Stage II: Summary Report Secondary Findings in Adults Non-diagnostic, excludes newborn screening & prenatal testing/screening Stage 2 Status (Adult):Complete (Actionability curation complete.)
GENE/GENE PANEL: DNAJB11, GANAB, PKD1, PKD2
Condition: Autosomal Dominant Polycystic Kidney Disease
Narrative Description of Evidence
1. What is the nature of the threat to health for an individual carrying a deleterious allele?
Prevalence of the Genetic Disorder
Estimates of population prevalence of autosomal dominant polycystic kidney disease (ADPKD) have varied widely depending on methodology from 1:400 to a more modest 2.7:10,000. It is estimated to affect approximately 300,000 persons in the United States.
(Signs / symptoms)
(Signs / symptoms)
ADPKD is a late-onset, multisystem disorder characterized by bilateral renal cysts; cysts in other organs including the liver, seminal vesicles, pancreas, and arachnoid membrane; cardiovascular abnormalities including intracranial aneurysms (ICAs), dilatation of the aortic root, thoracic aortic dissection (TAAD), left ventricular hypertrophy, diastolic dysfunction, and mitral valve prolapse (MVP); and abdominal wall hernias. Renal manifestations due to the development of renal cysts include hypertension, abdominal fullness and pain, renal insufficiency and progression to end-stage renal disease (ESRD); renal stones, urinary tract infection (UTI) and cyst infection also can develop. Cysts that manifest in the liver, seminal vesicles, pancreas, and arachnoid membrane are typically asymptomatic and rarely result in clinical manifestations or complications; these complications can include cyst hemorrhage, infection, or rupture. Women may have higher risk pregnancies.
(Important subgroups & survival / recovery)
(Important subgroups & survival / recovery)
Although all individuals with ADPKD develop renal cysts, substantial variability occurs in severity of renal disease and other manifestations. Because the disease is progressive, few cysts may be evident during childhood or young adulthood, especially for those with mild phenotypes. Hypertension usually onsets before detectable renal decline; renal decline (detected as increased serum creatine) usually begins about 12 years prior to ESRD. The prevalence of liver cysts, the most common extrarenal manifestation, increases with age. Hypertension is often diagnosed late in the disease course, and cardiovascular disease is the main cause of death. In general, women with ADPKD that have normal blood pressure and kidney function have a favorable course during pregnancy. Polycystic liver disease (PLD) develops at a younger age in women than men and is more severe in women who have had multiple pregnancies; multiple pregnancies may also be associated with greater risk of renal decline. However, males have a higher incidence of ESRD and more severe renal disease. Genotype is predictive of phenotype. Pathogenic variants in GANAB cause mild cystic kidney disease, usually without a decline in renal function, with a range of liver involvement (none to severe). Pathogenic variants in DNAJB11 result in small renal cysts, usually without renal enlargement; liver cysts are present in about half of patients. DNAJB11-related ADPKD is associated with progression to renal insufficiency or ESRD most often after the 6th decade. Approximately 50% of individuals with PKD1-related ADPKD have end-stage renal disease (ESRD) by age 60 years. The mean age of onset of ESRD is age 58 for PKD1-related ADPKD (range: infancy to 80 years) and age 79 for PKD2-related ADPKD, with a lower probability of reaching ESRD in PKD2-related ADPKD.
2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
Multidisciplinary care is recommended, with all relevant specialties in one center or clinic based on evidence in rare disease settings in general. (Tier 2)
Consultation with a clinical geneticist and/or genetic counselor is recommended if the nephrologist is not an expert in inherited disorders. (Tier 4)
Initial assessment should include renal and liver imaging to determine the extent of disease. (Tier 2)
Other initial evaluations recommended are standardized blood pressure screening, measurement of blood lipid concentrations, cardiographic studies in individuals with murmurs, systolic clicks, or family history of thoracic aortic dissections, and urine studies. (Tier 4)
Head magnetic resonance angiography (MRA) or CT angiography is recommended at the time of diagnosis in individuals with a family history of ICA or subarachnoid hemorrhage (SAH). Some recommendations indicate this screening can also be considered in patients with symptoms suggestive of ICA, a job or hobby where loss of consciousness may be lethal, preparation for major elective surgery, or extreme anxiety regarding the risk of having an ICA. (Tier 2)
Thoracic aortic replacement is indicated in patients with ADPKD. (Tier 4)
Evidence on effectiveness of thoracic aortic replacement is not available for patients with ADPKD. Based on guidelines for Marfan syndrome, prophylactic surgical repair of the aorta is recommended for aortic diameters >5.0 cm, though some guidelines indicate repair at >4.0 or >4.5 cm with special consideration for the rate of aortic diameter expansion, progressive aortic regurgitation, family history of aortic dissection, and the height of the patient.Timely repair of aortic aneurysms among patients with Marfan syndrome prolongs survival such that it approaches that of age-matched controls. (Tier 2)
Antihypertensive therapies to treat hypertension are recommended with a suggested blood pressure target of ≤130/80mmHg or ≤140/90 mmHg, depending on guideline. Guidelines recommend that angiotensin-converting-enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARB). Sodium restricted diets should be used in combination. (Tier 2)
A recent systematic review of antihypertensive therapies in ADPKD found that ACEi significantly reduced diastolic BP but had uncertain effects on mortality, ESRD, kidney volumes, GFR, creatinine levels and albuminuria. Both this systematic review and a separate meta-analysis found that ACEi did not produce different effects on kidney function (as measured by eGFR) when compared with beta blockers or ARBs. (Tier 1)
Patients should be educated regarding risk factors, specifically hypertension, for disease progression. A longitudinal study of a hypertension education program showed that the proportion of patients with a controlled BP and the use of ACEi therapy increased from baseline over the course of the program. (Tier 2)
Lipid lowering agents (LLA) are recommended following care recommendations for those with CKD. There is limited and conflicting evidence on the effectiveness of LLA therapies in ADPKD. This recommendation was made on the basis of a meta-analysis in patients with CDK of any etiology (n=28,276), which found that LLA therapy reduced the risk of death, major cardiovascular events, and myocardial infarction by 20%. However, the effect of LLA therapy on renal dysfunction was uncertain. (Tier 2)
Some guidelines recommend treatment with tolvaptan for patients who have CKD, are at risk of rapidly progressive renal disease, and fulfill guideline-specific criteria; others recommend this treatment in a research study setting or cite insufficient evidence for a recommendation. (Tier 2)
In a meta-analysis of controlled trials examining treatments to slow progression of ADPKD, a single trial (N = 1445) of tolvaptan was identified. The meta-analysis reported that this study showed that use of tolvaptan compared to placebo in patients with ADPKD slowed the rate of total kidney volume (TKV) growth (from 5.5% to 2.8% per year) and reduced the rates of worsening kidney function (2 vs 5 events per 100 person-years of follow-up) but did not do further calculations. A Cochrane systematic review reported that high dose tolvaptan significantly reduced systolic and diastolic blood pressure in comparison to low-dose tolvaptan but found no other significant differences in included studies for other outcomes comparing tolvaptan to placebo or high vs. low dose tolvaptan. (Tier 1)
Patients with ADPKD should restrict their sodium intake to <100 mmol/day, as it has been shown to reduce blood pressure in a single randomized, double-blind, placebo-controlled, cross-over trial investigating the impact of sodium intake on ADPKD with hypertension, although it was limited by sample size. (Tier 2)
All women of reproductive potential should receive counseling including potential aggravation of polycystic liver disease (PLD) with exogenous estrogen or progesterone exposures and pregnancy. (Tier 2)
Pregnant women with ADPKD should be monitored for the development of UTIs and hypertensive women should be followed as a high-risk pregnancy. Compared to a control cohort of patients diagnosed with simple cyst, pregnant ADPKD patients (N = 54; all diagnosed by ultrasound) had higher risks for gestational hypertension (12.0% vs 3.9%) and UTI (14.1% vs 0.7%) during their pregnancies. Increased fetal prematurity rates were found in preeclamptic women with ADPKD as compared with normotensive ADPKD women (28% vs 10%). More maternal complications occurred in women with PKD than in their unaffected family members (35% versus 19% P < 0.001) with preexisting hypertension being the most important risk factor for a maternal complication to occur. (Tier 2)
The guideline recommended frequency of ICA surveillance by MRA/CT angiography can vary among those with a negative result from their initial screening from no additional imaging, to imaging every 5-10 years, imaging in selective populations, or imaging in the event of symptom onset or prior to ESRD. Decision modeling has indicated that screening and treatment of ICAs in patients with ADPKD increases the life expectancy without neurological disability by 1 year. Detection of ICA should be followed by referral to neurosurgeon or expert center and allows for management by watchful waiting or surgery. No randomized controlled trials have been conducted to determine the optimal management of ICAs. (Tier 2)
Screening for TAAD using either echocardiography or chest MRI examination every two to three years is indicated for first-degree relatives of individuals with TAAD. (Tier 4)
Ambulatory or home blood pressure monitoring is recommended for early diagnosis of hypertension. (Tier 2)
Guidelines differ on how to monitor disease progression, with some guidelines recommending routine measurement of renal function by eGFR and others by either once yearly measurement of TKV by MRI, CT, or ultrasound, or assessing TKV by MRI only in clinical trials. (Tier 2)
ADPKD adults without renal failure should have yearly follow-up visits. Follow-up in other patients should be scheduled according to CKD stage. (Tier 2)
No family management recommendations have been provided.
Circumstances to Avoid
It is recommended that patients avoid caffeine in large amounts. (Tier 3)
Patients should stop or avoid starting active smoking and avoid passive smoking. Smokers with ADPKD have a statistically significant increased risk for ESRD (odds ratio, 3.5-5.8; CI: 2.0-17). (Tier 2)
3. What is the chance that this threat will materialize?
Mode of Inheritance
Autosomal DominantBiallelic PKD1- or PKD2-related ADPKD has been reported in individuals with very early-onset ADPKD. Digenic ADPKD (pathogenic variants in both PKD1 and PKD2) has been described in individuals with more severe renal disease than was reported in heterozygous relatives.
Prevalence of Genetic Mutations
Among ADPKD cases with a known pathogenic variant, PKD1, PKD2, GANAB and DNAJB11 account for 78%, 15%, ~0.3%, and ~0.1% of these cases, respectively. However, approximately 7% of individuals who undergo comprehensive mutation screening of these genes have no pathogenic variant identified. This indicates that pathogenic variants in PKD1, PKD2, GANAB, or DNAJB11 are likely to have a similar, although slightly lower, summed prevalence as that estimated for ADPKD, or between 2.7:10,000 to 1:400. (Tier 3)
(Include any high risk racial or ethnic subgroups)
(Include any high risk racial or ethnic subgroups)
ADPKD has a high penetrance for renal cysts, with virtually all patients developing bilateral renal cysts. Penetrance is reduced for ESRD and varies by genotype. The mean age of onset of ESRD is age 58 for PKD1-related ADPKD (range: infancy to 80 years) with a penetrance of 50% by age 60. Penetrance of ESRD in other genotypes was not specified, though the following comparisons were made: ESRD average age of onset is 79 for PKD2-related ADPKD, with a lower probability of reaching ESRD in PKD2-related ADPKD. DNAJB11-related ADPKD is associated with progression to renal insufficiency or ESRD most often after the 6th decade. Pathogenic variants in GANAB are not typically associated with a decline in renal function. (Tier 4)
A study of 333 patients with pathogenic variant-associated ADPKD found that in those with PKD1-related ADPKD, 34% (N=110 patients) reached ESRD by a mean age of 54.3 years. In those with PKD2-related ADPKD, 14% (N = 40 patients) reached ESRD by a mean age of 74.0 years. (Tier 5)
According to MRI results, hepatic cysts have a prevalence of up to 94% by age 46. (Tier 3)
Systematic reviews of ADPKD patient cohorts have found ICA prevalence rates of 10-11.5%. One systematic review included data from two cohorts of patients (total N = 88 patients) who were not found to have an ICA at the time of baseline evaluation. In these patients, 1 patient (0.13%) had an ICA rupture in the study observation time (792-person years across all individuals). (Tier 1)
The rupture of an ICA in those with clinically diagnosed ADPKD is associated with a mortality rate of 30-40% and a disability rate of 30%. Risk of rupture depends on additional clinical factors. (Tier 2)
MVP occurs in up to 25% of individuals. (Tier 3)
Multiple pregnancies (>3) have been reported to be associated with a greater risk for decline in kidney function. (Tier 3)
Individuals diagnosed with ADPKD and with a family history of hemorrhagic stroke or ICA (ruptured or unruptured) were 2.33 (95% CI: 1.60-3.38) times more likely to have an aneurysm than those individuals diagnosed with ADPKD and without a family history of stroke or ICA. (Tier 1)
In a large population-based cohort study of ADPKD patients (n = 2076) individuals diagnosed with ADPKD have a 5.49-fold (95% CI 2.86-10.52) greater risk for aortic aneurysm and dissection in comparison to non-ADPKD counterparts (n = 20760) after adjusting for age, sex, and comorbidities. (Tier 5)
Marked discordant renal disease severity among affected family members has been well documented suggesting a role for other genetic and environmental modifiers. (Tier 3)
Recent studies have found that truncating variants of PKD1 and PKD2 are associated with more severe disease. (Tier 3)
4. What is the Nature of the Intervention?
Nature of Intervention
In experienced centers, elective repair of TAAD, depending on location of aneurysm, carries a mortality of at least 1-5%.
A meta-analysis reported the mortality rate after surgical treatment of ICA to be 12.7%. A randomized controlled trial found the combined morbidity (dependency) or mortality associated with ICA surgical treatment to be 23.7%-30.6% depending on procedure type.
A meta-analysis of the use of LLA in CKD of any etiology noted adverse events of elevated creatine kinase and liver dysfunction.
Adverse events associated with tolvaptan use were increased thirst, dry mouth, and liver enzyme levels. It has the potential to induce fatal liver toxicity and requires regular monitoring of liver enzymes. Patients may require considerable assistance in order to manage the aquaretic side effects of tolvaptan. Tolvaptan is only available through a restricted distribution and monitoring program due to these possible side effects.
5. Would the underlying risk or condition escape detection prior to harm in the settting of recommended care?
Chance to Escape Clinical Detection
ICAs are usually asymptomatic. The rupture of an ICA results in a SAH, which may cause death or disability. (Tier 2)
TAAD’s are largely asymptomatic until a sudden and catastrophic event, including aortic rupture or dissection, occurs, and is rapidly fatal in a large proportion of patients. (Tier 2)
Final Consensus Scores
Outcome / Intervention Pair
Nature of the
Progression to ESRD / Pharmacologic management of renal function
Neurologic disability or death due to ICA / ICA surveillance
Morbidity due to thoracic aortic disease / TAAD surveillance to guide surgical intervention
1. Evidence level downgraded due to extrapolation from Marfan syndrome.
Description of sources of evidence:
Tier 1: Evidence from a systematic review, or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.
Date of Search: 07.27.2015 (updated 11.05.2018)
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