Stage II: Summary Report Secondary Findings in Adults Non-diagnostic, excludes newborn screening & prenatal testing/screening Stage I Survey Update History Stage 2 Status (Adult):Complete (Actionability curation complete.)

GENE/GENE PANEL: PKD1, PKD2
Condition: Autosomal Dominant Polycystic Kidney Disease
GENEDISEASE PAIRS: PKD1173900 PKD2613095
Topic
Narrative Description of Evidence
Ref
1. What is the nature of the threat to health for an individual carrying a deleterious allele?
Prevalence of the Genetic Disorder
Autosomal dominant polycystic kidney disease (ADPKD) is the most common potentially lethal single-gene disorder, with a birth prevalence of 1/400 to 1/1000. It affects approximately 600,000 persons in the United States.
1 2
Clinical Features
(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; vascular abnormalities including intracranial aneurysms (ICAs), dilatation of the aortic root, and dissection of the thoracic aorta; mitral valve prolapse (MVP); and abdominal wall hernias. Renal manifestations due to the development of renal cysts include hypertension, renal pain, and renal insufficiency. Cysts that manifest in the liver, seminal vesicles, pancreas, and arachnoid membrane are typically asymptomatic and rarely result in clinical manifestations.
1 2
Natural History
(Important subgroups & survival / recovery)
Although all individuals with ADPKD will develop renal cysts, substantial variability occurs in the severity of renal disease and other manifestations. Patients with mutations in PKD1 (PDK1) tend to have more severe disease with larger, more, and earlier development of cysts compared to patients with mutations in PKD2 (PDK2). Because the disease is progressive, few cysts may be evident during childhood or young adulthood, especially for PKD2. Approximately 50% of individuals with ADPKD have end-stage renal disease (ESRD) by age 60 years. The mean age of onset of ESRD is age 58 for PDK1 and age 79 for PKD2. The prevalence of liver cysts, the most common extrarenal manifestation, is associated with age. Hypertension is often diagnosed late in the disease course, and cardiovascular disease is the main cause of death.
1 2
2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
Patient Management
Following the initial diagnosis, patients are recommended to undergo a series of evaluations to establish the extent of the disease: renal ultrasound, abdominal CT or MRI, standardized blood pressure screening, measurement of blood lipid concentrations, and urine studies. Echocardiography is recommended in individuals with heart murmurs or systolic clicks, and echocardiography or cardiac MRI is recommended in individuals with a family history of thoracic aortic dissections. Head magnetic resonance angiography (MRA) or CT angiography is recommended in individuals with a family history of intracranial aneurysms. (Tier 4)
1
Thoracic aortic replacement is indicated in patients with ADPKD. (Tier 4)
1
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 MFS prolongs survival such that it approaches that of age-matched controls. (Tier 5)
3 4 5 6 7 8 9 10
Blood pressure (BP) control should remain a component of managing patients with ADPKD. However, the effectiveness of blood pressure control in the prevention of renal disease progression in patients with ADPKD has not been established by clinical trials. Several studies have compared standard SP control to more aggressive BP control protocols. Earlier control trials show no effect of BP control on ESRD progression, but were limited by size, duration, and patient selection. The most recent randomized control trial, HALT PKD, showed a benefit of more aggressive BP control on total kidney volume, albumin excretion rate and left-ventricular mass index, but not overall kidney function. (Tier 2)
11
Surveillance
Screening for ICAs by MRA is recommended for patients with a family history of ICA or stroke, symptoms suggestive of ICA, a job or hobby where loss of consciousness may be lethal, preparation for major elective surgery, or extreme patient anxiety regarding the risk of having an ICA. The recommended frequency of screening can vary among those with a negative result from their initial screening, from not rescreening at all to rescreening every 10 years. (Tier 2)
2
The identification of an ICA allows for surgical treatment, for example through clipping of the ruptured aneurysm at the neck. Asymptomatic aneurysms measuring ≤5.0 mm in diameter can be observed and followed initially at yearly intervals for increasing size. Surgical intervention is usually indicated for aneurysms > 10.0 mm in diameter while management of aneurysms 6.0-9.0 mm in size remains controversial. (Tier 4)
1
Decision modeling has indicated that screening and treatment of ICAs increases the life expectancy of patients with ADPKD by at least one year. (Tier 3)
1
Ambulatory or home blood pressure monitoring is recommended for early diagnosis of hypertension. (Tier 2)
2
Family Management
Patients with a diagnosis of ADPKD should be advised to inform first degree adult relatives of their diagnosis. Screening and genetic counseling should be offered to these relatives. (Tier 2)
2
At risk relatives should undergo ultrasonography to screen for cysts in the kidneys, liver, and pancreas and confirm a diagnosis of ADPKD. (Tier 2)
2
Genetic testing is not recommended when imaging diagnosis is clear. However, it may be performed in specific cases based on family characteristics and patient needs. (Tier 2)
2
Circumstances to Avoid
Patients should avoid long-term administration of nephrotoxic agents such as combination analgesics and NSAIDs, caffeine which interferes with the breakdown of cAMP and may promote renal cyst growth, and smoking. (Tier 4)
1
3. What is the chance that this threat will materialize?
Mode of Inheritance
Autosomal Dominant
 
Prevalence of Genetic Mutations
Among ADPKD cases with a known mutation, PKD1 and PDK2 account for 85% and 15% of cases, respectively. However, approximately 10% of individuals who undergo comprehensive mutation screening of PKD1 and PKD2 have no mutation identified. (Tier 3)
2 1
Penetrance
OR
Relative Risk
(Include any high risk racial or ethnic subgroups)
ADPKD has a high penetrance, with virtually all patients developing bilateral renal cysts. Penetrance is reduced for ESRD, with approximately 50% of individuals developing ESRD by age 60 years. (Tier 4)
1
According to MRI results, hepatic cysts have a prevalence of up to 94% by age 46. (Tier 3)
1
Pancreatic cysts occur in approximately 8% of individuals with ADPKD. (Tier 4)
1
Seminal vesicle cysts present in 40% of males with ADPKD. (Tier 3)
1
Arachnoid membrane cysts present in 8% of individuals. (Tier 3)
1
Intracranial aneurysms occur in approximately 8-10% of individuals with ADPKD. The prevalence is higher in those individuals with a positive family history of intracranial or subarachnoid hemorrhage (22%) than in those individuals without (6%) such a family history. (Tier 3)
2 1
MVP occurs in 25% of cases. (Tier 4)
1
 
Information on relative risk was not available.
 
 
Expressivity
Substantial variability in severity of renal disease and other extrarenal manifestations occurs even within the same family. (Tier 4)
1
4. What is the Nature of the Intervention?
Nature of Intervention
Interventions identified included imaging and circumstances to avoid and aortic valve replacement, which are likely associated with moderate to high risk and burden. Early diagnosis and monitoring of hypertension is imperative to avoid the mortality associated with cardiovascular disease.
 
5. Would the underlying risk or condition escape detection prior to harm in the settting of recommended care?
Chance to Escape Clinical Detection
Renal and other cysts are detected via ultrasound, CT, and MRI, applications not generally used as part of typical clinical care. Early diagnosis and monitoring of hypertension is imperative to avoid the mortality associated with cardiovascular disease.
 

 
Final Consensus Scores
Outcome / Intervention Pair
Severity
Likelihood
Effectiveness
Nature of the
Intervention
Total
Score
End stage renal disease / Blood pressure control
2
3C
1B
3
9CB
Intracranial aneurysm / MRA surveillance
2
2C
1C
3
8CC
Aortic valve replacement / Monitoring TAAAA
2
0D
3N
3
8DN
To see the scoring key, please go to: https://clinicalgenome.org/working-groups/actionability/projects-initiatives/actionability-evidence-based-summaries/
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.
Reference List
1. Harris PC, Torres VE. Polycystic kidney disease, autosomal dominant.. 1999 May 14 [Updated 2010 Mar 09]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1246
2. Ars E, Bernis C, Fraga G, Martinez V, Martins J, Ortiz A, Rodriguez-Perez JC, Sans L, Torra R. Spanish guidelines for the management of autosomal dominant polycystic kidney disease. Nephrol Dial Transplant. (2014) 29 Suppl 4:iv95-105.
3. Guidelines for diagnosis and treatment of aortic aneurysm and aortic dissection (jcs 2011): digest version. Circ J. (2013) 77(3):789-828.
4. Guidelines for the diagnosis and management of marfan syndrome. Other. (2011) Website: http://www.csanz.edu.au/wp-content/uploads/2014/12/Marfan_Syndrome.pdf
5. Boodhwani M, Andelfinger G, Leipsic J, Lindsay T, McMurtry MS, Therrien J, Siu SC. Canadian cardiovascular society position statement on the management of thoracic aortic disease. Can J Cardiol. (2014) 30(6):577-89.
6. Hiratzka LF, Bakris GL, Beckman JA, Bersin RM, Carr VF, Casey DE Jr, Eagle KA, Hermann LK, Isselbacher EM, Kazerooni EA, Kouchoukos NT, Lytle BW, Milewicz DM, Reich DL, Sen S, Shinn JA, Svensson LG, Williams DM. 2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM Guidelines for the diagnosis and management of patients with thoracic aortic disease. A report of the american college of cardiology foundation/american heart association task force on practice guidelines, american association for thoracic surgery, american college of radiology,american stroke association, society of cardiovascular anesthesiologists, society for cardiovascular angiography and interventions, society of interventional radiology, society of thoracic surgeons,and society for vascular medicine. J Am Coll Cardiol. (2010) 55(14):e27-e129.
7. Mufti UB, Nalagatla SK. Nephrolithiasis in autosomal dominant polycystic kidney disease. J Endourol. (2010) 24(10):1557-61.
8. Pyeritz RE. Evaluation of the adolescent or adult with some features of marfan syndrome. Genet Med. (2012) 14(1):171-7.
9. Svensson LG, Adams DH, Bonow RO, Kouchoukos NT, Miller DC, O'Gara PT, Shahian DM, Schaff HV, Akins CW, Bavaria JE, Blackstone EH, David TE, Desai ND, Dewey TM, D'Agostino RS, Gleason TG, Harrington KB, Kodali S, Kapadia S, Leon MB, Lima B, Lytle BW, Mack MJ, Reardon M, Reece TB, Reiss GR, Roselli EE, Smith CR, Thourani VH, Tuzcu EM, Webb J, Williams MR. Aortic valve and ascending aorta guidelines for management and quality measures. Ann Thorac Surg. (2013) 95(6 Suppl):S1-66.
10. Vahanian A, Alfieri O, Andreotti F, Antunes MJ, Baron-Esquivias G, Baumgartner H, Borger MA, Carrel TP, De Bonis M, Evangelista A, Falk V, Iung B, Lancellotti P, Pierard L, Price S, Schafers HJ, Schuler G, Stepinska J, Swedberg K, Takkenberg J, Von Oppell UO, Windecker S, Zamorano JL, Zembala M. Guidelines on the management of valvular heart disease (version 2012). Eur Heart J. (2012) 33(19):2451-96.
11. Thomas MC. The CARI guidelines. Prevention of progression of kidney disease: autosomal-dominant polycystic kidney disease. Nephrology (Carlton). (2007) 12 Suppl 1:S52-6.
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