NephrologyTier 2Disease (DEADMAN)

Inherited and genetic renal disease - Alport syndrome

Description

Hereditary type IV collagen disease - defective alpha3/alpha4/alpha5(IV) heterotrimer of the GBM, cochlea and lens capsule
Triad: persistent glomerular haematuria -> proteinuria -> progressive CKD, plus sensorineural hearing loss and ocular abnormalities

Genotypes - now the classification

Form	Gene	Share	Course
X-linked	COL4A5	~65-80%	Males: near-universal ESKD. Females: variable, ~15-30% ESKD by 60
Autosomal recessive	Biallelic COL4A3/COL4A4	~15%	Severe in both sexes, ESKD typically <30 y
Autosomal dominant	Heterozygous COL4A3/COL4A4	~20% of "familial haematuria"	*Formerly called thin basement membrane nephropathy / benign familial haematuria - it is NOT reliably benign*
Digenic	COL4A3 + COL4A4	Rare	Intermediate

"Thin basement membrane nephropathy" has been retired as a benign label - ~1 in 5 develop CKD, and these are heterozygous carriers of an Alport gene

Commonest inherited glomerular disease; ~1 in 50,000 for classic X-linked Alport
- Heterozygous COL4A3/A4 variants are far commoner - ~1 in 100 in population databases
~1-2% of prevalent ESKD, but ~10-15% of paediatric/young-adult ESKD
No sex difference in gene frequency; phenotype far worse in X-linked males

Normal mature GBM switches from alpha1.alpha1.alpha2(IV) to alpha3.alpha4.alpha5(IV) during development
- This mature network is crosslinked and protease-resistant -> mechanical durability
Loss of any one chain -> the whole heterotrimer fails to assemble -> a COL4A5 defect removes alpha3 and alpha4 from the GBM as well
Persistence of the immature alpha1.alpha1.alpha2 network -> thin, protease-susceptible GBM
- Progressive splitting, lamellation and thickening -> podocyte stress -> proteinuria -> glomerulosclerosis and tubulointerstitial fibrosis
Same collagen in cochlear basilar membrane (SNHL) and lens capsule (lenticonus)

Genotype-phenotype in XL males

Large deletions, nonsense, frameshift -> ESKD ~median 20-25 y
Missense (esp. glycine substitutions) -> ESKD ~median 30-40 y
Position and type of variant is the strongest prognostic tool available at diagnosis

Clinical clues

Persistent microscopic haematuria from childhood (universal in XL males; ~95% of XL females)
- Episodic macroscopic haematuria with intercurrent infection in children
Bilateral high-frequency sensorineural hearing loss - never congenital; appears late childhood/adolescence
Ocular
- Anterior lenticonus - pathognomonic (~15-20%, XL males)
- Dot-and-fleck retinopathy - commonest ocular sign
- Posterior polymorphous corneal dystrophy, recurrent corneal erosion
Family history of haematuria or ESKD - absent in ~10-15% (de novo variants)

Testing

A. Genetic testing is now FIRST-LINE - NGS panel covering COL4A3/COL4A4/COL4A5
- Replaces biopsy in most; establishes inheritance mode, prognosis and family screening
B. Renal biopsy - if genetics negative/uninformative
- EM is the diagnostic modality: GBM thinning early -> irregular thickening, lamellation and "basket-weave" splitting later
- IF: absent alpha3/alpha4/alpha5(IV) staining (mosaic in XL females)
C. Skin biopsy - absent alpha5(IV) in epidermal basement membrane in XL males; normal result does not exclude
Audiometry and ophthalmology review at diagnosis and periodically
Urine ACR + eGFR - the variables that drive treatment

Steroid-resistant nephrotic syndrome or "FSGS" in a young person with haematuria: sequence COL4A3/4/5 before immunosuppressing**

1. Nephroprotection - start EARLY, before proteinuria if the genotype is high risk

ACE inhibitor (ramipril) is the cornerstone - earlier initiation delays ESKD by years; strongest evidence for ACEi over ARB
- Start at: onset of microalbuminuria in XL males/AR disease, or from diagnosis in high-risk genotypes
- ARB if ACEi intolerant
SGLT2 inhibitor - add in adults with CKD G2A3 or worse (or G3-G4 with albuminuria) despite RAS blockade
- No paediatric data - not recommended in children
Blood pressure control, salt restriction
Avoid nephrotoxins - NSAIDs, aminoglycosides
*Immunosuppression has no role* - the lesion is structural, not immune

2. Extrarenal

Hearing aids - audiology from mid-childhood; the loss is not preventable
Ophthalmology - lenticonus may need lens replacement
Screen for aortic root/thoracic aneurysm in AR disease and males with large COL4A5 deletions

3. ESKD and transplantation

Transplantation is the treatment of choice - excellent graft outcomes
*Anti-GBM disease in the allograft (Alport post-transplant nephritis) - ~2-5%, almost exclusively XL males with large deletions/null variants*
- Recipient has never been tolerised to alpha3/alpha5(IV) -> allograft GBM is foreign
- Presents in the first year, usually causes graft loss; recurrence in a second graft is very high
*Do not use an affected or carrier family member as a living donor* - screen all potential related donors genetically

4. Family

Genetic counselling and cascade testing - X-linked, AR and AD each carry different recurrence risks
Screen all first-degree relatives with urinalysis + ACR; carrier females need lifelong surveillance, not reassurance

Sensorineural hearing loss (~80-90% XL males by adulthood)
Anterior lenticonus, dot-and-fleck retinopathy, posterior polymorphous corneal dystrophy
Leiomyomatosis - oesophageal, tracheobronchial, genital; contiguous COL4A5-COL4A6 deletion
AMME complex - Alport, Mental retardation, Midface hypoplasia, Elliptocytosis (Xq22 contiguous deletion)
Thoracic aortic aneurysm/dissection (autosomal forms)
Anti-GBM disease post-transplant
Thin basement membrane nephropathy in relatives (heterozygous carriers)

Haematuria (childhood) -> microalbuminuria (adolescence) -> overt proteinuria -> hypertension -> ESKD
XL males: >90% ESKD by 40, earlier with truncating variants
XL females: ~15-30% ESKD by 60; pregnancy, obesity and proteinuria worsen the trajectory - carrier status is not benign
AR disease: ESKD usually before 30, both sexes
AD (heterozygous COL4A3/4): ~15-20% reach CKD; risk raised by proteinuria, hypertension, obesity and coincident nephropathy
Deafness parallels but does not predict renal decline
Early ACEi shifts median age at ESKD substantially - the single most important intervention, and the reason to diagnose in childhood

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