commonly associated with clinical kidney disease, and the glomerular lesions can be clas­ sified as follows: class I is a mesangioproliferative glomerulonephritis; class II is an extracapillary proliferative glomerulonephritis; class III is a membranoproliferative glomerulonephritis; class IV is a focal segmental glomerulonephritis; and class V is amyloidosis. Classes I–II often remit with treatment of the infection, but class III and IV lesions are associ­ ated with IgA immune deposits and progress despite antiparasitic and/ or immunosuppressive therapy. CHAPTER 326 Other Parasites  Kidney involvement with toxoplasmosis infec­ tions is rare. When it occurs, patients present with nephrotic syndrome and have a histologic picture of MPGN. Fifty percent of patients with leishmaniasis will have mild to moderate proteinuria and microscopic hematuria, but decreased GFR is rare. Acute DPGN, MGN, and mesan­ gioproliferative glomerulonephritis have all been observed on biopsy. Filariasis and trichinosis are caused by nematodes and are sometimes associated with glomerular injury presenting with proteinuria, hema­ turia, and a variety of histologic lesions that typically resolve with eradication of the infection. Glomerular Diseases Acknowledgment The authors wish to thank Nicole Wyatt for her assistance with this chapter. ■ ■FURTHER READING De Vriese AS et al: Differentiating primary, genetic, and secondary FSGS in adults: A clinicopathologic approach. J Am Soc Nephrol 29:759, 2018. Kupin WL: Viral-associated GN: Hepatitis C and HIV. Clin J Am Soc Nephrol 12:1337, 2017. Hou J et al: C3 glomerulopathy: a review with emphasis on ultrastruc­ tural features. Glomerular Dis 2:107, 2022. Lebleu VS et al: Origin and functional heterogeneity of fibroblasts. FASEB J 34(3):3519-, 2020. Miller P, Caza T: The expanding spectrum and utility of antigens in membranous nephropathology. Curr Opin Nephrol Hypertens 32:232, 2023. Papazachariou L et al: Frequent COL4 mutations in familial micro­ heamaturia accompanied by later-onset/alport nephropathy due to focal segmental glomerulosclerosis. Clin Genet 92:517, 2017. Ronco P et al: Membranous nephropathy. Nat Rev Dis Primers 7:69, 2021. Sethi S et al: Mayo Clinic/Renal Pathology Society consensus report on pathologic classification, diagnosis, and reporting of GN. J Am Soc Nephrol 27:1278, 2016. Smith RJH et al: C3 glomerulopathy - understanding a rare complementdriven renal disease. Nat Rev Nephrol 15:129, 2019. Yau K et al: Prescribing SGLT2 inhibitors in patients with CKD: Expanding indications and practical considerations. Kidney Int Rep 7:1463, 2022.

10 - 328 Tubulointerstitial Diseases of the Kidney

328 Tubulointerstitial Diseases of the Kidney

Laurence H. Beck, Jr., David J. Salant

Tubulointerstitial

Diseases of the Kidney Inflammation or fibrosis of the renal interstitium and atrophy of the tubular compartment are common consequences of diseases that target the glomeruli or vasculature. Distinct from these secondary phenom­ ena, however, are a group of disorders that primarily affect the tubules and interstitium, with relative sparing of the glomeruli and renal ves­ sels. Such disorders are conveniently divided into acute and chronic tubulointerstitial nephritis (TIN) (Table 328-1). Acute TIN most often presents with acute kidney injury (Chap. 321). The acute nature of this group of disorders may be caused by aggressive inflammatory infiltrates that lead to tissue edema, tubular cell injury, and compromised tubular flow, or by frank obstruction of the tubules with casts, cellular debris, or crystals. There is sometimes flank pain due to distention of the renal capsule. Urinary sediment is often active with leukocytes and cellular casts but depends on the exact nature of the disorder in question. The clinical features of chronic TIN are more indolent and may manifest with disorders of tubular function, including polyuria from impaired concentrating ability (nephrogenic diabetes insipidus), defec­ tive proximal tubular reabsorption leading to features of Fanconi’s syndrome (glycosuria, phosphaturia, aminoaciduria, hypokalemia, and type II renal tubular acidosis [RTA] from bicarbonaturia), or nonanion-gap metabolic acidosis and hyperkalemia (type IV RTA) due to impaired ammoniagenesis, as well as progressive azotemia (rising creatinine and blood urea nitrogen [BUN]). There is often modest pro­ teinuria (rarely >2 g/d) attributable to decreased tubular reabsorption of filtered proteins; however, nephrotic-range albuminuria may occur in some conditions due to the development of secondary focal seg­ mental glomerulosclerosis (FSGS). Renal ultrasonography may reveal changes of “medical renal disease,” such as increased echogenicity of the renal parenchyma with loss of corticomedullary differentiation, prominence of the renal pyramids, and cortical scarring in some conditions. The predominant pathology in chronic TIN is interstitial fibrosis with patchy mononuclear cell infiltration and widespread tubular atrophy, luminal dilation, and thickening of tubular basement membranes. Because of the nonspecific nature of the histopathology, biopsy specimens rarely provide a specific diagnosis. Thus, diagnosis relies on careful analysis of history, drug or toxin exposure, associated symptoms, and imaging studies. ACUTE INTERSTITIAL NEPHRITIS In 1897, Councilman reported eight cases of acute interstitial nephritis (AIN) in the Medical and Surgical Reports of the Boston City Hospital— three as a postinfectious complication of scarlet fever and two from diphtheria. Later, he described the lesion as “an acute inflammation of the kidney characterized by cellular and fluid exudation in the intersti­ tial tissue, accompanied by, but not dependent on, degeneration of the epithelium; the exudation is not purulent in character, and the lesions may be both diffuse and focal.” Today AIN is far more often encoun­ tered as an allergic reaction to a drug (Table 328-1). Immune-mediated AIN may also occur as part of a known autoimmune syndrome, but in some cases, there is no identifiable cause despite features suggestive of an immunologic etiology (Table 328-1). ■ ■ALLERGIC INTERSTITIAL NEPHRITIS Although biopsy-proven AIN accounts for no more than ~15% of cases of unexplained acute kidney injury, this is likely a substantial under­ estimate of the true incidence. This is because potentially offending medications are more often identified and empirically discontinued in a patient noted to have a rising serum creatinine, without the benefit of a kidney biopsy to establish the diagnosis of AIN.

TABLE 328-1  Classification of the Causes of Tubulointerstitial Diseases of the Kidney Acute Tubulointerstitial Disorders Acute Interstitial Nephritis Therapeutic agents • Antibiotics (β-lactams, sulfonamides, quinolones, vancomycin, erythromycin, linezolid, minocycline, rifampin, ethambutol, acyclovir) • Nonsteroidal anti-inflammatory drugs, COX-2 inhibitors • Diuretics (rarely thiazides, loop diuretics, triamterene) • Anticonvulsants (phenytoin, valproate, carbamazepine, phenobarbital) • Immune modulators (immune checkpoint inhibitors, vedolizumab, lenalidomide) • Miscellaneous (proton pump inhibitors, H2 blockers, captopril, mesalazine, indinavir, allopurinol) Infection • Bacteria (Streptococcus, Staphylococcus, Legionella, Salmonella, Brucella, Yersinia, Corynebacterium diphtheriae) • Viruses (EBV, CMV, hantavirus, polyomavirus, HIV) • Miscellaneous (Leptospira, Rickettsia, Mycoplasma, Histoplasma) Autoimmune • Tubulointerstitial nephritis with uveitis (TINU) • Sjögren’s syndrome • Systemic lupus erythematosus • Granulomatous interstitial nephritis • IgG4-related systemic disease • Tubulointerstitial disease related to checkpoint inhibitors • Anti-brush border disease (anti-LRP2 nephropathy) • Idiopathic autoimmune interstitial nephritis Acute Obstructive Disorders • Light chain cast nephropathy (“myeloma kidney”) • Acute phosphate nephropathy • Acute urate nephropathy CHAPTER 328 Tubulointerstitial Diseases of the Kidney Chronic Tubulointerstitial Disorders • Vesicoureteral reflux/reflux nephropathy • Sickle cell disease • Chronic exposure to toxins or therapeutic agents • Analgesics, especially those containing phenacetin • Lithium • Heavy metals (lead, cadmium) • Aristolochic acid (Chinese herbal and Balkan endemic nephropathies) • Calcineurin inhibitors (cyclosporine, tacrolimus) • Chronic interstitial nephritis in agricultural communities Metabolic Disturbances • Hypercalcemia and/or nephrocalcinosis • Hyperuricemia • Prolonged hypokalemia • Hyperoxaluria • Cystinosis (see Chap. 327) Cystic and Hereditary Disorders (see Chap. 327) • Polycystic kidney disease • Nephronophthisis • Autosomal dominant tubulointerstitial kidney disease (medullary cystic kidney disease) • Medullary sponge kidney Miscellaneous • Aging • Chronic glomerulonephritis • Chronic urinary tract obstruction • Ischemia and vascular disease • Radiation nephritis (rare) Abbreviations: CMV, cytomegalovirus; COX, cyclooxygenase; EBV, Epstein-Barr virus.

Clinical Features  The classic presentation of AIN, namely, fever, rash, peripheral eosinophilia, and oliguric kidney injury occurring after 7–10 days of treatment with methicillin or another β-lactam antibiotic, is the exception rather than the rule. More often, patients are found incidentally to have a rising serum creatinine or present with symptoms attributable to acute kidney injury (Chap. 321). Atypical reactions can occur, most notably with nonsteroidal anti-inflammatory drug (NSAID)–induced AIN, in which fever, rash, and eosinophilia are rare, but acute kidney injury with heavy proteinuria is common. A par­ ticularly severe and rapid-onset AIN may occur upon reintroduction of rifampin after a drug-free period. More insidious reactions to the agents listed in Table 328-1 may lead to progressive tubulointerstitial damage. Examples include proton pump inhibitors and, rarely, sulfon­ amide and 5-aminosalicylate (mesalazine and sulfasalazine) derivatives and antiretrovirals. It is not clear if the association of proton pump inhibitors with incident chronic kidney disease involves an intermedi­ ate step of prolonged, subclinical interstitial nephritis. Diagnosis  The finding of otherwise unexplained kidney injury with or without oliguria and exposure to a potentially offending agent usually points to the diagnosis. Peripheral blood eosinophilia adds supporting evidence but is present in only a minority of patients. Urinaly­ sis reveals pyuria with white blood cell casts and hematuria. Urinary eosinophils are neither sensitive nor specific for AIN; therefore, test­ ing is not recommended. Kidney biopsy is generally not required for diagnosis but reveals extensive interstitial and tubular infiltration of leukocytes, including eosinophils. PART 9 Disorders of the Kidney and Urinary Tract TREATMENT Allergic Interstitial Nephritis Discontinuation of the offending agent often leads to reversal of the kidney injury. However, depending on the duration of exposure and degree of tubular atrophy and interstitial fibrosis that has occurred, the kidney damage may not be completely reversible. Glucocor­ ticoid therapy may accelerate kidney recovery but is not required in most cases. It is best reserved for those cases with severe kidney injury in which dialysis is imminent and should be started promptly if kidney function continues to deteriorate despite stopping the AKI with features of AIN Withdraw offending agent Supportive care and close observation No improvement in 1 week OR rapid progression Improvement Classic allergic AIN Atypical features Continue observation Corticosteroids Renal biopsy Fibrosis Classic AIN Granulomatous or other immune IN Conservative Corticosteroids Immunosuppressive drugs FIGURE 328-1  Algorithm for the treatment of allergic and other immune-mediated acute interstitial nephritis (AIN). AKI, acute kidney injury; IN, interstitial nephritis. See text for immunosuppressive drugs used for refractory or relapsing AIN. (From Treatment of acute interstitial nephritis, S Reddy & DJ Salant: Renal Failure, 07 Jul 2009, Taylor and Francis. Reprinted by permission of the publisher: Taylor and Francis Ltd, http://www.tandfonline.com.)

TABLE 328-2  Indications for Corticosteroids and Immunosuppressives in Interstitial Nephritis Absolute Indications • Sjögren’s syndrome • Sarcoidosis • SLE interstitial nephritis • Adults with TINU • Interstitial nephritis from IgG4-related disease • Idiopathic and other granulomatous interstitial nephritis Relative Indications • Drug-induced or idiopathic AIN with: • Rapid progression of renal failure • Diffuse infiltrates on biopsy • Impending need for dialysis • Delayed recovery • Children with TINU • Postinfectious AIN with delayed recovery (?) Abbreviations: AIN, acute interstitial nephritis; SLE, systemic lupus erythematosus; TINU, tubulointerstitial nephritis with uveitis. Source: From Treatment of acute interstitial nephritis, S Reddy & DJ Salant: Renal Failure, 07 Jul 2009, Taylor and Francis. Reprinted by permission of the publisher: Taylor and Francis Ltd, http://www.tandfonline.com. offending drug; delay in initiating dialysis leads to worse long-term outcomes (Fig. 328-1 and Table 328-2). SJÖGREN’S SYNDROME Sjögren’s syndrome is a systemic autoimmune disorder that primarily targets the exocrine glands, especially the lacrimal and salivary glands, and thus results in symptoms, such as dry eyes and mouth, which constitute the “sicca syndrome” (Chap. 373). TIN with a predomi­ nant lymphocytic infiltrate is the most common renal manifestation of Sjögren’s syndrome and can be associated with impaired kidney function, distal RTA, and nephrogenic diabetes insipidus. Diagnosis is strongly supported by positive serologic testing for anti-Ro (SS-A) and anti-La (SS-B) antibodies. A large proportion of patients with Sjögren’s syndrome also have polyclonal hypergammaglobulinemia. Treatment

is initially with glucocorticoids, although patients may require mainte­ nance therapy with azathioprine or mycophenolate mofetil to prevent relapse (Fig. 328-1 and Table 328-2). ■ ■TUBULOINTERSTITIAL NEPHRITIS WITH UVEITIS Tubulointerstitial nephritis with uveitis (TINU) is a systemic autoim­ mune disease of unknown etiology. It accounts for <5% of all cases of AIN, affects females three times more often than males, and has a median age of onset of 15 years. Its hallmark feature, in addition to a lymphocyte-predominant interstitial nephritis (Fig. 328-2), is a painful anterior uveitis, often bilateral and accompanied by blurred vision and photophobia. Diagnosis is often confounded by the fact that the ocular symptoms precede or accompany the kidney disease in only one-third of cases. Additional extrarenal features include fever, anorexia, weight loss, abdominal pain, and arthralgia. The presence of such symptoms as well as elevated creatinine, sterile pyuria, mild proteinuria, features of Fanconi’s syndrome, and elevated erythrocyte sedimentation rate should raise suspicion for this disorder. Serologies suggestive of the more common autoimmune diseases are usually negative, and TINU is often a diagnosis of exclusion after other causes of uveitis and kidney disease, such as Sjögren’s syndrome, Behçet’s disease, sarcoidosis, and systemic lupus erythematosus, have been considered. Clinical symp­ toms are typically self-limited in children but are more apt to follow a relapsing course in adults. The renal and ocular manifestations gener­ ally respond well to oral glucocorticoids, although maintenance ther­ apy with agents such as methotrexate, azathioprine, or mycophenolate may be necessary to prevent relapses (Fig. 328-1 and Table 328-2). ■ ■SYSTEMIC LUPUS ERYTHEMATOSUS An interstitial mononuclear cell inflammatory reaction accompanies the glomerular lesion in most cases of class III or IV lupus nephritis (Chap. 326), and deposits of immune complexes can be identified in tubular basement membranes in ~50% of cases. Occasionally, however, the tubulointerstitial inflammation predominates and may manifest with azotemia and type IV RTA rather than features of glomerulonephritis. ■ ■GRANULOMATOUS INTERSTITIAL NEPHRITIS Some patients may present with features of AIN but follow a protracted and relapsing course. Kidney biopsy in such patients reveals a more chronic inflammatory infiltrate with granulomas and multinucleated * T * G T T FIGURE 328-2  Acute interstitial nephritis (AIN) in a patient who presented with acute iritis, low-grade fever, erythrocyte sedimentation rate of 103, pyuria and cellular casts on urinalysis, and a newly elevated serum creatinine of 2.4 mg/dL. Both the iritis and AIN improved after intravenous methylprednisolone. This PASstained kidney biopsy shows a mononuclear cell interstitial infiltrate (asterisks) and edema separating the tubules (T) and a normal glomerulus (G). Some of the tubules contain cellular debris and infiltrating inflammatory cells. The findings in this biopsy are indistinguishable from those that would be seen in a case of drug-induced AIN. PAS, periodic acid–Schiff.

giant cells. Most often, no associated disease or cause is found; how­ ever, some of these cases may have or subsequently develop the pulmo­ nary, cutaneous, or other systemic manifestations of sarcoidosis such as hypercalcemia. Most patients experience some improvement in kidney function if treated early with glucocorticoids before the development of significant interstitial fibrosis and tubular atrophy (Table 328-2). Other immunosuppressive agents may be required for those who relapse fre­ quently upon steroid withdrawal (Fig. 328-1). Tuberculosis should be ruled out before starting treatment because this too is a rare cause of granulomatous interstitial nephritis.

■ ■CRYSTAL DEPOSITION DISORDERS AND OBSTRUCTIVE TUBULOPATHIES Acute kidney injury may occur when crystals of various types are deposited in tubular cells and interstitium or when they obstruct tubules. Impaired kidney function, often accompanied by flank pain from tubular obstruction, may occur in patients treated with sulfa­ diazine for toxoplasmosis, indinavir and atazanavir for HIV, and intra­ venous acyclovir for severe herpesvirus infections. Urinalysis reveals “sheaf of wheat” sulfonamide crystals, individual or parallel clusters of needle-shaped indinavir crystals, or red-green birefringent needleshaped crystals of acyclovir. This adverse effect is generally precipitated by hypovolemia and is reversible with saline volume repletion and drug withdrawal. Distinct from the obstructive disease, a frank AIN from indinavir crystal deposition has also been reported.

Acute tubular obstruction is also the cause of oliguric kidney injury in patients with acute urate nephropathy. It typically results from severe hyperuricemia from tumor lysis syndrome in patients with lympho- or myeloproliferative disorders treated with cytotoxic agents but also may occur spontaneously before the treatment has been initiated (Chap. 80). Uric acid crystallization in the tubules and collecting system leads to partial or complete obstruction of the collecting ducts, renal pelvis, or ureter. A dense precipitate of birefringent uric acid crys­ tals is found in the urine, usually in association with microscopic or gross hematuria. Prophylactic allopurinol reduces the risk of uric acid nephropathy but is of no benefit once tumor lysis has occurred. Once oliguria has developed, attempts to increase tubular flow and solubility of uric acid with alkaline diuresis may be of some benefit; however, emergent treatment with hemodialysis or rasburicase, a recombinant urate oxidase, is usually required to rapidly lower uric acid levels and restore kidney function. PART 9 Disorders of the Kidney and Urinary Tract Calcium oxalate crystal deposition in tubular cells and interstitium may lead to permanent kidney dysfunction in patients who survive ethylene glycol intoxication, in patients with enteric hyperoxaluria from ileal resection or small-bowel bypass surgery, and in patients with hereditary hyperoxaluria (Chap. 330). Acute phosphate nephropathy is an uncommon but serious complication of oral Phosphosoda used as a laxative or for bowel preparation for colonoscopy. It results from calcium phosphate crystal deposition in tubules and interstitium and occurs especially in subjects with underlying kidney disease and hypo­ volemia. Consequently, Phosphosoda should be avoided in patients with chronic kidney disease, and appropriately, the product is no lon­ ger widely available in the United States. ■ ■LIGHT CHAIN CAST NEPHROPATHY Patients with multiple myeloma may develop acute kidney injury in the setting of hypovolemia, infection, or hypercalcemia or after exposure to NSAIDs or radiographic contrast media. The diagnosis of light chain cast nephropathy (LCCN)—commonly known as myeloma kidney—should be considered in patients who fail to recover when the precipitating factor is corrected or in any elderly patient with otherwise unexplained acute kidney injury. In this disorder, filtered monoclonal immunoglobulin light chains (Bence-Jones proteins) form intratubular aggregates with secreted Tamm-Horsfall protein in the distal tubule. Casts, in addition to obstructing the tubular flow in affected nephrons, incite a giant cell or foreign-body reaction and can lead to tubular rupture, resulting in interstitial fibrosis (Fig. 328-3). Although LCCN generally occurs in patients with known multiple myeloma and a large plasma cell burden, the disorder should also be considered as a possible diagnosis in patients who have known monoclonal gammopathy even in the absence of frank myeloma. Filtered monoclonal light chains may also cause less pronounced renal manifestations in the absence of obstruc­ tion, due to direct toxicity to proximal tubular cells and intracellular crystal formation. This may result in isolated tubular disorders such as RTA or full Fanconi’s syndrome. Diagnosis  Clinical clues to the diagnosis include anemia, bone pain, hypercalcemia, and an abnormally narrow anion gap due to hypoalbuminemia and hypergammaglobulinemia. Urinary dipsticks

FIGURE 328-3  Histologic appearance of myeloma cast nephropathy. A hematoxylineosin–stained kidney biopsy shows many atrophic tubules filled with eosinophilic casts (consisting of Bence-Jones protein), which are surrounded by giant cell reactions. (Courtesy of Dr. Michael N. Koss, University of Southern California Keck School of Medicine; with permission.) detect albumin but not immunoglobulin light chains; however, labora­ tory detection of increased amounts of protein in a spot urine speci­ men and a negative dipstick result are highly suggestive that the urine contains Bence-Jones protein. Serum and urine should both be sent for protein electrophoresis and for immunofixation for the detection and identification of a potential monoclonal band. A sensitive method is available to detect urine and serum free light chains. TREATMENT Light Chain Cast Nephropathy The goals of treatment are to correct precipitating factors such as hypovolemia and hypercalcemia, discontinue potential nephrotoxic agents, and treat the underlying plasma cell dyscrasia (Chap. 116); plasmapheresis to remove light chains is of questionable value for LCCN. ■ ■LYMPHOMATOUS INFILTRATION OF THE KIDNEY Interstitial infiltration by malignant B lymphocytes is a common autopsy finding in patients dying of chronic lymphocytic leukemia and non-Hodgkin’s lymphoma; however, this is usually an incidental finding. Rarely, such infiltrates may cause massive enlargement of the kidneys and oliguric acute kidney injury. Although high-dose gluco­ corticoids and subsequent chemotherapy often result in recovery of kidney function, the prognosis in such cases is generally poor. CHRONIC TUBULOINTERSTITIAL DISEASES Improved occupational and public health measures, together with the banning of over-the-counter phenacetin-containing analgesics, has led to a dramatic decline in the incidence of chronic interstitial nephritis (CIN) from heavy metal—particularly lead and cadmium—exposure and analgesic nephropathy in North America. Today, CIN is most often the result of renal ischemia or secondary to a primary glomerular dis­ ease (Chap. 326). Other important forms of CIN are the result of devel­ opmental anomalies or inherited diseases such as reflux nephropathy or sickle cell nephropathy and may not be recognized until adolescence or adulthood. Although it is impossible to reverse damage that has already occurred, further deterioration may be prevented or at least slowed in such cases by treating glomerular hypertension, a common denominator in the development of secondary FSGS and progressive loss of functioning nephrons. Therefore, awareness and early detection of patients at risk may prevent them from developing end-stage renal disease (ESRD).

■ ■VESICOURETERAL REFLUX AND REFLUX NEPHROPATHY Reflux nephropathy is the consequence of vesicoureteral reflux (VUR) or other urologic anomalies in early childhood. It was previously called chronic pyelonephritis because it was believed to result from recurrent urinary tract infections (UTIs) in childhood. VUR stems from abnor­ mal retrograde urine flow from the bladder into one or both ureters and kidneys because of mislocated and incompetent ureterovesical valves (Fig. 328-4). Although high-pressure sterile reflux may impair normal growth of the kidneys, when coupled with recurrent UTIs in early childhood, the result is patchy interstitial scarring and tubular atrophy. Loss of functioning nephrons leads to hypertrophy of the remnant glomeruli and eventual secondary FSGS. Reflux nephropathy often goes unnoticed until early adulthood when chronic kidney disease is detected during routine evaluation or during pregnancy. Affected adults are frequently asymptomatic but may give a history of prolonged A C FIGURE 328-4  Radiographs of vesicoureteral reflux (VUR) and reflux nephropathy. A. Voiding cystourethrogram in a 7-month-old baby with bilateral high-grade VUR evidenced by clubbed calyces (arrows) and dilated tortuous ureters (U) entering the bladder (B). B. Abdominal computed tomography scan (coronal plane reconstruction) in a child showing severe scarring of the lower portion of the right kidney (arrow). C. Sonogram of the right kidney showing loss of parenchyma at the lower pole due to scarring (arrow) and hypertrophy of the mid-region (arrowhead). (Courtesy of Dr. George Gross, University of Maryland Medical Center; with permission.)

bed-wetting or recurrent UTIs during childhood and may exhibit vari­ able degrees of kidney injury as well as hypertension, mild to moderate proteinuria, and an unremarkable urine sediment. When both kidneys are affected, the disease often progresses inexorably over several years to ESRD, despite the absence of ongoing urinary infections or reflux. A single affected kidney may go undetected, except for the presence of hypertension. Kidney ultrasound in adults characteristically shows asymmetric small kidneys with irregular outlines, thinned cortices, and regions of compensatory hypertrophy (Fig. 328-4).

TREATMENT Vesicoureteral Reflux and Reflux Nephropathy While it was previously believed that maintenance of sterile urine in childhood limits scarring of the kidneys, a recent study found CHAPTER 328 Tubulointerstitial Diseases of the Kidney B

no such benefit, at least for 2 years. Surgical reimplantation of the ureters into the bladder to restore competency is indicated in young children with persistent high-grade reflux but is ineffective and is not indicated in adolescents or adults after scarring has occurred. Aggressive control of blood pressure and/or glomerular hyperfiltra­ tion with an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) and other agents (e.g., sodiumglucose cotransporter 2 [SGLT2] inhibitors) is effective in reducing proteinuria and may significantly forestall further deterioration of kidney function.

■ ■SICKLE CELL NEPHROPATHY The pathogenesis and clinical manifestations of sickle cell nephropathy are described in Chap. 329. Evidence of tubular injury may be evi­ dent in childhood and early adolescence in the form of polyuria due to decreased concentrating ability or type IV RTA years before there is significant nephron loss and proteinuria from secondary FSGS. Early recognition of these subtle renal abnormalities or development of microalbuminuria in a child with sickle cell disease may warrant consultation with a nephrologist and/or therapy with low-dose ACEIs. Papillary necrosis may result from ischemia due to sickling of red cells in the relatively hypoxemic and hypertonic medullary vasculature and present with gross hematuria and ureteric obstruction by sloughed ischemic papillae (Table 328-3). PART 9 Disorders of the Kidney and Urinary Tract ■ ■TUBULOINTERSTITIAL ABNORMALITIES ASSOCIATED WITH GLOMERULONEPHRITIS Primary glomerulopathies are often associated with damage to tubules and interstitium. This may occasionally be due to the same pathologic process affecting the glomerulus and tubulointerstitium, as is the case with immune-complex deposition in lupus nephritis. More often, how­ ever, chronic tubulointerstitial changes occur as a secondary conse­ quence of prolonged glomerular dysfunction. Potential mechanisms by which glomerular disease might cause tubulointerstitial injury include proteinuria-mediated damage to the epithelial cells, activation of tubu­ lar cells by cytokines and complement, or reduced peritubular blood flow leading to downstream tubulointerstitial ischemia, especially in the case of glomeruli that are globally obsolescent due to severe glo­ merulonephritis. It is often difficult to discern the initial cause of injury by kidney biopsy in a patient who presents with advanced kidney dis­ ease in this setting. ■ ■ANALGESIC NEPHROPATHY Analgesic nephropathy results from the long-term use of compound analgesic preparations containing phenacetin (banned in the United States since 1983), aspirin, and caffeine. In its classic form, analgesic nephropathy is characterized by impaired kidney function, papillary necrosis (Table 328-3) attributable to the presumed concentration of the drug to toxic levels in the inner medulla, and a radiographic constellation of small, scarred kidneys with papillary calcifications. Patients may also have polyuria due to impaired concentrating ability and non-anion-gap metabolic acidosis from tubular damage. Shedding of a sloughed necrotic papilla can cause gross hematuria and ureteric colic due to ureteral obstruction. Individuals with ESRD as a result of analgesic nephropathy are at increased risk of a urothelial malignancy compared to patients with other causes of kidney failure. ■ ■ARISTOLOCHIC ACID NEPHROPATHY Two seemingly unrelated forms of CIN, Chinese herbal nephropathy and Balkan endemic nephropathy, have recently been linked by the underlying etiologic agent aristolochic acid and are now collectively TABLE 328-3  Major Causes of Papillary Necrosis Analgesic nephropathy Sickle cell nephropathy Diabetes with urinary tract infection Prolonged NSAID use (rare) Abbreviation: NSAID, nonsteroidal anti-inflammatory drug.

termed aristolochic acid nephropathy (AAN). In Chinese herbal nephropathy, first described in the early 1990s in young women tak­ ing traditional Chinese herbal preparations as part of a weight-loss regimen, one of the offending agents has been identified as aristolo­ chic acid, a known carcinogen from the plant Aristolochia. Multiple Aristolochia species have been used in traditional herbal remedies for centuries and continue to be available despite official bans on their use in many countries. Molecular evidence has also implicated aristolochic acid in Balkan endemic nephropathy, a chronic TIN found primarily in towns along the tributaries of the Danube River and first described in the 1950s. Although the exact route of exposure is not known with cer­ tainty, contamination of local grain preparations with the seeds of Aris­ tolochia species seems most likely. Aristolochic acid, after prolonged exposure, produces renal interstitial fibrosis with a relative paucity of cellular infiltrates. The urine sediment is bland, with rare leukocytes and only mild proteinuria. Anemia may be disproportionately severe relative to the level of kidney dysfunction. Definitive diagnosis of AAN requires two of the following three features: characteristic histology on kidney biopsy; confirmation of aristolochic acid ingestion; and detec­ tion of aristolactam-DNA adducts in kidney or urinary tract tissue. These latter lesions represent a molecular signature of aristolochic acid–derived DNA damage and often consist of characteristic A:T-toT:A transversions. Due to this mutagenic activity, AAN is associated with a very high incidence of upper urinary tract urothelial cancers, with risk related to cumulative dose. Surveillance with computed tomography, ureteroscopy, and urine cytology is warranted, and con­ sideration should be given to bilateral nephroureterectomy once a patient has reached ESRD. ■ ■KARYOMEGALIC INTERSTITIAL NEPHRITIS Karyomegalic interstitial nephritis is an unusual form of slowly pro­ gressive chronic kidney disease with mild proteinuria, interstitial fibrosis, tubular atrophy, and oddly enlarged nuclei of proximal tubular epithelial cells. It has been linked to mutations in FAN1, a nuclease involved in DNA repair, which may render carriers of the mutation susceptible to environmental DNA-damaging agents. ■ ■LITHIUM-ASSOCIATED NEPHROPATHY The use of lithium salts for the treatment of manic-depressive illness may have several renal sequelae, the most common of which is neph­ rogenic diabetes insipidus manifesting as polyuria and polydipsia. Lithium accumulates in principal cells of the collecting duct by enter­ ing through the epithelial sodium channel (ENaC), where it inhibits glycogen synthase kinase 3β and downregulates vasopressin-regulated aquaporin water channels. Less frequently, chronic TIN develops after prolonged (>10–20 years) lithium use and is most likely to occur in patients who have experienced repeated episodes of toxic lithium lev­ els. Findings on kidney biopsy include interstitial fibrosis and tubular atrophy that are out of proportion to the degree of glomerulosclerosis or vascular disease, a sparse lymphocytic infiltrate, and small cysts or dilation of the distal tubule and collecting duct that are highly char­ acteristic of this disorder. The degree of interstitial fibrosis correlates with both duration and cumulative dose of lithium. Individuals with lithium-associated nephropathy are typically asymptomatic, with mini­ mal proteinuria, few urinary leukocytes, and normal blood pressure. Some patients develop more severe proteinuria due to secondary FSGS, which may contribute to further loss of kidney function. TREATMENT Lithium-Associated Nephropathy Kidney function should be followed regularly in patients taking lithium, and caution should be exercised in patients with underly­ ing kidney disease. The use of amiloride to inhibit lithium entry via ENaC has been effective to prevent and treat lithium-induced nephrogenic diabetes insipidus, but it is not clear if it will pre­ vent lithium-induced CIN. Once lithium-associated nephropathy is detected, the discontinuation of lithium in attempt to forestall

further deterioration of kidney function can be problematic, as lith­ ium is an effective mood stabilizer that is often incompletely sub­ stituted by other agents. Furthermore, despite discontinuation of lithium, chronic kidney disease in such patients is often irreversible and can slowly progress to ESRD. The most prudent approach is to monitor lithium levels frequently and adjust dosing to avoid toxic levels (preferably <1 meq/L). This is especially important because lithium is cleared less effectively as kidney function declines. ■ ■CALCINEURIN INHIBITOR NEPHROTOXICITY The calcineurin inhibitor (CNI) immunosuppressive agents cyclospo­ rine and tacrolimus can cause both acute and chronic kidney injury. Acute forms can result from vascular causes such as vasoconstriction or the development of thrombotic microangiopathy or can be due to a toxic tubulopathy. Chronic CNI-induced kidney injury is typically seen in solid organ (including heart-lung and liver) transplant recipi­ ents and manifests with a slow but irreversible reduction of glomerular filtration rate, with mild proteinuria and arterial hypertension. Hyper­ kalemia is a relatively common complication and is caused, in part, by tubular resistance to aldosterone. The histologic changes in kidney tissue include patchy interstitial fibrosis and tubular atrophy, often in a “striped” pattern. In addition, the intrarenal vasculature often demon­ strates hyalinosis, and focal glomerulosclerosis can be present as well. Similar changes may occur in patients receiving CNIs for autoimmune diseases, although the doses are generally lower than those used for organ transplantation. Dose reduction or CNI avoidance appears to mitigate the chronic tubulointerstitial changes but may increase the risk of rejection and graft loss. ■ ■HEAVY METAL (LEAD) NEPHROPATHY Heavy metals, such as lead or cadmium, can lead to a chronic tubu­ lointerstitial process after prolonged exposure. The disease entity is no longer commonly diagnosed, because such heavy metal exposure has been greatly reduced due to the known health risks from lead and the consequent removal of lead from most commercial products and fuels. Nonetheless, occupational exposure is possible in workers involved in the manufacture or destruction of batteries, removal of lead paint, or manufacture of alloys and electrical equipment (cadmium) in countries where industrial regulation is less stringent. In addition, ingestion of moonshine whiskey distilled in lead-tainted containers has been one of the more frequent sources of lead exposure. Early signs of chronic lead intoxication are attributable to proximal tubule dysfunction, particularly hyperuricemia as a result of dimin­ ished urate secretion. The triad of “saturnine gout,” hypertension, and impaired kidney function should prompt a practitioner to ask specifi­ cally about lead exposure. Unfortunately, evaluating lead burden is not as straightforward as ordering a blood test; the preferred methods involve measuring urinary lead after infusion of a chelating agent or by radiographic fluoroscopy of bone. Several recent studies have shown an association between chronic low-level lead exposure and decreased kidney function, although either of these two factors may have been the primary event. In patients who have CIN of unclear origin and an elevated total body lead burden, repeated treatments of lead chelation therapy have been shown to slow the decline in kidney function. METABOLIC DISORDERS Disorders leading to excessively high or low levels of certain elec­ trolytes and products of metabolism can also lead to chronic kidney disease if untreated. ■ ■CHRONIC URIC ACID NEPHROPATHY The constellation of pathologic findings that represent gouty nephropa­ thy is very uncommon nowadays and is more of historical interest than clinical importance, as gout is typically well managed with allopurinol and other agents. However, there is emerging evidence that hyperuri­ cemia is an independent risk factor for the development of chronic kidney disease, perhaps through endothelial damage. The complex interactions of hyperuricemia, hypertension, and kidney failure are still incompletely understood.

Presently, gouty nephropathy is most likely to be encountered in patients with severe tophaceous gout and prolonged hyperuricemia from a hereditary disorder of purine metabolism. This should be distinguished from juvenile hyperuricemic nephropathy, a form of medullary cystic kidney disease caused by mutations in uromodulin (UMOD) (Chap. 327) and now grouped into the larger category of autosomal dominant tubulointerstitial kidney disease. Histologically, the distinctive feature of gouty nephropathy is the presence of crystal­ line deposits of uric acid and monosodium urate salts in the kidney parenchyma. These deposits not only cause intrarenal obstruction but also incite an inflammatory response, leading to lymphocytic infiltra­ tion, foreign-body giant cell reaction, and eventual fibrosis, especially in the medullary and papillary regions of the kidney. Since patients with gout frequently suffer from hypertension and hyperlipidemia, degenerative changes of the renal arterioles may constitute a striking feature of the histologic abnormality, out of proportion to the other morphologic defects. Clinically, gouty nephropathy is an insidious cause of chronic kidney disease. Early in its course, glomerular filtra­ tion rate may be near normal, often despite morphologic changes in medullary and cortical interstitium, proteinuria, and diminished urinary concentrating ability. Treatment with allopurinol and urine alkalinization is generally effective in preventing uric acid nephro­ lithiasis and the consequences of recurrent kidney stones; however, gouty nephropathy may be intractable to such measures. Furthermore, the use of allopurinol in asymptomatic hyperuricemia has not been consistently shown to improve kidney function.

CHAPTER 328 ■ ■HYPERCALCEMIC NEPHROPATHY (See also Chap. 422) Chronic hypercalcemia, as occurs in primary hyperparathyroidism, sarcoidosis, multiple myeloma, vitamin D intox­ ication, or metastatic bone disease, can cause tubulointerstitial disease and progressive kidney injury. The earliest lesion is a focal degenerative change in renal epithelia, primarily in collecting ducts, distal tubules, and loops of Henle. Tubular cell necrosis leads to nephron obstruction and stasis of intrarenal urine, favoring local precipitation of calcium salts and infection. Dilation and atrophy of tubules eventually occur, as do interstitial fibrosis, mononuclear leukocyte infiltration, and inter­ stitial calcium deposition (nephrocalcinosis). Calcium deposition may also occur in glomeruli and the walls of renal arterioles. Tubulointerstitial Diseases of the Kidney Clinically, the most striking defect is an inability to maximally con­ centrate the urine, due to reduced collecting duct responsiveness to arginine vasopressin and defective transport of sodium and chloride in the loop of Henle. Reductions in both glomerular filtration rate and renal blood flow can occur, both in acute and in prolonged hypercal­ cemia. Eventually, uncontrolled hypercalcemia leads to severe tubu­ lointerstitial damage and overt kidney injury. Abdominal x-rays may demonstrate nephrocalcinosis as well as nephrolithiasis, the latter due to the hypercalciuria that often accompanies hypercalcemia. Treatment consists of reducing the serum calcium concentration toward normal and correcting the primary abnormality of calcium metabolism (Chap. 422). Acute kidney injury from acute hypercalce­ mia may be completely reversible. Gradual progressive kidney dysfunc­ tion related to chronic hypercalcemia, however, may not improve even with correction of the calcium disorder. ■ ■HYPOKALEMIC NEPHROPATHY Patients with prolonged and severe hypokalemia from chronic laxative or diuretic abuse, surreptitious vomiting, or primary aldosteronism may develop a reversible tubular lesion characterized by vacuolar degeneration of proximal and distal tubular cells. Eventually, tubular atrophy and cystic dilation accompanied by interstitial fibrosis may ensue, leading to irreversible chronic kidney disease. Timely correc­ tion of the hypokalemia will prevent further progression, but persistent hypokalemia can cause ESRD. GLOBAL PERSPECTIVE The causes of AIN and CIN vary widely across the globe. Analgesic nephropathy continues to be seen in countries where phenacetincontaining compound analgesic preparations are readily available.

11 - 329 Thrombotic Renovascular Disorders

329 Thrombotic Renovascular Disorders

Adulterants in unregulated herbal and traditional medicaments pose a threat of toxic interstitial nephritis, as exemplified by aristolochic acid contamination of herbal slimming preparations. Contamination of food sources with toxins, such as an outbreak of nephrolithiasis and acute kidney injury from melamine contamination of infant milk formula, poses a continuing risk. Large-scale exposure to aristolochic acid remains prevalent in many Asian countries where traditional herbal medicine use is common. Although industrial exposure to lead and cadmium has largely disappeared as a cause of CIN in developed nations, it remains a risk for nephrotoxicity in countries where such exposure is less well controlled.

New endemic forms of chronic kidney disease continue to be described. In particular, nephropathies with features of CIN have been increasing in prevalence among Pacific coastal plantation work­ ers in Central America (Mesoamerican nephropathy), Sri Lanka (Sri Lankan nephropathy), and southern India (Uddanam nephropathy). Together, these disorders have been called chronic interstitial nephritis of agricultural communities (CINAC) or chronic kidney disease of unknown etiology (CKDu) and may be related to repetitive episodes of heat exposure, dehydration, and volume depletion in the field work­ ers. However, toxins, pesticides, and infective agents also remain as possible etiologic agents. Global warming and regional temperature variability have been proposed as contributors to these newly described forms of kidney disease, and tens of thousands of lives have been lost due to ESRD in these resource-poor areas in which renal replacement therapy is often not an option. PART 9 Disorders of the Kidney and Urinary Tract ■ ■FURTHER READING Eckardt KU et al: Autosomal dominant tubulointerstitial kidney disease: Diagnosis, classification, and management: A KDIGO con­ sensus report. Kidney Int 88:676, 2015. Johnson RJ et al: Chronic kidney disease of unknown cause in agricul­ tural communities. N Engl J Med 380:1843, 2019. Perazella MA, Rosner MH: Drug-induced acute kidney injury. Clin J Am Soc Nephrol 17:1220, 2022. Praga M et al: Changes in the aetiology, clinical presentation and management of acute interstitial nephritis, an increasingly common cause of acute kidney injury. Nephrol Dial Transplant 30:1472, 2015. Seethapathy H et al: The incidence, causes, and risk factors of acute kidney injury in patients receiving immune checkpoint inhibitors. Clin J Am Soc Nephrol 14:1692, 2019. Elisabeth M. Battinelli, Rebecca L. Zon

Thrombotic

Renovascular Disorders The renal circulation is complex and is characterized by a highly perfused arteriolar network, reaching cortical glomerular structures adjacent to lower-flow vasa recta that descend into medullary segments. This chapter examines primary disorders of the microvessels, many of which are associated with thrombosis and hemolysis. Disorders of the larger vessels, including renal artery stenosis and atheroembolic disease, are discussed elsewhere (Chap. 289). THROMBOTIC MICROANGIOPATHY Thrombotic microangiopathy (TMA) is a pathologic lesion character­ ized by endothelial cell injury in the terminal arterioles and capillaries. Platelet and hyaline thrombi causing partial or complete occlusion are integral to the histopathology of TMA. TMA is usually accompanied by microangiopathic hemolytic anemia (MAHA) with its typical features of thrombocytopenia and schistocytes, but not always. In the kidney,

TMA is characterized by swollen endocapillary cells (endotheliosis), fibrin thrombi, platelet plugs, arterial intimal fibrosis, and a membra­ noproliferative pattern in the glomerulus. Fibrin thrombi may extend into the arteriolar vascular pole, producing glomerular collapse and at times cortical necrosis. In kidneys that recover from acute TMA, secondary focal segmental glomerulosclerosis may develop. Throm­ botic vascular diseases include thrombotic thrombocytopenic purpura (TTP), hemolytic-uremic syndrome (HUS), malignant hypertension, scleroderma renal crisis, antiphospholipid syndrome, preeclampsia/ HELLP (hemolysis, elevated liver enzymes, low platelet count) syn­ drome, HIV infection, cancer-associated TMA, and microvascular disease associated with COVID-19. ■ ■HEMOLYTIC-UREMIC SYNDROME/THROMBOTIC THROMBOCYTOPENIC PURPURA HUS and TTP are the prototypes for MAHA. Historically, HUS and TTP were distinguished mainly by their clinical and epidemiologic differences. TTP develops more commonly in adults and was thought to have more neurologic complications, while HUS occurs more frequently in children, particularly when associated with hemorrhagic diarrhea. However, atypical HUS (aHUS) can have its first appearance in adulthood, and neurologic involvement can be as common in HUS as in TTP. Currently, HUS and TTP can be differentiated etiologically and treated according to their specific pathophysiologic features. Hemolytic-Uremic Syndrome  HUS is loosely defined by the presence of MAHA and renal impairment. At least four variants are recognized. The most common is Shiga toxin–producing Escherichia coli (STEC) HUS, which is also known as D+ (diarrhea-associated) HUS or enterohemorrhagic E. coli (EHEC) HUS. Most cases involve children <5 years of age, but adults also are susceptible, as evidenced by a 2011 outbreak in northern Europe. Diarrhea, often bloody, precedes MAHA within 1 week in >80% of cases. Abdominal pain, cramping, and vomiting are frequent, whereas fever is typically absent. Neurologic symptoms, including dysphasia, hyperreflexia, blurred vision, memory deficits, encephalopathy, perseveration, and agraphia, often develop, especially in adults. Seizures and cerebral infarction can occur in severe cases. STEC HUS is caused by the Shiga toxins (Stx1 and Stx2), which are also referred to as verotoxins. These toxins are produced by certain strains of E. coli and Shigella dysenteriae. In the United States and Europe, the most common STEC strain is O157:H7, but HUS has been reported with other strains (O157/H–, O111:H–, O26:H11/H–, O145:H28, and O104:H4). After entry into the circulation, Shiga toxin binds to the glycolipid surface receptor globotriaosylceramide (Gb3), which is richly expressed on cells of the renal microvasculature. Upon binding, the toxin enters the cells, inducing inflammatory cytokines (interleukin 8 [IL-8], monocyte chemotactic protein 1 [MCP-1], and stromal cell–derived factor 1 [SDF-1]) and chemokine receptors (CXCR4 and CXCR7); this action results in platelet aggregation and the microangiopathic process. Streptococcus pneumoniae can also cause HUS. Certain strains produce a neuraminidase that cleaves the N-acetylneuraminic acid moieties normally covering the ThomsenFriedenreich antigen on platelets and endothelial cells. Exposure of this cryptic antigen to preformed IgM results in severe MAHA. aHUS or complement-mediated HUS is the result of complement dysregulation. The complement dysregulation can be congenital or acquired. The affected patients often have low C3 and normal C4 levels characteristic of alternative pathway activation. Factor H deficiency, the most common defect, has been linked to families with aHUS. Factor H competes with factor B to prevent the formation of C3bBb and acts as a cofactor for factor I, which proteolytically degrades C3b. More than 70 mutations of the factor H gene have been identified. Most are missense mutations that produce abnormalities in the C-terminus region, affecting its binding to C3b but not its concentration. Other mutations result in low levels or the complete absence of the protein. Deficiencies in other complement-regulatory proteins, such as fac­ tor I, factor B, membrane cofactor protein (CD46), C3, complement factor H (CFH)–related protein 1 (CFHR1), CFHR3, CFHR5, and thrombomodulin, have also been reported. Finally, an autoimmune variant of aHUS, DEAP (deficiency of CFHR plasma proteins and

CFH autoantibody positive) HUS, occurs when an autoantibody to factor H is formed. DEAP HUS is often associated with a deletion of an 84-kb fragment of the chromosome that encodes for CFHR1 and CFHR3. The autoantibody blocks the binding of factor H to C3b and surface-bound C3 convertase. Renal injury is often severe, resulting in end-stage renal disease. The severity of the renal injury and recurrence after kidney transplant depend on the complement regulatory protein. Thrombotic Thrombocytopenic Purpura  Traditionally, TTP is characterized by the pentad of MAHA, thrombocytopenia, neuro­ logic symptoms, fever, and renal failure; however, <5% of individuals with immune-mediated TTP will have the full pentad. The patho­ physiology of TTP involves the accumulation of ultra-large multim­ ers of von Willebrand factor as a result of the absence or markedly decreased activity of the plasma protease ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13. TTP is now defined as MAHA associated with ADAMTS13 activity of <5–10%. These ultra-large multimers form clots and shear erythro­ cytes, resulting in MAHA; however, the absence of ADAMTS13 alone may not by itself produce TTP. Often, an additional inflammatory trig­ ger (such as infection, surgery, pancreatitis, or pregnancy) is required to initiate clinical TTP. This may be mediated by human neutrophil peptides that inhibit cleavage of von Willebrand factor by ADAMTS13. TTP can be congenital from ADAMTS13 mutation (cTTP) or acquired from autoantibody against ADAMTS13 protein (iTTP). cTTP, also known as Upshaw-Schülman syndrome, is characterized by congenital deficiency of ADAMTS13. cTTP can start within the first weeks of life but, in some instances, may not present until adulthood, especially during pregnancy. Both environmental and genetic factors are thought to influence the development of cTTP. Plasma transfusion is an effective strategy for prevention and treatment. In iTTP, autoantibody to ADAMTS13 (IgG or IgM) either increases its clearance or inhibits its activity. Data from the Oklahoma TTP/HUS Registry suggest an iTTP incidence rate of 2.9 cases/106 patients in the United States. The median age of onset is 40 years. The incidence is more than nine times higher among blacks than nonblacks. Like that of systemic lupus erythemato­ sus, the incidence of iTTP is nearly three times higher among women than among men. If untreated, iTTP has a mortality rate exceeding 90%. Even with modern therapy, 20% of patients die within the first month from complications of microvascular thrombosis. Drug-induced TMA is a recognized complication of treatment with some chemotherapeutic agents, immunosuppressive agents, and quinine. Two different mechanisms are now recognized. Toxic or endothelial damage (pathologically similar to that of HUS) is the main cause of the TMA that develops in association with chemotherapeu­ tic agents (e.g., proteasome inhibitors [bortezomib, carfilzomib, and ixazomib], mitomycin C, and gemcitabine) and immunosuppressive agents (cyclosporine, interferon, sirolimus, and tacrolimus). This process is usually dose-dependent. Alternatively, TMA may develop as a result of drug-induced autoantibodies. This form is less likely to be dose-dependent and can, in fact, occur after a single dose in patients with previous exposure (quinine). ADAMTS13 deficiency is found in fewer than half of patients with clopidogrel-associated TTP. Quinine appears to induce autoantibodies to granulocytes, lymphocytes, endo­ thelial cells, and platelet glycoprotein Ib/IX or IIb/IIIa complexes, but not to ADAMTS13. Quinine-associated TTP is more common among women. TMA has also been reported with drugs that inhibit vascular endothelial growth factor, such as bevacizumab; the mechanism is not completely understood. TREATMENT Hemolytic-Uremic Syndrome/Thrombotic Thrombocytopenic Purpura Treatment should be based on pathophysiology. iTTP and DEAP HUS respond to the combination of plasma exchange and predni­ sone. In addition to removing the autoantibodies, plasma exchange with fresh-frozen plasma replaces ADAMTS13. Twice-daily plasma

exchanges with administration of rituximab may be effective in refractory cases. The use of caplacizumab, a monoclonal antibody fragment that binds to the A1 domain of von Willebrand fac­ tor, blocking its interaction with platelets, was recently shown to improve platelet count recovery and reduce the composite risk of death, disease exacerbation, and thromboembolic events. It is now approved for use in iTTP in conjunction with plasma exchange and immunosuppressive therapy. Plasma infusion is usually sufficient to replace the ADAMTS13 in cTTP. Plasma exchange should be con­ sidered if larger volumes are necessary. Additionally, newer medica­ tions are being studied and utilized in TTP, such as caplacizumab, a humanized monoclonal antibody fragment that binds to von Willebrand factor and blocks its interaction with platelet glycopro­ teins. Caplacizumab can be considered as an additive medication, especially in those with severe features of TTP or in cases with con­ tinued thrombocytopenia that does not respond to initial therapy.

Plasma infusion/exchange is effective in certain types of aHUS because it replaces complement-regulatory proteins. Eculizumab and ravulizumab, anti-C5 monoclonal antibodies, are approved for use in aHUS and have been shown to abort MAHA and improve renal function. Antibiotics and washed red cells should be given in neuraminidase-associated HUS, and plasmapheresis may be helpful; however, plasma and whole-blood transfusion should be avoided since these products contain IgM, which may exacerbate MAHA. Combined factor H and ADAMTS13 deficiency has been reported. The affected patients are generally less responsive to plasma infusion, an outcome that illustrates the complexity of the management of these cases. CHAPTER 329 Thrombotic Renovascular Disorders Drug-induced TMA secondary to endothelial damage typically does not respond to plasma exchange and is treated primarily by discontinuing the use of the agent and, if refractory, a trial of C5 inhibitors. Similarly, STEC HUS should be treated with supportive measures as plasma exchange has not been found to be effective. Antimotility agents and antibiotics increase the incidence of HUS among children, but azithromycin may decrease the duration of bacterial shedding in adults. ■ ■HEMATOPOIETIC STEM CELL TRANSPLANTATION–ASSOCIATED THROMBOTIC MICROANGIOPATHY Hematopoietic stem cell transplantation (HSCT)–associated TMA develops after allogeneic HSCT, with an incidence of ~8%. Etiologic factors include conditioning regimens, immunosuppression, infec­ tions, and graft-versus-host disease. Other risk factors include female sex and human leukocyte antigen (HLA)–mismatched donor grafts. HSCT-TMA usually occurs within the first 100 days of HSCT. Table 329-1 lists definitions of HSCT-TMA currently used for clinical trials. Diagnosis may be difficult since thrombocytopenia, anemia, and renal insufficiency are common after HSCT. HSCT-TMA carries a high mortality rate (75% within 3 months). The majority of patients have

10% ADAMTS13 activity, and plasma exchange is beneficial in <25% TABLE 329-1  Criteria for Establishing Microangiopathic Kidney Injury Associated with Hematopoietic Stem Cell Transplantation INTERNATIONAL

WORKING GROUP BLOOD AND MARROW TRANSPLANT CLINICAL TRIALS NETWORK TOXICITY COMMITTEE

4% schistocytes in the blood RBC fragmentation and at least 2 schistocytes per high-power field De novo, prolonged, or progressive thrombocytopenia Concurrent increase in LDH above baseline A sudden and persistent increase in LDH Negative direct and indirect Coombs test Decrease in hemoglobin or increased RBC transfusion requirement Concurrent renal and/or neurologic dysfunction without other explanations Decrease in haptoglobin concentration Abbreviations: LDH, lactate dehydrogenase; RBC, red blood cell.

of patients. Discontinuation of calcineurin inhibitors and treatment of infections or sinusoidal obstruction syndrome (if present) are recom­ mended. There are increasing reports of successful use of eculizumab, but clinical trial data are lacking.

■ ■CANCER-ASSOCIATED TMA When MAHA and thrombocytopenia are present, one should assess for evidence of malignancy and consider the diagnosis of cancerassociated TMA. The mechanism of TMA in cancer is thought to be tumor cell obstruction in the microvasculature leading to cell frag­ mentation and platelet consumption: TMAs in cancer can occur on initial diagnosis of the cancer or when the cancer becomes refractory, and have been identified in both solid malignancies and hematologic malignancies. Clinical features, such as bone pain and respiratory symptoms, have been found to occur more in cancer-associated TMA than in TTP. Additionally, compared to immune-mediated TTP, there is no role for plasma exchange, steroids, or other immunosuppression in cancer-associated TMA; instead, the management is treatment of the underlying malignancy. ■ ■HIV-RELATED THROMBOTIC MICROANGIOPATHY HIV-related TMA is a complication encountered mainly before wide­ spread use of highly active antiretroviral therapy. It is seen in patients with advanced AIDS and low CD4+ T-cell counts, although it can be the first manifestation of HIV infection. The presence of MAHA, thrombocytopenia, and renal failure is suggestive, but renal biopsy is required for diagnosis since other renal diseases are also associated with HIV infection. Thrombocytopenia may prohibit renal biopsy in some patients. The mechanism of injury is unclear, although HIV can induce apoptosis in endothelial cells. ADAMTS13 activity is not reduced in these patients. Cytomegalovirus co-infection may also be a risk factor. Effective antiviral therapy is key, while plasma exchange should be limited to patients who have evidence of TTP. PART 9 Disorders of the Kidney and Urinary Tract ■ ■PROGRESSIVE SYSTEMIC SCLEROSIS (SCLERODERMA) MAHA can also be present in scleroderma renal crisis, which is also characterized by acute kidney injury, abrupt onset of hypertension, and a normal urine sediment, although each of these aspects is not required for the diagnosis. Scleroderma renal crisis occurs in 12% of patients with diffuse systemic sclerosis but in only 2% of those with limited systemic sclerosis. Although MAHA is present in more than half of patients, coagulopathy is rare. Retinopathy and encephalopathy may accompany the hypertension. Salt and water retention with micro­ vascular injury can lead to pulmonary edema. Cardiac manifestations, including myocarditis, pericarditis, and arrhythmias, denote an espe­ cially poor prognosis. The renal lesion in scleroderma renal crisis is characterized by arcu­ ate artery intimal and medial proliferation with luminal narrowing. This lesion is described as “onion-skinning” and can be accompanied by glo­ merular collapse due to reduced blood flow. Histologically, scleroderma renal crisis is indistinguishable from malignant hypertension, with which it can coexist. Fibrinoid necrosis and thrombosis are common. Before the availability of angiotensin-converting enzyme (ACE) inhibitors, the mor­ tality rate for scleroderma renal crisis was >90% at 1 month. Introduction of renin-angiotensin system blockade has lowered the mortality rate to 30% at 3 years. Nearly two-thirds of patients with scleroderma renal cri­ sis may require dialysis support, with recovery of renal function in 50% (median time, 1 year). Glomerulonephritis and vasculitis associated with antineutrophil cytoplasmic antibodies and systemic lupus erythematosus have been described in patients with scleroderma. An association has been found with a speckled pattern of antinuclear antibodies and with antibodies to RNA polymerases I and III. Anti-U3-RNP may identify young patients at risk for scleroderma renal crisis. Anticentromere antibody, in contrast, is a negative predictor of this disorder. Because of the overlap between scleroderma renal crisis and other autoimmune disorders, a renal biopsy is recommended for patients with atypical renal involvement, especially if hypertension is absent. Treatment with ACE inhibition is the first-line therapy unless contraindicated. The goal of therapy is to reduce systolic and diastolic

blood pressure by 20 mmHg and 10 mmHg, respectively, every 24 h until blood pressure is normal. Additional antihypertensive therapy may be given once the dose of drug for ACE inhibition is maximized. Angiotensin II receptor antagonists are less effective at preventing renal failure; thus, they are only recommended if the patient is intolerant of ACE inhibitors. ACE inhibition alone does not prevent scleroderma renal crisis, but it does reduce the impact of hypertension. In addition, it has been observed that patients on ACE inhibitors have a higher renal recovery rate after initiation of dialysis, and thus, ACE inhibi­ tors are continued even after starting dialysis. Intravenous iloprost has been used in Europe for blood pressure management and improve­ ment of renal perfusion. Kidney transplantation is not recommended for 2 years after the start of dialysis since delayed recovery may occur. Bosentan (endothelin-1 antagonist) and eculizumab have both been investigated for use in this disease. ■ ■ANTIPHOSPHOLIPID SYNDROME Antiphospholipid syndrome (APLS) (Chap. 369) can be either primary or secondary, with the most common rheumatologic association being with systemic lupus erythematosus. It is characterized by a predisposi­ tion to systemic thrombosis (arterial and venous) and/or recurrent fetal loss mediated by antiphospholipid antibodies: anticardiolipin antibodies, lupus anticoagulant, and/or anti-β-2 glycoprotein I anti­ bodies (antiβ2GPI). In addition to the antibody laboratory findings, classification criteria based on the 2023 American College of Rheu­ matology and European Alliance of Associations for Rheumatology include clinical features, such as macrovascular venous and arterial thromboses, microvascular thrombotic events, specific obstetric com­ plications, cardiac valve abnormalities, and thrombocytopenia. Being positive for lupus anticoagulant, antiβ2GPI, and anticardiolipin anti­ bodies (“triple positive”) is associated with the highest thrombosis risk. APLS is the leading cause of stroke in patients <45 years old. The vascular compartment within the kidney is the main site of renal involvement. Arteriosclerosis is commonly present in the arcuate and intralobular arteries. In the intralobular arteries, fibrous intimal hyperplasia characterized by intimal thickening secondary to intense myofibroblastic intimal cellular proliferation with extracellular matrix deposition is frequently seen along with onion-skinning. Arterial and arteriolar fibrous and fibrocellular occlusions are present in more than two-thirds of biopsy samples. Cortical necrosis and focal cortical atro­ phy may result from vascular occlusion. TMA is commonly present in renal biopsies, although signs of MAHA and platelet consumption are usually absent. TMA is especially common in the catastrophic variant of antiphospholipid syndrome, which is a life-threatening syndrome characterized by rapid onset of symptoms, multiorgan failure, and severe thrombotic events. Treatment entails lifelong anticoagulation. For most individuals with APLS, warfarin is the preferred anticoagulant over direct oral anticoagulants (DOACs), with an international normalized ratio (INR) goal of 2–3. One can consider DOACs in a few, specific instances, such as a single venous thrombosis event or in those intolerant to warfarin, but never in those with arterial thrombotic events. Providers should have clear risk-benefit discussions with the patient if choosing a DOAC over warfarin given inferiority in many instances. In those with arterial thrombotic events, antiplatelet therapy is often a recommended addi­ tion to warfarin. Catastrophic APLS management includes anticoagu­ lation, glucocorticoids, plasma exchange, and/or IV immunoglobulin (IVIG). Addition of rituximab and eculizumab can be considered, often in the refractory setting, although ongoing studies are evaluating earlier use of these agents. ■ ■HELLP SYNDROME HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome is a dangerous complication of pregnancy associated with microvascular injury. Occurring in 0.2–0.9% of all pregnancies and in 10–20% of women with severe preeclampsia, this syndrome carries a mortality rate of 7.4–34%. Most commonly developing in the third trimester, 20% of cases occur before week 28, and 30% occur postpartum. Although a strong association exists between HELLP syndrome and preeclampsia,

nearly 20% of cases are not preceded by recognized preeclampsia. Risk factors include abnormal placentation, family history, and elevated levels of fetal mRNA for FLT1 (vascular endothelial growth factor receptor 1) and endoglin. Patients with HELLP syndrome have higher levels of inflammatory markers (C-reactive protein, IL-1Ra, and IL-6) and soluble HLA-DR than do those with preeclampsia alone. Renal failure occurs in half of patients with HELLP syndrome, although the etiology is not well understood. Limited data suggest that renal failure is the result of both preeclampsia and acute tubular necrosis. Proteinuria is present in 86–100% of cases. Renal histologic findings are those of TMA with endothelial cell swelling and occlusion of the capillary lumens, but luminal thrombi are typically absent. How­ ever, thrombi become more common in severe eclampsia and HELLP syndrome. Although renal failure is common, the organ that defines this syndrome is the liver. Subcapsular hepatic hematomas sometimes produce spontaneous rupture of the liver and can be life-threatening. Neurologic complications such as cerebral infarction, hemorrhage, and edema are other potentially life-threatening complications. Nonfatal complications include placental abruption, permanent vision loss due to Purtscher-like (hemorrhagic and vaso-occlusive vasculopathy) reti­ nopathy, pulmonary edema, bleeding, and fetal demise. Many features are shared by HELLP syndrome and MAHA. Diag­ nosis of HELLP syndrome is complicated by the fact that aHUS and TTP also can be triggered by pregnancy; in addition, complement gene mutations and complement pathway dysfunction are common (30–40%) among patients with HELLP syndrome. Patients with antiphospholipid syndrome also have an elevated risk of HELLP syndrome. A history of MAHA before pregnancy is of diagnostic value. Serum levels of ADAMTS13 activity are reduced (by 30–60%) in HELLP syndrome but not to the levels seen in TTP (<10%). Determination of the ratio of lactate dehydrogenase to aspartate aminotransferase may be helpful. This ratio is 13:1 in patients with HELLP syndrome and preeclampsia as opposed to 29:1 in patients without preeclampsia. Other markers, such as antithrombin III (decreased in HELLP syndrome but not in TTP) and D-dimer (elevated in HELLP syndrome but not in TTP), may also be useful. HELLP syndrome usually resolves spontaneously after delivery. Management includes administering magnesium sulfate for seizure prophylaxis and treating hypertension if present. A key component of treatment is delivery; timing of delivery is based on severity of symptoms and age of the fetus. In pregnancies with serious maternal or fetal complications, prompt delivery is recommended. In those without serious complications, the age of the fetus and fetal maturity can help distinguish between prompt delivery or a course of antenatal steroids. Plasma exchange has no benefit in HELLP but may be indicated if TTP has not yet been ruled out. Eculizumab has been reported to be effective in a small number of cases, but dosing, efficacy, and indications remain undetermined. ■ ■POEMS SYNDROME POEMS syndrome is a systemic disease characterized by polyneu­ ropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes, with polyneuropathy and monoclonal gammopathy being mandatory major criteria. Peripheral neuropathy often presents with severe motor-sensory deficit. Three other major criteria, at least one of which is required, are elevated vascular endothelial growth factor (VEGF) levels, evidence of Castleman disease, and sclerotic bone lesions. Patients also commonly have elevated IL-6. Another characteristic is that >95% of monoclonal light chain is of the lambda isotype. IgA also makes up ~50% of the monoclonal proteins involved. Organomegaly can involve any organ and often presents as lymphade­ nopathy. Other findings can include skin changes, thrombocytosis, polycythemia, papilledema, and volume overload. POEMS syndrome can occur with Castleman disease. In the kidney, the hypertro­ phy frequently is unilateral. One study suggests the difference in kidney size is due to unilateral contraction; however, a volumetric study showed that enlargement is responsible for the difference in kidney size in some patients. Glomerulomegaly is not uncommon. Lobular appearance, endothelial cell swelling, hypercellularity, mesan­ giolysis, microaneurysm, and glomerular enlargement are reminiscent

of membranoproliferative glomerulonephritis. Most patients present with mild to moderate renal impairment and low-grade proteinuria. Progression to end-stage renal disease is rare.

■ ■SICKLE CELL NEPHROPATHY Renal complications in sickle cell disease result from occlusion of the vasa recta in the renal medulla. The low partial pressure of oxygen and high osmolarity predispose to hemoglobin S polymerization and erythrocyte sickling. Sequelae include hyposthenuria, hematuria, and papillary necrosis (which can also occur in sickle trait). The kidney responds by increasing blood flow and glomerular filtration rate mediated by prostaglandins. This dependence on prostaglandins may explain the greater reduction of glomerular filtration rate by nonste­ roidal anti-inflammatory drugs in these patients than in others. The glomeruli are typically enlarged. Intracapillary fragmentation and phagocytosis of sickled erythrocytes are thought to be responsible for the membranoproliferative glomerulonephritis–like lesion, and focal segmental glomerulosclerosis is seen in more advanced cases. Screening for sickle cell nephropathy should include blood pres­ sure monitoring, urine studies for albumin-to-creatinine ratio, and metabolic panel. Proteinuria is present in 20–30%, and nephroticrange proteinuria is associated with progression to renal failure. ACE inhibitors reduce proteinuria, although data are lacking on prevention of renal failure. Patients with sickle cell disease are also more prone to acute renal failure. The cause is thought to reflect microvascular occlusion associated with nontraumatic rhabdomyolysis, high fever, infection, and generalized sickling. Chronic kidney disease from sickle cell nephropathy is present in 25–33% of patients. Despite the fre­ quency of renal disease, hypertension is significantly lower in patients with sickle cell disease compared to the general population of black individuals. Treatment can include medications, such as hydroxyurea, which has been shown to decrease vaso-occlusive events and lessen albuminuria. Two gene therapies for patients with sickle cell who have recurrent vaso-occlusive episodes and are >12 years old were approved in December 2023. Exagamglogene autotemcel uses CRISPR/Cas9 gene editing to modify BCL11A and increased fetal hemoglobin, whereas lovotibeglogene autotemcel uses lentiviral technology to pro­ duce a modified hemoglobin similar to hemoglobin A. Evaluation of outcomes in these individuals is ongoing. CHAPTER 329 Thrombotic Renovascular Disorders RENAL VEIN THROMBOSIS Renal vein thrombosis either can present with flank pain, tender­ ness, hematuria, rapid decline in renal function, and proteinuria or can be silent. Occasionally, renal vein thrombosis is identified during a workup for pulmonary embolism. The left renal vein is more com­ monly involved, and two-thirds of cases are bilateral. Etiologies can be divided into three broad categories: endothelial damage, venous stasis, and hypercoagulability. Homocystinuria, endovascular intervention, and surgery can produce vascular endothelial damage. Dehydration, which is more common among male patients, is a common cause of stasis in the pediatric population. Stasis also can result from compression and kinking of the renal veins from retroperitoneal processes such as retroperitoneal fibrosis and abdominal neoplasms. Thrombosis can occur throughout the renal circulation, including the renal veins, with antiphospholipid syndrome. Renal vein thrombosis can also be secondary to nephrotic syndrome, particularly membranous nephropathy. Other hypercoagu­ lable states less commonly associated with renal vein thrombosis include proteins C and S, antithrombin deficiency, factor V Leiden, disseminated malignancy, and oral contraceptives. Severe nephrotic syndrome may also predispose patients to renal vein thrombosis. Diagnostic screening can be performed with Doppler ultrasonog­ raphy, which is more sensitive than ultrasonography alone. Computed tomography angiography is almost 100% sensitive. Magnetic resonance angiography is another option but is more expensive. Treatment for renal vein thrombosis consists of anticoagulation and therapy for the underlying cause. Endovascular thrombolysis may be considered in severe cases. Occasionally, nephrectomy may be undertaken for lifethreatening complications. In patients who cannot receive anticoagula­ tion, suprarenal inferior vena cava filters can be considered.

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330 Nephrolithiasis

COVID-19 AND MICROVASCULAR DISEASE The COVID-19 pandemic, cause by SARS-CoV-2, has led to many com­ plications, including both macrovascular and microvascular thrombo­ ses. SARS-CoV-2 attaches to the cell membrane via interaction of the viral spike protein with the ACE2 protein and then enters the cell via endocytosis, leading to increased cytokine release, inflammatory cell activation, and cellular and tissue damage. Endothelial injury and dys­ function in the setting of COVID-19 have led to many microvascular phenotypes including renal injury, heart disease, liver complications, strokes, and respiratory distress syndrome. In response to SARSCoV-2, endothelial exocytosis occurs, releasing von Willebrand factor and P-selectin from granules. Autopsy specimens have shown evidence of small-vessel occlusions in the heart, kidneys, and lungs. Certain fac­ tors related to microvascular damage, such as ADAMTS13, VEGF-A, and Angpt-2, have been shown to predict mortality. In the renal sys­ tem, autopsies showed diffuse proximal tubule injury, which is thought to be due to the immune dysregulation and inflammatory cytokines, in addition to poor renal perfusion. In certain instances, viral particles have been observed in the tubular epithelium, although direct infection of SARS-CoV-2 in the kidney remains controversial. Having previous chronic kidney disease or diabetic nephropathy is a risk factor for developing acute kidney injury with COVID-19. Treatment includes antiviral medications and remdesivir, with these medications needing to be adjusted or avoided based on kidney function.

PART 9 Disorders of the Kidney and Urinary Tract Acknowledgment Ronald S. Go and Nelson Leung contributed to this chapter in the 21st edition and some material from that chapter has been retained here. ■ ■FURTHER READING Al-Nouri ZL et al: Drug-induced thrombotic microangiopathy: A systematic review of published reports. Blood 125:616, 2015. Barbhaiya M et al: ACR/EULAR APS Classification Criteria Collabo­ rators. The 2023 ACR/EULAR antiphospholipid syndrome classifica­ tion criteria. Arthritis Rheumatol 75:1687, 2023. Brocklebank V et al: Thrombotic microangiopathy and the kidney. Clin J Am Soc Nephrol 13:300, 2018. Fakhouri F et al: How I diagnose and treat atypical hemolytic uremic syndrome. Blood 141:984, 2023. George JN, Nester CM: Syndromes of thrombotic microangiopathy. N Engl J Med 371:1847, 2014. Go RS et al: Thrombotic microangiopathy care pathway: A consensus statement for the Mayo Clinic Complement Alternative PathwayThrombotic Microangiopathy (CAP-TMA) Disease-Oriented Group. Mayo Clin Proc 91:1189, 2016. Liu N et al: Direct promoter repression by BCL11A controls the fetal to adult hemoglobin switch. Cell 2018173:430, 2018. Zabatta E et al: Therapy of scleroderma renal crisis: State of the art. Autoimmun Rev 17:882, 2018. Gary C. Curhan

Nephrolithiasis Nephrolithiasis, or kidney stone disease, is a common, painful, and costly condition. Each year, billions of dollars are spent on nephroli­ thiasis-related activity, with the majority of expenditures on surgical treatment of existing stones. While a stone may form due to crystalliza­ tion of lithogenic factors in the upper urinary tract, it can subsequently move into the ureter and cause renal colic. Although nephrolithiasis is rarely fatal, patients who have had renal colic report that it is the worst pain they have ever experienced. The evidence on which to base

clinical recommendations is not as strong as desired; nonetheless, most experts agree that the recurrence of most, if not all, types of stones can be prevented with careful evaluation and targeted recommenda­ tions. Preventive treatment may be lifelong; therefore, an in-depth understanding of this condition must inform the implementation of tailored interventions that are most appropriate for and acceptable to the patient. There are several types of kidney stones. It is clinically important to identify the stone type, which informs prognosis and selection of the optimal preventive regimen. Calcium oxalate stones are most common (~75%); next, in order, are calcium phosphate (~15%), uric acid (~8%), struvite (~1%), and cystine (<1%) stones. Many stones are a mixture of crystal types (e.g., calcium oxalate and calcium phosphate) and also contain protein in the stone matrix. Rarely, stones are composed of medications, such as acyclovir, atazanavir, and triamterene. Stones that form as a result of an upper tract infection, if not appropriately treated, can have devastating consequences and lead to end-stage renal disease. Consideration should be given to teaching practitioners strategies to prevent recurrence of all stone types and the related morbidity. ■ ■EPIDEMIOLOGY Nephrolithiasis is a global disease. Data suggest an increasing preva­ lence, likely due to Westernization of lifestyle habits (e.g., dietary changes, increasing body mass index). National Health and Nutrition Examination Survey data for 2007–2016 indicate that up to 20% of men and 10% of women will develop at least one stone during their lifetime. The prevalence is ~50% lower among black individuals than among whites. The incidence of nephrolithiasis (i.e., the rate at which previously unaffected individuals develop their first stone) also varies by age, sex, and race. Among white men, the peak annual incidence is ~3.5 cases/1000 at age 40 and declines to ~2 cases/1000 by age 70. Among white women in their thirties, the annual incidence is ~2.5 cases/1000; the figure decreases to ~1.5/1000 at age 50 and beyond. In addition to the medical costs associated with nephrolithiasis, this condition also has a substantial economic impact, as those affected are often of working age. Once an individual has had a stone, the preven­ tion of a recurrence is essential. Published recurrence rates vary by the definitions and diagnostic methods used. Some reports have relied on symptomatic events, while others have been based on imaging. Most experts agree that radiographic evidence of a second stone should be considered to represent a recurrence, even if the stone has not yet caused symptoms. ■ ■ASSOCIATED MEDICAL CONDITIONS Nephrolithiasis is a systemic disorder. Several conditions predispose to stone formation, including gastrointestinal malabsorption (e.g., Crohn’s disease, gastric bypass surgery), primary hyperparathyroid­ ism, obesity, type 2 diabetes mellitus, and distal renal tubular acidosis. A number of other medical conditions are more likely to be present in individuals with a history of nephrolithiasis, including hypertension, gout, cardiovascular disease, cholelithiasis, reduced bone mineral den­ sity, and chronic kidney disease. Although nephrolithiasis does not directly cause upper urinary tract infections (UTIs), a UTI in the setting of an obstructing stone is a uro­ logic emergency (“pus under pressure”) and requires urgent interven­ tion to reestablish drainage. ■ ■PATHOGENESIS In the consideration of the processes involved in crystal formation, it is helpful to view urine as a complex solution. A clinically useful con­ cept is supersaturation (the point at which the concentration product exceeds the solubility product). However, even though the urine in most individuals is supersaturated with respect to one or more types of crystals, the presence of inhibitors of crystallization prevents the majority of the population from continuously forming stones. The most clinically important inhibitor of calcium-containing stones is urine citrate. While the calculated supersaturation value does not per­ fectly predict stone formation, it is a useful guide as it integrates the multiple factors that are measured in a 24-h urine collection.

Recent studies have changed the paradigm for the site of initiation of stone formation. Renal biopsies of stone formers have revealed calcium phosphate in the renal interstitium. It is hypothesized that this calcium phosphate deposits at the thin limb of the loop of Henle and then extends down to the papilla and erodes through the papillary epithelium, where it provides a site for deposition of calcium oxalate and calcium phosphate crystals. The majority of calcium oxalate stones grow on calcium phosphate at the tip of the renal papilla (Randall’s plaque). Tubular plugs of calcium phosphate may be the initiating event in calcium phosphate stone development. Thus, the process of stone formation may begin years before a clinically detectable stone is identified. The processes involved in interstitial deposition are under active investigation. ■ ■RISK FACTORS Risk factors for nephrolithiasis can be categorized as dietary, nondi­ etary, or urinary. These risk factors vary by stone type and clinical characteristics. Dietary Risk Factors  Patients who develop stones often change their diet; therefore, studies that retrospectively assess diet may be hampered by recall bias. Some studies have examined the relation between diet and changes in the lithogenic composition of the urine, often using calculated supersaturation. However, the composition of the urine does not perfectly predict risk, and not all components that modify risk are included in the calculation of supersaturation. Thus, dietary associations are best investigated by prospective studies that examine actual stone formation as the outcome. Dietary factors that are associated with an increased risk of nephrolithiasis include animal protein, oxalate, sodium, sucrose, and fructose. Dietary factors associ­ ated with a lower risk include calcium, potassium, phytate, and higher fluid intake. CALCIUM  The role of dietary calcium deserves special attention. Although in the distant past dietary calcium had been suspected of increasing the risk of stone disease, several prospective observational studies and a randomized controlled trial have demonstrated that higher dietary calcium intake is related to a lower risk of stone forma­ tion. The reduction in risk associated with higher calcium intake may be due to a reduction in intestinal absorption of dietary oxalate that results in lower urine oxalate. Low calcium intake is contraindicated as it increases the risk of stone formation and may contribute to lower bone density in stone formers. Despite similar bioavailability, supplemental calcium may increase the risk of stone formation. The discrepancy between the risks from dietary calcium and calcium supplements may be due to the timing of supplemental calcium intake or to higher total calcium consumption leading to higher urinary calcium excretion. OXALATE  Urinary oxalate is derived from both endogenous produc­ tion and absorption of dietary oxalate. Owing to its low and often variable bioavailability, much of the oxalate in food may not be read­ ily absorbed. However, absorption may be higher in stone formers. Although observational studies demonstrate that dietary oxalate is only a weak risk factor for stone formation, urinary oxalate is a strong risk factor for calcium oxalate stone formation, and efforts to avoid high oxalate intake should thus be beneficial. OTHER NUTRIENTS  Several other nutrients have been studied and implicated in stone formation. Higher intake of animal protein may lead to increased excretion of calcium and uric acid as well as to decreased urinary excretion of citrate, all of which increase the risk of stone formation. Higher sodium and sucrose intake increases calcium excretion independent of calcium intake. Higher potassium intake decreases calcium excretion, and many potassium-rich foods increase urinary citrate excretion due to their alkali content. Other dietary factors that have been inconsistently associated with lower stone risk include magnesium and phytate. Vitamin C supplements are associated with an increased risk of calcium oxalate stone formation in men, possibly owing to raised levels of oxalate in urine. Thus, male calcium oxalate stone formers should

be advised to avoid high-dose vitamin C supplements. Although high doses of supplemental vitamin B6 may be beneficial in selected patients with type 1 primary hyperoxaluria, the risk is not reduced in other patients.

FLUIDS AND BEVERAGES  The risk of stone formation increases as urine volume decreases. When the urine output is <1 L/d, the risk of stone formation more than doubles. Fluid intake is the main determi­ nant of urine volume, and the importance of fluid intake in preventing stone formation has been demonstrated in observational studies and in a randomized controlled trial. Observational studies of individual beverages have found that coffee, tea, beer, wine, and orange juice are associated with a reduced risk of stone formation. Sugar-sweetened beverage consumption may increase risk. Nondietary Risk Factors  Age, race, body size, and environment are important risk factors for nephrolithiasis. The incidence of stone disease is highest in middle-aged white men, but stones can form in infants as well as in the elderly. There is geographic variability, with the highest prevalence in the southeastern United States. Weight gain increases the risk of stone formation, and the increasing prevalence of nephrolithiasis in the United States may be due in part to the increasing prevalence of obesity. Environmental and occupational influences that may lead to lower urine volume, such as working in a hot environment or lack of ready access to water or a bathroom, are important consid­ erations. Several observational studies, but not all, have reported that antibiotic use in early adulthood and middle age is associated with higher risk for nephrolithiasis in later life. The largest of these studies found an increased risk for five different classes of antibiotics. CHAPTER 330 Nephrolithiasis Urinary Risk Factors  URINE VOLUME  Lower urine volume results in higher concentrations of lithogenic factors and is a common and readily modifiable risk fac­ tor. A randomized trial has demonstrated the effectiveness of higher fluid intake in increasing urine volume and reducing the risk of stone recurrence. URINE CALCIUM  Higher urine calcium excretion increases the likeli­ hood of formation of calcium oxalate and calcium phosphate stones. While the term hypercalciuria is often used, there is no cutoff that distinguishes between normal and abnormal urine calcium excretion. In fact, the relation between urine calcium and stone risk appears to be continuous; thus, the use of an arbitrary threshold should be avoided. Levels of urine calcium excretion are higher in individuals with a history of nephrolithiasis; however, the mechanisms remain poorly understood. Greater gastrointestinal calcium absorption is one impor­ tant contributor, and greater bone turnover (with a resultant reduction in bone mineral density) may be another. Primary renal calcium loss, with lower serum calcium concentrations and elevated serum levels of parathyroid hormone (PTH) (and a normal 25-hydroxy vitamin D level), is rare. URINE OXALATE  Higher urine oxalate excretion increases the likeli­ hood of calcium oxalate stone formation. As for urine calcium, no definition for “abnormal” urine oxalate excretion is widely accepted. Given that the relation between urine oxalate and stone risk is continu­ ous, simple dichotomization of urine oxalate excretion is not helpful in assessing risk. The two sources of urine oxalate are endogenous generation and dietary intake. Dietary oxalate is the major contribu­ tor and also the source that can be modified. Notably, higher dietary calcium intake reduces gastrointestinal oxalate absorption and thereby reduces urine oxalate. URINE CITRATE  Urine citrate is a natural inhibitor of calcium-containing stones; thus, lower urine citrate excretion increases the risk of stone formation. Citrate reabsorption is influenced by the intracellular pH of proximal tubular cells. Metabolic acidosis, including that due to higher animal flesh intake, will lead to a reduction in citrate excretion by increasing reabsorption of filtered citrate. However, a notable propor­ tion of patients have lower urine citrate for reasons that remain unclear.

URINE URIC ACID  Higher urine levels of uric acid—a risk factor for uric acid stone formation—are found in individuals with excess purine consumption and rare genetic conditions that lead to overproduction of uric acid. This characteristic is not associated with the risk of cal­ cium oxalate stone formation.

URINE pH  Urine pH influences the solubility of some crystal types. Uric acid stones form when the urine pH is consistently ≤5.5, whereas calcium phosphate stones are more likely to form when the urine pH is ≥6.5. Cystine is more soluble at higher urine pH. Calcium oxalate stones are not influenced by urine pH. Genetic Risk Factors  The risk of nephrolithiasis is more than twofold greater in individuals with a family history of stone disease. This association is likely due to a combination of genetic predisposition and similar environmental exposures. While a number of rare monogenic disorders cause nephrolithiasis, genome-wide asso­ ciation studies have begun to reveal genetic contributors to common forms of stone disease. The two most common and well-characterized rare monogenic disorders that lead to stone formation are primary hyperoxaluria and cystinuria. Primary hyperoxaluria is an autosomal recessive disorder that causes excessive endogenous oxalate generation by the liver, with consequent calcium oxalate stone formation and crystal deposition in organs. Intraparenchymal calcium oxalate deposition in the kidney can eventually lead to renal failure. Cystinuria is an autosomal recessive dis­ order that causes abnormal reabsorption of filtered basic amino acids. The excessive urinary excretion of cystine, which is poorly soluble, leads to cystine stone formation. Cystine stones are visible on plain radiographs and often manifest as staghorn calculi or multiple bilateral stones. Repeat episodes of obstruction and instrumentation can cause a reduction in the glomerular filtration rate (GFR). PART 9 Disorders of the Kidney and Urinary Tract APPROACH TO THE PATIENT Nephrolithiasis Evidence-based guidelines for the evaluation and treatment of nephrolithiasis have been published. Although there is limited evi­ dence for several aspects, there are standard approaches to patients with acute and chronic presentations that can reasonably guide the clinical evaluation. It typically requires weeks to months (and often much longer) for a kidney stone to grow to a clinically detectable size. Although the passage of a stone is a dramatic event, stone formation and growth are characteristically clinically silent. A stone can remain asymptomatic in the kidney for years or even decades before signs (e.g., hematuria) or symptoms (e.g., pain) become apparent. Thus, it is important to remember that the onset of symptoms, typically attributable to a stone moving into the ureter, does not provide insight into when the stone actually formed. The factors that induce stone movement are unknown. CLINICAL PRESENTATION AND DIFFERENTIAL DIAGNOSIS There are two common presentations for individuals with an acute stone event: renal colic and painless gross hematuria. Renal colic is a misnomer because pain typically does not subside completely; rather, it varies in intensity. When a stone moves into the ureter, the discomfort often begins with a sudden onset of unilateral flank pain. The intensity of the pain can increase rapidly, and there are no alleviating factors. This pain, which is accompanied often by nau­ sea and occasionally by vomiting, may radiate, depending on the location of the stone. If the stone lodges in the upper part of the ureter, pain may radiate anteriorly; if the stone is in the lower part of the ureter, pain can radiate to the ipsilateral testicle in men or the ipsilateral labium in women. Occasionally, a patient has gross hematuria without pain. Other diagnoses may be confused with acute renal colic. If the stone is lodged at the right ureteropelvic junction, symptoms may

mimic those of acute cholecystitis. If the stone blocks the ureter as it crosses over the right pelvic brim, symptoms may mimic acute appendicitis, whereas blockage at the left pelvic brim may be confused with acute diverticulitis. If the stone lodges in the ureter at the ureterovesical junction, the patient may experience urinary urgency and frequency. In female patients, the latter symptoms may lead to an incorrect diagnosis of bacterial cystitis; the urine will contain red and white blood cells, but the urine culture will be negative. An obstructing stone with proximal infection may present as acute pyelonephritis. A UTI in the setting of ureteral obstruc­ tion is a medical emergency that requires immediate restoration of drainage by placement of either a ureteral stent or a percutaneous nephrostomy tube. Other conditions to consider in the differential diagnosis include muscular or skeletal pain, herpes zoster, duodenal ulcer, abdominal aortic aneurysm, gynecologic conditions, ureteral stricture, and ureteral obstruction by materials other than a stone, such as a blood clot or sloughed papilla. Extraluminal processes can lead to ureteral compression and obstruction; however, because of the gradual onset, these conditions do not typically present with renal colic. DIAGNOSIS AND INTERVENTION Serum chemistry findings are typically normal, but the white blood cell count may be elevated. Examination of the urine sediment will usually reveal red and white blood cells and occasionally crystals (Fig. 330-1). The absence of hematuria does not exclude a stone, particularly when urine flow is completely obstructed by a stone. The diagnosis is often made on the basis of the history, physical examination, and urinalysis. Thus, it may not be necessary to wait for radiographic confirmation before treating the symptoms. The diagnosis is confirmed by an appropriate imaging study—preferably noncontrast helical computed tomography (CT), which is highly sensitive and allows visualization of uric acid stones (traditionally considered “radiolucent”) (Fig. 330-2). Helical CT detects stones as small as 1 mm that may be missed by other imaging modalities. Typically, helical CT reveals a ureteral stone or evidence of recent passage (e.g., perinephric stranding or hydronephrosis), whereas a plain abdominal radiograph (kidney/ureter/bladder [KUB]) can miss a stone in the ureter or kidney, even if it is radiopaque, and does not provide information on obstruction. Abdominal ultra­ sound offers the advantage of avoiding radiation and provides information on hydronephrosis, but it is not as sensitive as CT and images only the kidney and possibly the proximal segment of the ureter; thus, most ureteral stones are not detectable by ultrasound. Many patients who experience their first episode of colic seek emergent medical care. Randomized trials have demonstrated that parenterally administered nonsteroidal anti-inflammatory drugs (e.g., ketorolac) are just as effective as opioids in relieving symptoms and have fewer side effects. Excessive fluid administration has not been shown to be beneficial; therefore, the goal should be to main­ tain euvolemia. If the pain can be adequately controlled and the patient is able to take fluids orally, hospitalization can be avoided. Use of an alpha blocker may increase the rate of spontaneous stone passage. Urologic intervention should be postponed unless there is evi­ dence of UTI, a low probability of spontaneous stone passage (e.g., a stone measuring ≥6 mm or an anatomic abnormality), or intrac­ table pain. A ureteral stent may be placed cystoscopically, but this procedure typically requires general anesthesia, and the stent can be quite uncomfortable, may cause gross hematuria, and may increase the risk of UTI. If an intervention is indicated, the selection of the most appropri­ ate intervention is determined by the size, location, and composi­ tion of the stone; the urinary tract anatomy; and the experience of the urologist. Extracorporeal shockwave lithotripsy (ESWL), the least invasive option, uses shockwaves generated outside the body to fragment the stone, but is being used less frequently. An endourologic approach, now more frequently used than ESWL,

FIGURE 330-1  Urine sediment from a patient with calcium oxalate stones (left) and a patient with cystine stones (right). Calcium oxalate dihydrate crystals are bipyramidally shaped, and cystine crystals are hexagonal. (Left panel image courtesy of Dr. Mark Perazella, Yale School of Medicine. Right panel image courtesy Dr. John Lieske, Mayo Clinic.) can remove a stone by basket extraction or laser fragmentation. For large upper-tract stones, percutaneous nephrostolithotomy has the highest likelihood of rendering the patient stone-free. Advances in urologic approaches and instruments have nearly eliminated the need for open surgical procedures such as ureterolithotomy or pyelolithotomy. EVALUATION FOR STONE PREVENTION More than half of first-time stone formers will have a recurrence within 10 years. A careful evaluation is indicated to identify pre­ disposing factors, which can then be modified to reduce the risk of new stone formation or growth of existing renal stones. It is appropriate to proceed with an evaluation even after the first stone if the patient is interested because recurrences are common and are usually preventable with inexpensive lifestyle modifications or other treatments. HISTORY A detailed history, obtained from the patient and from a thor­ ough review of medical records, should include the number and FIGURE 330-2  Coronal noncontrast CT image from a patient who presented with left-sided renal colic. An obstructing calculus, present in the distal left ureter at the level of S1, measures 10 mm in maximal dimension. There is severe left hydroureteronephrosis and associated left perinephric fat stranding. In addition, there is a nonobstructing 6-mm left renal calculus in the interpolar region. (Image courtesy of Dr. Stuart Silverman, Brigham and Women’s Hospital.)

CHAPTER 330 frequency of episodes (distinguishing stone passage from stone for­ mation) and previous imaging studies, interventions, evaluations, and treatments. Inquiries about the patient’s medical history should cover UTIs, gastric bypass surgery and other malabsorptive condi­ tions, gout, hypertension, and diabetes mellitus. A family history of stone disease may reveal a genetic predisposition. A complete list of current prescription and over-the-counter medications as well as vitamin and mineral supplements is essential. The review of systems should focus on identifying possible etiologic factors related to low urine volume (e.g., high insensible losses) and gastrointestinal malabsorption as well as on ascertaining how frequently the patient voids during the day and overnight. Nephrolithiasis A large body of compelling evidence has demonstrated the important role of diet in stone disease. Thus, the dietary history should encompass information on usual dietary habits (meals and snacks), calcium intake, consumption of high-oxalate foods (spin­ ach, rhubarb, potatoes), and fluid intake (including amount of spe­ cific beverages typically consumed). Amount and frequency of use of vitamin and mineral supplements should be carefully assessed. PHYSICAL EXAMINATION The physical examination should assess weight, blood pressure, costovertebral angle tenderness, and lower-extremity edema as well as signs of other systemic conditions such as primary hyperpara­ thyroidism and gout. LABORATORY EVALUATION If not recently measured, the following serum levels should be determined: electrolytes (to uncover hypokalemia or renal tubular acidosis), creatinine, calcium, phosphorus, and uric acid. The PTH level should be measured if indicated by elevated, high-normal, or low-normal serum and urine calcium concentrations. 25-Hydroxy vitamin D should be measured in concert with PTH to investigate the possible role of secondarily elevated PTH levels in the setting of vitamin D insufficiency. The urinalysis, including examination of the sediment, can pro­ vide useful information. In individuals with asymptomatic residual renal stones, red and white blood cells are frequently present in urine. If there is concern about the possibility of an infection, a urine culture should be performed. The sediment may also reveal crystals (Fig. 330-1), which may help identify the stone type and also provide prognostic information as crystalluria is a strong risk factor for new stone formation. The results from 24-h urine collections serve as the cornerstone on which therapeutic recommendations are based. Recommen­ dations on lifestyle modification should be deferred until urine

collection is complete. As a baseline assessment, patients should collect at least two 24-h urine samples while consuming their usual diet and usual volume of fluid. The following factors should be measured: total volume, calcium, oxalate, citrate, uric acid, sodium, potassium, phosphorus, magnesium, pH, and creatinine. When available, the calculated supersaturation is also informative. There is substantial day-to-day variability in the 24-h excretion of many relevant factors; therefore, obtaining values from two collections is important before committing a patient to long-term lifestyle changes or medication. The interpretation of the 24-h urine results should take into account that the collections are usually performed on a weekend day when the patient is staying at home; an individ­ ual’s habits may differ dramatically (beneficially or detrimentally) at work or outside the home. Specialized testing, such as calcium loading or restriction, is not recommended as it does not influence clinical recommendations. Stone composition analysis is essential if a stone or fragment is available; patients should be encouraged to retrieve passed stones. The stone type cannot be determined with certainty from 24-h urine results, but pure uric acid stones can be identified by low Hounsfield units on CT. IMAGING The “gold standard” diagnostic test is helical CT without contrast. If not already performed during an acute episode, a low-dose renal-limited noncontrast CT should be considered to establish definitively the baseline stone burden. A suboptimal imaging study may not detect a residual stone that, if subsequently passed, would be mistaken for a new stone. In this instance, the preventive medical regimen might be unnecessarily changed as the result of a preexist­ ing stone. PART 9 Disorders of the Kidney and Urinary Tract Recommendations for follow-up imaging should be tailored to the individual patient. While CT provides the best information, the radiation dose is higher than from other modalities; therefore, CT should be performed only if the results will lead to a change in clinical recommendations. Although less sensitive, renal ultrasound is typically used to minimize radiation exposure, with recognition of the limitations. PREVENTION OF NEW STONE FORMATION Recommendations for preventing stone formation depend on the stone type and the results of metabolic evaluation. After remediable secondary causes of stone formation (e.g., primary hyperparathy­ roidism) are excluded, the focus should turn to modification of the urine composition to reduce the risk of new stone formation. The urinary constituents and calculated urine supersaturation are con­ tinuous variables, and the associated risk is continuous; thus, there are no definitive thresholds. Dichotomization into “normal” and “abnormal” can be misleading and should be avoided. For all stone types, consistently diluted urine reduces the likeli­ hood of crystal formation. The urine volume should be at least 2 L/d. Because of differences in insensible fluid losses and fluid intake from food sources, the required total fluid intake will vary from person to person. Rather than specify how much to drink, it is more helpful to educate patients about how much more they need to drink in light of their 24-h urine volume. For example, if the daily urine volume is 1.5 L, then the patient should be advised to drink consistently at least 0.5 L more per day in order to increase the urine volume to the goal of 2 L/d. ■ ■RECOMMENDATIONS FOR SPECIFIC

STONE TYPES Calcium Oxalate  Risk factors for calcium oxalate stones include higher urine calcium, higher urine oxalate, and lower urine citrate. This stone type is insensitive to urine pH in the physiologic range. Individuals with higher urine calcium excretion tend to absorb a higher percentage of ingested calcium. Nevertheless, dietary calcium restriction is not beneficial and, in fact, is likely to be harmful (see

“Dietary Risk Factors,” above). In a randomized trial in men with high urine calcium and recurrent calcium oxalate stones, a diet containing 1200 mg of calcium and a low intake of sodium and animal protein significantly reduced subsequent stone formation compared with a low-calcium diet (400 mg/d). Excessive calcium intake (>1200 mg/d) should be avoided. A thiazide diuretic, in doses higher than those used to treat hyper­ tension, can substantially lower urine calcium excretion. Several ran­ domized controlled trials, but not all, have demonstrated that thiazide diuretics can reduce calcium oxalate stone recurrence by ~50%. When a thiazide is prescribed, dietary sodium restriction is essential to obtain the desired reduction in urinary calcium excretion and minimize uri­ nary potassium losses. While bisphosphonates may reduce urine cal­ cium excretion in some individuals, there are only observational data to suggest whether this class of medication can reduce stone formation; therefore, bisphosphonates cannot be recommended solely for stone prevention at present, but they can be used to treat those individuals with low bone density. A reduction in urine oxalate will, in turn, reduce the supersaturation of calcium oxalate. In patients with the common form of nephroli­ thiasis, avoiding high-dose vitamin C supplements is the only known strategy that reduces endogenous oxalate production. In patients with primary hyperoxaluria (type I), an siRNA-based therapy (lumasiran, nedosiran) can reduce oxalate generation in the liver. Oxalate is a metabolic end product; therefore, any dietary oxalate that is absorbed will be excreted in the urine. Reducing absorption of exogenous oxalate involves two approaches. First, the avoidance of foods that contain high amounts of oxalate, such as spinach, rhubarb, almonds, and potatoes, is prudent. However, extreme oxalate restriction has not been demonstrated to reduce stone recurrence and could be harmful to overall health, given other health benefits of many foods that are erroneously considered to be high in oxalate. Second, the absorption of oxalate is reduced by higher calcium intake; therefore, individuals with higher-than-desired urinary oxalate should be counseled to consume adequate calcium. Oxalate absorption can be influenced by the intestinal microbiota, depending on the presence of oxalate-degrading bacteria. Currently, however, there are no available therapies to alter the micro­ biota that beneficially affect urinary oxalate excretion over the long term. Citrate is a natural inhibitor of calcium oxalate and calcium phos­ phate stones. Increased consumption of foods rich in alkali (i.e., fruits and vegetables) can increase urine citrate. For patients with lower urine citrate in whom dietary modification does not adequately increase urine citrate, the addition of supplemental alkali (typically potassium citrate or bicarbonate) will lead to an increase in urinary citrate excre­ tion. Sodium salts, such as sodium bicarbonate, while successful in raising urine citrate, are typically avoided due to the adverse effects of sodium on urine calcium excretion. Past reports suggested that higher levels of urine uric acid may increase the risk of calcium oxalate stones, but more recent studies do not support this association. However, allopurinol reduced stone recurrence in one randomized controlled trial in patients with calcium oxalate stones and high urine uric acid levels. The lack of association between urine uric acid level and calcium oxalate stones suggests that a different mechanism underlies the observed beneficial effect of allo­ purinol in this setting. Additional dietary modifications may be beneficial in reducing stone recurrence. Restriction of nondairy animal protein (e.g., meat, chicken, seafood) is a reasonable approach and may result in higher excretion of citrate and lower excretion of calcium. In addition, reduc­ ing sodium intake to <2.5 g/d may decrease urinary excretion of cal­ cium. Sucrose and fructose intake should be minimized. For adherence to a dietary pattern that is more manageable for patients than manipulating individual nutrients, the Mediterranean diet or the DASH (Dietary Approaches to Stop Hypertension) diet provides an appropriate and readily available option. Randomized tri­ als have conclusively shown the DASH diet to reduce blood pressure. At present, only data from observational studies are available, but these demonstrate a strong and consistent inverse association between these healthy dietary patterns and risk of stone formation.

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331 Urinary Tract Obstruction

Calcium Phosphate  Calcium phosphate stones share risk factors with calcium oxalate stones, including higher concentrations of urine calcium and lower concentrations of urine citrate, but additional fac­ tors deserve attention. Higher urine phosphate levels and higher urine pH (typically ≥6.5) are associated with an increased likelihood of cal­ cium phosphate stone formation. Calcium phosphate stones are more common in patients with distal renal tubular acidosis and primary hyperparathyroidism. There are no randomized trials on which to base preventive recom­ mendations for calcium phosphate stone formers, so the interventions are focused on modification of the recognized risk factors. Thiazide diuretics (with sodium restriction) may be used to reduce urine cal­ cium, as described above for calcium oxalate stones. In patients with low urine citrate levels, alkali supplements (e.g., potassium citrate or bicarbonate) may be used to increase urine citrate. However, the urine pH of these patients should be monitored initially because supple­ mental alkali can raise urine pH, thereby potentially increasing the risk of stone formation. Because these patients tend to have a urinary acidification defect, reducing the urine pH is not an option. Reduction of dietary phosphate may be beneficial by reducing urine phosphate excretion. Uric Acid  The two main risk factors for uric acid stones are per­ sistently low urine pH and higher uric acid excretion. Urine pH is the predominant influence on uric acid solubility; therefore, the mainstay of prevention of uric acid stone formation entails increasing urine pH. Alkalinizing the urine can be achieved by increasing the intake of foods rich in alkali (e.g., fruits and vegetables) and reducing the intake of foods that produce acid (e.g., animal flesh). If necessary, supplementa­ tion with bicarbonate or citrate salts (preferably potassium-based) can be used to reach the recommended pH goal of 6.5 throughout the day and night. Urine uric acid excretion is determined by uric acid generation. Uric acid is the end product of purine metabolism; thus, reduced consumption of purine-containing foods can lower urine uric acid excretion. It is noteworthy that the serum uric acid level is dependent on the fractional excretion of uric acid and, therefore, does not provide information on urine uric acid excretion. For example, an individual with high uric acid generation and concurrent high fractional excre­ tion of uric acid will have high urine uric acid excretion with a normal (or even low) serum uric acid level. If alkalinization of the urine alone is not successful and if dietary modifications do not reduce urine uric acid sufficiently, then the addition of a xanthine oxidase inhibitor, such as allopurinol or febuxostat, can reduce urine uric acid excretion by 40–50%. Cystine  Cystine excretion is not easily modified. Long-term dietary cystine restriction is not feasible and is unlikely to be successful; thus, the focus for cystine stone prevention is on increasing cystine solu­ bility. This goal may be achieved by treatment with medication that covalently binds to cystine (tiopronin or penicillamine) and a medica­ tion that raises urine pH. Tiopronin is the preferred choice owing to its better adverse event profile. The preferred alkalinizing agent to achieve a urine pH of 7.5 is potassium citrate or bicarbonate as sodium salts may increase cystine excretion. As with all stone types, and especially in patients with cystinuria, maintaining a high urine volume is an essential component of the preventive regimen. Struvite  Struvite stones, also known as infection stones or triplephosphate stones, form only when the upper urinary tract is infected with urease-producing bacteria such as Proteus mirabilis, Klebsiella pneumoniae, or Providencia species. Urease produced by these bacteria hydrolyzes urea and may elevate the urine pH to a supraphysiologic level (>8.0). Struvite stones may grow quickly and fill the renal pelvis (staghorn calculi). Struvite stones require complete removal by a urologist. New stone formation can be avoided by the prevention of UTIs. In patients with recurrent upper UTIs (e.g., some individuals with surgically altered urinary drainage or spinal cord injury), the urease inhibitor

acetohydroxamic acid can be considered; however, this agent should be used with caution because of potential side effects.

■ ■LONG-TERM FOLLOW-UP In general, the preventive regimens described above do not cure the underlying pathophysiologic process. Thus, these recommendations typically need to be followed for the patient’s lifetime, and it is essential to tailor recommendations in a way that is acceptable to the patient. Because the memory of the acute stone event fades and patients often return to old habits (e.g., insufficient fluid intake), long-term followup, including repeat 24-h urine collections typically annually, is impor­ tant to ensure that the preventive regimen has been implemented and has resulted in the desired reduction in the risk of new stone formation. Follow-up imaging should be planned thoughtfully. Many patients with recurrent episodes of renal colic that lead to emergency room visits often undergo repeat CT studies. While CT does provide the best information, the radiation dose is higher than that with plain abdominal radiography (KUB). Small stones may be missed by KUB, and ultrasound has a limited ability to determine the size and num­ ber of stones. Minimizing radiation exposure should be a goal of the long-term follow-up plan and must be balanced against the gain in diagnostic information. CHAPTER 331 ■ ■FURTHER READING Coe FL: The physiology of kidney stone prevention: A narrative for patients and physicians. Available at https://bpb-us-w2.wpmucdn.com/ voices.uchicago.edu/dist/c/3637/files/2022/10/KIDNEY-STONES_Pathogenesis-and-Prevention.pdf.  Accessed November 2, 2023. Coe FL, Worcester EM, Evan AP, Lingeman JE (eds): Kidney Stones: Urinary Tract Obstruction Medical and Surgical Management, 2nd ed. New Dehli, Jaypee Brothers Medical Publishing, 2019. European Association of Urology Guidelines on Urolithiasis. Available at https://d56bochluxqnz.cloudfront.net/documents/full-guideline/EAUGuidelines-on-Urolithiasis-2023.pdf. Accessed November 22, 2023. Pearle MS et al: Medical management of kidney stones: AUA guide­ line. J Urol 192:316, 2014. Julian L. Seifter

Urinary Tract Obstruction Obstruction to the flow of urine, with attendant stasis and elevation in urinary tract pressure, impairs renal and urinary conduit functions and is a common cause of acute and chronic kidney disease (obstruc­ tive nephropathy). Early recognition and prompt treatment of urinary tract obstruction (UTO) can prevent or reverse devastating effects on kidney structure and function, and decrease susceptibility to hyperten­ sion, infection, and stone formation. Chronic obstruction may lead to permanent loss of renal mass (renal atrophy) and excretory capability. Because obstructive disease may be secondary to serious underlying inflammatory, vascular, or malignant disease, familiarity with clinical findings, appropriate diagnostic testing, and the therapeutic approach is of great importance to the clinician. Recent developments have advanced our knowledge of fetal and genetic causes of lower urinary tract obstruction (LUTO) and chronic anomalies of the kidneys and urinary tracts (CAKUT), the rubric for a cluster of developmental uropathies associated with cysts and obstruction. In the last few years, studies in mice, zebrafish, and plu­ ripotent stem cells (kidney organoids) have identified possible genetic mutations implicated in cases of CAKUT producing low nephron number, including duplications and deletions (copy number vari­ ants) and familial candidate genes (HFN1β, PAX2, SIX1, GATA3, and

many others). Given that there is no nephrogenesis in humans after birth, obstructive disease manifesting in early or middle adulthood may in fact have origins in a decreased number of nephrons during fetal development. Fetal LUTO, if untreated, often results in pulmo­ nary hypoplasia and death in infancy; kidney failure may be a more long-term outcome. Since amniotic fluid is produced by fetal inges­ tion of urine, LUTO should be suspected when the mother develops oligohydramnios or anhydramnios. Improvements in second-trimester diagnosis and treatment with vesicoamniotic shunting have improved neonatal survival.

One of the most significant concerns in renal medicine is progres­ sion to a chronically fibrotic failing kidney. To date, there has been no demonstration of reversal of scarring, but many investigations are underway to find antifibrosis drugs, including those that address fibrosis in genetic diseases that lead to obstructive nephropathy. Many mechanisms contribute to this progression, including inflammatory responses, hemodynamic consequences of the declining number of healthy nephrons, and compression of normal nephrons by cysts in genetic diseases such as autosomal dominant polycystic kidney disease (ADPKD), where a gene mutation in polycystin causes proliferation of cystic masses. In ADPKD, primary cilia of tubule epithelial cells have been implicated in the development of cysts, resulting in inflamma­ tory processes and cell death. Polycystic disease is one of several such ciliopathies that ultimately lead to fibrosis. PART 9 Disorders of the Kidney and Urinary Tract ■ ■ETIOLOGY Obstruction to urine flow can result from intrinsic or extrinsic mechan­ ical blockade as well as from functional defects not associated with fixed occlusion of the urinary drainage system. Mechanical obstruction can occur at any level of the urinary tract, from within the renal tubules or the renal calyces to the external urethral meatus (obstructive uropa­ thy). Normal points of narrowing, such as the ureteropelvic and ure­ terovesical junctions, bladder neck, and urethral meatus, are common sites of obstruction. When lower UTO is above the level of the bladder, unilateral dilatation of the ureter (hydroureter) and renal pyelocalyceal system (hydronephrosis) occurs; lesions at or below the level of the bladder cause bilateral involvement. Common forms of obstruction are listed in Table 331-1. Childhood causes include congenital malformations, such as narrowing of the ure­ teropelvic junction (UPJ) and abnormal insertion of the ureter into the bladder, the most common cause. Vesicoureteral reflux in the absence of urinary tract infection or bladder neck obstruction often resolves with age. Reinsertion of the ureter into the bladder is indicated if reflux is severe and unlikely to improve spontaneously, if renal function dete­ riorates, or if urinary tract infections recur despite chronic antimicro­ bial therapy. Vesicoureteral reflux may cause prenatal hydronephrosis and, if severe, can lead to recurrent urinary infections, hypertension, and renal scarring in childhood. Posterior urethral valves are the most common cause of bilateral hydronephrosis in boys. In adults, UTO has usually been attributed to acquired defects. Pelvic tumors, calculi, and urethral stricture predominate. Ligation of, or injury to, the ureter during pelvic or colonic surgery can lead to hydronephrosis, which, if unilateral, may remain undetected. Obstructive uropathy may also result from extrinsic neoplastic (carcinoma of cervix or colon) or inflammatory disorders. Lymphomas, particularly follicular, and pel­ vic or colonic neoplasms with retroperitoneal involvement are causes of ureteral obstruction. As many as 50% of men aged >40 years may have lower urinary tract symptoms associated with benign prostatic hypertrophy, but these symptoms may occur without bladder outlet obstruction. Regardless of the primary cause, the chronic kidney dis­ ease that results may be exacerbated by a secondary contributor like diabetes mellitus, hypertension, kidney stones, infection, and meta­ bolic disturbances. Functional impairment of urine flow occurs when voiding is altered by abnormal pontine or sacral centers of micturition control. It may be asymptomatic or associated with lower urinary tract symptoms such as frequency, urgency, and postmicturition incontinence, nocturia, straining to void, slow stream, hesitancy, or a feeling of incomplete emptying. A history should be sought for trauma, back injury, surgery,

TABLE 331-1  Common Mechanical Causes of Urinary Tract Obstruction URETER BLADDER OUTLET URETHRA Congenital Ureteropelvic junction narrowing or obstruction Ureterovesical junction narrowing or obstruction and reflux Ureterocele Retrocaval ureter Bladder neck obstruction Ureterocele Posterior urethral valves Anterior urethral valves Stricture Meatal stenosis Phimosis Acquired Intrinsic Defects Calculi Inflammation Infection Trauma Sloughed papillae Tumor Blood clots Benign prostatic hyperplasia Cancer of prostate Cancer of bladder Calculi Diabetic neuropathy Spinal cord disease Anticholinergic drugs and α-adrenergic agonists Stricture Tumor Calculi Trauma Phimosis Acquired Extrinsic Defects Pregnant uterus Retroperitoneal fibrosis Aortic aneurysm Uterine leiomyomata Carcinoma of uterus, prostate, bladder, colon, rectum Lymphoma Pelvic inflammatory disease, endometriosis Accidental surgical ligation Carcinoma of cervix, colon Trauma Trauma diabetes mellitus, neurologic or psychiatric conditions, and medica­ tions. Causes include neurogenic bladder, often with adynamic ureter, and vesicoureteral reflux. Reflux in children may result in severe uni­ lateral or bilateral hydroureter and hydronephrosis. Overflow urinary incontinence combined with sudden-onset fecal incontinence, severe lower back pain, and saddle anesthesia, requires emergency evalua­ tion for possible cauda equina syndrome. Urinary retention may be the consequence of α-adrenergic and anticholinergic agents, as well as opiates. Hydronephrosis in pregnancy is due to relaxational effects of progesterone on smooth muscle of the renal pelvis, as well as ureteral compression by the enlarged uterus, more often on the right side. Diagnostic tools to identify anatomic obstruction include urinary flow measurements and a postvoid residual measurement. Bladder vol­ ume may be readily assessed by bedside ultrasound. Cystourethroscopy and urodynamic studies may be reserved for the symptomatic patient to assess the filling phase (cystometry), pressure-volume relation­ ship of the bladder, bladder compliance, and capacity. Pressure-flow analysis evaluates bladder contractility and bladder outlet resistance during voiding. Bladder obstruction is characterized by high pressures in women, whereas in men, a diagnosis of bladder outlet obstruction is based on flow rate and voiding pressures. A voiding cystourethrogram may be useful in evaluating incomplete emptying and bladder neck and urethral pathology. ■ ■CLINICAL FEATURES AND PATHOPHYSIOLOGY The pathophysiology and clinical features of UTO are summarized in Table 331-2. Flank pain, the symptom that most commonly leads to medical attention, is due to distention of the collecting system or renal capsule. Pain severity is influenced more by the rate at which distention develops than by the degree of distention. Acute supravesical

TABLE 331-2  Pathophysiology of Bilateral Ureteral Obstruction HEMODYNAMIC EFFECTS TUBULE EFFECTS CLINICAL FEATURES Acute Pain (capsule distention) Azotemia, oliguria, or anuria ↑ Renal blood flow ↓ GFR ↓ Medullary blood flow ↑ Vasodilator prostaglandins, nitric oxide ↑ Ureteral and tubule pressures ↑ Reabsorption of Na+, urea, water Chronic Azotemia Hypertension AVP-insensitive polyuria Natriuresis Hyperkalemic, hyperchloremic acidosis ↓ Renal blood flow ↓↓ GFR ↑ Vasoconstrictor prostaglandins ↑ Renin-angiotensin production ↓ Medullary osmolarity ↓ Concentrating ability Structural damage; parenchymal atrophy ↓ Transport functions for Na+, K+, H+ Release of Obstruction Postobstructive diuresis Potential for volume depletion and electrolyte imbalance due to losses of Na+, K+, PO4 Slow ↑ in GFR (variable) ↓ Tubule pressure ↑ Solute load per nephron (urea, NaCl) Natriuretic factors present 2–, Mg2+, and water Abbreviations: AVP, arginine vasopressin; GFR, glomerular filtration rate. obstruction, as from a stone lodged in a ureter (Chap. 330), is associ­ ated with excruciating, sometimes intermittent, pain, known as renal colic. This pain often radiates to the lower abdomen, testes, or labia. By contrast, more insidious causes of obstruction, such as chronic nar­ rowing of the UPJ, may produce little or no pain and yet result in total destruction of the affected kidney. Flank pain that occurs only with micturition is pathognomonic of vesicoureteral reflux. Obstruction of urine flow results in an increase in hydrostatic pres­ sures proximal to the site of obstruction. It is this buildup of pressure that leads to the accompanying pain, the distention of the collecting system in the kidney, and elevated intratubular pressures that initiate tubular dysfunction. In the first days of obstruction, the dilatation of the poorly compliant collecting system may be minimal. As the increased hydrostatic pressure is expressed in the urinary space of the glomeruli, further filtration decreases or stops completely. Azotemia develops when overall excretory function is impaired, often in the setting of bladder outlet obstruction, bilateral renal pelvic or ureteric obstruction, or unilateral disease in a patient with a solitary functioning kidney. Complete bilateral obstruction should be sus­ pected when acute renal failure is accompanied by anuria. Any patient with renal failure otherwise unexplained, or with a history of neph­ rolithiasis, hematuria, diabetes mellitus, prostatic enlargement, pelvic surgery, trauma, or tumor should be evaluated for UTO. In the acute setting, partial, bilateral obstruction may mimic pre­ renal azotemia with a high blood urea nitrogen–to–creatinine ratio, concentrated urine, and sodium retention. Renal vascular resistance may be increased. However, with more prolonged obstruction, symp­ toms of polyuria and nocturia commonly accompany partial UTO and result from loss of medullary hypertonicity with diminished renal con­ centrating ability. Failure to produce urine free of salt (natriuresis) is due to downregulation of salt reabsorption in the proximal tubule and of transport proteins including the Na+, K+ adenosine triphosphatase (ATPase), Na:K:2Cl cotransporter (NKCC2) in the thick ascending limb, and the epithelial Na+ channel (ENaC) in collecting duct cells. In addition to direct effects on renal transport mechanisms, increased prostaglandin E2 (PGE2) (due to induction of cyclooxygenase-2 [COX-2]), angiotensin II (with its downregulation of Na+ transport­ ers), and atrial or B-type natriuretic peptides (ANP or BNP) due to volume expansion in the azotemic patient contribute to decreased salt reabsorption along the nephron. Nitric oxide synthases (NOS)

in ureteral smooth muscle and urothelial tissues have been found to oppose the high ureteral pressure in unilateral obstruction.

Dysregulation of aquaporin-2 water channels in the collecting duct contributes to the polyuria. The defect usually does not improve with administration of vasopressin and is, therefore, a form of acquired nephrogenic diabetes insipidus. Wide fluctuations in urine output in a patient with azotemia should always raise the possibility of intermittent or partial UTO. If fluid intake is inadequate, severe dehydration and hypernatremia may develop. However, as with other causes of poor renal function, excesses of salt and water intake may result in edema and hyponatremia. Partial bilateral UTO often results in acquired distal renal tubular acidosis, hyperkalemia, and renal salt wasting. The H+-ATPase, situated on the apical membrane of the α-intercalated cells of the collecting duct, is critical for distal H+ secretion. The trafficking of intracellular H+ pumps from the cytoplasm to the cell membrane is disrupted in UTO. The decreased function of the ENaC, in the apical membrane of neighboring collecting duct principal cells, contributes to decreased Na+ reabsorption (salt wasting) and, therefore, decreased K+ secretion via K+ channels. Ammonium (NH+) excretion important to the elimi­ nation of H+ is impaired. These defects in tubule function are often accompanied by renal tubulointerstitial damage. Azotemia with hyper­ kalemia and metabolic acidosis should prompt consideration of UTO. CHAPTER 331 The renal interstitium becomes edematous and infiltrated with mononuclear inflammatory cells early in UTO. Later, interstitial fibro­ sis and atrophy of the papillae and medulla occur and precede these processes in the cortex. The increase in angiotensin II noted in UTO contributes to the inflammatory response and fibroblast accumulation through mechanisms involving profibrotic cytokines. With time, this process leads to chronic kidney damage. Urinary Tract Obstruction UTO must always be considered in patients with urinary tract infections or urolithiasis. Urinary stasis encourages the growth of organisms. Urea-splitting bacteria are associated with magnesium ammonium phosphate (struvite) calculi that may take on a staghorn appearance. Hypertension is frequent in acute and subacute unilateral obstruction and is usually a consequence of increased release of renin by the involved kidney. Chronic kidney disease from bilateral UTO, often associated with extracellular volume expansion, may result in significant hypertension. Erythrocytosis, an infrequent complication of obstructive uropathy, is secondary to increased erythropoietin production. ■ ■DIAGNOSIS A history of difficulty in voiding, pain, infection, or change in urinary volume is common. Evidence for distention of the kidney or urinary bladder can often be obtained by palpation and percussion of the abdo­ men. A careful rectal and genital examination may reveal enlargement or nodularity of the prostate, abnormal rectal sphincter tone, or a rectal or pelvic mass. Urinalysis may reveal hematuria, pyuria, and bacteriuria. The urine sediment is often normal, even when obstruction leads to marked azotemia and extensive structural damage. An abdominal scout film, although insensitive, may detect nephrocalcinosis or a radiopaque stone. As indicated in Fig. 331-1, if UTO is suspected, a bladder catheter should be inserted. Abdominal ultrasonography should be performed to evaluate renal and bladder size, as well as pyelocalyceal contour. Ultrasonography is ~90% specific and sensitive for detection of hydronephrosis. False-positive results are associated with diuresis, renal cysts, or the presence of an extrarenal pelvis, a normal congenital variant. Congenital UPJ obstruction may be mistaken for renal cystic disease. Hydronephrosis may be absent on ultrasound when obstruc­ tion is <48 h in duration or associated with volume contraction, staghorn calculi, retroperitoneal fibrosis, or infiltrative renal disease. Duplex Doppler ultrasonography may detect an increased resistive index in urinary obstruction. The radiodensity of renal stones is mea­ sured in Hounsfield units (HUs). Calcium oxalate and calcium phos­ phate stones may be distinguished from uric acid calculi by their HU radiodensities on noncontrast computed tomography (CT) scan, the test of choice for acute flank pain.

Unexplained renal failure Insert bladder catheter No diuresis: do ultrasound Diuresis Obstruction below bladder neck Hydronephrosis Do CT scan to identify site and etiology of obstruction Urologic evaluation Positive or negative but still high suspicion PART 9 Disorders of the Kidney and Urinary Tract Retrograde urography and ureteral stent considered Antegrade urography and percutaneous nephrostomy considered FIGURE 331-1  Diagnostic approach for urinary tract obstruction in unexplained renal failure. CT, computed tomography. Recent advances in technology have led to alternatives and have replaced the once standard intravenous urogram in the further evalu­ ation of UTO. The high-resolution multidetector row CT scan, in particular, has the advantages of visualizing the retroperitoneum, as well as identifying both intrinsic and extrinsic sites of obstruction. Noncontrast CT scans improve visualization of the urinary tract in the patient with renal impairment and are safer for patients at risk for contrast nephropathy. Magnetic resonance urography is not at this time superior to the CT scan, and certain gadolinium agents carry a risk of systemic sclerosis in patients with renal insufficiency. Recently, prom­ ising alternatives to gadolinium have emerged, including iron-based contrast and inhalation of xenon gas, although thus far, gadolinium produces the clearest images and most-established safety. CT scanning may define the site of obstruction, identify and characterize kidney stones, and demonstrate dilatation of the calyces, renal pelvis, and ureter above the obstruction. The ureter may be tortuous in chronic obstruction. Though radionuclide scans give less anatomic detail than CT scans, they are able to give differential renal function. In the case of asymmetric renal function, the clinician may decide on a preferable kidney to decompress in the case of bilateral obstruction. Furosemide is sometimes given to increase detection with imaging and to distin­ guish functional from anatomic obstruction. The increase in urinary flow may bring out the pain of an acute obstructive process. To facilitate visualization of a suspected lesion in a ureter or renal pelvis, retrograde or antegrade urography should be attempted. These procedures do not carry risk of contrast-induced acute kidney injury in patients with renal insufficiency. The retrograde approach involves catheterization of the involved ureter under cystoscopic control, whereas the antegrade technique necessitates percutaneous placement of a catheter into the renal pelvis. Although the antegrade approach may provide immediate decompression of a unilateral obstructing lesion, many urologists initially attempt the retrograde approach unless the catheterization is unsuccessful. Voiding cystourethrography is of value in the diagnosis of vesico­ ureteral reflux and bladder neck and urethral obstructions. Postvoiding films reveal residual urine. Endoscopic visualization by the urologist often permits precise identification of lesions involving the urethra, prostate, bladder, and ureteral orifices.

No hydronephrosis High suspicion Low suspicion No further workup for obstruction Negative TREATMENT Urinary Tract Obstruction UTO complicated by infection requires immediate relief of obstruc­ tion to prevent development of generalized sepsis and progressive renal damage. Sepsis necessitates prompt urologic intervention. Drainage may be achieved by nephrostomy, ureterostomy, or ure­ teral, urethral, or suprapubic catheterization. Prolonged antibiotic treatment may be necessary. Chronic or recurrent infections in a poorly functioning obstructed kidney may necessitate nephrec­ tomy. When infection is not present, surgery is often delayed until acid-base, fluid, and electrolyte status is restored. Nevertheless, the site of obstruction should be ascertained as soon as feasible. Elective relief of obstruction is usually recommended in patients with urinary retention, recurrent urinary tract infections, persis­ tent pain, or progressive loss of renal function. Benign prostatic hypertrophy may be treated medically with α-adrenergic block­ ers and 5α-reductase inhibitors. Renal colic may be treated with anti-inflammatory medication as edema often contributes to an obstructing ureteral stone, and α-adrenergic blockers may also be of benefit. The clinician should be aware of the risk of intraoperative floppy iris syndrome associated with cataract surgery in patients taking α-adrenergic blockers. Use of nonsteroidal anti-inflamma­ tory medication must take into account the potential for renal harm, and opiates in patients with decreased renal function may be dangerous and should be used with caution. Functional obstruction secondary to neurogenic bladder may be decreased with the combi­ nation of frequent voiding and cholinergic drugs. ■ ■PROGNOSIS With relief of obstruction, the prognosis regarding return of renal func­ tion depends largely on whether irreversible renal damage has occurred. When obstruction is not relieved, the course will depend mainly on whether the obstruction is complete or incomplete and bilateral or uni­ lateral, as well as whether or not urinary tract infection is also present. Complete obstruction with infection can lead to total destruction of the kidney within days. Partial return of glomerular filtration rate may

follow relief of complete obstruction of 1 and 2 weeks’ duration, but after 8 weeks of obstruction, recovery is unlikely. In the absence of definitive evidence of irreversibility, every effort should be made to decompress the obstruction in the hope of restoring renal function at least partially. A renal radionuclide scan, performed after a prolonged period of decom­ pression, may be used to predict the reversibility of renal dysfunction. ■ ■POSTOBSTRUCTIVE DIURESIS Relief of bilateral, but not unilateral, complete obstruction commonly results in polyuria, which may be massive. The urine is usually hypo­ tonic and may contain large amounts of sodium chloride, potassium, phosphate, and magnesium. The natriuresis is due in part to the correc­ tion of extracellular volume expansion, the increase in natriuretic fac­ tors accumulated during the period of renal failure, and depressed salt and water reabsorption when urine flow is reestablished. The retained urea is excreted with improved glomerular filtration rate, resulting in an osmotic diuresis that increases the urine volume of electrolyte-free water. Electrolyte-free water excretion (hypotonic urine) is recognized as being present when the sum of the urinary concentrations of sodium and potassium is lower than the serum sodium concentration. Precipi­ tating factors include suppression of antidiuretic hormone at arterial baroreceptor sites, elevation of natriuretic peptides, or nephrogenic diabetes insipidus due to obstructive tubular injury. In the majority of patients, this diuresis results in the appropriate excretion of the excesses of retained salt and water. When extracellular volume and composition return to normal, the diuresis usually abates spontaneously. Occasion­ ally, iatrogenic expansion of extracellular volume is responsible for, or sustains, the diuresis observed in the postobstructive period. Replace­ ment with intravenous fluids in amounts less than urinary losses usu­ ally prevents this complication. More aggressive fluid management is required in the setting of hypovolemia, hypotension, or disturbances in serum electrolyte concentrations. The loss of electrolyte-free water with urea may result in hyper­ natremia. Measured urinary output and serum and urine sodium, potassium, and osmolal concentrations should guide the use of

appropriate intravenous replacement. Often replacement with 0.45% saline is required because of the likelihood of appropriately matching urine electrolyte concentrations. Relief of obstruction may be followed by urinary salt and water losses severe enough to provoke profound dehydration and vascular collapse. In these patients, decreased tubule reabsorptive capacity is probably responsible for the marked diuresis. Appropriate therapy in such patients includes intravenous administra­ tion of salt-containing solutions to replace sodium and volume deficits.

■ ■FURTHER READING Capone V et al: Definition, diagnosis and management of fetal lower urinary tract obstruction: Consensus of the Erknet Cakut-Obstructive Uropathy Work Group. Nature Rev Urol 19:295, 2022. Frokiaer J: Urinary tract obstruction, in Brenner and Rector’s The Kidney, 10th ed, Skorecki K et al (eds). Philadelphia, W.B. Saunders & Company, 2016, pp 1257–1282. McConnachie DJ et al: Ciliopathies and the kidney: A review. Am J Kidney Dis 77: 410, 2021. Meldrum KK: Pathophysiology of urinary tract obstruction, in Campbell Walsh Wein Urology, Partin AW et al (eds). Philadelphia, Elsevier, 2020, Chapter 48. Murugapoopathy V, Gupta IR: A primer on congenital anomalies of the kidneys and urinary tracts (CAKUT). Clin J Am Soc Nephrol 15:723, 2020. Smith-Bindman R et al: Ultrasonography versus computed tomogra­ CHAPTER 331 phy for suspected nephrolithiasis. N Engl J Med 371:1100, 2014. Stoller ML: Urinary obstruction and stasis, in Smith and Tanagho’s General Urology, 18th ed. JW McAninch, TF Lue (eds). New York, McGraw-Hill, 2013, pp 170–182. Tanagho EA, Nguyen HT: Vesicoureteral reflux, in Smith and Urinary Tract Obstruction Tanagho’s General Urology, 18th ed. WJ McAninch, TF Lue (eds). New York, McGraw-Hill, 2013, pp 182–197. Vollman DE et al: Intraoperative floppy iris and prevalence of intra­ operative complications: Results from ophthalmic surgery outcomes database. Am J Ophthalmol 157:1130, 2014.

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