Write a short note on autosomal dominant polycystic kidney disease.

Definition and Genetics

Autosomal dominant polycystic kidney disease (ADPKD) is the commonest inherited kidney disease, affecting about 1 in 400 to 1 in 1000 individuals, and accounts for 5–10% of patients on renal replacement therapy.

• PKD1 gene (chromosome 16) — ~85% of cases, encoding polycystin-1. Associated with earlier onset and progression to end-stage renal disease around the age of 55.
• PKD2 gene (chromosome 4) — ~15%, encoding polycystin-2; milder disease with end-stage failure around 75.

Autosomal dominant inheritance means each child of an affected parent has a 50% risk — which makes family screening and counselling central to management. About 10% of cases arise from new mutations.

Pathogenesis:

• polycystins are located in the primary cilium of tubular epithelial cells and regulate calcium signalling and cell proliferation. Their dysfunction causes progressive formation and enlargement of fluid-filled cysts from tubular segments, which detach from the parent tubule and continue to secrete fluid.
• Cyst growth compresses adjacent normal parenchyma, causing progressive interstitial fibrosis and loss of function. Kidneys may reach enormous size, weighing several kilograms.

Note the contrast with autosomal RECESSIVE PKD, which presents in infancy with massively enlarged kidneys, oligohydramnios (Potter sequence) and congenital hepatic fibrosis.

Clinical Features

Renal:

• Often asymptomatic until the third or fourth decade.
• Hypertension — very common and OFTEN THE EARLIEST manifestation, preceding any fall in GFR; caused by cyst-mediated compression with activation of the renin–angiotensin system.
• Loin or abdominal pain — chronic dull ache from cyst enlargement, or acute severe pain from cyst haemorrhage, infection or stone.
• Haematuria — macroscopic, from cyst rupture into the collecting system; usually self-limiting.
• Palpable, ballotable, knobbly kidneys; abdominal distension and early satiety with massive enlargement.
• Renal stones (in ~20%) — uric acid and calcium oxalate, promoted by urinary stasis and low urine pH.
• Cyst infection — fever and localised loin tenderness; difficult to treat, requiring lipid-soluble antibiotics (fluoroquinolones, co-trimoxazole) that penetrate cysts.
• Progressive chronic kidney disease leading to end-stage renal failure; urine concentrating defect with nocturia and polyuria appears early.

Extra-renal — the "systemic" nature of the disease is a favourite examination point:

Investigations

• ULTRASOUND — the investigation of choice for diagnosis and screening: cheap, non-invasive and radiation-free. Age-dependent Ravine criteria are used in those with a family history — broadly, at least 3 cysts (unilateral or bilateral) between 15 and 39 years, at least 2 in each kidney between 40 and 59, and 4 or more in each kidney at 60 and above.
• CT or MRI — more sensitive for small cysts, and MRI measurement of total kidney volume is the best predictor of subsequent decline in function and is used to select patients for treatment.
• Genetic testing — for equivocal imaging, potential living related donors, young at-risk individuals, and pre-implantation or prenatal diagnosis.
• Monitoring: blood pressure, renal function and eGFR, urinalysis, and total kidney volume.
• Screening for intracranial aneurysm by MR angiography — NOT routine, but indicated for: a family history of subarachnoid haemorrhage or intracranial aneurysm, previous aneurysm, high-risk occupations (pilots), before major elective surgery, and where the patient requests it after counselling about the implications.

Management

There is no cure; the goals are to slow progression, manage complications and screen the family.

1. Slow progression

• Rigorous blood pressure control — the single most important intervention, with a target of about ≤ 130/80 mmHg (lower in young patients with preserved function). ACE inhibitors or ARBs are first-line, as the renin–angiotensin system is activated.
• TOLVAPTAN — a vasopressin V2 receptor antagonist, the first disease-modifying therapy, which slows cyst growth and the decline in eGFR in patients with rapidly progressive disease. It causes marked aquaresis with polyuria and thirst, and requires monitoring of liver function because of hepatotoxicity; cost limits access in India.
• High fluid intake (2.5–3 litres daily) to suppress vasopressin; dietary sodium restriction; avoidance of caffeine; weight control.

2. Manage complications

• Pain: analgesia (avoid NSAIDs), cyst aspiration or sclerotherapy, laparoscopic cyst decompression in selected cases.
• Haematuria: rest, hydration and analgesia; it is usually self-limiting. Investigate persistent or atypical bleeding to exclude malignancy.
• Cyst infection: lipid-soluble antibiotics with good cyst penetration, for a prolonged course; drainage for abscess.
• Stones: hydration, alkalinisation for uric acid stones, and urological management.
• Hepatic cysts: usually need no treatment; drainage or resection for symptomatic disease.
• Intracranial aneurysm: neurosurgical or endovascular treatment based on size and site; strict blood pressure control and smoking cessation for all.

3. Renal replacement therapy

Dialysis or transplantation — outcomes after transplantation are good. Native nephrectomy may be needed before or at the time of transplantation if the kidneys are massively enlarged and there is no room for the graft, or for recurrent infection or bleeding.

Genetic Counselling and Family Screening

• Explain the 50% risk to each child and the implications for insurance, employment and reproductive planning.
• Screen at-risk first-degree relatives, ideally after counselling about the consequences of a positive result. Screening of asymptomatic children is generally deferred until adulthood, but blood pressure should be checked in at-risk children.
• Screen potential living related donors rigorously — genetic testing is required, since imaging alone cannot exclude the disease in a young donor.