Polycystic kidney disease and inherited nephropathies: Viva

Branch 1: The diagnosis and its genetic basis

The candidate should recognise this as probable X-linked Alport syndrome. The combination of persistent microscopic haematuria in a boy, a mother with haematuria suggesting she is a carrier, and a maternal uncle with kidney failure and hearing loss, points to a COL4A5 mutation on the X chromosome. The candidate should state that Alport syndrome results from mutations in the type IV collagen genes, with COL4A5 causing the X-linked form that accounts for about 85 percent of cases, and COL4A3 or COL4A4 causing autosomal recessive or dominant forms. The type IV collagen alpha-3, alpha-4 and alpha-5 chains form a specialised network in the glomerular basement membrane, lens capsule and cochlea, and their absence causes progressive basement membrane thinning, splitting and thickening, producing the haematuria, the eventual hearing loss and the ocular features. ^[1]

If the examiner asks what investigations would confirm the diagnosis, the candidate should propose genetic testing as the primary approach. A next-generation sequencing panel covering COL4A3, COL4A4 and COL4A5 would identify the pathogenic variant, confirm the inheritance pattern, and enable cascade testing of at-risk relatives. The candidate should mention that the 2024 ERKNet guideline recommends genetic testing for all suspected cases of Alport syndrome. If genetic testing is inconclusive, a renal biopsy with electron microscopy showing the lamellated, thickened glomerular basement membrane is definitive. Pure-tone audiometry should be performed from about age five and repeated annually, and ophthalmology review should look for anterior lenticonus and macular flecks. ^[3]

If pressed on the differential diagnosis, the candidate should distinguish Alport syndrome from benign familial haematuria from heterozygous COL4A3 or COL4A4 (thin basement membrane nephropathy), which carries a much milder course though it can progress in some families, and from IgA nephropathy, which presents with episodic gross haematuria following infection rather than persistent microscopic haematuria. The family history of hearing loss and kidney failure in an X-linked pattern is the key discriminator for Alport syndrome. ^[1]