What are the methods for diagnosing and managing polycystic kidney disease (PKD)?

Diagnosis of Polycystic Kidney Disease

For adults with a positive family history of ADPKD, renal ultrasonography is the diagnostic method of choice, requiring ≥3 cysts (total in both kidneys) by age 40 years to confirm diagnosis, while adults with incidentally detected cysts and no family history require kidney MRI or CT followed by genetic testing if imaging is atypical or equivocal. 1

Diagnostic Approach Based on Family History

Adults WITH Positive Family History (Ages 16-40 years)

• Use renal ultrasonography as the first-line diagnostic test because it is inexpensive, non-invasive, and does not require ionizing radiation 1
• Apply age-specific ultrasound criteria for PKD1/PKD2 families: The presence of ≥3 renal cysts (total in both kidneys) by age 40 is diagnostic 1
• For equivocal ultrasound findings, proceed to MRI: The cutoff of >10 cysts on MRI confirms ADPKD, while <5 cysts excludes it 1
• Reserve genetic testing for specific scenarios: targeted screening for the known familial pathogenic variant is sufficient when the family mutation is already identified 1

Critical caveat: These ultrasound and MRI criteria apply ONLY to families with PKD1 or PKD2 pathogenic variants, not to minor genes 1

Adults WITHOUT Family History (Incidental Cyst Detection)

• If few cysts with normal kidney function and size: Proceed directly to kidney MRI (or CT with/without contrast) to characterize cysts 1, 2
• If multiple cysts and/or discordant imaging/GFR or atypical findings: Obtain both kidney MRI AND genetic testing 1
• Genetic testing should include: PKD1, PKD2, and genes listed in ACMG criteria using multigene panels 1
• If both MRI and genetics are equivocal: Schedule future imaging/genetic follow-up in approximately 2 years 1

The absence of family history does NOT exclude ADPKD, as de novo mutations occur 3, 4

Genetic Testing Indications

Genetic testing is particularly helpful and should be prioritized in these specific clinical scenarios: 1

• Few kidney cysts present with otherwise suggestive clinical picture 1
• Variable intrafamilial disease severity, including very-early-onset ADPKD 1
• Discordant imaging and glomerular filtration rate that don't match expected disease progression 1
• Young (<30 years) living-related kidney donors at risk based on family history 1
• Family planning and preimplantation diagnosis considerations 1
• Infants and children with very-early-onset symptomatic disease independent of family history 1
• Progressive disease (increasing cyst number or kidney volume) with negative family history 1

Use multigene panel testing rather than single-gene analysis because unusual genetic constellations (biallelic mutations, digenic inheritance, contiguous gene deletions) can radically alter phenotype and prognosis 1, 3, 4

Pediatric Diagnostic Considerations

Children with Positive Family History

• Ultrasonography remains the radiological method of choice in children due to smaller body size, no sedation requirement, and no radiation exposure 1
• In children <15 years with positive family history: Detection of ≥1 kidney cyst on ultrasound is highly suggestive of ADPKD (89% specificity <5 years, 100% specificity >5 years) 1
• In fetuses/neonates with positive family history: Hyperechogenic and/or enlarged kidneys (>2 standard deviations) are suggestive of ADPKD 1, 3
• Multiple kidney cysts in childhood are highly suggestive of ADPKD or another cystic nephropathy, as simple cysts are very rare in children 1

Important limitation: A normal ultrasound in childhood has LIMITED negative predictive value because cysts develop gradually and may not be detectable in milder phenotypes or PKD2 families 1, 3

When to Perform Genetic Testing in Children

• Offer genetic testing for very-early-onset symptomatic disease independent of family history 1
• Offer genetic testing for progressive disease (increasing cyst number/kidney volume) with negative family history 1
• Consider genetic testing with unusually severe clinical course despite positive family history 1
• DO NOT perform genetic testing in patients with single cyst, no extrarenal findings, and negative family history 1

Counseling Considerations for Pediatric Testing

• Parents must receive non-directional counseling about potential benefits and uncertainties of diagnostic screening before testing 1
• Two equally valid approaches exist: (1) immediate diagnostic screening (ultrasound or genetic testing), or (2) repeated screening for treatable manifestations (hypertension, proteinuria) without diagnostic confirmation 1
• Involve minors in decision-making when developmentally appropriate, using shared decision-making between parents and healthcare professionals 1

Differential Diagnosis and Mimics

Several inherited disorders present with kidney and/or liver cysts and may mimic ADPKD: 1

• HNF1B-related kidney disease (developmental disorder, autosomal dominant) 1
• Alagille syndrome (JAG1, NOTCH2 genes) 1
• HANAC syndrome (COL4A1 gene) causing hereditary angiopathy with nephropathy 1, 4
• COL4A-related diseases (COL4A3, COL4A4, COL4A5) 1
• Autosomal dominant tubulointerstitial kidney disease (UMOD, MUC1, REN, SEC61A genes) 1

Genetic testing with multigene panels is essential to distinguish these conditions, as they have different prognoses, comorbidities (e.g., congenital hepatic fibrosis in PKHD1, MODY5 diabetes in HNF1B), and sibling recurrence risks 1, 3

Prognostic Assessment After Diagnosis

Once ADPKD is diagnosed, employ the Mayo Imaging Classification (MIC) to predict future kidney function decline and timing of kidney failure: 1

• MIC divides ADPKD into typical (class 1) and atypical (class 2) presentations 1
• Prognostic information is valid ONLY for class 1 patients with typical imaging findings 1
• MIC uses height-adjusted total kidney volume (htTKV) adjusted for age to stratify typical patients into 5 groups (1A-1E) indicating accelerating kidney function decline 1
• Measure htTKV most accurately by MRI or CT using automated/semi-automated tools, or alternatively estimate using the ellipsoid equation 1
• DO NOT use MIC in patients with pathogenic variants in genes other than PKD1 or PKD2 1

Additional prognostic factors include: 1

• Causal gene: PKD1 > PKD2 or minor genes in severity 1
• Type of PKD1 mutation: truncating > nontruncating 1
• Sex: male > female for severity 1
• Environmental factors: obesity and salt intake worsen outcomes 1

Common Diagnostic Pitfalls to Avoid

• Do not apply adult ultrasound criteria to children <15 years as they typically have far fewer cysts than adults and may have no detectable cysts despite having ADPKD 1
• Do not assume a normal childhood ultrasound excludes ADPKD because cysts develop gradually and negative predictive value is limited, especially in PKD2 families 1, 3
• Do not use PKD1-specific ultrasound criteria for PKD2 families as PKD2 has milder phenotype with later cyst development 1
• Do not overlook parental ultrasound examination when evaluating children with cysts and "negative" family history, as this may reveal previously undetected ADPKD 1, 3
• A solitary cyst in a child with positive family history requires follow-up imaging as it may represent early ADPKD, though rare false positives can occur 1, 5
• Do not perform MRI as first-line in young children as it typically requires sedation and is more expensive than ultrasound 1
• Recognize that digenic inheritance or biallelic mutations can cause severe early-onset disease that differs dramatically from typical ADPKD 1, 4