Polycystic Kidney Disease 1 With Or Without Polycystic Liver Disease

A number sign (#) is used with this entry because of evidence that autosomal dominant polycystic kidney disease-1 with or without polycystic liver disease (PKD1) is caused by heterozygous mutation in the PKD1 gene (601313) on chromosome 16p13.

Description

PKD1, an autosomal dominant form of polycystic kidney disease (ADPKD), has the cardinal manifestations of renal cysts, liver cysts, and intracranial aneurysm. Acute and chronic pain and nephrolithiasis are common complications. The most serious renal complication is end-stage renal disease, which occurs in approximately 50% of patients by the age of 60 years. The typical age of onset is in middle life, but the range is from infancy to 80 years (summary by Wu and Somlo, 2000).

Genetic Heterogeneity of Polycystic Kidney Disease

Also see polycystic kidney disease-2 (PKD2; 613095), caused by mutation in the PKD2 gene (173910) on chromosome 4q22; PKD3 (600666), caused by mutation in the GANAB gene (104160) on chromosome 11q13; PKD4 (263200), caused by mutation in the PKHD1 gene (606702) on chromosome 6p12; PKD5 (617610), caused by mutation in the DZIP1L gene (617570) on chromosome 3q22; and PKD6 (618061), caused by mutation in the DNAJB11 gene (611341) on chromosome 3q27.

Clinical Features

The phenotypic variability in PKD1 involves differences in the rate of loss of glomerular filtration, the age of reaching end-stage renal disease (ESRD), and the occurrence of hypertension, symptomatic extrarenal cysts, and subarachnoid hemorrhage from intracranial 'berry' aneurysm.

Kidney

Age at onset of renal failure is variable, even within families. Shokeir (1978) described families with typical adult cystic kidney disease in which single individuals died early in life from polycystic renal disease. Zerres et al. (1984) suggested that in patients at risk, detection of 'solitary cysts,' even in 1 kidney, and enlargement of the kidney should be taken as signs of the disease. Zerres et al. (1985) suggested that early manifestation of APKD may aggregate in families because of genetic modifier(s). They diagnosed such a case in utero by ultrasound. A brother and a cousin also had early manifestation. Reeders (1986) described a phenomenal family ascertained through a fetus found incidentally on ultrasonography to have polycystic kidney disease. Adults had more conventional PKD in an autosomal dominant pedigree pattern. This is a situation comparable to the ascertainment of familial tuberous sclerosis by the finding of cardiac rhabdomyomata on prenatal ultrasonography (see 191100).

Among 321 offspring of probands with polycystic kidney disease, Ravine et al. (1991) identified 68 (21%) who had ultrasound evidence of polycystic kidney disease. Of this previously undiagnosed group, 25 (37%) had one or more treatable complications at the time of diagnosis, including 20 cases of hypertension, 7 cases of impaired renal function, and 4 cases of bacterial urinary tract infection. The findings underscored the importance of screening at-risk family members. In 13 large Spanish families, Coto et al. (1992) found that all subjects over the age of 30 who were shown by linkage to carry the mutation had renal cysts by ultrasonography, whereas 40% of carriers of the mutation younger than 30 did not have renal cysts. Hypertension was found to be more frequent in those with renal cysts.

Wirth et al. (1987) studied 6 kindreds in which polycystic kidney disease had early onset with cystic enlargement of the kidneys detected by prenatal sonography in some cases and with death soon after birth in several. Linkage analysis indicated that the gene locus mutant in these families is the same as that in standard adult-onset cases, i.e., the locus on chromosome 16p.

Jeffery et al. (1998) presented a family with adult-onset autosomal dominant polycystic kidney disease in 2 generations, linked to the PKD1 locus and with paternal transmission to the fetus. The fetus carried the PKD1 haplotype and was, therefore, a gene carrier. Progressive hyperechogenic renal enlargement, but no cysts, was documented by serial fetal ultrasounds at 21, 23, and 34 weeks of gestation. Unexpectedly, the newborn renal scan showed normal-sized kidneys with apparently normal corticomedullary differentiation. However, at 11 months of age, the evolution of cysts in 1 kidney, and then in the other kidney at 20 months, was documented by ultrasound in the absence of clinical symptoms or signs.

Germino (1998) indicated that approximately 50% of polycystic kidney disease leads to ESRD and that 4 to 5% of ESRD is due to PKD. The kidneys may achieve an enormous size, approximately 50 pounds in the case of a woman 62 inches tall.

Gastrointestinal

Dalgaard (1963) found liver cysts in 43% of 173 autopsied cases in Denmark. In a review of cases, largely from the literature, Poinso et al. (1954) found that polycystic kidneys occurred in 53% of 224 cases of polycystic livers. Dalgaard (1963) said he had found a regular transition from polycystic liver degeneration to the solitary liver cyst in association with polycystic kidney. Ellis and Putschar (1968) presented the case of a 42-year-old woman with polycystic kidneys and portal hypertension for which splenorenal shunt was performed. Liver biopsy showed 'disseminated microcystic biliary hamartomas, with congenital fibrosis.' The mother died with hypertension, renal disease, and stroke at age 64. Two of her sisters died of renal disease. Two sisters of the proband were said to have polycystic kidney disease. Congenital hepatic fibrosis may occur with normal kidneys or with a variety of renal malformations, most often ectatic renal tubules resembling medullary sponge kidneys (see polycystic kidney, infantile, type I, 263200). Terada and Nakanuma (1988) demonstrated nonobstructive diffuse dilatation of intrahepatic bile ducts in 3 autopsy cases of autosomal dominant adult polycystic disease. Meyenburg complexes and liver cysts not communicating with the biliary tract lumen were also seen. Jordon et al. (1989) described the very rare association of Caroli disease with adult-type polycystic kidney disease. Caroli disease is a rare form of fibropolycystic disease of the hepatobiliary system characterized by segmental cystic dilatation of intrahepatic ducts and associated with intrahepatic cholelithiasis, cholangitis, and hepatic abscesses. It is found more commonly with other forms of cystic renal disease (see 263200). Telenti et al. (1990) reviewed 5 cases of infected hepatic cyst in polycystic kidney disease together with 9 reported cases. Clinical and laboratory features and the use of scanning techniques facilitated diagnosis. The treatment of choice was a combination of percutaneous drainage and antimicrobial therapy.

Scheff et al. (1980) pointed out the high incidence of diverticulosis and diverticulitis in patients with chronic renal failure from polycystic disease. Colonic diverticula affect about 80% of patients with end-stage renal disease (Scheff et al., 1980), and colonic perforation is rather frequent in these patients.

Involvement of the liver is more frequent, more striking, and earlier in onset in females than in males (Germino, 1998).

Cerebrovascular and Cardiovascular

Ditlefsen and Tonjum (1960) described a family in which there were 15 verified and 2 suspected cases of polycystic kidney disease. Six of the patients suffered from cerebral hemorrhage. In 1 of the 6, aneurysm of the middle cerebral artery was verified. Intracranial 'berry' aneurysm is a rather frequently associated malformation. Levey et al. (1983) used decision analysis to assess whether patients with polycystic renal disease should have routine cerebral arteriography for intracranial aneurysms and prophylactic surgery if an aneurysm is detected. They concluded 'no' because the benefit exceeds 1 year only if the prevalence of aneurysm exceeds 30%, the surgical complication rate is 1% or less, and the patient is under 25 years of age. Newer noninvasive tests, such as digital-subtraction angiography, may change this decision.

To determine the prevalence of intracranial aneurysms, Chapman et al. (1992) studied 92 subjects with autosomal dominant polycystic kidney disease who had no symptoms or signs of any neurologic disorder. High-resolution computed tomography (CT) was performed in 60 subjects, 4-vessel cerebral angiography in 21, and both procedures in 11. In 4 of the 88 subjects in whom the radiologic studies were successfully completed, intracranial aneurysms were found, as compared with the prevalence of 1% reported for an angiographic study of the general population. Multiple aneurysms were found in 3 of the 4 subjects. Chapman et al. (1992) concluded that an increased frequency of asymptomatic intracranial aneurysms occurs with polycystic kidney disease, although the 95% confidence interval for their finding (0.1 to 9%) included the possibility of no difference from the prevalence of 1% reported in the general population. They recommended high-resolution CT as a screening test.

Chapman and Hilson (1980) suggested a relationship between polycystic kidneys and abdominal aortic aneurysm. Of 31 patients on chronic dialysis for polycystic kidneys, 3 had aortic aneurysm. Torra et al. (1996) examined this question in detail by means of a sonographic study of the abdominal aorta in 139 APKD patients and in 149 healthy family members. In both groups, an increase in aortic diameter related to age and sex was found, the aortic diameter being wider in older men than in women. In APKD patients, neither a wider aortic diameter nor a higher prevalence of abdominal aortic aneurysms could be found in any age group. They concluded that, although these patients are prone to develop aortic aneurysms because of hypertension and possibly associated connective tissue disorders, abdominal aortic aneurysm does not appear to be a frequent feature.

Hossack et al. (1988) used echocardiography, including Doppler analysis, to assess the prevalence of cardiac abnormalities in 163 patients with autosomal dominant polycystic kidney disease, 130 unaffected family members, and 100 control subjects. In these 3 groups the prevalence of mitral valve prolapse was 26, 14, and 2%, respectively. A higher prevalence of mitral regurgitation, aortic regurgitation, tricuspid regurgitation, and tricuspid valve prolapse was also found in the patients with polycystic kidney disease. Hossack et al. (1988) interpreted these findings as reflecting the systemic nature of polycystic kidney disease and supporting the hypothesis that the disorder results from a defect in the extracellular matrix and that the cardiac abnormalities are an expression of that defect.

A combination of hypertension and fundamental defect may be involved in the occurrence of dissecting aneurysm of the aorta, as described in an African American man in his twenties (Germino, 1998). (The patient had a history of PKD and was known to have hypertension at the age of 18 years, 2 intracranial aneurysms at the age of 24 years, and dissecting aneurysm at the age of 27 years.) Both intracranial and aortic aneurysm appear to cluster in families.

Miscellaneous

Emery et al. (1967) observed the coincidence of myotonic dystrophy (160900) and polycystic kidneys in at least 3 members of a family.

Zerres et al. (1984) gave a comprehensive review of all forms of cystic kidney disease. They suggested that since the Potter type III is pathogenetically and genetically heterogeneous, the term should not be used synonymously for autosomal dominant polycystic kidney disease. Zerres et al. (1985) pointed out that patients on long-term renal hemodialysis develop cystic kidneys that can be nearly impossible to distinguish from autosomal dominant cystic kidney disease.

Gabow (1993) reviewed all aspects of the genetics, pathogenesis, clinical manifestations, and diagnosis of autosomal dominant polycystic kidney disease. She indicated that approximately 50% of patients have hepatic cysts and that these increase with age. Hypertension affects more than 80% of patients with end-stage renal disease. Renal failure is estimated to affect 45% of patients by the age of 60.

In the 10 families with a PKD1 mutation (i.e., linked to markers on chromosome 16) reported by Parfrey et al. (1990), 46% of the members less than 30 years old who had a 50% risk of inheriting a mutation had renal cysts, as compared with 11% of such members in the 2 families without linkage (P less than 0.001). In the PKD1 families, all 67 diagnoses made by ultrasonography were confirmed by determination of the genotype as inferred from linkage. Of the 48 members less than 30 years old who inherited the PKD1 mutation, 40 had renal cysts. All 27 members 30 years old or older who inherited the mutation had renal cysts, suggesting that the probability of a false-negative diagnosis did not exceed 0.13 in this age group. The mean age at onset of end-stage renal disease among members of the PKD1 families was 56.7 +/- 1.9 years, as compared with 69.4 +/- 1.7 years among members of the unlinked families (P = 0.0025). Hypertension and renal impairment were less frequent and occurred later in the families without the PKD1 mutation.

In a survey in France involving 889 affected subjects, Simon (1995) found no difference in the cumulative survival to end-stage renal disease between males and females. By the age of 50 years, 22% of the patients had ESRD, by the age of 58, 42%, and by the age of 73, 72%. They found that males under 65 years of age have a rate of progression toward renal failure that is significantly more rapid than in females of the same age group. The risk linked to gender disappeared after 65 years of age.

Somlo et al. (1993) described a family in which an overlap connective tissue disorder (OCTD) cosegregated with the chromosome 16-linked form of APKD. The connective tissue phenotype in this family included aortic root dilation, aortic and vertebral artery aneurysms with dissection, and aortic valve incompetence, as well as pectus abnormalities, pes planus, joint laxity, arachnodactyly, scoliosis, dolichostenomelia, and high arched palate. Two markers flanking the PKD1 region were tightly linked to both APKD and OCTD.

Perrone (1997) led a discussion of extrarenal manifestations of APKD. The increased frequency of diverticular disease was reviewed, including the increased risk of colonic perforation after renal transplantation. The mechanism of this, as well as other extrarenal complications, is unclear.

Mapping

Reeders et al. (1985) showed that the PKD1 locus is closely linked to the alpha-globin locus (141800) on 16p (lod = 25.85, theta = 0.05, 99% confidence limits = 2-11 cM). In establishing this linkage, they used a highly polymorphic region about 8 kb beyond the 3-prime end of the alpha-globin cluster (3-prime-HVR = 3-prime-hypervariable region). In the Oxford data (Reeders, 1985), PKD1 versus phosphoglycolate phosphatase (172280) showed a lod score of 8.21 at theta = 0.0. PGP and HBA showed a lod score of 11.61 at theta = 0.0. In 13 South Wales kindreds, Lazarou et al. (1987) found a maximum lod score of 24.187 at a recombination fraction of 0.03 for linkage between PKD1 and alpha-globin. Despite phenotypic heterogeneity, they found no evidence of linkage heterogeneity.

Watson et al. (1987) found tight linkage of PKD1 and PGP; the maximum likelihood value of the recombination fraction was 0.0 with a lod score of 5.5. Together with the PKD1 versus HVR linkage data, these findings may indicate that PKD1 and PGP are on the 5-prime side of the alpha-globin cluster. The polarity of the HBAC viz-a-viz the centromere is unknown. The recombination fraction for the 3-prime-HVR and PKD1 is somewhat greater in males than in females (Reeders, 1986)--an anomalous finding. Reeders et al. (1985) found no definite recombination between PGP and PKD1. HBAC is distal to PKD1 but whether PGP is proximal or distal to PKD1 is unknown. The evidence on location of HBAC is conflicting, with assignments from 16p13.11 to 16p13.33. Reeders et al. (1988) described an array of linked markers that bracket the PKD1 locus. Germino et al. (1990) demonstrated a DNA marker, D16S84, that showed no recombination with PKD1 in 201 informative meioses.

Pound et al. (1992) presented evidence for linkage disequilibrium between PKD1 and D16S94. Breuning et al. (1990) further defined the location of markers on 16p in the vicinity of the PKD1 locus. Harris et al. (1991) identified closely linked microsatellite polymorphisms that could be used in a PCR-based assay for a rapid, inexpensive, and nonradioactive method of linkage analysis.

Gal et al. (1989) studied 10 families in which early manifestation of the disorder was a frequent finding. In all families studied, close linkage was observed between the chromosome 16 alpha-globin marker and the PKD1 locus. They concluded that there is no evidence for genetic heterogeneity of APKD in families with early- and later-onset disease. In 28 northern European pedigrees from England, Scotland, Holland, and eastern Finland, Reeders et al. (1987) found no evidence of heterogeneity of the linkage of PKD1 with alpha-globin. (The recessive form of early-onset polycystic kidney disease is probably not linked to HBA (Reeders, 1986).)

Zerres et al. (1993) also investigated 79 children with early manifestation of autosomal dominant polycystic kidney disease. They belonged to 64 families (64 index patients and 15 affected sibs). Early manifestation was defined as clinical manifestations (hypertension, proteinuria, impaired renal function, palpably enlarged kidneys) occurring before the age of 15 years. A strong familial clustering for early manifesting APKD was found; out of the total of 65 sibs of the 64 index patients, 15 showed comparably early manifestation. Another 10 symptom-free children were diagnosed sonographically as having ADPKD before the age of 18 years. The authors noted that high recurrence risk to sibs has important implications for genetic counseling and clinical care of affected families.

Among the same 17 families reported by Bear et al. (1984, 1992), Parfrey et al. (1990) found that polycystic kidney disease cosegregated with polymorphic DNA markers flanking the PKD1 locus in 10; in 2 families cosegregation did not occur, and in 5 families linkage could not be determined because of uninformativeness of the markers.

Ryynanen et al. (1987) did linkage studies in a 4-generation Finnish family with polycystic kidney disease; all affected members of the extended pedigree were asymptomatic and none had developed renal failure. They showed that the mutation in this family was closely linked to the alpha-globin cluster. This might be an allelic disorder. Using DNA from a set of multigenerational families from CEPH (Centre d'etude polymorphisme humaine, Paris), Keith et al. (1987) constructed a genetic map of chromosome 16 based on 40 polymorphic DNA markers. The map spanned 142 cM in males, somewhat larger than the 108 cM previously estimated by chiasma counts. Males had higher recombination fractions near the alpha-globin gene cluster, but females showed higher recombination in other regions.

Germino et al. (1992) demonstrated that the PKD1 gene lies within an extremely CpG-rich 750-kb segment of 16p13.3. Its genetic localization with respect to physically mapped markers in this segment was refined by Somlo et al. (1992).

In the Spanish population, Peral et al. (1993) typed 31 families from different geographic areas using marker loci flanking PKD1 on 16p. Multilocus linkage analysis indicated that in 26 families the disease resulted from PKD1 mutations, whereas in 3 families it resulted from mutations in a locus other than PKD1; 2 other families were not informative. Using the HOMOG test, they estimated that PKD1-linked mutations were responsible for 85% of families with PKD in Spain.

Heterogeneity

In a study of genetic heterogeneity of autosomal dominant polycystic kidney disease in the French Canadian population, Daoust et al. (1995) identified a family in which a classic clinical presentation of APKD resulted from a mutation at a locus genetically distinct from both 16p and 4q.

In a group of Portuguese families with polycystic kidney disease, de Almeida et al. (1995) excluded linkage to both the PKD1 and PKD2 loci, indicating genetic heterogeneity.

On the basis of linkage studies in a large Danish kindred with a form of adult PKD unlinked to chromosome 16, Norby and Schwartz (1990) had suggested that the locus is on chromosome 2 (maximum lod score of 2.12 at marker D2S44 on 2q). However, Peters et al. (1993) found linkage to 4q in the family of Norby and Schwartz (1990).

Ariza et al. (1997) described a 2-generation Spanish family with PKD in which linkage to the PKD1 and PKD2 loci was excluded. The proband, a 36-year-old female, suffered from hypertension attributed to atrophy of the left kidney. There was no family history of any inherited kidney disorder. The proband, her father, who was diagnosed as mildly hypertensive at age 67, and an asymptomatic sib were found to have bilateral renal cysts. Ariza et al. (1997) suggested that the mild phenotype in this family could imply that a number of non-PKD1/non-PKD2 families might remain undiagnosed, leading to an underestimate of the frequency of this condition.

Paterson and Pei (1998) reviewed the common confounders that could lead to false exclusion of linkage to the known genes for APKD and thus to presumption of the existence of a PKD3 gene. Based on theoretical arguments, they suggested that families with bilineal APKD (i.e., transmission of 2 independent PKD mutations within the same family) may exist and may result in apparent exclusion of linkage to the known genes. Indeed, they pointed out that careful inspection of PKD1 haplotypes in the Portuguese 'PKD3' family reported by de Almeida et al. (1995) showed 4 intermarker recombinants between 2 markers 9.0 cM apart. Approximately one intermarker recombinant would be expected for every 10 chromosomes genotyped for markers this close. The authors cited problems with the interpretation of the linkage results in other families as well.

McConnell et al. (2001) described a family unlinked to PKD1 or PKD2 in which the presenting feature was subarachnoid hemorrhage secondary to cerebral aneurysm in 3 sisters. Two of the 3 sisters also had cysts, one of liver and kidney and one of liver alone. The remaining sister did not have any cysts, but had a parent with multiple renal cysts and a son with renal cysts. The individuals who presented with subarachnoid hemorrhage secondary to cerebral aneurysm were normotensive at the time of presentation.

Molecular Genetics

The European Polycystic Kidney Disease Consortium (1994) isolated the PKD1 gene, which they called PBP for 'polycystic breakpoint,' by analysis of the translocation breakpoint in a family with polycystic kidney disease. The mother and daughter, who both carried a balanced translocation, 46,XX t(16;22)(p13.3;q11.21), had clinical features of PKD1. The authors then identified mutations in the PBP gene in other patients with PKD1.

Peral et al. (1995) sought mutations in the PKD1 gene in this disorder. Analysis of 3 regions in the 3-prime part of the gene revealed 2 mutations that occurred by a novel mechanism. Both were deletions (of 18 or 20 bp) within the same 75-bp intron and, although these deletions did not disrupt the splice donor or acceptor sites at the boundary of the intron, they nevertheless resulted in aberrant splicing. Two different transcripts were produced in each case; one included the normally deleted intron while the other had a 66-bp deletion due to activation of a cryptic 5-prime splice site. No normal product was generated from the deletion-mutant gene. Peral et al. (1995) speculated that aberrant splicing probably occurred because the deletion made the intron too small for spliceosome assembly using the authentic splice sites. They also identified a 9-bp direct repeat within the intron, which probably facilitated the intronic deletion by promoting misalignment of sequence.

Qian et al. (1996) developed a novel method for isolating renal cystic epithelia from single cysts and showed that individual renal cysts in PKD1 are monoclonal. Loss of heterozygosity (LOH) was discovered within a subset of cysts for 2 closely linked polymorphic markers located within the PKD1 gene. Genetic analysis revealed that it was the normal haplotype that was lost. The findings provided a molecular explanation for the focal nature of cyst formation and a probable mechanism whereby mutations cause disease. The high rate at which 'second hits' must occur to account for the large number of cysts observed suggested to Qian et al. (1996) that unique structural features of the PKD1 gene may be responsible for its mutability. (This is a remarkable example of the Knudson 2-hit mechanism, which has been established in a considerable number of neoplasms whose causation is based on inactivation of both copies of a tumor-suppressor gene.) They previously reported an extremely unusual 2.5-kb polypyrimidine tract within intron 21 of the PKD1 gene that they postulated as being responsible for the gene's increased rate of mutation (Burn et al., 1995). Qian et al. (1996) postulated that the polypyrimidine tract may cause ongoing errors in its transcription-coupled repair, thus resulting in a high frequency of somatic mutation. Thus, they concluded that PKD1 is a recessive disorder when viewed at the level of the individual renal lesions.

Brasier and Henske (1997) likewise found evidence of clonal chromosomal abnormalities in some renal cyst epithelial cells with loss of the wildtype copy of PKD1. Twenty nine cysts from 4 patients were studied using microsatellite markers from the 16p13 region and looking for LOH. This supported a loss-of-function model for autosomal dominant PKD, with a germline mutation inactivating one copy of PKD1 and somatic mutation or deletion inactivating the remaining wildtype copy.

For a review of the molecular mechanisms underlying ADPKD, see Wu and Somlo (2000).

Genotype/Phenotype Correlations

Familial clustering of intracranial aneurysms suggested that genetic factors are important in the etiology of ADPKD. Rossetti et al. (2003) characterized mutations in 58 ADPKD families with vascular complications; 51 were PKD1 (88%) and 7 were PKD2 (12%). The median position of the PKD1 mutation was significantly further 5-prime in the vascular population than in the 87 control pedigrees (amino acid position 2163 vs. 2773, p = 0.0034). Subsets of the vascular population with aneurysmal rupture, early rupture, or families with more than 1 vascular case had median mutation locations even further 5-prime.

Pathogenesis

Chapman et al. (1990) reported that the renin-angiotensin-aldosterone system is stimulated significantly more in hypertensive patients with polycystic kidney disease than in comparable patients with essential hypertension. They interpreted this as indicating that increased renin release, perhaps due to renal ischemia caused by cyst expansion, probably contributes to the early development of hypertension in polycystic kidney disease.

Reeders (1992) put forward an interesting 2-hit mutational hypothesis for PKD1. He pointed out the several unusual features such as the absence of detectable abnormalities in most nephrons; even in the end-stage disease, less than 10% of the roughly 1 million nephrons in each kidney contain cysts. Furthermore, any segment of the nephron, from the glomerulus to the collecting duct, may harbor a cyst. The hypothesis suggests that at the sites of cyst formation, a somatic mutation occurs in the chromosome 16 that does not carry the inherited mutation. A prediction of the 2-hit model is that renal cysts will occasionally be found in persons without an inherited predisposition as a result of two somatic mutations occurring in a single cell. One or 2 renal cysts are a common radiologic finding in the general population and the probability of finding a cyst in an individual does, as predicted, rise with age. The 2-hit model predicts that the number of cysts would increase with age in PKD1.

Wilson et al. (1991) found evidence of reversed polarity of sodium-potassium-ATPase in renal tubule cells lining the cysts in this disorder. Immunostaining with antibodies directed against the catalytic alpha-subunit (182310) was confined to apical, luminal plasma membranes of PKD epithelia, a complete reversal of the normal renal tubule polarized location in basolateral membranes. Mislocated sodium-potassium-ATPase was shown to be functionally active, because identical intense apical staining was observed by use of a cytochemical assay. There was also an overall 6-fold stimulation of specific activity of the ATPase in the cystic areas of early-stage APKD kidneys.

Ye and Grantham (1993) studied in vitro intact cysts that were excised from kidneys removed from patients with end-stage polycystic kidney disease. They demonstrated that the cysts can secrete fluid, and that net fluid secretion can be increased by an unidentified secretagogue in cyst fluid. These results suggested that the process of cyst enlargement may be susceptible to pharmacologic intervention. Normal and polycystic human kidney cells can be cultured as monolayers in vitro. Woo et al. (1994) reported that, when placed in a stationary suspension culture system free from the influences of glomerular filtration, renal tubular obstruction, and uremia, epithelial cells from human and mouse polycystic kidneys spontaneously develop into cysts in a process that superficially resembles the formation of the blastocele cavity. The ability of primary cells from polycystic kidneys to form cysts in vitro indicates that they possess intrinsic morphogenetic information that is absent in normal kidney cells. Inhibitors of DNA, RNA, and protein synthesis did not prevent in vitro cyst formation, but it was reversibly inhibited by ouabain, amiloride, and the microtubule-specific agents colchicine, vinblastine, and taxol. As discussed elsewhere (263200), cpk mice is a well-characterized recessive polycystic kidney disease model. Woo et al. (1994) found that the cpk/cpk mouse developed PKD and died from uremia by 4-5 weeks of age, but when treated weekly with taxol they survived for more than 200 days with minimal loss of renal function, showed limited collecting-duct cyst enlargement, and obtained adult size. The results were interpreted as indicating that the microtubule cytoskeleton has a central role in the pathogenesis of PKD in cpk mice and that taxol may be useful also in treating human polycystic kidney disease. Woo et al. (1994) considered it plausible that aberrations of cellular functions mediated by microtubules may lead to the apical mislocation of Na(+), K(+)-ATPase, and epithelial growth factor receptors in both human and murine PKD.

Hypothesizing that the progressive deterioration of renal function in polycystic kidney disease might result from a form of programmed cell death (apoptosis), Woo (1995) assayed apoptotic DNA fragmentation in normal and polycystic kidneys biochemically by gel electrophoresis and histochemically by in situ end-labeling. A DNA-specific dye, Hoechst 33258, was used to detect morphologic apoptosis in renal samples from patients with normal kidneys, polycystic kidney disease, and other kidney diseases. Apoptotic DNA fragmentation was detected in polycystic kidneys from 5 patients without renal failure and 11 patients with renal failure but not in kidneys from 12 patients with no renal disease. In situ end-labeling revealed apoptotic cells in glomeruli, cyst walls, and in both cystic and noncystic tubules of the polycystic kidneys. No tubular apoptosis was detected in renal-biopsy specimens from 5 patients with IgA nephropathy, 3 patients with nephrosclerosis, 2 patients with focal glomerulosclerosis, 1 patient with diabetic nephropathy, 6 patients with acute tubular necrosis, or 4 patients with acute and 4 patients with chronic renal-transplant rejection. The capacity of polycystic kidney cells to undergo apoptosis was retained in vitro in the absence of uremia, ischemia, and other confounding pathologic conditions.

At a point when only 7 mutations in the PKD1 gene had been described, Peral et al. (1996) reported a systematic screen covering nearly 80% of the approximately 2.5 kb of translated transcript that is encoded by a single-copy DNA. They identified and characterized 6 novel mutations that, together with the previously described changes, amounted to a detection rate of 10 to 15% in the population studied. Study of the PKD1 mutation search in the PKD1 gene is complicated by the fact that most of the gene lies in a genomic region reiterated several times elsewhere on chromosome 16. The results of the study of Peral et al. (1996) had important implications for genetic diagnosis of PKD1 because they indicated that most of the mutations lie within the duplicated area that is difficult to study. Peral et al. (1996) provided a diagram of the structure of the polycystin protein with an indication of the site of the mutations described to date. Comparison of the phenotypes of patients with large frameshifting or terminating changes and those with more subtle in-frame changes showed no obvious differences, suggesting that they may all be inactivating changes. They cited evidence of an alternatively spliced form of PKD1 that contains an additional exon in intron 16. Inclusion of this exon would change the reading frame and result in the production of a much smaller protein product. Hence they suggested that all PKD1 mutations may be inactivating, but those in typical families disrupt just the full-length polycystin, whereas those associated with large deletions disrupt both forms of the PKD1 protein, resulting in a more severe, early-onset disease.

Peral et al. (1996) described a tyr3818-to-ter mutation in the PKD1 gene (601313.0007) in a severely affected child. They found the same mutation in her clinically normal twin brother and in her father who had typical adult-onset disease. Because the same stable mutation was associated with very different disease severity in this family, Peral et al. (1996) proposed that a small number of modifying factors may radically affect the course of type 1 polycystic kidney disease.

A central problem in the study of PKD pathogenesis is to understand the cellular mechanisms that trigger cyst formation. Lin et al. (2003) provided new insight into this problem by showing that kidney-specific Cre-loxP inactivation of the gene for the KIF3A (604687) subunit of kinesin II, an anterograde (outward moving) ciliary motor protein, causes PKD, thus directly implicating cilia in the cyst-forming mechanism. Nauli et al. (2003) showed that polycystin-1 (601313) and polycystin-2 (173910) mediate the mechanosensory function of cilia. It was unclear whether polycystic kidney disease is caused by loss of cilia or by loss of the polycystins from the cilia.

Wilson (2004) provided a review of the pathogenetic mechanisms in the various forms of polycystic kidney disease.

To elucidate the molecular pathways that modulate renal cyst growth in ADPKD, Song et al. (2009) used cDNA microarray gene profiling of cysts of different size and minimally cystic tissue (MCT) from 5 PKD1 human polycystic kidneys. The authors found downregulation of kidney epithelial-restricted genes (e.g., nephron segment-specific markers and cilia-associated cystic genes such as HNF1B (189907), PKHD1 (606702), IFT88 (600595), and CYS1) in the PKD1 renal cysts. Upregulated genes in PKD1 cysts included those associated with renal development, mitogen-mediated proliferation, cell cycle progression, epithelial-mesenchymal transition, hypoxia, aging, and immune/inflammatory responses. The authors suggested that upregulated signaling of Wnt/beta-catenin, pleiotropic growth factors, such as VEGF (192240), and G protein-coupled receptors, such as PTGER2 (176804), was associated with renal cystic growth. By integrating these pathways with a number of dysregulated networks of transcription factors, including SRF (600589), Song et al. (2009) suggested that epithelial dedifferentiation accompanied by aberrant activation and crosstalk of specific signaling pathways may be required for PKD1 cyst growth and disease progression.

Diagnosis

By Ultrasound

Begleiter et al. (1977) noted that ultrasound is a valuable addition to our armamentarium for study of cystic kidney families. Sahney et al. (1982) suggested that when an adult with end-stage renal disease due to polycystic kidneys is encountered without previous genetic counseling (as was usually the case in their experience), any children over 16 years of age should have intravenous pyelography with nephrotomography; those with negative studies should be tested periodically with ultrasonography until age 25 years. Diagnosis by ultrasonography not only in adults but also in the fetus was demonstrated by Zerres et al. (1982). Sahney et al. (1983) recommended ultrasonography as the initial screening method in asymptomatic relatives, followed by intravenous pyelography if the sonogram is abnormal but not diagnostic.

Sedman et al. (1987) performed ultrasonography or excretory urography in 154 children aged 18 years or younger from 83 families with ADPKD. They concluded that those children diagnosed under 1 year of age may have a deterioration of renal function early in life; however, those identified in childhood by screening may have a benign early course. In their opinion, the finding of a single renal cyst in a child in an ADPKD family should be considered suggestive of the disease. Further, with history, physical examination, and ultrasonography, ADPKD may be identifiable in as many as two-thirds of affected subjects during childhood.

From a study of 371 at-risk persons in 17 kindreds in Newfoundland, Bear et al. (1984) estimated the probability of clinical diagnosis of APKD to be 0.011 by age 20, 0.041 by age 30, 0.115 by age 40, 0.299 by age 50, and 0.404 by age 60 years (expected = 0.50). Ultrasonography of 172 asymptomatic at-risk persons showed definite APKD in 60. The probability of ultrasonographic detection of asymptomatic APKD was estimated as 0.222, 0.657, and 0.855 at ages 5, 15, and 25 years, respectively. On the basis of further analyses, Bear et al. (1992) stated that in 2 families in which the disorder was not coinherited with chromosome 16 markers, only 11% of members aged less than 30 years had kidney cysts and the mean age of onset of end-stage renal disease was later (68.7 years) than for persons with the chromosome 16 form of the disease (56.3 years). In PKD1 families, the age of onset of ESRD was unrelated to the sex of the affected person but was earlier in persons inheriting the disease from their mother than in those inheriting it from the father: 50.5 versus 64.8 years (P = 0.004). In PKD1 families, resemblance in age of onset of ESRD was less within than between families, and risk of false negative ultrasonographic diagnosis appeared to be restricted largely to families in which ESRD occurred relatively late.

Dobin et al. (1993) reported the results of classic segregation analysis on 159 families with PKD. They found that penetrance at the early ages of onset had increased during the previous decade, presumably because of improvements in renal imaging and consequent earlier age of diagnosis. In their study, the mean age of diagnosis was estimated to be 20 years, with a standard deviation of 15.94. Over 70% penetrance was estimated by age 30 years, over 95% by 50 years, and 99% by 55 years. The segregation ratio was not significantly different from 0.50, but its confidence limits were broad: 0.36 to 0.64. Neither transmission probability nor penetrance was significantly influenced by gender. The mutation was estimated to be 6.9 x 10(-5), consistent with the previously observed high mutation rate for PKD. Dobin et al. (1993) suspected, however, that the mutation rate was overestimated in their study because it neglected low penetrance alleles and phenocopies.

Ravine et al. (1994) used DNA linkage among subjects from 128 sibships within 18 PKD1 families to assess ultrasound sensitivity. Currently used criteria (bilateral cysts with at least 2 in one kidney) provided good sensitivity (88.5% at age 15-29 years and 100% at 30 years and above), but performance could be improved by less stringent criteria in subjects aged 15-29 years and more stringent criteria in older family members in whom simple renal cysts are frequent. The presence of at least 2 renal cysts (unilateral or bilateral) in individuals at risk and younger than 30 years may be regarded as sufficient to establish a diagnosis; among those aged 30-59 years, the presence of at least 2 cysts in each kidney may be required, and among those aged 60 years and above, at least 4 cysts in each kidney should be required.

By Linkage

Trent and Wallace (1989) and Vinet et al. (1989) demonstrated that the presence of deletion type alpha(+)-thalassemia is a potential source of error in DNA linkage studies for PKD1. The Caucasian family studied by Vinet et al. (1989) had the leftward type of deletion alpha(+)-thalassemia which, except for 1 case in a Mediterranean population (Troungos et al., 1984), had been described only in Asiatic populations (Winichagoon et al., 1984).

Hannig et al. (1991) reported on experiences with presymptomatic testing for APKD by DNA linkage analysis on potential renal donors among relatives of patients. They emphasized that thorough counseling before DNA analysis (including discussion of accuracy and possible testing outcomes of presymptomatic diagnosis of APKD, diagnosis of noncarrier status, false paternity, and noninformative study) was essential for informed consent and to preserve confidentiality within the family. Confidentiality of potential donors found presymptomatically to be affected (with a 94% or greater probability) was especially difficult to maintain. Since the use of living, related donors for renal transplants provides significant advantages over cadaver donors, Hannig et al. (1992) focused on the fact that presymptomatic testing to determine the PKD status of potential donors is an important consideration and DNA linkage analysis is potentially more accurate than renal ultrasound for prospective donors less than 30 years of age. Hannig et al. (1992) found that of 5,026 renal transplants done in 1988, 390 (7.8%) involved a PKD1 recipient. Only 7% of these 390 transplants used a living, related donor compared to the 20% rate reported for all renal transplants. DNA linkage studies were not used by any of the centers surveyed and only 29% reported provision of risk counseling. Hannig et al. (1992) suggested that this represented an unfortunate failure to take full advantage of DNA testing. In 13 large Spanish families, Coto et al. (1992) found that all subjects over the age of 30 who were shown by linkage to carry the mutation had renal cysts by ultrasonography, whereas 40% of carriers of the mutation younger than 30 did not have renal cysts.

Prenatal Diagnosis

Breuning et al. (1990) recommended that prenatal diagnosis of PKD by chorionic villus sampling should be attempted only after the linkage phase of the DNA markers has been established by haplotyping the index family. Furthermore, the families should be of sufficient size to rule out the rare form of PKD not caused by a mutation on 16p.

A survey by Hodgkinson et al. (1990) seemed to indicate that there would be little demand for prenatal diagnosis of this disorder on the basis of linkage or any other method.

Although ADPKD is typically a late-onset disorder, ultrasonography has permitted the detection of the disorder in the newborn or infant in some instances and occasionally even prenatally (Pretorius et al., 1987; Ceccherini et al., 1989). Turco et al. (1993) described a case of bilateral microcystic kidneys being detected by fetal ultrasonography at 20 weeks' gestation. Polycystic kidneys were demonstrated at birth. The mother and at least 14 other members of the family had typical ADPKD. In addition to the renal involvement, the newborn had complex skeletal manifestations including bilateral complete syndactyly of the hands and feet, bilateral polydactyly of the feet, and bilateral agenesis of the tibia. Molecular studies indicated that the infant had inherited the disease-bearing chromosome 16 haplotype from his mother.

Clinical Management

Pirson (1996) reviewed recent advances in the clinical management of autosomal dominant polycystic kidney disease. He pointed out that, as in other kidney diseases in adults, males reach end stage renal failure (ESRF) 5 to 6 years earlier than females. A deleterious role of hypertension was suggested by Geberth et al. (1995), who showed that the renal prognosis of ADPKD was worse in individuals born to an unaffected parent with essential hypertension than in those born to a normotensive unaffected parent. By contrast, intervention studies failed to demonstrate a beneficial effect of reduction of blood pressure on the 3-year progression of renal failure in patients with creatinine clearance between 13 and 60 ml/min. This does not mean, however, that earlier