InternalMed_Harrison

InternalMed_Harrison. Within 1–2 years after the onset of clinical diabetes, morphologic changes appear in the kidney. Thickening of the GBM is a sensitive indicator for the presence of diabetes but correlates poorly with the presence or absence of clinically significant nephropathy. The composition of the GBM is altered notably with a loss of heparan sulfate moieties that form the negatively charged filtration barrier. This change results in increased filtration of serum proteins into the urine, predominately negatively charged albumin. The expansion of the mesangium due to the accumulation of extracellular matrix correlates with the clinical manifestations of diabetic nephropathy (see stages in Fig. 62e-20). This expansion in mesangial matrix is associated with the development of mesangial sclerosis. Some patients also develop eosinophilic, PAS+ nodules called nodular glomerulosclerosis or Kimmelstiel-Wilson nodules. Immunofluorescence microscopy often reveals the nonspecific deposition of IgG (at times


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InternalMed_Harrison. also develop eosinophilic, PAS+ nodules called nodular glomerulosclerosis or Kimmelstiel-Wilson nodules. Immunofluorescence microscopy often reveals the nonspecific deposition of IgG (at times in a linear pattern) or complement staining without immune deposits on electron microscopy. Prominent vascular changes are frequently seen with hyaline and hypertensive arteriosclerosis. This is associated with varying degrees of chronic glomerulosclerosis and tubulointerstitial changes. Renal biopsies from patients with types 1 and 2 diabetes are largely indistinguishable.


InternalMed_Harrison

InternalMed_Harrison. These pathologic changes are the result of a number of postulated factors. Multiple lines of evidence support an important role for increases in glomerular capillary pressure (intraglomerular hypertension) in alterations in renal structure and function. Direct effects of hyperglycemia on the actin cytoskeleton of renal mesangial and vascular smooth-muscle cells as well as diabetes-associated changes in circulating factors such as atrial natriuretic factor, angiotensin II, and insulin-like growth factor (IGF) may account for this. Sustained glomerular hypertension increases matrix production, alterations in the GBM with disruption in the filtration barrier (and hence proteinuria), and glomerulosclerosis. A number of factors have also been identified that alter matrix production, including the accumulation of advanced glycosylation end products, circulating factors including growth hormone, IGF-I, angiotensin II, connective tissue growth factor, TGF-β, and dyslipidemia.


InternalMed_Harrison

InternalMed_Harrison. The natural history of diabetic nephropathy in patients with types 1 and 2 diabetes is similar. However, since the onset of type 1 diabetes is readily identifiable and the onset of type 2 diabetes is not, a patient newly diagnosed with type 2 diabetes may present with advanced diabetic nephropathy. At the onset of diabetes, renal hypertrophy and glomerular hyperfiltration are present. The degree of glomerular hyperfiltration correlates with the subsequent risk of clinically significant nephropathy. In the approximately 40% of patients with diabetes who develop diabetic nephropathy, the earliest manifestation is an increase in albuminuria detected by sensitive radioimmunoassay (Table 338-1). Albuminuria in the range of 30–300 mg/24 h is called microalbuminuria. Microalbuminuria appears 5–10 years after the onset of diabetes. It is currently recommended to test patients with type 1 disease for microalbuminuria 5 years after diagnosis of diabetes and yearly thereafter and, because the


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InternalMed_Harrison. years after the onset of diabetes. It is currently recommended to test patients with type 1 disease for microalbuminuria 5 years after diagnosis of diabetes and yearly thereafter and, because the time of onset of type 2 diabetes is often unknown, to test type 2 patients at the time of diagnosis of diabetes and yearly thereafter.


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InternalMed_Harrison. Patients with small increases in albuminuria increase their levels of urinary albumin excretion, typically reaching dipstick positive levels of proteinuria (>300 mg albuminuria) 5–10 years after the onset of early albuminuria. Microalbuminuria is a potent risk factor for cardiovascular events and death in patients with type 2 diabetes. Many patients with type 2 diabetes and microalbuminuria succumb to cardiovascular events before they progress to proteinuria or renal failure. Proteinuria in frank diabetic nephropathy can be variable, ranging from 500 mg to 25 g/24 h, and is often associated with nephrotic syndrome. More than 90% of patients with type 1 diabetes and nephropathy have diabetic retinopathy, so the absence of retinopathy in type 1 patients with proteinuria should prompt consideration of a diagnosis other than diabetic nephropathy; only 60% of patients with type 2 diabetes with nephropathy have diabetic retinopathy. There is a significant correlation between the presence of


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InternalMed_Harrison. of a diagnosis other than diabetic nephropathy; only 60% of patients with type 2 diabetes with nephropathy have diabetic retinopathy. There is a significant correlation between the presence of retinopathy and the presence of Kimmelstiel-Wilson nodules (see Fig. 62e-20). Also, characteristically, patients with advanced diabetic nephropathy have normal to enlarged kidneys, in contrast to other glomerular diseases where kidney size is usually decreased. Using the above epidemiologic and clinical data, and in the absence of other clinical or serologic data suggesting another disease, diabetic nephropathy is usually diagnosed without a renal biopsy. After the onset of proteinuria, renal function inexorably declines, with 50% of patients reaching renal failure over another 5–10 years; thus, from the earliest stages of microalbuminuria, it usually takes 10–20 years to reach end-stage renal disease. Once renal failure appears, however, survival on dialysis is shorter for patients with


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InternalMed_Harrison. from the earliest stages of microalbuminuria, it usually takes 10–20 years to reach end-stage renal disease. Once renal failure appears, however, survival on dialysis is shorter for patients with diabetes compared to other dialysis patients. Survival is best for patients with type 1 diabetes who receive a transplant from a living related donor.


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InternalMed_Harrison. Good evidence supports the benefits of blood sugar and blood pressure control as well as inhibition of the renin-angiotensin system in retarding the progression of diabetic nephropathy. In patients with type 1 diabetes, intensive control of blood sugar clearly prevents the development or progression of diabetic nephropathy. The evidence for benefit of intensive blood glucose control in patients with type 2 diabetes is less certain, with current studies reporting conflicting results.


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InternalMed_Harrison. Controlling systemic blood pressure decreases renal and cardiovascular adverse events in this high-risk population. The vast majority of patients with diabetic nephropathy require three or more antihypertensive drugs to achieve this goal. Drugs that inhibit the renin-angiotensin system, independent of their effects on systemic blood pressure, have been shown in numerous large clinical trials to slow the progression of diabetic nephropathy at early (microalbuminuria) and late (proteinuria with reduced glomerular filtration) stages, independent of any effect they may have on systemic blood pressure. Since angiotensin II increases efferent arteriolar resistance and, hence, glomerular capillary pressure, one key mechanism for the efficacy of ACE inhibitors or angiotensin receptor blockers (ARBs) is reducing glomerular hypertension. Patients with type 1 diabetes for 5 years who develop albuminuria or declining renal function should be treated with ACE inhibitors. Patients with type 2


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InternalMed_Harrison. (ARBs) is reducing glomerular hypertension. Patients with type 1 diabetes for 5 years who develop albuminuria or declining renal function should be treated with ACE inhibitors. Patients with type 2 diabetes and microalbuminuria or proteinuria may be treated with ACE inhibitors or ARBs. Evidence suggests increased risk for cardiovascular adverse events in some patients with a combination of two drugs (ACE inhibitors, ARBs, renin inhibitors, or aldosterone antagonists) that suppress several components of the reninangiotensin system.


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InternalMed_Harrison. Plasma cell dyscrasias producing excess light chain immunoglobulin sometimes lead to the formation of glomerular and tubular deposits that cause heavy proteinuria and renal failure; the same is true for the accumulation of serum amyloid A protein fragments seen in several inflammatory diseases. This broad group of proteinuric patients has glomerular deposition disease.


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InternalMed_Harrison. Light Chain Deposition Disease The biochemical characteristics of nephrotoxic light chains produced in patients with light chain malignancies often confer a specific pattern of renal injury; that of either cast nephropathy (see Fig. 62e-17), which causes renal failure but not heavy proteinuria or amyloidosis, or light chain deposition disease (see Fig. 62e-16), which produces nephrotic syndrome with renal failure. These latter patients produce kappa light chains that do not have the biochemical features necessary to form amyloid fibrils. Instead, they self-aggregate and form granular deposits along the glomerular capillary and mesangium, tubular basement membrane, and Bowman’s capsule. When predominant in glomeruli, nephrotic syndrome develops, and about 70% of patients progress to dialysis. Light-chain deposits are not fibrillar and do not stain with Congo red, but they are easily detected with anti–light chain antibody using immunofluorescence or as granular deposits on electron


InternalMed_Harrison

InternalMed_Harrison. Light-chain deposits are not fibrillar and do not stain with Congo red, but they are easily detected with anti–light chain antibody using immunofluorescence or as granular deposits on electron microscopy. A combination of the light chain rearrangement, self-aggregating properties at neutral pH, and abnormal metabolism probably contribute to the deposition. Treatment for light chain deposition disease is treatment of the primary disease and, if possible, autologous stem cell transplantation.


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InternalMed_Harrison. Renal Amyloidosis Most renal amyloidosis is either the result of primary fibrillar deposits of immunoglobulin light chains known as amyloid L (AL), or secondary to fibrillar deposits of serum amyloid A (AA) protein fragments (Chap. 137). Even though both occur for different reasons, their clinicopathophysiology is quite similar and will 1845 be discussed together. Amyloid infiltrates the liver, heart, peripheral nerves, carpal tunnel, upper pharynx, and kidney, producing restrictive cardiomyopathy, hepatomegaly, macroglossia, and heavy proteinuria sometimes associated with renal vein thrombosis. In systemic AL amyloidosis, also called primary amyloidosis, light chains produced in excess by clonal plasma cell dyscrasias are made into fragments by macrophages so they can self-aggregate at acid pH. A disproportionate number of these light chains (75%) are of the lambda class. About 10% of these patients have overt myeloma with lytic bone lesions and infiltration of the bone marrow with


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InternalMed_Harrison. acid pH. A disproportionate number of these light chains (75%) are of the lambda class. About 10% of these patients have overt myeloma with lytic bone lesions and infiltration of the bone marrow with >30% plasma cells; nephrotic syndrome is common, and about 20% of patients progress to dialysis. AA amyloidosis is sometimes called secondary amyloidosis and also presents as nephrotic syndrome. It is due to deposition of β-pleated sheets of serum amyloid A protein, an acute phase reactant whose physiologic functions include cholesterol transport, immune cell attraction, and metalloproteases activation. Forty percent of patients with AA amyloid have rheumatoid arthritis, and another 10% have ankylosing spondylitis or psoriatic arthritis; the rest derive from other lesser causes. Less common in Western countries but more common in Mediterranean regions, particularly in Sephardic and Iraqi Jews, is familial Mediterranean fever (FMF). FMF is caused by a mutation in the gene encoding pyrin,


InternalMed_Harrison

InternalMed_Harrison. in Western countries but more common in Mediterranean regions, particularly in Sephardic and Iraqi Jews, is familial Mediterranean fever (FMF). FMF is caused by a mutation in the gene encoding pyrin, whereas Muckle-Wells syndrome, a related disorder, results from a mutation in cryopyrin; both proteins are important in the apoptosis of leukocytes early in inflammation; such proteins with pyrin domains are part of a new pathway called the inflammasome. Receptor mutations in tumor necrosis factor receptor 1 (TNFR1)-associated periodic syndrome also produce chronic inflammation and secondary amyloidosis. Fragments of serum amyloid A protein increase and self-aggregate by attaching to receptors for advanced glycation end products in the extracellular environment; nephrotic syndrome is common, and about 40–60% of patients progress to dialysis. AA and AL amyloid fibrils are detectable with Congo red or in more detail with electron microscopy (see Fig. 62e-15). Currently developed serum free


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InternalMed_Harrison. and about 40–60% of patients progress to dialysis. AA and AL amyloid fibrils are detectable with Congo red or in more detail with electron microscopy (see Fig. 62e-15). Currently developed serum free light chain nephelometry assays are useful in the early diagnosis and follow-up of disease progression. Biopsy of involved liver or kidney is diagnostic 90% of the time when the pretest probability is high; abdominal fat pad aspirates are positive about 70% of the time, but apparently less so when looking for AA amyloid. Amyloid deposits are distributed along blood vessels and in the mesangial regions of the kidney. The treatment for primary amyloidosis, melphalan and autologous hematopoietic stem cell transplantation, can delay the course of disease in about 30% of patients. Secondary amyloidosis is also relentless unless the primary disease can be controlled. Some new drugs in development that disrupt the formation of fibrils may be available in the future.


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InternalMed_Harrison. Fibrillary-Immunotactoid Glomerulopathy Fibrillary-immunotactoid glomerulopathy is a rare (<1.0% of renal biopsies), morphologically defined disease characterized by glomerular accumulation of nonbranching randomly arranged fibrils. Some classify amyloid and nonamyloid fibril-associated renal diseases all as fibrillary glomerulopathies with immunotactoid glomerulopathy reserved for nonamyloid fibrillary disease not associated with a systemic illness. Others define fibrillary glomerulonephritis as a nonamyloid fibrillary disease with fibrils 12–24 nm and immunotactoid glomerulonephritis with fibrils >30 nm. In either case, fibrillar/microtubular deposits of oligoclonal or oligotypic immunoglobulins and complement appear in the mesangium and along the glomerular capillary wall. Congo red stains are negative. The cause of this “nonamyloid” glomerulopathy is mostly idiopathic; reports of immunotactoid glomerulonephritis describe an occasional association with chronic lymphocytic leukemia


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InternalMed_Harrison. are negative. The cause of this “nonamyloid” glomerulopathy is mostly idiopathic; reports of immunotactoid glomerulonephritis describe an occasional association with chronic lymphocytic leukemia or B cell lymphoma. Both disorders appear in adults in the fourth decade with moderate to heavy proteinuria, hematuria, and a wide variety of histologic lesions, including DPGN, MPGN, MGN, or mesangioproliferative glomerulonephritis. Nearly half of patients develop renal failure over a few years. There is no consensus on treatment of this uncommon disorder. The disease has been reported to recur following renal transplantation in a minority of cases.


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InternalMed_Harrison. α5.α5.α6(IV) network appears in skin, smooth muscle, and esophagus and along Bowman’s capsule in the kidney. This switch probably occurs because the α3.α4.α5(IV) network is more resistant to proteases and ensures the structural longevity of critical tissues. When basement membranes are the target of glomerular disease, they produce moderate proteinuria, some hematuria, and progressive renal failure. Autoimmune disease where antibodies are directed against the α3 NC1 domain of collagen IV produces an anti-GBM disease often associated with RPGN and/or a pulmonary-renal syndrome called Goodpasture’s syndrome. Discussion of this disease is covered earlier in “Acute Nephritic Syndromes.”


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InternalMed_Harrison. Classically, patients with Alport’s syndrome develop hematuria, thinning and splitting of the GBMs, mild proteinuria (<1–2 g/24 h), which appears late in the course, followed by chronic glomerulosclerosis leading to renal failure in association with sensorineural deafness. Some patients develop lenticonus of the anterior lens capsule, “dot and fleck” retinopathy, and rarely, mental retardation or leiomyomatosis. Approximately 85% of patients with Alport’s syndrome have an X-linked inheritance of mutations in the α5(IV) collagen chain on chromosome Xq22–24. Female carriers have variable penetrance depending on the type of mutation or the degree of mosaicism created by X inactivation. Fifteen percent of patients have autosomal recessive disease of the α3(IV) or α4(IV) chains on chromosome 2q35–37. Rarely, some kindred have an autosomal dominant inheritance of dominant-negative mutations in α3(IV) or α4(IV) chains.


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InternalMed_Harrison. Pedigrees with the X-linked syndrome are quite variable in their rate and frequency of tissue damage leading to organ failure. Seventy percent of patients have the juvenile form with nonsense or missense mutations, reading frame shifts, or large deletions and generally develop renal failure and sensorineural deafness by age 30. Patients with splice variants, exon skipping, or missense mutations of α-helical glycines generally deteriorate after the age of 30 (adult form) with mild or late deafness. Early severe deafness, lenticonus, or proteinuria suggests a poorer prognosis. Usually females from X-linked pedigrees have only microhematuria, but up to 25% of carrier females have been reported to have more severe renal manifestations. Pedigrees with the autosomal recessive form of the disease have severe early disease in both females and males with asymptomatic parents.


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InternalMed_Harrison. Clinical evaluation should include a careful eye examination and hearing tests. However, the absence of extrarenal symptoms does not rule out the diagnosis. Since α5(IV) collagen is expressed in the skin, some X-linked Alport’s patients can be diagnosed with a skin biopsy revealing the lack of the α5(IV) collagen chain on immunofluorescent analysis. Patients with mutations in α3(IV) or α4(IV) require a renal biopsy. Genetic testing can be used for the diagnosis of Alport’s syndrome and the demonstration of the mode of inheritance. Early in their disease, Alport’s patients typically have thin basement membranes on renal biopsy (see Fig. 62e-19), which thicken over time into multilamellations surrounding lucent areas that often contain granules of varying density—the so-called split basement membrane. In any Alport’s kidney, there are areas of thinning mixed with splitting of the GBM. Tubules drop out, glomeruli scar, and the kidney eventually succumbs to interstitial fibrosis. All


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InternalMed_Harrison. membrane. In any Alport’s kidney, there are areas of thinning mixed with splitting of the GBM. Tubules drop out, glomeruli scar, and the kidney eventually succumbs to interstitial fibrosis. All affected members of a family with X-linked Alport’s syndrome should be identified and followed, including mothers of affected males. Primary treatment is control of systemic hypertension and use of ACE inhibitors to slow renal progression. Although patients who receive renal allografts usually develop anti-GBM antibodies directed toward the collagen epitopes absent in their native kidney, overt Goodpasture’s syndrome is rare and graft survival is good.


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InternalMed_Harrison. Thin basement membrane disease (TBMD) characterized by persistent or recurrent hematuria is not typically associated with proteinuria, hypertension, or loss of renal function or extrarenal disease. Although not all cases are familial (perhaps a founder effect), it usually presents 1847 in childhood in multiple family members and is also called benign familial hematuria. Cases of TBMD have genetic defects in type IV collagen but in contrast to Alport behave as an autosomal dominant disorder that in ~40% of families segregates with the COL(IV) α3/ COL(IV) α4 loci. Mutations in these loci can result in a spectrum of disease ranging from TBMD to autosomal dominant or recessive Alport’s. The GBM shows diffuse thinning compared to normal values for the patient’s age in otherwise normal biopsies (see Fig. 62e-19). The vast majority of patients have a benign course.


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InternalMed_Harrison. Patients with nail-patella syndrome develop iliac horns on the pelvis and dysplasia of the dorsal limbs involving the patella, elbows, and nails, variably associated with neural-sensory hearing impairment, glaucoma, and abnormalities of the GBM and podocytes, leading to hematuria, proteinuria, and FSGS. The syndrome is autosomal dominant, with haploinsufficiency for the LIM homeodomain transcription factor LMX1B; pedigrees are extremely variable in the penetrance for all features of the disease. LMX1B regulates the expression of genes encoding α3 and α4 chains of collagen IV, interstitial type III collagen, podocin, and CD2AP that help form the slit-pore membranes connecting podocytes. Mutations in the LIM domain region of LMX1B associate with glomerulopathy, and renal failure appears in as many as 30% of patients. Proteinuria or isolated hematuria is discovered throughout life, but usually by the third decade, and is inexplicably more common in females. On renal biopsy there is


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InternalMed_Harrison. in as many as 30% of patients. Proteinuria or isolated hematuria is discovered throughout life, but usually by the third decade, and is inexplicably more common in females. On renal biopsy there is lucent damage to the lamina densa of the GBM, an increase in collagen III fibrils along glomerular capillaries and in the mesangium, and damage to the slit-pore membrane, producing heavy proteinuria not unlike that seen in congenital nephrotic syndrome. Patients with renal failure do well with transplantation.


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InternalMed_Harrison. A variety of diseases result in classic vascular injury to the glomerular capillaries. Most of these processes also damage blood vessels elsewhere in the body. The group of diseases discussed here lead to vasculitis, renal endothelial injury, thrombosis, ischemia, and/or lipid-based occlusions.


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InternalMed_Harrison. Aging in the developed world is commonly associated with the occlusion of coronary and systemic blood vessels. The reasons for this include obesity, insulin resistance, smoking, hypertension, and diets rich in lipids that deposit in the arterial and arteriolar circulation, producing local inflammation and fibrosis of small blood vessels. When the renal arterial circulation is involved, the glomerular microcirculation is damaged, leading to chronic nephrosclerosis. Patients with GFRs <60 mL/min have more cardiovascular events and hospitalizations than those with higher filtration rates. Several aggressive lipid disorders can accelerate this process, but most of the time atherosclerotic progression to chronic nephrosclerosis is associated with poorly controlled hypertension. Approximately 10% of glomeruli are normally sclerotic by age 40, rising to 20% by age 60 and 30% by age 80. Serum lipid profiles in humans are greatly affected by apolipoprotein E polymorphisms; the E4 allele is


InternalMed_Harrison

InternalMed_Harrison. 10% of glomeruli are normally sclerotic by age 40, rising to 20% by age 60 and 30% by age 80. Serum lipid profiles in humans are greatly affected by apolipoprotein E polymorphisms; the E4 allele is accompanied by increases in serum cholesterol and is more closely associated with atherogenic profiles in patients with renal failure. Mutations in E2 alleles, particularly in Japanese patients, produce a specific renal abnormality called lipoprotein glomerulopathy associated with glomerular lipoprotein thrombi and capillary dilation.


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InternalMed_Harrison. Uncontrolled systemic hypertension causes permanent damage to the kidneys in about 6% of patients with elevated blood pressure. As many as 27% of patients with end-stage kidney disease have hypertension as a primary cause. Although there is not a clear correlation between the extent or duration of hypertension and the risk of end-organ damage, hypertensive nephrosclerosis is fivefold more frequent in African Americans than whites. Risk alleles associated with APOL1, a functional gene for apolipoprotein L1 expressed in podocytes 1848 substantially explains the increased burden of end-stage renal disease among African Americans. Associated risk factors for progression to end-stage kidney disease include increased age, male gender, race, smoking, hypercholesterolemia, duration of hypertension, low birth weight, and preexisting renal injury. Kidney biopsies in patients with hypertension, microhematuria, and moderate proteinuria demonstrate arteriolosclerosis, chronic nephrosclerosis, and


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InternalMed_Harrison. low birth weight, and preexisting renal injury. Kidney biopsies in patients with hypertension, microhematuria, and moderate proteinuria demonstrate arteriolosclerosis, chronic nephrosclerosis, and interstitial fibrosis in the absence of immune deposits (see Fig. 62e-21). Today, based on a careful history, physical examination, urinalysis, and some serologic testing, the diagnosis of chronic nephrosclerosis is usually inferred without a biopsy. Treating hypertension is the best way to avoid progressive renal failure; most guidelines recommend lowering blood pressure to <130/80 mmHg if there is preexisting diabetes or kidney disease. In the presence of kidney disease, most patients begin antihypertensive therapy with two drugs, classically a thiazide diuretic and an ACE inhibitor; most will require three drugs. There is strong evidence in African Americans with hypertensive nephrosclerosis that therapy initiated with an ACE inhibitor can slow the rate of decline in renal function


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InternalMed_Harrison. will require three drugs. There is strong evidence in African Americans with hypertensive nephrosclerosis that therapy initiated with an ACE inhibitor can slow the rate of decline in renal function independent of effects on systemic blood pressure. Malignant acceleration of hypertension complicates the course of chronic nephrosclerosis, particularly in the setting of scleroderma or cocaine use (see Fig. 62e-24). The hemodynamic stress of malignant hypertension leads to fibrinoid necrosis of small blood vessels, thrombotic microangiography, a nephritic urinalysis, and acute renal failure. In the setting of renal failure, chest pain, or papilledema, the condition is treated as a hypertensive emergency. Slightly lowering the blood pressure often produces an immediate reduction in GFR that improves as the vascular injury attenuates and autoregulation of blood vessel tone is restored.


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InternalMed_Harrison. Aging patients with clinical complications from atherosclerosis sometimes shower cholesterol crystals into the circulation—either spontaneously or, more commonly, following an endovascular procedure with manipulation of the aorta—or with use of systemic anticoagulation. Spontaneous emboli may shower acutely or shower subacutely and somewhat more silently. Irregular emboli trapped in the microcirculation produce ischemic damage that induces an inflammatory reaction. Depending on the location of the atherosclerotic plaques releasing these cholesterol fragments, one may see cerebral transient ischemic attacks; livedo reticularis in the lower extremities; Hollenhorst plaques in the retina with visual field cuts; necrosis of the toes; and acute glomerular capillary injury leading to focal segmental glomerulosclerosis sometimes associated with hematuria, mild proteinuria, and loss of renal function, which typically progresses over a few years. Occasional patients have fever, eosinophilia,


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InternalMed_Harrison. glomerulosclerosis sometimes associated with hematuria, mild proteinuria, and loss of renal function, which typically progresses over a few years. Occasional patients have fever, eosinophilia, or eosinophiluria. A skin biopsy of an involved area may be diagnostic. Since tissue fixation dissolves the cholesterol, one typically sees only residual, biconvex clefts in involved vessels (see Fig. 62e-22). There is no therapy to reverse embolic occlusions, and steroids do not help. Controlling blood pressure and lipids and cessation of smoking are usually recommended for prevention.


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InternalMed_Harrison. Although individuals with SA-hemoglobin are usually asymptomatic, most will gradually develop hyposthenuria due to subclinical infarction of the renal medulla, thus predisposing them to volume depletion. There is an unexpectedly high prevalence of sickle trait among dialysis patients who are African American. Patients with homozygous SS-sickle cell disease develop chronic vasoocclusive disease in many organs. Polymers of deoxygenated SS-hemoglobin distort the shape of red blood cells. These cells attach to endothelia and obstruct small blood vessels, producing frequent and painful sickle cell crises over time. Vessel occlusions in the kidney produce glomerular hypertension, FSGS, interstitial nephritis, and renal infarction associated with hyposthenuria, microscopic hematuria, and even gross hematuria; some patients also present with MPGN. Renal function can be overestimated due to the increased tubular secretion of creatinine seen in many patients with SS-sickle cell. By the second


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InternalMed_Harrison. hematuria; some patients also present with MPGN. Renal function can be overestimated due to the increased tubular secretion of creatinine seen in many patients with SS-sickle cell. By the second or third decade of life, persistent vasoocclusive disease in the kidney leads to varying degrees of renal failure, and some patients end up on dialysis. Treatment is directed to reducing the frequency of painful crises and administering ACE inhibitors in the hope of delaying a progressive decline in renal function. In sickle cell patients undergoing renal transplantation, renal graft survival is comparable to African Americans in the general transplant population.


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InternalMed_Harrison. Thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS) represent a spectrum of thrombotic microangiopathies. Thrombotic thrombocytopenic purpura and hemolytic-uremic syndrome share the general features of idiopathic thrombocytopenic purpura, hemolytic anemia, fever, renal failure, and neurologic disturbances. When patients, particularly children, have more evidence of renal injury, their condition tends to be called HUS. In adults with neurologic disease, it is considered to be TTP. In adults there is often a mixture of both, which is why they are often referred to as having TTP/ HUS. On examination of kidney tissue, there is evidence of glomerular capillary endotheliosis associated with platelet thrombi, damage to the capillary wall, and formation of fibrin material in and around glomeruli (see Fig. 62e-23). These tissue findings are similar to what is seen in preeclampsia/HELLP (hemolysis, elevated liver enzymes, and low platelet count syndrome), malignant


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InternalMed_Harrison. in and around glomeruli (see Fig. 62e-23). These tissue findings are similar to what is seen in preeclampsia/HELLP (hemolysis, elevated liver enzymes, and low platelet count syndrome), malignant hypertension, and the antiphospholipid syndrome. TTP/HUS is also seen in pregnancy; with the use of oral contraceptives or quinine; in renal transplant patients given OKT3 for rejection; in patients taking the calcineurin inhibitors, cyclosporine and tacrolimus, or in patients taking the antiplatelet agents, ticlopidine and clopidogrel; or following HIV infection.


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InternalMed_Harrison. Although there is no agreement on how much they share a final common pathophysiology, two general groups of patients are recognized: childhood HUS associated with enterohemorrhagic diarrhea and TTP/HUS in adults. Childhood HUS is caused by a toxin released by Escherichia coli 0157:H7 and occasionally by Shigella dysenteriae. This shiga toxin (verotoxin) directly injures endothelia, enterocytes, and renal cells, causing apoptosis, platelet clumping, and intravascular hemolysis by binding to the glycolipid receptors (Gb3). These receptors are more abundant along endothelia in children compared to adults. Shiga toxin also inhibits the endothelial production of ADAMTS13. In familial cases of adult TTP/HUS, there is a genetic deficiency of the ADAMTS13 metalloprotease that cleaves large multimers of von Willebrand’s factor. Absent ADAMTS13, these large multimers cause platelet clumping and intravascular hemolysis. An antibody to ADAMTS13 is found in many sporadic cases of adult TTP/HUS,


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InternalMed_Harrison. of von Willebrand’s factor. Absent ADAMTS13, these large multimers cause platelet clumping and intravascular hemolysis. An antibody to ADAMTS13 is found in many sporadic cases of adult TTP/HUS, but not all; many patients also have antibodies to the thrombospondin receptor on selected endothelial cells in small vessels or increased levels of plasminogen-activator inhibitor 1 (PAI-1). Some children with complement protein deficiencies express atypical HUS (aHUS), which can be treated with liver transplant. The treatment of adult TTP/HUS is daily plasmapheresis, which can be lifesaving. Plasmapheresis is given until the platelet count rises, but in relapsing patients it normally is continued well after the platelet count improves, and in resistant patients twice-daily exchange may be helpful. Most patients respond within 2 weeks of daily plasmapheresis. Since TTP/HUS often has an autoimmune basis, there is an anecdotal role in relapsing patients for using splenectomy, steroids,


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InternalMed_Harrison. helpful. Most patients respond within 2 weeks of daily plasmapheresis. Since TTP/HUS often has an autoimmune basis, there is an anecdotal role in relapsing patients for using splenectomy, steroids, immunosuppressive drugs, bortezomib, or rituximab, an anti-CD20 antibody. Patients with childhood HUS from infectious diarrhea are not given antibiotics, because antibiotics are thought to accelerate the release of the toxin and the diarrhea is usually self-limited. No intervention appears superior to supportive therapy in children with postdiarrheal HUS.


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InternalMed_Harrison. ANTIPHOSPHOLIPID ANTIBODY SYNDROME (SEE CHAP. 379) A number of infectious diseases will injure the glomerular capillaries as part of a systemic reaction producing an immune response or from direct infection of renal tissue. Evidence of this immune response is collected by glomeruli in the form of immune deposits that damage the kidney, producing moderate proteinuria and hematuria. A high prevalence of many of these infectious diseases in undeveloped countries results in infection-associated renal disease being the most common cause of glomerulonephritis in many parts of the world. Poststreptococcal Glomerulonephritis This form of glomerulonephritis is one of the classic complications of streptococcal infection. The discussion of this disease can be found earlier, in the section “Acute Nephritic Syndromes.”


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InternalMed_Harrison. Subacute Bacterial Endocarditis Renal injury from persistent bacteremia absent the continued presence of a foreign body, regardless of cause, is treated presumptively as if the patient has endocarditis. The discussion of this disease can be found earlier, in the section “Acute Nephritic Syndromes.”


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InternalMed_Harrison. Human Immunodeficiency Virus Renal disease is an important complication of HIV disease. The risk of development of end-stage renal disease is much higher in HIV-infected African Americans than in HIV-infected whites. About 50% of HIV-infected patients with kidney disease have HIV-associated nephropathy (HIVAN) on biopsy. The lesion in HIVAN is FSGS, characteristically revealing a collapsing glomerulopathy (see Fig. 62e-3) with visceral epithelial cell swelling, microcystic dilatation of renal tubules, and tubuloreticular inclusion. Renal epithelial cells express replicating HIV virus, but host immune responses also play a role in the pathogenesis. MPGN and DPGN have also been reported but more commonly in HIV-infected whites and in patients coinfected with hepatitis B or C. HIV-associated TTP has also been reported. Other renal lesions include DPGN, IgA nephropathy, and MCD. Renal biopsy may be indicated to distinguish between these lesions.


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InternalMed_Harrison. HIV patients with FSGS typically present with nephrotic-range proteinuria and hypoalbuminemia, but unlike patients with other etiologies for nephrotic syndrome, they do not commonly have hypertension, edema, or hyperlipidemia. Renal ultrasound also reveals large, echogenic kidneys despite the finding that renal function in some patients declines rapidly. Treatment with inhibitors of the reninangiotensin system decreases the proteinuria. Effective antiretroviral therapy benefits both the patient and the kidney and improves survival of HIV-infected patients with chronic kidney disease (CKD) or end-stage renal disease. In HIV-infected patients not yet on therapy, the presence of HIVAN is an indication to initiate therapy. Following the introduction of antiretroviral therapy, survival on dialysis for the HIV-infected patient has improved dramatically. Renal transplantations in HIV-infected patients without detectable viral loads or histories of opportunistic infections provide a better


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InternalMed_Harrison. for the HIV-infected patient has improved dramatically. Renal transplantations in HIV-infected patients without detectable viral loads or histories of opportunistic infections provide a better survival benefit over dialysis. Following transplantation, patient and graft survival are similar to the general transplant population despite frequent rejections.


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InternalMed_Harrison. Hepatitis B and C Typically infected patients present with microscopic hematuria, nonnephrotic or nephrotic-range proteinuria, and hypertension. There is a close association between hepatitis B infection and polyarteritis nodosa with vasculitis appearing generally in the first 6 months following infection. Renal manifestations include renal artery aneurysms, renal infarction, and ischemic scars. Alternatively, the hepatitis B carrier state can produce a MGN that is more common in children than adults, or MPGN that is more common in adults than in children. Renal histology is indistinguishable from idiopathic MGN or type I MPGN. Viral antigens are found in the renal deposits. There are no good treatment guidelines, but interferon α-2b and lamivudine have been used to some effect in small studies. Children have a good prognosis, with 60–65% achieving spontaneous remission within 4 years. In contrast, 30% of adults have renal insufficiency and 10% have renal failure 5 years after


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InternalMed_Harrison. small studies. Children have a good prognosis, with 60–65% achieving spontaneous remission within 4 years. In contrast, 30% of adults have renal insufficiency and 10% have renal failure 5 years after diagnosis.


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InternalMed_Harrison. Up to 30% of patients with chronic hepatitis C infection have some renal manifestations. Patients often present with type II mixed cryoglobulinemia, nephrotic syndrome, microscopic hematuria, abnormal liver function tests, depressed C3 levels, anti–hepatitis C virus (HCV) antibodies, and viral RNA in the blood. The renal lesions most commonly seen, in order of decreasing frequency, are cryoglobulinemic glomerulonephritis, MGN, and type I MPGN. Treatment with pegylated interferon and ribavirin is typical to reduce the viral load.


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InternalMed_Harrison. Other Viruses Other viral infections are occasionally associated with 1849 glomerular lesions, but cause and effect are not well established. These viral infections and their respective glomerular lesions include: cytomegalovirus producing MPGN; influenza and anti-GBM disease; measles-associated endocapillary proliferative glomerulonephritis, with measles antigen in the capillary loops and mesangium; parvovirus causing mild proliferative or mesangioproliferative glomerulonephritis or FSGS; mumps and mesangioproliferative glomerulonephritis; Epstein-Barr virus producing MPGN, diffuse proliferative nephritis, or IgA nephropathy; dengue hemorrhagic fever causing endocapillary proliferative glomerulonephritis; and coxsackievirus producing focal glomerulonephritis or DPGN.


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InternalMed_Harrison. Syphilis Secondary syphilis, with rash and constitutional symptoms, develops weeks to months after the chancre first appears and occasionally presents with the nephrotic syndrome from MGN caused by subepithelial immune deposits containing treponemal antigens. Other lesions have also rarely been described including interstitial syphilitic nephritis. The diagnosis is confirmed with nontreponemal and treponemal tests for Treponema pallidum. The renal lesion responds to treatment with penicillin or an alternative drug, if allergic. Additional testing for other sexually transmitted diseases is an important part of disease management.


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InternalMed_Harrison. Leprosy Despite aggressive eradication programs, approximately 400,000 new cases of leprosy appear annually worldwide. The diagnosis is best made in patients with multiple skin lesions accompanied by sensory loss in affected areas, using skin smears showing paucibacillary or multibacillary infection (WHO criteria). Leprosy is caused by infection with Mycobacterium leprae and can be classified by Ridley-Jopling criteria into various types: tuberculoid, borderline tuberculoid, mid-borderline and borderline lepromatous, and lepromatous. Renal involvement in leprosy is related to the quantity of bacilli in the body, and the kidney is one of the target organs during splanchnic localization. In some series, all cases with borderline lepromatous and lepromatous types of leprosy have various forms of renal involvement including FSGS, mesangioproliferative glomerulonephritis, or renal amyloidosis; much less common are the renal lesions of DPGN and MPGN. Treatment of the infection can cause


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InternalMed_Harrison. of renal involvement including FSGS, mesangioproliferative glomerulonephritis, or renal amyloidosis; much less common are the renal lesions of DPGN and MPGN. Treatment of the infection can cause remission of the renal disease.


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InternalMed_Harrison. Malaria There are 300–500 million incident cases of malaria each year worldwide, and the kidney is commonly involved. Glomerulonephritis is due to immune complexes containing malarial antigens that are implanted in the glomerulus. In malaria from P. falciparum, mild proteinuria is associated with subendothelial deposits, mesangial deposits, and mesangioproliferative glomerulonephritis that usually resolve with treatment. In quartan malaria from infection with Plasmodium malariae, children are more commonly affected and renal involvement is more severe. Transient proteinuria and microscopic hematuria can resolve with treatment of the infection. However, resistant nephrotic syndrome with progression to renal failure over 3–5 years does happen, as <50% of patients respond to steroid therapy. Affected patients with nephrotic syndrome have thickening of the glomerular capillary walls, with subendothelial deposits of IgG, IgM, and C3 associated with a sparse membranoproliferative lesion.


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InternalMed_Harrison. Affected patients with nephrotic syndrome have thickening of the glomerular capillary walls, with subendothelial deposits of IgG, IgM, and C3 associated with a sparse membranoproliferative lesion. The rare mesangioproliferative glomerulonephritis reported with Plasmodium vivax or Plasmodium ovale typically has a benign course.


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InternalMed_Harrison. Schistosomiasis Schistosomiasis affects more than 300 million people worldwide and primarily involves the urinary and gastrointestinal tracts. Glomerular involvement varies with the specific strain of schistosomiasis; Schistosoma mansoni is most commonly associated with clinical renal disease, and the glomerular lesions can be classified: Class I is a mesangioproliferative glomerulonephritis; class II is an extracapillary proliferative glomerulonephritis; class III is a membranoproliferative glomerulonephritis; class IV is a focal segmental glomerulonephritis; and class V is amyloidosis. Classes I–II often remit with treatment of the infection, but classes III and IV lesions are associated with IgA immune deposits and progress despite antiparasitic and/or immunosuppressive therapy.


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InternalMed_Harrison. Other Parasites Renal involvement with toxoplasmosis infections is rare. When it occurs, patients present with nephrotic syndrome 1850 and have a histologic picture of MPGN. Fifty percent of patients with leishmaniasis will have mild to moderate proteinuria and microscopic hematuria, but renal insufficiency is rare. Acute DPGN, MGN, and mesangioproliferative glomerulonephritis have all been observed on biopsy. Filariasis and trichinosis are caused by nematodes and are sometimes associated with glomerular injury presenting with proteinuria, hematuria, and a variety of histologic lesions that typically resolve with eradication of the infection.


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InternalMed_Harrison. polycystic Kidney Disease and Other Inherited Disorders of tubule growth and Development Jing Zhou, Martin R. Pollak The polycystic kidney diseases are a group of genetically heteroge-339Disorders of the Kidney and Urinary Tract neous disorders and a leading cause of kidney failure. The autosomal dominant form of polycystic kidney disease (ADPKD) is the most common life-threatening monogenic disease, affecting 12 million people worldwide. The autosomal recessive form of polycystic kidney disease (ARPKD) is rarer but affects the pediatric population. Kidney cysts are often seen in a wide range of syndromic diseases. Recent studies have shown that defects in the structure or function of the primary cilia may underlie this group of genetic diseases collectively termed ciliopathies (Table 339-1).


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InternalMed_Harrison. AuTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE Etiology and Pathogenesis (Fig. 339-1) ADPKD is characterized by progressive formation of epithelial-lined cysts in the kidney. Although cysts only occur in 5% of the tubules in the kidney, the enormous growth of these cysts ultimately leads to the loss of normal surrounding tissues and loss of renal function. The cellular defects in ADPKD that have been known for a long time are increased cell proliferation and fluid secretion, decreased cell differentiation, and abnormal extracellular matrix. ADPKD is caused by mutations in PKD1 and PKD2, which, respectively, code for polycystin-1 (PC1) and polycystin-2 (PC2). PC1 is a large 11-transmembrane protein that functions like a G protein–coupled receptor. PC2 is a calcium-permeable six-transmembrane protein that structurally belongs to the transient receptor potential (TRP) cation channel family. PC1 and PC2 are widely expressed in almost all tissues and organs. PC1 expression is high in


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InternalMed_Harrison. protein that structurally belongs to the transient receptor potential (TRP) cation channel family. PC1 and PC2 are widely expressed in almost all tissues and organs. PC1 expression is high in development and low in the adult, whereas PC2 expression is relatively constant. PC1 and PC2 are found on the primary cilium, a hair-like structure present on the apical membrane of a cell, in addition to the cell membranes and cell-cell junctions of tubular epithelial cells. Defects in the primary cilia are linked to a wide spectrum of human diseases, collectively termed ciliopathies. The most common phenotype shared by many ciliopathies is kidney cysts. PC1 and PC2 bind to each other via their respective C-terminal tails to form a receptor-channel complex and regulate each other’s function. The PC1/2 protein complex serves as a mechanosensor or chemical sensor and regulates calcium and G-protein signaling. The PC1/2 protein complex may also directly regulate a number of cellular functions


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InternalMed_Harrison. PC1/2 protein complex serves as a mechanosensor or chemical sensor and regulates calcium and G-protein signaling. The PC1/2 protein complex may also directly regulate a number of cellular functions including the cell cycle, the actin cytoskeleton, planar cell polarity (PCP), and cell migration. This protein complex has also been implicated in regulating a number of signaling pathways, including Wnt, mammalian target of rapamycin (mTOR), STAT3, cMET, phosphoinositide 3-kinase (PI3K)/AKT, G protein–coupled receptor (GPCR), and epidermal growth factor receptor (EGFR), as well as in the localization and activity of cystic fibrosis transmembrane conductance (CFTR). One hypothesis is


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InternalMed_Harrison. Mode of Renal Disease Inheritance Abnormalities Other Clinical Features Genes Renal cysts Liver, pancreatic cysts, hypertension, subarachnoid hemorrhage Oligohydramnios if severe, hypertension, ascending cholangitis, liver fibrosis In adults, gout Growth retardation, anemia (visual loss, liver fibrosis, cerebellar ataxia if associated with another syndrome) Juvenile nephronophthisis, Leber’s amaurosis Visual impairment in first year of life, pigmentary retinopathy CNS anomalies, polydactyly, congenital heart defects Obesity, polydactyly, retinitis pigmentosa, anosmia, congenital heart defects, mental retardation Oral cavity, face, and digit anomalies; CNS abnormalities; cystic kidney disease; X-linked with male lethality, primary ciliary dyskinesia Skeletal dysplasia, thoracic deformities, polydactyly, renal cysts, retinitis pigmentosa Angiomyolipomas, renal cell carcinoma, facial angiofibromas, CNS hamartomas


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InternalMed_Harrison. Skeletal dysplasia, thoracic deformities, polydactyly, renal cysts, retinitis pigmentosa Angiomyolipomas, renal cell carcinoma, facial angiofibromas, CNS hamartomas Renal cell carcinoma, retinal angiomas, CNS hemangioblastomas, pheochromocytomas PKD1, PKD2 MCKD1, MCKD2/UMOD NPHP1-4, IQCB1, CEP290, GLIS2, RPGRIP1L, NEK8, SDCCAG8, TMEM67, TTC21B NPHP1-6, SDCCAG8 GUCY2D, RPE65, LCA3-14 (including LCA10, CEP290) MKS1, TMEM216, TMEM67, CEP290, RPGRIP1L, CC2D2A, TCTN2, B9D1, B9D2, NPHP3 BBS1, 2, ARL6, BBS4,5, MKKS, BBS7, TTC8, BBS9, 10, TRIM32, BBS12, MKS1, CEP290, C2ORF86; modifiers MKS1, MKS3, CCDC28B TSC1, TSC2 Abbreviations: AD, autosomal dominant; AR, autosomal recessive; CNS, central nervous system. Extracellular signals Receptors Ca2+, Wnt, SHH, cAMP and other signaling events Defective Planar cell polarity Cell proliferation During development morphogenesis Polycystic Kidney Disease and Other Inherited Disorders of Tubule Growth and Development


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InternalMed_Harrison. Polycystic Kidney Disease and Other Inherited Disorders of Tubule Growth and Development FIGuRE 339-1 Scheme of the primary cilium and cystic kidney disease proteins. Left. A scheme of the primary cilium. Primary cilia share a “9+0” organization of microtubule doublets. Proteins are transported into the cilium by motor protein kinesin 2 and transported out of the cilium by dynein. The cilium is connected to the basal body through the transition zone. Middle. Topology of autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD) proteins polycystin-1, polycystin-2, and fibrocystin/ polyductin (FPC) are shown. PC1 also interacts with other proteins such as components of the BBSome and NPHP1. PC2 and FPC both interact with kinesin 2 (KIF 3A/B). Localization of disease proteins in the cilium, the transition zone, and the basal body is color coded. Right. Potential disease mechanisms due to cilium-mediated signaling events.


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InternalMed_Harrison. that loss of ciliary function of PC1 and PC2 leads to reduced calcium signaling and a subsequent increase of adenylyl cyclase activity and decrease of phosphodiesterase activity, which, in turn, causes increased cellular cyclic AMP (cAMP). Increased cAMP promotes protein kinase A activity, among other effectors, and, in turn, leads to cyst growth by promoting proliferation and fluid secretion of cyst-lining cells through chloride and aquaporin channels in ADPKD kidneys.


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InternalMed_Harrison. Genetic Considerations ADPKD is inherited as an autosomal dominant trait with complete penetrance but variable expressivity. The disease affects all ethnic groups worldwide with an estimated prevalence of 1:1000 to 1:400. Only half of the patients with ADPKD are clinically diagnosed during their lifetime. ADPKD is genetically heterogeneous. The first disease gene (PKD1) was localized to the region of the α-globin gene on chromosome 16p13 in 1985, and a second disease gene (PKD2) locus was mapped to chromosome 4q21-q23 in 1993. Mutations of PKD1 and PKD2 are responsible for ~85% and ~15% of ADPKD cases, respectively. However, patients with PKD2 mutations may be higher than 15% because they tend to have milder clinical disease and, as a result, may be underdiagnosed. Embryonic lethality of Pkd1 and Pkd2 knockout mice suggests that human homozygotes may be lethal and thus not clinically recognized. PKD1 is comprised of 46 exons occupying ~52 kb of genomic DNA. It produces an ~14-kb


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InternalMed_Harrison. of Pkd1 and Pkd2 knockout mice suggests that human homozygotes may be lethal and thus not clinically recognized. PKD1 is comprised of 46 exons occupying ~52 kb of genomic DNA. It produces an ~14-kb transcript that encodes PC1, a protein of ~4300 amino acids. A feature of the PKD1 gene is that the 5´ three-quarters of PKD1 have been duplicated at six other sites on chromosome 16p, and many of them produce mRNA transcripts, which provides a major challenge for genetic analysis of the duplicated region. PKD2 is a single-copy gene with 15 exons producing an ~5.3-kb mRNA transcript that encodes PC2, a protein of 968 amino acids. The presence of additional genes for ADPKD was suggested based on several families linked to neither PKD1 nor PKD2 genes. However, careful analyses have excluded the existence of a third ADPKD gene.


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InternalMed_Harrison. In ADPKD patients, every cell carries a germline mutant allele of either PKD1 or PKD2. However, cysts develop in only a small fraction of the nephrons. Cysts are thought to originate from clonal growth of single cells that have received a somatic “second hit” mutation in the “normal” allele of the PKD1 or PKD2 gene. Accumulating evidence in mouse models now shows that partial loss of function of the second allele of Pkd1 in a proliferative environment is sufficient for cystogenesis, suggesting that a critical amount of PKD1 is needed in a cell. Somatic inactivation of the second allele of Pkd1 in adult mice results in very slow onset of cyst development in the kidney, but a “third hit,” such as an additional genetic or epigenetic event, the inactivation of a growth-suppressor gene, the activation of a growth-promoting gene(s), or an event like renal injury that activates the developmental program, may promote rapid cyst formation.


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InternalMed_Harrison. Clinical Manifestations ADPKD is characterized by the progressive bilateral formation of renal cysts. Focal renal cysts are typically detected in affected subjects before 30 years of age. Hundreds to thousands of cysts are usually present in the kidneys of most patients in the fifth decade (Fig. 339-2). Enlarged kidneys can each reach a fourfold increase in length and weigh up to 20 times the normal weight. The clinical presentations of ADPKD are highly variable. Although many patients are asymptomatic until the fourth to fifth decade of life and are diagnosed by incidental discoveries of hypertension or abdominal masses, back or flank pain is a frequent symptom in ~60% of patients with ADPKD. The pain may result from renal cyst infection, hemorrhage, or nephrolithiasis. Gross hematuria resulting from cyst rupture occurs in ~40% of patients during the course of their disease, and many of them will have recurrent episodes. Flank pain and hematuria


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InternalMed_Harrison. FIGuRE 339-2 Photograph showing a kidney from a patient with autosomal dominant polycystic kidney disease. The kidney has been cut open to expose the parenchyma and internal aspects of cysts.


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InternalMed_Harrison. may coexist if the cyst that ruptures is connected with the collecting system. Proteinuria is usually a minor feature of ADPKD. Infection is the second most common cause of death for patients with ADPKD. Up to half of patients with ADPKD will have one or more episodes of renal infection during their lifetime. An infected cyst and acute pyelonephritis are the most common renal infections often due to gram-negative bacteria, which are associated with fever and flank pain, with or without bacteremia. These complications and renal insufficiency often correlate with structural abnormality of the renal parenchyma. Kidney stones occur in ~20% of patients with ADPKD. Different from the general population, more than half of the stones in patients with ADPKD are composed of uric acid, with the remainder due to calcium oxalate. Distal acidification defects, abnormal ammonium transport, low urine pH, and hypocitraturia may be important in the pathogenesis of renal stones in ADPKD. Renal cell


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InternalMed_Harrison. remainder due to calcium oxalate. Distal acidification defects, abnormal ammonium transport, low urine pH, and hypocitraturia may be important in the pathogenesis of renal stones in ADPKD. Renal cell carcinoma is a rare complication of ADPKD with no apparent increased frequency compared to the general population. However, in ADPKD, these tumors are more often bilateral at presentation, multicentric, and sarcomatoid in type. Radiologic imaging is often not helpful in distinguishing cyst infection and cyst hemorrhage because of their complexity. Computed tomography (CT) scan and magnetic resonance imaging (MRI) are often useful in distinguishing a malignancy from a complex cyst. Cardiovascular complications are the major cause of mortality in patients with ADPKD. Hypertension is common and typically occurs before any reduction in glomerular filtration rate (GFR). Hypertension is a risk factor for both cardiovascular and kidney disease progression in ADPKD. Notably, some normotensive


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InternalMed_Harrison. typically occurs before any reduction in glomerular filtration rate (GFR). Hypertension is a risk factor for both cardiovascular and kidney disease progression in ADPKD. Notably, some normotensive patients with ADPKD may also have left ventricular hypertrophy. Hypertension in ADPKD may result from the increased activation of the renin-angiotensin-aldosterone system, increased sympathetic nerve activity, and impaired endothelial cilium function-dependent relaxation of small resistant blood vessels.


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InternalMed_Harrison. The progression of ADPKD has striking interand intrafamilial variability. The disease can present as early as in utero, but end-stage renal disease typically occurs in late middle age. Risk factors include early diagnosis of ADPKD, hypertension, gross hematuria, multiple pregnancies, and large kidney size. Liver cysts derived from the biliary epithelia are the most common extrarenal complication. Polycystic liver disease associated with ADPKD is different from autosomal dominant polycystic liver disease (ADPLD), which is caused by mutations in at least two distinct genes (PRKCSH and SEC63) and does not progress to renal failure. Massive polycystic liver disease occurs almost exclusively in women with ADPKD, particularly those with multiple pregnancies.


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InternalMed_Harrison. Intracranial aneurysm (ICA) occurs four to five times more frequently in ADPKD patients than in the general population and causes high mortality. The disease gene products PC1 and PC2 may be directly responsible for defects in arterial smooth muscle cells and myofibroblasts. The focal nature and the natural history of ICA in ADPKD remain unclear. A family history of ICA is a risk factor of aneurysm rupture in ADPKD, but whether hypertension and cigarette smoking are independent risk factors is not clear. About 20–50% of patients may experience “warning headaches” preceding the index episode of subarachnoid hemorrhage due to ruptured ICA. A CT scan is generally used as the first diagnostic test. A lumbar puncture may be used to confirm the diagnosis. The role of radiologic screening for ICA in asymptomatic patients with ADPKD remains unclear. ADPKD patients with a positive family history of ICAs may undergo presymptomatic screening of ICAs by magnetic resonance angiography. Other


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InternalMed_Harrison. ICA in asymptomatic patients with ADPKD remains unclear. ADPKD patients with a positive family history of ICAs may undergo presymptomatic screening of ICAs by magnetic resonance angiography. Other vascular abnormalities in ADPKD patients include diffuse arterial dolichoectasias of the anterior and posterior cerebral circulation, which can predispose to arterial dissection and stroke. Mitral valve prolapse occurs in up to 30% of patients with ADPKD, and tricuspid valve prolapse is less common. Other valvular abnormalities occurring with increased frequency in ADPKD patients include insufficiency of the mitral, aortic, and tricuspid valves. Most patients are asymptomatic, but some may progress and require valve replacement. The prevalence of colonic diverticulae and abdominal wall hernias is also increased in ADPKD patients.


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InternalMed_Harrison. Diagnosis Diagnosis is typically made from a positive family history consistent with autosomal dominant inheritance and multiple kidney cysts bilaterally. Renal ultrasonography is often used for presymptomatic screening of at-risk subjects and for evaluation of potential living-related kidney donors from ADPKD families. The presence of at least two renal cysts (unilateral or bilateral) is sufficient for diagnosis among at-risk subjects between 15 and 29 years of age with a sensitivity of 96% and specificity of 100%. The presence of at least two cysts in each kidney and the presence at least four cysts in each kidney are required for the diagnosis of at-risk subjects age 30 to 59 years and age 60 years or older, respectively, with a sensitivity of 100% and specificity of 100%. This is because there is an increased frequency of developing simple renal cysts with age. Conversely, in subjects between age 30 and 59 years, the absence of at least two cysts in each kidney, which is


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InternalMed_Harrison. is because there is an increased frequency of developing simple renal cysts with age. Conversely, in subjects between age 30 and 59 years, the absence of at least two cysts in each kidney, which is associated with a false-negative rate of 0%, can be used for disease exclusion. These criteria have a lower sensitivity for patients with a PKD2 mutation because of a late onset of ADPKD2. CT scan and T2-weighted MRI, with and without contrast enhancement, are more sensitive than ultrasonography and can detect cysts of smaller size. However, a CT scan exposes the patient to radiation and radiocontrast, which may cause serious allergic reactions and nephrotoxicity in patients with renal insufficiency. T2-weighted MRI, with gadolinium as a contrast agent, has minimal renal toxicity and can detect cysts of only 2–3 mm in diameter. However, a large majority of cysts may still be below the detection level. Genetic testing by linkage analyses and mutational analyses is available for ambiguous


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InternalMed_Harrison. cysts of only 2–3 mm in diameter. However, a large majority of cysts may still be below the detection level. Genetic testing by linkage analyses and mutational analyses is available for ambiguous cases. Because of the large size of the PKD1 gene and the presence of multiple highly homologous pseudogenes, mutational analysis of the PKD1 gene is difficult and costly. Application of new technologies, such as paired-end next-generation sequencing with multiplexing individually bar-coded long-range polymerase chain reaction libraries, may reduce the costs and improve the sensitivity for clinical genetic testing.


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InternalMed_Harrison. No specific treatment to prevent cyst growth or the decline of renal function has been approved by U.S. Food and Drug Administration. Blood pressure control to a target of 140/90 mmHg is recommended according to the guidelines from the eighth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VIII report) for reducing cardiovascular complications in ADPKD and renal disease progression. More rigorous blood pressure control does not equal greater clinical benefits. Maintaining a target systolic blood pressure to 110 mmHg in patients with moderate or advanced disease may increase the risk of renal disease progression by reducing renal blood flow. Lipid-soluble antibiotics against common gram-negative enteric organisms, such as trimethoprim-sulfamethoxazole, quinolones, and chloramphenicol, are preferred for cyst infection because most renal cysts are not connected to glomerular filtration and antibiotics that are capable


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InternalMed_Harrison. trimethoprim-sulfamethoxazole, quinolones, and chloramphenicol, are preferred for cyst infection because most renal cysts are not connected to glomerular filtration and antibiotics that are capable of penetrating the cyst walls are likely to be more effective. Treatment often requires 4–6 weeks. The treatment of kidney stones in ADPKD includes standard measures such as analgesics for pain relief and hydration to ensure adequate urine flow. Management of chronic flank, back, or abdominal pain due to renal enlargement may include both pharmacologic (nonnarcotic and narcotic analgesics) and nonpharmacologic measures (transcutaneous electrical nerve stimulation, acupuncture, and biofeedback). Occasionally, surgical decompression of cysts may be necessary. More than half of ADPKD patients eventually require peritoneal dialysis, hemodialysis, or kidney transplantation. Peritoneal dialysis may not be suitable for some patients with massively enlarged polycystic kidneys due to the small


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InternalMed_Harrison. eventually require peritoneal dialysis, hemodialysis, or kidney transplantation. Peritoneal dialysis may not be suitable for some patients with massively enlarged polycystic kidneys due to the small intraabdominal space for efficient peritoneal exchange of fluid and solutes and increased chance of abdominal hernia and back pain. Patients with very large polycystic kidneys and recurrent renal cyst infection may require pretransplant nephrectomy or bilateral nephrectomy to accommodate the allograft and reduce the pain.


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InternalMed_Harrison. Specific treatment strategies for ADPKD have focused on slowing renal disease progression and lowering cardiovascular risk. For the latter, the main approach is to control blood pressure by inhibiting the renin-angiotensin-aldosterone system. The ongoing HALT PKD trial was set to evaluate the impact of intensive blockade of the renin-angiotensin-aldosterone system and levels of blood pressure control on progressive renal disease. Most approaches target the slowing of renal disease progression by inhibiting cell proliferation and fluid secretion. Several clinical trials have been conducted targeting cell proliferation, including studies on sirolimus and everolimus, inhibitors of the mTOR pathway; OPC31260 and tolvaptan, which inhibit cAMP pathways by antagonizing the activation of vasopressin V2 receptor (V2R) in collecting ducts and reduce cell proliferation by decreasing renal cAMP levels; and somatostatin analogues, which reduce cAMP levels by binding to several GPCRs. Both the V2R


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InternalMed_Harrison. V2 receptor (V2R) in collecting ducts and reduce cell proliferation by decreasing renal cAMP levels; and somatostatin analogues, which reduce cAMP levels by binding to several GPCRs. Both the V2R antagonists and somatostatin analogues appear to slow the decline of renal function, although with some side effects such as liver function impairment, polydipsia, and diarrhea. A combination of different growth inhibitors may enhance efficacy and reduce side effects. Additional preclinical studies in animal models include the use of inhibitors to nonreceptor tyrosine kinase Src, B-raf, cyclin-dependent kinase (CDK), transcription factors STAT3 and STAT6 (pyrimethamine and leflunomide), purinergic receptors, hepatocyte growth factor receptor, and glucosylceramide, and agonists to peroxisome proliferator activated receptor-γ (PPARγ receptors (thiazolidodinediones).


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InternalMed_Harrison. Genetic Considerations ARPKD is a significant hereditary renal disease in childhood, with an estimated prevalence of 1 in 20,000 live births. A carrier frequency of up to 1:70 has been reported. Mutations in a single gene, PKHD1, are responsible for all the clinical presentations of ARPKD. PKHD1, localized on human chromosome region 6p21.1-6p12.2, is one of the largest genes in the genome, occupies ~450 kb of DNA, and contains at least 86 exons. It produces multiple alternatively spliced transcripts. The largest transcript encodes fibrocystin/polyductin (FPC), which is a large receptor-like integral membrane protein of 4074 amino acids. FPC has a single transmembrane, a large N-terminal extracellular region, and a short intracellular cytoplasmic domain. FPC is localized on the primary cilia of epithelia cells of cortical and medullary collecting ducts and cholangiocytes of bile ducts, similar to polycystins and several other ciliopathy proteins. FPC is also expressed on the basal body


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InternalMed_Harrison. of epithelia cells of cortical and medullary collecting ducts and cholangiocytes of bile ducts, similar to polycystins and several other ciliopathy proteins. FPC is also expressed on the basal body and plasma membrane. The large extracellular domain of FPC is presumed to bind to an as yet unknown ligand(s) and is involved in cell-cell and cell-matrix interactions. FPC interacts with ADPKD protein PC2 and may also participate in regulation of the mechanosensory function of the primary cilia, calcium signaling, and PCP, suggesting a common mechanism underlying cystogenesis between ADPKD and ARPKD. FPC is also found on the centrosomes and mitotic spindle and may regulate centrosome duplication and mitotic spindle assembly during cell division. A large number of various mutations have been found throughout PKHD1 and are unique to individual families. Most patients are compound heterozygotes for PKHD1 mutations. Patients with two truncation mutations appear to have an earlier onset of the


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InternalMed_Harrison. throughout PKHD1 and are unique to individual families. Most patients are compound heterozygotes for PKHD1 mutations. Patients with two truncation mutations appear to have an earlier onset of the disease.


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InternalMed_Harrison. Clinical Features Classic ARPKD is generally diagnosed in utero or within the neonatal period and characterized by greatly enlarged echogenic kidneys in diseased fetuses. Reduced fetal urine production may contribute to oligohydramnios and pulmonary hypoplasia. About 30% of affected neonates die shortly after birth due to respiratory insufficiency. Close to 60% of mortality occurs within the first month of life. In the classic group, most patients are born with renal insufficiency and ESRD. However, infants often have a transient improvement in their GFR; death from renal insufficiency at this stage is rare. Some patients are diagnosed after the neonatal stage and form the older group. Morbidity and mortality in this group often involve systemic hypertension, progressive renal insufficiency, and liver manifestations. The hallmarks of ARPKD liver disease are biliary dysgenesis due to a primary ductal plate malformation with associated periportal fibrosis, namely congenital hepatic


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InternalMed_Harrison. and liver manifestations. The hallmarks of ARPKD liver disease are biliary dysgenesis due to a primary ductal plate malformation with associated periportal fibrosis, namely congenital hepatic fibrosis (CHF) and dilatation of intrahepatic bile ducts (Caroli’s disease). CHF and Caroli’s disease can then lead to portal hypertension exhibiting hepatosplenomegaly, variceal bleeding, and cholangitis. Some patients with the diagnosis of ARPKD at 1 year of age with nephromegaly exhibit slowly declining renal function over 20 years with only minimally enlarged kidneys at ESRD and markedly atrophic kidneys following renal transplantation. The slow progression of renal disease is likely due to increasing fibrosis rather than the development of cysts. Systemic hypertension is common in all ARPKD patients, even those with normal renal function.


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InternalMed_Harrison. Diagnosis Ultrasonography, CT, and MRI all can be used for diagnosis. Ultrasonography reveals large, echogenic kidneys with poor corticomedullary differentiation. The diagnosis can be made in utero after 24 weeks of gestation in severe cases. Macrocysts generally are not common at birth in ARPKD patients. The absence of renal cysts in either parent, particularly if they are more than 40 years of age on ultrasonography, helps distinguish ARPKD from ADPKD in older patients. Clinical, laboratory, or radiographic evidence of hepatic fibrosis, hepatic pathology demonstrating characteristic ductal plate abnormalities, family history of affected siblings, or parental consanguinity suggestive of autosomal recessive inheritance is helpful. The lack of mutational hotspots and the large and complex genomic structure of PKHD1 make molecular diagnosis difficult; however, presymptomatic screening of other at-risk members in a family with already identified ARPKD mutations is straightforward and


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InternalMed_Harrison. genomic structure of PKHD1 make molecular diagnosis difficult; however, presymptomatic screening of other at-risk members in a family with already identified ARPKD mutations is straightforward and inexpensive.


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InternalMed_Harrison. Polycystic Kidney Disease and Other Inherited Disorders of Tubule Growth and Development There is no specific therapy for ARPKD. Appropriate neonatal intensive care, blood pressure control, dialysis, and kidney transplantation increase survival into adulthood. Complications of hepatic fibrosis may necessitate liver transplantation. Patients with severe Caroli’s disease may need portosystemic shunting. Upcoming therapies may target abnormal cell signaling mechanisms, as described above for ADPKD.


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InternalMed_Harrison. Tuberous sclerosis (TS) is a rare autosomal dominant syndrome caused by mutations in one of two genes, TSC1, encoding hamartin, or, TSC2, encoding tuberin. Published estimates of prevalence vary widely, but it certainly occurs in less than 1:5000 births. Kidney cysts are a frequent feature of this condition, as are two other abnormalities of kidney growth, renal cell carcinoma and renal angiomyolipomas. TS is a syndrome affecting multiple organ systems. Other features of TS include benign growths in the nervous system, eyes, heart, lung, liver, and skin. Essentially all TS patients have associated skin lesions, and a large proportion of patients have neurologic and cognitive manifestations. The TSC2 gene is adjacent to PKD1 in the human genome. Some patients have deletions in their genomic DNA that inactivate these two genes. Such individuals may have manifestations of both ADPKD and TS.


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InternalMed_Harrison. The most common kidney finding in TS is the presence of angiomyolipomas. These growths tend to be multiple and bilateral. Although they are usually benign, they may bleed. Surgical removal is often recommended as a prophylactic measure in people with angiomyolipomas larger than 4 cm in diameter. The cysts in TS are radio-graphically similar to those seen in ADPKD. In contrast to ADPKD, there is a clearly increased risk of renal cell carcinoma in TS patients. Regular periodic imaging is recommended in TS patients with kidney involvement to screen for the development of renal cell carcinoma. Although not common, TS may lead to significant chronic kidney disease (CKD) and progress to end-stage kidney failure. Patients with TS and CKD typically have an unremarkable urine sediment and only minimal to mild amounts of proteinuria.


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InternalMed_Harrison. Mechanistically, the TSC1 and TSC2 gene products tuberin and hamartin interact physically. This protein complex is localized to the base of the cilia and inhibits intracellular signaling processes mediated by mTOR, leading to abnormal growth in a number of tissues. Investigation of mTOR inhibitors as therapy for TS is ongoing.


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InternalMed_Harrison. Von Hippel-Lindau disease (VHL) is an inherited cancer syndrome with renal manifestations. VHL is an autosomal dominant condition caused by mutations in the VHL tumor-suppressor gene. VHL is localized to the primary cilia and is necessary for the formation of primary cilia. Like many autosomal dominant cancer syndromes, VHL is recessive at the cellular level: a somatic mutation in the second VHL allele leads to loss of VHL in the cell and abnormal growth. Kidney manifestations of VHL include multiple bilateral kidney cysts and renal cell carcinomas. Kidney cysts and carcinoma affect the majority of VHL patients. Nonrenal features of VHL include pheochromocytomas, cerebellar hemangioblastomas, and retinal hemangiomas. Annual screening of the kidneys by imaging with CT or MRI is recommended for early detection of renal cell carcinomas. Increasingly, nephron-sparing surgical approaches are being used for removal of cancerous lesions in order to preserve kidney function.


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InternalMed_Harrison. ADPKD is by far the most common adult-onset, single-gene form of kidney disease. The large cysts that are sometimes seen in VHL and TS are similar in appearance to the cysts seen in ADPKD. A variety of other inherited disorders affecting primarily tubule and renal interstitial function can lead to CKD and eventual end-stage kidney disease in the absence of large tubule-derived cysts. Inherited diseases affecting the tubulointerstitial compartment of the kidney can lead to secondary glomerular stress and glomerulosclerosis with some degree of concomitant proteinuria. Similarly, disorders of glomerular function will typically lead to secondary interstitial fibrosis and tubule atrophy. From a clinical perspective, therefore, distinguishing between a genetic disease of the renal tubules and a disease of the glomerulus may not be easy, particularly in the absence of a gross phenotype such as large kidney cysts.


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InternalMed_Harrison. The medullary cystic kidney diseases (MCKD) are autosomal dominant disorders. Despite the nosology, kidney cysts are not invariably present. Older literature often grouped MCKD together with the childhood-onset disorders known as the nephronophthises, but these are distinct clinical and genetic entities. Medullary Cystic Kidney Disease Type I Patients with MCKD type I (MCKD I) have mutations in the mucin 1 gene MUC1. In contrast to MCKD type II (MCKD II) patients, individuals with MCKD I do not have elevated uric acid levels. The disease-causing MUC1 mutations that have been reported all alter a repeat region within the MUC1 gene, leading to a large “neoprotein” fragment that may lead to toxic effects on the kidney tubule.


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InternalMed_Harrison. Clinically, patients with MCKD I exhibit slowly progressive CKD in adulthood, with only minimal amounts of increased urine protein and occasional renal cysts seen on ultrasound examination. Kidney histology shows tubulointerstitial fibrosis and tubular atrophy. The mechanisms by which MUC1 mutations cause human kidney disease are not known.


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InternalMed_Harrison. Medullary Cystic Kidney Disease Type II MCKD II is caused by mutations in the UMOD gene, which encodes the protein uromodulin, also known as Tamm-Horsfall protein. Uromodulin is also found on the centrosome, the mitotic spindle, and the primary cilia; it colocalizes with nephrocystin-1 and KIF3A on the cilia. UMOD mutations also cause the conditions that have been referred to as familial juvenile hyperuricemic nephropathy (HNFJ1) and glomerulocystic kidney disease (GCKD), although it is not clear that these different names represent clearly distinct disorders. The term uromodulin-associated kidney disease (UAKD) has been suggested as a better name for MCKD II and the various other related UMOD-associated diseases. Despite the name, kidney cysts are not a common feature of MCKD II. MCKD II should be suspected clinically in patients with a family history of late-onset kidney disease, benign urine sediments, absence of significant proteinuria, and hyperuricemia. Large genome-wide


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InternalMed_Harrison. MCKD II should be suspected clinically in patients with a family history of late-onset kidney disease, benign urine sediments, absence of significant proteinuria, and hyperuricemia. Large genome-wide association studies have suggested that certain common noncoding sequence variants in UMOD are associated with a moderately increased risk of CKD in the general population.


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InternalMed_Harrison. Other Forms of Familial Tubulointerstitial Kidney Disease A small number of families have been identified with autosomal dominant tubulointerstitial kidney disease and hyperuricemia who lack UMOD mutations. Some of these families carry disease-segregating mutations in the renin gene REN. There are other families who lack mutations in UMOD, MUC1, or REN. Thus, mutations in other yet-to-be identified genes are able to produce similar interstitial kidney disease, both with and without hyperuricemia. Kidney biopsies in patients with any of the various forms of MCKD typically show interstitial fibrosis. These histologic features are not diagnostic of any particular genetic entity, and the specific diagnosis must be made by other means. Genetic tests for alterations in specific genes are increasingly available in the clinical setting.


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InternalMed_Harrison. Patients with autosomal dominant interstitial kidney disease, UMOD or REN mutations, or hyperuricemia and gout should be treated similarly to others with these findings, with uric acid–lowering agents, such allopurinol or febuxostat. A large and growing number of genetically distinct but related autosomal recessive disorders are referred to as nephronophthises. These should not be confused with the adult-onset autosomal dominant medullary cystic kidney diseases discussed above, despite the often confusing nomenclature seen in older medical literature. Nephronophthisis is quite rare but is nevertheless the most common inherited childhood form of kidney failure requiring kidney replacement therapy.


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InternalMed_Harrison. Like ADPKD and ARPKD, the various genetically heterogeneous entities that fall under the category of nephronophthisis (NPHP) are disorders of ciliary function. Mutations in a very large number of genes have been identified that lead to NPHP under an autosomal recessive pattern of inheritance. The various forms of NPHP share common features, including tubulointerstitial fibrosis, corticomedullary cysts, and progressive CKD, leading to renal failure. Proteinuria is absent or mild, and the urine sediment is not active.


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InternalMed_Harrison. NPHP is often divided into infantile, juvenile, and adolescent forms. The juvenile form is the most frequent and usually caused by mutations in the NPHP2 gene. The infantile form, usually caused by NPHP2 mutations, is associated with end-stage kidney failure in early childhood. Patients with the adolescent form of NPHP typically develop end-stage kidney failure in early adulthood. The products of the NPHP genes are referred to as nephrocystins. NPHP1 through NPHP16 have been reported; some are referred to by other names as well.


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InternalMed_Harrison. NPHP can present as an isolated finding or be part of several multiorgan syndromes. Neurologic abnormalities are present in a significant number of patients. Bone and liver abnormities are seen in some NPHP patients. Senior-Løken syndrome is defined by the presence of NPHP with retinitis pigmentosa. Joubert’s syndrome is defined by multiple neurologic findings, including hypoplasia of the cerebellar vermis. Some forms of this genetically heterogeneous syndrome include NPHP as a component.


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InternalMed_Harrison. The multisystem disease Bardet-Biedl syndrome (BBS) is defined clinically by a spectrum of features, including truncal obesity, cognitive impairment, retinal dystrophy, polydactyly, developmental urogenital abnormalities, and kidney cysts. The kidney phenotype is NPHP-like, with small cysts deriving from the tubules, tubulointerstitial and often secondary glomerular disease, and urine concentrating defects. There are 18 BBS genes cloned. BBS follows autosomal recessive inheritance. Like ADPKD, ARPKD, and NPHP, BBS is a disease of abnormal ciliary function. The multiple genes and gene products (nephrocystins) that are responsible for NPHP are expressed in cilia, basal bodies, and the centrosomes of kidney tubule cells. It has been hypothesized that all of the NPHP gene defects lead to a clinical phenotype by interfering with the regulation of PCP.


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InternalMed_Harrison. There are no specific clinical tests that define NPHP. Genetic diagnosis is possible but cumbersome because of the large number of genes that can be responsible. There are no specific therapies for NPHP. Rather, therapy is aimed at treating signs of these diseases as well as the systemic abnormalities seen with all CKDs. Chronic dialysis or kidney transplantation is eventually required for NPHP-affected individuals.


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InternalMed_Harrison. Karyomegalic tubulointerstitial nephritis is an exceptionally rare form of kidney disease with adult-onset progressive kidney failure. Kidney biopsy shows chronic tubulointerstitial nephritis, as well as interstitial fibrosis. This is a recessive disorder caused by inheritance of two mutant copies of the FAN1 gene. FAN1 encodes a component of a DNA repair machinery complex. Individuals with two mutant FAN1 genes are genetically sensitized to the effect of DNA damage. Kidney histology shows karyomegaly in addition to the nonspecific findings of interstitial fibrosis and tubular atrophy. Medullary sponge kidney (MSK) is often grouped together with inherited disorders of the kidney affecting tubule growth and development, although it is usually a sporadic finding rather than an inherited phenotype. MSK is caused by developmental malformation and cystic 1855 dilatation of the renal collecting ducts. The medullary cysts seen in this entity can be quite variable in size.


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InternalMed_Harrison. MSK is usually a benign entity. The diagnosis of MSK is often made incidentally. In the past, the diagnosis of MSK was often made by intravenous pyelography (IVP). CT scans, which have replaced IVPs for much routine kidney imaging, are not as sensitive in detecting MSK. MSK is associated with an increased frequency of calcium phosphate and calcium oxalate kidney stones. Altered flow characteristics in the kidney tubules may lead to the development of formation of a nidus for stone formation. Kidney stones in this group are treated the same as are kidney stones in the general population. MSK patients also often exhibit reduced kidney concentrating ability and an increased frequency of urinary tract infections.


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InternalMed_Harrison. The structural abnormalities known as the congenital abnormalities of the kidney and urinary tract (CAKUTs) are a group of etiologically and phenotypically heterogeneous disorders. Some form of CAKUT is estimated to occur in up to 1 in 500 live births. Specific abnormalities classified as part of the CAKUT spectrum include kidney hypoplasia, kidney agenesis, ureteropelvic junction obstruction, and vesicoureteral reflux. CAKUT can be the cause of clinically significant problems in both adults and children. However, it is a major contributor to kidney failure in children, accounting for more than one-third of end-stage kidney disease in this group.


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InternalMed_Harrison. CAKUT is typically a sporadic finding but can also cluster in families. Familial forms can be observed as parts of multisystem developmental syndromes. A growing list of specific genes have been identified, which when mutated lead to syndromic forms of CAKUT. For example, the branchio-oto-renal syndrome, characterized by developmental abnormalities in the neck, ears, and kidney, can be caused by mutations in the EYA1 and SIX1 genes. Mutations in the PAX2 transcription factor gene can cause the autosomal dominant renal coloboma syndrome, characterized by optic nerve malformations and hypoplastic kidneys. In many instances, CAKUT is caused by environmental influences rather than genetic alterations. For example, renal tubular dysgenesis, defined by altered tubule development, can be caused by prenatal exposure to angiotensin-converting enzyme inhibitors or angiotensin receptor blockers.


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InternalMed_Harrison. Inherited disorders of the mitochondrial genome (discussed elsewhere in this text [Chap. 85e]) commonly affect kidney function. Thirteen of the genes involved in encoding components of the mitochondrial respiratory chain are located on the mitochondrial genome that is inherited maternally. The remainder of these components is encoded by the nuclear genome. These defects of oxidative phosphorylation may affect multiple organs and tissues.


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InternalMed_Harrison. Neuromuscular disease is the best recognized part of this complex phenotype. Kidney disease is now recognized as a common component as well. Tubulointerstitial disease may be seen on kidney biopsy, and progression to kidney failure may occur. Glomerular involvement, manifest as proteinuria and glomerulosclerosis, can also develop. Changes in proximal tubule activity are the most common renal phenotype. Patients may have several defects in proximal tubule transport, including the Fanconi syndrome. Some patients may also have acidosis, hypophosphatemic rickets, hypercalciuria, glycosuria, and tubular proteinuria. Decreased urine concentrating ability is common. The disorders discussed above are all seen worldwide. In addition, a previously unrecognized epidemic of kidney disease is leading to very high rates of kidney failure in and near the


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InternalMed_Harrison. Polycystic Kidney Disease and Other Inherited Disorders of Tubule Growth and Development may be involved as well. tubulointerstitial Diseases of the Kidney Laurence H. Beck, David J. Salant Inflammation or fibrosis of the renal interstitium and atrophy of the tubular compartment are common consequences of diseases that 340Disorders of the Kidney and Urinary Tract 1856 western coast of Central America. This Mesoamerican nephropathy is particularly common in Nicaragua and El Salvador. Mesoamerican nephropathy patients do not have significant proteinuria, suggesting that this is a disease of the kidney tubules and interstitium. The cause is unknown, but some have suggested that a combination of toxic environmental factors and heat stress underlies the development of this kidney disease, which has a striking male predominance. However, the fact that, in many families, a large fraction of the men are affected with kidney disease has suggested that a strong genetic component target the


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InternalMed_Harrison. which has a striking male predominance. However, the fact that, in many families, a large fraction of the men are affected with kidney disease has suggested that a strong genetic component target the glomeruli or vasculature. Distinct from these secondary phenomena, however, are a group of disorders that primarily affect the tubules and interstitium, with relative sparing of the glomeruli and renal vessels. Such disorders are conveniently divided into acute and chronic tubulointerstitial nephritis (TIN) (Table 340-1).


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InternalMed_Harrison. Acute TIN most often presents with acute renal failure (Chap. 334). The acute nature of this group of disorders may be caused by aggressive inflammatory infiltrates that lead to tissue edema, tubular cell injury, and compromised tubular flow, or by frank obstruction of the tubules with casts, cellular debris, or crystals. There is sometimes flank pain due to distention of the renal capsule. Urinary sediment is often active with leukocytes and cellular casts, but depends on the exact nature of the disorder in question.


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InternalMed_Harrison. The clinical features of chronic TIN are more indolent and may manifest with disorders of tubular function, including polyuria from impaired concentrating ability (nephrogenic diabetes insipidus), defective proximal tubular reabsorption leading to features of Fanconi’s syndrome (glycosuria, phosphaturia, aminoaciduria, hypokalemia, and type II renal tubular acidosis [RTA] from bicarbonaturia), or non-anion-gap metabolic acidosis and hyperkalemia (type IV RTA) due to impaired ammoniagenesis, as well as progressive azotemia (rising creatinine and blood urea nitrogen [BUN]). There is often modest proteinuria (rarely >2 g/d) attributable to decreased tubular reabsorption of filtered proteins; however, nephrotic-range albuminuria may occur in some conditions due to the development of secondary focal segmental glomerulosclerosis (FSGS). Renal ultrasonography may reveal changes of “medical renal disease,” such as increased echogenicity of the renal parenchyma with loss of corticomedullary


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InternalMed_Harrison. focal segmental glomerulosclerosis (FSGS). Renal ultrasonography may reveal changes of “medical renal disease,” such as increased echogenicity of the renal parenchyma with loss of corticomedullary differentiation, prominence of the renal pyramids, and cortical scarring in some conditions. The predominant pathology in chronic TIN is interstitial fibrosis with patchy mononuclear cell infiltration and widespread tubular atrophy, luminal dilation, and thickening of tubular basement membranes. Because of the nonspecific nature of the histopathology, biopsy specimens rarely provide a specific diagnosis. Thus, diagnosis relies on careful analysis of history, drug or toxin exposure, associated symptoms, and imaging studies.


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InternalMed_Harrison. In 1897, Councilman reported on eight cases of acute interstitial nephritis (AIN) in the Medical and Surgical Reports of the Boston City Hospital; three as a postinfectious complication of scarlet fever and two from diphtheria. Later, he described the lesion as “an acute inflammation of the kidney characterized by cellular and fluid exudation in the interstitial tissue, accompanied by, but not dependant on, degeneration (β-lactams, sulfonamides, quinolones, vancomycin, erythromycin, linezolid, minocycline, rifampin, ethambutol, acyclovir) anti-inflammatory drugs, COX-2 inhibitors (rarely thiazides, loop diuretics, triamterene) (phenytoin, valproate, carbamazepine, phenobarbital) (proton pump inhibitors, H2 blockers, captopril, mesalazine, indinavir, allopurinol, lenalidomide) (Streptococcus, Staphylococcus, Legionella, Salmonella, Brucella, Yersinia, Corynebacterium diphtheriae) (EBV, CMV, hantavirus, polyomavirus, HIV) (Leptospira, Rickettsia, Mycoplasma, Histoplasma) nephritis with


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InternalMed_Harrison. Staphylococcus, Legionella, Salmonella, Brucella, Yersinia, Corynebacterium diphtheriae) (EBV, CMV, hantavirus, polyomavirus, HIV) (Leptospira, Rickettsia, Mycoplasma, Histoplasma) nephritis with uveitis (TINU) exposure to toxins or therapeutic agents • Analgesics, metals (lead, cadmium) inhibitors (cyclosporine, tacrolimus) (see Chap. 339) Cystic and Hereditary Disorders (see Chap. 339)