Genetics & natural history
Genes
- PKD1 (chromosome 16) — ~78% of cases; encodes polycystin-1; median age to ESKD ~ 55
- PKD2 (chromosome 4) — ~15%; encodes polycystin-2; median age to ESKD ~ 70
- GANAB, DNAJB11, IFT140 — rarer, milder phenotypes, often missed
- De novo mutations in 5–10%
- NHS National Genomic Test Directory R193 — ADPKD panel
Natural History
- Cysts present at birth; grow exponentially through life
- eGFR usually preserved until 4th–5th decade despite enlarging kidneys
- Hypertension typically appears 10–20 yr before eGFR decline — earliest sign
- Annual eGFR decline averages 3–5 mL/min/yr in PKD1
- Pain, haematuria, cyst infection, stones, nocturia all common
Extra-renal Disease
- Liver cysts (PLD) > 80% by age 35 — F > M; oestrogen-driven; rarely symptomatic
- Intracranial aneurysms 5–10% (vs 1% population)
- Mitral valve prolapse ~25%
- Diverticulosis, abdominal wall hernias, seminal vesicle cysts
Risk stratification & diagnosis
Diagnosis
- Ultrasound criteria (Pei-Ravine, 2009) — age-stratified cyst counts in at-risk individual with positive family history
- MRI more sensitive in young adults (< 30) or atypical cases
- Genetic testing — needed if family history negative, atypical imaging, or considering living-related donation
Mayo Imaging Classification
- T2-weighted MRI without contrast → calculate htTKV (kidney volume / height)
- Use online Mayo calculator (mayo.edu) → class 1A to 1E based on age-htTKV slope
- 1A — slow progressors; 1B — slow to moderate
- 1C–1E — rapid progressors; eligible for tolvaptan
- Class 2 — atypical imaging (asymmetric, unilateral, lopsided) — separate prognosis
PROPKD SCORE (clinical):
- Male = 1
- Hypertension before 35 = 2
- First urological event before 35 = 2
- Truncating PKD1 = 4; non-truncating PKD1 = 2; PKD2 = 0
- Total ≥ 7 → rapid progressor
Key Tests At Diagnosis
- BP, urinalysis, ACR, eGFR, U&E, calcium, phosphate, LFTs, urate
- Renal USS first; T2-MRI if entering tolvaptan pathway
- Family pedigree; offer genetic counselling
- MRA for ICA only if FH SAH, high-risk job, or pre-major-surgery
Management (UK pathway)
Foundations
- Strict BP control < 130/80 (HALT-PKD: lower BP slows TKV growth in young patients)
- First-line: ACE inhibitor or ARB
- Restrict sodium < 100 mmol/day (< 5 g salt)
- Moderate protein 0.8–1.0 g/kg/day
- Fluids ≥ 3 L/day to suppress vasopressin (caveat: harder to tolerate on tolvaptan)
- Avoid caffeine excess; avoid NSAIDs and nephrotoxic herbals
Tolvaptan (NICE Ta358)
- Indication: ADPKD + CKD 2–4 + evidence of rapid progression (Mayo 1C–1E, PROPKD ≥ 7, or eGFR fall > 5 mL/min/yr)
- Initial dose 45 mg AM / 15 mg PM; titrate up to 90/30 over 3 weeks if tolerated
- AQUARETIC EFFECT: polyuria 5–8 L/day, nocturia, thirst — counsel and discuss QoL
- HEPATOTOXICITY: monthly LFTs for 18 months → 3-monthly thereafter; STOP if ALT > 3× ULN persistently
- Pregnancy / breastfeeding contraindicated
- Usually stopped at CKD 5 or dialysis
Cyst Complications
- Cyst infection: ciprofloxacin or co-trimoxazole (penetrates cyst wall) for 4–6 weeks
- Cyst haemorrhage: bed rest, analgesia, hydration; usually self-limits
- Pain: paracetamol, topical heat; consider cyst aspiration/sclerotherapy or laparoscopic fenestration for refractory cases
- Stones: ureteroscopy preferred (avoid SWL through cystic parenchyma)
- Nephrectomy reserved for refractory pain, recurrent bleeding/infection, mass effect, or to make space for transplant
Advanced CKD / Transplant
- Pre-emptive listing at eGFR ≤ 20 if rapid progression
- Living donation preferred — donor must be genotyped if related and aged < 40
- Native nephrectomy only if cysts displace transplant bed, recurrent infection, or refractory pain
- Post-transplant: cysts shrink without dialysis; tolvaptan stopped
Family
- 50% inheritance risk for each child
- Predictive testing for adults; not generally offered to children unless symptomatic
- PGD available
- Cascade BP screening for family members from age 5
