The polycystic kidney diseases are a group of genetically heterogeneous disorders and a leading cause of kidney failure. The autosomal dominant form of polycystic kidney disease (ADPKD) is the most common life-threatening monogenic disease, affecting 12 million people worldwide. The autosomal recessive form of polycystic kidney disease (ARPKD) is rarer but affects the pediatric population. Kidney cysts are often seen in a wide range of syndromic diseases. Recent studies have shown that defects in the structure or function of the primary cilia may underlie this group of genetic diseases collectively termed ciliopathies (Table 339-1).
TABLE 339-1Inherited Diseases Commonly Associated with a Cystic Phenotype |Favorite Table|Download (.pdf) TABLE 339-1 Inherited Diseases Commonly Associated with a Cystic Phenotype
|Disease ||Mode of Inheritance ||Renal Abnormalities ||Other Clinical Features ||Genes |
|Autosomal dominant polycystic kidney disease ||AD ||Cortical and medullary cysts ||Liver, pancreatic cysts, hypertension, subarachnoid hemorrhage ||PKD1, PKD2 |
|Autosomal recessive polycystic kidney disease ||AR ||Distal and collecting duct cysts ||Oligohydramnios if severe, hypertension, ascending cholangitis, liver fibrosis ||PKHD1 |
|Medullary cystic kidney ||AD ||Small fibrotic kidneys; medullary cysts ||In adults, gout ||MCKD1, MCKD2/UMOD |
|Nephronophthisis ||AR ||Small fibrotic kidneys; medullary cysts ||Growth retardation, anemia (visual loss, liver fibrosis, cerebellar ataxia if associated with another syndrome) ||NPHP1-4, IQCB1, CEP290, GLIS2, RPGRIP1L, NEK8, SDCCAG8, TMEM67, TTC21B |
|Senior-L⊘ken syndrome ||AR ||Renal cysts ||Juvenile nephronophthisis, Leber’s amaurosis ||NPHP1-6, SDCCAG8 |
|Leber’s congenital amaurosis ||AR ||Renal cysts ||Visual impairment in first year of life, pigmentary retinopathy ||GUCY2D, RPE65, LCA3-14 (including LCA10, CEP290) |
|Meckel-Gruber syndrome ||AR ||Cortical and medullary cysts ||CNS anomalies, polydactyly, congenital heart defects ||MKS1, TMEM216, TMEM67, CEP290, RPGRIP1L, CC2D2A, TCTN2, B9D1, B9D2, NPHP3 |
|Bardet-Biedl syndrome ||AR ||Renal cysts ||Obesity, polydactyly, retinitis pigmentosa, anosmia, congenital heart defects, mental retardation ||BBS1, 2, ARL6, BBS4,5, MKKS, BBS7, TTC8, BBS9, 10, TRIM32, BBS12, MKS1, CEP290, C2ORF86; modifiers MKS1, MKS3, CCDC28B |
|Oral-facial-digital syndrome type I ||AR ||Renal cysts ||Oral cavity, face, and digit anomalies; CNS abnormalities; cystic kidney disease; X-linked with male lethality, primary ciliary dyskinesia ||OFD1 |
|Cranioectodermal dysplasia (Sensenbrenner’s syndrome) ||AR ||Renal cysts ||Skeletal dysplasia, thoracic deformities, polydactyly, renal cysts, retinitis pigmentosa ||IFT80 |
|Tuberous sclerosis ||AD ||Renal cysts ||Angiomyolipomas, renal cell carcinoma, facial angiofibromas, CNS hamartomas ||TSC1, TSC2 |
|Von Hippel-Lindau disease ||AD ||Renal cysts ||Renal cell carcinoma, retinal angiomas, CNS hemangioblastomas, pheochromocytomas ||VHL |
AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE
Etiology and Pathogenesis
ADPKD is characterized by progressive formation of epithelial-lined cysts in the kidney (Fig. 339-1). Although cysts only occur in 5% of the tubules in the kidney, the enormous growth of these cysts ultimately leads to the loss of normal surrounding tissues and loss of renal function. The cellular defects in ADPKD that have been known for a long time are increased cell proliferation and fluid secretion, decreased cell differentiation, and abnormal extracellular matrix. ADPKD is caused by mutations in PKD1 and PKD2, which, respectively, code for polycystin-1 (PC1) and polycystin-2 (PC2). PC1 is a large 11-transmembrane protein that functions like a G protein–coupled receptor. PC2 is a calcium-permeable six-transmembrane protein that structurally belongs to the transient receptor potential (TRP) cation channel family. PC1 and PC2 are widely expressed in almost all tissues and organs. PC1 expression is high in development and low in the adult, whereas PC2 expression is relatively constant. PC1 and PC2 are found on the primary cilium, a hair-like structure present on the apical membrane of a cell, in addition to the cell membranes and cell-cell junctions of tubular epithelial cells. Defects in the primary cilia are linked to a wide spectrum of human diseases, collectively termed ciliopathies. The most common phenotype shared by many ciliopathies is kidney cysts. PC1 and PC2 bind to each other via their respective C-terminal tails to form a receptor-channel complex and regulate each other’s function. The PC1/2 protein complex serves as a mechanosensor or chemical sensor and regulates calcium and G-protein signaling. The PC1/2 protein complex may also directly regulate a number of cellular functions including the cell cycle, the actin cytoskeleton, planar cell polarity (PCP), and cell migration. This protein complex has also been implicated in regulating a number of signaling pathways, including Wnt, mammalian target of rapamycin (mTOR), STAT3, cMET, phosphoinositide 3-kinase (PI3K)/AKT, G protein–coupled receptor (GPCR), and epidermal growth factor receptor (EGFR), as well as in the localization and activity of cystic fibrosis transmembrane conductance (CFTR). One hypothesis is that loss of ciliary function of PC1 and PC2 leads to reduced calcium signaling and a subsequent increase of adenylyl cyclase activity and decrease of phosphodiesterase activity, which, in turn, causes increased cellular cyclic AMP (cAMP). Increased cAMP promotes protein kinase A activity, among other effectors, and, in turn, leads to cyst growth by promoting proliferation and fluid secretion of cyst-lining cells through chloride and aquaporin channels in ADPKD kidneys.
Scheme of the primary cilium and cystic kidney disease proteins. Left. A scheme of the primary cilium. Primary cilia share a “9+0” organization of microtubule doublets. Proteins are transported into the cilium by motor protein kinesin 2 and transported out of the cilium by dynein. The cilium is connected to the basal body through the transition zone. Middle. Topology of autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD) proteins polycystin-1, polycystin-2, and fibrocystin/polyductin (FPC) are shown. PC1 also interacts with other proteins such as components of the BBSome and NPHP1. PC2 and FPC both interact with kinesin 2 (KIF 3A/B). Localization of disease proteins in the cilium, the transition zone, and the basal body is color coded. Right. Potential disease mechanisms due to cilium-mediated signaling events.
ADPKD is inherited as an autosomal dominant trait with complete penetrance but variable expressivity. The disease affects all ethnic groups worldwide with an estimated prevalence of 1:1000 to 1:400. Only half of the patients with ADPKD are clinically diagnosed during their lifetime. ADPKD is genetically heterogeneous. The first disease gene (PKD1) was localized to the region of the α-globin gene on chromosome 16p13 in 1985, and a second disease gene (PKD2) locus was mapped to chromosome 4q21-q23 in 1993. Mutations of PKD1 and PKD2 are responsible for ~85% and ~15% of ADPKD cases, respectively. However, patients with PKD2 mutations may be higher than 15% because they tend to have milder clinical disease and, as a result, may be underdiagnosed. Embryonic lethality of Pkd1 and Pkd2 knockout mice suggests that human homozygotes may be lethal and thus not clinically recognized.
PKD1 is comprised of 46 exons occupying ~52 kb of genomic DNA. It produces an ~14-kb transcript that encodes PC1, a protein of ~4300 amino acids. A feature of the PKD1 gene is that the 5´ three-quarters of PKD1 have been duplicated at six other sites on chromosome 16p, and many of them produce mRNA transcripts, which provides a major challenge for genetic analysis of the duplicated region. PKD2 is a single-copy gene with 15 exons producing an ~5.3-kb mRNA transcript that encodes PC2, a protein of 968 amino acids. The presence of additional genes for ADPKD was suggested based on several families linked to neither PKD1 nor PKD2 genes. However, careful analyses have excluded the existence of a third ADPKD gene.
In ADPKD patients, every cell carries a germline mutant allele of either PKD1 or PKD2. However, cysts develop in only a small fraction of the nephrons. Cysts are thought to originate from clonal growth of single cells that have received a somatic “second hit” mutation in the “normal” allele of the PKD1 or PKD2 gene. Accumulating evidence in mouse models now shows that partial loss of function of the second allele of Pkd1 in a proliferative environment is sufficient for cystogenesis, suggesting that a critical amount of PKD1 is needed in a cell. Somatic inactivation of the second allele of Pkd1 in adult mice results in very slow onset of cyst development in the kidney, but a “third hit,” such as an additional genetic or epigenetic event, the inactivation of a growth-suppressor gene, the activation of a growth-promoting gene(s), or an event like renal injury that activates the developmental program, may promote rapid cyst formation.
ADPKD is characterized by the progressive bilateral formation of renal cysts. Focal renal cysts are typically detected in affected subjects before 30 years of age. Hundreds to thousands of cysts are usually present in the kidneys of most patients in the fifth decade (Fig. 339-2). Enlarged kidneys can each reach a fourfold increase in length and weigh up to 20 times the normal weight. The clinical presentations of ADPKD are highly variable. Although many patients are asymptomatic until the fourth to fifth decade of life and are diagnosed by incidental discoveries of hypertension or abdominal masses, back or flank pain is a frequent symptom in ~60% of patients with ADPKD. The pain may result from renal cyst infection, hemorrhage, or nephrolithiasis. Gross hematuria resulting from cyst rupture occurs in ~40% of patients during the course of their disease, and many of them will have recurrent episodes. Flank pain and hematuria may coexist if the cyst that ruptures is connected with the collecting system. Proteinuria is usually a minor feature of ADPKD. Infection is the second most common cause of death for patients with ADPKD. Up to half of patients with ADPKD will have one or more episodes of renal infection during their lifetime. An infected cyst and acute pyelonephritis are the most common renal infections often due to gram-negative bacteria, which are associated with fever and flank pain, with or without bacteremia. These complications and renal insufficiency often correlate with structural abnormality of the renal parenchyma. Kidney stones occur in ~20% of patients with ADPKD. Different from the general population, more than half of the stones in patients with ADPKD are composed of uric acid, with the remainder due to calcium oxalate. Distal acidification defects, abnormal ammonium transport, low urine pH, and hypocitraturia may be important in the pathogenesis of renal stones in ADPKD. Renal cell carcinoma is a rare complication of ADPKD with no apparent increased frequency compared to the general population. However, in ADPKD, these tumors are more often bilateral at presentation, multicentric, and sarcomatoid in type. Radiologic imaging is often not helpful in distinguishing cyst infection and cyst hemorrhage because of their complexity. Computed tomography (CT) scan and magnetic resonance imaging (MRI) are often useful in distinguishing a malignancy from a complex cyst. Cardiovascular complications are the major cause of mortality in patients with ADPKD. Hypertension is common and typically occurs before any reduction in glomerular filtration rate (GFR). Hypertension is a risk factor for both cardiovascular and kidney disease progression in ADPKD. Notably, some normotensive patients with ADPKD may also have left ventricular hypertrophy. Hypertension in ADPKD may result from the increased activation of the renin-angiotensin-aldosterone system, increased sympathetic nerve activity, and impaired endothelial cilium function-dependent relaxation of small resistant blood vessels.
Photograph showing a kidney from a patient with autosomal dominant polycystic kidney disease. The kidney has been cut open to expose the parenchyma and internal aspects of cysts.
The progression of ADPKD has striking inter- and intrafamilial variability. The disease can present as early as in utero, but end-stage renal disease typically occurs in late middle age. Risk factors include early diagnosis of ADPKD, hypertension, gross hematuria, multiple pregnancies, and large kidney size. Liver cysts derived from the biliary epithelia are the most common extrarenal complication. Polycystic liver disease associated with ADPKD is different from autosomal dominant polycystic liver disease (ADPLD), which is caused by mutations in at least two distinct genes (PRKCSH and SEC63) and does not progress to renal failure. Massive polycystic liver disease occurs almost exclusively in women with ADPKD, particularly those with multiple pregnancies.
Intracranial aneurysm (ICA) occurs four to five times more frequently in ADPKD patients than in the general population and causes high mortality. The disease gene products PC1 and PC2 may be directly responsible for defects in arterial smooth muscle cells and myofibroblasts. The focal nature and the natural history of ICA in ADPKD remain unclear. A family history of ICA is a risk factor of aneurysm rupture in ADPKD, but whether hypertension and cigarette smoking are independent risk factors is not clear. About 20–50% of patients may experience “warning headaches” preceding the index episode of subarachnoid hemorrhage due to ruptured ICA. A CT scan is generally used as the first diagnostic test. A lumbar puncture may be used to confirm the diagnosis. The role of radiologic screening for ICA in asymptomatic patients with ADPKD remains unclear. ADPKD patients with a positive family history of ICAs may undergo presymptomatic screening of ICAs by magnetic resonance angiography. Other vascular abnormalities in ADPKD patients include diffuse arterial dolichoectasias of the anterior and posterior cerebral circulation, which can predispose to arterial dissection and stroke. Mitral valve prolapse occurs in up to 30% of patients with ADPKD, and tricuspid valve prolapse is less common. Other valvular abnormalities occurring with increased frequency in ADPKD patients include insufficiency of the mitral, aortic, and tricuspid valves. Most patients are asymptomatic, but some may progress and require valve replacement. The prevalence of colonic diverticulae and abdominal wall hernias is also increased in ADPKD patients.
Diagnosis is typically made from a positive family history consistent with autosomal dominant inheritance and multiple kidney cysts bilaterally. Renal ultrasonography is often used for presymptomatic screening of at-risk subjects and for evaluation of potential living-related kidney donors from ADPKD families. The presence of at least two renal cysts (unilateral or bilateral) is sufficient for diagnosis among at-risk subjects between 15 and 29 years of age with a sensitivity of 96% and specificity of 100%. The presence of at least two cysts in each kidney and the presence at least four cysts in each kidney are required for the diagnosis of at-risk subjects age 30 to 59 years and age 60 years or older, respectively, with a sensitivity of 100% and specificity of 100%. This is because there is an increased frequency of developing simplerenal cysts with age. Conversely, in subjects between age 30 and 59 years, the absence of at least two cysts in each kidney, which is associated with a false-negative rate of 0%, can be used for disease exclusion. These criteria have a lower sensitivity for patients with a PKD2 mutation because of a late onset of ADPKD2. CT scan and T2-weighted MRI, with and without contrast enhancement, are more sensitive than ultrasonography and can detect cysts of smaller size. However, a CT scan exposes the patient to radiation and radiocontrast, which may cause serious allergic reactions and nephrotoxicity in patients with renal insufficiency. T2-weighted MRI, with gadolinium as a contrast agent, has minimal renal toxicity and can detect cysts of only 2–3 mm in diameter. However, a large majority of cysts may still be below the detection level. Genetic testing by linkage analyses and mutational analyses is available for ambiguous cases. Because of the large size of the PKD1 gene and the presence of multiple highly homologous pseudogenes, mutational analysis of the PKD1 gene is difficult and costly. Application of new technologies, such as paired-end next-generation sequencing with multiplexing individually bar-coded long-range polymerase chain reaction libraries, may reduce the costs and improve the sensitivity for clinical genetic testing.
TREATMENT Autosomal Dominant Polycystic Kidney Disease
No specific treatment to prevent cyst growth or the decline of renal function has been approved by U.S. Food and Drug Administration. Blood pressure control to a target of 140/90 mmHg is recommended according to the guidelines from the eighth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VIII report) for reducing cardiovascular complications in ADPKD and renal disease progression. More rigorous blood pressure control does not equal greater clinical benefits. Maintaining a target systolic blood pressure to 110 mmHg in patients with moderate or advanced disease may increase the risk of renal disease progression by reducing renal blood flow. Lipid-soluble antibiotics against common gram-negative enteric organisms, such as trimethoprim-sulfamethoxazole, quinolones, and chloramphenicol, are preferred for cyst infection because most renal cysts are not connected to glomerular filtration and antibiotics that are capable of penetrating the cyst walls are likely to be more effective. Treatment often requires 4–6 weeks. The treatment of kidney stones in ADPKD includes standard measures such as analgesics for pain relief and hydration to ensure adequate urine flow. Management of chronic flank, back, or abdominal pain due to renal enlargement may include both pharmacologic (nonnarcotic and narcotic analgesics) and nonpharmacologic measures (transcutaneous electrical nerve stimulation, acupuncture, and biofeedback). Occasionally, surgical decompression of cysts may be necessary. More than half of ADPKD patients eventually require peritoneal dialysis, hemodialysis, or kidney transplantation. Peritoneal dialysis may not be suitable for some patients with massively enlarged polycystic kidneys due to the small intraabdominal space for efficient peritoneal exchange of fluid and solutes and increased chance of abdominal hernia and back pain. Patients with very large polycystic kidneys and recurrent renal cyst infection may require pretransplant nephrectomy or bilateral nephrectomy to accommodate the allograft and reduce the pain.
Specific treatment strategies for ADPKD have focused on slowing renal disease progression and lowering cardiovascular risk. For the latter, the main approach is to control blood pressure by inhibiting the renin-angiotensin-aldosterone system. The ongoing HALT PKD trial was set to evaluate the impact of intensive blockade of the renin-angiotensin-aldosterone system and levels of blood pressure control on progressive renal disease. Most approaches target the slowing of renal disease progression by inhibiting cell proliferation and fluid secretion. Several clinical trials have been conducted targeting cell proliferation, including studies on sirolimus and everolimus, inhibitors of the mTOR pathway; OPC31260 and tolvaptan, which inhibit cAMP pathways by antagonizing the activation of vasopressin V2 receptor (V2R) in collecting ducts and reduce cell proliferation by decreasing renal cAMP levels; and somatostatin analogues, which reduce cAMP levels by binding to several GPCRs. Both the V2R antagonists and somatostatin analogues appear to slow the decline of renal function, although with some side effects such as liver function impairment, polydipsia, and diarrhea. A combination of different growth inhibitors may enhance efficacy and reduce side effects. Additional preclinical studies in animal models include the use of inhibitors to nonreceptor tyrosine kinase Src, B-raf, cyclin-dependent kinase (CDK), transcription factors STAT3 and STAT6 (pyrimethamine and leflunomide), purinergic receptors, hepatocyte growth factor receptor, and glucosylceramide, and agonists to peroxisome proliferator activated receptor-γ (PPARγ receptors (thiazolidodinediones).
AUTOSOMAL RECESSIVE POLYCYSTIC KIDNEY DISEASE
ARPKD is a significant hereditary renal disease in childhood, with an estimated prevalence of 1 in 20,000 live births. A carrier frequency of up to 1:70 has been reported. Mutations in a single gene, PKHD1, are responsible for all the clinical presentations of ARPKD. PKHD1, localized on human chromosome region 6p21.1-6p12.2, is one of the largest genes in the genome, occupies ~450 kb of DNA, and contains at least 86 exons. It produces multiple alternatively spliced transcripts. The largest transcript encodes fibrocystin/polyductin (FPC), which is a large receptor-like integral membrane protein of 4074 amino acids. FPC has a single transmembrane, a large N-terminal extracellular region, and a short intracellular cytoplasmic domain. FPC is localized on the primary cilia of epithelia cells of cortical and medullary collecting ducts and cholangiocytes of bile ducts, similar to polycystins and several other ciliopathy proteins. FPC is also expressed on the basal body and plasma membrane. The large extracellular domain of FPC is presumed to bind to an as yet unknown ligand(s) and is involved in cell-cell and cell-matrix interactions. FPC interacts with ADPKD protein PC2 and may also participate in regulation of the mechanosensory function of the primary cilia, calcium signaling, and PCP, suggesting a common mechanism underlying cystogenesis between ADPKD and ARPKD. FPC is also found on the centrosomes and mitotic spindle and may regulate centrosome duplication and mitotic spindle assembly during cell division. A large number of various mutations have been found throughout PKHD1 and are unique to individual families. Most patients are compound heterozygotes for PKHD1 mutations. Patients with two truncation mutations appear to have an earlier onset of the disease.
Classic ARPKD is generally diagnosed in utero or within the neonatal period and characterized by greatly enlarged echogenic kidneys in diseased fetuses. Reduced fetal urine production may contribute to oligohydramnios and pulmonary hypoplasia. About 30% of affected neonates die shortly after birth due to respiratory insufficiency. Close to 60% of mortality occurs within the first month of life. In the classic group, most patients are born with renal insufficiency and ESRD. However, infants often have a transient improvement in their GFR; death from renal insufficiency at this stage is rare. Some patients are diagnosed after the neonatal stage and form the older group. Morbidity and mortality in this group often involve systemic hypertension, progressive renal insufficiency, and liver manifestations. The hallmarks of ARPKD liver disease are biliary dysgenesis due to a primary ductal plate malformation with associated periportal fibrosis, namely congenital hepatic fibrosis (CHF) and dilatation of intrahepatic bile ducts (Caroli’s disease). CHF and Caroli’s disease can then lead to portal hypertension exhibiting hepatosplenomegaly, variceal bleeding, and cholangitis. Some patients with the diagnosis of ARPKD at 1 year of age with nephromegaly exhibit slowly declining renal function over 20 years with only minimally enlarged kidneys at ESRD and markedly atrophic kidneys following renal transplantation. The slow progression of renal disease is likely due to increasing fibrosis rather than the development of cysts. Systemic hypertension is common in all ARPKD patients, even those with normal renal function.
Ultrasonography, CT, and MRI all can be used for diagnosis. Ultrasonography reveals large, echogenic kidneys with poor corticomedullary differentiation. The diagnosis can be made in utero after 24 weeks of gestation in severe cases. Macrocysts generally are not common at birth in ARPKD patients. The absence of renal cysts in either parent, particularly if they are more than 40 years of age on ultrasonography, helps distinguish ARPKD from ADPKD in older patients. Clinical, laboratory, or radiographic evidence of hepatic fibrosis, hepatic pathology demonstrating characteristic ductal plate abnormalities, family history of affected siblings, or parental consanguinity suggestive of autosomal recessive inheritance is helpful. The lack of mutational hotspots and the large and complex genomic structure of PKHD1 make molecular diagnosis difficult; however, presymptomatic screening of other at-risk members in a family with already identified ARPKD mutations is straightforward and inexpensive.
TREATMENT Autosomal Recessive Polycystic Kidney Disease
There is no specific therapy for ARPKD. Appropriate neonatal intensive care, blood pressure control, dialysis, and kidney transplantation increase survival into adulthood. Complications of hepatic fibrosis may necessitate liver transplantation. Patients with severe Caroli’s disease may need portosystemic shunting. Upcoming therapies may target abnormal cell signaling mechanisms, as described above for ADPKD.