10 - 328 Tubulointerstitial Diseases of the Kidney

328 Tubulointerstitial Diseases of the Kidney

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

Tubulointerstitial

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

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

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

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

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

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

■ ■IgG4-RELATED SYSTEMIC DISEASE A form of AIN characterized by a dense inflammatory infiltrate con­ taining IgG4-expressing plasma cells can occur as a part of a syndrome known as IgG4-related systemic disease (Chap. 380). Autoimmune pancreatitis, sclerosing cholangitis, retroperitoneal fibrosis, and a chronic sclerosing sialadenitis (mimicking Sjögren’s syndrome) may variably be present as well. Fibrotic lesions that form pseudotumors in the affected organs soon replace the initial inflammatory infiltrates and often lead to biopsy or excision for fear of true malignancy. Although the involvement of IgG4 in the pathogenesis is not understood, glu­ cocorticoids have been successfully used as first-line treatment in this group of disorders, once they are correctly diagnosed. CHAPTER 328 ■ ■AIN ASSOCIATED WITH THE USE OF IMMUNE CHECKPOINT INHIBITORS The use of immune checkpoint inhibitors has had a major impact in cancer care by disrupting mechanisms by which tumor cells elude the body’s immune surveillance systems. However, such success comes at the cost of increasing the incidence of autoimmune phenomena. While dermatologic, gastrointestinal, and endocrine manifestations prevail, the kidney is impacted in 2% of cases with monotherapy and up to 5% when dual checkpoint inhibitor therapy is used. An acute rise in serum creatinine is typically noted within 15 weeks after starting therapy, although it can occur later during therapy or up to 2 months following the final dose. Biopsy, when performed, typically shows acute interstitial inflammation, although glomerular pathologies may also be found. Patients are often taking medications commonly known to cause acute drug-associated TIN such as proton pump inhibitors or NSAIDs. Treatment for severe acute kidney injury includes corticoste­ roids, discontinuation of potential inciting medications, and avoidance of further checkpoint inhibitor doses until the kidney function has recovered. Reinitiation of these agents for continued treatment of the underlying malignancy may be possible in some cases. Tubulointerstitial Diseases of the Kidney ■ ■IDIOPATHIC AIN Some patients present with typical clinical and histologic features of AIN but have no evidence of drug exposure or clinical or serologic features of an autoimmune disease. The presence in some cases of auto­ antibodies to a tubular antigen, similar to that identified in rats with an induced form of interstitial nephritis, suggests that an autoimmune response may be involved. Like TINU and granulomatous interstitial nephritis, idiopathic AIN is responsive to glucocorticoid therapy but may follow a relapsing course requiring maintenance treatment with another immunosuppressive agent (Fig. 328-1 and Table 328-2). Recently, cases have been identified in which autoantibodies that may be impor­ tant in disease pathogenesis were seen to target antigens expressed by the collecting duct or proximal tubular brush border. * ■ ■INFECTION-ASSOCIATED AIN AIN may also occur as a local inflammatory reaction to microbial infection (Table 328-1) and should be distinguished from acute bacte­ rial pyelonephritis (Chap. 140). Acute bacterial pyelonephritis does not generally cause acute kidney injury unless it affects both kidneys or causes septic shock. Presently, infection-associated AIN is most often seen in immunocompromised patients, particularly kidney transplant recipients with reactivation of polyomavirus BK (Chaps. 148 and 325). A significant increase in cases of acute TIN (without uveitis) or TINU has been noted in children after infection with SARS-CoV-2.

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

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

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

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

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

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

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

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

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

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

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

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