Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Definition, Etiology, PathogenesisTop

Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent genetic kidney disease (~1/1000) leading to innumerable bilateral kidney cysts, increased total kidney volume, and progressive chronic kidney disease. ADPKD accounts for ~7% of cases of kidney failure. Hypertension, flank pain, polyuria, liver cysts (up to 90% of patients but usually asymptomatic), kidney stones (~20% of patients), hematuria, cyst infections, diverticulosis, hernias, and vascular abnormalities including intracranial aneurysms (~8% of patients) are more common in patients with ADPKD. Despite autosomal dominant inheritance, family history may be missing in 10% to 25% of cases. In clinically ascertained samples, 60% of patients with ADPKD have a pathogenic PKD1 variant and 25% have a PKD2 variant. Less than 5% of families have pathogenic variants in additional cystogenic genes (ie, IFT140, GANAB, DNAJB11, ALG8, ALG9, and more) if evaluated. Families with pathogenic PKD1 variants tend to be the most severely affected, and protein-truncating variants are more severe than nontruncating variants. The exact mechanism by which these pathogenic variants lead to kidney cysts remains unclear.

DiagnosisTop

For those with a family history of ADPKD, ultrasound-based diagnostic criteria for ADPKD have been formulatedEvidence 1High Quality of Evidence (high confidence that we know true effects of intervention). Pei Y, Obaji J, Dupuis A, et al. Unified criteria for ultrasonographic diagnosis of ADPKD. J Am Soc Nephrol. 2009 Jan;20(1):205-12. doi: 10.1681/ASN.2008050507. Epub 2008 Oct 22. PMID: 18945943; PMCID: PMC2615723.:

1) Patients 15 to 39 years of age: ≥3 unilateral or bilateral kidney cysts.

2) Patients 40 to 59 years of age: ≥2 cysts in each kidney.

3) Patients ≥60 years: ≥4 cysts in each kidney.

Genetic testing is not routinely required but can be considered if there is diagnostic uncertainty: atypical presentation, no family history, requirement for early diagnosis (age <25 years); or for preimplantation genetic diagnosis.

TreatmentTop

First-line therapy includes maintenance of a healthy body habitus, smoking cessation, blood pressure control, and supportive management of hematuria, cyst infections, and pain. Episodes of hematuria are treated with conservative expectant observation. Renin-angiotensin-aldosterone system (RAAS) inhibitors are recommended but dual RAAS blockade provides no additive benefit.Evidence 2Strong recommendation (downsides clearly outweigh benefits; right action for all or almost all patients) for not using double RAA blockade; weak recommendation for using a single RAA inhibitor and for aiming at lower BP among those with a GFR >60 mL/min/1.73 m^2. High Quality of Evidence (high confidence that we know true effects of the intervention; we did not lower QoE for indirectness). Torres VE, Abebe KZ, Chapman AB, et al; HALT-PKD Trial Investigators. Angiotensin blockade in late autosomal dominant polycystic kidney disease. N Engl J Med. 2014 Dec 11;371(24):2267-76. doi: 10.1056/NEJMoa1402686. Epub 2014 Nov 15. PMID: 25399731; PMCID: PMC4284824. Schrier RW, Abebe KZ, Perrone RD, et al; HALT-PKD Trial Investigators. Blood pressure in early autosomal dominant polycystic kidney disease. N Engl J Med. 2014 Dec 11;371(24):2255-66. doi: 10.1056/NEJMoa1402685. Epub 2014 Nov 15. PMID: 25399733; PMCID: PMC4343258. A blood pressure target of <110/75 mm Hg may benefit those with estimated glomerular filtration rate (eGFR) >60 mL/min/1.73 m2.Evidence 3Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients) for using a single RAA inhibitor and for aiming at lower BP among those with a GFR >60 mL/min/1.73 m²; strong recommendation for not using double RAA blockade. High Quality of Evidence (high confidence that we know true effects of the intervention; we did not lower QoE for indirectness). Torres VE, Abebe KZ, Chapman AB, et al; HALT-PKD Trial Investigators. Angiotensin blockade in late autosomal dominant polycystic kidney disease. N Engl J Med. 2014 Dec 11;371(24):2267-76. doi: 10.1056/NEJMoa1402686. Epub 2014 Nov 15. PMID: 25399731; PMCID: PMC4284824. Schrier RW, Abebe KZ, Perrone RD, et al; HALT-PKD Trial Investigators. Blood pressure in early autosomal dominant polycystic kidney disease. N Engl J Med. 2014 Dec 11;371(24):2255-66. doi: 10.1056/NEJMoa1402685. Epub 2014 Nov 15. PMID: 25399733; PMCID: PMC4343258. Maintenance of a high water intake (>3 L/d) to suppress antidiuretic hormone may be of benefit for slowing disease progression and is unlikely to be harmful.Evidence 4Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of evidence lowered due to indirectness to patient-important outcomes. Barash I, Ponda MP, Goldfarb DS, Skolnik EY. A pilot clinical study to evaluate changes in urine osmolality and urine cAMP in response to acute and chronic water loading in autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol. 2010 Apr;5(4):693-7. doi: 10.2215/CJN.04180609. Epub 2010 Feb 18. PMID: 20167686; PMCID: PMC2849694. Specialist consultation for the evaluation of the rate of ADPKD progression and potential for initiation of tolvaptan (a vasopressin V2 receptor antagonist) is recommended.Evidence 5Strong recommendation (downsides clearly outweigh benefits; right action for all or almost all patients). High Quality of Evidence (high confidence that we know true effects of the intervention). Quality of Evidence was not lowered due to indirectness to patient-important outcomes. Torres VE, Chapman AB, Devuyst O, et al; TEMPO 3:4 Trial Investigators. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med. 2012 Dec 20;367(25):2407-18. doi: 10.1056/NEJMoa1205511. Epub 2012 Nov 3. PMID: 23121377; PMCID: PMC3760207. Torres VE, Chapman AB, Devuyst O, et al; REPRISE Trial Investigators. Tolvaptan in later-stage autosomal dominant polycystic kidney disease. N Engl J Med. 2017 Nov 4;377(20):1930-42. doi: 10.1056/NEJMao1710030. PMID: 29105594. Patients with ADPKD and kidney failure are good transplant candidates.