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Polycystic Kidney Disease, Autosomal Dominant

Synonym: ADPKD. Includes: Polycystic Kidney Disease Type 1 (PKD1), Polycystic Kidney Disease Type 2 (PKD2)

, PhD and , MD.

Author Information
, PhD
Division of Nephrology and Hypertension
Mayo Clinic
Rochester, Minnesota
, MD
Division of Nephrology and Hypertension
Mayo Clinic
Rochester, Minnesota

Initial Posting: ; Last Update: December 8, 2011.


Disease characteristics. Autosomal dominant polycystic kidney disease (ADPKD) is generally a late-onset multisystem disorder characterized by bilateral renal cysts; cysts in other organs including the liver, seminal vesicles, pancreas, and arachnoid membrane; vascular abnormalities including intracranial aneurysms, dilatation of the aortic root, and dissection of the thoracic aorta; mitral valve prolapse; and abdominal wall hernias. Renal manifestations include hypertension, renal pain, and renal insufficiency. Approximately 50% of individuals with ADPKD have end-stage renal disease (ESRD) by age 60 years. The prevalence of liver cysts, the most common extrarenal manifestation of ADPKD, increases with age and may have been underestimated by ultrasound and CT studies. The prevalence of intracranial aneurysms is higher in those with a positive family history of aneurysms or subarachnoid hemorrhage (22%) than in those without such a family history (6%). Mitral valve prolapse, the most common valvular abnormality, occurs in up to 25% of affected individuals. Substantial variability in severity of renal disease and other extrarenal manifestations occurs even within the same family.

Diagnosis/testing. The diagnosis of ADPKD is established primarily by imaging studies of the kidneys. In 85% of individuals with ADPKD, mutations in PKD1 are causative; in 15% mutations in PKD2 are causative.

Management. Treatment of manifestations: Treatment for hypertension may include ACE inhibitors or angiotensin II receptor blockers and diet modification. Conservative treatment of flank pain includes nonopioid agents, tricyclic antidepressants, narcotic analgesics, and splanchnic nerve blockade. More aggressive treatments include cyst decompression with cyst aspiration and sclerosis, laparoscopic or surgical cyst fenestration, and renal denervation. Cyst hemorrhage and/or gross hematuria are usually self-limited. Treatment of nephrolithiasis is standard. Treatment of cyst infections is difficult. The mainstay of therapy for ruptured or symptomatic intracranial aneurysm is surgical clipping of the ruptured aneurysm at its neck; however, for some individuals, endovascular treatment with detachable platinum coils may be indicated. Thoracic aortic replacement when the aortic root diameter exceeds established size.

Surveillance: MRI screening for intracranial aneurysms in those determined to be at high risk.

Agents/circumstances to avoid: Long-term administration of nephrotoxic agents, caffeine (which may promote renal cyst growth), use of estrogens by individuals with severe polycystic liver disease, and smoking.

Evaluation of relatives at risk: Testing of adult relatives at risk permits early detection and treatment of complications and associated disorders.

Genetic counseling. ADPKD is inherited in an autosomal dominant manner. About 95% of individuals with ADPKD have an affected parent and about 5% have a de novo mutation. Each child of an affected individual has a 50% chance of inheriting the mutation. Prenatal testing for pregnancies at increased risk is possible if the family-specific mutation is known or if linkage has been established in the family.


Clinical Diagnosis

Autosomal dominant polycystic kidney disease (ADPKD) is a multisystem disorder characterized by the following:

  • Bilateral renal cysts (see Renal cysts)
  • Cysts in other organs including the liver, seminal vesicles, pancreas, and arachnoid membrane
  • Extrarenal abnormalities including intracranial aneurysms and dolichoectasias, dilatation of the aortic root and dissection of the thoracic aorta, mitral valve prolapse, and abdominal wall hernias
  • The absence of manifestations suggestive of a different renal cystic disease

In an individual with a positive family history of ADPKD

  • The enlargement of the kidneys or liver on physical examination is highly suggestive of the diagnosis;
  • The presence of hypertension, mitral valve prolapse, or abdominal wall hernia is suggestive of the diagnosis.

Note: Definitive diagnosis relies on imaging and/or molecular genetic testing.

In the absence of a family history of ADPKD, the presence of bilateral renal enlargement and cysts with or without the presence of hepatic cysts and the absence of other manifestations suggestive of a different renal cystic disease provide presumptive, but not definite, evidence for the diagnosis. Molecular testing may provide a definitive diagnosis (see Testing Strategy).

Renal cysts

  • Age-specific ultrasound criteria to confirm a diagnosis of ADPKD have been proposed for individuals who are at 50% risk for ADPKD because they have an affected first-degree relative [Pei et al 2009].

    Note: The positive predictive value of these criteria is 100%, regardless of the underlying genetic cause or the age of the individual at the time of initial evaluation. However, the sensitivity of the criteria depends on the underlying genotype and the age of the individual at the time of evaluation (see Table 1).

    • The presence of three or more (unilateral or bilateral) renal cysts in an individual aged 15-39 years
    • The presence of two or more cysts in each kidney in an individual aged 40-59 years
  • Large echogenic kidneys without distinct macroscopic cysts in an infant/child at 50% risk for ADPKD are diagnostic.

Note: Although the ultrasound criteria listed above are appropriate to establish a diagnosis of ADPKD in an individual at risk, their sensitivity is low (Table 1, 81.7%-95.5%), particularly in families who have a PKD2 mutation (69.5%-94.9%). In this situation, a significant number of affected individuals may not be diagnosed, which may pose a problem when exclusion of the diagnosis is critical (see Testing Strategy, Presymptomatic diagnosis).

Table 1. Ultrasound Criteria for Diagnosis of ADPKD in Individuals at 50% Risk for ADPKD Based on Family History

AgePKD1PKD2Unknown ADPKD Genotype
15-30 years≥3 cysts 1
PPV = 100%
SEN = 94.3%
≥3 cysts 1
PPV = 100%
SEN = 69.5%
≥3 cysts 1
PPV = 100%
SEN = 81.7%
30-39 years≥3 cysts 1
PPV = 100%
SEN = 96.6%
≥3 cysts 1
PPV = 100%
SEN = 94.9%
≥3 cysts 1
PPV = 100%
SEN = 95.5%
40-59 years≥2 cysts in each kidney
PPV = 100%
SEN = 92.6%
≥2 cysts in each kidney
PPV = 100%
SEN = 88.8%
≥2 cysts in each kidney
PPV = 100%
SEN = 90%

Derived from Pei et al [2009]. All values presented are mean estimates.

PPV= Positive predictive value

SEN = Sensitivity

1. Unilateral or bilateral

Molecular Genetic Testing

Genes. The two genes in which mutations are known to cause ADPKD are PKD1 and PKD2 (see Table 2).

Evidence for additional locus heterogeneity. At least one additional locus representing a small fraction of families not linked to either the PKD1 or PKD2 locus is hypothesized but not proven [Daoust et al 1995, Rossetti et al 2007]. Approximately 10% of individuals who undergo comprehensive mutation screening of PKD1 and PKD2 have no mutation identified [Rossetti et al 2007, Consugar et al 2008]. It is unclear if this finding is the result of missed mutations at the known loci or further genetic heterogeneity.

Table 2. Summary of Molecular Genetic Testing Used in ADPKD

Gene SymbolProportion of ADPKD Attributed to Mutations in This Gene 1Test MethodMutations DetectedMutation Detection Frequency by Test Method 2
PKD1 85%Sequence analysisSequence variants 3~88% 4
Linkage analysisNot applicableSee footnote 5
Deletion / duplication analysis 6Partial- or whole-gene deletions and duplications~4% 7
PKD2 15%Sequence analysisSequence variants 3~92% 8
Deletion / duplication analysis 6Partial- or whole-gene deletions<1% 7
Linkage analysisNot applicableSee footnote 5

1. This proportion refers to individuals with ADPKD caused by a known mutation in either PKD1 or PKD2. It does not include those with ADPKD in whom no mutation has been found.

2. The ability of the test method used to detect a mutation that is present in the indicated gene

3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

4. Rossetti et al [2007]

5. Testing by linkage analysis is possible in larger families using highly informative microsatellite markers flanking PKD1 and PKD2. A significant drawback with linkage analysis is the need for a relatively large number of affected family members in order to establish within each family which of the two possible genes is the responsible one. Linkage studies are based on accurate clinical diagnosis of ADPKD in the affected family members, understanding of the genetic relationships in the family, and the availability and willingness of family members to be tested. Because of these constraints, linkage analysis is probably suitable in fewer than 50% of families, but is accurate if all the provisos mentioned are met. Linkage testing is not available to families with a single affected individual, and linkage testing may be complicated if a de novo mutation has occurred recently in the family. Mosaicism [Connor et al 2008, Consugar et al 2008] and hypomorphic alleles [Rossetti et al 2009] can also complicate linkage analysis.

6. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

7. Consugar et al [2008]

8. Estimated detection rate by direct sequencing based on data derived from studies of PKD1 and the low frequency of large deletions in PKD2. The overall detection rate for ADPKD as a whole is approximately 88% [Rossetti et al 2007, Consugar et al 2008].

Interpretation of test results

  • For issues to consider in interpretation of sequence analysis results, click here.
  • Because an estimated 70% of mutations are unique and approximately 25% of PKD1 changes are missense, the pathogenicity of some allelic variants is difficult to prove. However, the development of specific algorithms to score missense variants has helped to assess likely pathogenicity [Rossetti et al 2007, Rossetti et al 2009]. The ADPKD Mutation Database (see Table A. Genes and Databases) also contains scored information on published variants for research use.

Testing Strategy

To confirm/establish the diagnosis in a proband. The diagnosis of ADPKD is established primarily by imaging studies of the kidneys; however, in some individuals, molecular genetic testing can be used to confirm or establish the diagnosis when it is uncertain, particularly in individuals who represent simplex cases (i.e., a single occurrence in a family) or individuals with unusually severe or unusually mild disease.

  • Kidney imaging methods including abdominal ultrasound, CT, or MR should be considered first for diagnosis.
  • A small number of cysts can be detected by MRI or contrast-enhanced CT in the general population.
  • Molecular genetic testing by sequence analysis can be helpful when the imaging results are equivocal.
  • When molecular genetic testing of PKD1 and PKD2 by sequencing does not reveal a mutation, deletion/duplication analysis of PKD1 and PKD2 should be considered.

Presymptomatic diagnosis. If the family-specific mutation is known, molecular genetic testing can be used for presymptomatic diagnosis when imaging results are equivocal and/or when a definitive diagnosis is required in a younger individual.

  • Exclusion of the diagnosis is of great importance for evaluating potential living-related kidney donors at risk for ADPKD. The absence of renal cysts by ultrasound examination virtually excludes a diagnosis of ADPKD caused by mutation of PKD1 in an at-risk person age 15-30 years (NPV=99.1%) or older (NPV=100%), but not in persons younger than age 40 years who are at risk for ADPKD caused by mutation of PKD2 or ADPKD of unknown genotype.

    Ultrasound criteria used to exclude an at-risk relative as a potential living-related kidney donor are shown in Table 3.

Table 3. Ultrasound Criteria that Exclude an Individual at 50% Risk for ADPKD from Being a Kidney Donor

AgePKD1PKD2Unknown ADPKD Genotype
15-30 years≥1 cyst
NPV = 99.1%
SPEC = 97.6%
≥1 cyst
NPV = 83.5%
SPEC = 96.6%
≥1 cyst
NPV = 90.8%
SPEC = 97%
30-39 years≥1 cyst
NPV = 100%
SPEC = 96%
≥1 cyst
NPV = 96.8%
SPEC = 93.8%
≥1 cyst
NPV = 98.3%
SPEC = 94.8%
40-59 years≥2 cysts
NPV = 100%
SPEC = 98.4%
≥2 cysts
NPV = 100%
SPEC = 97.8%
≥2 cysts
NPV = 100%
SPEC = 98.2%

Derived from Pei et al [2009]. All values presented are mean estimates.

NPV = negative predictive value

SPEC = specificity

  • When familial genotype information is not available:
    • An ultrasound scan finding of normal kidneys in a 30- to 39-year old or of normal kidneys or only one renal cyst in an individual age 40 years or older has a negative predictive value of 100%.
    • The family history of renal disease severity can be used to predict the gene most likely to be mutated (PKD1 vs PKD2) [Barua et al 2009].
      • The presence of at least one family member who developed ESRD at or before age 55 years is highly predictive of PKD1 (positive predictive value [PPV]: 100%).
      • The presence of at least one family member with ESRD at or over age 70 years is highly predictive of a mutation in PKD2 (PPV 100%).
  • A negative ultrasound does not exclude ADPKD with certainty in an at-risk individual younger than age 30 years.
  • MRI or contrast-enhanced CT, which has much higher sensitivity than ultrasound to detect cysts and is routinely performed in most transplant centers to define the donor kidney anatomy, provides further assurance for the exclusion of the diagnosis if cysts are absent. However, data to quantify the predictive accuracy of these imaging modalities are not available. Note: Recent reports of hypomorphic PKD mutations causing mild cystic disease by themselves and severe disease in association with another pathogenic mutation may complicate the evaluation of at-risk individuals [Rossetti et al 2009].

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Note: Molecular testing for prenatal diagnosis or preimplantation diagnosis is not usually requested for ADPKD because the disease usually first occurs in adulthood. A possible exception is rare families in which severe early-onset disease in one child suggests a significant risk for recurrence of severe disease in a sibling [Zerres et al 1993, Rossetti et al 2009].

Clinical Description

Natural History

Renal Manifestations

Although all individuals with autosomal dominant polycystic kidney disease (ADPKD) develop cysts within the kidneys, substantial variability occurs in severity of renal disease and other manifestations of the disease, even within the same family. Poor prognostic factors include: diagnosis before age 30 years; first episode of hematuria before age 30 years; onset of hypertension before age 35 years; hyperlipidemia; low concentration of high-density lipoprotein (HDL) cholesterol; and presence of sickle cell trait [Gabow 1996].

Cyst development and growth. The renal manifestations of ADPKD include renal function abnormalities, hypertension, renal pain, and renal insufficiency. These manifestations are directly related to the development and enlargement of renal cysts. A study by the Consortium of Imaging Studies to assess the Progression of Polycystic Kidney Disease (CRISP) of 241 non-azotemic affected individuals followed prospectively with yearly MR examinations showed that total kidney volume and cyst volumes increase exponentially [Grantham et al 2006]. At baseline total kidney volume was 1060 ± 642 mL; the mean increase over three years was 204 mL or 5.3% per year.

Occasionally, enlarged and echogenic kidneys with or without renal cysts are detected in an at-risk fetus prenatally. The prognosis is favorable in most children with prenatal ADPKD, at least during childhood.

The kidneys in persons with a PKD1 mutation (so called PKD1 phenotype) were significantly larger and had a higher number of cysts than the kidneys of persons with the PKD2 phenotype; however, the rates of cystic growth were not different, indicating that PKD1 is more severe than PKD2 because more cysts develop earlier, not because they grow faster [Harris et al 2006].

In ADPKD, rate of renal enlargement as determined through imaging studies (termed total kidney volume) increased over time. The baseline total kidney volume predicted the subsequent rate of increase in renal volume, meaning that the larger the kidney was at baseline, the faster the rate of renal enlargement over time. Declining glomerular filtration rate (GFR) was observed in persons with baseline total kidney volume above 1500 mL [Grantham et al 2006].

Higher urine sodium excretion and lower renal blood flow and serum HDL cholesterol were also associated with a faster increase in kidney volume [Torres et al 2011a].

Renal function abnormalities. Reduction in urinary concentrating capacity and excretion of ammonia occur early and may be caused by disruption of the renal architecture by cysts, interference with the countercurrent exchange and multiplication mechanisms, and defective trapping of solutes and ammonia in the renal medulla. In the early stages of the disease, these defects are moderate and the overlap between affected and unaffected individuals is significant. The reduction of urinary excretion of ammonia in the presence of metabolic stresses (e.g., dietary indiscretions) may contribute to the development of uric acid and calcium oxalate stones, which, in association with low urine pH values and hypocitric aciduria, occur with increased frequency in ADPKD.

Recent studies suggest that the urinary concentrating defect and elevated serum concentration of vasopressin may contribute to cystogenesis [Gattone et al 1999, Gattone et al 2003, Torres et al 2004, Nagao et al 2006]. They may also contribute to the glomerular hyperfiltration seen in children and young adults, development of hypertension, and progression of chronic kidney disease [Torres 2005].

Plasma copeptin concentration (a marker of endogenous vasopressin levels) has been associated with various markers of disease severity (positively with total kidney volume and albuminuria and negatively with GFR and effective renal blood flow) in a cross-sectional analysis of people with ADPKD [Meijer et al 2011].

Hypertension. Another early functional abnormality is a reduction in renal blood flow, which can be detected in young individuals (when systolic and diastolic blood pressures are still normal) and precedes the development of hypertension [Torres et al 2007b].

Hypertension usually develops before any decline in glomerular filtration rate (GFR). It is characterized by the following:

  • An increase in renal vascular resistance and filtration fraction
  • Normal or high peripheral plasma renin activity
  • Resetting of the pressure-natriuresis relationship
  • Normal or increased extracellular fluid volume, plasma volume, and cardiac output
  • Partial correction of renal hemodynamics and sodium handling by converting-enzyme inhibition

Hypertension in ADPKD is often diagnosed late in the disease course. Twenty-four hour monitoring of ambulatory blood pressure of children or young adults without hypertension may reveal elevated blood pressures, attenuated decrease in nocturnal blood pressure, and exaggerated blood pressure response during exercise, which may be accompanied by left ventricular hypertrophy and diastolic dysfunction [Seeman et al 2003].

Early detection and treatment of hypertension in ADPKD is important because cardiovascular disease is the main cause of death. Uncontrolled high blood pressure increases the risk for:

  • Proteinuria, hematuria, and a faster decline of renal function;
  • Morbidity and mortality from valvular heart disease and aneurysms; and
  • Fetal and maternal complications during pregnancy.

Renal pain. Pain is a common manifestation of ADPKD [Bajwa et al 2004]. Potential etiologies include: cyst hemorrhage, nephrolithiasis, cyst infection, and, rarely, tumor. Discomfort, ranging from a sensation of fullness to severe pain, can also result from renal enlargement and distortion by cysts. Gross hematuria can occur in association with complications such as cyst hemorrhage and nephrolithiasis or as an isolated event. Passage of clots can also be a source of pain. Cyst hemorrhage can be accompanied by fever, possibly caused by cyst infection. Most often, the pain is self-limited and resolves within two to seven days. Rarely, pain may be caused by retroperitoneal bleeding that may be severe and may require transfusion.

Nephrolithiasis. The prevalence of renal stone disease in individuals with ADPKD is approximately 20% [Torres et al 1993]. The majority of stones are composed of uric acid and/or calcium oxalate. Urinary stasis thought to be secondary to distorted renal anatomy and metabolic factors plays a role in the pathogenesis [Torres et al 2007a]. Postulated factors predisposing to the development of renal stone disease in ADPKD include: decreased ammonia excretion, low urinary pH, and low urinary citrate concentration. However, these factors occur with the same frequency in individuals with ADPKD with and without a history of nephrolithiasis [Nishiura et al 2009].

Urinary tract infection and cyst infection. In the past, the incidence of urinary tract infection may have been overestimated in individuals with ADPKD because of the frequent occurrence of sterile pyuria. As in the general population, females experience urinary tract infections more frequently than males; the majority of infections are caused by E. coli and other enterobacteriaceae. Retrograde infection from the bladder may lead to pyelonephritis or cyst infection.

Renal cyst infections account for approximately 9% of hospitalizations in individuals with ADPKD [Sallée et al 2009].

Renal cell carcinoma (RCC) does not occur more frequently in individuals with ADPKD than in the general population. However, when RCC develops in individuals with ADPKD, it has a different biologic behavior, including: earlier age of presentation; frequent constitutional symptoms; and a higher proportion of sarcomatoid, bilateral, multicentric, and metastatic tumors. Males and females with ADPKD are equally likely to develop RCC. A solid mass on ultrasound; speckled calcifications on CT; and contrast enhancement, tumor thrombus, and regional lymphadenopathies on CT or MRI should raise suspicion for a carcinoma.

An increased risk for RCC in individuals with ADPKD who are on dialysis for end-stage renal disease (ESRD) can be explained by the increased incidence of RCC with advanced kidney disease (rather than by an increased risk for RCC in individuals with ADPKD) [Hajj et al 2009, Nishimura et al 2009]. A retrospective study of 40,821 Medicare primary renal transplant recipients transplanted from January 1, 2000 to July 31, 2005 (excluding those with pre-transplant nephrectomy), demonstrated that acquired renal cystic disease pre-transplant, but not ADPKD, was associated with post-transplant RCC.

Other. Massive renal enlargement can cause complications resulting from compression of local structures, such as inferior vena cava compression and gastric outlet obstruction (mainly by cysts of the right kidney).

Renal failure. Approximately 50% of individuals with ADPKD have ESRD by age 60 years. Once renal insufficiency has begun, the average yearly rate of decline in glomerular filtration rate (GFR) is approximately 5 mL/min. Several mechanisms account for decline in renal function. Compression of the normal renal parenchyma by expanding cysts, vascular sclerosis, interstitial inflammation and fibrosis, and apoptosis of the tubular epithelial cells are the causative mechanisms. The Consortium of Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) [Grantham et al 2006] confirmed previous studies suggesting a strong relationship with renal enlargement [King et al 2000, Fick-Brosnahan et al 2002] and showed that kidney and cyst volumes are the strongest predictors of renal functional decline.

CRISP also found that renal blood flow (or vascular resistance) is an independent predictor of renal function decline [Torres et al 2007b]. This points to the importance of vascular remodeling in the progression of the disease and may account for cases in which the decline of renal function seems to be out of proportion to the severity of the cystic disease. Angiotensin II, transforming growth factor-β, and reactive oxygen species may contribute to the vascular lesions and interstitial fibrosis by stimulating the synthesis of chemokines, extracellular matrix, and metalloproteinase inhibitors.

Other factors including heavy use of analgesics may contribute to kidney disease progression in some individuals.

Extrarenal Manifestations

Polycystic liver disease is the most common extrarenal manifestation of ADPKD. The severity of polycystic liver disease usually parallels that of polycystic kidney disease, but exceptions are common.

Hepatic cysts are rare in children. The frequency of hepatic cysts increases with age and may have been underestimated by ultrasound and CT studies. Their prevalence by MRI in the CRISP study is 58% in 15- to 24-year old participants, 85% in 25- to 34-year olds, and 94% in 35- to 46-year olds [Bae et al 2006]. Polycystic liver disease develops at a younger age in women than men and is more severe in women who have had multiple pregnancies. After menopause, the size of the liver cysts increases in those women who receive estrogen replacement therapy, suggesting that estrogens have an important effect on the progression of polycystic liver disease [Everson & Taylor 2005].

Liver cysts are usually asymptomatic and never cause liver failure. Symptoms, when they occur, are caused by the mass effect of the cysts, the development of complications, or rare associations. Mass effects include: abdominal distention and pain, early satiety, dyspnea, and low back pain. Liver cysts can also cause extrinsic compression of the inferior vena cava (IVC), hepatic veins, or bile ducts [Torres 2007].

The liver cyst epithelia produce and secrete carbohydrate antigen 19-9 (CA19-9), a tumor marker for gastrointestinal cancers. The concentration of CA19-9 is increased in the serum of individuals with polycystic liver disease and markedly elevated in hepatic cyst fluid. Serum CA19-9 levels correlate with polycystic liver volume.

Complications of polycystic liver disease include: cyst hemorrhage, infection, or rupture. Hemorrhagic cysts may cause fever and masquerade as cholecystitis or cyst infection. Usually cyst infections are monomicrobial, are caused by enterobacteriaceae, and present with localized pain or tenderness, fever, leukocytosis, elevated erythrocyte sedimentation rate, and high serum concentration of alkaline phosphatase and CA19-9. Elevations of CA19-9, however, can also be observed in other conditions causing abdominal pain and fever, such as acute cholangitis or diverticulitis. CT scan and MRI are helpful in the diagnosis of cyst infection but have low specificity. On CT scanning the following have been associated with infection: fluid-debris levels within cysts, cyst wall thickening, intracystic gas bubbles, and heterogeneous or increased density. White blood cell scans are more specific but not always conclusive. Radionuclide imaging and more recently 18F-fluorodoxyglucose positron emission tomography scanning have been used for diagnosis [Bleeker-Rovers et al 2003]. The rupture of a hepatic cyst can cause acute abdominal pain and ascites.

Other liver disease

  • Dilatation of biliary ducts may be associated with episodes of cholangitis.
  • Congenital hepatic fibrosis is rare in individuals with ADPKD.
  • Cholangiocarcinoma is infrequently associated with ADPKD.
  • Adenomas of the ampulla of Vater have been rarely reported.

Pancreatic lesions

  • Pancreatic cysts occur in approximately 8% of individuals with ADPKD. They are usually less prominent than those observed in von Hippel-Lindau disease. They are almost always asymptomatic, with very rare occurrences of recurrent pancreatitis [Başar et al 2006].
  • Intraductal papillary mucinous tumors (IPMN) have been reported with increased frequency, but their prevalence and prognosis in ADPKD are uncertain [Naitoh et al 2005].
  • Some authors have reported an association between ADPKD and pancreatic carcinomas [Sakurai et al 2001]; however, these cases may represent chance associations of two common disorders.

Cysts in other organs

Vascular and cardiac manifestations. The most important non-cystic manifestations of ADPKD include: intracranial and other arterial aneurysms and, more rarely, dolichoectasias, dilatation of the aortic root, dissection of the thoracic aorta and cervicocephalic arteries, abnormalities of the cardiac valves, and, possibly, coronary artery aneurysms [Pirson et al 2002]. Evidence of familial clustering of thoracic aortic dissections in ADPKD also exists.

Intracranial aneurysms occur in approximately 10% of individuals with ADPKD [Pirson et al 2002]. The prevalence is higher in those individuals with a positive family history of intracranial or subarachnoid hemorrhage (22%) than in those individuals without (6%) such a family history. The majority of intracranial aneurysms are asymptomatic. Focal findings, such as cranial nerve palsy or seizure, may result from compression of local structures by an enlarging aneurysm.

The mean age of rupture of intracranial aneurysms is lower in individuals with ADPKD than in the general population (39 years vs 51 years).

The risk of rupture of asymptomatic intracranial aneurysms depends on the history of rupture from a different site [International Study of Unruptured Intracranial Aneurysms Investigators 1998].

In the absence of a history of rupture from a different site, the risk for rupture is:

  • 0.05% per year for aneurysms smaller than 10 mm in diameter;
  • Approximately 1% per year for aneurysms 10-24 mm in diameter;
  • 6% within one year for aneurysms 25 mm or larger.

In the presence of a history of rupture from a different site, the risk of rupture is 0.5% to 1% per year regardless of size.

The risk of rupture of symptomatic aneurysms is higher, approximately 4% per year.

Intracranial aneurysm rupture has a 35% to 55% risk of combined severe morbidity and mortality at three months [Inagawa 2001]. At the time of rupture of an aneurysm, most individuals have normal renal function; and up to 30% have normal blood pressure.

Follow-up studies of individuals with ADPKD with intracranial aneurysms found a moderate risk for the development of new aneurysms or enlargement of an existing one in previously symptomatic individuals and a low risk of enlargement of asymptomatic aneurysms detected by presymptomatic screening [Belz et al 2003, Gibbs et al 2004].

Individuals with ADPKD may be at increased risk for vasospasm and transient ischemic complications following cerebral angiography.

They may also have an increased risk for central retinal arterial and venous occlusions, possibly as a result of enhanced vasoconstriction to adrenergic stimulation and arterial wall remodeling [Qian et al 2007b].

Mitral valve prolapse, the most common valvular abnormality in ADPKD, has been demonstrated by echocardiography in up to 25% of affected individuals.

Aortic insufficiency may occur in association with dilatation of the aortic root. Although these lesions may progress with time, they rarely require valve replacement. Screening echocardiography is not indicated unless a murmur is detected on examination.

Several studies have shown increased left ventricular mass, left ventricular diastolic dysfunction, endothelial dysfunction, increased carotid intima-media thickness, and exaggerated blood pressure response during exercise even in young normotensive individuals with ADPKD with well-preserved renal function. Even normotensive individuals with ADPKD may show significant biventricular diastolic dysfunction, suggesting cardiac involvement early in the course of the disease [Martinez-Vea et al 2004, Oflaz et al 2005]. The clinical significance of this finding remains to be determined.

Pericardial effusion occurs with an increased frequency in individuals with ADPKD, possibly because of increased compliance of the parietal pericardium. These effusions are generally well tolerated and clinically inconsequential. In the absence of known predisposing factors, extensive investigative and/or therapeutic interventions for silent pericardial effusion in persons with ADPKD are not indicated [Qian et al 2007a].

Diverticular disease. Colonic diverticulosis and diverticulitis are more common in individuals with ESRD associated with ADPKD than in those with other renal diseases [Sharp et al 1999, Lederman et al 2000]. Whether this increased risk extends to persons with ADPKD prior to development of ESRD is uncertain.

Extracolonic diverticular disease may also occur with increased frequency and become clinically significant in a minority of affected individuals [Kumar et al 2006].

Genetic modifiers and demographics. Significant intrafamilial phenotypic variability is seen in the severity of renal disease and the number and type of extrarenal manifestations, indicating that genetic modifiers and the environment significantly influence the disease presentation and course. Analysis of the variability in renal function between monozygotic twins and sibs supports the role of genetic modifying factors [Persu et al 2004]. Quantitative studies estimate that 18% to 59% of the variance in age at which ESRD occurs may result from as-yet unidentified heritable modifying factors [Fain et al 2005, Paterson et al 2005].

Whether African Americans or individuals with specific genotypes at various genes are at an increased risk for disease progression or not is controversial [Rossetti & Harris 2007].

In the PKD2 phenotype, males progress to ESRD more rapidly than females [Magistroni et al 2003]. If there is a gender difference in individuals with the PKD1 phenotype, it appears to be more modest [Hateboer et al 1999, Rossetti et al 2002a, Harris et al 2006].

Genotype-Phenotype Correlations

Genetic heterogeneity, mutation position in PKD1, mutation type, modifier genes, and environmental factors account for the substantial variability in severity of renal disease and other manifestations of ADPKD [Rossetti & Harris 2007, Rossetti et al 2009].

A clear association exists between the severity of renal disease and the gene involved (PKD1 or PKD2). Mutations in PKD1 are associated with more severe disease with an earlier age at diagnosis and mean age of onset of ESRD (54.3 years for PKD1; 74.0 years for PKD2) [Hateboer et al 1999]. Therefore, while most individuals with mutations associated with PKD1 experience renal failure by age 70 years, more than 50% of individuals with mutations in PKD2 have adequate renal function at that age. The difference in severity between the PKD1 phenotype and the PKD2 phenotype may be related to the rate of cyst development (especially early in the disease) rather than to differences in the rate of cyst expansion [Harris et al 2006].

The extrarenal manifestations of ADPKD, including severe polycystic liver disease and an increased risk for intracranial aneurysm, are associated with mutation in either gene [Rossetti et al 2003].

Among individuals with PKD1 mutations, the position of the mutation may correlate with the severity of the disease [Rossetti et al 2002a]. Rossetti et al [2003] suggested that mutations in the 5' half of PKD1 are more likely to result in the development of intracranial aneurysms than 3' changes [Rossetti et al 2003]. These associations with mutation position may result from the cleavage of polycystin-1 into more than one protein product [Qian et al 2002]. Population studies of the type of PKD1 mutation have not found an association with disease severity [Rossetti et al 2002a].

No clear correlations with mutation type or position were found in PKD2 [Magistroni et al 2003].

Homozygous or compound heterozygous mutations in either PKD1 or PKD2 in humans are predicted to be incompatible with live birth, consistent with Pkd1 or Pkd2 knockout mice that have cystic kidneys but are embryonic lethal [Lu et al 1997, Wu et al 2000]. Accordingly, a consanguineous family in which both parents were affected with PKD1 had two spontaneous miscarriages at four and six months' gestation; fetal tissue for histologic analysis was not available [Paterson et al 2002].

Conversely, hypomorphic alleles leading to incomplete penetrance in a family of individuals homozygous for a PKD1 mutation were reported by Rossetti et al [2009]. Heterozygosity for a hypomorphic allele may be associated with mild cystic disease; homozygosity for a hypomorphic allele or compound heterozygosity for a hypomorphic allele and a typical disease-causing allele are associated with typical to severe disease [Vujic et al 2010]. A combination of a null and a hypomorphic allele in trans configuration (i.e., on different chromosomes) accounts for some early-onset ADPKD.

Two individuals in one family who were double heterozygotes for both a PKD1 and a PKD2 mutation had more severe renal disease than those heterozygous for either a PKD1 or PKD2 mutation, but lived into adulthood [Pei et al 2001].


Cyst development. Penetrance of ADPKD is very high: practically all older adults with a PKD1 or PKD2 mutation develop multiple bilateral cysts. Because the disease is progressive, few cysts may be evident during childhood or young adulthood, especially for PKD2.

End-stage renal disease (ESRD). Penetrance is reduced for ESRD. While the majority of individuals with PKD1 experience ESRD during their lifetimes, many individuals with PKD2 (especially females) have adequate renal function into old age.

According to the Danish National Registry on Regular Dialysis and Transplantation (NRDT), the age at which individuals with ADPKD reach ESRD has increased from 55.9 years (1990 through 1995) to 60.6 years (2002 through 2007).


Anticipation has been suggested in ADPKD; however, natural history studies reveal that despite considerable intrafamilial phenotypic variability, parent-child pairs are as likely to show more severe disease in the parent as in the child [Geberth et al 1995].


A term for ADPKD that is no longer in use is “adult polycystic kidney disease” (APKD).


ADPKD is the most common potentially lethal single-gene disorder. Its prevalence at birth is between 1:400 and 1:1,000; and it affects approximately 600,000 persons in the United States [Iglesias et al 1983].

Approximately 2700 persons with ADPKD started renal replacement therapy (RRT) in 2008 in the US with more than 26,000 RRT patients (4.8%) having this disease [US Renal Data System 2010].

The prevalence of ADPKD-related ESRD has increased (6.45 per million to 7.59 per million) over time, likely as a result of improved survival [US Renal Data System 2009, Orskov et al 2010].

Yearly prevalence rates in men and women (respectively) for ESRD caused by ADPKD:

Age-adjusted sex ratios have approached unity (from 1.6 to 1.1) in recent years [US Renal Data System 2009, Orskov et al 2010].

The percentage of ESRD attributable to ADPKD is lower among African Americans than among whites because of the higher incidence of other causes of ESRD among African Americans.

Differential Diagnosis

In the absence of a family history of autosomal dominant polycystic kidney disease (ADPKD) and in the presence of atypical presentations, benign simple cysts and other cystic diseases should be considered in the differential diagnosis. See Table 4.

Table 4. Prevalence of Simple Renal Cysts in Unaffected Individuals on Ultrasound Examination

Age in YearsSimple Renal Cysts 1Bilateral Renal Cysts 2

Ravine et al [1993]

1. ≥1 renal cyst

2. ≥1 cyst in each kidney

Simple hepatic cysts occur in 2.5% to 4.6% of individuals referred for abdominal ultrasound examination. They are more common among women than men and increase in frequency with age. The majority of simple hepatic cysts are solitary, and no more than three cysts are present in those individuals with multiple cysts.

The following conditions are occasionally confused with ADPKD.

Renal cysts and diabetes (RCAD) syndrome, also known as type 5 maturity-onset diabetes of the young (MODY5), is characterized by maturity-onset diabetes of the young, exocrine pancreatic failure and pancreatic atrophy, renal and genital malformations, and liver function abnormalities. Renal involvement ranges from urinary tract malformations and unilateral or bilateral renal hypoplasia/dysplasia to bilateral cystic renal disease mimicking ADPKD. RCAD is caused by mutations in HNF1B [Faguer et al 2007, Heidet et al 2010].

Autosomal recessive polycystic kidney disease (ARPKD) is characterized by various combinations of bilateral renal cystic disease resulting from the fusiform dilatation of the collecting tubules and congenital hepatic fibrosis. Congenital hepatic fibrosis or biliary dysgenesis is a developmental abnormality that leads to portal hypertension and is characterized by enlarged and fibrotic portal areas with apparent proliferation of bile ducts, absence of central bile ducts, hypoplasia of the portal vein branches, and sometimes prominent fibrosis around the central veins. Individuals with ARPKD have unaffected parents, whereas individuals with ADPKD usually have an affected parent. In a minority of individuals, ARPKD can present later in childhood or adulthood with significant liver disease and focal cystic renal disease similar to ADPKD [Adeva et al 2006].

Rarely, a combination of PKD1 mutations can mimic the ARPKD phenotype [Vujic et al 2010]. See Genetically Related Disorders.

Autosomal dominant polycystic liver disease (ADPLD) without kidney involvement, an inherited disorder distinct from ADPKD, is genetically heterogenous [Reynolds et al 2000, Qian et al 2003a, Tahvanainen et al 2003]. Two genes, PRKCSH (19p13) and SEC63 (6q21) are thought to account for only a minority of families [Drenth et al 2003, Li et al 2003, Davila et al 2004]. Distinguishing between ADPLD and ADPKD caused by a PKD2 mutation may be difficult when PLD is present in conjunction with only a few renal cysts.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder often associated with abnormalities of the skin, brain, heart, and kidneys. Renal findings include: renal angiomyolipomas, renal cysts, and, less frequently, renal cell carcinoma. The coexistence of renal cysts and angiomyolipomas is pathognomonic for tuberous sclerosis complex. However, renal cysts can occur in the absence of angiomyolipomas, particularly in the first year of life. In these cases, the radiographic findings mimic those of ADPKD.

Individuals with a contiguous deletion of the adjacent genes PKD1 and TSC2 typically manifest clinical features of TSC and early onset PKD [Sampson et al 1997, Consugar et al 2008]. See Genetically Related Disorders.

Von Hippel-Lindau syndrome is an autosomal dominant disorder that manifests with retinal and/or central nervous system hemangioblastomas, renal cysts, renal cell carcinoma, pancreatic cysts, pheochromocytomas, and papillary cystadenomas of the epididymis. Renal cysts are usually multiple and bilateral and are often associated with multiple solid tumors. In the absence of solid tumors, the appearance of the kidneys in von Hippel-Lindau syndrome may mimic that of ADPKD.

Oral-facial-digital syndrome type 1 is a rare X-linked dominant disorder that is lethal in males. Affected females may have cysts that are indistinguishable from those seen in ADPKD. Liver cysts may also be present. The correct diagnosis should be suggested by the extrarenal manifestations, including oral abnormalities (e.g., hyperplastic frenula, cleft tongue, cleft palate or lip, malpositioned teeth), facial abnormalities (e.g., broad nasal root with hypoplasia of nasal alae and malar bone), and digital abnormalities.

Glomerulocystic kidney disease is a term used to describe a poorly defined disease or group of diseases characterized by the predominance of glomerular cysts, absence of or minimal tubular involvement and lack of urinary tract obstruction, renal dysplasia, or evidence of a recognizable cystic disease or malformation syndrome. Most individuals initially described who met this definition were infants or young children without a family history of renal disease, presenting with enlarged kidneys or variable degrees of renal insufficiency. More recently, this disease has been described in children and adults from families with an autosomal dominant pattern of inheritance. While glomerular cysts can be found during the fetal period in ADPKD [Reederset al 1986, Vujic et al 2010], linkage analysis in two families has shown that glomerulocystic kidney disease is not linked to PKD1 or PKD2.

Hajdu-Cheney syndrome can be associated with renal enlargement with cortical and medullary cysts with or without impairment of renal function [Kaplan et al 1995]. This rare autosomal dominant disorder, caused by mutations in NOTCH2 [Simpson et al 2011], is also characterized by short stature, midfacial flattening with proptosis, receding chin, hirsutism, acro-osteolysis of terminal phalanges, and basilar invagination of the skull.

Localized renal cystic disease is characterized by the cystic degeneration of a portion of one kidney with a histologic appearance that strongly resembles that of advanced ADPKD but is neither progressive nor familial. This entity should be differentiated from asymmetric presentation of ADPKD as well as from other lesions including multilocular cystic nephroma, cystic renal cell carcinoma, and segmental multicystic renal dysplasia.

Acquired renal cystic disease refers to the cystic degeneration of the renal parenchyma that occurs in ESRD. Affected individuals are often asymptomatic; occasional complications include hematuria, hemorrhage into cysts, cyst rupture with retroperitoneal hemorrhage, cyst infection, and development of adenomas or carcinomas.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).


Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with autosomal dominant polycystic kidney disease (ADPKD), the following evaluations are recommended:

  • Renal ultrasound examination, helpful in screening all individuals except those with a PKD2 mutation who are younger than age 30 years. In those individuals, CT or MRI is preferable because of the low sensitivity of renal ultrasound examination.
  • CT or MRI of the abdomen without and with contrast enhancement to help determine the extent of cystic disease in the kidneys and liver, as well as to estimate the prognosis. CT, but not MRI, can detect stones and parenchymal calcifications. CT or MR angiography (MRA) can be used when visualization of the renal arteries is necessary. MRI can be used when administration of iodinated contrast material is contraindicated.
  • Standardized blood pressure screening per the recommendations of the American Heart Association to detect early stages of hypertension. When "white coat" hypertension (i.e., blood pressure that is elevated when measured in the clinic, but normal when measured outside of the clinic) is suspected, ambulatory blood pressure monitoring is appropriate.
  • Measurement of blood lipid concentrations because hyperlipidemia is a correctable risk factor for progressive renal disease, including ADPKD.
  • Urine studies to detect the presence of microalbuminuria or proteinuria, which in the presence of severe renal cystic disease indicates an increased likelihood of disease progression and mandates strict control of the blood pressure
  • Echocardiography in persons with heart murmurs or systolic clicks possibly resulting from valvular heart disease, mitral valve prolapse, or congenital cardiac abnormalities
  • Echocardiography or cardiac MRI to screen persons at high risk because of a family history of thoracic aortic dissections
  • Head MRA or CT angiography to screen persons at high risk because of a family history of intracranial aneurysms. Note: Screening for intracranial aneurysms in individuals without a family history of intracranial aneurysms is not recommended [Irazabal et al 2011].

Treatment of Manifestations

Current therapy for ADPKD is directed toward reducing morbidity and mortality from the renal and extrarenal complications of the disease.

Hypertension. The antihypertensive agent(s) of choice in ADPKD have not been clearly established. Because of the role of the renin angiotensin system in the pathogenesis of hypertension in ADPKD, ACE inhibitors and angiotensin II receptor antagonists may be superior to other agents in individuals with preserved renal function. ACE inhibitors and angiotensin II receptor blockers increase renal blood flow, have a low side-effect profile, and may reduce vascular smooth muscle proliferation and development of atherosclerosis:

  • The administration of ACE inhibitors, but not the administration of calcium channel blockers, has been shown to reduce microalbuminuria in individuals with ADPKD [Ecder & Schrier 2001].
  • In an historic, non-randomized study, the administration of ACE inhibitors without diuretics was found to result in a lower rate of decline in glomerular filtration rate (GFR) and less proteinuria than the administration of a diuretic without an ACE inhibitor for similar control of blood pressure [Ecder & Schrier 2001].
  • Another study found no renal protective effect of an ACE inhibitor over a β-blocker [van Dijk et al 2003]; another study found that although more rigorous blood pressure control did not preserve renal function, it did lead to a greater decrease in left ventricular mass [Schrier et al 2002].
  • A long-term follow-up of the Modification of Diet in Renal Disease (MDRD) Study showed that individuals with ADPKD randomized to a low blood pressure target (mean arterial pressure [MAP] <92 mmHg) experienced significantly less ESRD and combined ESRD/death than those randomized to the usual blood pressure target (MAP <107 mmHg) [Sarnak et al 2005].

Flank pain. After excluding causes of flank pain that may require intervention, such as infection, stone, or tumor, an initial conservative approach to pain management is best:

  • Nonopioid agents are preferred and care should be taken to avoid long-term administration of nephrotoxic agents such as combination analgesic and nonsteroidal anti-inflammatory drugs.
  • Tricyclic antidepressants are helpful, as in all chronic pain syndromes, and are well tolerated.
  • Narcotic analgesics should be reserved for the management of acute episodes, as chronic use can lead to physical and psychological dependence.
  • Splanchnic nerve blockade with local anesthetics or steroids can result in pain relief beyond the duration of the local anesthetic.

When conservative measures fail, therapy can be directed toward cyst decompression with cyst aspiration and sclerosis:

  • Cyst aspiration, under ultrasound or CT guidance, is a relatively simple procedure carried out routinely by interventional radiologists. Complications from aspiration of centrally located cysts are more common, and the morbidity of the procedure is proportional to the number of cysts treated. Cyst aspiration can help to establish causality between a cyst and the presence of pain, but seldom provides long-lasting relief because of fluid reaccumulation.
  • Sclerosing agents, such as 95% ethanol or acidic solutions of minocycline, are commonly used to prevent the reaccumulation of cyst fluid. Good results have been obtained with 95% ethanol, achieving a success rate of 90% in benign renal cysts. Minor complications include: microhematuria, localized pain, transient fever, and systemic absorption of the alcohol. More serious complications such as pneumothorax, perirenal hematoma, arteriovenous fistula, urinoma, and infection are rare.

In individuals with many cysts contributing to pain, laparoscopic or surgical cyst fenestration through lumbotomy or flank incision, renal denervation, and (in those who have reached ESRD) nephrectomy may be of benefit:

  • Surgical decompression was effective in 80% to 90% of individuals for one year; 62% to 77% had sustained pain relief for longer than two years. Surgical intervention neither accelerates the decline in renal function nor preserves remaining renal function.
  • Laparoscopic fenestration has been shown to be as effective as open surgical fenestration in short-term follow-up for individuals with limited disease and has a shorter, less complicated recovery period than open surgery.
  • Renal denervation via a thoracoscopic approach was successful in one affected individual [Chapuis et al 2004].
  • Laparoscopic and retroperitonoscopic nephrectomy and arterial embolization have been used to treat symptomatic polycystic kidneys in individuals with ADPKD who have ESRD [Ubara et al 1999, Dunn et al 2000].
  • Hand-assisted laparoscopic nephrectomy may be preferable to standard laparoscopic nephrectomy because of shorter operating time and lower morbidity [Lee & Clayman 2004].

Cyst hemorrhage and gross hematuria. Episodes of cyst hemorrhage or of gross hematuria are usually self-limited and respond well to conservative management with bed rest, analgesics, and adequate hydration to prevent development of obstructing clots.

Rarely, episodes of bleeding are severe with extensive subcapsular or retroperitoneal hematoma, significant drop in hematocrit, and hemodynamic instability. In such cases, individuals require hospitalization, transfusion, and investigation by CT or angiography. In cases of unusually severe or persistent hemorrhage, segmental arterial embolization can be successful. If not, surgery may be required to control bleeding.

Gross hematuria persisting more than one week or developing for the first time in an individual older than age 50 years requires thorough investigation.

Nephrolithiasis. Small uric acid stones can be missed on nephrotomography and are best detected by CT. CT should be obtained before and after the administration of contrast material to confirm the localization within the collecting system and to differentiate calculi from parenchymal calcifications. Dual absorption CT now facilitates the differentiation of uric acid stones from calcium-containing stones.

Excretory urography detects precaliceal tubular ectasia in 15% of individuals with ADPKD.

The treatment of nephrolithiasis in individuals with ADPKD is the same as that for individuals without ADPKD:

  • High fluid intake and potassium citrate are the treatment of choice in uric acid lithiasis, hypocitric calcium oxalate nephrolithiasis, and distal acidification defects.
  • Medical dissolution of uric acid stones can usually be achieved by a program of high fluid intake, urine alkalinization (to maintain a pH of 6-6.5), and administration of allopurinol.
  • Extracorporeal shock-wave lithotripsy and percutaneous nephrostolithotomy can be successful in individuals with ADPKD without excessive complications [Umbreit et al 2010].

Cyst infection. If cyst infection is suspected, diagnostic imaging should be undertaken to assist in the diagnosis:

  • CT and MRI are sensitive for detecting complicated cysts and provide anatomic definition, but the findings are not specific for infection.
  • Nuclear imaging, especially indium-labeled white cell scanning, is useful, but false negative and false positive results are possible.
  • 18F-fluorodoxyglucose positron emission tomography scanning is the most sensitive method to detect an infected cyst, but it is expensive, not readily available and may not be reimbursed by insurance companies [Sallée et al 2009].

In the appropriate clinical setting of fever, flank pain, and suggestive diagnostic imaging, cyst aspiration under ultrasound or CT guidance should be undertaken to culture the organism and assist in selection of antimicrobial therapy, particularly if blood and urine cultures are negative [Torres et al 2007a].

Cyst infection is often difficult to treat. It has a high treatment failure rate despite prolonged therapy with an antibiotic to which the organism is susceptible. Treatment failure results from the inability of certain antibiotics to penetrate the cyst epithelium successfully and achieve therapeutic concentrations within the cyst. The epithelium that lines gradient cysts has functional and ultrastructural characteristics of the distal tubule epithelium. Penetration is via tight junctions, allowing only lipid-soluble agent access. Non-gradient cysts, which are more common, allow solute access via diffusion. However, kinetic studies indicate that water-soluble agents penetrate non-gradient cysts slowly and irregularly, resulting in unreliable drug concentrations within the cysts. Lipophilic agents have been shown to penetrate both gradient and non-gradient cysts equally and reliably and have a pKa that allows for favorable electrochemical gradients into acidic cyst fluids.

Therapeutic agents of choice include trimethoprim-sulfamethoxazole and fluoroquinolones. Clindamycin, vancomycin, and metronidazole are also able to penetrate cysts well. Chloramphenicol has shown therapeutic efficacy in otherwise refractory disease.

If fever persists after one to two weeks of appropriate antimicrobial therapy, percutaneous or surgical drainage of infected cysts should be undertaken. If fever recurs after discontinuation of antibiotics, complicating features such as obstruction, perinephric abscess, or stones should be considered and treated appropriately. If complicating features are not identified, the course of previously effective therapy should be extended; several months may be required to completely eradicate the infection.

Malignancy. The diagnosis of renal cell carcinoma (RCC) in a polycystic kidney requires a high index of suspicion. MRI with gadolinium enhancement is particularly helpful to detect atypical solid or cystic masses, tumor thrombi, and regional lymphadenopathy.

The diagnosis of transitional cell carcinoma in a polycystic kidney is equally challenging and usually requires retrograde pyelography or ureteroscopy.

End-stage renal disease (ESRD). Therapeutic interventions aimed at slowing the progression of ESRD in ADPKD include control of hypertension and hyperlipidemia, dietary protein restriction, control of acidosis, and prevention of hyperphosphatemia.

Animal data support the role of dietary protein restriction and careful control of hypertension in slowing the rate of renal failure in PKD [Qian et al 2001]. However, the Modification of Diet in Renal Disease (MDRD) trial showed no beneficial effect on renal function of strict (compared with standard) blood pressure control and only a slight (borderline significant) beneficial effect of a very low protein diet. Because these interventions were introduced at a late state of the disease (GFR 13-55 mL/min per 1.73 m2), the results do not exclude a beneficial effect of interventions introduced at an earlier stage of the disease.

Actuarial data indicate that individuals with ADPKD do better on dialysis than individuals with ESRD from other causes. Females appear to do better than males. The reason for this improved outcome is unclear but may relate to better-maintained hemoglobin levels through higher endogenous erythropoietin production. Rarely, hemodialysis can be complicated by intradialytic hypotension if the inferior vena cava is compressed by a medially located renal cyst. Despite renal size, peritoneal dialysis can usually be performed in individuals with ADPKD; although these individuals are at increased risk for inguinal and umbilical hernias, which require surgical repair.

There is no difference in patient or graft survival between individuals with ADPKD and those with ESRD caused by other conditions. Living donor transplantation for ADPKD, which requires exclusion of ADPKD in the donor (see Testing Strategy), has increased in the last two decades. Nephrectomy of the native kidneys is reserved for affected individuals with a history of infected cysts, frequent bleeding, severe hypertension, or massive renal enlargement. There is no consensus on the optimal timing of nephrectomy; whether nephrectomy is performed before, at, or following transplantation depends to some extent on the indication for the nephrectomy and other patient-specific considerations [Lucas et al 2010, Kirkman et al 2011]. Hand-assisted laparoscopic nephrectomy is increasingly being used [Lee & Clayman 2004]. Complications after transplantation are no greater than in the general population. Complications directly related to ADPKD are rare. One study has suggested an increased risk for thromboembolic complications [Jacquet et al 2011]. Whether individuals with ADPKD are at increased risk for new-onset diabetes mellitus after transplantation (NODAT) is questionable [Ruderman et al 2011].

Polycystic liver disease. Most individuals with polycystic liver disease have no symptoms and require no treatment.

The treatment of symptomatic disease includes the avoidance of estrogens and caffeine and the use of H2 blockers or proton pump inhibitors for symptomatic relief.

Severe symptoms may require percutaneous aspiration and sclerosis, laparoscopic fenestration, combined hepatic resection and cyst fenestration, liver transplantation, or selective hepatic artery embolization. Any of these interventions should be tailored to the individual [Torres 2007, Drenth et al 2010].

  • Cyst aspiration and sclerosis with alcohol or minocyline is the treatment of choice for symptoms caused by one or a small number of dominant cysts. Before instillation of the sclerosing agent, a contrast medium is injected into the cyst to evaluate for communication with the bile ducts. The success rate of this procedure (70% after a single treatment and an additional 20% after repeated treatment) is inversely correlated with the size of the cyst(s).
  • Laparoscopic fenestration of hepatic cysts, a less commonly performed procedure, is complicated by transient ascites in 40% of individuals; and the results are often short-lived. Thus, laparoscopic cyst fenestration is indicated only for the treatment of disproportionally large cysts as an alternative to percutaneous sclerosis.
  • Neither percutaneous sclerosis nor laparoscopic fenestration is helpful in individuals with large polycystic livers with many small- and medium-sized cysts. In most individuals, part of the liver is spared, allowing treatment by combined hepatic resection and cyst fenestration. Because the surgery and recovery can be difficult, with complications such as transient ascites and bile leaks and a perioperative mortality of 2.5%, it should be performed only in specialized centers [Schnelldorfer et al 2009]. The surgery has good long-term results in individuals with severe polycystic liver disease and is often preferable to liver transplantation, which is reserved for those individuals for whom liver resection is not feasible or for those individuals in whom liver function is impaired.
  • Because individuals with severe polycystic liver disease have mostly normal liver function, their MELD (model for end-stage liver disease) scores are low, placing them at a disadvantage for organ allocation. For highly selected individuals in this group, caval sparing hepatectomy and subsequent living donor liver transplantation could provide a potential alternative [Mekeel et al 2008].
  • Selective hepatic artery embolization can be considered for highly symptomatic patients who are not surgical candidates [Takei et al 2007].

Ruptured or symptomatic intracranial aneurysm. The mainstay of therapy is surgical clipping of the ruptured aneurysm at its neck.

Asymptomatic aneurysms

  • Those aneurysms measuring 5.0 mm or smaller in diameter and diagnosed by presymptomatic screening can be observed and followed initially at yearly intervals. If the size increases, surgery is indicated.
  • The management of aneurysms 6.0-9.0 mm in size remains controversial.
  • Surgical intervention is usually indicated for aneurysms larger than 10.0 mm in diameter.

For individuals with high surgical risk or with technically difficult-to-manage lesions, endovascular treatment with detachable platinum coils may be indicated. Endovascular treatment seems to be associated with fewer complications than clipping, but the long-term efficacy of this method is as yet unproven [Pirson et al 2002].

Aortic dissection. When the aortic root diameter reaches 55 mm to 60 mm, replacement of the aorta is indicated.


Intracranial aneurysms. Widespread screening is not cost effective or indicated because most intracranial aneurysms found by screening asymptomatic individuals are small, have a low risk of rupture, and require no treatment [Gibbs et al 2004, Irazabal et al 2011].

Indications for screening in 20- to 50-year-olds with a good life expectancy include a family history of intracranial aneurysms or subarachnoid hemorrhage, previous rupture of an aneurysm, preparation for elective surgery with potential hemodynamic instability, high-risk occupations such as airplane pilots, and significant anxiety on the part of the individual despite adequate risk information.

Magnetic resonance angiography (MRA) is the diagnostic imaging modality of choice for presymptomatic screening because it is noninvasive and does not require intravenous contrast material. Because only one of 76 individuals with an initial negative study had a new intracranial aneurysm after a mean follow-up of 9.8 years, rescreening after an interval of ten years has been suggested as a reasonable approach [Schrier et al 2004].

Aortic dissection. Until more information becomes available, it is reasonable to screen first-degree adult relatives of individuals with thoracic aortic dissection using either echocardiography or MRI. If aortic root dilatation is found, yearly follow-up and strict blood pressure control with beta blockers should be recommended.

Agents/Circumstances to Avoid

The following should be avoided:

  • Long-term administration of nephrotoxic agents such as combination analgesics and NSAIDs
  • Caffeine because it interferes with the breakdown of cAMP and hence may promote renal cyst growth
  • Use of estrogens in individuals with severe polycystic liver disease
  • Smoking

Evaluation of Relatives at Risk

Testing of adult relatives at risk. The initial evaluation of at-risk relatives over age 18 years should be imaging with abdominal ultrasound examination, CT, or MRI. When the findings on imaging are equivocal or if the disease-causing mutation in the family is known, molecular genetic testing may be appropriate.

Early diagnosis:

  • Allows those found to be affected to become better educated on the disease;
  • Permits early detection and treatment of complications and associated disorders;
  • Reassures those found to be unaffected.

Note: (1) Appropriate counseling prior to screening, including a discussion of the possible impact on insurability and employability, is most important. (2) At present, there is no indication for testing of asymptomatic children. This may change in the future, if and when effective therapies are found.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

The literature on pregnancy and PKD is limited.

  • Pregnant women with ADPKD should be monitored closely for the development of hypertension and urinary tract infections.
  • Pregnant women who develop hypertension during pregnancy or who have impaired renal function are at increased risk and should be monitored closely for the development of preeclampsia, intrauterine fetal growth restriction, and oligohydramnios.
  • A second-trimester prenatal sonographic examination is indicated if either parent has ADPKD to assess fetal kidney size and echogenicity, presence of fetal kidney cysts, and amniotic fluid volume [Vora et al 2008].

Therapies Under Investigation

Significant advances in the understanding of the genetics of ADPKD and the mechanisms of cyst growth have revealed likely targets for therapeutic intervention.

Of particular interest are recent studies that have shown that modulation of cAMP levels by targeting the vasopressin V2 receptor can dramatically inhibit cyst development in animal models of nephronophthisis, ARPKD, and ADPKD [Gattone et al 2003, Torres et al 2004, Wang et al 2005, Wang et al 2008]. A phase II open-label clinical trial with a vasopressin V2 receptor antagonist has been completed [Higashihara et al 2011] and a phase III/IV global, randomized, double-blind, placebo-controlled trial is currently in progress [Torres 2008, Torres et al 2011b].

Octreotide, a long-acting form of somatostatin, has been shown to slow the enlargement of polycystic kidneys and livers in an animal model of PKD [Masyuk et al 2007] and of polycystic kidneys and liver in a small randomized, placebo-controlled, crossover study [Ruggenenti et al 2005, Caroli et al 2010]. Two randomized, placebo controlled trials of octreotide and lanreotide for polycystic kidney and liver disease have shown that the administration of these somatostatin analogs causes a moderate but significant reduction in liver volume and decreases the growth velocity of polycystic kidneys compared to placebo [van Keimpema et al 2009, Hogan et al 2010]. Larger and longer studies are needed to determine whether these drugs can be administered safely to patients with ADPKD and/or polycystic liver disease and whether the beneficial effects are sustained.

mTOR inhibitors modulate the enlargement of polycystic kidneys in animal models of PKD. Their effectiveness, however, depends on the blood levels that can be achieved in different models. They are consistently effective in mouse models but not rat models because mice tolerate higher doses and blood levels compared to rats [Shillingford et al 2010, Spirli et al 2010, Zafar et al 2010]. mTOR inhibitors are effective in a paradigm in which cysts develop from the proximal tubules [Tao et al 2005, Shillingford et al 2006, Wahl et al 2006], but not in one in which cysts derive from the distal nephron and collecting duct [Renken et al 2011], as is the case in human ADPKD.

  • A small retrospective study of individuals with ADPKD following renal transplantation showed that sirolimus (an mTOR inhibitor) was able to promote regression of polycystic kidneys and livers [Shillingford et al 2006], while a similar study indicated that sirolimus was more effective in the liver than in the kidney [Qian et al 2008].
  • A randomized, crossover study of 15 individuals with ADPKD and an eGFR ≥40 mL/min/1.73 m2 demonstrated that treatment with sirolimus for six months was associated with a smaller increase in total kidney volume compared to placebo [Perico et al 2010].
  • A randomized, open-label, placebo controlled study of 100 affected individuals with an estimated creatinine clearance >70 ml/min and mean kidney volume of 907 mL (treated group) and 1003 mL (placebo group) showed no significant effect of treatment with sirolimus for 18 months on either kidney volume or GFR [Serra et al 2010], possibly because intended dosage was limited by toxicity of the drug and blood levels achieved might not have been enough to inhibit mTOR activity in the kidney [Canaud et al 2010].
  • A randomized, double-blind, placebo controlled study of everolimus (another mTOR inhibitor) in 431 affected individuals with an estimated glomerular filtration rate (eGFR) >30 ml/min/1.73 m2 and mean kidney volume of 2028 mL (treated group) and 1911 mL (placebo group) demonstrated that the administration of everolimus for 24 months was associated with a slower rate of increase in total kidney volume and a faster rate of decline in eGFR [Walz et al 2010]. Limitations of this study include the advanced stage of renal insufficiency of many study subjects (6.2% with an eGFR at enrollment below the inclusion limit of 30 mL/min) and the high dropout rate among study subjects, particularly in the study group (33%).

These three randomized clinical trials of mTOR inhibitors [Perico et al 2010, Serra et al 2010, Walz et al 2010] have been accompanied by significant drug toxicity.

Antagonists of the epidermal growth factor receptor [Sweeney et al 2000] and other agents targeting cell proliferation or fluid secretion have been effective in animal models of polycystic kidney disease, but are not yet in clinical trials [Torres et al 2007c]. A clinical trial of the Src inhibitor bosutinib has recently been started.

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Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Autosomal dominant polycystic kidney disease (ADPKD) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Most affected individuals have one parent who has ADPKD.
  • The incidence of de novo mutations is significant, occurring in about 10% of affected families.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include adequate screening by imaging methods, especially in the case of PKD2; and/or molecular genetic testing of both parents if the mutation in the proband is known.

Note: The family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent.

Sibs of a proband

  • The risk to sibs of the proband depends on the genetic status of the parents.
  • If a parent is affected, the risk to sibs is 50%.
  • When renal image analysis suggests that the parents are unaffected and the disease-causing mutation found in the proband cannot be detected in the DNA of either parent, the disease in the proband is likely caused by a de novo mutation and the risk to sibs is small. However, studies recently reported two families in which the parent of an individual with ADPKD, or the individual him/herself, had mosaicism [Connor et al 2008, Consugar et al 2008]. These findings have implications for the risk to sibs of a proband with an apparent de novo mutation.

Offspring of a proband. Every child of an individual with ADPKD has a 50% chance of inheriting the mutation.

Other family members of the proband. The risk to other family members depends on the genetic status of the proband's parents. If a parent is affected or has a disease-causing mutation, his or her relatives are at risk.

Related kidney donor. Relatives being considered as kidney donors need to be evaluated to determine if they have ADPKD. Evaluation usually consists of comprehensive renal image analysis by ultrasound, CT, and/or MRI. If a disease-causing mutation has been identified in the affected relative or if studies have established linkage in the family, molecular genetic testing is appropriate to establish the genetic status of the potential donor.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Testing of at-risk asymptomatic adults. Testing of at-risk asymptomatic adults for ADPKD should first involve renal image analysis. Molecular genetic testing is also possible. Because generalizations can be made about the phenotype expected in individuals with mutations in PKD1 versus PKD2, knowledge of the involved gene and causative mutation may provide some information on likely disease severity in asymptomatic individuals.

Testing for the disease in the absence of definite symptoms of the disease is predictive testing. Renal imaging should be considered as the first means to test for ADPKD. Molecular genetic testing should be considered if the imaging results are equivocal or if a definite diagnosis in a young person (age <30 years) is required, as for a potential renal transplant donor. At-risk, asymptomatic, adult family members may seek testing in order to make personal decisions. Others may have different motivations including simply the "need to know." Testing of asymptomatic, at-risk, adult family members usually involves pre-test interviews in which the motives for requesting the test, the individual's knowledge of ADPKD, and the possible impact of positive and negative test results are assessed. Those seeking testing should be counseled about possible problems that they may encounter with regard to health, life, and disability insurance coverage, employment discrimination, and changes in social and family interaction. Other issues to consider are implications for the at-risk status of other family members. Informed consent should be procured and records kept confidential. Individuals with a positive test result need arrangements for long-term follow up and evaluations.

Molecular genetic testing of asymptomatic individuals younger than age 18 years who are at risk for adult-onset disorders for which no treatment exists is not considered appropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause. However, the consensus holds that clinical monitoring for early disease presentations in individuals at risk for an adult-onset disorder is important.

Individuals who become symptomatic during childhood usually benefit from having a specific diagnosis established. See also the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Society of Human Genetics and American College of Medical Genetics points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents.

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. Mosaicism and complex inheritance may also play a role in a minority of patients [Rossetti et al 2009]. Possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Molecular genetic testing. Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks' gestation) or chorionic villus sampling (usually performed at ~10-12 weeks' gestation). The disease-causing allele of an affected family member must be identified or linkage established in the family before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for adult-onset conditions which (like ADPKD) do not affect intellect and have some treatment available are not common. The possible exception is rare families with perinatal lethality as a result of severe renal disease or with infants with grossly enlarged kidneys. Because such families are thought to be at high risk for a subsequent severely affected child, ultrasound monitoring for early evidence of renal enlargement is appropriate and prenatal molecular genetic testing may be considered if the disease-causing mutation in the family is known [Zerres et al 1993, Rossetti et al 2009].

Differences in perspective may exist among medical professionals and in families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Surveys of families with ADPKD suggest that only 4% to 8% of family members would terminate a pregnancy for ADPKD [Sujansky et al 1990]. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) has been reported [De Rycke et al 2005] and may be an option for some families in which the disease-causing mutation has been identified or linkage established in the family.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Library of Medicine Genetics Home Reference
  • NCBI Genes and Disease
  • PKD Foundation
    8330 Ward Parkway
    Suite 510
    Kansas City MO 64114-2000
    Phone: 800-753-2873 (toll-free); 816-931-2600
    Fax: 816-931-8655
  • The PKD Charity (Polycystic Kidney Disease)
    Scarcliffe S44 6TH
    United Kingdom
    Phone: 0300 111 1234
  • Kidney Foundation of Canada
    1599 Hurontario Street
    Suite 201
    Mississauga Ontario L5G 4S1
    Phone: 800-387-4474 (toll-free); 905-278-3003
    Fax: 905-271-4990
  • National Kidney Foundation (NKF)
    30 East 33rd Street
    New York NY 10016
    Phone: 800-622-9010 (toll-free); 212-889-2210
    Fax: 212-689-9261

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Polycystic Kidney Disease, Autosomal Dominant: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Polycystic Kidney Disease, Autosomal Dominant (View All in OMIM)


Molecular Genetic Pathogenesis

Polycystin-1 and polycystin-2 are thought to interact to form a functional complex. Accumulating evidence indicates that, in common with many other PKD proteins, polycystin-1 and polycystin-2 are localized to primary cilia [Pazour et al 2002, Yoder et al 2002]; PKD is a ciliopathy.

One theory proposes that the polycystin complex plays a role in the detection of fluid flow within the tubule [Nauli et al 2003]. Hence, flow within tubules of the normal kidney results in bending of cilia and activation of the polycystin flow sensor that results in a Ca2+ influx into the cell [Praetorius & Spring 2001, Nauli et al 2003]. Inactivation of the polycystin complex as a result of mutations in PKD1 or PKD2 (plus somatic events) results in altered Ca2+ homeostasis that may be associated with the multiple cellular changes (e.g., increased proliferation and apoptosis and altered polarity and secretory properties) that are characteristic of ADPKD cells [Torres & Harris 2006, Torres et al 2007c]. It is possible that urinary vesicles (or exosomes) that contain significant amounts of the polycystins help mediate this flow response [Hogan et al 2009].

An alternative hypothesis is that planar cell polarity (PCP)-related non-canonical Wnt signaling, which regulates the angle of mitotic divisions and ensures that they occur in the direction of elongating tubules, is abnormal in PKD [Fischer et al 2006]. However, more recent data cast doubt on whether PCP defects occur before cyst development and whether mitotic angle abnormalities always result in cyst development [Nishio et al 2010].

Common to the vascular and cardiac lesions is the disruption of the connective tissue framework responsible for their mechanical properties. Abnormalities of the internal elastic lamina, which is responsible for most of the tensile strength of the wall of the intracranial arteries, cause intracranial aneurysms and dolichoectasias. Dissection of the thoracic aorta and cervicocephalic arteries is characterized by disruption of the normal myoelastic lamellar structure of the arterial wall. It seems likely that PKD1 and PKD2 mutations are directly responsible for the vascular and cardiac manifestations of ADPKD because polycystin-1 and polycystin-2 are strongly expressed in the medial myocytes of elastic and large distributive arteries as well as in the cardiac myocytes and valvular myofibroblasts [Torres et al 2001, Qian et al 2003b].


Normal allelic variants. PKD1 encodes an approximately 14-kb transcript and comprises 46 exons within 50 kb of genomic DNA [Hughes et al 1995]. The genomic region encoding PKD1 has undergone a complex duplication such that six reiterated copies of the 5' three-quarters of the gene are present as pseudogenes elsewhere on chromosome 16 [European Polycystic Kidney Disease Consortium 1994, Loftus et al 1999]. The high sequence homology among these pseudogenes and PKD1 has complicated molecular genetic testing. Several alternatively spliced forms of PKD1 have also been described; the functional significance of any of these is not known.

PKD1 orthologs have been sequenced from a wide range of mammalian species and from amphibians and fish. No true orthologs are found in more primitive species, but homologous proteins in C elegans and sea urchins have provided insights into the function of polycystin-1-like proteins [Barr & Sternberg 1999, Mengerink et al 2002].

Pathologic allelic variants. PKD1 is characterized by extreme allelic variability, with approximately 70% of mutations unique to a single family [Rossetti et al 2007]. The mutations are spread throughout the gene and the majority predicted to truncate the product. The pattern is consistent with the mutations inactivating the allele, and it has been suggested that a somatic mutation disrupting the normal allele is required for cyst development [Qian et al 1996]. In the latest version of the ADPKD Mutation Database a total of approximately 880 likely pathogenic PKD1 changes are listed, accounting for more than 1300 families with PKD1.

Normal gene product. The PKD1 product, polycystin, is a 4303 amino-acid (aa) protein with a calculated molecular mass of 460 kd [Hughes et al 1995, International Polycystic Kidney Disease Consortium 1995, Sandford et al 1997]. The protein is membrane associated with a large extracellular region and short cytoplasmic tail. Cleavage of the protein occurs at the GPS domain [Ponting et al 1999, Qian et al 2002, Yu et al 2007]. The extracellular area contains several characterized domains that are generally involved in interactions with proteins or carbohydrates. The function of the protein is not known. It may be a receptor, although the ligand has not been identified [Ong & Harris 2005].

Polycystin-1 is expressed in the epithelia of maturing tubules in the kidney and epithelial cells in many other organs, with the highest expression in the embryo and downregulation in the adult. Expression is also found in smooth, skeletal, and cardiac muscle, suggesting that polycystin has a direct role in many of the extrarenal manifestations of the disease.

Abnormal gene product. The wide array of truncating mutations in PKD1 that causes ADPKD suggests that they inactivate the gene with no functional protein produced. Disease may subsequently develop after loss of the normal allele by a two-hit mechanism [Qian et al 1996]. However, evidence of genotype/phenotype correlations associated with mutation position and the fact that polycystin-1 may be cleaved into more than one protein product indicate that all mutations may not simply inactivate all products [Qian et al 2002, Rossetti et al 2002b, Rossetti et al 2003, Chauvet et al 2004, Low et al 2006]. Recent evidence indicates that a reduction in the level of polycystin-1 protein may be sufficient for cyst development and that cyst expansion may be a complex process [Lantinga-van Leeuwen et al 2004, Nishio et al 2005, Jiang et al 2006, Rossetti et al 2009, Harris 2010].


Normal allelic variants. PKD2 has an approximately 3-kb open reading frame and comprises 15 exons in a genomic area of approximately 70 kb.

PKD2 orthologs or homologs have been characterized in many mammalian species, frog, fish, and many invertebrates including C elegans and Drosophila. Polycystin-2-like proteins in these species have a range of roles from influencing mating behavior to modulating sperm motility [Barr & Sternberg 1999, Gao et al 2003].

Pathologic allelic variants. PKD2 is characterized by extreme allelic variability, with approximately 60% of mutations unique to a single family [Rossetti et al 2007]. As in PKD1, the mutations are spread throughout the gene and the majority of them are predicted to truncate the protein, consistent with inactivation of the allele. Approximately 150 different PKD2 mutations have been described, accounting for more than 330 families.

Normal gene product. Polycystin-2 is predicted to have six transmembrane domains with cytoplasmic N- and C-termini. It shares a region of homology with polycystin-1 in the transmembrane region. It also has sequence similarity to TRP channels and is now considered to be a TRP protein (TRPP2). Polycystin-2 acts as a Ca2+-permeable cation channel and the basic defect in ADPKD may be in aberrant regulation of intracellular Ca2+ [Hanaoka et al 2000, González-Perrett et al 2001, Vassilev et al 2001, Koulen et al 2002]. A recent focus has been the role of polycystin-2 on the primary cilia and its function in the influx of Ca2+ associated with flow, although it may also be associated with intracellular Ca2+ stores in the ER. Polycystin-2 expression is similar to that of polycystin-1, but it continues at a more consistent level in the adult.

Abnormal gene product. The wide array of truncating mutations in PKD2 suggests that they inactivate the gene with no functional protein produced and a two-hit disease mechanism [Wu et al 1998].


Published Guidelines/Consensus Statements

  1. American Society of Human Genetics and American College of Medical Genetics. Points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents. Available online. 1995. Accessed 9-26-12. [PMC free article: PMC1801355] [PubMed: 7485175]
  2. National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset disorders. Available online. 2012. Accessed 9-26-12.

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Suggested Reading

  1. Harris PC, Torres VE. Polycystic kidney disease. Annu Rev Med. 2009;60:321–37. [PMC free article: PMC2834200] [PubMed: 18947299]
  2. Various review articles on ADPKD. Adv Chronic Kidney Dis. 2010;17:115–80.
  3. Chapin HC, Caplan MJ. The cell biology of polycystic kidney disease. J Cell Biol. 2010;191:701–10. [PMC free article: PMC2983067] [PubMed: 21079243]
  4. Harris PC, Rossetti S. Molecular diagnostics for autosomal dominant polycystic kidney disease. Nat Rev Nephrol. 2010;6:197–206. [PMC free article: PMC4050432] [PubMed: 20177400]
  5. Torres VE, Harris PC. Autosomal dominant polycystic kidney disease: the last 3 years. Kidney Int. 2009;76:149–68. [PMC free article: PMC2812475] [PubMed: 19455193]
  6. US Renal Data System. USRDS 2000 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. Available online. 2000. Accessed 12-2-11.

Chapter Notes

Revision History

  • 8 December 2011 (me) Comprehensive update posted live
  • 2 June 2009 (cd) Revision: deletion/duplication analysis available clinically for PKD2
  • 15 December 2008 (cd) Revision: FISH (deletion/duplication analysis) no longer listed in the GeneTests Laboratory Directory as being offered for PKD1
  • 7 October 2008 (me) Comprehensive update posted live
  • 6 June 2006 (me) Comprehensive update posted to live Web site
  • 5 March 2004 (me) Comprehensive update posted to live Web site
  • 10 January 2002 (me) Review posted to live Web site
  • 22 August 2001 (ph) Original submission
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