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InternalMed_Harrison. Abbreviations: CMV, cytomegalovirus; COX, cyclooxygenase; EBV, Epstein-Barr virus. 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 encountered as an allergic reaction to a drug (Table 340-1). 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 340-1). more than ~15% of cases of unexplained acute renal failure, this is likely a substantial underestimate 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 renal biopsy to establish the diagnosis of AIN.


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InternalMed_Harrison. Clinical Features The classic presentation of AIN, namely, fever, rash, peripheral eosinophilia, and oliguric renal failure 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 renal failure (Chap. 334). Atypical reactions can occur, most notably nonsteroidal anti-inflammatory drug (NSAID)-induced AIN, in which fever, rash, and eosinophilia are rare, but acute renal failure with heavy proteinuria is common. A particularly 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 340-1 may lead to progressive tubulointerstitial damage. Examples include proton pump inhibitors and, rarely, sulfonamide and 5-aminosalicylate (mesalazine and sulfasalazine) derivatives and antiretrovirals.


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InternalMed_Harrison. Diagnosis Finding otherwise unexplained renal failure 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. Urinalysis reveals pyuria with white blood cell casts and hematuria. Urinary eosinophils are neither sensitive nor specific for AIN; therefore, testing is not recommended. Renal biopsy is generally not required for diagnosis but reveals extensive interstitial and tubular infiltration of leukocytes, including eosinophils.


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InternalMed_Harrison. Discontinuation of the offending agent often leads to reversal of the renal injury. However, depending on the duration of exposure and degree of tubular atrophy and interstitial fibrosis that has occurred, the renal damage may not be completely reversible. Glucocorticoid therapy may accelerate renal recovery, but does not appear to impact long-term renal survival. It is best reserved for those cases with severe renal failure in which dialysis is imminent or if renal function continues to deteriorate despite stopping the offending drug (Fig. 340-1 and Table 340-2).


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InternalMed_Harrison. 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, that constitute the “sicca syndrome” (Chap. 383). Tubulointerstitial nephritis with a predominant lymphocytic infiltrate is the most common renal manifestation of Sjögren’s syndrome and can be associated with distal RTA, nephrogenic diabetes insipidus, and moderate renal failure. 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


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InternalMed_Harrison. Tubulointerstitial Diseases of the Kidney Chapter 340Continue observation Improvement Supportive˜care˜and close observation No˝improvement˝in˝1˝week OR˝rapid˝progression Classic˝allergic˝AIN Atypical˝features Corticosteroids Renal biopsy Fibrosis Classic˝AIN Conservative Corticosteroids Immunosuppressive˜drugs Granulomatous or˝other˝immune˝IN FIGuRE 340-1 Algorithm for the treatment of allergic and other immune-mediated acute interstitial nephritis (AIN). ARF, acute renal failure; IN, interstitial nephritis. See text for immunosuppressive drugs used for refractory or relapsing AIN. (Modified from S Reddy, DJ Salant: Ren Fail 20:829, 1998.) is initially with glucocorticoids, although patients may require maintenance therapy with azathioprine or mycophenolate mofetil to prevent relapse (Fig. 340-1 and Table 340-2).


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InternalMed_Harrison. TINU is a systemic autoimmune disease of unknown etiology. It accounts for fewer than 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. 340-2), is a painful anterior uveitis, often bilateral and accompanied by blurred vision and photophobia. Diagnosis is • Drug-induced or idiopathic AIN with: Rapid progression of renal failure Diffuse infiltrates on biopsy Impending need for dialysis Delayed recovery AIN with delayed recovery (?) Abbreviations: AIN, acute interstitial nephritis; SLE, systemic lupus erythematosus; TINU, tubulointerstitial nephritis with uveitis. Source: Modified from S Reddy, DJ Salant: Ren Fail 20:829, 1998.


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InternalMed_Harrison. Source: Modified from S Reddy, DJ Salant: Ren Fail 20:829, 1998. FIGuRE 340-2 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 PAS-stained renal 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.


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InternalMed_Harrison. often confounded by the fact that the ocular symptoms precede or accompany the renal 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 renal disease, such as Sjögren’s syndrome, Behçet’s disease, sarcoidosis, and systemic lupus erythematosus, have been considered. Clinical symptoms are typically self-limited in children, but are more apt to follow a relapsing course in adults. The renal and ocular manifestations generally respond well to oral glucocorticoids, although maintenance therapy with agents such as methotrexate,


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InternalMed_Harrison. are more apt to follow a relapsing course in adults. The renal and ocular manifestations generally respond well to oral glucocorticoids, although maintenance therapy with agents such as methotrexate, azathioprine, or mycophenolate may be necessary to prevent relapses (Fig. 340-1 and Table 340-2).


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InternalMed_Harrison. An interstitial mononuclear cell inflammatory reaction often accompanies the glomerular lesion in most cases of class III or IV lupus nephritis (Chap. 338), and deposits of immune complexes can be identified in tubule basement membranes in about 50% of cases. Occasionally, however, the tubulointerstitial inflammation predominates and may manifest with azotemia and type IV RTA rather than features of glomerulonephritis.


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InternalMed_Harrison. Some patients may present with features of AIN but follow a protracted and relapsing course. Renal biopsy in such patients reveals a more chronic inflammatory infiltrate with granulomas and multinucleated giant cells. Most often, no associated disease or cause is found; however, some of these cases may have or subsequently develop the pulmonary, cutaneous, or other systemic manifestations of sarcoidosis such as hypercalcemia. Most patients experience some improvement in renal function if treated early with glucocorticoids before the development of significant interstitial fibrosis and tubular atrophy (Table 340-2). Other immunosuppressive agents may be required for those who relapse frequently upon steroid withdrawal. Other immunosuppressive agents may be required for those who relapse frequently upon steroid withdrawal (Fig. 340-1). Tuberculosis should be ruled out before starting treatment because this too is a rare cause of granulomatous interstitial nephritis.


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InternalMed_Harrison. A form of AIN characterized by a dense inflammatory infiltrate containing IgG4-expressing plasma cells can occur as a part of a syndrome known as IgG4-related systemic disease. 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, glucocorticoids have been successfully used as first-line treatment in this group of disorders, once they are correctly diagnosed.


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InternalMed_Harrison. 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. 340-1 and Table 340-2).


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InternalMed_Harrison. AIN may also occur as a local inflammatory reaction to microbial infection (Table 340-1) and should be distinguished from acute bacterial pyelonephritis (Chap. 162). Acute bacterial pyelonephritis does not generally cause acute renal failure unless it affects both kidneys or causes septic shock. Presently, infection-associated AIN is most often seen in immunocompromised patients, particularly renal transplant recipients with reactivation of polyomavirus BK (Chaps. 169 and 337).


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InternalMed_Harrison. Acute renal failure may occur when crystals of various types are deposited in tubular cells and interstitium or when they obstruct tubules. Oliguric acute renal failure, often accompanied by flank pain from tubular obstruction, may occur in patients treated with sulfadiazine for toxoplasmosis, indinavir and atazanavir for HIV, and intravenous acyclovir for severe herpesvirus infections. Urinalysis reveals “sheaf of wheat” sulfonamide crystals, individual or parallel clusters of needle-shaped indinavir crystals, or red-green birefringement needle-shaped 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.


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InternalMed_Harrison. Acute tubular obstruction is also the cause of oliguric renal failure in patients with acute urate nephropathy. It typically results from severe hyperuricemia from tumor lysis syndrome in patients with lymphoor myeloproliferative disorders treated with cytotoxic agents, but also may occur spontaneously before the treatment has been initiated (Chap. 331). 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 crystals 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


InternalMed_Harrison

InternalMed_Harrison. 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 renal function.


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InternalMed_Harrison. Calcium oxalate crystal deposition in tubular cells and interstitium may lead to permanent renal 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. 342). Acute phosphate nephropathy is an uncommon but serious complication of oral Phospho-soda 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 renal impairment and hypovolemia. Consequently, Phospho-soda should be avoided in patients with chronic kidney disease.


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InternalMed_Harrison. Patients with multiple myeloma may develop acute renal failure 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 renal failure.


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InternalMed_Harrison. 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. 340-3). 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 obstruction, 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.


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InternalMed_Harrison. Diagnosis Clinical clues to the diagnosis include anemia, bone pain, hypercalcemia, and an abnormally narrow anion gap due to hypoalbuminemia and hypergammaglobulinemia. Urinary dipsticks detect albumin but not immunoglobulin light chains; however, laboratory detection of increased amounts of protein in a spot urine specimen 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.


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InternalMed_Harrison. FIGuRE 340-3 Histologic appearance of myeloma cast nephropathy. A hematoxylin-eosin–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.) 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. 136); plasmapheresis to remove light chains is of questionable value for LCCN.


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InternalMed_Harrison. 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 renal failure. Although high-dose glucocorticoids and subsequent chemotherapy often result in recovery of renal function, the prognosis in such cases is generally poor.


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InternalMed_Harrison. 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 disease (Chap. 338). Other important forms of CIN are the result of developmental 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


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InternalMed_Harrison. 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).


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InternalMed_Harrison. 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 abnormal retrograde urine flow from the bladder into one or both ureters and kidneys because of mislocated and incompetent ureterovesical valves (Fig. 340-4). 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 bed-wetting or recurrent UTIs


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InternalMed_Harrison. when chronic kidney disease is detected during routine evaluation or during pregnancy. Affected adults are frequently asymptomatic, but may give a history of prolonged bed-wetting or recurrent UTIs during childhood, and exhibit variable renal insufficiency, hypertension, mild to moderate proteinuria, and 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. Renal ultrasound in adults characteristically shows asymmetric small kidneys with irregular outlines, thinned cortices, and regions of compensatory hypertrophy (Fig. 340-4).


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InternalMed_Harrison. Maintenance of sterile urine in childhood has been shown to limit scarring of the kidneys. 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 Tubulointerstitial Diseases of the Kidney FIGuRE 340-4 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).


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InternalMed_Harrison. 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.) not indicated in adolescents or adults after scarring has occurred. Aggressive control of blood pressure with an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) and other agents is effective in reducing proteinuria and may significantly forestall further deterioration of renal function.


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InternalMed_Harrison. The pathogenesis and clinical manifestations of sickle cell nephropathy are described in Chap. 341. Evidence of tubular injury may be evident in childhood and early adolescence in the form of polyuria due to decreased concentrating ability or type IV renal tubular acidosis 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 340-3).


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InternalMed_Harrison. 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, however, chronic tubulointerstitial changes occur as a secondary Diabetes with urinary tract infection Abbreviation: NSAID, nonsteroidal anti-inflammatory drug.


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InternalMed_Harrison. Diabetes with urinary tract infection Abbreviation: NSAID, nonsteroidal anti-inflammatory drug. consequence of prolonged glomerular dysfunction. Potential mechanisms by which glomerular disease might cause tubulointerstitial injury include proteinuria-mediated damage to the epithelial cells, activation of tubular 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 glomerulonephritis. It is often difficult to discern the initial cause of injury by renal biopsy in a patient who presents with advanced renal disease in this setting.


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InternalMed_Harrison. 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 renal insufficiency, papillary necrosis (Table 340-3) 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 best appreciated by computed tomography (Fig. 340-5). 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 renal failure. Recent cohort studies in individuals with normal baseline renal


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InternalMed_Harrison. of analgesic nephropathy are at increased risk of a urothelial malignancy compared to patients with other causes of renal failure. Recent cohort studies in individuals with normal baseline renal function suggest that the moderate chronic use of current analgesic preparations available in the United States, including acetaminophen and NSAIDs, does not seem to cause the constellation of findings known as analgesic nephropathy, although volume-depleted individuals and those with chronic kidney disease are at higher risk of NSAID-related renal toxicity. Nonetheless, it is recommended that heavy users of acetaminophen and NSAIDs be screened for evidence of renal disease.


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InternalMed_Harrison. 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 termed aristolochic acid nephropathy (AAN). In Chinese herbal nephropathy, first described in the early 1990s in young women tak-1861 ing traditional Chinese herbal preparations as part of a weight-loss regimen, one of the offending agents has been identified as aristolochic 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 tubulointerstitial nephritis 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 certainty,


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InternalMed_Harrison. tubulointerstitial nephritis 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 certainty, contamination of local grain preparations with the seeds of Aristolochia 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 renal dysfunction. Definitive diagnosis of AAN requires two of the following three features: characteristic histology on kidney biopsy; confirmation of aristolochic acid ingestion; and detection 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-to-T:A transversions. Due to this


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InternalMed_Harrison. 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-to-T: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 consideration should be given to bilateral nephroureterectomy once a patient has reached ESRD.


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InternalMed_Harrison. FIGuRE 340-5 Radiologic appearance of analgesic nephropathy. A noncontrast computed tomography scan shows an atrophic left kidney with papillary calcifications in a garland pattern. (Reprinted by permission from Macmillan Publishers, Ltd., MM Elseviers et al: Kidney International 48:1316, 1995.) Karyomegalic interstitial nephritis is an unusual form of slowly progressive 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.


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InternalMed_Harrison. The use of lithium salts for the treatment of manic-depressive illness may have several renal sequelae, the most common of which is nephrogenic diabetes insipidus manifesting as polyuria and polydipsia. Lithium accumulates in principal cells of the collecting duct by entering through the epithelial sodium channel (ENaC), where it inhibits glycogen synthase kinase 3β and downregulates vasopressin-regulated aquaporin water channels. Less frequently, chronic tubulointerstitial nephritis develops after prolonged (>10–20 years) lithium use and is most likely to occur in patients who have experienced repeated episodes of toxic lithium levels. Findings on renal 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 characteristic of this disorder. The degree of interstitial fibrosis


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InternalMed_Harrison. disease, a sparse lymphocytic infiltrate, and small cysts or dilation of the distal tubule and collecting duct that are highly characteristic 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 minimal 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 renal function.


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InternalMed_Harrison. Renal function should be followed regularly in patients taking lithium, and caution should be exercised in patients with underlying renal 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 prevent lithium-induced CIN. Once lithium-associated nephropathy is detected, the discontinuation of lithium in attempt to forestall further renal deterioration can be problematic, as lithium is an effective mood stabilizer that is often incompletely substituted by other agents. Furthermore, despite discontinuation of lithium, chronic


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InternalMed_Harrison. Tubulointerstitial Diseases of the Kidney 1862 renal 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 renal function declines. In patients who develop significant proteinuria, ACEI or ARB treatment should be initiated.


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InternalMed_Harrison. The calcineurin inhibitor (CNI) immunosuppressive agents cyclosporine and tacrolimus can cause both acute and chronic renal 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 renal injury is typically seen in solid organ (including heart-lung and liver) transplant recipients and manifests with a slow but irreversible reduction of glomerular filtration rate, with mild proteinuria and arterial hypertension. Hyperkalemia is a relatively common complication and is caused, in part, by tubular resistance to aldosterone. The histologic changes in renal tissue include patchy interstitial fibrosis and tubular atrophy, often in a “striped” pattern. In addition, the intrarenal vasculature often demonstrates hyalinosis, and focal glomerulosclerosis can be present as well. Similar changes may occur in patients receiving CNIs for autoimmune diseases, although the


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InternalMed_Harrison. intrarenal vasculature often demonstrates 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.


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InternalMed_Harrison. Heavy metals, such as lead or cadmium, can lead to a chronic tubulointerstitial 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.


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InternalMed_Harrison. Early signs of chronic lead intoxication are attributable to proximal tubule dysfunction, particularly hyperuricemia as a result of diminished urate secretion. The triad of “saturnine gout,” hypertension, and renal insufficiency should prompt a practitioner to ask specifically 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 renal function, although either of these two factors may have been the primary event. In those 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 renal function.


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InternalMed_Harrison. Disorders leading to excessively high or low levels of certain electrolytes and products of metabolism can also lead to chronic kidney disease if untreated. The constellation of pathologic findings that represent gouty nephropathy are very uncommon nowadays and are more of historical interest than clinical importance, as gout is typically well managed with allopurinol and other agents. However, there is emerging evidence that hyperuricemia is an independent risk factor for the development of chronic kidney disease, perhaps through endothelial damage. The complex interactions of hyperuricemia, hypertension, and renal failure are still incompletely understood.


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InternalMed_Harrison. 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 (Chap. 431e). This should be distinguished from juvenile hyperuricemic nephropathy, a form of medullary cystic kidney disease caused by mutations in uromodulin (UMOD) (Chap. 339). Histologically, the distinctive feature of gouty nephropathy is the presence of crystalline 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 infiltration, 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


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InternalMed_Harrison. 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 filtration 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 nephrolithiasis 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 renal function.


InternalMed_Harrison

InternalMed_Harrison. (See also Chap. 424) Chronic hypercalcemia, as occurs in primary hyperparathyroidism, sarcoidosis, multiple myeloma, vitamin D intoxication, or metastatic bone disease, can cause tubulointerstitial disease and progressive renal failure. 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 interstitial calcium deposition (nephrocalcinosis). Calcium deposition may also occur in glomeruli and the walls of renal arterioles.


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InternalMed_Harrison. Clinically, the most striking defect is an inability to maximally concentrate 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 hypercalcemia. Eventually, uncontrolled hypercalcemia leads to severe tubulointerstitial damage and overt renal failure. 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. 424). Renal dysfunction of acute hypercalcemia may be completely reversible. Gradual progressive renal insufficiency related to chronic hypercalcemia, however, may not improve even with correction of the calcium disorder.


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InternalMed_Harrison. 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 correction of the hypokalemia will prevent further progression, but persistent hypokalemia can cause ESRD.


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InternalMed_Harrison. The causes of acute and chronic interstitial nephritis vary widely across the globe. Analgesic nephropathy continues to be seen in countries where phenacetin-containing compound analgesic preparations are readily available. Adulterants in unregulated herbal and traditional medicaments pose a threat of toxic interstitial nephritis, as exemplified by aristolochic acid contamination of herbal slimming preparations. Contamination of food sources with toxins, such as the recent outbreak of nephrolithiasis and acute renal failure from melamine contamination of infant milk formula, poses a continuing risk. Large-scale exposure to aristolochic acid remains prevalent in many Asian countries where traditional herbal medicine use is common. Although industrial exposure to lead and cadmium has largely disappeared as a cause of chronic interstitial nephritis in developed nations, it remains a risk for nephrotoxicity in countries where such exposure is less well controlled. New endemic forms of


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InternalMed_Harrison. disappeared as a cause of chronic interstitial nephritis in developed nations, it remains a risk for nephrotoxicity in countries where such exposure is less well controlled. New endemic forms of chronic kidney disease continue to be described, such as the nephropathy found among Pacific coastal plantation workers in Central America, which may be related to repetitive heat exposure and fluid losses.


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InternalMed_Harrison. Vascular Injury to the Kidney Nelson Leung, Stephen C. Textor The renal circulation is complex and is characterized by a highly perfused arteriolar network, reaching cortical glomerular structures adjacent to lower-flow vasa recta that descend into medullary seg-ments. Disorders of the larger vessels, including renal artery stenosis 341 and atheroembolic disease, are discussed elsewhere (Chap. 354). This chapter examines primary disorders of the renal microvessels, many of which are associated with thrombosis and hemolysis.


InternalMed_Harrison

InternalMed_Harrison. Thrombotic microangiopathy (TMA) is characterized by injured endothelial cells that are thickened, swollen, or detached mainly from arterioles and capillaries. Platelet and hyaline thrombi causing partial or complete occlusion are integral to the histopathology of TMA. TMA is usually the result of microangiopathic hemolytic anemia (MAHA), with its typical features of thrombocytopenia and schistocytes. In the kidney, TMA is characterized by swollen endocapillary cells (endotheliosis), fibrin thrombi, platelet plugs, arterial intimal fibrosis, and a membranoproliferative pattern. Fibrin thrombi may extend into the arteriolar vascular pole, producing glomerular collapse and at times cortical necrosis. In kidneys that recover from acute TMA, secondary focal segmental glomerulosclerosis may be seen. Diseases associated with this lesion include thrombotic thrombocytopenic purpura (TTP), hemolytic-uremic syndrome (HUS), malignant hypertension, scleroderma renal crisis, antiphospholipid


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InternalMed_Harrison. be seen. Diseases associated with this lesion include thrombotic thrombocytopenic purpura (TTP), hemolytic-uremic syndrome (HUS), malignant hypertension, scleroderma renal crisis, antiphospholipid syndrome, preeclampsia/HELLP (hemolysis, elevated liver enzymes, low platelet count) syndrome, HIV infection, and radiation nephropathy.


InternalMed_Harrison

InternalMed_Harrison. HUS and TTP are the prototypes for MAHA. Historically, HUS and TTP were distinguished mainly by their clinical and epidemiologic differences. TTP develops more commonly in adults and was thought to include neurologic involvement more often. HUS occurs more commonly in children, particularly when associated with hemorrhagic diarrhea. However, atypical HUS (aHUS) can first appear in adulthood, and better testing has revealed that neurologic involvement is as common in HUS as in TTP. Accordingly, HUS and TTP now should be differentiated and treated according to their specific pathophysiologic features. Hemolytic-uremic Syndrome HUS is loosely defined by the presence of MAHA and renal impairment. At least four variants are recognized. The most common is Shiga toxin–producing Escherichia coli (STEC) HUS, which is also known as D+HUS or enterohemorrhagic


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InternalMed_Harrison. E. coli (EHEC) HUS. Most cases involve children <5 years of age, but adults also are susceptible, as evidenced by a 2011 outbreak in northern Europe. Diarrhea, often bloody, precedes MAHA within 1 week in >80% of cases. Abdominal pain, cramping, and vomiting 1863 are frequent, whereas fever is typically absent. Neurologic symptoms, including dysphasia, hyperreflexia, blurred vision, memory deficits, encephalopathy, perseveration, and agraphia, often develop, especially in adults. Seizures and cerebral infarction can occur in severe cases. STEC HUS is caused by the Shiga toxins (Stx1 and Stx2), which are also referred to as verotoxins. These toxins are produced by certain strains of E. coli and Shigella dysenteriae. In the United States and Europe, the most common STEC strain is O157:H7, but HUS due to other strains (O157/H−, O111:H−, O26:H11/H−, O145:H28, and


InternalMed_Harrison

InternalMed_Harrison. O104:H4) has occurred. After entry into the circulation, Shiga toxin binds to the glycolipid surface receptor globotriaosylceramide (Gb3), which is richly expressed on cells of the renal microvasculature. Upon binding, the toxin enters the cells, inducing inflammatory cytokines (interleukin 8 [IL-8], monocyte chemotactic protein 1 [MCP-1], and stromal cell–derived factor 1 [SDF-1]) and chemokine receptors (CXCR4 and CXCR7); this action results in platelet aggregation and the microangiopathic process. Streptococcus pneumoniae can also cause HUS. Certain strains produce a neuraminidase that cleaves the N-acetylneuraminic acid moieties covering the Thomsen-Friedenreich antigen on platelets and endothelial cells. Exposure of this normally cryptic antigen to preformed IgM results in severe MAHA.


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InternalMed_Harrison. Atypical HUS is the result of congenital complement dysregulation. The affected patients have the low C3 and normal C4 levels characteristic of alternative pathway activation. Factor H deficiency, the most common defect, has been linked to families with aHUS. Factor H competes with factor B to prevent the formation of C3bBb and acts as a cofactor for factor I, which proteolytically degrades C3b. More than 70 mutations of the factor H gene have been identified. Most are missense mutations that produce abnormalities in the C-terminus region, affecting its binding to C3b but not its concentration. Other mutations result in low levels or the complete absence of the protein. Deficiencies in other complement-regulatory proteins, such as factor I, factor B, membrane cofactor protein (CD46), C3, complement factor H–related protein 1 (CFHR1), CFHR3, CFHR5, and thrombomodulin, have also been reported. Finally, an autoimmune variant of aHUS has been discovered. DEAP (deficient for CFHR protein


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InternalMed_Harrison. complement factor H–related protein 1 (CFHR1), CFHR3, CFHR5, and thrombomodulin, have also been reported. Finally, an autoimmune variant of aHUS has been discovered. DEAP (deficient for CFHR protein and positive for factor H autoantibody) HUS occurs when an autoantibody to factor H is formed. DEAP HUS is often associated with a deletion of an 84-kb fragment of the chromosome that encodes for CFHR1 and CFHR3. The autoantibody blocks the binding of factor H to C3b and surface-bound C3 convertase.


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InternalMed_Harrison. Thrombotic Thrombocytopenic Purpura Traditionally, TTP is characterized by the pentad: MAHA, thrombocytopenia, neurologic symptoms, fever, and renal failure. The pathophysiology of TTP involves the accumulation of ultra-large multimers of von Willebrand factor as a result of the absence or markedly decreased activity (<5–10%) of the plasma protease ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13. These ultra-large multimers form clots and shear erythrocytes, resulting in MAHA; however, the absence of ADAMTS13 alone may not itself produce TTP. Often, an additional trigger (such as infection, surgery, pancreatitis, or pregnancy) is required to initiate clinical TTP.


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InternalMed_Harrison. Data from the Oklahoma TTP/HUS Registry suggest an incidence rate of 11.3 cases/106 patients in the United States. The median age of onset is 40 years. The incidence is more than nine times higher among blacks than among non-blacks. Like that of systemic lupus erythematosus, the incidence of TTP is nearly three times higher among women than among men. If untreated, TTP has a mortality rate exceeding 90%. Even with modern therapy, 20% of patients die within the first month from complications of microvascular thrombosis.


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InternalMed_Harrison. The classic form of TTP is idiopathic TTP, which is usually the result of a deficiency in ADAMTS13. While TTP had traditionally been associated with infection, malignancy, and intense inflammation (e.g., pancreatitis), ADAMTS13 activity usually is not decreased in these conditions. In idiopathic TTP, the formation of an autoantibody to ADAMTS13 (IgG or IgM) either increases its clearance or inhibits its activity. Upshaw-Schülman syndrome is a hereditary condition characterized by congenital deficiency of ADAMTS13. TTP in these


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InternalMed_Harrison. Vascular Injury to the Kidney 1864 patients can start within the first weeks of life but in some instances may not present until the patient is several years of age. Both environmental and genetic factors are thought to influence the development of TTP. Plasma transfusion is an effective strategy for prevention and treatment. Drug-induced TMA is a recognized complication of treatment with some chemotherapeutic agents, immunosuppressive agents, antiplatelet agents, and quinine. Two different mechanisms have been described. Endothelial damage (pathologically similar to that in HUS) is the main cause of the TMA that develops in association with chemotherapeutic agents (e.g., mitomycin C, gemcitabine) and immunosuppressive agents (cyclosporine, tacrolimus, and sirolimus). This process is usually dose-dependent. Alternatively, TMA may develop as a result of drug-induced autoantibodies. This form is less likely to be dose-dependent and can, in fact, occur after a single dose in patients


InternalMed_Harrison

InternalMed_Harrison. dose-dependent. Alternatively, TMA may develop as a result of drug-induced autoantibodies. This form is less likely to be dose-dependent and can, in fact, occur after a single dose in patients with previous exposure. Ticlopidine produces TTP by inducing an autoantibody to ADAMTS13, but ADAMTS13 deficiency is found in fewer than half of patients with clopidogrel-associated TTP. Quinine appears to induce autoantibodies to granulocytes, lymphocytes, endothelial cells, and platelet glycoprotein IbB/IX or IIb/IIIa complexes, but not to ADAMTS13. Quinine-associated TTP is more common among women. TMA has been reported with drugs that inhibit vascular endothelial growth factor, such as bevacizumab; the mechanism is not completely understood.


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InternalMed_Harrison. Treatment should be based on pathophysiology. Autoantibodymediated TTP and DEAP HUS respond to plasma exchange or plasmapheresis. In addition to removing the autoantibodies, plasma exchange with fresh-frozen plasma replaces ADAMTS13. Twice-daily plasma exchanges with administration of vincristine and rituximab may be effective in refractory cases. Plasma infusion is usually sufficient to replace the ADAMTS13 in Upshaw-Schülman syndrome. Plasma exchange should be considered if larger volumes are necessary. Drug-induced TMA secondary to endothelial damage typically does not respond to plasma exchange and is treated primarily by discontinuing use of the agent and providing supportive care. Similarly, STEC HUS should be treated with supportive measures. Plasma exchange has not been found to be effective. Antimotility agents and antibiotics increase the incidence of HUS among children, but azithromycin was recently found to decrease the duration of bacterial shedding by adults. Eculizumab


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InternalMed_Harrison. effective. Antimotility agents and antibiotics increase the incidence of HUS among children, but azithromycin was recently found to decrease the duration of bacterial shedding by adults. Eculizumab is a monoclonal antibody to C5 that is approved for use in aHUS, for which ongoing therapy may be necessary. Plasma infusion/exchange may play a role in aHUS by replacing complement-regulatory proteins. Antibiotics and washed red cells should be given in neuraminidase-associated HUS, and plasmapheresis may be helpful. However, plasma and whole-blood transfusion should be avoided since these products contain IgM, which may exacerbate MAHA. Finally, combined factor H and ADAMTS13 deficiency have been reported. The affected patients are generally less responsive to plasma infusion, a result illustrating the complexity of the management of these cases.


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InternalMed_Harrison. HSCT-TMA develops after HSCT, with an incidence of 8.2%. Etiologic factors include conditioning regimens, immunosuppression, infections, and graft-versus-host disease. Other risk factors include female sex and human leukocyte antigen (HLA)–mismatched donor grafts. HSCT-TMA usually occurs within the first 100 days of HSCT. Table 341-1 lists definitions of HSCT-TMA currently used for clinical trials. Diagnosis may be difficult since thrombocytopenia, anemia, and renal insufficiency are common after HSCT. HSCTTMA carries a high mortality rate (75% within 3 months). The majority of patients have >5% ADAMTS13 activity, and plasma exchange is beneficial in <50% of patients. Discontinuation of calcineurin inhibitors and substitution with daclizumab (antibody to >4% schistocytes in the blood RBC fragmentation and at least 2 schistocytes per high-power field De novo, prolonged, or progressive Concurrent increase in LDH concenthrombocytopenia tration above baseline


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InternalMed_Harrison. De novo, prolonged, or progressive Concurrent increase in LDH concenthrombocytopenia tration above baseline Note: These features underscore the need to identify pathways of hemolysis and thrombocytopenia that accompany deterioration of kidney function. Abbreviations: LDH, lactate dehydrogenase; RBC, red blood cell. the IL-2 receptor) are recommended. Treatment with rituximab and defibrotide may also be helpful.


InternalMed_Harrison

InternalMed_Harrison. Abbreviations: LDH, lactate dehydrogenase; RBC, red blood cell. the IL-2 receptor) are recommended. Treatment with rituximab and defibrotide may also be helpful. HIV-related TMA is a complication encountered mainly before widespread use of highly active antiretroviral therapy. It is seen in patients with advanced AIDS and low CD4+ T cell counts although it can be the first manifestation of HIV infection. The presence of MAHA, thrombocytopenia, and renal failure are suggestive, but renal biopsy is required for diagnosis since other renal diseases are also associated with HIV infection. Thrombocytopenia may prohibit renal biopsy in some patients. The mechanism of injury is unclear, although HIV can induce apoptosis in endothelial cells. ADAMTS13 activity is not reduced in these patients. Cytomegalovirus co-infection may also be a risk factor. Effective antiviral therapy is key, while plasma exchange should be limited to patients who have evidence of TTP.


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InternalMed_Harrison. Either local or total body irradiation can produce microangiopathic injury. The kidney is one of the most radiosensitive organs, and injury can result with as little as 4–5 Gy. Such injury is characterized by renal insufficiency, proteinuria, and hypertension usually developing ≥6 months after radiation exposure. Renal biopsy reveals classic TMA with damage to glomerular, tubular, and vascular cells, but systemic evidence of MAHA is uncommon. Because of its high incidence after allogeneic HSCT, radiation nephropathy is often referred to as bone marrow transplant nephropathy. No specific therapy is available, although observational evidence supports renin-angiotensin system blockade.


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InternalMed_Harrison. Kidney involvement is common (up to 52%) in patients with widespread scleroderma, with 20% of cases resulting directly from scleroderma renal crisis. Other renal manifestations in scleroderma include transient (prerenal) or medication-related forms of acute kidney injury (e.g., associated with D-penicillamine, nonsteroidal anti-inflammatory drugs, or cyclosporine). Scleroderma renal crisis occurs in 12% of patients with diffuse systemic sclerosis but in only 2% of those with limited systemic sclerosis. Scleroderma renal crisis is the most severe manifestation of renal involvement, and is characterized by accelerated hypertension, a rapid decline in renal function, nephrotic proteinuria, and hematuria. Retinopathy and encephalopathy may accompany the hypertension. Salt and water retention with microvascular injury can lead to pulmonary edema. Cardiac manifestations, including myocarditis, pericarditis, and arrhythmias, denote an especially poor prognosis. Although MAHA is present in


InternalMed_Harrison

InternalMed_Harrison. with microvascular injury can lead to pulmonary edema. Cardiac manifestations, including myocarditis, pericarditis, and arrhythmias, denote an especially poor prognosis. Although MAHA is present in more half of patients, coagulopathy is rare.


InternalMed_Harrison

InternalMed_Harrison. The renal lesion in scleroderma renal crisis is characterized by arcuate artery intimal and medial proliferation with luminal narrowing.


InternalMed_Harrison

InternalMed_Harrison. This lesion is described as “onion-skinning” and can be accompanied by glomerular collapse due to reduced blood flow. Histologically, scleroderma renal crisis is indistinguishable from malignant hypertension, with which it can coexist. Fibrinoid necrosis and thrombosis are common. Before the availability of angiotensin-converting enzyme (ACE) inhibitors, the mortality rate for scleroderma renal crisis was >90% at 1 month. Introduction of renin-angiotensin system blockade has lowered the mortality rate to 30% at 3 years. Nearly two-thirds of patients with scleroderma renal crisis may require dialysis support, with recovery of renal function in 50% (median time, 1 year). Glomerulonephritis and vasculitis associated with antineutrophil cytoplasmic antibodies and systemic lupus erythematosus have been described in patients with scleroderma. An association has been found with a speckled pattern of antinuclear antibodies and with antibodies to RNA polymerases I and III. Anti-U3-RNP may


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InternalMed_Harrison. have been described in patients with scleroderma. An association has been found with a speckled pattern of antinuclear antibodies and with antibodies to RNA polymerases I and III. Anti-U3-RNP may identify young patients at risk for scleroderma renal crisis. Anticentromere antibody, in contrast, is a negative predictor of this disorder. Because of the overlap between scleroderma renal crisis and other autoimmune disorders, a renal biopsy is recommended for patients with atypical renal involvement, especially if hypertension is absent.


InternalMed_Harrison

InternalMed_Harrison. Treatment with ACE inhibition is the first-line therapy unless contraindicated. The goal of therapy is to reduce systolic and diastolic blood pressure by 20 mmHg and 10 mmHg, respectively, every 24 h until blood pressure is normal. Additional antihypertensive therapy may be given once the dose of drug for ACE inhibition is maximized. Both ACE inhibitors and angiotensin II receptor antagonists are effective, although data suggest that treatment with ACE inhibitors is superior. ACE inhibition alone does not prevent scleroderma renal crisis, but it does reduce the impact of hypertension. Intravenous iloprost has been used in Europe for blood pressure management and improvement of renal perfusion. Kidney transplantation is not recommended for 2 years after the start of dialysis since delayed recovery may occur.


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InternalMed_Harrison. Antiphospholipid syndrome (Chap. 379) can be either primary or secondary to systemic lupus erythematosus. It is characterized by a predisposition to systemic thrombosis (arterial and venous) and fetal morbidity mediated by antiphospholipid antibodies—mainly anticardiolipin antibodies (IgG, IgM, or IgA), lupus anticoagulant, or anti-β-2 glycoprotein I antibodies (antiβ2GPI). Patients with both anticardiolipin antibodies and antiβ2GPI appear to have the highest risk of thrombosis. The vascular compartment within the kidney is the main site of renal involvement. Arteriosclerosis is commonly present in the arcuate and intralobular arteries. In the intralobular arteries, fibrous intimal hyperplasia characterized by intimal thickening secondary to intense myofibroblastic intimal cellular proliferation with extracellular matrix deposition is frequently seen along with onion-skinning. Arterial and arteriolar fibrous and fibrocellular occlusions are present in more than two-thirds of biopsy


InternalMed_Harrison

InternalMed_Harrison. with extracellular matrix deposition is frequently seen along with onion-skinning. Arterial and arteriolar fibrous and fibrocellular occlusions are present in more than two-thirds of biopsy samples. Cortical necrosis and focal cortical atrophy may result from vascular occlusion. TMA is commonly present in renal biopsies, although signs of MAHA and platelet consumption are usually absent. TMA is especially common in the catastrophic variant of antiphospholipid syndrome. In patients with secondary antiphospholipid syndrome, other glomerulopathies may be present, including membranous nephropathy, minimal change disease, focal segmental glomerulosclerosis, and pauci-immune crescentic glomerulonephritis.


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InternalMed_Harrison. Large vessels can be involved in antiphospholipid syndrome and may form the proximal nidus near the ostium for thrombosis of the renal artery. Renal vein thrombosis can occur and should be suspected in patients with lupus anticoagulant who develop nephroticrange proteinuria. Progression to end-stage renal disease can occur, and a thrombosis may form in the vascular access and the renal allografts. Hypertension is common. Treatment entails lifelong anticoagulation. Glucocorticoids may be beneficial in accelerated hypertension. Immunosuppression and plasma exchange may be helpful for catastrophic episodes of antiphospholipid syndrome but by themselves do not reduce recurrent thrombosis.


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InternalMed_Harrison. HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome is a dangerous complication of pregnancy associated with microvascular injury. Occurring in 0.2–0.9% of all pregnancies and in 10–20% of women with severe preeclampsia, this syndrome carries a mortality rate of 7.4–34%. Most commonly developing in the third trimester, 10% of cases occur before week 27 and 30% post-partum. Although a strong association exists between HELLP syndrome and preeclampsia, nearly 20% of cases are not preceded by recognized preeclampsia. Risk factors include abnormal placentation, family history, and elevated levels of fetal mRNA for FLT1 (vascular endothelial growth factor receptor 1) and endoglin. Patients with HELLP syndrome have higher levels of inflammatory markers (C-reactive protein, IL-1Ra, and IL-6) and soluble HLA-DR than do those with preeclampsia alone.


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InternalMed_Harrison. Renal failure occurs in half of patients with HELLP syndrome, although the etiology is not well understood. Limited data suggest that renal failure is the result of both preeclampsia and acute tubular necrosis. Renal histologic findings are those of TMA with endothelial cell swelling and occlusion of the capillary lumens, but luminal thrombi are typically absent. However, thrombi become more common in severe eclampsia and HELLP syndrome. Although renal failure is common, the organ that defines this syndrome is the liver. Subcapsular hepatic hematomas sometimes produce spontaneous rupture of the liver and can be life-threatening. Neurologic complications such as cerebral infarction, cerebral and brainstem hemorrhage, and cerebral edema are other potentially life-threatening complications. Nonfatal complications include placental abruption, permanent vision loss due to Purtscher-like (hemorrhagic and vaso-occlusive vasculopathy) retinopathy, pulmonary edema, bleeding, and fetal demise.


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InternalMed_Harrison. Many features are shared by HELLP syndrome and MAHA. Diagnosis of HELLP syndrome is complicated by the fact that aHUS and TTP also can be triggered by pregnancy. Patients with antiphospholipid syndrome also have an elevated risk of HELLP syndrome. A history of MAHA before pregnancy is of diagnostic value. Serum levels of ADAMTS13 activity are reduced (by 30–60%) in HELLP syndrome but not to the levels seen in TTP (<5%). Determination of the ratio of lactate dehydrogenase to aspartate aminotransferase may be helpful; this ratio is 13:1 in patients with HELLP syndrome and preeclampsia as opposed to 29:1 in patients without preeclampsia. Other markers, such as antithrombin III (decreased in HELLP syndrome but not in TTP) and D-dimer (elevated in HELLP syndrome but not in TTP), may also be useful. HELLP syndrome usually resolves spontaneously after delivery, although a small percentage of HELLP cases occur post-partum. Glucocorticoids may decrease inflammatory markers, although two


InternalMed_Harrison

InternalMed_Harrison. be useful. HELLP syndrome usually resolves spontaneously after delivery, although a small percentage of HELLP cases occur post-partum. Glucocorticoids may decrease inflammatory markers, although two randomized controlled trials failed to show much benefit. Plasma exchange should be considered if hemolysis is refractory to glucocorticoids and/or delivery, especially if TTP has not been ruled out.


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InternalMed_Harrison. Renal complications in sickle cell disease result from occlusion of the vasa recta in the renal medulla. The low partial pressure of oxygen and high osmolarity predispose to hemoglobin S polymerization and erythrocyte sickling. Sequelae include hyposthenuria, hematuria, and papillary necrosis (which can also occur in sickle trait). The kidney responds by increases in blood flow and glomerular filtration rate mediated by prostaglandins. This dependence on prostaglandins may explain the greater reduction of glomerular filtration rate by nonsteroidal anti-inflammatory drugs in these patients than in others. The glomeruli are typically enlarged. Intracapillary fragmentation and phagocytosis of sickled erythrocytes are thought to be responsible for the membranoproliferative glomerulonephritis–like lesion, and focal segmental glomerulosclerosis is seen in more advanced cases. Proteinuria is present in 20–30%, and nephrotic-range proteinuria is associated with progression to renal failure.


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InternalMed_Harrison. lesion, and focal segmental glomerulosclerosis is seen in more advanced cases. Proteinuria is present in 20–30%, and nephrotic-range proteinuria is associated with progression to renal failure. ACE inhibitors reduce proteinuria, although data are lacking on prevention of renal failure. Patients with sickle cell disease are also more prone to acute renal failure. The cause is thought to reflect microvascular occlusion associated with nontraumatic rhabdomyolysis, high fever, infection, and


InternalMed_Harrison

InternalMed_Harrison. Vascular Injury to the Kidney 1866 generalized sickling. Chronic kidney disease is present in 12–20% of patients. Despite the frequency of renal disease, hypertension is uncommon in patients with sickle cell disease.


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InternalMed_Harrison. Renal vein thrombosis either can present with flank pain, tenderness, hematuria, rapid decline in renal function, and proteinuria or can be silent. Occasionally, renal vein thrombosis is identified during a workup for pulmonary embolism. The left renal vein is more commonly involved, and two-thirds of cases are bilateral. Etiologies can be divided into three broad categories: endothelial damage, venous stasis, and hypercoagulability. Homocystinuria, endovascular intervention, and surgery can produce vascular endothelial damage. Dehydration, which is more common among male patients, is a common cause of stasis in the pediatric population. Stasis also can result from compression and kinking of the renal veins from retroperitoneal processes such as retroperitoneal fibrosis and abdominal neoplasms. Thrombosis can occur throughout the renal circulation, including the renal veins, with antiphospholipid antibody syndrome. Renal vein thrombosis can also be secondary to nephrotic syndrome,


InternalMed_Harrison

InternalMed_Harrison. Thrombosis can occur throughout the renal circulation, including the renal veins, with antiphospholipid antibody syndrome. Renal vein thrombosis can also be secondary to nephrotic syndrome, particularly membranous nephropathy. Other hypercoagulable states less commonly associated with renal vein thrombosis include proteins C and S, antithrombin deficiency, factor V Leiden, disseminated malignancy, and oral contraceptives. Severe nephrotic syndrome may also predispose patients to renal vein thrombosis.


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InternalMed_Harrison. Diagnostic screening can be performed with Doppler ultrasonography, which is more sensitive than ultrasonography alone. CT angiography is nearly 100% sensitive. Magnetic resonance angiography is another option but is more expensive. Treatment for renal vein thrombosis consists of anticoagulation and therapy for the underlying cause. Endovascular thrombolysis may be considered in severe cases. Occasionally, nephrectomy may be undertaken for life-threatening complications. Vena caval filters are often used to prevent migration of thrombi.


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InternalMed_Harrison. nephrolithiasis Gary C. Curhan Nephrolithiasis, or kidney stone disease, is a common, painful, and costly condition. Each year, billions of dollars are spent on nephrolithiasis-related activity, with the majority of expenditures on surgical treatment of existing stones. While a stone may form due to 342 crystallization of lithogenic factors in the upper urinary tract, it can subsequently move into the ureter and cause renal colic. Although nephrolithiasis is rarely fatal, patients who have had renal colic report that it is the worst pain they have ever experienced. The evidence on which to base clinical recommendations is not as strong as desired; nonetheless, most experts agree that the recurrence of most, if not all, types of stones can be prevented with careful evaluation and targeted recommendations. Preventive treatment may be lifelong; therefore, an in-depth understanding of this condition must inform the implementation of tailored interventions that are most appropriate for and


InternalMed_Harrison

InternalMed_Harrison. Preventive treatment may be lifelong; therefore, an in-depth understanding of this condition must inform the implementation of tailored interventions that are most appropriate for and acceptable to the patient.


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InternalMed_Harrison. There are various types of kidney stones. It is clinically important to identify the stone type, which informs prognosis and selection of the optimal preventive regimen. Calcium oxalate stones are most common (~75%); next, in order, are calcium phosphate (~15%), uric acid (~8%), struvite (~1%), and cystine (<1%) stones. Many stones are a mixture of crystal types (e.g., calcium oxalate and calcium phosphate) and also contain protein in the stone matrix. Rarely, stones are composed of medications, such as acyclovir, indinavir, and triamterene. Infectious stones, if not appropriately treated, can have devastating consequences and lead to end-stage renal disease. Consideration should be given to teaching practitioners strategies to prevent stone recurrence and its related morbidity.


InternalMed_Harrison

InternalMed_Harrison. Nephrolithiasis is a global disease. Data suggest an increasing prevalence, likely due to Westernization of lifestyle habits (e.g., dietary changes, increasing body mass index). National Health and Nutrition Examination Survey data for 2007–2010 indicate that up to 19% of men and 9% of women will develop at least one stone during their lifetime. The prevalence is ~50% lower among black individuals than among whites. The incidence of nephrolithiasis (i.e., the rate at which previously unaffected individuals develop their first stone) also varies by age, sex, and race. Among white men, the peak annual incidence is ~3.5 cases/1000 at age 40 and declines to ~2 cases/1000 by age 70. Among white women in their thirties, the annual incidence is ~2.5 cases/1000; the figure decreases to ~1.5/1000 at age 50 and beyond. In addition to the medical costs associated with nephrolithiasis, this condition also has a substantial economic impact, as those affected are often of working age. Once an


InternalMed_Harrison

InternalMed_Harrison. at age 50 and beyond. In addition to the medical costs associated with nephrolithiasis, this condition also has a substantial economic impact, as those affected are often of working age. Once an individual has had a stone, the prevention of a recurrence is essential. Published recurrence rates vary by the definitions and diagnostic methods used. Some reports have relied on symptomatic events, while others have been based on imaging. Most experts agree that radiographic evidence of a second stone should be considered to represent a recurrence, even if the stone has not yet caused symptoms.


InternalMed_Harrison

InternalMed_Harrison. Nephrolithiasis is a systemic disorder. Several conditions predispose to stone formation, including gastrointestinal malabsorption (e.g., Crohn’s disease, gastric bypass surgery), primary hyperparathyroidism, obesity, type 2 diabetes mellitus, and distal renal tubular acidosis. A number of other medical conditions are more likely to be present in individuals with a history of nephrolithiasis, including hypertension, gout, cholelithiasis, reduced bone mineral density, and chronic kidney disease.


InternalMed_Harrison

InternalMed_Harrison. Individuals with medullary sponge kidney (MSK), a condition designated by an anatomic description, often have metabolic abnormalities, such as higher levels of urine calcium and lower levels of urine citrate, and are more likely to form calcium phosphate stones. As intravenous urography is now rarely used, the diagnosis of MSK has become less frequent. Fortunately, the diagnosis of MSK does not change either the evaluation or the treatment recommendations; thus, it is not essential in pursuing the diagnosis of nephrolithiasis. Although nephrolithiasis does not directly cause upper urinary tract infections (UTIs), a UTI in the setting of an obstructing stone is a urologic emergency (“pus under pressure”) and requires urgent intervention to reestablish drainage.


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InternalMed_Harrison. In the consideration of the processes involved in crystal formation, it is helpful to view urine as a complex solution. A clinically useful concept is supersaturation (the point at which the concentration product exceeds the solubility product). However, even though the urine in most individuals is supersaturated with respect to one or more types of crystals, the presence of inhibitors of crystallization prevents the majority of the population from continuously forming stones. The most clinically important inhibitor of calcium-containing stones is urine citrate. While supersaturation is a calculated value (rather than being directly measured) and does not perfectly predict stone formation, it is a useful guide as it integrates the multiple factors that are measured in a 24-h urine collection.


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InternalMed_Harrison. Recent studies have changed the paradigm for the site of initiation of stone formation. Renal biopsies of stone formers have revealed calcium phosphate in the renal interstitium. It is hypothesized that this calcium phosphate extends down to the papilla and erodes through the papillary epithelium, where it provides a site for deposition of calcium oxalate and calcium phosphate crystals. The majority of calcium oxalate stones grow on calcium phosphate at the tip of the renal papilla (Randall’s plaque). Thus, the process of stone formation may begin years before a clinically detectable stone is identified. The processes involved in interstitial deposition are under active investigation. Risk factors for nephrolithiasis can be categorized as dietary, nondietary, or urinary.These risk factors vary by stone type and by clinical characteristics.


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InternalMed_Harrison. Risk factors for nephrolithiasis can be categorized as dietary, nondietary, or urinary.These risk factors vary by stone type and by clinical characteristics. Dietary Risk Factors Patients who develop stones often change their diet; therefore, studies that retrospectively assess diet may be hampered by recall bias. Some studies have examined the relation between diet and changes in the lithogenic composition of the urine, often using calculated supersaturation. However, the composition of the urine does not perfectly predict risk, and not all components that modify risk are included in the calculation of supersaturation. Thus, dietary associations are best investigated by prospective studies that examine actual stone formation as the outcome. Dietary factors that are associated with an increased risk of nephrolithiasis include animal protein, oxalate, sodium, sucrose, and fructose. Dietary factors associated with a lower risk include calcium, potassium, and phytate.


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InternalMed_Harrison. CALCIUM The role of dietary calcium deserves special attention. Although in the past dietary calcium had been suspected of increasing the risk of stone disease, several prospective observational studies and a randomized controlled trial have demonstrated that higher dietary calcium intake is related to a lower risk of stone formation. The reduction in risk associated with higher calcium intake may be due to a reduction in intestinal absorption of dietary oxalate that results in lower urine oxalate. Low calcium intake is contraindicated as it increases the risk of stone formation and may contribute to lower bone density in stone formers. Despite similar bioavailability, supplemental calcium may increase the risk of stone formation. The discrepancy between the risks from dietary calcium and calcium supplements may be due to the timing of supplemental calcium intake or to higher total calcium consumption leading to higher urinary calcium excretion.


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InternalMed_Harrison. OXALATE Urinary oxalate is derived from both endogenous production and absorption of dietary oxalate. Owing to its low and often variable bioavailability, much of the oxalate in food may not be readily absorbed. However, absorption may be higher in stone formers. Although observational studies demonstrate that dietary oxalate is only a weak risk factor for stone formation, urinary oxalate is a strong risk factor for calcium oxalate stone formation, and efforts to avoid high oxalate intake should thus be beneficial.


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InternalMed_Harrison. OTHER NUTRIENTS Several other nutrients have been studied and implicated in stone formation. Higher intake of animal protein may lead to increased excretion of calcium and uric acid as well as to decreased urinary excretion of citrate, all of which increase the risk of stone formation. Higher sodium and sucrose intake increases calcium excretion independent of calcium intake. Higher potassium intake decreases calcium excretion, and many potassium-rich foods increase urinary citrate excretion due to their alkali content. Other dietary factors that have been inconsistently associated with lower stone risk include magnesium and phytate.


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InternalMed_Harrison. Vitamin C supplements are associated with an increased risk of calcium oxalate stone formation, possibly because of raised levels of oxalate in urine. Thus, calcium oxalate stone formers should be advised to avoid vitamin C supplements. Although high doses of supplemental vitamin B6 may be beneficial in selected patients with type 1 primary hyperoxaluria, the benefit of supplemental vitamin B6 in other patients is uncertain.


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InternalMed_Harrison. FLUIDS AND BEVERAGES The risk of stone formation increases as urine volume decreases. When the urine output is less than 1 L/d, the risk of stone formation more than doubles. Fluid intake is the main determinant of urine volume, and the importance of fluid intake in preventing stone formation has been demonstrated in observational studies and in a randomized controlled trial. Observational studies have found that coffee, tea, beer, and wine are associated with a reduced risk of stone formation. Sugar-sweetened carbonated beverage consumption may 1867 increase risk. Nondietary Risk Factors Age, race, body size, and environment are important risk factors for nephrolithiasis. The incidence of stone disease is highest in middle-aged white men, but stones can form in infants as well as in the elderly. There is geographic variability, with the highest prevalence in the southeastern United States. Weight gain increases the risk of stone formation, and the increasing prevalence of


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InternalMed_Harrison. as in the elderly. There is geographic variability, with the highest prevalence in the southeastern United States. Weight gain increases the risk of stone formation, and the increasing prevalence of nephrolithiasis in the United States may be due in part to the increasing prevalence of obesity. Environmental and occupational influences that may lead to lower urine volume, such as working in a hot environment or lack of ready access to water or a bathroom, are important considerations.


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InternalMed_Harrison. urinary Risk Factors • URINE VOLUME As mentioned above, lower urine volume results in increased concentrations of lithogenic factors and is a common and readily modifiable risk factor. A randomized trial has demonstrated the effectiveness of elevated fluid intake in increasing urine volume and reducing the risk of stone recurrence.


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InternalMed_Harrison. URINE CALCIUM Higher urine calcium excretion increases the likelihood of formation of calcium oxalate and calcium phosphate stones. While the term hypercalciuria is often used, there is no widely accepted cutoff that distinguishes between normal and abnormal urine calcium excretion. In fact, the relation between urine calcium and stone risk appears to be continuous; thus the use of an arbitrary threshold should be avoided. Levels of urine calcium excretion are higher in individuals with a history of nephrolithiasis; however, the mechanisms remain poorly understood. Greater gastrointestinal calcium absorption is one important contributor, and greater bone turnover (with a resultant reduction in bone mineral density) may be another. Primary renal calcium loss, with lower serum calcium concentrations and elevated serum levels of parathyroid hormone (PTH) (and a normal 25-hydroxy vitamin D level), is rare.


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InternalMed_Harrison. URINE OXALATE Higher urine oxalate excretion increases the likelihood of calcium oxalate stone formation. As for urine calcium, no definition for “abnormal” urine oxalate excretion is widely accepted. Given that the relation between urine oxalate and stone risk is continuous, simple dichotomization of urine oxalate excretion is not helpful in assessing risk. The two sources of urine oxalate are endogenous generation and dietary intake. Dietary oxalate is the major contributor and also the source that can be modified. Notably, higher dietary calcium intake reduces gastrointestinal oxalate absorption and thereby reduces urine oxalate.


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InternalMed_Harrison. URINE CITRATE Urine citrate is a natural inhibitor of calcium-containing stones; thus, lower urine citrate excretion increases the risk of stone formation. Citrate reabsorption is influenced by the intracellular pH of proximal tubular cells. Metabolic acidosis will lead to a reduction in citrate excretion by increasing reabsorption of filtered citrate. However, a notable proportion of patients have lower urine citrate for reasons that remain unclear. URINE URIC ACID Higher urine levels of uric acid—a risk factor for uric acid stone formation—are found in individuals with excess purine consumption and rare genetic conditions that lead to overproduction of uric acid. This characteristic does not appear to be associated with the risk of calcium oxalate stone formation.


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InternalMed_Harrison. URINE pH Urine pH influences the solubility of some crystal types. Uric acid stones form only when the urine pH is consistently ≤5.5 or lower, whereas calcium phosphate stones are more likely to form when the urine pH is ≥6.5 or higher. Cystine is more soluble at higher urine pH. Calcium oxalate stones are not influenced by urine pH. Genetic Risk Factors The risk of nephrolithiasis is more than twofold greater in individuals with a family history of stone dis ease. This association is likely due to a combination of genetic predisposition and similar environmental exposures. While a number of monogenic disorders cause nephrolithiasis, the genetic contributors to common forms of stone disease remain to be determined.


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InternalMed_Harrison. 1868 The two most common and well-characterized rare monogenic disorders that lead to stone formation are primary hyperoxaluria and cystinuria. Primary hyperoxaluria is an autosomal recessive disorder that causes excessive endogenous oxalate generation by the liver, with consequent calcium oxalate stone formation and crystal deposition in organs. Intraparenchymal calcium oxalate deposition in the kidney can eventually lead to renal failure. Cystinuria is an autosomal recessive disorder that causes abnormal reabsorption of filtered dibasic amino acids. The excessive urinary excretion of cystine, which is poorly soluble, leads to cystine stone formation. Cystine stones are visible on plain radiographs and often manifest as staghorn calculi or multiple bilateral stones. Repeat episodes of obstruction and instrumentation can cause chronic renal impairment. APPROACH TO THE PATIENT:


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InternalMed_Harrison. APPROACH TO THE PATIENT: At present, there are no widely accepted, evidence-based guidelines for the evaluation and treatment of nephrolithiasis. However, there are standard approaches to patients with acute and chronic presentations that can reasonably guide the clinical evaluation. It typically requires weeks to months (and often much longer) for a kidney stone to grow to a clinically detectable size. Although the passage of a stone is a dramatic event, stone formation and growth are characteristically clinically silent. A stone can remain asymptomatic in the kidney for years or even decades before signs (e.g., hematuria) or symptoms (e.g., pain) become apparent. Thus, it is important to remember that the onset of symptoms, typically attributable to a stone moving into the ureter, does not provide insight into when the stone actually formed. The factors that induce stone movement are unknown.


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InternalMed_Harrison. Clinical Presentation and Differential Diagnosis There are two common presentations for individuals with an acute stone event: renal colic and painless gross hematuria. Renal colic is a misnomer because pain typically does not subside completely; rather, it varies in intensity. When a stone moves into the ureter, the discomfort often begins with a sudden onset of unilateral flank pain. The intensity of the pain can increase rapidly, and there are no alleviating factors. This pain, which is accompanied often by nausea and occasionally by vomiting, may radiate, depending on the location of the stone. If the stone lodges in the upper part of the ureter, pain may radiate anteriorly; if the stone is in the lower part of the ureter, pain can radiate to the ipsilateral testicle in men or the ipsilateral labium in women. Occasionally, a patient has gross hematuria without pain.


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InternalMed_Harrison. Other diagnoses may be confused with acute renal colic. If the stone is lodged at the right ureteral pelvic junction, symptoms may mimic those of acute cholecystitis. If the stone blocks the ureter as it crosses over the right pelvic brim, symptoms may mimic acute appendicitis, whereas blockage at the left pelvic brim may be confused with acute diverticulitis. If the stone lodges in the ureter at the ureterovesical junction, the patient may experience urinary urgency and frequency. In female patients, the latter symptoms may lead to an incorrect diagnosis of bacterial cystitis; the urine will contain red and white blood cells, but the urine culture will be negative. An obstructing stone with proximal infection may present as acute pyelonephritis. A UTI in the setting of ureteral obstruction is a medical emergency that requires immediate restoration of drainage by placement of either a ureteral stent or a percutaneous nephrostomy tube. Other conditions to consider in the differential


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InternalMed_Harrison. is a medical emergency that requires immediate restoration of drainage by placement of either a ureteral stent or a percutaneous nephrostomy tube. Other conditions to consider in the differential diagnosis include muscular or skeletal pain, herpes zoster, duodenal ulcer, abdominal aortic aneurysm, gynecologic conditions, ureteral stricture, and ureteral obstruction by materials other than a stone, such as a blood clot or sloughed papilla. Extraluminal processes can lead to ureteral compression and obstruction; however, because of the gradual onset, these conditions do not typically present with renal colic.


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InternalMed_Harrison. Diagnosis and Intervention Serum chemistry findings are typically normal, but the white blood cell count may be elevated. Examination of the urine sediment will usually reveal red and white blood cells and occasionally crystals (Fig. 342-1). The absence of hematuria does not exclude a stone, particularly when urine flow is completely obstructed by a stone.


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InternalMed_Harrison. The diagnosis is often made on the basis of the history, physical examination, and urinalysis. Thus, it may not be necessary to wait for radiographic confirmation before treating the symptoms. The diagnosis is confirmed by an appropriate imaging study—preferably helical CT, which is highly sensitive, allows visualization of uric acid stones (traditionally considered “radiolucent”), and is able to avoid radiocontrast (Fig. 342-2). Helical CT detects stones as small as 1 mm that may be missed by other imaging modalities. Typically, helical CT reveals a ureteral stone or evidence of recent passage (e.g., perinephric stranding or hydronephrosis), whereas a plain abdominal radiograph (kidney/ureter/bladder, or KUB) can miss a stone in the ureter or kidney, even if it is radiopaque, and does not provide information on obstruction. Abdominal ultrasound offers the advantage of avoiding radiation and provides


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InternalMed_Harrison. FIGuRE 342-1 Urine sediment from a patient with calcium oxalate stones (left) and a patient with cystine stones (right). Calcium oxalate dihydrate crystals are bipyramidally shaped, and cystine crystals are hexagonal. (Left panel image courtesy of Dr. John Lieske, Mayo Clinic.) FIGuRE 342-2 Coronal noncontrast CT image from a patient who presented with left-sided renal colic. An obstructing calculus, present in the distal left ureter at the level of S1, measures 10 mm in maximal dimension. There is severe left hydroureteronephrosis and associated left perinephric fat stranding. In addition, there is a non-obstructing 6-mm left renal calculus in the interpolar region. (Image courtesy of Dr. Stuart Silverman, Brigham and Women’s Hospital.) information on hydronephrosis, but it is not as sensitive as CT and images only the kidney and possibly the proximal segment of the ureter; thus most ureteral stones are not detectable by ultrasound.


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InternalMed_Harrison. Many patients who experience their first episode of colic seek emergent medical care. Randomized trials have demonstrated that parenterally administered nonsteroidal anti-inflammatory drugs (such as ketorolac) are just as effective as opioids in relieving symptoms and have fewer side effects. Excessive fluid administration has not been shown to be beneficial; therefore, the goal should be to maintain euvolemia. If the pain can be adequately controlled and the patient is able to take fluids orally, hospitalization can be avoided. Use of an alpha-blocker may increase the rate of spontaneous stone passage.


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InternalMed_Harrison. Urologic intervention should be postponed unless there is evidence of UTI, a low probability of spontaneous stone passage (e.g., a stone measuring ≥6 mm or an anatomic abnormality), or intractable pain. A ureteral stent may be placed cystoscopically, but this procedure typically requires general anesthesia, and the stent can be quite uncomfortable, may cause gross hematuria, and may increase the risk of UTI.


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InternalMed_Harrison. If an intervention is indicated, the selection of the most appropriate intervention is determined by the size, location, and composition of the stone; the urinary tract anatomy; and the experience of the urologist. Extracorporeal shockwave lithotripsy, the least invasive option, uses shock waves generated outside the body to fragment the stone. An endourologic approach can remove a stone by basket extraction or laser fragmentation. For large upper-tract stones, percutaneous nephrostolithotomy has the highest likelihood of rendering the patient stone-free. Advances in urologic approaches and instruments have nearly eliminated the need for open surgical procedures such as ureterolithotomy or pyelolithotomy.


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InternalMed_Harrison. Evaluation for Stone Prevention More than half of first-time stone formers will have a recurrence within 10 years. A careful evaluation is indicated to identify predisposing factors, which can then be modified to reduce the risk of new stone formation. It is appropriate to proceed with an evaluation even after the first stone because recurrences are common and are usually preventable with inexpensive lifestyle modifications or other treatments.


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InternalMed_Harrison. History A detailed history, obtained from the patient and from a thorough review of medical records, should include the number and frequency of episodes (distinguishing stone passage from stone formation) and previous imaging studies, interventions, evaluations, and treatments. Inquiries about the patient’s medical history should cover UTIs, bariatric surgery, gout, hypertension, and diabetes mellitus. A family history of stone disease may reveal a genetic predisposition. A complete list of current prescription and over-the-counter medications as well as vitamin and mineral supplements is essential. The review of systems should focus on identifying possible etiologic factors related to low urine volume (e.g., high insensible losses; low fluid intake) and gastrointestinal malabsorption as well as on ascertaining how frequently the patient voids during the day and overnight.


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InternalMed_Harrison. A large body of compelling evidence has demonstrated the important role of diet in stone disease. Thus, the dietary history should encompass information on usual dietary habits (meals and snacks), calcium intake, consumption of high-oxalate foods (spinach, rhubarb, potatoes), and fluid intake (including specific beverages typically consumed). Physical Examination The physical examination should assess weight, blood pressure, costovertebral angle tenderness, and lower-extremity edema as well as signs of other systemic conditions such as primary hyperparathyroidism and gout.


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InternalMed_Harrison. Laboratory Evaluation If not recently measured, the following serum levels should be determined: electrolytes (to uncover hypokalemia or renal tubular acidosis), creatinine, calcium, and uric acid. The PTH level should be measured if indicated by high-normal or elevated serum and urine calcium concentrations. Often, 25-hydroxy vitamin D is measured in concert with PTH to investigate the possible role of secondarily elevated PTH levels in the setting of vitamin D insufficiency. The urinalysis, including examination of the sediment, can provide useful information. In individuals with asymptomatic residual renal stones, red and white blood cells are frequently present in urine. If there is concern about the possibility of an infection, a urine culture should be performed. The sediment may also reveal crystals (Fig. 342-1), which may help identify the stone type and also provide prognostic information, as crystalluria is a strong risk factor for new stone formation.


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InternalMed_Harrison. The results from 24-h urine collections serve as the cornerstone on which therapeutic recommendations are based. Recommendations on lifestyle modification should be deferred until urine collection is complete. As a baseline assessment, patients should collect at least two 24-h urine samples while consuming their usual diet and usual volume of fluid. The following factors should be measured: total volume, calcium, oxalate, citrate, uric acid, sodium, potassium, phosphorus, pH, and creatinine. When available, the calculated supersaturation is also informative. There is substantial day-to-day variability in the 24-h excretion of many relevant factors; therefore, obtaining values from two collections is important before committing a patient to long-term lifestyle changes or medication. The interpretation of the 24-h urine results should take into account that the collections are usually performed on a weekend day when the patient is staying at home; an individual’s habits may differ