Alport Syndrome

Alport syndrome is an inherited type IV collagen disorder causing progressive haematuric nephritis, sensorineural deafness and ocular abnormalities.

• Genetics: X-linked (COL4A5, 80%, males severely affected, females variably), autosomal recessive (COL4A3 or COL4A4, 15%), autosomal dominant (COL4A3/4, 5%). Heterozygous COL4A3/4 variants account for much of familial "thin basement membrane" disease and carry a risk of CKD.
• Prevalence about 1 in 5,000 to 10,000.
• Pathology: GBM splitting and lamellation ("basket weave") on electron microscopy; absent alpha-5 staining.
• X-linked males: ESKD by age 25 (severe truncating), by age 40 (missense), 90% by age 40; carrier females: haematuria in 95%, ESKD in 15% by age 60.
• Extra-renal: sensorineural hearing loss (high frequency, bilateral), anterior lenticonus (pathognomonic), perimacular retinal flecks, corneal erosions, leiomyomatosis (COL4A5-COL4A6 deletion), aortic disease (rare).

• Persistent microscopic haematuria from childhood, episodes of gross haematuria with infections.
• Proteinuria develops in adolescence; hypertension; progression to CKD.
• Progressive hearing loss in late childhood or teen years.
• Visual disturbance from lenticonus, cataracts.
• Family history of kidney failure, deafness (maternal in X-linked).

• Urinalysis: dysmorphic haematuria; urine protein/creatinine ratio; eGFR.
• Genetic testing (COL4A3, COL4A4, COL4A5 panel), the preferred first-line diagnostic test.
• Skin biopsy (absent alpha-5 chain staining in X-linked males) or renal biopsy with electron microscopy and immunostaining.
• Audiometry and ophthalmology (slit lamp, retinal examination, OCT).
• Family screening with urinalysis and genetic testing.
• Exclude IgA nephropathy, thin basement membrane disease, FSGS.

• ACE inhibitor or ARB started early in affected children (before proteinuria in males with severe variants, ramipril 1.5 to 6 mg/m2) and in adults with proteinuria, titrated to maximum, reducing proteinuria and delaying ESKD by about 10 years.
• Add SGLT2 inhibitor (dapagliflozin 10 mg daily) in CKD with proteinuria; MRA (finerenone) as adjunct.
• Blood pressure below 130/80 mmHg; avoid nephrotoxins; statins; bicarbonate for acidosis.
• Hearing aids and cochlear implants; ophthalmological follow-up; lens replacement for lenticonus.
• Dialysis and transplantation: outcomes are excellent; 3 to 5% of transplanted males develop anti-GBM disease (de novo, mostly with truncating variants and deletions), presenting early with crescentic GN and graft loss.
• Living related donors must be screened (exclude X-linked carriers with significant disease).
• Genetic counselling, prenatal diagnosis, and pre-implantation genetic testing.
• Monitor annually: urine protein, eGFR, blood pressure, audiology.