GeneticsTier 2Medical Sciences concept

Autosomal dominant polycystic kidney disease genetics (PKD1, PKD2)

Core concept

Commonest inherited cause of ESKD (~5-10% of the dialysis population); prevalence ~1 in 1,000
PKD1 (16p13.3) -> polycystin-1; PKD2 (4q22) -> polycystin-2
- The two proteins form a complex in the primary cilium of the tubular epithelial cell
- Polycystin-2 is a TRPP2 calcium channel; polycystin-1 is the mechanosensor
- Loss -> dec intracellular Ca2+ -> inc cAMP -> inc PKA, mTOR and B-Raf signalling -> proliferation + fluid secretion (via CFTR) -> cyst growth
- -> a ciliopathy
Two-hit - germline mutation in every cell, plus a somatic second hit in the individual tubular cell
- Explains why only a small fraction of nephrons become cysts, and why cysts are clonal
Cysts detach from the tubule and grow independently; the kidney enlarges while GFR is preserved for decades - GFR falls late

	PKD1	PKD2
Proportion	~78-85%	~15%
Cyst number/onset	More, earlier	Fewer, later
Median age at ESKD	~54 years	~74 years
Hypertension, haematuria	Earlier	Later
Truncating vs non-truncating	Truncating PKD1 worst (~55 y) vs non-truncating (~67 y)	-

~10% have no family history - de novo mutation or mild/unrecognised parental disease
GANAB, DNAJB11, IFT140 - rarer atypical genes; ALG9. ADPKD is now understood as a spectrum, not two genes
PKHD1 = autosomal RECESSIVE PKD - infantile, congenital hepatic fibrosis, Potter sequence

Diagnosis

Ultrasound, Ravine/Pei criteria by age with a positive family history
- 15-39 y: >=3 cysts (unilateral or bilateral)
- 40-59 y: >=2 cysts in each kidney
- >=60 y: >=4 cysts in each kidney
- <2 cysts at age >=40 excludes disease in an at-risk individual (important for living donor assessment)
MRI total kidney volume with the Mayo imaging classification (1A-1E) is the best predictor of progression, and determines drug eligibility
PROPKD score combines genotype, sex, hypertension and urological events before 35
Genetic testing where imaging is equivocal, in a young potential living donor, for reproductive planning, or in atypical disease
- Direct sequencing is complicated by six PKD1 pseudogenes; ~10% of variants are of uncertain significance and ~70% are family-private
- Linkage analysis is largely historical - needed >=4 affected relatives and was applicable in <50% of families

Extrarenal manifestations - the exam list

Polycystic liver disease (commonest; more severe in women and with oestrogen exposure; rarely affects LFTs)
Intracranial aneurysm ~5-10% (~4x population risk) - screen only if family history of aneurysm or SAH, high-risk occupation, or before major surgery; not universally
Mitral valve prolapse ~25%, aortic regurgitation, aortic root dilatation and dissection
Cysts in pancreas, seminal vesicles, arachnoid; diverticular disease; abdominal wall and inguinal hernias

Management

BP target <=110/75 in ages 18-50 with eGFR >60 (HALT-PKD) - ACE inhibitor or ARB first-line
Tolvaptan (V2 receptor antagonist) - blocks vasopressin -> dec cAMP -> slows TKV growth and eGFR decline in rapidly progressive disease
- Requires monthly LFTs - idiosyncratic hepatotoxicity; aquaresis causes marked polyuria and thirst, the main reason for discontinuation
High fluid intake, low sodium, avoid caffeine excess and nephrotoxins; treat cyst infection with lipophilic antibiotics (ciprofloxacin, trimethoprim penetrate cysts; beta-lactams do not)
Cyst haemorrhage and nephrolithiasis (uric acid) are common causes of pain and haematuria
Living related donation requires exclusion of disease in the donor by age-appropriate imaging +/- genetics

3 more sections, plus exam facts

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