# 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.