Key Facts

IgA nephropathy is a mesangioproliferative glomerulonephritis characterised by IgA deposition in the glomerular mesangium. It has a highly variable course, from benign microscopic haematuria to rapidly progressive glomerulonephritis.

Epidemiology

• Most common primary GN worldwide; accounts for 25-30% of biopsied GN cases
• Peak age: 20-30 years; M:F ratio 2-3:1
• Higher incidence in East Asian and Caucasian populations
• Lower incidence in Afro-Caribbean populations
• UK incidence: approximately 2-3 per 100,000/year

Aetiology

• Genetic predisposition (GWAS studies identify HLA and complement loci)
• Multi-hit hypothesis: abnormal IgA1 glycosylation → autoantibodies against galactose-deficient IgA1 → immune complex formation → mesangial deposition
• Environmental triggers: mucosal infections (URTI, GI)

Pathophysiology

• Defective O-glycosylation of IgA1 in the hinge region (galactose-deficient IgA1)
• Anti-glycan IgG antibodies form immune complexes with galactose-deficient IgA1
• Complexes deposit in the glomerular mesangium → complement activation (lectin pathway) → mesangial proliferation and matrix expansion
• Progressive inflammation → glomerulosclerosis and tubulointerstitial fibrosis
• Crescent formation indicates severe disease with potential for RPGN

Classic Presentation

• Synpharyngitic macroscopic haematuria: painless, dark/cola-coloured urine occurring within 1-2 days of URTI or GI infection
• Episodes last 2-5 days then resolve spontaneously
• Between episodes: persistent microscopic haematuria (most common finding)

Other Presentations

• Asymptomatic microscopic haematuria with or without proteinuria (most common overall)
• Nephrotic syndrome (5-10% of cases)
• RPGN with crescents (rare but serious)
• Chronic renal impairment detected incidentally

Prognostic Indicators

• Proteinuria >1g/day: strongest modifiable risk factor for progression
• eGFR at presentation: lower = worse prognosis
• Hypertension: associated with progression
• Histological findings: crescents, tubular atrophy, interstitial fibrosis

Red Flags

• Rapidly declining eGFR → consider crescentic IgAN → urgent biopsy and immunosuppression
• Nephrotic-range proteinuria → more aggressive disease
• Associated purpura, arthralgia, abdominal pain → IgA vasculitis (HSP)

Bedside

• Urinalysis: haematuria (dipstick positive for blood), proteinuria; urine microscopy for red cell casts
• Blood pressure: hypertension assessment

Bloods

• U&Es: creatinine, eGFR – assess renal function
• Urine PCR: quantify proteinuria
• Serum IgA: elevated in ~50% (but neither sensitive nor specific)
• C3/C4: normal (unlike post-infectious GN)
• FBC, CRP: exclude systemic disease
• Immunology: ANA, ANCA, anti-GBM if indicated

Imaging

• Renal ultrasound: usually normal; assess kidney size

Special Tests

• Renal biopsy: definitive diagnosis
  • Light microscopy: mesangial hypercellularity, +/- crescents
  • Immunofluorescence: granular mesangial IgA deposition (diagnostic; often with C3 co-deposition)
  • Electron microscopy: mesangial electron-dense deposits
• Oxford MEST-C classification applied to biopsy for prognosis

Non-pharmacological

• Supportive care: dietary sodium restriction, weight management
• Fish oil supplementation (omega-3): limited evidence; some studies suggest modest benefit

Pharmacological

First-line (all patients with proteinuria):

• ACE inhibitor (ramipril 2.5-10mg) or ARB (losartan 50-100mg): target proteinuria <0.5g/day and BP <130/80
• Maximise dose and ensure adequate compliance for 3-6 months before considering immunosuppression

SGLT2 inhibitors:

• Dapagliflozin 10mg OD: renoprotection based on DAPA-CKD subgroup data

Immunosuppression (if proteinuria >1g/day despite 3-6 months optimised RAAS blockade):

• Corticosteroids: TESTING trial protocol – methylprednisolone 0.4mg/kg/day (max 32mg) tapering over 6-9 months; STOP-IgAN showed benefit for steroid pulse therapy
• Mycophenolate mofetil: used in some centres, particularly in Asian populations
• Cyclophosphamide + steroids: reserved for crescentic IgAN (treat as RPGN)

Emerging therapies:

• Sparsentan (dual endothelin/angiotensin receptor antagonist): PROTECT trial showed superior proteinuria reduction
• Budesonide (Nefecon/Tarpeyo): targeted-release budesonide to Peyer's patches (NefIgArd trial – 34% reduction in proteinuria)

Referral Criteria

• All suspected IgA nephropathy → nephrology for biopsy consideration
• Persistent proteinuria >0.5g/day despite RAAS blockade
• Declining eGFR
• Crescentic disease or RPGN

• 20-40% progress to ESRD over 20 years
• ~30% have spontaneous remission, particularly those presenting with isolated haematuria
• Proteinuria <0.5g/day after treatment: excellent prognosis (<5% progress to ESRD)
• Proteinuria >1g/day: poor prognosis; 50% progress to ESRD within 10-20 years
• Recurrence rate in transplant: 30-50%, but graft loss from recurrence is only ~5-10%
• Children generally have better prognosis than adults

Oxford MEST-C Classification

IgA Nephropathy vs Post-Streptococcal GN