Alport Syndrome
Summary
Alport syndrome is an inherited disorder of type IV collagen affecting the basement membranes of the kidney, cochlea, and eye. It is caused by mutations in COL4A3, COL4A4 (autosomal), or COL4A5 (X-linked) genes. The classic triad includes progressive renal disease (haematuria progressing to proteinuria and renal failure), sensorineural hearing loss, and characteristic ocular abnormalities (anterior lenticonus). X-linked inheritance accounts for 80% of cases, with affected males progressing to end-stage renal disease (ESRD) by age 25-40. Treatment focuses on ACE inhibition to slow progression and renal transplantation for ESRD.
Key Facts
- Prevalence: 1 in 5000-10,000 live births
- Inheritance: X-linked dominant (80%), autosomal recessive (15%), autosomal dominant (5%)
- Triad: Nephropathy + Sensorineural deafness + Ocular abnormalities
- ESRD timing: Males (X-linked) reach ESRD by 25-40 years
- Key management: ACE inhibitors slow progression; transplantation for ESRD
- Post-transplant risk: 3-5% develop anti-GBM disease
Clinical Pearls
The Hearing Clue: Sensorineural hearing loss in a young male with haematuria should prompt consideration of Alport syndrome. The hearing loss typically affects high frequencies first and is progressive.
X-Linked Pattern: Mothers pass to sons (severe disease) and daughters (carrier/mild). Fathers with X-linked Alport pass to all daughters (carriers) but no sons.
Post-Transplant Anti-GBM: Patients with severe mutations who have never been exposed to normal collagen IV may develop antibodies to the "new" collagen in transplanted kidneys, causing rapidly progressive glomerulonephritis.
Why This Matters Clinically
Alport syndrome is a leading genetic cause of ESRD in young adults. Early diagnosis enables genetic counselling, family screening, and early ACE inhibitor therapy which significantly delays progression to ESRD. Recognition of the multisystem nature prevents delays in audiology and ophthalmology referrals.
Incidence & Prevalence
- Prevalence: 1 in 5000-10,000 live births
- Proportion of ESRD: 2-3% of all ESRD; 10% of children on RRT
- Accounts for: 2.5% of children requiring renal transplantation
Demographics
| Factor | Details |
|---|---|
| Age at presentation | Childhood haematuria; ESRD 25-40 years (X-linked males) |
| Sex | X-linked: Males severely affected; females carriers/mild |
| Ethnicity | All ethnic groups |
| Geography | Worldwide distribution |
Inheritance Patterns
| Pattern | Frequency | Gene(s) | Features |
|---|---|---|---|
| X-linked | 80% | COL4A5 | Males severe; females variable |
| Autosomal recessive | 15% | COL4A3, COL4A4 | Both sexes equally affected |
| Autosomal dominant | 5% | COL4A3, COL4A4 | Milder, later onset |
Mechanism
Step 1: Genetic Mutation
- Mutations in COL4A3, COL4A4 (chromosome 2), or COL4A5 (X chromosome)
- These genes encode α3, α4, and α5 chains of type IV collagen
- Type IV collagen is a major component of basement membranes
Step 2: Abnormal Basement Membrane
- Defective α3α4α5 collagen network cannot form properly
- Replaced by α1α2α1 network (FetalGBM composition)
- This network is less stable and more susceptible to damage
Step 3: Progressive Structural Damage
- Glomerular basement membrane (GBM) shows characteristic changes:
- Initially thin
- Progressive thickening and splitting ("lamellated" or "basket-weave")
- Eventually scarring
- Similar changes in basilar membrane of cochlea
- Lens capsule affected (anterior lenticonus)
Step 4: Clinical Disease
- Kidney: Haematuria → Proteinuria → ESRD
- Ear: Progressive high-frequency sensorineural hearing loss
- Eye: Anterior lenticonus, dot-fleck retinopathy
Classification
| Type | Inheritance | Gene | Clinical Features |
|---|---|---|---|
| X-linked | X-linked dominant | COL4A5 | Males: ESRD 25-40y, deafness 80%, ocular 30% |
| Autosomal recessive | AR | COL4A3/4 homozygous | Severe, similar to X-linked males |
| Autosomal dominant | AD | COL4A3/4 heterozygous | Milder, later ESRD (40-60y) |
Symptoms
Renal:
Auditory:
Ocular:
Signs
Red Flags
[!CAUTION] Red Flags — Urgent assessment required if:
- Rapidly progressive renal failure
- Post-transplant deterioration (possible anti-GBM disease)
- Gross haematuria with AKI
- Sudden hearing loss
Structured Approach
General:
- Blood pressure
- Volume status (oedema)
- Signs of chronic kidney disease
Renal:
- Dipstick urinalysis (haematuria, proteinuria)
- Check for oedema
Auditory:
- Otoscopy (usually normal)
- Rinne and Weber tests (sensorineural pattern)
- Formal audiometry needed
Ophthalmology:
- Slit-lamp examination for anterior lenticonus
- Fundoscopy for dot-fleck retinopathy
Special Tests
| Test | Technique | Positive Finding | Purpose |
|---|---|---|---|
| Urinalysis | Dipstick, microscopy | Persistent haematuria ± proteinuria | Renal involvement |
| Audiometry | Pure tone audiometry | High-frequency SNHL | Hearing assessment |
| Slit-lamp exam | Ophthalmology referral | Anterior lenticonus (oil droplet sign) | Ocular manifestation |
First-Line
- Urinalysis — Haematuria (often from childhood)
- Urine protein:creatinine ratio — Quantify proteinuria
- Renal function — Creatinine, eGFR
Laboratory Tests
| Test | Expected Finding | Purpose |
|---|---|---|
| U&Es | Elevated creatinine (progressive) | Monitor renal function |
| FBC | Normocytic anaemia (CKD) | CKD assessment |
| Urine ACR | Elevated | Proteinuria quantification |
| Serum albumin | May be low (nephrotic syndrome) | Assess proteinuria severity |
Genetic Testing
- Gold standard for diagnosis
- Identifies COL4A3/COL4A4/COL4A5 mutations
- Enables family screening and genetic counselling
Renal Biopsy
| Finding | Description |
|---|---|
| Light microscopy | Non-specific glomerulosclerosis (late stages) |
| Electron microscopy | Characteristic: Lamellated, "basket-weave" GBM with variable thickness |
| Immunofluorescence | Absent α5 chain staining (X-linked) |
Imaging
| Modality | Findings | Indication |
|---|---|---|
| Renal ultrasound | Small kidneys in advanced disease | Baseline, monitor |
| Audiometry | High-frequency SNHL | All patients |
| Ophthalmology | Anterior lenticonus, retinopathy | All patients |
Management Algorithm
ALPORT SYNDROME
↓
┌─────────────────────────────────────────┐
│ CONFIRM DIAGNOSIS │
│ Genetic testing (gold standard) │
│ Biopsy if diagnosis uncertain │
└─────────────────────────────────────────┘
↓
┌─────────────────────────────────────────┐
│ FAMILY SCREENING │
│ Genetic testing of at-risk relatives │
│ Urinalysis, audiometry │
└─────────────────────────────────────────┘
↓
┌─────────────────────────────────────────┐
│ RENOPROTECTION │
│ ACE inhibitor (start at diagnosis) │
│ ARB if ACE intolerant │
│ BP target < 130/80 │
└─────────────────────────────────────────┘
↓
┌─────────────────────────────────────────┐
│ MULTIDISCIPLINARY CARE │
│ Nephrology, Audiology, Ophthalmology │
│ Genetic counselling │
└─────────────────────────────────────────┘
↓
┌─────────────────────────────────────────┐
│ END-STAGE MANAGEMENT │
│ Dialysis or transplantation │
│ Monitor for anti-GBM disease │
└─────────────────────────────────────────┘
Conservative Management
- Low sodium diet
- Avoid nephrotoxic drugs (NSAIDs, aminoglycosides)
- Hearing aids for SNHL
- Corrective lenses for lenticonus if vision affected
Medical Management
| Drug Class | Drug | Dose | Purpose |
|---|---|---|---|
| ACE inhibitor | Ramipril | Titrate to max tolerated | Delay ESRD by years |
| ARB | Losartan | If ACE intolerant | Alternative |
| Statin | Atorvastatin | CVD risk reduction | CKD management |
Key Evidence:
- Early ACE inhibitors delay ESRD by ~10 years in X-linked males
- Should be started at first sign of proteinuria (even microalbuminuria)
Surgical Management
Renal Transplantation:
- Treatment of choice for ESRD
- Excellent outcomes (similar to other causes of ESRD)
- Post-transplant anti-GBM disease: 3-5% of transplanted patients
- Usually occurs within first year
- More common with large deletions/truncating mutations
- Treat with plasmapheresis, immunosuppression
Audiology:
- Hearing aids
- Cochlear implants for severe cases
Ophthalmology:
- Lensectomy with IOL for symptomatic lenticonus
Disposition
- Refer: All patients to nephrology, audiology, ophthalmology
- Genetic counselling: Essential for all families
- Follow-up: 3-6 monthly renal function, annual audiology/ophthalmology
Renal Complications
| Complication | Incidence | Presentation | Management |
|---|---|---|---|
| ESRD | 100% (X-linked males) | Progressive renal failure | RRT, transplant |
| Hypertension | 80% | Elevated BP | ACEi/ARB, lifestyle |
| Post-transplant anti-GBM | 3-5% | Rapid graft dysfunction | Plasmapheresis |
Extra-Renal Complications
- Sensorineural hearing loss (60-80%)
- Anterior lenticonus (15-20%)
- Macular fleck retinopathy (variable)
Natural History
- X-linked males: ESRD by 25-40 years (mean 25y for truncating mutations)
- X-linked females: Variable; 15-30% reach ESRD by age 60
- Autosomal recessive: ESRD by 20-30 years
- Autosomal dominant: ESRD by 40-60 years
Outcomes with Treatment
| Variable | Outcome |
|---|---|
| ACE inhibitors (early) | Delay ESRD by ~10 years |
| Transplant survival | Comparable to other causes |
| Post-transplant anti-GBM | 3-5%; treatable if caught early |
Prognostic Factors
Good Prognosis:
- Female (X-linked carrier)
- Later onset proteinuria
- Early ACE inhibitor use
- Autosomal dominant form
Poor Prognosis:
- Male (X-linked)
- Large/truncating COL4A5 mutation
- Early heavy proteinuria
- Co-existing hearing loss by age 15
Key Guidelines
- KDIGO Clinical Practice Guideline — Glomerulonephritis (includes Alport).
- Alport Syndrome Foundation Guidelines — alportsyndrome.org
- European Alport Therapy Registry — Treatment recommendations.
Landmark Studies
Gross et al. (2012) — Early ACE inhibition in Alport syndrome
- Retrospective cohort
- Key finding: ACE inhibitors delayed ESRD by median 10 years
- Clinical Impact: Supports very early treatment (even with microalbuminuria)
EARLY PRO-TECT Alport Trial (ongoing) — Prospective early treatment
- Assessing ramipril in children before proteinuria develops
- Clinical Impact: May change treatment paradigm to start even earlier
Evidence Strength
| Intervention | Level | Key Evidence |
|---|---|---|
| ACE inhibitors | 2a | Retrospective studies, strong signal |
| Transplantation | 2a | Registry data |
| Genetic testing | Expert consensus | Standard of care |
What is Alport Syndrome?
Alport syndrome is a genetic condition that affects the filters in your kidneys, your hearing, and sometimes your eyes. It happens because of a problem with a protein called collagen, which is an important building block of these organs.
Why does it matter?
Without treatment, Alport syndrome leads to kidney failure, usually in young adulthood for males with the X-linked form. Many people also develop hearing loss. The good news is that with early treatment (a blood pressure tablet called an ACE inhibitor), kidney failure can be delayed by many years.
How is it treated?
- Blood pressure tablets (ACE inhibitors): Starting these early — even before obvious kidney problems — can delay kidney failure by about 10 years.
- Regular monitoring: Blood tests and urine tests to track kidney function.
- Hearing aids: If hearing loss develops.
- Kidney transplant: If kidneys do fail, a transplant works very well for people with Alport syndrome.
What to expect
- Regular check-ups with kidney doctors, hearing specialists, and eye doctors
- Blood pressure tablets are usually needed lifelong
- Family members should be tested since it runs in families
- With good care, quality of life can be excellent
When to seek help
See your doctor if you:
- Notice blood in your urine
- Have increasing leg swelling or feel very tired
- Notice your hearing is getting worse
- Have a family history of Alport syndrome and haven't been tested
Primary Guidelines
- Savige J, et al. Expert guidelines for the management of Alport syndrome and thin basement membrane nephropathy. J Am Soc Nephrol. 2013;24(3):364-75. PMID: 23349312
Key Studies
- Gross O, et al. Early angiotensin-converting enzyme inhibition in Alport syndrome delays renal failure and improves life expectancy. Kidney Int. 2012;81(5):494-501. PMID: 22166847
- Kruegel J, et al. Alport syndrome: the paradigm of a genetic disease affecting kidney function and structure. Nephrol Dial Transplant. 2013;28(12):2891-8. PMID: 23969471
Further Resources
- Alport Syndrome Foundation: alportsyndrome.org
- Kidney Research UK: kidneyresearchuk.org
- Genetic Alliance UK: geneticalliance.org.uk
Last Reviewed: 2025-12-24 | MedVellum Editorial Team
Medical Disclaimer: MedVellum content is for educational purposes and clinical reference. Clinical decisions should account for individual patient circumstances. Always consult appropriate specialists.