The polycystic kidney diseases are among the most common life-threatening inherited diseases worldwide and frequently cause kidney failure. Autosomal dominant polycystic kidney disease (ADPKD) is seen predominantly in adults (Fig. 284-1), whereas autosomal recessive polycystic kidney disease (ARPKD) is mainly a disease of childhood. Renal cysts also are seen in several other hereditary kidney diseases (Table 284-1), some of which may have defects in a common signaling pathway with ADPKD and ARPKD. Other inherited tubular diseases manifest primarily with alterations in fluid, electrolyte, acid-base, and mineral balance (Table 284-2).
Autosomal Dominant Polycystic Kidney Disease
Etiology and Pathogenesis
ADPKD is a systemic disorder resulting from mutations in either the PKD-1 or the PKD-2 gene. The PKD-1-encoded protein, polycystin-1, is a large receptor-like molecule, whereas the PKD-2 gene product, polycystin-2, has features of a calcium channel protein. Both are transmembrane proteins that are present throughout all segments of the nephron. They have been localized to the luminal surface of tubular cells in primary cilia, where they appear to serve as flow sensors; on the basal surface in focal adhesion complexes; and on the lateral surface in adherens junctions. The proteins are thought to function independently, or as a complex, to regulate fetal and adult epithelial cell gene transcription, apoptosis, differentiation, and cell-matrix interactions. Disruption of these processes leads to epithelial dedifferentiation, unregulated proliferation and apoptosis, altered cell polarity, disorganization of surrounding extracellular matrix, excessive fluid secretion, and abnormal expression of several genes, including some that encode growth factors. Vasopressin-mediated elevation of cyclic AMP levels in cystepithelia plays a major role in cystogenesis by stimulating cell proliferation and fluid secretion into the cyst lumen through apical chloride and aquaporin channels. Cyst formation begins in utero from any point along the nephron, although <5% of total nephrons are thought to be involved. As the cysts accumulate fluid, they enlarge, separate entirely from the nephron, compress the neighboring renal parenchyma, and progressively compromise renal function.
ADPKD occurs in 1:400–1:1000 individuals worldwide and accounts for ~4% of end-stage renal disease (ESRD) in the United States. ADPKD is equally prevalent in all ethnic and racial groups. Over 90% of cases are inherited as an autosomal dominant trait, with the remainder probably representing spontaneous mutations. Mutations in the PKD-1 gene on chromosome 16 (ADPKD-1) account for 85% of cases, and mutations in the PKD-2 gene on chromosome 4 (ADPKD-2) account for the remainder. A few families appear to have a defect at a site that is different from either of these loci. Direct mutation analysis of isolated cysts suggests that there is loss of heterozygosity, whereby a somatic mutation in the normal allele of a small number of tubular epithelial cells leads to unregulated clonal proliferation of the cells that ultimately form the cyst lining.
Phenotypic heterogeneity is a hallmark of ADPKD, as evidenced by family members who have the same mutation but have a different clinical course. Affected individuals are often asymptomatic into the fourth or fifth decade. Presenting symptoms and signs include abdominal discomfort, hematuria, urinary tract infection, incidental discovery of hypertension, abdominal masses, elevated serum creatinine, and cystic kidneys on imaging studies (Fig. 284-1A and B). Frequently, the diagnosis is made before the onset of symptoms, when asymptomatic members in affected families request screening. In most patients, renal function declines progressively over the course of 10–20 years from the time of diagnosis, but not everyone with ADPKD develops ESRD; it occurs in about 60% of these patients by age 70. Those with ADPKD-2 tend to have later onset and slower progression. Hypertension is common and often precedes renal dysfunction, perhaps mediated by increased activity of the renin-angiotensin system. There is only mild proteinuria, and impaired urinary concentrating ability manifests early as polyuria and nocturia. Risk factors for progressive kidney disease include younger age at diagnosis, black race, male sex, presence of polycystin-1 mutation, and hypertension. There is a close correlation between the rate of kidney expansion, as measured by magnetic resonance imaging (MRI) scanning, and the rate of decline in kidney function. Dull, persistent flank and abdominal pain and early satiety are common due to the mass effect of the enlarged kidneys or liver. Cyst rupture or hemorrhage into a cyst may produce acute flank pain or symptoms and signs of localized peritonitis. Gross hematuria may result from cyst rupture into the collecting system or from uric acid or calcium oxalate kidney stones. Nephrolithiasis occurs in about 20% of patients. Urinary tract infection, including acute pyelonephritis, occurs with increased frequency in ADPKD. Infection in a kidney cyst is a particularly serious complication. It is most often due to Gram-negative bacteria and presents with flank pain, fever, and chills. Blood cultures are frequently positive, but urine culture may be negative because infected kidney cysts do not communicate directly with the collecting system. Distinguishing between infection and cyst hemorrhage is often challenging, and the diagnosis relies mainly on clinical and bacteriologic findings. Radiologic and nuclear imaging studies are generally not helpful.
Numerous extrarenal manifestations of ADPKD highlight the systemic nature of the disease. Patients with ADPKD have a twofold to fourfold increased risk of subarachnoid or cerebral hemorrhage from a ruptured intracranial aneurysm compared with the general population. Saccular aneurysms of the anterior cerebral circulation may be detected in up to 10% of asymptomatic patients on magnetic resonance angiography (MRA) screening, but most are small, have a low risk of spontaneous rupture, and do not merit the risk of intervention. In general, hemorrhage tends to occur before age 50 years, in patients with a family history of intracranial hemorrhage, and in those who have survived a previous bleed, have aneurysms >10 mm, and have uncontrolled hypertension. Other vascular abnormalities include aortic root and annulus dilation. Cardiac valvular abnormalities occur in 25% of patients, most commonly mitral valve prolapse and aortic regurgitation. Although most valvular lesions are asymptomatic, some may progress over time and warrant valve replacement. The incidence of hepatic cysts is 83% by MRI in patients age 15–46 years. Most patients are asymptomatic with normal liver function tests, but hepatic cysts may bleed, become infected, rupture, and cause pain. Although the frequency of liver cysts is equal between the sexes, women are more likely to have massive cysts (Fig. 284-1C). Colonic diverticulae are common, with a higher incidence of perforation in patients with ADPKD. Abdominal wall and inguinal hernias also occur with a higher frequency than in the general population.
Most often, the diagnosis of ADPKD is made from a positive family history and imaging studies showing large kidneys with multiple bilateral cysts and possibly liver cysts (Fig. 284-1). Criteria for the diagnosis of ADPKD by ultrasonography in asymptomatic individuals account for the later onset of ADPKD-2 and assume that the genotype of the individual and family being tested is unknown. The presence of three or more cysts in one or both kidneys is required to diagnose ADPKD in patients age 15–39 years with a specificity and positive predictive value of 100%; sensitivity varies from 82 to 96% for persons age 15–29 and 30–39 years, respectively. The presence of two or more cysts in each kidney is associated with a sensitivity and specificity of 90% and 100%, respectively, in patients age 40–59 years. In subjects older than 60 years, the presence of four or more cysts in each kidney is required to diagnose ADPKD because of the increased frequency of benign simple cysts, whereas fewer than two renal cysts in at-risk individuals age ≥40 years is sufficient to exclude the disease. Computed tomography (CT) scan and T2-weighted MRI are more sensitive for detecting presymptomatic disease in young patients. Genetic linkage analysis and mutational screening for ADPKD-1 and ADPKD-2 is available for equivocal cases, especially when a young adult from an affected family is being considered as a potential kidney donor. Genetic counseling is essential for those being screened. Screening for asymptomatic intracranial aneurysms should be restricted to patients with a personal or family history of intracranial hemorrhage and those in high-risk occupations. Intervention should be limited to aneurysms larger than 10 mm.
Treatment: Autosomal Dominant Polycystic Kidney Disease
No treatment has been proved to prevent cyst growth or the decline in kidney function. Hypertension control with a target blood pressure of 130/80 mmHg or less is recommended according to Joint National Committee (JNC) VII guidelines. A multidrug approach that includes agents to inhibit the renin-angiotensin system is frequently required. Studies are investigating the role of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) in slowing growth of kidney volume and loss of glomerular filtration rate (GFR). Lipid-soluble antimicrobials such as trimethoprim-sulfamethoxazole and fluoroquinolones that have good cyst penetration are the preferred therapy for infected kidney and liver cysts. Pain management occasionally requires cyst drainage by percutaneous aspiration, sclerotherapy with alcohol, or, rarely, surgical drainage. Patients with ADPKD appear to have a survival advantage on either peritoneal or hemodialysis compared with patients with other causes of ESRD. Those undergoing kidney transplantation may require bilateral nephrectomy if the kidneys are massively enlarged or have been the site of infected cysts. Posttransplantation survival rates are similar to those of patients with other causes of kidney failure, but these patients remain at risk for the extrarenal complications of ADPKD. Studies in animal models of inherited cystic diseases have identified promising therapeutic strategies, including vasopressin V2 receptor antagonists that suppress cyst growth by lowering intracellular cAMP, and inhibitors of cell dedifferentiation and proliferation that target the epidermal growth factor receptor tyrosine kinase and the mammalian target of rapamycin (mTOR). Clinical trials of these agents are ongoing.
Autosomal Recessive Polycystic Kidney Disease
ARPKD is primarily a disease of infants and children. The incidence is 1:20,000 births. The kidneys are enlarged, with small cysts, <5 mm, limited to the collecting tubules. The ARPKD gene on chromosome 6p21, PKHD1, encodes several alternatively spliced transcripts (Table 284-1). The largest transcript produces a multidomain transmembrane protein termed fibrocystin (polyductin) that is found in the cortical and medullary collecting ducts and the thick ascending limb of Henle's loop in the kidney as well as in biliary and pancreatic duct epithelia. Like the polycystins, fibrocystin has receptor-like features and may be involved in cell-cell and cell-matrix interactions. Fibrocystin, the polycystins, and several proteins involved in animal models of PKD are located in association with primary cilia on the tubular epithelial cell apical surface; this suggests that they may cooperate in a mechanosensory pathway. A large number of different mutations have been identified throughout PKHD1 and are unique to individual families. Most patients are compound heterozygotes. Those with two truncating mutations frequently die shortly after birth, whereas those who survive beyond the neonatal period generally have at least one missense mutation. Mutations in PKHD1 have also been identified in about 30% of children with congenital hepatic fibrosis (Caroli's syndrome) without evident kidney involvement.
The clinical presentation of ARPKD is highly variable. Up to 50% of affected neonates die of pulmonary hypoplasia, the result of oligohydramnios from severe intrauterine kidney disease. About 80% of those who survive the neonatal period are still alive after 10 years; however, one-third will have developed ESRD. Enlarged kidneys may be detected soon after birth as bilateral abdominal masses. Impaired urinary concentrating ability and metabolic acidosis ensue as tubular function deteriorates. Hypertension often occurs in the first few years of life. Kidney function deteriorates progressively from childhood into early adult life. Longer-term survivors frequently develop complications of portal hypertension from periportal fibrosis.
Ultrasonography reveals large, echogenic kidneys. The diagnosis can be made in utero after 24 weeks of gestation in severe cases, but cysts generally become visible only after birth. The absence of renal cysts in either parent on ultrasonography helps distinguish ARPKD from ADPKD in older patients. The wide range of different mutations and the large size of the gene complicate molecular diagnosis, although prenatal diagnosis is possible by gene linkage to the PKHD1 locus in families with a previous confirmed ARPKD birth.
Treatment: Autosomal Recessive Polycystic Kidney Disease
There is no specific therapy for ARPKD. Improvements in neonatal intensive care, blood pressure management, dialysis, and kidney transplantation have led to survival into adulthood. Complications of hepatic fibrosis may necessitate liver transplantation. Future therapies may target aberrant cell signaling mechanisms, as in ADPKD.
Genetics and Pathogenesis
Nephronophthisis (NPHP) is the most common genetic cause of ESRD in childhood and adolescence. Eleven distinct genetic mutations with autosomal recessive inheritance have been identified to date and produce different renal and extrarenal manifestations of NPHP (Table 284-1). Although their precise functions are unclear, the defective protein products, named nephrocystins and inversin, localize to the primary cilium and associated basal body of renal epithelial cells, similar to the polycystins and fibrocystin. NPHP is classified into infantile, juvenile, and adolescent forms based on the age of ESRD onset. In juvenile NPHP, the most common form, the kidneys are shrunken and histology shows tubular atrophy, thickening of tubular basement membranes, diffuse interstitial fibrosis, and microscopic medullary cysts. In the infantile form, the kidneys are large with histology similar to that of the juvenile form except that medullary cysts are more prominent and develop earlier.
In juvenile NPHP symptoms typically appear after 1 year of age. Impaired tubular function causes salt wasting and defective urinary concentration and acidification. Patients may present with polyuria, polydipsia, volume depletion, or systemic acidosis. Hypertension is usually absent due to salt wasting. Progressive kidney failure and volume depletion lead to growth retardation. On average, ESRD occurs by age 3 in the infantile form, age 13 in the juvenile form, and age 19 in the adolescent form. Up to 15% of patients with juvenile NPHP have extrarenal manifestations (Table 284-1), most commonly retinitis pigmentosa (Senior-Loken syndrome). Other abnormalities include blindness from amaurosis, oculomotor apraxia, cerebellar ataxia (Joubert syndrome), polydactyly, mental retardation, hepatic fibrosis, and ventricular septal defect. Situs inversus is seen in some cases of infantile NPHP, consistent with mutation in INVS (NPHP2), a gene critical for left-right patterning in the embryo.
The diagnosis of NPHP should be considered in patients with a family history of kidney disease, early-onset progressive renal failure, and a bland urine sediment with minimal proteinuria. Ultrasonography reveals small hyperechoic kidneys in juvenile NPHP and large kidneys with cysts in the infantile form.
There is no specific therapy to prevent loss of kidney function in NPHP. Salt and water replacement are required for patients with salt wasting and polyuria. Therapy should include sodium bicarbonate or citrate for acidosis, management of chronic kidney disease, and timely institution of dialysis and kidney transplantation. NPHP does not recur in transplanted kidneys.
Medullary Cystic Kidney Disease
The medullary cystic kidney diseases (MCKDs) generally present in young adults. Two genetic loci have been defined, both with autosomal dominant transmission (Table 284-1). The locus for MCKD1 has been mapped to chromosome 1q21. Mutations in the uromodulin gene (UMOD) that encodes the Tamm-Horsfall mucoprotein on chromosome 16p12 have been identified in MCKD2.
As with NPHP, patients with MCKD have atrophic kidneys with diffuse interstitial fibrosis, cysts restricted to the renal medulla, salt wasting, and polyuria. Disease onset is later than in NPHP. Consequently, there is no growth retardation, salt wasting is milder, and ESRD occurs later, usually between ages 20 and 70. There are no extrarenal manifestations in MCKD1, but most patients with MCKD2 have severe hyperuricemia and precocious onset of gout.
MCKD should be considered in young adults with a family history suggesting dominant inheritance of kidney disease who present with progressive renal failure, bland urinalysis with little or no proteinuria, and small dense kidneys with medullary cysts on radiographic imaging. The presence of hyperuricemia and gout is a further clue to the diagnosis of MCKD2, which can be confirmed by mutation analysis of UMOD.
Treatment: Medullary Cystic Kidney Disease
There is no specific therapy for MCKD. Allopurinol is indicated for patients with gout and is reasonable for those with asymptomatic hyperuricemia, although there is no evidence that it prevents progressive renal failure in MCKD2. Dialysis and transplantation outcomes appear to be favorable. The disease does not recur in transplanted kidneys.
Tuberous sclerosis (TS) is an autosomal dominant disorder that affects 1 in 6000 people. It results from mutations in either the TSC1 gene encoding hamartin or the TSC2 gene encoding tuberin (Table 284-1). Hamartin and tubulin form a complex that is thought to negatively regulate cell growth and proliferation through inhibition of mTOR. The presence of either mutation produces uncontrolled proliferation in numerous tissues, including the kidneys, skin, central nervous system, and heart. The kidneys are affected in 80% of patients. Renal TS occurs in three forms: renal angiomyolipomas, renal cysts, and renal cell carcinoma. Angiomyolipomas are the most common renal abnormality. They occur bilaterally, are often multiple, and are usually asymptomatic; however, they may cause spontaneous bleeding, flank pain, hematuria, and life-threatening retroperitoneal hemorrhage. Large lesions, >4 cm, are more likely to be symptomatic and may require transcatheter arterial embolization or surgical excision. Cysts are usually asymptomatic and are not evident on imaging studies until adulthood. Rarely, cysts may be large and numerous, sometimes leading to ESRD and producing a clinical scenario that can be confused with ADPKD, especially if there are few other systemic manifestations of TS. Multicentric renal cell carcinomas occur with increased frequency in TS. Patients with TS should be screened for renal involvement at initial diagnosis with ultrasonography or CT. Those with cysts or angiomyolipomas require regular imaging to monitor for the development of renal cell carcinoma.
Von Hippel-Lindau Disease
Von Hippel-Lindau disease (VHL) is a rare autosomal dominant disease characterized by abnormal angiogenesis with benign and malignant tumors that affect multiple tissues. The disease is inherited as a mutation in one allele of the VHL tumor-suppressor gene. Somatic mutation of the normal allele leads to retinal angiomas, central nervous system (CNS) hemangioblastomas, pheochromocytomas and multicentric clear cell cysts, hemangiomas, and adenomas of the kidney. The kidneys are affected in three-quarters of patients, and half these patients develop clear cell carcinomas in the renal cysts. It is noteworthy that VHL mutations also account for 60% of spontaneous clear cell carcinomas of the kidney. The mean age of diagnosis of renal cell carcinoma in VHL disease is 44 years, and 70% of patients who survive to age 60 develop renal cell carcinoma. The high risk of renal cell carcinoma mandates periodic surveillance (usually yearly in adults) by CT or MRI. Routine screening and awareness of the natural history of lesions has enabled renal-sparing approaches to disease management. Tumors <3 cm in size require careful monitoring for growth, whereas partial nephrectomy is indicated in those >3 cm in the absence of metastasis. Nonsurgical renal-sparing strategies, including percutaneous radio frequency ablation and selective arterial embolization, have shown promise in short-term trials.
Pathology and Clinical Features
Medullary sponge kidney (MSK) is a relatively common benign condition of unknown cause characterized by ectasia of the papillary collecting ducts of one or both kidneys. Urinary stasis in the dilated ducts, hypocitraturia, and occasionally incomplete distal renal tubular acidosis (dRTA) contribute to the formation of small calcium-containing calculi. Most cases are asymptomatic or are discovered during investigation of hematuria. Symptomatic patients typically present as young adults with renal colic and nephrolithiasis or recurrent urinary tract infections; however, MSK also may affect children. Most cases are sporadic, although MSK has been found rarely in association with other congenital anomalies of the urinary tract and with congenital hepatic ductal ectasia (Caroli's disease).
MSK is characteristically seen as hyperdense papillae with clusters of small stones on renal ultrasonography or abdominal x-ray (Fig. 284-2). The classical "paintbrush-like" features of MSK, representing the ectatic collecting ducts, are best seen on intravenous urography. However, this procedure has been supplanted by contrast-enhanced, high-resolution helical CT with digital reconstruction (Fig. 284-2).
Radiographs of medullary sponge kidney disease. A. Plain x-ray film of a patient with a history of recurrent nephrolithiasis showing clusters of stones in the papillae (arrows). B–E. CT scan of an 18-year-old male patient investigated for persistent microscopic hematuria. B and C. CT without contrast showing a few small stones in the papillae (arrows). D and E. Contrast-enhanced CT of the same region shown in B. In addition to the stone (arrow), a blush of contrast is seen filling the ectatic collecting ducts (arrowheads).
Treatment: Medullary Sponge Kidney
No treatment is necessary in asymptomatic individuals, aside from maintaining high fluid intake to reduce the risk of nephrolithiasis. Recurrent stone formation should prompt a metabolic evaluation and treatment as in any stone former (Chap. 287). In patients with hypocitraturia and incomplete dRTA, treatment with potassium citrate helps prevent new stone formation. Urinary tract infections should be treated promptly.