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]

Branch 2: The management and the timing of intervention

If asked how to manage this boy, the candidate should present the key evidence-based intervention: ACE inhibitor therapy, and the critical question of when to start it. The 2020 clinical practice recommendations represent a landmark shift. An ACE inhibitor is now recommended at the time of diagnosis in males with X-linked Alport syndrome, because they almost universally progress to kidney failure, and starting treatment before overt proteinuria develops delays the onset of kidney failure by years, with cohort evidence suggesting a median delay of over a decade. The candidate should state clearly that this boy, if confirmed to have a COL4A5 mutation, should start an ACE inhibitor now, not when proteinuria appears. [1]

The examiner may probe the mechanism. The candidate should explain that the fragile glomerular basement membrane in Alport syndrome allows protein leak, and the resulting proteinuria drives tubular injury, interstitial fibrosis and glomerular sclerosis through the same hyperfiltration and angiotensin-mediated pathways that drive progression in other kidney diseases. ACE inhibitor blockade reduces intraglomerular pressure, reduces proteinuria, and slows the cycle. The rationale is nephroprotective, and the evidence supports earlier rather than later initiation. [1]

If asked about surveillance, the candidate should outline annual monitoring of blood pressure, renal function, urinalysis and albumin-to-creatinine ratio, annual audiometry from age five, and periodic ophthalmology review. The candidate should also address family screening: testing the mother to confirm her carrier status, offering genetic testing to at-risk female relatives who may carry the COL4A5 mutation, and providing genetic counselling about the 50 percent risk of transmission in each pregnancy for a carrier mother. [3]

Branch 3: Broaching the wider inherited nephropathies

If the examiner broadens the discussion to the other inherited nephropathies, the candidate should demonstrate command of the gene-based classification. Autosomal recessive polycystic kidney disease from PKHD1, encoding fibrocystin, presents in the neonatal period with bilateral enlarged echogenic kidneys and congenital hepatic fibrosis, at an incidence of about 1 in 20,000 live births. Autosomal dominant polycystic kidney disease from PKD1 or PKD2, encoding polycystin, presents with bilateral cysts and is treated with tolvaptan, a vasopressin V2 receptor antagonist, in rapidly progressive cases identified by height-adjusted total kidney volume. Nephronophthisis from over 20 NPHP genes presents with disproportionate anaemia, small echogenic kidneys and progressive kidney failure, often with syndromic features like retinitis pigmentosa in Senior-Loken syndrome or the molar tooth sign in Joubert syndrome. [2]

If asked to compare the mechanisms, the candidate should explain that the polycystic diseases and nephronophthisis are ciliopathies, diseases of the primary cilium, while Alport syndrome is a basement membrane disease. The primary cilium is the antenna-like sensory organelle on every tubular epithelial cell, and defects in its proteins cause cystogenesis through cyclic AMP accumulation and loss of cell polarity. In nephronophthisis, the ciliary defect causes tubular cell apoptosis and interstitial fibrosis rather than cyst formation, which is why the kidneys are small rather than enlarged and the anaemia is disproportionately severe. [4]

If the examiner asks about prognosis and the end game, the candidate should state that males with X-linked Alport syndrome almost universally progress to kidney failure, typically by the second or third decade, though the timing is modified by the specific COL4A5 variant and the effectiveness of ACE inhibitor therapy. Pre-emptive kidney transplantation is the goal, and the candidate should note that transplantation is curative for the renal disease in all these conditions because the genetic defect is kidney-intrinsic rather than systemic, with no recurrence of the original disease in the graft. The candidate should also mention the need for a structured transition to adult nephrology as the boy approaches adolescence. [1]