Hereditary cystic kidney disease causing progressive enlargement and renal failure by middle age.
Also known as: ADPKD, polycystic kidney disease, PKD, PKD1, PKD2
Overview
An autosomal dominant systemic disorder characterized by progressive development and enlargement of bilateral renal cysts leading to massive nephromegaly and progressive loss of renal function. Caused by mutations in PKD1 (chromosome 16, ~78%) or PKD2 (chromosome 4, ~15%) encoding polycystin-1 and polycystin-2.
Epidemiology
Most common inherited kidney disease, prevalence ~1 in 400-1000. Accounts for ~5% of ESRD. PKD1 mutations cause earlier ESRD (median ~55 years) vs PKD2 (~75 years).
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Question 1RenalMedium
A 35-year-old female with autosomal dominant polycystic kidney disease (ADPKD) is referred for management. eGFR is 62 mL/min. Total kidney volume on MRI is 2,200 mL (Mayo Imaging Classification 1C). She has no pain or other complications. She asks about disease-modifying treatment to slow cyst growth and preserve renal function. Which of the following is the most appropriate disease-modifying therapy?
ASpironolactone
BFurosemide
COctreotide
DLisinopril
ETolvaptan
Reveal answer & full explanation
Correct answer: E — Tolvaptan
ASpironolactone
BFurosemide
COctreotide
DLisinopril
ETolvaptan✓
Why Tolvaptan is correct
Autosomal dominant polycystic kidney disease (ADPKD) results from mutations in PKD1 or PKD2 (encoding polycystin-1 and polycystin-2).
Tolvaptan is a selective vasopressin V2 receptor antagonist; V2 receptor activation raises intracellular cAMP, which drives cyst epithelial proliferation and fluid secretion, so V2 blockade slows cyst growth.
TEMPO 3:4 trial (NEJM 2012): tolvaptan reduced total kidney volume (TKV) growth by 49% and eGFR decline by 26% over 3 years.
Patient selection targets rapidly progressing disease (Mayo Class 1C-1E); this patient is Mayo Class 1C.
Why the others are wrong
Furosemide — Right-concept-wrong-mechanism: a loop diuretic reduces volume overload but has no disease-modifying effect on cyst growth in ADPKD.
Lisinopril — Confused-with BP management: an ACE inhibitor is first-line for blood pressure and proteinuria control in ADPKD, and intensive BP control in HALT-PKD Study A (ages 15-49 with eGFR >60; home BP target 95/60 to 110/75 mm Hg) only modestly slowed kidney-volume growth, but ACE inhibition is not the cyst-targeted disease-modifying therapy used for rapidly progressing disease.
Spironolactone — Anchoring on diuretics: a mineralocorticoid antagonist has no established disease-modifying role in ADPKD cyst growth.
Octreotide — right-pathway-wrong-drug: like tolvaptan, a somatostatin analog lowers cyst cAMP and has been studied in ADPKD, but its established role is reducing liver volume in symptomatic polycystic liver disease; it is not approved to slow kidney function decline in ADPKD, and she has no liver complications.
Additional high-yield points
Tolvaptan side effects: aquaresis (polyuria, polydipsia, nocturia) and hepatotoxicity — requires a REMS program with monthly liver function tests (LFTs) for 18 months.
Contraindications: liver disease, pregnancy, inability to maintain adequate fluids.
Adjuncts: low-sodium diet, moderate protein intake (about 0.8-1.0 g/kg/day; avoid both high-protein and protein-restricted diets), avoid excessive caffeine, and adequate water intake.
Question 2RenalMedium
A 30-year-old male has hypertension since age 25, hematuria, and a family history of kidney failure in his father at age 55 and unexplained sudden death in a paternal aunt at age 42. Renal ultrasound shows multiple bilateral kidney cysts. Which of the following best describes the mode of inheritance and the other organ that should be screened?
AAutosomal recessive; screen for congenital hepatic fibrosis
BMitochondrial inheritance; screen for multi-organ involvement
CAutosomal dominant; screen for mitral valve prolapse with echocardiography
DAutosomal dominant; screen for cerebral artery aneurysms with MRA
EX-linked recessive; screen for sensorineural hearing loss
Reveal answer & full explanation
Correct answer: D — Autosomal dominant; screen for cerebral artery aneurysms with MRA
AAutosomal recessive; screen for congenital hepatic fibrosis
BMitochondrial inheritance; screen for multi-organ involvement
CAutosomal dominant; screen for mitral valve prolapse with echocardiography
DAutosomal dominant; screen for cerebral artery aneurysms with MRA✓
EX-linked recessive; screen for sensorineural hearing loss
Why Autosomal dominant; screen for cerebral artery aneurysms with MRA is correct
This is autosomal dominant polycystic kidney disease (ADPKD): the most common inherited kidney disease, caused by mutations in PKD1 (85% of cases, more severe) or PKD2
Multiple bilateral cysts develop over decades; end-stage renal disease (ESRD) typically occurs by age 50-70
Intracranial (berry) aneurysms affect about 10% of ADPKD patients; screening MRA is targeted to higher-risk patients (family history of intracranial aneurysm, SAH, or unexplained sudden death; prior SAH; or high-risk occupation) rather than performed universally, and his paternal aunt's unexplained sudden death, possibly from a ruptured aneurysm, makes him a screening candidate
Why the others are wrong
Autosomal recessive; screen for congenital hepatic fibrosis — autosomal recessive polycystic kidney disease (ARPKD, PKHD1 mutation) is associated with congenital hepatic fibrosis, but it usually presents in infancy or childhood and the parents are unaffected carriers; kidney failure in his father (vertical transmission) with adult-onset hypertension fits autosomal dominant disease
Mitochondrial inheritance; screen for multi-organ involvement — mitochondrial inheritance is not associated with polycystic kidney disease in this pattern
X-linked recessive; screen for sensorineural hearing loss — Alport syndrome (a type IV collagen disorder) is usually X-linked, classically called X-linked dominant rather than recessive because heterozygous females are often affected, and less often autosomal; it causes hematuria plus sensorineural hearing loss plus lenticonus but not bilateral cysts on ultrasound, and the father-to-son transmission here excludes X-linked inheritance
Autosomal dominant; screen for mitral valve prolapse with echocardiography — the inheritance is right and mitral valve prolapse is a recognized extra-renal manifestation of ADPKD, but it is usually benign and routine echocardiographic screening is not recommended without a murmur or cardiac symptoms; in a family with ADPKD, an unexplained sudden death at a young age is the classic clue to a ruptured intracranial aneurysm, which is what makes MRA the screen to order
Additional high-yield points
Extra-renal manifestations of ADPKD: hepatic cysts (most common extra-renal finding), mitral valve prolapse, diverticulosis, abdominal hernias
Treatment: blood pressure control with ACE inhibitor (ACEi) or angiotensin receptor blocker (ARB); tolvaptan (V2 receptor antagonist) slows cyst progression
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Modified Ravine ultrasound criteria for at-risk individuals: Age 15-39: ≥3 cysts (unilateral or bilateral). Age 40-59: ≥2 cysts in each kidney. Age ≥60: ≥4 cysts in each kidney. Absence of criteria in PKD1 family >40 yr essentially excludes disease.
Labs
BMP — eGFR may be preserved well into adulthood
Urinalysis — hematuria during cyst hemorrhage; mild proteinuria
Lipid panel, A1c for cardiovascular risk
Genetic testing (PKD1, PKD2, GANAB) — confirms diagnosis when imaging equivocal or for early pre-symptomatic diagnosis
Imaging
Renal ultrasound — first-line screening; modified Ravine criteria diagnose ADPKD based on age and cyst number
MRI or CT — better characterization, total kidney volume (TKV) measurement for prognosis (Mayo classification)
MR angiography for screening intracranial aneurysm in patients with family history of aneurysm/SAH or high-risk occupation
Diagnostic algorithm
Feature
ADPKD
ARPKD
Inheritance
Autosomal dominant
Autosomal recessive
Gene
PKD1 (~78%), PKD2 (~15%)
PKHD1 (fibrocystin)
Typical presentation age
3rd-4th decade adult
Infancy/childhood
Kidney appearance
Large cysts of varying sizes, bilateral
Diffuse small cysts, ductal pattern
Hepatic involvement
Hepatic cysts (asymptomatic usually)
Congenital hepatic fibrosis, portal HTN
Extra-renal
Aneurysms, MVP, diverticula, hernias
Pulmonary hypoplasia (neonatal)
Prognosis
ESRD median 55 (PKD1) / 75 (PKD2)
30-50% mortality in 1st year; 70% survival to 15 yr
Comparison of ADPKD and ARPKD — inheritance, presentation, and prognosis.
Treatment
First-line
Aggressive BP control — KDIGO 2025, if tolerated: home BP ≤110/75 mm Hg at ages 18-49 with CKD G1-G2 and BP >130/85 (recommended; HALT-PKD Study A), and mean systolic <120 mm Hg by standardized office measurement at age ≥50 with CKD G1-G5 (suggested); individualize outside these groups; ACEi (lisinopril, ramipril, enalapril) or ARB (losartan, valsartan, irbesartan) first-line
Tolvaptan — vasopressin V2 receptor antagonist; FDA-approved for adults at risk of rapid progression (identified by Mayo class 1C-1E or eGFR decline ≥3 mL/min/1.73 m² per year; start if eGFR ≥25; REMS with LFT monitoring for hepatotoxicity); slows eGFR decline and TKV growth
High water intake (>2.5-3 L/day) to suppress vasopressin (theoretical benefit; recommended outside tolvaptan)
Low sodium diet, normal protein intake, weight control
Statin if dyslipidemia or CVD risk; avoid nephrotoxins
Cyst infection: lipophilic antibiotics (fluoroquinolones — ciprofloxacin, levofloxacin; trimethoprim-sulfamethoxazole) for ≥4-6 weeks; drainage if no response
Stones: management as for general urolithiasis; alpha-blocker, hydration, surgical removal as needed
Aneurysm screening: MRA in patients with family history of intracranial aneurysm or SAH; treat aneurysms >7 mm or symptomatic
RRT/transplant for ESRD — transplant outcomes equivalent to general population; native nephrectomy may be needed pre-transplant if massive nephromegaly
Complications
Hypertension (often early, before significant CKD)
Progressive CKD/ESRD by 4th-7th decade
Intracranial aneurysms (5-10%, higher with family history); subarachnoid hemorrhage
Cyst hemorrhage, infection, stones
Hepatic cysts (rarely symptomatic), pancreatic and seminal vesicle cysts
Hypertension is the most common and earliest clinical manifestation, usually diagnosed before age 30 and before GFR declines; it tracks with cyst burden and kidney volume.
Mayo Clinic imaging classification (A-E) uses height-adjusted total kidney volume + age to predict progression and identify tolvaptan candidates.
Tolvaptan side effects: polyuria (vasopressin antagonism), hepatotoxicity (monthly LFT monitoring for first 18 months mandatory).
Screen for intracranial aneurysm with MRA if family history of aneurysm or SAH, high-risk occupation (pilot), or prior to major elective surgery.
Avoid NSAIDs (nephrotoxic) and chronic anticoagulation when possible (cyst hemorrhage and SAH risk).
Genetic counseling and reproductive options (preimplantation genetic diagnosis) for affected families.
References
KDIGO 2025 — KDIGO 2025 Clinical Practice Guideline for the Evaluation, Management, and Treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD). Kidney Int. 2025;107(2S):S1-S239.
HALT-PKD — Schrier RW, et al. Blood Pressure in Early Autosomal Dominant Polycystic Kidney Disease. N Engl J Med. 2014;371(24):2255-2266.
TEMPO 3:4 — Tolvaptan in Patients with ADPKD (Torres et al., NEJM 2012)
REPRISE — Tolvaptan in Later-Stage ADPKD (Torres et al., NEJM 2017)
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