What is Alport syndrome?
Alport syndrome is caused by mutations in genes that code for type IV collagen — a vital structural protein in basement membranes throughout the body. When abnormal, the basement membranes of:
- Kidney glomeruli — leak blood and protein, then scar
- Inner ear — sensorineural hearing loss in teens/20s
- Eye lens — anterior lenticonus (cone-shaped lens)
- Retina — dot-and-fleck retinopathy
Inheritance Patterns
1. X-LINKED (XLAS) — 80% of cases:
- Mutation in COL4A5 (X chromosome)
- Males: severe — almost all reach kidney failure (median age 25 if untreated, 40 with treatment)
- Females: variable — mild haematuria most, but 25-40% reach kidney failure (often later in life)
- Affected men's daughters all carriers; sons unaffected
2. Autosomal Recessive (Aras)
- Mutations in BOTH copies of COL4A3 or COL4A4
- Severe in both sexes — kidney failure in teens-20s
- Parents are carriers (heterozygotes) — often have isolated microscopic haematuria
- 25% recurrence risk in siblings
3. Autosomal Dominant (Adas)
- Single mutation in COL4A3 or COL4A4
- Highly variable — many have only haematuria for life
- Some progress to CKD or kidney failure decades later
- Often previously diagnosed as 'thin basement membrane disease'
- Now recognised as commonest form
UK prevalence: ~1 in 5,000 (probably underdiagnosed).
Symptoms and diagnosis
Kidney
- Microscopic blood in urine from childhood (often the first clue)
- Episodes of visible blood with infections
- Proteinuria develops in adolescence/early adulthood
- High blood pressure
- Slowly progressive CKD
EAR (50-70% of XLAS males):
- Bilateral sensorineural hearing loss
- Starts age 8-15, high frequencies first
- Progressive — most need hearing aids
- Not present at birth
EYE (15-30%):
- Anterior lenticonus (cone-shaped lens — pathognomonic)
- Dot-and-fleck retinopathy
- Posterior polymorphous corneal dystrophy
- Rarely affects vision but useful diagnostic clue
Investigations
- Urine microscopy — dysmorphic red cells
- Urine ACR — proteinuria
- Creatinine, eGFR
- Audiology — high frequency loss
- Ophthalmology — slit lamp for lenticonus
- GENETIC TESTING — now first-line in UK; usually replaces kidney biopsy
- Kidney biopsy if genetic test inconclusive: electron microscopy shows characteristic 'basket-weave' splitting of glomerular basement membrane
- Skin biopsy can confirm X-linked Alport (collagen IV alpha-5 staining)
FAMILY HISTORY: ask about haematuria, deafness, kidney failure in relatives — draw a 3-generation pedigree.
Kidney Vitality is a daily multivitamin developed by a UK Consultant Nephrologist using renal nutrition principles. It contains no added potassium, magnesium, phosphorus or iron, and no herbal blends. See the formulation.
Treatment
Proven Core Treatment
- ACE INHIBITOR (ramipril, lisinopril) or ARB — start when proteinuria appears (or earlier in males with XLAS)
- Delays kidney failure by ~10 years in XLAS males
- Earlier start = better outcome
- Even childhood treatment is now standard (paediatric nephrology)
Add-on
- SGLT2 INHIBITOR (dapagliflozin, empagliflozin) — emerging evidence in genetic CKD; reasonable to use if proteinuria persists
- BP target < 125/75 if proteinuria > 1 g/day
- Salt restriction < 5 g/day
- Avoid NSAIDs lifelong
In Clinical Trials
- Sparsentan (dual endothelin/AT1 antagonist)
- Bardoxolone methyl (Nrf2 activator)
- Lademirsen (anti-miR-21)
- Gene therapy — early research
Non-renal
- Audiology referral once hearing loss detected — most need hearing aids; cochlear implants for severe cases
- Annual ophthalmology review
- Avoid loud noise exposure
- Avoid ototoxic drugs (aminoglycosides, high-dose furosemide)
Dialysis And Transplant
- When CKD progresses to stage 5
- Transplant outcomes excellent — Alport does NOT recur in the donor kidney
- Rare complication: anti-GBM disease in male XLAS recipients (~3%) — antibodies form against normal collagen IV
- Family donors must have genetic testing FIRST — affected relatives should not donate
Family screening and genetics
EVERYONE in the family needs screening when Alport is diagnosed in a relative.
Minimum Screen
- Urine dipstick (blood, protein)
- BP
- Audiology
- Genetic testing offered to all first-degree relatives
Genetic Counselling
- Clinical genetics service referral
- Pedigree analysis
- Discuss reproductive options:
- Natural conception with prenatal testing
- Preimplantation genetic testing (PGT) via IVF — NHS-funded for severe Alport in UK
- Egg/sperm donation
- Adoption
- Carrier women (XLAS) need monitoring even if mild — pregnancy can unmask kidney problems
Special Situations
- PREGNANCY in affected females: needs joint renal-obstetric care; higher BP and proteinuria risk
- CHILDREN of an affected parent: paediatric nephrology referral, screening from age 1
- LIVING DONOR ASSESSMENT: full genetic testing of potential family donors — never use an affected relative
Registries
- UK Alport Syndrome Patient Registry — held at Renal Association
- Patient organisation: Alport UK (alport.org.uk)
Living with Alport syndrome
Daily
- Take ACE inhibitor / ARB without missing doses
- Monitor BP at home
- Hearing aids — life-changing for daily quality of life
- Avoid loud noise (concerts, power tools without ear protection)
- Avoid NSAIDs lifelong
- Stop smoking; manage weight
- Aerobic exercise is encouraged
Monitoring
- 6-12 monthly nephrology review
- Annual audiology
- Annual ophthalmology
- Annual urine ACR, creatinine, eGFR, BP
- Family members in own pathway
Mental Health
- Diagnosis often comes in childhood/adolescence
- Combined hearing loss + progressive kidney disease is challenging
- Peer support via Alport UK very helpful
- Educational support at school
- Disability rights at work — reasonable adjustments
Looking Ahead
- New treatments in trials may transform prognosis for next generation
- Modern transplantation gives normal life expectancy after kidney failure
- Family planning with genetic counselling = informed choices
