Description
- AD systemic ciliopathy - progressive bilateral cyst formation -> kidney enlargement, loss of parenchyma, ESKD
- Commonest inherited kidney disease; ~5-10% of prevalent dialysis patients
- Not a renal-limited disease - liver, pancreas, cerebral vessels, cardiac valves, diverticula, herniae
Renal presentations
- Hypertension - often the first sign, precedes GFR decline
- Loin/flank pain - cyst haemorrhage, cyst infection, nephrolithiasis, mass effect
- Haematuria (cyst rupture into collecting system)
- Nephrolithiasis (~20-25%) - uric acid and calcium oxalate; low urine citrate, low pH
- Cyst infection - fever + focal pain + normal urine culture
- Reduced concentrating ability -> nocturia early
- CKD, then ESKD
Epidemiology
- 1:400 - 1:1,000 live births; M=F
- ~50% reach ESKD by age 60
- ~10% have no family history - de novo mutation or mosaicism
- Males and PKD1 truncating mutations progress faster
Aetiopathogenesis
Genetics
| Gene | % | Locus | Protein | ESKD (median) |
|---|---|---|---|---|
| PKD1 | ~78% | 16p13 | Polycystin-1 | ~55 yr (truncating ~around 50) |
| PKD2 | ~15% | 4q21 | Polycystin-2 | ~70 yr |
| GANAB, DNAJB11, IFT140, ALG9 | rare | Mildest; DNAJB11 -> small kidneys + CKD |
- PKD1 truncating > PKD1 non-truncating > PKD2 for severity
- Polycystin-1/2 form a Ca2+ channel complex in the primary cilium of tubular epithelium
- Loss -> dec intracellular Ca2+ -> inc cAMP -> inc PKA -> proliferation + inc Cl--driven fluid secretion into cysts
- Vasopressin drives cyst cAMP -> the entire rationale for tolvaptan and high water intake
- Cysts arise from <5% of nephrons; a somatic "second hit" explains focal cyst origin
- Cyst expansion -> compression, ischaemia, RAAS activation -> hypertension early, before GFR falls
- **Contiguous gene syndrome: PKD1 + TSC2 deletion -> tuberous sclerosis with severe early PKD**
Diagnosis
A. Ultrasound - at-risk individual with a positive family history (Unified/Ravine criteria)
| Age | Diagnostic | Excludes |
|---|---|---|
| 15-39 | >=3 cysts (uni- or bilateral) | |
| 40-59 | >=2 cysts in each kidney | <2 cysts total |
| >=60 | >=4 cysts in each kidney | <2 per kidney |
- Ultrasound cannot exclude ADPKD under 30-40 - use MRI or genetic testing if exclusion matters (e.g. living donor assessment)
B. MRI
- >10 cysts in a patient <40 with a family history
- Measures total kidney volume - the prognostic variable
C. Genetic testing
- Indicated when: no family history, atypical imaging, very early/severe disease, living related donor evaluation, reproductive planning
- PKD1 is difficult to sequence - 6 pseudogenes
Risk stratification - decides who gets tolvaptan
- Mayo imaging classification - height-adjusted total kidney volume vs age
- Class 1C-1E = rapid progression; 1A-1B slow
- eGFR decline >=3 mL/min/1.73m2/yr (confirmed over >=4-5 yr) = rapid progression
- PROPKD score - genotype + sex + hypertension <35 + urological event <35
Extra-renal screening
- MRA for intracranial aneurysm - SELECTIVE, not universal
- Family history of ICA or SAH, previous rupture, high-risk occupation (pilot), before major elective surgery, patient anxiety after counselling
- Echo only if murmur or symptoms
Distinguish from
- ARPKD - infancy, congenital hepatic fibrosis, no family history in parents
- Tuberous sclerosis - angiomyolipomas (fat density on CT)
- Von Hippel-Lindau - cysts + clear cell RCC
- Acquired cystic kidney disease - small kidneys, dialysis vintage
- Simple cysts, medullary cystic/ADTKD
Management1 exam ›
A. Slow progression - everyone
- Blood pressure
- Target SBP <=120 mmHg (standardised measurement); <=110/75 in younger patients with eGFR >60 (HALT-PKD) if tolerated
- ACEi or ARB first line (combination gives no added benefit)
- High water intake - aim urine output >2-3 L/day to suppress vasopressin
- Salt <2 g sodium/day; avoid obesity; stop smoking
- Avoid NSAIDs and nephrotoxins; caffeine restriction is not evidence-based
B. Tolvaptan - for rapidly progressive disease only
- V2 receptor antagonist -> dec cAMP -> slows TKV growth and eGFR decline (TEMPO 3:4, REPRISE)
- Select: eGFR >=25 and rapid progression (Mayo 1C-1E or eGFR decline >=3/yr)
- Aquaresis is near-universal - polyuria, nocturia, thirst; the main reason for discontinuation
- *Idiosyncratic hepatotoxicity - LFTs monthly for 18 months, then 3-monthly*
- Counsel on free water access, avoiding hypernatraemia during intercurrent illness
C. Pain
- Exclude infection, stone, haemorrhage, malignancy
- Paracetamol; *avoid NSAIDs*; tramadol/opioid sparingly
- Refractory: cyst aspiration +/- sclerotherapy, laparoscopic fenestration, coeliac plexus block, nephrectomy as last resort
D. Cyst infection
- Urine culture is often negative; blood cultures more useful
- Lipophilic antibiotics penetrate cysts: ciprofloxacin, trimethoprim-sulfamethoxazole
- Beta-lactams penetrate poorly
- 4-6 weeks; drainage if >5 cm or not responding by 72 h
- PET/CT or MRI to localise if the source is unclear
E. Cyst haemorrhage / haematuria
- Usually self-limiting - bed rest, analgesia, hydration
- Persistent or first episode >50 yr -> image to exclude RCC
F. ESKD
- Transplantation preferred; native nephrectomy only if space needed, recurrent infection, intractable pain or bleeding
- Peritoneal dialysis is usually feasible despite kidney size
G. Extra-renal
- Polycystic liver disease - symptomatic only; oestrogen (HRT/OCP) worsens it; tolvaptan does not treat it
- Aneurysm - treat per neurosurgery; rigorous BP control and smoking cessation
H. Reproductive
- 50% transmission - genetic counselling, PGD/prenatal options available
- Pregnancy: stop ACEi/ARB and tolvaptan; inc risk of pre-eclampsia, especially if hypertensive or CKD
Associations2 exam ›
- Intracranial (berry) aneurysm (~9-12%, higher with family history) - thunderclap headache in ADPKD = SAH until excluded
- Polycystic liver disease - commonest extra-renal feature, F>M, oestrogen-dependent; rarely affects liver function
- Cardiac valve disease - mitral valve prolapse (~25%), aortic regurgitation
- Thoracic aortic and coronary artery aneurysm/dissection
- Colonic diverticulosis and diverticulitis
- Abdominal wall and inguinal herniae
- Pancreatic and seminal vesicle cysts; arachnoid cysts
- Left ventricular hypertrophy - early, driven by hypertension
- Bronchiectasis
Natural history & complications
- Long asymptomatic phase - kidney volume grows ~5%/yr while eGFR stays normal for decades
- GFR falls late - TKV, not creatinine, tracks early disease
- Hypertension in >50% before any fall in GFR
- ~50% ESKD by 60; PKD2 ~15 yr later than PKD1
- Cardiovascular disease, not ESKD, is the leading cause of death
- RCC is NOT increased in frequency, but when it occurs is more often bilateral, multicentric and sarcomatoid
Poor prognostic markers
- PKD1 truncating mutation, male sex, hypertension before 35, urological event before 35, Mayo class 1D-1E, large TKV for age
7 of 7 sections written · drafted 2026-09-12