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Polycystic Kidney Disease, Autosomal Dominant

Synonym: ADPKD

, PhD and , MD.

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Initial Posting: ; Last Update: July 19, 2018.

Estimated reading time: 1 hour, 5 minutes

Summary

Clinical characteristics.

Autosomal dominant polycystic kidney disease (ADPKD) is generally a late-onset multisystem disorder characterized by bilateral renal cysts, liver cysts, and an increased risk of intracranial aneurysms. Other manifestations include: cysts in the pancreas, seminal vesicles, and arachnoid membrane; 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 increases with age and occasionally results in clinically significant severe polycystic liver disease (PLD). Overall the prevalence of intracranial aneurysms is fivefold higher than in the general population and further increased in those with a positive family history of aneurysms or subarachnoid hemorrhage. There is substantial variability in the severity of renal disease and other extrarenal manifestations even within the same family.

Diagnosis/testing.

The diagnosis of ADPKD is established in a proband with age-specific renal imaging criteria and an affected first-degree relative with ADPKD or identification of a heterozygous pathogenic variant in PKD1, PKD2, GANAB, or DNAJB11.

Management.

Treatment of manifestations: Vasopressin V2 receptor antagonists (e.g., tolvaptan) to slow disease progression. 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, renal denervation, and nephrectomy. Cyst hemorrhage and/or gross hematuria is usually self-limiting. Treatment of nephrolithiasis is standard. Treatment of cyst infections is difficult, with a high failure rate. Therapeutic agents of choice may include trimethoprim-sulfamethoxazole, fluoroquinolones, clindamycin, vancomycin, and metronidazole. The diagnosis of malignancy requires a high index of suspicion. 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. Most individuals with PLD have no symptoms and require no treatment, but rare severe cases may require surgical resection or even liver transplantation. 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 is indicated when the aortic root diameter exceeds established size.

Prevention of secondary manifestations (lifestyle and therapeutic factors that may modulate disease): Maintain appropriate blood pressure and urine osmolarity; low osmolar intake (e.g., moderate sodium and protein); increase hydration by moderate water intake; maintain sodium bicarbonate ≥22 mEq/L; moderate dietary phosphorus intake; moderate caloric intake to maintain normal BMI; low-impact exercise; lipid control; tolvaptan therapy.

Surveillance: Early blood pressure monitoring starting in childhood; MRI screening for intracranial aneurysms in those determined to be at high risk; screening echocardiography in those with a heart murmur and those with a family history of a first-degree relative with a thoracic aortic dissection.

Agents/circumstances to avoid: Long-term administration of nephrotoxic agents, high levels of caffeine, use of estrogens and possibly progestogens by individuals with severe PLD, smoking, and obesity.

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

Pregnancy management: Pregnant women with ADPKD should be monitored for the development of hypertension, urinary tract infections, oligohydramnios, and preeclampsia; the fetus should be monitored for intrauterine fetal growth restriction, oligohydramnios, and fetal kidney anomalies including cysts, enlarged size, and atypical echogenicity.

Genetic counseling.

ADPKD is inherited in an autosomal dominant manner. About 95% of individuals with ADPKD have an affected parent, but at least 10% of families can be traced to a de novo pathogenic variant. Each child of an affected individual has a 50% chance of inheriting the pathogenic variant. Once the pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for ADPKD are possible.

Diagnosis

Diagnostic criteria for autosomal dominant polycystic kidney disease (ADPKD) are discussed in the executive summary of the KDIGO Controversies Conference [Chapman et al 2015].

Suggestive Findings

ADPKD should be suspected in individuals with the following:

  • Multiple bilateral renal cysts and the absence of manifestations suggestive of a different renal cystic disease
  • Cysts in other organs, especially the liver, but also seminal vesicles, pancreas, and arachnoid membrane
  • Enlargement of the kidneys or liver on physical examination
  • Hypertension in an individual younger than age 35 years
  • An intracranial aneurysm
  • A family history of ADPKD

Establishing the Diagnosis

The diagnosis of ADPKD is established in a proband with ANY of the following:

Age-Specific Ultrasound Criteria

Age-specific ultrasound criteria in an individual with an affected first-degree relative [Pei et al 2009]:

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

Note: (1) The positive predictive value of these criteria is described as 100%, regardless of (a) whether the disorder is PKD1- or PKD2-related ADPKD and (b) the age of the individual at the time of initial evaluation (see Table 1). Note that there are other genetic causes of renal cysts in addition to pathogenic variants in PKD1 or PKD2 (Table 3, Table 5). (2) The sensitivity is low (Table 1; 81.7%-95.5%), particularly in families with a pathogenic variant in PKD2 (69.5%-94.9%). A low sensitivity is likely true for families with a nontruncating PKD1 pathogenic variant (does not truncate or shorten the protein product, polycystin-1), and for pathogenic variants in GANAB or DNAJB11, which are typically associated with mild cystic disease (Table 3). In these situations, a significant number of affected individuals may not be diagnosed, which may pose a problem when exclusion of the diagnosis is critical (see Excluding the 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 yrs≥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 yrs≥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 yrs≥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

Age-specific MRI criteria are particularly useful when ultrasound results are equivocal [Pei et al 2015]. For individuals ages 16-40 years who are at 50% risk for ADPKD because they have an affected first-degree relative, the presence of more than ten cysts is sufficient for a diagnosis of ADPKD.

Note: These criteria may also be more appropriate to use when employing a modern, high-resolution ultrasound scanner that can detect cysts as small as 1-2 mm.

Excluding the Diagnosis

The absence of renal cysts by ultrasound examination virtually excludes a diagnosis of ADPKD caused by a truncating PKD1 pathogenic variant, which predicts a truncated polycystin-1, in an at-risk person age 15-30 years (negative predictive value [NPV] = 99.1%) or older (NPV = 100%). However, absence of renal cysts does not exclude the diagnosis in persons younger than age 40 years who are at risk for ADPKD caused by incompletely penetrant, nontruncating PKD1 variants or pathogenic variants in other ADPKD-related genes associated with milder disease.

A normal renal ultrasound does not exclude ADPKD with certainty in an at-risk individual younger than age 30 years (see Table 2).

Ultrasound criteria used to exclude an at-risk relative as a potential living-related kidney donor are shown in Table 2.

MRI or contrast-enhanced CT examination, which has much higher sensitivity than ultrasound to detect cysts and is routinely performed in most transplantation centers to define the donor kidney anatomy, provides further assurance for the exclusion of the diagnosis if cysts are absent (see Age-specific MRI criteria). When evaluating at-risk individuals in the same age group as living-related donors, fewer than five cysts is considered sufficient for exclusion of the disease.

When the family-specific pathogenic variant has not been identified:

  • Ultrasound examination showing normal kidneys in an individual age 30-39 years or no more than 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 as a rough guide to predict the severity of disease in other family members (see Genotype-Phenotype Correlations).

Table 2.

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

Molecular Genetic Testing

Testing approaches can include a multigene panel or concurrent gene testing.

Option 1 (recommended)

A multigene panel that includes PKD1, PKD2, GANAB, DNAJB11, and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) Multigene panels using next-generation sequencing should be carefully designed to maximize identification of a PKD1 pathogenic variant, which is complicated by several highly homologous pseudogenes [Trujillano et al 2014, Eisenberger et al 2015]. (2) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (3) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (4) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (5) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

Concurrent gene testing. Sequence analysis and deletion/duplication analysis of PKD1 and PKD2 can be performed concurrently. Note: Sequence analysis should be designed to maximize identification of a PKD1 pathogenic variant, which is complicated by several highly homologous pseudogenes [Trujillano et al 2014, Eisenberger et al 2015].

Table 3.

Molecular Genetic Testing Used in ADPKD

Gene 1Proportion of ADPKD Attributed to Pathogenic Variants in GeneProportion of Pathogenic Variants 2 Detectable by Method
Sequence analysis 3Gene-targeted deletion/duplication analysis 4
PKD1~78%~97% 5~3%
PKD2~15%~97% 5~3%
GANAB~0.3%7/7Unknown, none reported 6
DNAJB11~0.1%7/7Unknown, none reported 6
Unknown~7%NA
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Due to the segmental duplication of PKD1, such analysis may require specific methods that detect large rearrangements, such as multiplex ligation-dependent probe amplification (MLPA) [Consugar et al 2008, Cornec-Le Gall et al 2013] or chromosomal microarray (CMA) that includes this gene/chromosome segment.

5.
6.

No data on detection rate of gene-targeted deletion/duplication analysis are available.

Clinical Characteristics

Clinical Description

Renal Manifestations

Although all individuals with autosomal dominant polycystic kidney disease (ADPKD) develop cysts within the kidneys, there is substantial variability 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 [Gabow 1996]; first episode of hematuria before age 30 years; onset of hypertension before age 35 years [Cornec-Le Gall et al 2016]; hyperlipidemia and high body mass index (BMI) [Nowak et al 2018]; high urine sodium excretion [Torres et al 2017a]; lower renal blood flow; lower serum HDL cholesterol [Torres et al 2011a]; large total kidney volume (TKV) [Chapman et al 2012, Irazabal et al 2015]; and the presence of a truncating PKD1 variant [Cornec-Le Gall et al 2013, Heyer et al 2016].

The lower incidence of end-stage renal disease (ESRD) in affected females compared to affected males suggests that ADPKD is a more severe disease in males. Analysis of a population of individuals with PKD1-related ADPKD from the French Genkyst cohort showed poorer renal survival in males than females (mean age at onset of ESRD was 58.1 years for males and 59.5 years for females) [Cornec-Le Gall et al 2013]. Heyer et al [2016] showed lower estimated glomerular filtration rate (eGFR) and larger height-adjusted TKV (htTKV) in males compared to females in the total HALT PKD study population and in individuals with PKD1-related ADPKD. Males with PKD2-related ADPKD also had lower eGFR. Males with truncating PKD1 variants, onset of hypertension before age 35 years, and/or a urologic event before age 35 years were the most severely affected [Cornec-Le Gall et al 2016].

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 annual MRI examinations showed that TKV and cyst volumes increased exponentially. At baseline, TKV was 1,060 ± 642 mL; the mean increase over three years was 204 mL, or 5.3% per year. The baseline TKV predicted the subsequent rate of increase in renal volume, meaning that the larger the kidney, the faster the rate of renal enlargement over time. Declining glomerular filtration rate (GFR) was observed in persons with baseline TKV above 1,500 mL [Grantham et al 2006].

Kidney size has been shown to be a strong predictor of subsequent decline in renal function with an htTKV of ≥600 mL/m showing a high predictive value for the individual to develop renal insufficiency within eight years [Chapman et al 2012]. Compartmentalizing age-adjusted htTKV into five classes based on htTKV/age has also shown that this strongly predicts decline in renal function and ESRD. A model including htTKV (that can be estimated using renal dimensions and the ellipsoid equation), age, and eGFR (available via an online app) has good predictive value in estimating future eGFR [Irazabal et al 2015].

Individuals with PKD1-related ADPKD often have significantly larger kidneys with more cysts than individuals with PKD2-related ADPKD. However, the rates of cystic growth are not different, indicating that PKD1-related ADPKD is more severe because more cysts develop earlier, not because they grow faster [Harris et al 2006].

Occasionally, enlarged and echogenic kidneys with or without renal cysts are detected prenatally in a fetus at risk for ADPKD [Zerres et al 1993]. The prognosis in these individuals is often more favorable than expected given the large kidney size with a decrease in volume and no decline in renal function commonly seen, at least during childhood. However, ESRD develops earlier than is typically seen in adult-onset disease [Fick et al 1993, Zerres et al 1993]. Biallelic PKD1 or PKD2 pathogenic variants have been reported in individuals with very early-onset ADPKD (see Genotype-Phenotype Correlations) [Cornec-Le Gall et al 2018].

Renal function abnormalities. Reduction in urinary concentrating capacity and excretion of ammonia occur early in individuals with ADPKD. 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 individuals with ADPKD.

Studies suggest that the urinary concentrating defect and elevated serum concentration of vasopressin may contribute to cystogenesis [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 TKV and albuminuria and negatively with GFR and effective renal blood flow) in a cross-sectional analysis of people with ADPKD [Meijer et al 2011]. Plasma copeptin concentration has also been associated with the change in TKV during follow up in the CRISP study [Boertien et al 2013].

A decline in renal function, detected as a rise in serum creatinine, is generally seen only later in the course of disease, typically about a dozen years before ESRD. However, once kidney function starts to deteriorate, GFR has been observed to decline rapidly (~4-6 mL/min/yr) [Klahr et al 1995]. The severity of the kidney disease may influence the timing and rate of decline.

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 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
  • Salt sensitivity
  • Normal or increased extracellular fluid volume, plasma volume, and cardiac output
  • Partial correction of renal hemodynamics and sodium handling by converting enzyme inhibition

Hypertension is often diagnosed much later than when it first occurs in individuals with ADPKD. Twenty-four-hour monitoring of ambulatory blood pressure of children or young adults may reveal elevated blood pressure, 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]. Monitoring of blood pressure in children at risk for ADPKD is recommended [Massella et al 2018].

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;
  • 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 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 examination; and contrast enhancement, tumor thrombus, and regional lymphadenopathies on CT or MRI examination should raise suspicion for a carcinoma.

An increased risk for RCC in individuals with ADPKD who are on dialysis for ESRD can be explained by the increased incidence of RCC with advanced kidney disease [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.

When age and other co-variants were taken into consideration, the rate of all cancers in individuals with ADPKD after kidney transplantation was reported to be lower than in kidney transplant recipients who did not have ADPKD [Wetmore et al 2014].

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

Renal failure. Approximately 50% of individuals with ADPKD have ESRD by age 60 years. Mechanisms accounting for the decline in renal function include: compression of the normal renal parenchyma by expanding cysts, vascular sclerosis, interstitial inflammation and fibrosis, and apoptosis of the tubular epithelial cells. The CRISP study [Grantham et al 2006] confirmed a strong relationship with renal enlargement 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 reports in which the decline of renal function appears 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 (PLD) is the most common extrarenal manifestation of ADPKD.

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 participants age 15-24 years, 85% in those age 25-34 years, and 94% in those age 35-46 years [Bae et al 2006]. PLD 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 liver cysts increased in women who received estrogen replacement therapy, suggesting that estrogens have an important effect on the progression of PLD [Everson & Taylor 2005]. Analysis of liver volumes and liver cyst volumes in 534 individuals with ADPKD in the HALT PKD study showed an increase in parenchymal volume and a correlation between the severity of PLD and biochemical and hematologic features, in addition to reduced quality of life [Hogan et al 2015]. Analysis of individuals with severe PLD, defined as a height-adjusted total liver volume of 1.8 liters, showed no difference in frequency among those with truncating PKD1 variants, nontruncating PKD1 variants, and PKD2 pathogenic variants, suggesting that other factors are primarily responsible for the severity of PLD [Chebib et al 2016]. This study also showed that severe PLD often regressed in females after menopause.

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 PLD and markedly elevated in hepatic cyst fluid. Serum CA19-9 levels correlate with polycystic liver volume [Waanders et al 2009, Kanaan et al 2010].

Complications of PLD 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 and MRI examination are helpful in the diagnosis of cyst infection but have low specificity. On CT examination, the following have been associated with infection: fluid-debris levels within cysts, cyst wall thickening, intracystic gas bubbles, and heterogeneous or increased density. Indium-labeled white blood cell scans are more specific but not always conclusive. 18F-fluorodeoxyglucose positron emission tomography examination is the most sensitive technique for diagnosis of infected cysts [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 rarely seen 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 syndrome (see Table 5). They are almost always asymptomatic, and rarely associated with recurrent pancreatitis [Başar et al 2006].
  • Intraductal papillary mucinous tumors have been reported with increased frequency, but their prevalence and prognosis in ADPKD are uncertain [Naitoh et al 2005].
  • An association between ADPKD and pancreatic carcinomas was reported [Sakurai et al 2001]; however, this may represent a chance association of two common disorders.

Cysts in other organs

  • Seminal vesicle cysts, present in 40% of males, rarely result in infertility. Defective sperm motility is another cause of male infertility in ADPKD [Torra et al 2008].
  • Arachnoid membrane cysts, present in 8% of affected individuals [Danaci et al 1998], are usually asymptomatic, but may increase the risk for subdural hematomas [Wijdicks et al 2000].
  • Spinal meningeal diverticula may occur with increased frequency and individuals may present with intracranial hypotension secondary to cerebrospinal fluid leak [Schievink & Torres 1997].
  • Ovarian cysts are not associated with ADPKD [Stamm et al 1999, Heinonen et al 2002].

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 without such a family history (6%). 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 as follows:

  • 0.05% per year for aneurysms <10 mm in diameter
  • ~1% per year for aneurysms 10-24 mm
  • 6% within one year for aneurysms ≥25 mm

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

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

Intracranial aneurysm rupture confers a 35% to 55% risk for 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, Irazabal et al 2011].

Individuals with ADPKD may be at increased risk for vasospasm and transient ischemic complications following cerebral angiography. They may also be at 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. A study of 543 affected individuals with GFR >60 mL/min per 1.73 m2, short duration of hypertension, and prior use of angiotensin-converting enzyme inhibitors / angiotensin receptor blockers who underwent cardiac MRI found a very low prevalence of left ventricular hypertrophy, possibly due to early blood pressure intervention [Perrone et al 2011].

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]. Recent studies have suggested that individuals with ADPKD may be predisposed to idiopathic dilated and hypertrophic obstructed cardiomyopathy, and left ventricular non-compaction [Paavola et al 2013, Chebib et al 2017].

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].

Mosaicism

Variable disease presentation in a family and apparent de novo disease can be due to mosaicism. Four families with ADPKD in which an individual has been found to have a somatic and/or germline PKD1 pathogenic variant have been described [Connor et al 2008, Consugar et al 2008, Reiterová et al 2013, Tan et al 2015]. The disease phenotype in these families is variable, ranging from similar to other non-mosaic affected family members, to much milder disease, presumably reflecting the level of the pathogenic variant in the kidneys. A recent study of individuals with ADPKD without a family history found germline mosaicism in two families and somatic mosaicism in one [Iliuta et al 2017].

Phenotype Correlations by Gene

PKD1. Pathogenic variants in PKD1 are associated with more severe disease with an earlier age at diagnosis and mean age of onset of ESRD than in PKD2-related ADPKD (58.1 years for PKD1; 79.7 years for PKD2) [Hateboer et al 1999, Cornec-Le Gall et al 2013]. Most individuals with fully penetrant pathogenic variants in PKD1 experience renal failure by age 70 years; more than 50% of individuals with pathogenic variants in PKD2 have adequate renal function at that age.

GANAB. Pathogenic variants cause mild cystic kidney disease, usually without a decline in renal function, with the majority of affected individuals having liver cysts [Porath et al 2016]. However, some affected individuals have a phenotype of autosomal dominant polycystic liver disease (ADPLD) with severe liver cystic disease and few renal cysts [Porath et al 2016, Besse et al 2017, Besse et al 2018].

DNAJB11. The phenotype is quite consistent and results in the development of small, bilateral kidney cysts, usually without renal enlargement. In older individuals the kidneys become fibrotic and renal insufficiency often develops; ESRD is noted in seven individuals between ages 59 and 89 years [Cornec-Le Gall et al 2018]. The renal insufficiency without renal enlargement shows some characteristics of autosomal dominant tubulointerstitial kidney disease (ADTKD). Liver cysts are sometimes present.

Genotype-Phenotype Correlations

PKD1. The average age at onset of ESRD in affected individuals with truncating PKD1 variants is 55.6 years compared to 67.9 years for those with nontruncating PKD1 variants, suggesting that a significant proportion of in-frame changes are likely hypomorphic (i.e., resulting in partial loss of gene function, which is manifested as a reduced level of functional protein) [Cornec-Le Gall et al 2013, Hwang et al 2016].

More detailed bioinformatic analysis divided nontruncating PKD1 pathogenic variants into two mutation strength groups (MSG), with nonconservative substitutions at well-conserved sites in orthologs and domains (MSG2) found to have similar severity to truncating PKD1 pathogenic variants in terms of eGFR and htTKV [Heyer et al 2016]. Therefore, it is likely that approximately 50% of missense and other in-frame changes are fully penetrant pathogenic variants [Harris & Hopp 2013]. However, a group of variants with more conservative substitutions at less well-conserved sites (MSG3) was found to be hypomorphic by analysis of eGFR and htTKV.

Family studies have identified incompletely penetrant nontruncating PKD1 variants that are associated with less severe disease [Rossetti et al 2009, Pei et al 2012]. One such well-studied PKD1 variant, p.Arg3277Cys, causes just a few cysts or no evidence of disease in heterozygotes [Rossetti et al 2009]. These hypomorphic alleles often result in a reduced level of functional protein. Thus the phenotype depends on whether a hypomorphic allele occurs in isolation or in combination with other PKD1 and/or PKD2 pathogenic variants (see Biallelic PKD1- and PKD2-related ADPKD).

PKD2. Recently, truncating PKD2 pathogenic variants were found to be associated with more severe disease with lower eGFR than nontruncating pathogenic variants [Cornec-Le Gall et al 2017].

Biallelic PKD1- or PKD2-related ADPKD. Fully penetrant (i.e., non-hypomorphic) biallelic pathogenic variants in either PKD1 or PKD2 in humans are predicted to be incompatible with live birth, consistent with Pkd1 or Pkd2 knockout mice that develop fetal cystic kidneys and are embryonic lethal [Lu et al 1997, Wu et al 2000]. However, biallelic pathogenic variants where at least one variant is hypomorphic can be compatible with life. Rossetti et al [2009] reported two families with individuals homozygous for PKD1 pathogenic variants, including p.Arg3277Cys. A hypomorphic allele in trans configuration with a typical disease-causing allele can also explain some cases of in utero-onset ADPKD [Zerres et al 1993, Rossetti et al 2009, Bergmann et al 2011, Audrézet et al 2016]. Biallelic pathogenic variants in which both are hypomorphic alleles can also result in early-onset disease with an apparently negative family history, and therefore can be mistaken for ARPKD [Vujic et al 2010].

Neonatal-onset ADPKD has also been associated with homozygosity of a hypomorphic PKD2 allele, which arose by uniparental disomy [Losekoot et al 2012].

Digenic ADPKD. Individuals with pathogenic variants in both PKD1 and PKD2 have been described. Two individuals in one family were double heterozygotes for a pathogenic variant in both PKD1 and PKD2 and developed more severe renal disease than was reported in heterozygous relatives [Pei et al 2001].

It has been suggested that early-onset PKD may be caused by a heterozygous pathogenic variant in both PKD1 and HNF1B (digenic inheritance) [Bergmann et al 2011]. Variants in HNF1B are associated with ADTKD (see Table 5).

Penetrance

Penetrance in ADPKD is age and genotype dependent. The penetrance of multiple bilateral renal cysts in older adults is close to 100%. However, because the disease is progressive, few cysts may be evident during childhood or young adulthood, especially in individuals with nontruncating PKD1 pathogenic variants or pathogenic variants in PKD2, GANAB, or DNAJB11.

Nomenclature

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

Prevalence

ADPKD is the most common potentially lethal single-gene disorder. Its prevalence at birth is approximately 1:1,000; and it affects approximately 300,000 persons in the United States.

Differential Diagnosis

In the absence of a family history of PKD and/or in the presence of atypical presentations, benign simple cysts (see Table 4) and other cystic diseases should be considered in the differential diagnosis. Studies of potential kidney donors using contrast-enhanced CT, which detects smaller cysts (1-2 mm), showed that from age 19 to 49 years, 39%, 22%, 7.9%, and 1.6% had at least one cyst ≥2 mm, ≥5 mm, ≥10 mm, and ≥20 mm in diameter, respectively, while from age 50 to 75 years, 63%, 43%, 22%, and 7.8% had at least one cyst ≥2 mm, ≥5 mm, ≥10 mm, and ≥20 mm in diameter, respectively [Rule et al 2012].

Table 4.

Prevalence of Simple Renal Cysts in Unaffected Individuals on Ultrasound Examination

Age in YearsSimple Renal Cysts 1Bilateral Renal Cysts 2
15-290%--
30-491.7%1%
50-6911.5%4%
≥7022.1%9%
1.

≥1 renal cyst

2.

≥1 cyst in each kidney

The conditions in Table 5 can be confused with ADPKD.

Table 5.

Disorders to Consider in the Differential Diagnosis of ADPKD

DisorderGene(s)MOIClinical Features of Differential Diagnosis Disorder
Overlapping w/ADPKDDistinguishing from ADPKD
AD tubulointerstitial kidney disease (type 5 maturity-onset diabetes of the young)HNF1BADCystic renal disease
  • Diabetes
  • Pancreatic disease
  • ↑ liver enzymes
  • Hypomagnesemia
  • Congenital renal & urinary tract anomalies
AR polycystic kidney diseasePKHD1ARBilateral renal cystic disease
  • Majority present in neonatal period
  • Pulmonary hypoplasia
  • Early-onset renal failure
  • Liver fibrosis rather than cysts
  • TKV ↓over time (rather than ↑)
AD polycystic liver disease 1
(OMIM PS174050)
ALG8
GANAB
LRP5
PRKCSH
SEC63
SEC61B
AD
  • Liver cysts
  • Occasional kidney cysts
  • Predominant phenotype is liver disease w/very mild kidney disease if present.
  • Note an overlap between ADPKD & ADPLD w/GANAB pathogenic variants causing either disease.
AD tubulointerstitial kidney disease, UMOD-relatedUMODADRenal cysts
  • Kidney function ↓ w/out ↑ in TKV
  • No liver cysts
  • Gout
AD tubulointerstitial kidney disease, MUC1-relatedMUC1ADRenal cysts
  • Kidney function ↓ w/out ↑ in TKV
  • No liver cysts
Familial juvenile hyperuricemic nephropathy type 4
(OMIM 617056)
SEC61A1ADRenal cysts
  • Kidney function ↓ w/out ↑ in TKV
  • No liver cysts
Tuberous sclerosis complexTSC1
TSC2
ADRenal cysts
  • Renal angiomyolipomas
  • Skin & brain manifestations
  • Rhabdomyomas
  • Lymphangioleiomyomatosis
Von Hippel-Lindau syndromeVHLAD
  • Renal cysts
  • Pancreatic cysts
  • Hemangioblastomas
  • Pheochromocytoma
  • Neuroendocrine tumors
Oral-facial-digital syndrome type 1OFD1XLRenal cysts in affected females
  • Hyperplastic frenula
  • Cleft tongue
  • Cleft lip or palate
  • Malpositioned teeth
  • Broad nasal root w/hypoplasia of nasal alae & malar bone & digital abnormalities
  • X-linked inheritance; usually male lethal during gestation
Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps
(see COL4A1-Related Disorders)
COL4A1ADRenal cysts
  • Hematuria
  • Muscle cramps or ↑ CPK
  • Tortuosity of retinal artery
  • Brain small-vessel disease
Hajdu-Cheney syndrome
(OMIM 102500)
NOTCH2ADRenal enlargement w/cortical & medullary cysts
  • Short stature
  • Midfacial flattening w/proptosis
  • Receding chin
  • Hirsutism
  • Acroosteolysis of terminal phalanges
  • Basilar invagination of the skull
Localized renal cystic diseaseNANAHistologic appearance strongly resembling advanced ADPKD
  • Cystic degeneration of a portion of 1 kidney
  • Non-progressive
  • Nonfamilial
Acquired renal cystic diseaseNANARenal cystsCysts develop after ESRD onset.

AD = autosomal dominant; AR = autosomal recessive; CPK = creatinine phosphokinase; ESRD = end-stage renal disease; MOI = mode of inheritance; NA = not applicable; XL = X-linked

1.

See Polycystic Kidney disease: OMIM Phenotypic Series to view genes associated with this phenotype in OMIM.

Management

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 if they have not already been completed:

  • Renal ultrasound examination (if CT or MRI examination is unavailable) to determine the severity of disease and provide an estimate of size and distribution of cysts and kidney size
  • CT or MRI examination of the abdomen with and without contrast enhancement, which is more sensitive and allows better quantification of the disease severity 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.
  • Blood pressure examination to detect 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].
  • Consultation with a clinical geneticist and/or genetic counselor if the nephrologist is not an expert in inherited disorders

Treatment of Manifestations

Treatment guidelines formulated at the ADPKD KDIGO conference are summarized in Chapman et al [2015].

Current therapy for ADPKD is directed toward reducing morbidity and mortality from the renal and extrarenal complications of the disease, although specific treatments are becoming available.

Vasopressin V2 Receptor Antagonists

Studies 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 [Higashihara et al 2011] and a Phase III global randomized double-blind placebo-controlled trial with a vasopressin V2 receptor antagonist (tolvaptan) have been completed [Torres 2008, Torres et al 2011b, Torres et al 2012]. The Phase III trial, which extended over three years, included 1,445 affected individuals with preserved renal function but large kidney volumes. The increase in kidney volume in the treated group was 2.8% per year compared to 5.5% in the untreated group. Use of tolvaptan was also associated with a slower decline in kidney function. There were fewer kidney-related adverse events in the treated group but more aquaresis, and reversible elevations in liver enzyme levels occurred in approximately 5% of individuals on tolvaptan. These elevations met Hy's law criteria denoting a 10% risk of liver failure.

Recently a one-year Phase III global randomized double-blind placebo-controlled trial of tolvaptan in 1,370 affected individuals with renal insufficiency has been completed [Torres et al 2017b]. Individuals were either 18-55 years with an eGFR of 25-65 mL/min/1.73 m2 or 56-65 years with an eGFR of 25-44 mL/min/1.73 m2. The change in eGFR was -2.34 mL/min/1.73 m2 in the treated group compared to -3.61 mL/min/1.73 m2 in the control group (p<0.001). As previously, elevations in liver enzymes were found in approximately 5% of treated subjects; elevations reversed on withdrawal from tolvaptan. No cases met Hy's law criteria likely because of more frequent monitoring of liver enzymes and earlier discontinuation of tolvaptan.

Tolvaptan has been approved for clinical use in persons with ADPKD in Japan, Canada, Europe, and the US. Various guidelines have been generated for guiding the administration of tolvaptan, focusing on selecting individuals with rapidly progressive disease that is likely to result in ESRD [Gansevoort et al 2016, Soroka et al 2017]. Factors considered for identifying rapidly progressive ADPKD are TKV/age, rate of change of TKV, eGFR/age, rate of decline of eGFR, genotype, and family history.

Hypertension

The antihypertensive agent(s) of choice in ADPKD have not been clearly established. However, 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 a 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]. However, 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 that involved protein restriction and low blood pressure targets showed that individuals with ADPKD randomized to the 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].
  • The HALT PKD trial did not show a benefit of the addition of an angiotensin II receptor blocker (ARB) to an ACE inhibitor in preservation of renal function [Torres et al 2014]. However, in the same trial, a lower blood pressure target (95-110/60-75 mm Hg) compared to the standard target (120-130/70-80 mm Hg) in younger affected individuals with preserved renal function was associated with a slower increase in kidney volume but no overall change in the decline in renal function, as measured by eGFR [Schrier et al 2014].

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 recommended:

  • 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] and percutaneous transluminal catheter-based denervation was effective in a small number of individuals [Shetty et al 2013, Casteleijn et al 2014].
  • Laparoscopic and retroperitonoscopic nephrectomy and arterial embolization have been used 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

Cyst hemorrhage and 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. These individuals require hospitalization, transfusion, and investigation by CT or angiography. In individuals with unusually severe or persistent hemorrhage, segmental arterial embolization can be successful. If not, surgery may be required to control bleeding. Some reports suggest a role for tranexamic acid in the treatment of life-threatening hematuria [Hulme & Wylie 2015].

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-fluorodeoxyglucose 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.

End-Stage Renal Disease (ESRD)

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.

Following transplantation, there is no difference in patient or graft survival between individuals with ADPKD and those with ESRD caused by other conditions, and complications 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 is questionable [Ruderman et al 2012].

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 considerations [Lucas et al 2010, Kirkman et al 2011]. Hand-assisted laparoscopic nephrectomy is increasingly being used [Lee & Clayman 2004].

Polycystic Liver Disease (PLD)

Most individuals with PLD 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 PLD and is often preferable to liver transplantation, which is reserved for individuals for whom liver resection is not feasible or in whom liver function is impaired.
  • Because individuals with severe PLD 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 individuals who are not candidates for surgery [Takei et al 2007].

Intracranial Aneurysm

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

Asymptomatic. Those aneurysms measuring ≤5.0 mm 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 >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 appears 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 55-60 mm, replacement of the aorta is indicated. Guidelines for management of thoracic aortic disease have been published [Hiratzka et al 2010]. Management of aortic dissection requires coordinated input from a multidisciplinary team including a cardiologist and cardiothoracic and vascular surgeons.

Prevention of Secondary Manifestations

Additional 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. The Modification of Diet in Renal Disease (MDRD) trial showed only a slight (borderline significant) beneficial effect of a very low protein diet when introduced at a late state of the disease (GFR 13-55 mL/min per 1.73 m2). In the CRISP study body mass indices ≥30 kg/m2 have been associated with faster increase in kidney volume and decline in glomerular filtration rate [Nowak et al 2018]. Animal studies have shown a possible benefit of caloric restriction in an ADPKD model [Warner et al 2016].

As indicated above (see Hypertension), a lower blood pressure target (95-110/60-75 mm Hg) compared to the standard target (120-130/70-80 mm Hg) in younger affected individuals with preserved renal function was associated with a slower increase in kidney volume in the HALT PKD study [Schrier et al 2014].

  • Blood pressure control (goal ≤110/75 mmHg if 18-50 years old and eGFR >60 mL/min; otherwise ≤130/85 mmHg)
  • Maintainance of UOsm at ≤280 mOsm/kg by moderately enhancing hydration spread out over 24 hours (during the day, at bedtime, and at night if waking up)
  • Low osmolar intake: moderate sodium (2-3 g/d) and protein (0.8-1 g/kg of ideal body weight) restriction
  • Maintainance of serum bicarbonate at ≥22 mEq/L; moderate dietary phosphorus intake (800 mg/d)
  • Moderation of caloric intake; normal BMI; low-impact exercise
  • Lipid control; low threshold to start statins (aim for LDL ≤100 mg/dL)
  • Consideration of disease-modifying treatment (at present tolvaptan is the only one approved) in individuals at risk for rapidly progressive disease (see Treatment of Manifestations)

Surveillance

Guidance on surveillance is provided in Chapman et al [2015].

Early detection of hypertension. Children with a family history of ADPKD should have their blood pressure monitored beginning at age five years, with an interval of three years in individuals in whom blood pressure is normal. The diagnosis of hypertension is made when systolic or diastolic BP is at or above the 95th percentile for age, height, and gender.

Intracranial aneurysms. Screening is usually not recommended since most intracranial aneurysms found by screening asymptomatic individuals are small, have a low risk of rupture, and require no treatment [Irazabal et al 2011, Chapman et al 2015], although dissenting opinions have been published [Rozenfeld et al 2014].

Indications for screening in affected individuals 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 pilot, and significant anxiety on the part of the individual despite adequate risk information.

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 chest MRI examination every two to three years. If aortic root dilatation is found, referral to a cardiologist is indicated.

Surveillance for renal cell carcinoma, cardiac valvular abnormalities, and colon diverticulosis is not indicated in individuals with ADPKD who do not have suggestive signs or symptoms of these complications.

Agents/Circumstances to Avoid

Avoid the following:

  • Long-term administration of nephrotoxic agents (e.g., combination analgesics, NSAIDs)
  • Caffeine in large amounts; there is no evidence that low or moderate use of caffeinated beverages accelerates the progression of ADPKD.
  • Use of estrogens and possibly progestogens in individuals with severe polycystic liver disease
  • Smoking
  • Obesity

Evaluation of Relatives at Risk

It is appropriate to clarify the clinical/genetic status of apparently asymptomatic at-risk adult (age ≥18 years) relatives of an affected individual in order to:

  • Allow those found to be affected to become better educated about ADPKD;
  • Permit early detection and treatment of complications and associated disorders;
  • Reassure those found to be unaffected;
  • Start treatment, where appropriate.

Evaluations of at-risk relatives include the following:

  • Imaging with abdominal ultrasound, CT, or MRI examination
  • Molecular genetic testing if the ADPKD-related pathogenic variant in the family is known. For families with a known pathogenic variant, molecular genetic testing may provide clarification if findings on imaging are equivocal.

Note: (1) Appropriate counseling prior to imaging or molecular testing, 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 for children are developed.

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 additional likely targets for therapeutic intervention.

Somatostatin analogs. 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]. A randomized, three-year, single-blind, placebo-controlled trial of octreotide long-acting release (LAR) in 75 affected individuals (38 of whom received octreotide-LAR and 37 of whom received placebo) was completed in Italy [Caroli et al 2013]. The numeric increase in kidney and liver size was significantly smaller in the treated group after one year; after three years, the size of the organs was smaller in the treated group vs the untreated group, but the difference was no longer statistically significant for either organ. A larger and longer randomized study is presently under way [Meijer et al 2014] to determine whether these drugs can be administered safely to persons with ADPKD and/or polycystic liver disease and whether they are efficacious. Studies of tolvaptan and the somatostatin analog pasireotide in a Pkd1 mouse model showed an additive effect of the combined treatment [Hopp et al 2015].

mTOR inhibitors. The results of clinical trials of mTOR inhibitors for ADPKD have been mostly disappointing. These studies have shown either no effect on TKV or eGFR [Serra et al 2010], an association with a slower rate of increase in TKV but a faster rate of decline in eGFR [Walz et al 2010], or a faster decline in GFR and increase in TKV [Ruggenenti et al 2016]. Clinical trials of mTOR inhibitors have also been accompanied by significant drug toxicity [Serra et al 2010, Walz et al 2010, Ruggenenti et al 2016]. Because the intended dosage was limited by toxicity of the drug, the blood levels achieved may not have been enough to effectively inhibit mTOR activity in the kidney [Canaud et al 2010].

Tyrosine kinase inhibitors. A Phase II clinical trial of the Src inhibitor bosutinib showed a slower rate of increase in TKV and no difference in decline in eGFR in the treated group [Tesar et al 2017]. However, there was a high level of dropout from the study with significant adverse events, especially with a higher dose of the compound.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions.

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 individuals diagnosed with ADPKD have an affected parent.
  • Some individuals diagnosed with ADPKD have the disorder as a result of a de novo pathogenic variant. The proportion of cases caused by a de novo pathogenic variant is approximately 15% [Iliuta et al 2017].
  • Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include screening by imaging methods, especially by MRI or CT examination in families where the renal manifestations are mild; and/or molecular genetic testing of both parents if the pathogenic variant in the proband is known.
  • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent. Parental germline mosaicism has been reported (see Clinical Description, Mosaicism).
  • The family history of some individuals diagnosed with ADPKD 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. Therefore, an apparently negative family history cannot be confirmed unless appropriate evaluations (e.g., imaging and/or molecular genetic testing) have been performed on the parents of the proband.
  • Note: If the parent is the individual in whom the pathogenic variant first occurred, s/he may have somatic mosaicism for the variant and may be mildly/minimally affected.

Sibs of a proband. The risk to sibs of the proband depends on the genetic status of the proband's parents:

  • If a parent of the proband is affected/has the pathogenic variant, the risk to sibs of inheriting the variant is 50%.
  • When renal image analysis suggests that the parents are unaffected and the pathogenic variant 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 pathogenic variant and the recurrence risk to sibs is small but greater than that of the general population because of the possibility of parental germline mosaicism. Parental germline mosaicism has been reported (see Clinical Description, Mosaicism).
  • Complex inheritance may also play a role in a minority of individuals [Rossetti et al 2009, Cornec-Le Gall et al 2018] and is important when considering the risk to other family members.

Offspring of a proband. A child of an individual heterozygous for an ADPKD-related pathogenic variant has a 50% chance of inheriting the pathogenic variant.

Other family members. The risk to other family members depends on the genetic status of the proband's parents: if a parent is affected/has a pathogenic variant, his or her family members may be at risk.

Related kidney donor. At-risk relatives being considered as kidney donors need to be evaluated to determine if they have ADPKD. Evaluation consists of comprehensive renal image analysis by ultrasound, CT, and/or MRI examination, which is routine for any kidney donor regardless of disease indication. If the imaging is equivocal, if the potential donor is young (age <30 years), or in other cases where evidence of the disease status is considered unproven, molecular genetic testing can establish the genetic status of the potential donor. If a known pathogenic variant has already been identified in an affected relative this analysis is straightforward. In genetically uncharacterized families, screening of an affected relative to identify the pathogenic variant must be performed before analysis of the potential donor. In cases where the pathogenic status of a detected variant(s) is not certain, molecular studies need to be interpreted with caution. If the pathogenic variant in an affected relative is not identified, or if the family has not had genetic testing, molecular testing is only informative if a confirmed pathogenic variant is detected in the potential donor; a "negative" test does not prove that a potential donor does not have ADPKD.

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.

Predictive testing (i.e., testing of asymptomatic at-risk individuals)

  • Predictive testing for at-risk relatives is straightforward if the ADPKD-related pathogenic variant has been identified in an affected family member. If not, a "negative" test does not prove that they do not have ADPKD.
  • Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.

Predictive testing in minors (i.e., testing of asymptomatic at-risk individuals age <18 years)

  • For asymptomatic minors at risk for adult-onset conditions for which early treatment is not available, predictive genetic testing is considered inappropriate, 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.
  • For more information, see the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Academy of Pediatrics and American College of Medical Genetics and Genomics policy statement: ethical and policy issues in genetic testing and screening of children.

In a family with an established diagnosis of ADPKD, it is appropriate to consider testing of symptomatic individuals regardless of age.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and 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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. Banking of DNA from individuals with atypical presentation (e.g., lethal in utero onset) is particularly valuable to understanding the disease etiology and offering family planning choices to the family.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis is increasingly being employed by families at risk for ADPKD [De Rycke et al 2005, Zeevi et al 2013].

Resources

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
    Email: pkdcure@pkdcure.org
  • The PKD Charity (Polycystic Kidney Disease)
    91 Royal College
    London W1 0SE
    United Kingdom
    Phone: 0300 111 1234
    Email: info@pkdcharity.org.uk
  • Ciliopathy Alliance
    United Kingdom
    Phone: 44 20 7387 0543
  • European Rare Kidney Disease Reference Network (ERKNet)
    Heidelberg
    Germany
    Phone: 49-6221-56-2349
    Fax: 49-6221-56-5166
    Email: contact@erknet.org
  • Kidney Foundation of Canada
    310-5160 Decarie Blvd.
    Montreal Ontario H3X 2H9
    Canada
    Phone: 800-361-7494 (toll-free); 514-369-4806
    Fax: 514-369-2472
    Email: info@kidney.ca
  • National Kidney Foundation (NKF)
    30 East 33rd Street
    New York NY 10016
    Phone: 800-622-9010 (toll-free); 212-889-2210
    Email: info@kidney.org

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 from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

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

104160GLUCOSIDASE, ALPHA, NEUTRAL AB; GANAB
173900POLYCYSTIC KIDNEY DISEASE 1 WITH OR WITHOUT POLYCYSTIC LIVER DISEASE; PKD1
173910POLYCYSTIN 2; PKD2
600666POLYCYSTIC KIDNEY DISEASE 3 WITH OR WITHOUT POLYCYSTIC LIVER DISEASE; PKD3
601313POLYCYSTIN 1; PKD1
611341DNAJ/HSP40 HOMOLOG, SUBFAMILY B, MEMBER 11; DNAJB11
613095POLYCYSTIC KIDNEY DISEASE 2 WITH OR WITHOUT POLYCYSTIC LIVER DISEASE; PKD2

Molecular Pathogenesis

There is good evidence that polycystin-1 and polycystin-2 interact to form a functional polycystin complex and data shows that this interaction is central for the maturation and localization of these proteins [Kim et al 2014, Gainullin et al 2015]. Strong evidence indicates that, in common with the proteins associated with syndromic forms of PKD (e.g., Meckel syndrome), polycystin-1 and polycystin-2 are localized to primary cilia [Pazour et al 2002, Yoder et al 2002, Liu et al 2018]; PKD is a ciliopathy [Hildebrandt et al 2011], with loss of cilia associated with PKD [Lin et al 2003].

The cilium is known to be essential for a number of signaling pathways (e.g., sonic hedgehog and possibly planar cell polarity) that likely play a role in some ciliopathy phenotypes. Proteins causative of syndromic forms of PKD (e.g., Meckel sydrome, Joubert syndrome), with ciliopathy phenotypes in other organs, are involved in regulating the protein composition of the cilium [Fischer et al 2006, Hildebrandt et al 2011, Garcia-Gonzalo & Reiter 2012, Yang et al 2015].

However, the precise role that the polycystin complex normally plays with respect to the cilium is controversial. It is likely that the polycystins have a sensory/mechano-sensory/receptor role [Ong & Harris 2015], with changes in fluid flow within the tubule [Nauli et al 2003] or binding of Wnt ligands [Kim et al 2016] possibly regulating the complex. Evidence that inactivation of the polycystins in combination with loss of cilia results in a milder cystic phenotype than polycystin loss alone has been interpreted as the polycystin complex regulating a ciliary pathway that promotes cystogenesis [Ma et al 2013]. Key downstream signaling from the polycystin complex is also controversial, with Ca2+, cAMP, and G-protein signaling all considered as important [Torres & Harris 2014, Chebib et al 2015, Hama & Park 2016, Lemos & Ehrlich 2018].

Another location of the polycystins and the ARPKD protein, fibrocystin, is in urinary vesicles [Hogan et al 2009, Bakeberg et al 2011], where the secreted protein may play a signaling role in the nephron. The localization of the polycystins to other phenotypic sites (e.g., the vascular system) indicate that reductions in the level of these proteins underlie disease complications such as intracranial aneurysms [Kim et al 2000].

PKD1

Gene structure. PKD1 encodes an approximately 14-kb transcript and comprises 46 exons [Hughes et al 1995]. The genomic region encoding PKD1 has undergone a complex segmental 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, Symmons et al 2008]. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. About 50%-70% of pathogenic PKD1 variants are unique to a single family [Rossetti et al 2007, Audrézet et al 2012]. The ADPKD Mutation Database (Table A) lists a total of approximately 1,650 likely pathogenic PKD1 changes, accounting for about 2,450 families with PKD1-related ADPKD. The pathogenic variants are spread throughout the gene; an estimated 65% are predicted to truncate the protein product. Recent data also indicate that as many as one half of in-frame pathogenic variants are hypomorphic (alleles that cause partial loss of gene function through reduced RNA, protein, or protein function) and are associated with milder kidney disease [Cornec-Le Gall et al 2013, Heyer et al 2016, Hwang et al 2016].

Table 6.

PKD1 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.9829C>T 1p.Arg3277CysNM_001009944​.2
NP_001009944​.2

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Normal gene product. The PKD1 product, polycystin-1, is a 4,303-amino-acid protein with a calculated, unglycosylated molecular mass of 460 kd [Hughes et al 1995, International Polycystic Kidney Disease Consortium 1995, Sandford et al 1997]. The protein has 11 transmembrane domains with a large extracellular region and short cytoplasmic tail. Cleavage of the protein occurs at the G-protein coupled receptor proteolytic site (GPS) domain but the protein products appear to stay attached [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 is thought to play a role in regulating the polycystin-2 channel as part of a polycystin complex [Ong & Harris 2015].

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

Abnormal gene product. The wide array of truncating pathogenic PKD1 variants indicates that the mechanism of disease involves inactivation of an allele and that cysts develop when less or no functional protein is present. The threshold hypothesis holds that below a certain level of polycystin-1 cysts can develop and that this threshold can be reached by loss of the normal allele by somatic mutation [Qian et al 1996] or other non-genetic changes, and that cyst development and expansion is a complex process [Lantinga-van Leeuwen et al 2004, Jiang et al 2006, Gallagher et al 2010, Hopp et al 2012, Cornec-Le Gall et al 2014].

There is increasing evidence that some hypomorphic nontruncating PKD1 pathogenic variants have a folding/trafficking defect of polycystin-1 [Hopp et al 2012, Cai et al 2014, Gainullin et al 2015].

PKD2

Gene structure. PKD2 has a transcript of approximately 5.5 kb (NM_000297.3) and is composed of 15 exons [Mochizuki et al 1996]. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Approximately 50% of pathogenic PKD2 variants are unique to a family [Rossetti et al 2007, Audrézet et al 2012]. According to the ADPKD Mutation Database (Table A), approximately 250 different PKD2 pathogenic variants have been described, accounting for nearly 550 families. The pathogenic variants are spread throughout the gene and the majority (~85%) are predicted to truncate the protein, consistent with inactivation of the allele. Only one example of a clearly hypomorphic allele in PKD2 has been described [Losekoot et al 2012].

Normal gene product. Polycystin-2 is predicted to have 968 amino acids (NP_000288.1) and contain six transmembrane domains with cytoplasmic N- and C-termini [Mochizuki et al 1996]. It shares a region of homology with polycystin-1 in the transmembrane region. It also has structural similarity to transient receptor potential (TRP) channels and is now considered to be a member of the TRP family of proteins (TRPP2). Recently a cryo-electron microscopy homotetrameric structure of polycystin-2 has been described; it shows a novel polycystin-specific "tetragonal opening for polycystins" (TOP) domain bound to the top of a classic TRP channel that likely regulates the opening of the channel [Shen et al 2016, Grieben et al 2017]. Electrophysiologic analysis of polycystin-2 in the primary cilium shows that it preferentially conducts K+ and Na+, and intraciliary Ca2+ enhances its open probability [Liu et al 2018]. Polycystin-2 is widely expressed and expression continues at an approximately consistent level in the adult.

Abnormal gene product. As with PKD1, the mechanism of disease is associated with reduction or loss of functional protein below a particular threshold.

GANAB

Gene structure. GANAB covers a genomic region of 21.9 kb. The longest transcript variant (NM_198335.3) has 25 exons and encodes the longest protein isoform (NP_938149.2) [Treml et al 2000]. Many transcript variants have been described; for a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. To date, 11 pathogenic variants of GANAB have been described in 12 affected families. These include three frameshifting deletions, three splicing changes, three missense changes, and two nonsense changes, with pathogenic variants found in all parts of the gene [Porath et al 2016, Besse et al 2017, Besse et al 2018].

Normal gene product. GANAB encodes glucosidase IIα, a 966-amino-acid protein (NP_938149.2) that plays a role in trimming the glycans of glycosylated proteins, and as part of the calnexin/calreticulin cycle, plays a major role in quality control of membrane and secreted proteins [Xu & Ng 2015]. Note that the glucosidase IIβ subunit is encoded by ADPLD-related gene PRKCSH [Drenth et al 2003, Li et al 2003].

Abnormal gene product. Single GANAB pathogenic variants are likely inactivating and disease is associated with a dosage reduction of the glucosidase IIα subunit. Studies of polycystin-1 have shown that its maturation and trafficking is particularly sensitive to loss or reduction of GANAB [Porath et al 2016, Besse et al 2017]. The development of liver and kidney cysts is a common phenotype associated with disruptions in the biogenesis pathway of membrane proteins, and is likely perpetrated through disrupted polycystin-1 trafficking [Fedeles et al 2011].

DNAJB11

Gene structure. The longest DNAJB11 transcript (NM_006145.2) consists of ten exons in a genomic region of approximately 15 kb. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. To date, five different DNAJB11 pathogenic variants have been described in seven families with 23 affected individuals [Cornec-Le Gall et al 2018]. These consist of two frameshifting changes, two pathogenic missense variants, and a nonsense variant.

Normal gene product. DNAJB11 encodes the DNAJ/HSP40 homolog, subfamily B, member 11 (DNAJB11). It is a 358-amino-acid soluble ER protein (NP_006136.1) that is a co-chaperone with BiP, which is required for the efficient folding of membrane and secreted proteins [Shen et al 2002, Shen & Hendershot 2005].

Abnormal gene product. The heterozygous DNAJB11 pathogenic variants are likely inactivating and disease is associated with a dosage reduction of DNAJB11. Studies of polycystin-1 have shown that its maturation and trafficking is particularly sensitive to loss of DNAJB11 [Cornec-Le Gall et al 2018].

References

Published Guidelines / Consensus Statements

  • Chapman AB, Devuyst O, Eckardt KU, Gansevoort RT, Harris T, Horie S, Kasiske BL, Odland D, Pei Y, Perrone RD, Pirson Y, Schrier RW, Torra R, Torres VE, Watnick T, Wheeler DC. for Conference Participants. Autosomal-dominant polycystic kidney disease (ADPKD): executive summary from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. 2015. Kidney Int. 2015;88:17–27. [PMC free article: PMC4913350] [PubMed: 25786098]
  • Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available online. 2013. Accessed 7-8-19. [PubMed: 23428972]
  • National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available online. 2018. Accessed 7-8-19.

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Chapter Notes

Revision History

  • 19 July 2018 (sw) Comprehensive update posted live
  • 11 June 2015 (me) Comprehensive update posted live
  • 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 live
  • 5 March 2004 (me) Comprehensive update posted live
  • 10 January 2002 (me) Review posted live
  • 22 August 2001 (ph) Original submission
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