Key Facts

Alport syndrome results from defective type IV collagen in basement membranes of kidneys, cochlea, and eyes. Early ACEi therapy significantly delays ESRD.

Epidemiology

• Incidence: 1 in 5,000-10,000
• Accounts for 1-2% of ESRD
• X-linked (80%): COL4A5 mutations; affects males severely
• Autosomal recessive (15%): COL4A3/4 mutations; both sexes equally
• Autosomal dominant (5%): milder, later onset

Aetiology

• Mutations in alpha-3, alpha-4, or alpha-5 chains of type IV collagen
• These chains form the collagen IV network of GBM, cochlear basement membrane, and lens capsule
• X-linked: hemizygous males have no functional alpha-5(IV) collagen; heterozygous females have mosaic expression

Pathophysiology

• Defective collagen IV → structurally abnormal GBM
• GBM initially thin (childhood) → progressive thickening, splitting, and lamellation (basket-weave)
• Secondary FSGS develops as disease progresses
• Absence of alpha-3/4/5(IV) collagen network from GBM confirmed on immunohistochemistry
• Cochlear basement membrane abnormalities → progressive sensorineural hearing loss

Renal

• Persistent microscopic haematuria from early childhood (often from birth in males)
• Episodic macroscopic haematuria (often with infections)
• Progressive proteinuria developing in adolescence/early adulthood
• Hypertension as CKD develops
• ESRD: X-linked males by age 20-30; autosomal recessive by 20-30; X-linked females variable (10-15% ESRD)

Hearing

• Bilateral sensorineural hearing loss: high-frequency initially, progressive
• Develops in late childhood/adolescence
• Not present at birth (unlike congenital deafness)
• Affects 80% of X-linked males

Ocular

• Anterior lenticonus: pathognomonic (cone-shaped lens protrusion); 25-40% of X-linked males
• Dot-and-fleck retinopathy: perimacular region
• Posterior polymorphous corneal dystrophy

Red Flags

• Family history of haematuria + deafness + early renal failure → strong suspicion
• Young male with unexplained haematuria → consider Alport
• Proteinuria developing in childhood with haematuria → initiate ACEi

Bloods

• U&Es: eGFR, creatinine
• Urine ACR/PCR: quantify proteinuria
• Urinalysis: persistent haematuria
• Audiometry: bilateral high-frequency sensorineural hearing loss

Imaging

• Renal USS: normal initially; may become small in advanced disease
• Slit-lamp examination: anterior lenticonus, retinal flecks

Special Tests

• Genetic testing: now first-line for diagnosis (NGS panels for COL4A3/4/5)
• Renal biopsy (if genetic testing inconclusive):
  • EM: GBM thickening, thinning, splitting with basket-weave lamellation (pathognomonic)
  • IF: absence of alpha-5(IV) collagen staining in GBM (X-linked males)
  • Skin biopsy: absence of alpha-5(IV) in epidermal basement membrane (non-invasive alternative for X-linked)
• Family screening: urinalysis, audiometry, and genetic testing for at-risk relatives

Non-pharmacological

• Genetic counselling: essential for family planning
• Hearing aids: for sensorineural hearing loss
• Regular ophthalmology review: monitor for lens abnormalities

Pharmacological

• ACE inhibitors (ramipril): started at first sign of proteinuria (even in childhood)
  • EARLY-PROTECT trial: ACEi in children with haematuria-only delays proteinuria onset
  • Significantly delays progression to ESRD by years to decades
• ARBs: alternative if ACEi intolerant
• BP control: target <130/80 in adults
• Standard CKD management: as disease progresses (anaemia, bone disease, etc.)

Renal Replacement Therapy

• Transplantation: treatment of choice for ESRD
• Risk of anti-GBM disease in transplant (~3-5%): recipient develops antibodies against "normal" alpha-3/4/5(IV) collagen in the allograft
• Patients should be counselled about this risk
• Living related donors: must be screened genetically (heterozygous females may be carriers)

Referral Criteria

• All suspected Alport syndrome → paediatric/adult nephrology + clinical genetics
• Hearing loss → audiology/ENT
• Ocular symptoms → ophthalmology

• X-linked males: ESRD by age 20-30 without treatment; ACEi can delay ESRD by 10-15 years
• X-linked females (carriers): 10-15% develop ESRD (usually later in life); variable severity
• Autosomal recessive: ESRD by age 20-30 (both sexes equally affected)
• Autosomal dominant: later onset, ESRD uncommon before age 50
• Post-transplant anti-GBM disease: 3-5% of X-linked males; usually early post-transplant
• Hearing loss: progressive but does not improve with renal transplantation

Alport Syndrome Genetics

Thin Basement Membrane Disease vs Alport Syndrome