How do autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD) differ in inheritance pattern, age of onset, clinical manifestations, and management?

ADPKD vs ARPKD: Key Differences

ADPKD and ARPKD are fundamentally distinct genetic disorders that differ in inheritance pattern, age of presentation, severity, and clinical course—recognizing these differences is critical for accurate diagnosis, genetic counseling, and management planning. 1, 2

Inheritance Pattern

• ADPKD follows autosomal dominant inheritance, meaning a single mutated gene copy from one parent confers 50% risk to offspring 3
• ARPKD follows autosomal recessive inheritance, requiring mutations in both gene copies (one from each parent) for disease manifestation 1, 4
• ADPKD can occur as de novo mutations in approximately 10% of cases, while ARPKD requires both parents to be carriers 2

Genetic Basis

• ADPKD is primarily caused by PKD1 (85%) or PKD2 (15%) mutations, with PKD1 causing more severe disease (kidney failure in 50s) compared to PKD2 (kidney failure in 70s) 1, 5
• ARPKD results from mutations in PKHD1, DZIP1L, CYS1, or PKD1 genes (biallelic mutations) 1, 5
• Minor ADPKD genes (ALG5, ALG9, DNAJB11, GANAB, IFT140, NEK8) account for <0.5-2% of cases and typically present with milder phenotypes 1

Age of Onset and Clinical Presentation

ADPKD

• Typically presents in adulthood (3rd-5th decade), though cysts develop gradually from childhood 1, 2
• Approximately 3% of children with ADPKD have very-early-onset or rapidly progressive disease, mimicking ARPKD 5
• Clinical manifestations include bilateral kidney enlargement, hypertension, hematuria, kidney stones, urinary tract infections, and progressive CKD 1, 4
• Normal fetal or childhood ultrasound does NOT exclude ADPKD, as cysts may not be detectable early in milder phenotypes 5

ARPKD

• Presents perinatally or in early childhood, often detected on prenatal ultrasound with enlarged echogenic kidneys and oligohydramnios 2, 6
• Significant mortality in the first month of life due to pulmonary hypoplasia from massively enlarged kidneys causing respiratory compromise 4, 6
• Cysts develop primarily in collecting ducts due to maturation failure 4
• More severe and rapidly progressive course compared to typical ADPKD 2

Extrarenal Manifestations

ADPKD

• Polycystic liver disease is the most frequent extrarenal manifestation, present in >80% by age 30 years 3, 4
• Intracranial aneurysms (particularly with PKD1 mutations), cardiac valvular abnormalities, pancreatic cysts, and hernias 1, 4
• Liver cysts increase with age and are more severe in women 1

ARPKD

• Congenital hepatic fibrosis is the hallmark hepatic manifestation, leading to portal hypertension rather than cystic liver disease 6
• Portal hypertension complications (variceal bleeding, splenomegaly) require gastroenterology follow-up 6
• Risk for neurocognitive dysfunction requiring neuropsychological assessment 6

Diagnostic Approach

ADPKD Diagnosis

• For adults at risk (positive family history, ages 15-39 years): ≥3 total kidney cysts on ultrasound confirms diagnosis; ≤1 cyst rules it out 1
• For ages 40-59 years: ≥2 cysts in each kidney confirms; ≤2 total cysts rules out 1
• For ages ≥60 years: ≥4 cysts in each kidney confirms diagnosis 1, 3
• MRI criteria (ages 16-40 years): >10 total cysts confirms ADPKD; <5 cysts rules it out 1
• Genetic testing is particularly helpful for: few kidney cysts, variable intrafamilial severity, very-early-onset disease, young living-related kidney donors, and family planning 1

ARPKD Diagnosis

• Prenatal ultrasound showing enlarged echogenic kidneys with oligohydramnios 6
• Genetic testing for PKHD1, DZIP1L, CYS1, or biallelic PKD1 mutations confirms diagnosis 1, 5
• Liver biopsy may show congenital hepatic fibrosis 6

Prognosis and Disease Severity

ADPKD

• PKD1 truncating mutations: CKD stage 3 around age 40, kidney failure in 50s 1
• PKD2 mutations: CKD stage 3 around age 55, kidney failure in 70s 1
• Male sex, obesity, and high salt intake worsen prognosis 1
• Mayo Imaging Classification (MIC) predicts kidney function decline using height-adjusted total kidney volume 1

ARPKD

• More severe course with earlier progression to kidney failure 2
• Significant perinatal mortality from pulmonary complications 4, 6
• Those surviving infancy face chronic kidney disease and portal hypertension complications 6

Management Differences

ADPKD Management

• Tolvaptan is the cornerstone disease-modifying therapy for patients at risk of rapid progression, reducing eGFR decline by 1.3 mL/min/1.73 m²/year 7
• Blood pressure control targeting systolic <120 mmHg 7
• Increased water intake (2-3 liters daily) and dietary sodium restriction 7
• Kidney transplantation is preferred treatment for kidney failure, ideally preemptive living-donor transplantation 7
• Native nephrectomy only for specific indications (severe symptoms, recurrent infection, insufficient space for graft) 7

ARPKD Management

• Multidisciplinary approach required: neonatology, nephrology, gastroenterology, surgery 6
• Neonatal management focuses on respiratory support and managing massively enlarged kidneys 6
• Portal hypertension management by gastroenterology (variceal surveillance, treatment) 6
• Consideration of nephrectomy to relieve mass effect in severely affected infants 6
• Dialysis and kidney transplantation for kidney failure, with potential combined liver-kidney transplantation if severe portal hypertension 6

Critical Diagnostic Pitfalls

• Do not assume all early-onset PKD is ARPKD—3% of ADPKD cases present with very-early-onset disease 5
• Negative family history does not exclude ADPKD—up to 10% are de novo mutations 2
• Normal childhood imaging does not rule out ADPKD—cysts develop gradually over time 5
• Multiple inherited disorders can mimic both ADPKD and ARPKD, including HNF1B-related disease, tuberous sclerosis, and syndromic ciliopathies 1, 5