Key Facts

ADPKD is a systemic ciliopathy with progressive cyst formation in kidneys and other organs. It is the most common genetic cause of renal failure.

Epidemiology

• Prevalence: 1 in 400-1,000
• Accounts for 5-10% of ESRD in the UK
• Autosomal dominant with near-complete penetrance
• 5-10% of cases are de novo mutations (no family history)

Aetiology

• PKD1 (85%): encodes polycystin-1; earlier, more severe disease
• PKD2 (15%): encodes polycystin-2; later onset, milder
• Autosomal recessive PKD (ARPKD): PKHD1 gene; presents in neonates/infants

Pathophysiology

• Polycystins are expressed in renal tubular cilia and regulate intracellular calcium signalling
• Loss of polycystin function → aberrant cAMP signalling → fluid secretion and cell proliferation
• Two-hit hypothesis: inherited mutation + somatic second hit → cyst initiation
• Cysts gradually enlarge (1-2% per year volume increase), compressing normal parenchyma
• Vasopressin (ADH) stimulates cAMP and cyst growth → rationale for tolvaptan
• Progressive renal enlargement: kidneys can reach >30 cm in length

Renal Manifestations

• Bilateral palpable kidneys (often ballotable)
• Hypertension: earliest and most common manifestation (develops before GFR decline)
• Loin/flank pain: cyst haemorrhage, infection, or mass effect
• Haematuria: cyst rupture or infection; can be macroscopic
• UTI/cyst infection: more common in women; cyst infections can be difficult to treat
• Renal stones: 20-30% (uric acid and calcium oxalate)
• Progressive CKD: gradual decline to ESRD

Extra-renal Manifestations

• Hepatic cysts: 70-80% (usually asymptomatic; more common/larger in women)
• Intracranial aneurysms: 5-10% (risk of SAH; screen if family history of aneurysm/SAH)
• Mitral valve prolapse: 25%
• Aortic root dilatation, aortic regurgitation
• Diverticular disease: increased prevalence
• Abdominal/inguinal herniae

Red Flags

• Sudden severe headache → subarachnoid haemorrhage (ruptured aneurysm)
• Fever with loin pain → cyst infection (may not show on standard cultures)
• Rapidly declining GFR → cyst haemorrhage, obstruction, or superimposed disease

Bedside

• Blood pressure: often elevated before renal impairment
• Family history: essential (autosomal dominant pattern)
• Urinalysis: haematuria

Bloods

• U&Es: eGFR, creatinine
• FBC: polycythaemia (increased EPO production by cysts)
• Urine ACR: proteinuria assessment

Imaging

• Renal ultrasound: first-line diagnostic tool; bilateral enlarged cystic kidneys
  • Ravine criteria (at-risk individuals): ≥3 cysts aged 15-39; ≥2 cysts per kidney aged 40-59
• MRI with TKV (total kidney volume): best predictor of progression; used for Mayo classification (1A-1E)
• MR angiography (brain): screen for intracranial aneurysms if family history of aneurysm/SAH (screening from age 20)

Special Tests

• Genetic testing: PKD1/PKD2 mutation analysis; useful if equivocal imaging, young living donor candidates, or reproductive counselling
• CT/MRI: complicated cyst assessment (haemorrhage, infection, malignancy)
• PET-CT: may help differentiate cyst infection from haemorrhage

Non-pharmacological

• Adequate hydration: 2.5-3L/day (suppresses vasopressin and may slow cyst growth)
• Sodium restriction: <6g/day
• Regular exercise: maintain cardiovascular fitness
• Avoid contact sports: risk of cyst rupture with enlarged kidneys
• Genetic counselling: 50% transmission risk

Pharmacological

Blood pressure:

• ACEi (ramipril) or ARB (candesartan): first-line
• Target <130/80 (HALT-PKD trial: intensive BP control slowed TKV growth in early disease)

Tolvaptan (V2 receptor antagonist):

• NICE TA876: approved for adults with ADPKD and evidence of rapidly progressive disease
• Criteria: CKD stages 2-3, TKV growth >5%/year or eGFR decline >2.5 mL/min/year
• Dose: titrated from 45/15mg to 90/30mg (split dosing)
• TEMPO 3:4 trial: reduced TKV growth by 49% and eGFR decline by 26%
• Monitoring: LFTs monthly for 18 months then 3-monthly (risk of hepatotoxicity ~5%)
• Side effects: polyuria, polydipsia, nocturia, hepatotoxicity

Other:

• Pain management: paracetamol, avoid NSAIDs; consider nerve blocks for chronic pain
• Cyst infection: lipophilic antibiotics penetrate cysts better (ciprofloxacin, co-trimoxazole); prolonged course 4-6 weeks
• Renal stones: treat as per standard guidelines

Surgical

• Cyst aspiration/sclerotherapy: for symptomatic large cysts
• Nephrectomy: prior to transplant if very large kidneys (space, infection risk)
• Hepatic cyst fenestration: for massive hepatomegaly

Renal Replacement Therapy

• Transplantation is treatment of choice for ESRD
• Living related donors must be screened (genetic testing/USS)
• Peritoneal dialysis or haemodialysis as bridge to transplant

Referral Criteria

• All diagnosed ADPKD → nephrology
• Rapidly progressive disease → assess for tolvaptan
• Family history of intracranial aneurysm → MRA screening

• PKD1: median age to ESRD 54 years
• PKD2: median age to ESRD 74 years
• TKV >1500 mL: strong predictor of progression to ESRD
• Tolvaptan delays ESRD by an estimated 4-7 years
• Intracranial aneurysm rupture: mortality 50% (justifies screening in high-risk families)
• Post-transplant outcomes: excellent; ADPKD patients tend to do well on transplant
• CKD complications (anaemia, bone disease) may develop later than other causes of CKD due to preserved EPO production

Mayo Classification for ADPKD Prognosis

PKD1 vs PKD2