Other Cystic Kidney Diseases

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Other Cystic Kidney Diseases Lisa M. Guay-Woodford

In addition to autosomal dominant polycystic kidney disease (ADPKD), there are numerous other disorders that share renal cysts as a common feature (Fig. 45.1).1 These disorders may be inherited or acquired; their manifestations may be confined to the kidney or expressed systemically. They may present at a wide range of ages, from the perinatal period to old age (Fig. 45.2). The renal cysts may be single or multiple, and the associated renal morbidity may range from clinical insignificance to progressive parenchymal destruction with resultant renal impairment. The clinical context often helps distinguish these renal cystic disorders from one another. Echogenic, enlarged kidneys in a neonate or infant should raise suspicion about autosomal recessive polycystic kidney disease (ARPKD), ADPKD, tuberous sclerosis complex, or one of the many congenital syndromes associated with renal cystic disease. Renal impairment in an adolescent suggests juvenile nephronophthisis–medullary cystic disease complex and ARPKD as possible causes. The finding of a solitary cyst in a 5-year-old may indicate a calyceal diverticulum, whereas this finding in a 50-year-old is most compatible with a simple renal cyst. Renal stones occur in ADPKD and medullary sponge kidneys. For those disorders with systemic manifestations, such as ADPKD, tuberous sclerosis complex, and von Hippel–Lindau disease, the associated extrarenal features may provide other important differential diagnostic clues. For an increasing number of conditions, genetic testing is available in expert laboratories around the world. These are listed at http://www.genetests.org.

AUTOSOMAL RECESSIVE POLYCYSTIC KIDNEY DISEASE Definition ARPKD is an inherited malformation complex with varying degrees of renal collecting duct dilation, biliary ductal ectasia, and associated fibrosis.2

Genetic Basis of ARPKD All typical forms of ARPKD are caused by mutations in a single gene, PKHD1 (polycystic kidney and hepatic disease), which encodes multiple alternatively spliced isoforms predicted to form both membrane-bound and secreted proteins.3 The largest protein product of PKHD1, termed fibrocystin/polyductin complex (FPC), contains one membrane spanning domain and an intracellular C-terminal tail. FPC localizes, at least in part, to the primary cilium and the centrosome in renal epithelial cells.4

The basic defects observed in ARPKD suggest that FPC mediates the terminal differentiation of the collecting duct and biliary tract. However, the exact function of the numerous isoforms has not been defined, and the widely varying clinical spectrum of ARPKD may depend, in part, on the nature and number of splice variants that are disrupted by specific PKHD1 mutations.

Pathogenesis ARPKD typically begins in utero, and the renal cystic lesion appears to be superimposed on a normal developmental sequence. The tubular abnormality primarily involves fusiform dilation of the collecting ducts. Detailed microdissection studies have excluded tubular obstruction as a primary pathogenic mechanism. The biliary lesion appears to involve defective remodeling of the ductal plate in utero. As a result, primitive bile duct configurations persist and progressive portal fibrosis evolves.5 The remainder of the liver parenchyma develops normally. The defect in ductal plate remodeling is accompanied by abnormalities in the branching of the portal vein. The resulting histopathologic pattern is referred to as congenital hepatic fibrosis. The primary cilium plays a central role in the pathogenesis of hepatorenal fibrocystic diseases.6 The weight of the experimental evidence from human ARPKD and animal model studies suggests that ciliary dysfunction contributes to a maturational arrest in both renal and biliary tubuloepithelial differentiation.

Epidemiology The estimated incidence of ARPKD is 1 per 20,000 live births.7 It occurs more frequently in Caucasians than in other ethnic populations.

Clinical Manifestations The clinical spectrum of ARPKD is variable and depends on the age at presentation. The majority of cases are identified either in utero or at birth. The most severely affected fetuses have enlarged echogenic kidneys and oligohydramnios due to poor fetal urine output. These fetuses develop the Potter phenotype, with pulmonary hypoplasia, a characteristic facies, and deformities of the spine and limbs. At birth, these neonates often have a critical degree of pulmonary hypoplasia that is incompatible with survival. The estimated perinatal mortality is about 30%. Renal function, although frequently compromised, is rarely a cause of neonatal death. For those who survive the first month of life, the reported mean 5-year patient survival rate is 85% to 90%.2,8 Morbidity 543

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Renal Cystic Disorders MIM1

Renal Cystic Disorder Nongenetic

Developmental Medullary sponge kidney Renal cystic dysplasia Multicystic dysplasia Cystic dysplasia associated with lower urinary tract obstruction Diffuse cystic dysplasia—syndromal and nonsyndromal Acquired Simple cysts Solitary multiocular cysts Hypokalemic cystic disease Acquired cystic disease (in advanced renal failure) Genetic Autosomal dominant Autosomal dominant polycystic kidney disease Adult-onset medullary cystic disease Tuberous sclerosis von Hippel–Lindau syndrome Autosomal recessive Autosomal recessive polycystic kidney disease Juvenile nephronophthisis

601313; 173910 174000; 603860 191092: 605284 193300 263200 256100; 602088; 604387; 606966; 609254; 610142; 611498; 610937; 609799 249000; 603194; 607361; 611134; 611561; 612284

Meckel-Gruber syndrome

X-linked Orofaciodigital syndrome type I

311200

Figure 45.1  Renal cystic disorders.1 Mendelian Inheritance in Man (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM).

nt s ul

ts

ce Ad

es ol Ad

Autosomal dominant polycystic kidney disease (ADPKD)

N

eo

na

te s In f ch an ild ts re / n

Age Distribution of Renal Cystic Disorders

Autosomal recessive polycystic kidney disease (ARPKD) Nephronophthisis (NPHP) Medullary sponge kidney (MSK) Tuberous sclerosis complex (TSC) von Hippel–Lindau disease (VHL) Simple cysts

Figure 45.2  Age distribution of renal cystic disorders.

and mortality result from severe systemic hypertension, renal impairment, and portal hypertension due to portal tract hyperplasia and fibrosis.2,8,9 Hypertension usually develops in the first few months and ultimately affects 70% to 80% of patients. ARPKD patients have defects in both urinary diluting capacity and concentrating capacity. Newborns can have hyponatremia.

Whereas net acid excretion may be reduced, metabolic acidosis is not a significant clinical feature. Abnormal urinalysis is common in both infants and older children.2 Microscopic or gross hematuria, proteinuria, and sterile pyuria have all been reported. Two retrospective studies have noted an increased incidence of culture-confirmed urinary tract infections. In the first 6 months of life, ARPKD infants may have a transient improvement in glomerular filtration rate (GFR) due to renal maturation. Subsequently, a progressive but variable decline in renal function occurs, with some patients not progressing to end-stage renal disease (ESRD) until adolescence or early adulthood. With advances in effective therapy for ESRD, prolonged survival is common, and the hepatic complications become the dominant clinical issue for many patients. On average, those infants with serum creatinine values above 2.2 mg/dl (200 µmol/l) progress to ESRD within 5 years, but this is highly variable. In longitudinal studies, the probability of renal survival without ESRD is ~85% at 1 year, ~70% at 10 years, ~65% at 15 years, and ~40% at 20 years.8,9 In children who present later in childhood or in adolescence, portal hypertension is frequently the predominant clinical abnormality, with hepatosplenomegaly and bleeding esophageal or gastric varices as well as hypersplenism with consequent thrombocytopenia, anemia, and leukopenia. Hepatocellular function is usually preserved. Ascending suppurative cholangitis is a serious complication and can cause fulminant hepatic failure.10

Pathology Kidney The renal involvement is invariably bilateral and largely symmetric. The histopathology varies according to the age at presentation and the extent of cystic involvement (Fig. 45.3A, B). In the affected neonate, the kidneys can be 10 times normal size but retain their reniform configuration. Dilated, fusiform collecting ducts extend radially through the cortex. In the medulla, the dilated collecting ducts are more often cut tangentially or transversely. Up to 90% of the collecting ducts are involved. Associated interstitial fibrosis is minimal in neonates and infants but increases with progressive disease. In patients diagnosed later in childhood, the kidney size and extent of cystic involvement tend to be more limited. Cysts can expand up to 2 cm in diameter and assume a more spherical configuration. Progressive interstitial fibrosis is probably responsible for secondary tubular obstruction. In older children, medullary ductal ectasia is the predominant finding. Cysts are lined with a single layer of nondescript cuboidal epithelium. The glomeruli and nephron segments proximal to the collecting ducts are initially structurally normal but are often crowded between ectatic collecting ducts or displaced into subcapsular wedges. The presence of cartilage or other dysplastic elements indicates a diagnosis other than ARPKD, such as cystic dysplasia. Liver The liver lesion in ARPKD is characterized by ductal plate malformation.5 The liver can be either normal in size or somewhat enlarged. Bile ducts are dilated (biliary ectasia), and marked cystic dilation of the entire intrahepatic biliary system (Caroli’s disease) has been described. In neonatal ARPKD, the bile ducts are increased in number, tortuous in configuration, and often located around the periphery of the portal tract. In older children, the biliary ectasia is accompanied by increasing portal tract



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C

B

Figure 45.3  Pathologic features of ARPKD. A, Cut section: ARPKD kidney from 1-year-old child reveals discrete medullary cysts and dilated collecting ducts. B, Light microscopy: later-onset ARPKD kidney with prominent medullary ductal ectasia. (Hematoxylin and eosin; magnification ×10.) C, Light microscopy: congenital hepatic fibrosis. There is extensive fibrosis of the portal area with ectatic, tortuous bile ducts and hypoplasia of the portal vein. (Hematoxylin and eosin; magnification ×40.)

fibrosis and hypoplasia of the small portal vein branches (Fig. 45.3C). The hepatic parenchyma may be intersected by delicate fibrous septa that link the portal tracts, but the hepatocytes themselves are seldom affected.

Diagnosis ARPKD must be differentiated from a range of other pediatric renal cystic disorders (Fig. 45.4). Imaging In the past decade, clinical diagnosis has increasingly relied on imaging instead of histopathologic analysis. ARPKD belongs to a group of disorders described as hepatorenal fibrocystic diseases.11 Whereas most of these disorders are characterized by large, echogenic kidneys in the fetus and neonate, studies indicate that to a large extent they can be distinguished by ultrasound.12 ARPKD kidneys in utero are hyperechogenic and display decreased corticomedullary differentiation because of the hyperechogenic medulla (Fig. 45.5A). With high-resolution ultrasound, the radial array of dilated collecting ducts may be imaged. In comparison, ADPKD kidneys in utero tend to be moderately enlarged with a hyperechogenic cortex and relatively hypoechogenic medulla, causing increased corticomedullary differentiation. Kidney size typically peaks at 1 to 2 years of age, then gradually declines relative to the child’s body size and stabilizes by 4 to 5 years. As patients age, there is increased medullary echogenicity with scattered small cysts, measuring less than 2  cm in diameter. These cysts and progressive fibrosis can alter the reniform contour, causing ARPKD in some older children to be mistaken for ADPKD. Contrast-enhanced computed tomography (CT) can be useful in delineating the renal architecture in these children (Fig. 45.5B). Bilateral pelvicaliectasis and renal calcifications have been reported in 25% and 50% of ARPKD patients, respectively.9,13 In adults with medullary ectasia alone, the cystic lesion may be confused with medullary sponge kidney. The liver may be either normal in size or enlarged. It is usually less echogenic than the kidneys. Prominent intrahepatic bile duct dilation suggests associated Caroli’s disease. With age, the portal fibrosis tends to progress, and in older children, ultrasound typically shows hepatosplenomegaly and a patchy increase in hepatic echogenicity.

Genetic Testing With the identification of PKHD1 as the principal disease gene in ARPKD, genetic testing is available as a clinical diagnostic tool. The mutation detection rate is 80% to 87%. Current diagnostic algorithms include gene-based analysis and haplotype-based genotyping in informative families (http:// www.genetests.org/). Genetic testing is primarily applied in the context of prenatal testing14 and preimplantation genetic diagnosis.15 To date, there is limited evidence for genotype-phenotype correlations, although patients with two truncating mutations have a higher risk of perinatal demise.16,17 There is a high percentage of unique, missense changes in PKHD1, which can complicate the unequivocal interpretation of gene-based testing. Moreover, about 20% of ARPKD siblings have discordant clinical phenotypes.8 These data potentially complicate genetic counseling, and caution must be exercised in predicting the clinical outcome of future affected children.

Treatment The survival of ARPKD neonates has improved significantly in the last two decades because of advances in mechanical ventilation for neonates and other supportive measures. Aggressive interventions, such as unilateral or bilateral nephrectomies and continuous hemofiltration, have been advocated in neonatal management, but prospective, controlled studies have yet to be performed. For those children who survive the perinatal period, careful blood pressure monitoring is required. Angiotensin-converting enzyme (ACE) inhibitors, calcium channel blockers, β-blockers, and loop diuretics are effective antihypertensive agents. The management of ARPKD children with declining GFR should follow the standard guidelines established for chronic kidney disease (CKD) in children.18 Given the relative urinary concentrating defect, ARPKD children should be monitored for dehydration during intercurrent illnesses associated with fever, tachypnea, nausea, vomiting, or diarrhea. In those infants with severe polyuria, thiazide diuretics may be used to decrease distal nephron solute and water delivery. Acid-base balance should be closely monitored and supplemental bicarbonate therapy initiated as needed. Close monitoring for portal hypertension is warranted in all ARPKD patients. The severity of portal hypertension and its progression can be followed by serial ultrasound and Doppler flow studies. Hematemesis or melena suggests the presence of

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Clinical Characteristics of Pediatric Renal Cystic Disease ARPKD

Meckel-Gruber1

NPHP

ADPKD

TSC

Infancy, older children

Infancy3,

Infancy3, older children

Clinical onset (years)

Perinatal

NPHP2: 0–5 NPHP: 10–18

Enlarged kidneys

Yes

NPHP2: yes Yes NPHP3: some cases NPHP: no

No

Occurs

Occurs

Renal pathology

Multiple cysts

NPHP2: multiple cysts NPHP: few cysts at C-M junction

Multiple cysts

Multiple cortical cysts

Multiple cysts

Few to multiple cysts; angiomyolipoma

Cyst infection

Uncommon

No

Uncommon

No

Occurs

Uncommon

BP

Normal/increased NPHP2: increased NPHP: normal

Normal

Normal/ increased

Normal/ increased

Normal/ increased

Renal function

Normal/impaired

Normal/impaired

Normal/impaired

Normal

Normal

Normal

Nephrocalcinosis/ nephrolithiasis

Nephrocalcinosis up to 25%

No

No

No

Nephrolithiases occur

No

CHF

Yes

Rare

Yes

No

10%–15%infantile No ADPKD

Pancreas lesions

No

No

No

MODY5

No

No

Encephalocele; mental retardation

No

No

Seizures, mental retardation

CNS involvement

No

4

(Joubert)

Perinatal infancy

GCKD2

older children

Genetics of Pediatric Renal Cystic Disease Disease gene

PKHD1

NPHP1-NPHP4

MSK1-MSK6

PKD1 TCF2

PKD1 PKD2

TSC1 TSC2

Genetic testing5

Yes

Yes

No

Yes

Yes

Yes

Figure 45.4  Features of pediatric renal cystic disease.1 Meckel-Gruber syndrome is a severe, often lethal, autosomal recessive disorder characterized by bilateral renal cystic dysplasia, biliary ductal dysgenesis, bilateral postaxial polydactyly, and variable central nervous system malformations. The triad of renal cystic disease, occipital encephalocele, and polydactyly is most common. 2Glomerulocystic kidney disease (GCKD) can occur as the infantile manifestation of ADPKD. Familial hypoplastic GCKD, due to mutations in TCF2, the gene encoding hepatocyte nuclear factor 1β, can be associated with maturity-onset diabetes of the young, type 5 (MODY5). 3A contiguous germline deletion of both the PKD1 and TSC2 genes (the PKTS contiguous gene syndrome) occurs in a small group of patients with features of TSC as well as massive renal cystic disease reminiscent of ADPKD, severe hypertension, and a progressive decline in renal function with the onset of ESRD in the second or third decade of life. 4Joubert syndrome (JBTS; MIM 213300) is a genetically heterogeneous (JBTS1-7), autosomal recessive disorder characterized by developmental defects in the cerebellum (cerebellar vermis aplasia) and the eye (coloboma) as well as retinitis pigmentosa, congenital hypotonia, and either ocular motor apraxia or irregularities in breathing patterns during the neonatal period. The disease can be associated with NPHP, and mutations in NPHP1 have been described in a small subset of patients (JBTS4). Disease genes have been identified for JBTS3 and JBTS5-7. 5Listed at GeneTests (http://www.genetests.org). ADPKD, autosomal dominant polycystic kidney disease; ARPKD, autosomal recessive polycystic kidney disease; BP, blood pressure; CHF, congestive heart failure; CNS, central nervous system; NPHP, nephronophthisis; TSC, tuberous sclerosis complex.

A

B

Figure 45.5  Radiologic findings associated with ARPKD. A, ARPKD in a neonate. High-resolution ultrasound reveals radially arrayed dilated collecting ducts. B, ARPKD in a symptomatic 4-year-old girl. Contrast-enhanced CT shows a striated nephrogram and prolonged corticomedullary differentiation.



esophageal varices. Medical management may include sclerotherapy, variceal banding, or transjugular intrahepatic porto­ systemic shunt. Surgical approaches, such as portocaval or splenorenal shunting, may be indicated in some patients. Although hypersplenism occurs fairly commonly, splenectomy is seldom warranted. Unexplained fever with or without elevated transaminase levels suggests bacterial cholangitis and requires meticulous evaluation, sometimes including a percutaneous liver biopsy, to make the diagnosis and to guide aggressive antibiotic therapy. Effective management of systemic and portal hypertension, coupled with successful renal replacement therapy, has allowed long-term patient survival. Therefore, the prognosis in ARPKD, particularly for those children who survive the first month of life, is far less bleak than popularly thought, and aggressive medical therapy is warranted.

Transplantation A prolonged period of dialysis in childhood has been associated with both cognitive and educational impairment. Therefore, renal transplantation is the treatment of choice for ESRD in ARPKD patients, and at least one report advocates preemptive nephrectomy in neonates with markedly enlarged kidneys.19 Because ARPKD is a recessive disorder, either parent may be a suitable kidney donor. Native nephrectomies may be warranted in patients with massively enlarged kidneys to allow allograft placement. In some patients, combined kidney-liver transplantation is appropriate.20 Indications include the combination of renal failure and either recurrent cholangitis or significant complications of portal hypertension (e.g., recurrent variceal bleeding, refractory ascites, and the hepatopulmonary syndrome). In addition, liver transplantation may be a reasonable option for patients with a single episode of cholangitis in the context of marked abnormalities in the biliary system (Caroli’s syndrome).21

JUVENILE NEPHRONOPHTHISIS–MEDULLARY CYSTIC DISEASE COMPLEX Definitions Juvenile nephronophthisis (NPHP) and medullary cystic kidney disease share the same triad of histopathologic features: tubular basement membrane irregularities, tubular atrophy with cyst formation, and interstitial cell infiltration with fibrosis. These histopathologically similar disorders differ only in their mode of transmission, age at onset, and genetic defects. Juvenile NPHP is an autosomal recessive disorder that presents in childhood. Medullary cystic disease is an autosomal dominant disorder that occurs in adults. The inclusive term juvenile nephronophthisis– medullary cystic disease complex has been used to describe these disorders. However, juvenile NPHP is far more common than medullary cystic disease and has been reported both as an isolated renal disease and in association with retinitis pigmentosa, congenital hepatic fibrosis, oculomotor apraxia, and skeletal anomalies. Therefore, these entities are considered separately.

Autosomal Recessive Juvenile Nephronophthisis Genetic Basis of Nephronophthisis Nine genes (NPHP1-NPHP9) involved in juvenile NPHP have been identified.22 Defects in NPHP1 account for 21% of NPHP,

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with large, homozygous deletions detected in 80% of affected family members and in 65% of sporadic cases. Mutations in each of the remaining NPHP genes cause no more than 3% of NPHP-related disease. Clinical disease expression seems to be exacerbated by oligogenic inheritance, that is, patients carrying two mutations in a single NPHP gene as well as a single-copy mutation in an additional NPHP gene. In addition, multiple allelism, or distinct mutations in a single gene, appears to explain the continuum of multiorgan phenotypic abnormalities observed in NPHP, Meckel syndrome, and Joubert syndrome. The NPHP1 and NPHP3-5 genes encode novel cytosolic proteins that are collectively called the nephrocystins. The NPHP2 gene, involved in infantile NPHP, encodes inversin, a protein that localizes in a cell cycle–dependent manner to different subcellular locations. When it is expressed at the basal body of the primary cilium, inversin has been shown to regulate the Wnt signaling pathway. The gene products encoded by NPHP6/ CEP290, NPHP8/RPGRIP1L, and NPHP9/NEK8 are all expressed in or at the base of primary cilia in renal epithelial cells. The NPHP7/GLIS2 gene encodes the transcription factor Glisimilar protein 2, thus implicating the hedgehog signaling pathway in the pathogenesis of renal cystic diseases. All of the proteins encoded by NPHP1-9 are expressed in or at the base of primary cilia in renal epithelial cells, giving rise to a unifying theory that defines cystic kidney diseases as “ciliopathies.”22 However, the subcellular localization of these proteins is not confined to the cilium. For example, nephrocystin and nephrocystin 4 have also been localized to cell junctions and shown to interact with components of cell-cell and cell-matrix interaction complexes. These observations suggest that NPHP proteins may have multiple functions, depending on their localization in different cell compartments and their association with distinct protein complexes. Clinical Manifestations Renal Disease  NPHP accounts for 5% to 15% of ESRD in children and adolescents. Three distinct forms of the disease (infantile, juvenile, and adolescent) have been described on the basis of the age at onset of ESRD. However, further clinical, pathologic, and genetic analyses indicate that the adolescent and juvenile forms are virtually indistinguishable and should be described with the single designation juvenile NPHP.23 In juvenile NPHP (the most common form), ESRD occurs at a mean age of 13 years; in the infantile form, the onset of ESRD consistently occurs before 5 years of age. Decreased urinary concentrating capacity is invariable in NPHP and usually precedes the decline in renal function, with onset between 4 and 6 years of age. Polyuria and polydipsia are common. Salt wasting develops in most patients with renal impairment, and sodium supplementation is often required until the onset of ESRD. One third of patients become anemic before the onset of renal impairment, and this has been attributed to a defect in the functional regulation of erythropoietin production by peritubular fibroblasts.24 Growth retardation, out of proportion to the degree of renal impairment, is a common finding. Slowly progressive decline in renal function is typical of juvenile NPHP. Whereas symptoms can be detected after the age of 2 years, they may progress insidiously, such that 15% of affected patients are recognized only after ESRD has developed. There is no specific treatment. The disease is not known to recur in renal allografts. Children with the infantile variant develop symptoms in the first few months of life and rapidly progress to ESRD, usually

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before the age of 2 years but invariably by 5 years of age. Severe hypertension is common in this disorder. This disorder is a distinct genetic entity with a characteristic renal histopathology and has not been reported in sibships with classic juvenile NPHP.25 Unlike patients with polycystic kidney disease or medullary sponge kidney, NPHP patients rarely develop flank pain, hematuria, hypertension, urinary tract infections, or renal calculi. Associated Extrarenal Abnormalities  Extrarenal abnormalities have been described in approximately 10% to 15% of juvenile NPHP patients.23 The most frequently associated anomaly is retinal dystrophy due to tapetoretinal degeneration (SeniorLoken syndrome). Severely affected patients present with coarse nystagmus, early blindness, and a flat electroretinogram (Leber amaurosis); those with moderate retinal dystrophy typically have mild visual impairment and retinitis pigmentosa. Other extra­ renal anomalies include oculomotor apraxia (Cogan syndrome), cerebellar vermis aplasia (Joubert syndrome), and cone-shaped epiphyses of the bones. Congenital hepatic fibrosis occurs occasionally in NPHP patients, but the associated bile duct proliferation is mild and qualitatively different from that found in ARPKD. Pathology In juvenile NPHP, the kidneys are moderately contracted with parenchymal atrophy, causing a loss of corticomedullary demarcation. Histopathologic findings include tubular atrophy with thickened tubular basement membrane, diffuse and severe interstitial fibrosis, and cysts of variable size distributed in an irregular pattern at the corticomedullary junction and in the outer medulla. However, up to 25% of NPHP kidneys have no grossly visible cysts. In the typical NPHP renal lesion, clusters of atrophic tubules alternate either with groups of viable tubules showing dilation or with marked compensatory hypertrophy or with groups of collapsed tubules. Multilayered thickening of tubular basement membranes is a prominent histopathologic feature (Fig. 45.6). Whereas this histopathologic pattern is not unique, the abrupt transition from one type of tubular profile to another is suggestive of NPHP. Moderate interstitial fibrosis, usually without a significant inflammatory cell infiltrate, is interspersed among the atrophic tubules. Spherical, thin-walled cysts lined with a simple

Figure 45.6  Renal pathology in juvenile nephronophthisis. Light microscopy: tubulointerstitial nephropathy. Atrophic tubules with irregularly thickened basement membranes are surrounded by interstitial  fibrosis. Dilated tubules are evident at the corticomedullary junction. (Hematoxylin and eosin; magnification ×40.)

cuboidal epithelium may be evident at the corticomedullary junction, in the medulla, and even in the papillae. Microdissection studies indicate that these cysts arise from the loop of Henle, distal convoluted tubules, and collecting ducts. Glomeruli may be normal, although some may be completely sclerosed; others may show periglomerular fibrosis, and still others dilation of Bowman’s space. In comparison, the infantile form has features of both juvenile NPHP (such as tubular cell atrophy, interstitial fibrosis, and tubular cysts) and polycystic kidney disease, including enlarged kidneys and widespread cystic involvement.26 Diagnosis and Differential Diagnosis In a child with NPHP and renal impairment, ultrasound reveals normal-sized or small kidneys with increased echogenicity and loss of corticomedullary differentiation. On occasion, cysts can be detected at the corticomedullary junction or in the medulla. Thin-section CT scanning may be more sensitive than ultrasound in detecting these cysts. The pathologic findings in NPHP are not unique; hence, in the early stages of the disease, neither renal imaging nor histopathology can confirm the clinical diagnosis. As an alternative strategy, molecular testing has become increasingly useful in establishing the diagnosis of NPHP, with use of an algorithm for gene-based diagnosis27 that addresses four critical diagnostic issues: (1) detection of the classic homozygous deletion of NPHP1; (2) detection of rare, smaller homozygous deletions of NPHP1; (3) testing for a heterozygous deletion; and (4) potential exclusion of linkage to NPHP1. Genetic testing is currently available for NPHP1-related disease (http://www.genetests.org/). As new genes are identified and their relative contribution to the NPHP disease spectrum is determined, mutational algorithms will be expanded to include analyses of these NPHP genes.

Autosomal Dominant Medullary Cystic Kidney Disease Medullary cystic kidney disease is an autosomal dominant condition that is much rarer than autosomal recessive NPHP but histopathologically indistinguishable. Some patients have had phenotypically unaffected parents but an affected second- or third-degree relative, suggesting that the disease is poorly recognized in affected family members or that there is variable penetrance. Clinically, medullary cystic kidney disease is distinguished from NPHP by its dominant mode of inheritance, later age at onset, progression to ESRD in the third to fourth decade of life, and lack of associated growth retardation and extrarenal manifestations. Genetic linkage analyses indicate that defects in at least two loci (MCKD1 and MCKD2) can cause medullary cystic kidney disease. Uremia occurs after 60 years of age in MCKD1; whereas in MCKD2, progression to ESRD occurs around 30 years of age. Mutations in the gene UMOD, which encodes uromodulin or Tamm-Horsfall protein, have been identified in MCKD2 patients. Subsequently, UMOD mutations have also been identified in families with familial juvenile hyperuricemic nephropathy (FJHN; MIM 162000), a dominantly transmitted disorder characterized by medullary cystic kidney disease, hyperuricemia, and gout,28 as well as familial glomerulocystic disease with hyperuricemia (MIM 609886).29 The diagnosis can usually be made on the basis of the family history, the clinical associations of hyperuricemia and gout, and



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the ultrasound finding of medullary cysts. Genetic testing is available for UMOD-related disease (http://www.genetests.org/).

MEDULLARY SPONGE KIDNEY Definition Medullary sponge kidney (MSK) is a relatively common disorder characterized by dilated medullary and papillary collecting ducts that give the renal medulla a “spongy” appearance.30

Etiology and Pathogenesis The occasional presence of embryonal tissue in the affected papillae and coexistence of other urinary tract anomalies suggest that MSK results from a developmental defect in the medullary pyramids. In addition, MSK occurs more frequently in individuals with other congenital defects, (e.g., congenital hemihypertrophy, Beckwith-Wiedemann syndrome, Ehlers-Danlos syndrome, and Marfan syndrome).30 Less than 5% of cases are familial, and a clear genetic basis for MSK has not been established.

Epidemiology In the general population, the frequency of MSK may be underestimated because some affected individuals remain entirely asymptomatic. Up to 20% of patients with nephrolithiasis have at least a mild degree of MSK, but excretory urography in unselected patients indicates a disease frequency of approximately 1 in 5000 individuals.

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MSK patients are composed of either pure apatite (calcium phosphate) or a mixture of apatite and calcium oxalate. Several factors appear to contribute to stone formation, including urinary stasis within the ectatic ducts, hypercalciuria, and hyperoxaluria. Hyperparathyroidism has also been reported. Hematuria, unrelated to either coexisting stones or infection, may be recurrent. The bleeding is usually asymptomatic, unless gross hematuria causes clot-related colic. Urinary tract infection may occur in association with nephrolithiasis or as an independent event. In those patients with stones, infections are more likely to occur in females than in males. Approximately one third to one half of MSK patients have hypercalcemia,30 but the mechanism has not been established. Decreased renal concentrating ability and impaired urinary acidification have been reported. In most patients, the acidification defect is not associated with systemic acidosis.

Pathology The pathologic changes are confined to the renal medullary and intrapapillary collecting ducts. Multiple spherical or oval cysts measuring 1 to 8 mm may be detected in one or more papillae. These cysts may be isolated or may communicate with the collecting system. The cysts are frequently bilateral and often contain spherical concretions composed of apatite. The affected pyramids and associated calyces are usually enlarged, and nephromegaly can result when many pyramids are involved. The renal cortex, medullary rays, calyces, and pelvis appear normal, unless complications, such as pyelonephritis or urinary tract obstruction, become superimposed.

Diagnosis

Clinical Manifestations MSK disease is asymptomatic unless it is complicated by nephrolithiasis, hematuria, or infection. Symptoms typically begin between the fourth and fifth decades of life, but adolescent presentations have been reported. Stones and granular debris in

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B

Abdominal plain radiographs often reveal radiopaque concretions in the medulla (Fig. 45.7A). The diagnosis is established by intravenous urography (Fig. 45.7B). Retention of contrast media by the ectatic collecting ducts appears either as spherical cysts or more commonly as diffuse linear striations, which impart a

C

Figure 45.7  Radiologic findings associated with medullary sponge kidney. MSK in a 52-year-old symptomatic woman. A, Preliminary film shows medullary nephrolithiases. B, Ten-minute film from excretory urography shows clusters of rounded densities in the papillae amid discrete linear opacities (paintbrush appearance). C, Nonenhanced CT reveals densely echogenic foci in the medulla.

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characteristic blush-like pattern to the papillae, the so-called bouquet of flowers or paintbrush appearance. CT is usually not necessary, but nonenhanced CT may help distinguish MSK from papillary necrosis or even ADPKD (Fig. 45.7C).

TSC1/TSC2 Signaling Pathways Receptor tyrosine kinases

Treatment Asymptomatic patients in whom MSK is detected as an incidental finding require no therapy. Hematuria in the absence of stones or infection requires no intervention. If the tubular ectasia is unilateral and segmental, partial nephrectomy may alleviate recurrent nephrolithiasis and urinary tract infection. However, for the majority of patients who have bilateral disease, medical management is sufficient. Hypercalciuria is the predominant cause of nephrolithiasis in MSK. The mainstay of treatment is high fluid intake to increase urine output and to reduce the precipitation of calcium salts in ectatic ducts. Patients with documented hypercalciuria may benefit from thiazide diuretics. If thiazides are poorly tolerated or contraindicated, inorganic phosphate therapy may be useful. To avoid struvite stone formation, oral phosphates should not be used in patients with previous urinary tract infections caused by urease-producing organisms. Patients who form and pass stones recurrently may require lithotripsy or surgical intervention (see Chapter 57). Urinary tract infection should be treated with standard antibiotic regimens, and for some patients, prolonged therapy may be warranted. Urease-producing organisms, such as coagulase-negative staphylococcus, are particularly problematic as urinary pathogens in MSK. Positive urine cultures, even with relatively insignificant colony counts, must be vigorously pursued. With proper management of the clinical complications, the long-term prognosis is excellent. Progression to renal impairment is unusual.

TUBEROUS SCLEROSIS COMPLEX Definition Tuberous sclerosis complex (TSC) is an autosomal dominant, tumor-suppressor gene syndrome in which tumor-like malformations, called hamartomas, develop in multiple organ systems, including the kidneys, brain, heart, lungs and skin.

Genetic Basis of Tuberous Sclerosis Complex TSC results from inactivating mutations in one of two genes, TSC1 on chromosome 9q32-q3431 and TSC2 on chromosome 16p13, adjacent to the PKD1 gene.32 Large deletions involving both PKD1 and TSC2 can result in the PKD1/TSC2 (PKTS) contiguous gene deletion syndrome.33 The focal nature of TSC-associated disease and the variability of disease expression even within families have suggested that TSC1 and TSC2 function as tumor-suppressor genes.34 The tumor-suppressor gene paradigm hypothesizes that two successive mutations are necessary to inactivate a tumor-suppressor gene and to cause tumor formation. The first mutation, inherited and therefore present in all cells, is necessary but not sufficient to produce tumors. A second mutation occurs after fertilization and is required to induce tumor transformation. The inactivating germline mutations identified in TSC1 and TSC2 as well as the loss of heterozygosity detected in 50% of TSC2-associated

Cell energy status

Cell cycle

AMPK

Growth factor signaling TSC1/TSC2

CDK1

Rheb-GTP

Rapamycin

Akt

ERK/RSK1

Rheb-GDP

mTORC1

S6K

4EBP1

Protein translation and cell growth Figure 45.8  TSC1/TSC2 signaling pathways. Hamartin (TSC1) and tuberin (TSC2) integrate cues from extracellular growth factor binding (through Akt and ERK/RSK1), the intracellular energy status (through AMPK), and the cell cycle (through CDK1) to direct signaling pathways that regulate cellular proliferation, differentiation, and migration.34,36 Tuberin contains a GTPase-activating protein (GAP) domain in its carboxyl terminus, and when it forms a complex with hamartin (TSC1/TSC2 complex), the small GTPase Rheb is converted from its active GTP-bound state to an inactive GDP-bound state. Rheb is an activator of the mTORC1 kinase, which regulates a number of processes linked to protein synthesis and cell growth (through the ribosomal S6 kinases and the eukaryotic initiation factor 4E-binding protein [4EBP1]). mTORC1 is activated physiologically in response to growth factor signaling, which causes phosphorylation of tuberin, dissociation of the TSC1/TSC2 complex, and increased levels of Rheb-GTP. Inactivation of the TSC1/TSC2 complex through mutations in TSC1 or TSC2 leads to inappropriate activation of mTORC1. Rapamycin is an mTOR inhibitor. (Modified with permission from reference 34.)

hamartomas and ~10% of TSC1-associated hamartomas support the hypothesis that both TSC1 and TSC2 function as tumorsuppressor genes. The TSC2 gene product tuberin interacts with hamartin, the product of the TSC1 gene. As described in Figure 45.8, the hamartin/tuberin (TSC1/TSC2) complex functions in multiple cellular pathways, primarily by inhibiting the kinase activity of mTOR, the mammalian target of rapamycin. mTOR functions in a protein complex (mTORC1) to regulate nutrient uptake, cell cycle progression, cell growth, and protein translation.35,36 The PKD1 gene product polycystin 1 plays a key role in regulating mTORC1 activity by complexing with tuberin and mTOR, thereby inhibiting the mTOR pathway.37 In normal adult kidney, mTOR is inactive. With loss of function of either polycystin 1 or tuberin, mTOR activity is upregulated, contributing to dysregulated cell growth and cystogenesis. In addition, hamartin appears to function through TORC1-independent pathways to regulate the structural integrity of the primary cilium, suggesting that ciliary dysfunction is an additional mechanism in TSC pathogenesis.38



CHAPTER

Epidemiology TSC affects 1 in 6000 individuals.35 The disease penetrance is quite variable. About two thirds of TSC patients are sporadic cases with no family history, and the disease apparently results from new mutational events. Among patients with sporadic disease, mutations in TSC2 are approximately five times more common than mutations in TSC1, whereas the ratio is 1:1 in familial cases. TSC1-related disease is milder, apparently because of a reduced rate of second hits.

Clinicopathologic Manifestations The clinical features of TSC1- and TSC2-linked disease are similar, although TSC2-linked disease tends to be more severe. The most common clinical manifestations are seizures, mental retardation or autism, skin lesions, interstitial lung disease, and tumors in the brain, retina, kidney, and heart. In affected individuals older than 5 years, the most common skin lesions are facial angiofibromas (Fig. 45.9), hypomelanotic macules, and ungual fibromas.39 Kidney involvement occurs frequently in TSC; one large study reported renal lesions in 57% of TSC patients.40 The principal manifestations include angiomyolipomas (85%), cysts

Figure 45.9  Facial angiofibromas in a 49-year-old patient with tuberous sclerosis complex.

A

B

45  Other Cystic Kidney Diseases

551

(45%), and renal malignant neoplasms (4%). Some of the malignant tumors originally thought to be renal cell carcinoma (RCC) are now regarded as malignant epithelioid angiomyolipomas.41 Other renal neoplasms, interstitial fibrosis with focal segmental glomerulosclerosis (FSGS), glomerular microhamartomas, and peripelvic and perirenal lymphangiomatous cysts have also been observed in TSC patients. Renal involvement in TSC often progresses insidiously but can result in considerable morbidity, including retroperitoneal hemorrhage, renal impairment (~1%), and death. Renal complications are the most frequent cause of death in TSC.36 Renal Angiomyolipomas Angiomyolipomas are hamartomatous structures composed of abnormal, thick-walled vessels and varying amounts of smooth muscle–like cells and adipose tissue (Fig. 45.10A, B). These are the most common renal lesion in TSC patients, evident in ~80% of TSC patients by age 10 years.34 Whereas solitary angiomyolipomas are found in the general population, particularly among older women, TSC-associated angiomyolipomas are multiple and bilateral with a young age at onset. Angiomyolipomas rarely occur before 5 years of age but increase in frequency and size with age.42 These tumors can be locally invasive, extending into the perirenal fat or, more rarely, the collecting system, renal vein, and even the inferior vena cava and right atrium. Lymph node and splenic involvement probably represents multifocal origin rather than metastasis. Clinical manifestations are due to hemorrhage (intratumoral or retroperitoneal) or mass effects (abdominal or flank masses and tenderness, hypertension, renal impairment). Women tend to have more numerous and larger angiomyolipomas than men. Pregnancy appears to increase the risk of rupture and hemorrhage. Renal Cystic Disease Renal cysts occur less frequently than angiomyolipoma in TSC patients (47% versus 80%42). However, like angiomyolipomas, renal cysts tend to increase in size and number over time. The concurrence of cysts and angiomyolipomas, easily detected by CT, is strongly suggestive of TSC. The cysts in TSC can develop from any nephron segment. When limited in number and size, TSC-related cysts are predominantly cortical. In some cases, glomerular cysts predominate. The epithelial lining of the cysts is distinctive and appears to be unique to TSC, with large and acidophilic epithelia containing large hyperchromatic nuclei with occasional mitotic

C

Figure 45.10  Renal pathology in tuberous sclerosis complex. A, Cut section: multiple angiomyolipomas in the kidney of a 60-year-old symptomatic woman. B, Light microscopy: angiomyolipoma containing adipose tissue and spindle smooth muscle–like cells interspersed between abnormal vessels with thickened walls. (Hematoxylin and eosin; magnification ×16.) C, Light microscopy: TSC cysts lined with distinctive epithelia consisting of large, acidophilic cells with hyperchromatic nuclei. (Hematoxylin and eosin; magnification ×65.)

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Clinical Diagnostic Criteria for Tuberous Sclerosis Complex (TSC)* Major: Facial angiofibromas or forehead plaque Nontraumatic ungual or periungual fibroma Hypomelanotic macules (>3) Shagreen patch (connective tissue nevus) Multiple retinal nodular hamartomas Cortical tubers Subependymal nodule Subependymal giant cell astrocytoma Cardiac rhabdomyomas (≥1) Lymphangioleiomyomatosis Renal angiomyolipoma Minor: Multiple, random dental pits Hamartomatous gastrointestinal or rectal polyps Bone cysts White matter radial migration lines Gingival fibromas Nonrenal hamartoma Retinal achromic patch “Confetti” skin lesions Multiple renal cysts Figure 45.11  Clinical diagnostic criteria for tuberous sclerosis complex (TSC). *Two major features or one major feature with two minor features indicates definite TSC; one major feature and one minor feature indicate probable TSC; and one major feature or two minor features indicate possible TSC. (Modified with permission from reference 39.)

figures (Fig. 45.10C). Associated papillary hyperplasia and adenomas are common. A small subset of affected infants can present with massive renal cystic disease reminiscent of ADPKD, severe hypertension, and a progressive decline in renal function with the onset of ESRD in the second or third decade of life. The majority of these patients have a contiguous germline deletion involving both the TSC2 and PKD1 genes, the PKTS contiguous gene syndrome (MIM 600273).43 Early detection, strict blood pressure control, and prompt therapy for the associated infantile spasms may have a favorable impact on the overall prognosis. Renal Neoplasms Many cases of benign epithelial tumors, such as papillary adenomas and oncocytomas, have been reported in TSC patients. However, despite the multiplicity of benign tumors, neoplastic transformation is rare.44 TSC-associated renal neoplasms are primarily clear cell RCC, but there is pathologic heterogeneity, with papillary and chromophobe carcinomas reported.41 The prognosis of TSCassociated renal carcinomas compared with sporadic renal carcinomas in the general population is unknown. The lifetime risk for development of RCC in the context of TSC is 2% to 3%.44

Diagnosis TSC is a pleiotropic disease in which the size, number, and location of the lesions can be variable, even among members of the same family. Major and minor criteria (Fig. 45.11) have been developed to guide the diagnostic approach in TSC. The diagnosis is made when two major features or one major and two minor ones can be demonstrated.39 Imaging is the mainstay for

Figure 45.12  Radiologic findings associated with tuberous sclerosis complex. Contrast-enhanced CT scan showing bilateral angiomyolipomas in a 34-year-old symptomatic woman.

diagnosis of TSC-associated renal lesions. The presence of small cysts and fat-containing angiomyolipomas is strongly suggestive of TSC. Whereas the median age at presentation for both renal cysts and angiomyolipomas is 9 years, these lesions have been detected in patients as young as 16 days and 4 months, respectively.42 Annual renal imaging is advised for TSC patients. Ultrasound may be more sensitive than CT for detection of small angiomyolipomas because fatty tissue is highly echogenic. Conversely, CT may be superior for detection of small angiomyolipomas in diffusely hyperechoic kidneys and for differentiation of small angiomyolipomas from perinephric or renal sinus fat (Fig. 45.12). On occasion, the distinction between an angiomyolipoma and carcinoma cannot be reliably established by imaging, and biopsy is indicated. TSC-associated renal cysts can radiologically mimic simple cysts and, when numerous, ADPKD. In the absence of angiomyolipomas, TSC-related renal cystic disease is suggested by the limited number of cysts compared with ADPKD and the absence of associated hepatic cysts. Although 10% of TSC patients have hepatic angiomyolipomas, hepatic cysts are rare. Gene-based diagnosis is currently available for TSC1- and TSC2-related disease as well as to detect large-scale deletions associated with the PKTS contiguous gene syndrome (http:// www.genetests.org/).

Treatment Renal Angiomyolipomas Renal angiomyolipomas are benign lesions and often require no treatment. However, given the potential for growth and associated complications, such as pain, bleeding, and hypertension, annual re-evaluation with ultrasound or CT is recommended. Larger angiomyolipomas frequently develop microaneurysms and macroaneurysms, and the risk of serious hemorrhage correlates with aneurysms of more than 5 mm in diameter.36 Therefore, these large angiomyolipomas require preemptive treatment with either surgical removal in a nephron-sparing procedure or embolization.34 In addition to size and complications such as pain and hemorrhage, the inability to exclude an associated renal carcinoma is an indication for intervention. When an associated malignant neoplasm cannot be excluded, renal-sparing surgery, such as enucleation or partial nephrectomy, is preferred.



The increased frequency and size of the angiomyolipomas in women and the reports of hemorrhagic complications during pregnancy suggest that female sex hormones may accelerate the growth of these lesions. Therefore, it is prudent to caution patients with multiple angiomyolipomas about the potential risks of pregnancy and estrogen administration. As noted, defective mTORC1 signaling is a central feature of TSC. A small clinical trial of sirolimus (rapamycin), an mTOR inhibitor, has demonstrated regression of astrocytomas, angiofibromas, and angiomyolipomas as well as improved pulmonary function in TSC patients.45 The efficacy of everolimus, another mTOR inhibitor, is now being assessed in a clinical trial in TSC patients with angiomyolipomas (http://clinical trials.gov). Renal Cystic Disease The mainstay of treatment of the cystic disease associated with TSC is strict control of the hypertension. Surgical decompression of these cystic kidneys has been suggested, but no significant beneficial effect has been established. Renal Carcinoma Renal carcinoma should be suspected in enlarging, fat-poor lesions or when intratumoral calcifications are present. In these cases, biopsy is indicated. Because renal carcinoma is frequently bilateral in TSC, renal-sparing surgery should be performed whenever possible.

Transplantation CKD, although rare in tuberous sclerosis, can occur by several different mechanisms, including angiomyolipoma-related parenchymal destruction, progressive renal cystic disease, interstitial fibrosis, and FSGS. A survey of 260 French dialysis centers indicated that the approximate prevalence of tuberous sclerosis– associated ESRD is 0.7 case per million and that of ESRD in tuberous sclerosis is 1 per 100.46 CKD in tuberous sclerosis was more frequent in females (63%) and was diagnosed at a mean age of 29 years. Renal impairment was the first TSC manifestation in about half the cases. Renal tumors were frequent, with angiomyolipomas in 23%, cysts in 18%, and both in 54%, although malignant neoplasms were observed in only 14%. All but one of the 48 patients with ESRD were treated by dialysis; 20 were transplanted, with good results. Therefore, both dialysis and renal transplantation provide an adequate means of survival, but the risk of renal hemorrhage related to angiomyolipomas and malignant degeneration in TSC poses special problems. Therefore, it is advisable that patients with TSC and ESRD undergo bilateral nephrectomy when renal replacement therapy is initiated.

VON HIPPEL–LINDAU DISEASE

CHAPTER

Genetic Basis of von Hippel–Lindau Disease VHL results from germline mutations in the VHL tumorsuppressor gene. In approximately 80% of patients, VHL is

553

familial, and disease in ~20% of cases results from de novo mutations. Moreover, VHL mutations have been identified in the germline of VHL patients as well as in sporadic clear cell RCCs, implying that VHL plays an important role in the pathogenesis of clear cell RCC. The VHL protein (pVHL) plays a critical role as a negative regulator of hypoxia-inducible genes.36,48 In the normal physiologic state, pVHL functions in a multiprotein complex that directs the α subunits of the transcription factor hypoxiainducible factor (HIF-α) for destruction through the ubiquination pathway. In cells that lack pVHL, HIF-α subunits are stabilized and bind to HIF-β family member proteins. The heterodimer then translocates to the nucleus, leading to overexpression of HIF target genes, which encode proteins that regulate glucose uptake, metabolism, extracellular pH, angiogenesis (vascular endothelial growth factor and platelet-derived growth factor B), and mitogenesis (transforming growth factor β and erythropoietin). This transcriptional dysregulation promotes the pathologic growth and survival of endothelial cells, pericytes, and stromal cells and ultimately their malignant transformation.47,48

Clinical Manifestations VHL has an incidence of 1 in 36,000 newborns and has been observed in all ethnic groups.47 Biallelic VHL inactivation leads to increased risk of central nervous system (CNS) and retinal hemangioblastomas, clear cell RCCs, pheochromocytomas, pancreatic islet cell tumors, endolymphatic sac tumors, and papillary cystadenomas of the broad ligament (females) and epididymis (males). In addition, cystic changes can occur in the kidney and pancreas.48 VHL-associated disease appears to cluster into two disease complexes (Fig. 45.13). In the initial stratification, VHL patients can be subclassified on the basis of a low risk (type 1) or high risk (type 2) for development of pheochromocytoma. Type 2 patients can be further subtyped according to the risk for development of RCC—low in type 2A and high in type 2B. In type 2C, patients present with familial pheochromocytoma without the other VHL-associated malignant neoplasms. Deletions and protein-truncating mutations are associated with the VHL type

Classification of VHL Based on Tumor Spectrum VHL Subtype

Tumor Manifestations

Type 1

Hemangioblastoma (CNS, retina), renal cell carcinoma Low risk for pheochromocytoma and pancreatic endocrine tumors

Type 2A

Hemangioblastoma (CNS, retina), pheochromocytoma, pancreatic endocrine tumors Low risk for renal cell carcinoma

Type 2B

Hemangioblastoma (CNS, retina), renal cell carcinoma, pheochromocytoma, pancreatic endocrine tumors

Type 2C

Predominantly pheochromocytoma Very limited risks for hemangioblastoma and renal cell carcinoma

Definition von Hippel–Lindau disease (VHL) is a dominantly transmitted, multisystem cancer predisposition syndrome associated with tumors of the eyes, cerebellum, spinal cord, adrenal glands, pancreas, and epididymis as well as renal and pancreatic cysts.47

45  Other Cystic Kidney Diseases

Figure 45.13  Classification of VHL based on tumor spectrum. CNS, central nervous system. (Modified with permission from reference 48.)

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1 phenotype, whereas type 2 disease primarily involves missense mutations.47,48 RCCs are typically multiple and bilateral. Whereas RCC may present with hematuria or back pain, more often detection occurs as an incidental finding on unrelated imaging studies or when VHL families are screened for occult renal disease. The mean age at presentation is 35 to 40 years, although patients have been diagnosed in adolescence. In VHL, men and women are equally affected with RCC, in contrast to the male predominance in sporadic RCC. VHL-associated RCC metastasizes to the lymph nodes, liver, lungs, and bones and accounts for about 50% of VHL deaths. In VHL, renal cysts arise from tubular cells that have undergone somatic loss of the wild-type allele. Renal cysts occur in about 60% of patients and are commonly bilateral; deterioration of renal function due to cystic kidney disease has been reported but is exceptional. However, some of these cysts become malignant over time, presumably because of mutations affecting other loci.36

Pathology RCC is one of the most common tumors in VHL, occurring in up to 75% of patients by age 60 years.47 VHL-associated RCCs are mostly of the clear cell type and usually bilateral and multi­ focal in distribution. Detailed microscopic examination of VHL-associated renal cystic lesions often reveals small foci of carcinoma; these RCCs tend to have low-grade histology and a better 10-year survival than sporadic RCC. More advanced RCCs do metastasize, and metastatic disease is a major cause of death in VHL patients.

Diagnosis The minimal clinical criteria for the diagnosis of VHL in an at-risk individual include the presence of a single retinal or cerebellar hemangioblastoma, or RCC, or pheochromocytoma. As many as 50% of affected family members may manifest only one feature of the syndrome. In presumed sporadic cases, the clinical diagnosis requires two or more retinal or CNS hemangioblastomas or a single hemangioblastoma and a characteristic visceral tumor. Molecular analysis of the VHL gene is indicated in patients with known or suspected VHL or in at-risk children from VHL families, given that unsuspected, untreated tumors can cause significant morbidity.47 Presymptomatic genotyping can be useful in determining the phenotypic classification of VHL and be used to direct monitoring for a specific subset of tumors. In addition, genotyping can be useful in distinguishing whether a pheochromocytoma has occurred in the context of VHL type 2 or in multiple endocrine neoplasia type 2 or is nonsyndromic.47,48 Genetic testing information is available at http://www.genetests.org/. In proven gene carriers or those at-risk individuals who cannot be evaluated at the molecular level, regular surveillance for occult disease manifestations is indicated. A comprehensive screening program, typically initiated at age 18 years and performed annually, includes gadolinium-enhanced magnetic resonance imaging (MRI) of the brain and spinal cord, detailed ophthalmologic examination, and a CT or MRI scan of the abdomen and pelvis to screen for visceral manifestations.36 About 40% of patients with VHL develop radiographically apparent renal cancers, which may appear as simple or complex cysts or solid renal masses. Comparison of images before and after the

administration of contrast material distinguishes whether lesions are enhancing. Ultrasound can be helpful in the further characterization of indeterminate renal lesions but should not be the primary mode of diagnostic imaging. For individuals with VHL type 2 mutations, annual surveillance for pheochromocytoma should include a 24-hour urine collection for metanephrines and catecholamines, abdominal magnetic resonance tomography, or m-iodobenzylguanidine (MIBG) scintigraphy.47 Germline mutations in the VHL gene have been detected in some families who do not meet the clinical criteria for VHL. Such families should be considered to have VHL and be managed like typical VHL families, including periodic clinical screening. For those at-risk individuals who do not inherit the mutant gene, further clinical surveillance is not necessary.

Differential Diagnosis The differential diagnosis of VHL-associated renal lesions includes several conditions, most notably ADPKD and TSC (Fig. 45.14). Like VHL, ADPKD affects both sexes with a similar mean age at presentation. However, kidney involvement in VHL is characterized by a few bilateral cysts (Fig. 45.15A), RCC, normal kidney size, normal blood pressure, and usually normal renal function. Cyst infection, a frequent finding in ADPKD, is uncommon in VHL. RCC is an infrequent complication of ADPKD. Cysts in the liver are frequent in ADPKD and rare in VHL. Pancreatic cysts are rare in ADPKD but can be numerous and scattered through the pancreas in VHL (Fig. 45.15A). The CNS in ADPKD is affected by arterial aneurysms, whereas hemangioblastomas are the CNS manifestation of VHL (Fig. 45.15B). TSC should be considered in the differential diagnosis of multiple renal tumors. In both TSC and VHL, multiple renal cysts occur. However, the TSC-associated renal tumor is usually an angiomyolipoma, and extrarenal lesions readily distinguish VHL and TSC.

Treatment At present, surgery is the mainstay for RCC therapy in VHL patients. Optimal management requires surgical intervention before renal vein invasion and distant metastases occur because metastatic lesions respond poorly to chemotherapy and radiation therapy. Nephron-sparing surgery is the procedure of choice when possible. Repeated surgical intervention may be required as tumors continue to develop. Laparoscopic surgery may have a role in the future management of these patients. Bilateral nephrectomy and renal transplantation may be an acceptable alternative to repeated nephron-sparing surgery in patients with VHL-associated RCC. It remains to be determined whether post-transplantation immunosuppression enhances the growth of the retinal and CNS hemangioblastomas and other lesions found in patients with VHL. In terms of medical management, drugs that inhibit HIF-α, or its downstream targets, could be therapeutically useful in pVHL-related hemangioblastomas and clear cell RCCs.48 Whereas DNA-binding transcription factors such as HIF have not proved to be tractable as drug targets per se, agents such as mTOR inhibitors that downregulate HIF-α protein levels are attractive as therapeutic agents; preclinical studies indicate that pVHL-defective cells are quite sensitive to mTOR inhibitors. Antibodies directed against vascular endothelial growth factor have shown significant efficacy in RCC in terms of tumor



CHAPTER

45  Other Cystic Kidney Diseases

555

Clinical and Genetic Features of Adult Renal Cystic Disease Acquired Cystic Disease

Simple Cysts

ADPKD

MSK

VHL

TSC

Clinical onset (years)

>40

30–40

20–40

30–40

10–30

Chronic renal failure

Cysts

Single, multiple

Multiple

Multiple

Few, bilateral

Multiple

Multiple

Cyst infection

Uncommon

Common

Common

Uncommon

Uncommon

Uncommon

Tumors

No

Rare

No

RCC, often bilateral AML/RCC

Common

BP

Normal, increased

Increased

Normal

Normal/ increased

Normal/ increased

Normal/ increased

Renal function

Normal

Normal/impaired

Normal

Normal

Normal/impaired

Impaired/ESRD

Nephrolithiasis

No

Common

Common

No

No

No

Liver cysts

No

Common

No

Rare

No

No

Pancreas cysts

No

Few

No

Multiple

No

No

CNS involvement

No

Aneurysms

No

Hemangioblastomas Seizures, mental retardation

No

Skin lesions

No

No

No

No

See Fig. 45.9

No

Genetics of adult renal cystic disease Disease gene

No

PKD1 PKD2

MKS1MSK6

VHL

TSC1 TSC2

No

Genetic testing1

No

Yes

Yes

Yes

Yes

No

Figure 45.14  Features of adult renal cystic disease. ADPKD, autosomal dominant polycystic kidney disease; AML, angiomyolipoma; BP, blood pressure; CNS, central nervous system; ESRD, end-stage renal disease; MSK, medullary sponge kidney; TSC, tuberous sclerosis complex; VHL, von Hippel–Lindau disease; RCC, renal cell carcinoma. 1Listed at GeneTests (http://www.genetests.org).

A

B

Figure 45.15  Radiologic findings associated with VHL. A, Non–contrast-enhanced CT image shows massive cystic involvement of the pancreas (arrowheads) and bilateral renal cysts (arrows). B, Contrast-enhanced MR image shows a right cerebellar hemangioblastoma with a small enhancing mass (arrow).

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shrinkage and disease stabilization.48 A number of clinical trials are in progress (http://clinical trials.gov).

SIMPLE CYSTS Definition Simple renal cysts are the most commonly acquired renal cystic lesion and occur twice as frequently in men as in women. Simple cysts are usually unilateral and may be either solitary or multiple. They occur rarely in children but become increasingly common with age.49 In one large ultrasound study, unilateral cysts were detected in 1.7% of patients 30 to 49 years of age, 11% of patients 50 to 70 years of age, and 22% to 30% of patients older than 70 years.50 This age-related increase in cyst incidence has been corroborated by MR studies.51

Etiology and Pathogenesis Simple renal cysts likely originate from the distal convoluted tubule or collecting ducts and may arise from renal tubular diverticula, but the pathogenic mechanism is unknown. Focal tubular obstruction and renal parenchymal ischemia have both been suggested as etiologic processes. Less likely is the possibility that simple cysts arise from calyceal diverticula because simple cysts are often found in the renal cortex and their frequency increases with age. In addition to age, smoking, renal dysfunction, and hypertension52 have been implicated as risk factors in the occurrence of simple cysts. However, these associations may be coincidental, given that the studies were largely retrospective, the cohorts had variable reasons for diagnostic referral, and the observations were not optimally controlled for age of the patient.49

Clinical Manifestations Simple cysts are typically asymptomatic. On occasion, patients present with hypertension, hematuria, abdominal or back pain due to bleeding, palpable abdominal mass, evidence of infection, or obstruction of the collecting system. Clinical symptoms are more common with neoplasms than with simple cysts. Therefore, the onset of symptoms should raise the possibility of an associated malignant neoplasm and prompt additional diagnostic studies.49,53

Pathology Whether unilateral or bilateral, simple cysts are usually spherical and unilocular. They may be solitary or multiple. On average, simple cysts measure 0.5 to 1.0 cm in diameter, but 3- to 4-cm cysts are not uncommon. Simple cysts can occur in the cortex (where they often protrude from the cortical surface), the corticomedullary junction, or the medulla. By definition, they do not communicate with the renal pelvis. The cyst walls are typically thin and transparent, lined with a single layer of flattened epithelium. Cyst fluid is essentially an ultrafiltrate of plasma. In the wake of infection, cyst walls can become thickened, fibrotic, and even calcified.

Diagnosis Simple cysts are most often detected as incidental findings during abdominal imaging studies. They are occasionally discovered

during radiologic evaluation of palpable abdominal masses, pyelonephritis, or hematuria following abdominal trauma. The critical clinical issue is to distinguish single or multiple simple cysts from cysts associated with ADPKD, other cystic diseases, or RCC. This distinction can usually be made on the basis of the patient’s age, family history, and renal imaging patterns.49,54 The ultrasound features of simple cysts include smooth walls, no septa, and no intracystic debris. If the ultrasound pattern is indeterminate, CT scanning should be performed. A classification system for renal cysts based on their appearance and enhancement on CT, described by Bosniak, is widely used (see Fig. 59.11).54 Benign cysts (class I) have homogeneous attenuation, no contrast enhancement, thin and smooth cyst walls, and no associated calcifications unless prior infection has occurred.

Treatment Simple cysts associated with pain or renin-dependent hypertension can be punctured with ultrasound guidance and drained, and a sclerosing agent is instilled into the cyst cavity. Laparoscopic or retroperitoneoscopic cyst unroofing may be more appropriate for large cysts containing volumes in excess of 100 ml. Infection with Enterobacteriaceae, staphylococci, and Proteus has been reported in simple cysts, and operative or percutaneous drainage is often required in addition to antibiotic treatment.

SOLITARY MULTILOCULAR CYSTS Solitary multilocular cysts are generally benign neoplasms that arise from the metanephric blastema.55 These solitary cysts have also been designated multilocular cystic nephroma, benign cystic nephroma, and papillary cystadenoma. By definition, the cystic structures are unilateral, solitary, and multilocular. The cystic locules do not communicate with each other or with the renal pelvis. These locules are lined with a simple epithelium, and the interlocular septa do not contain differentiated renal epithelia structures. Multilocular cysts represent a spectrum56; at one end is cystic nephroma, and at the other end is cystic partially differentiated nephroblastoma (CPDN), in which the septa contain foci of blastemal cells. It is not certain whether a multilocular cyst represents a congenital abnormality in nephrogenesis, a hamartoma, a partially or completely differentiated Wilms’ tumor, or a benign variant of Wilms’ tumor. A bimodal age distribution has been described55; approximately half the cases occur in children younger than 4 years, and half the cases are detected in adults. The childhood cases (mostly CPDN) are usually found in boys, whereas multilocular cysts presenting in adulthood (mostly cystic nephroma) occur more commonly in women. An abdominal or flank mass is the most common clinical feature, as these cysts are typically quite large and often replace an entire pole. Associated hematuria, calculi, urinary tract obstruction, and infection occur in rare instances. Diagnosis can be made by either ultrasound or CT (Fig. 45.16). Almost all multilocular cysts are Bosniak class III (see Fig. 59.11), complex renal cysts suggestive of malignancy.54 CPDN in children may contain blastema and incompletely differentiated metanephric tissue but usually has a benign course.57 In adults, associated foci of RCC or sarcoma must be excluded; partial nephrectomy is usually required. However, the typical prognosis of solitary multilocular cysts is excellent.



Figure 45.16  Solitary multilocular cyst. Contrast-enhanced CT image shows a solitary, septated, and well-circumscribed renal cystic lesion in the right kidney.

RENAL LYMPHANGIOMATOSIS Renal lymphangiomatosis is a rare, generally benign disorder characterized by developmental malformation of renal lymphatic channels.58 It has also been referred to as hilar, pericalyceal, paracalyceal, peripelvic, or parapelvic lymphangiectasis. The cystic phenotype is widely variable and the underlying pathogenesis is unclear. The dilation may involve a single lymphatic channel or multiple channels. The lymphangiectasis may be unilateral or bilateral, may be limited to the hilar region, or may extend into the renal parenchyma to the corticomedullary junction. On occasion, renal lymphangiomatosis may be very extensive and simulate ADPKD. The thin-walled cysts are lined by lymphatic endothelium, and the cyst fluid is quite distinct from that in ADPKD cysts as it contains lymphatic constituents such as albumin and lipid. The characteristic ultrasound or CT findings include multiple, bilateral small peripelvic cysts that splay the renal hilum as well as capsular cysts in the perirenal space, both separated by thin septations.59 Renal lymphangiomas are most often asymptomatic and require no treatment. However, the condition may be exacerbated by pregnancy, resulting in large perinephric lymph collections and ascites that may require percutaneous drainage.60

GLOMERULOCYSTIC KIDNEY DISEASE Cystic glomeruli are evident in three different clinical contexts: (1) isolated glomerulocystic kidney disease (GCKD); (2) glomerulocystic kidneys associated with heritable malformation syndromes, such as tuberous sclerosis, Meckel syndrome, medullary cystic kidney disease, orofaciodigital syndrome type I, trisomy 9, trisomy 13, trisomy 18, the short-rib polydactyly syndromes, and Zellweger cerebrohepatorenal syndrome; and (3) glomerular cysts present in dysplastic kidneys.61 GCKD can occur as a sporadic condition, a familial disorder, or the infantile manifestation of ADPKD. On pathologic examination, the kidney architecture is normal, with no dysplastic elements in the cortex and no evidence of urinary tract obstruction. Cystic dilation predominantly involves Bowman’s space and the initial proximal tubule; it is defined as a twofold to threefold dilation of Bowman’s space versus the normal glomerular dimension.61 Glomerular cysts can be distributed from the subcapsular

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zone to the inner cortex. The typical ultrasound pattern in GCKD involves increased echogenicity of the renal cortex with minute cysts, smaller than those evident in ADPKD. Young infants with either familial or sporadic forms of GCKD may also have renal medullary dysplasia and biliary dysgenesis.61 GCKD is usually transmitted as an autosomal dominant trait. It is usually discovered in infants with a familial history of ADPKD. In these infants, the kidneys are bilaterally enlarged and diffusely cystic. In addition, familial GCKD has been observed in infants, older children, and adults in whom the disease locus is not linked to PKD1 or PKD2, but the specific causative gene has yet to be identified.62 In these non–ADPKDassociated GCKD families, the kidneys are typically normal in size, although enlarged kidneys are occasionally observed. Finally, several sporadic cases of nonsyndromal GCKD have been described, suggesting either new spontaneous mutations or a recessively transmitted disorder.63 Familial hypoplastic GCKD (MIM 137920) is probably a different type of GCKD. The kidneys are smaller than normal and often associated with medullocalyceal abnormalities. The disease is pleiotropic among affected family members with variable associations of hypoplastic GCKD, gynecologic abnormalities, and maturity-onset diabetes of the young, type 5, which results from mutations in TCF2, the gene encoding hepatocyte nuclear factor 1β.64

ACQUIRED CYSTIC DISEASE Hypokalemic Cystic Disease Renal cysts are often seen in association with chronic hypokalemia due to primary hyperaldosteronism or other renal potassiumwasting disorders. Nearly 50% of patients with idiopathic adrenal hyperplasia and 60% of patients with adrenal tumors have been found to have renal cysts, which were distributed primarily in the renal medulla. These cysts typically regress after adrenalectomy.65

Hilar Cysts Hilar cysts are spherical accumulations of clear, fat droplet– containing fluid within the renal sinus. These cystic structures are not lined by epithelia. They are most commonly seen in debilitated patients and may represent atrophy of the renal sinus fat.

Perinephric Pseudocysts Perinephric pseudocysts are also unlined cavities. They typically occur under the renal capsule or in the perirenal fascia as a result of urine extravasation from a renal cyst after traumatic or spontaneous rupture or as the posterior extension of a pancreatic pseudocyst. Surgical intervention is indicated for associated urinary tract obstruction. Otherwise, treatment is directed to the underlying cause.

ACQUIRED CYSTIC DISEASE IN RENAL FAILURE Acquired cystic disease is a significant complication of prolonged renal failure. It should be considered in the differential diagnosis of cystic disease presenting with long-standing chronic renal failure (see Fig. 45.14). Acquired cystic disease is discussed further in Chapter 85.

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VIII  Hereditary and Congenital Diseases of the Kidney

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