Collagen IV Related Nephropathy

Collagen IV related nephropathy is the group of inherited glomerular basement membrane disorders caused by pathogenic variants in COL4A3, COL4A4 and COL4A5. These genes encode the alpha 3, alpha 4 and alpha 5 chains of type IV collagen.

The group includes:

• Alport syndrome: X-linked in about 80%, autosomal recessive in about 15%, and autosomal dominant or digenic in the rest.
• The heterozygous carrier state (previously called thin basement membrane nephropathy), which is more common than was once thought (about 1 in 100 to 1 in 200 people).

Defective collagen leads to a split and thinned glomerular basement membrane, haematuria, proteinuria, progressive glomerulosclerosis, sensorineural hearing loss and eye abnormalities. Alport syndrome accounts for about 1 to 2% of adults and up to 3% of children reaching kidney failure.

Genotype and severity.

• X-linked males with truncating variants or large deletions: kidney failure at a median age of about 25 years; with missense variants, at about 35 to 40 years.
• X-linked females: about 25% reach kidney failure by age 60, with a wide range of severity (higher risk with proteinuria, hearing loss and truncating variants).
• Autosomal recessive disease: kidney failure at a median age of about 20 to 25 years in both sexes.
• Heterozygous COL4A3 and COL4A4 carriers: usually isolated haematuria, but 20 to 30% develop proteinuria and some progress to kidney failure, especially with a family history.

• Haematuria from early childhood (microscopic, with episodes of macroscopic haematuria after infections or exercise), later proteinuria and hypertension.
• Hearing loss: high frequency sensorineural loss developing in late childhood or adolescence in males with X-linked and autosomal recessive disease.
• Eye: anterior lenticonus (virtually pathognomonic), perimacular retinal flecks, corneal endothelial vesicles, posterior polymorphous dystrophy, rarely cataracts and retinal tears.
• Extrarenal: aortic aneurysm and dissection (rare, with COL4A5 deletions); diffuse leiomyomatosis with COL4A5 and COL4A6 deletions.
• Family history of kidney failure, deafness or haematuria, with an X-linked, recessive or dominant pattern.

Red flags

• Proteinuria in a child or young adult with persistent haematuria and hearing loss.
• Rapid decline in function (consider another diagnosis or superimposed disease).
• Haemoptysis or acute kidney injury after transplantation in a male with a large deletion (anti-GBM disease of the allograft).
• Aortic dilatation or leiomyomatosis in a patient with a COL4A5 deletion.

• Urinalysis (dysmorphic red cells), urine protein:creatinine ratio or albumin:creatinine ratio, creatinine, eGFR; blood pressure.
• Audiometry; slit lamp and fundus examination.
• Genetic testing (COL4A3, COL4A4, COL4A5 panel, including copy number analysis) is the preferred diagnostic test and enables cascade testing of relatives.
• Kidney biopsy when genetic testing is not available or the result is unclear:
  • light microscopy shows non-specific changes (focal segmental glomerulosclerosis, foam cells, interstitial fibrosis)
  • electron microscopy shows thickening, thinning and splitting (lamellation, basket weave appearance) of the glomerular basement membrane
  • immunostaining shows absent or mosaic alpha 3, 4 and 5 (IV) chains in the basement membrane (X-linked males: absent; females: mosaic)
  Skin biopsy for alpha 5 chain is an alternative in some centres.
• Screen relatives and potential donors with genetic testing before living donation.

Differential diagnosis

• IgA nephropathy and other glomerulonephritis causing familial haematuria
• thin basement membrane nephropathy without family history of kidney failure
• focal segmental glomerulosclerosis from podocyte gene variants
• MYH9 related disorders (macrothrombocytopenia, deafness)
• Fabry disease, nail patella syndrome, polycystic kidney disease, isolated hearing loss

There is no cure; early renoprotection delays kidney failure by years.

• ACE inhibitor from the time of diagnosis in males with X-linked disease and in autosomal recessive disease (before proteinuria appears), and in all patients when albuminuria or hypertension develops.
• Dosing: ramipril 2.5 mg daily increased to 10 mg daily in adults. In children, ramipril 6 mg/m² daily, maximum 10 mg, started once proteinuria appears or early in severe genotypes.
• Check creatinine and potassium at 1 to 2 weeks. Accept a creatinine rise up to 30%; stop if potassium exceeds 6.0 mmol/L. If an ACE inhibitor is not tolerated, use losartan 50 to 100 mg daily.
• Blood pressure target below 130/80 mmHg in adults and under the 90th centile in children.
• Dapagliflozin 10 mg daily (eGFR at least 25) or empagliflozin 10 mg daily (eGFR at least 20) for persistent albuminuria in adults. Finerenone 10 mg daily (20 mg if eGFR is at least 60) with potassium under 5.0 mmol/L may be added in selected adults.
• Sodium under 2 g daily; statin for dyslipidaemia; avoid nephrotoxins (NSAIDs, aminoglycosides) and contact sports with kidney injury risk.
• Hearing: yearly audiometry, hearing aids, and cochlear implantation when severe. Eye: yearly ophthalmology review; surgery for lenticonus when vision is affected.
• Avoid smoking; manage cardiovascular risk; screening for aortic aneurysm in carriers of large COL4A5 deletions.

Kidney failure

• Haemodialysis or peritoneal dialysis at eGFR 5 to 10 with symptoms. Transplantation is the treatment of choice and graft survival is excellent.
• Living related donors must be tested genetically. Affected carriers should not donate; female X-linked carriers carry a risk of progression and are usually excluded.
• Anti-GBM disease of the allograft occurs in about 3 to 5% of male recipients (those with large deletions or truncating variants who lack alpha 5 (IV) chains). Treatment:
  • plasma exchange (50 mL/kg of 4% albumin daily for 14 days)
  • cyclophosphamide 2 mg/kg orally daily (reduced above age 60) for 3 months
  • prednisolone 1 mg/kg daily reduced to 20 mg by week 6
  • rituximab 375 mg/m² weekly for 4 doses if refractory

Genetic counselling and family care. Cascade testing for relatives; offer reproductive options (prenatal and pre-implantation genetic testing) to families who want them; explain inheritance patterns to patients and relatives. Early recognition of carriers allows monitoring and renoprotection.

Monitoring. Creatinine, eGFR and albuminuria every 6 to 12 months (every 3 months when progressing); blood pressure at each visit; yearly audiometry and eye review.

Referral and escalation. Paediatric or adult nephrology with a clinical geneticist; transplant centre when eGFR is under 20 mL/min/1.73 m²; urgent for acute kidney injury, haemoptysis or hypertensive crisis.

Special groups

• Pregnancy: females with X-linked or autosomal recessive disease carry a higher risk of pre-eclampsia, preterm birth and decline in function. Stop ACE inhibitors and angiotensin receptor blockers before conception (use labetalol 100 to 400 mg twice daily or nifedipine modified release 30 to 90 mg daily); aspirin 75 to 150 mg daily from 12 weeks.
• Children: start monitoring at diagnosis, with early treatment for males with severe genotypes; hearing and school support.
• Heterozygous carriers: follow up annually even with isolated haematuria because proteinuria may develop later.