IgA nephropathy
Description
- Mesangial deposition of galactose-deficient IgA1 immune complexes -> mesangial proliferation and glomerular injury
- The most common primary chronic glomerular disease worldwide
- IgA vasculitis (Henoch-Schonlein purpura) is the systemic form - identical renal histology plus purpura, arthritis and abdominal pain
The classic presentation
- Synpharyngitic macroscopic haematuria - gross haematuria within 1-3 days of a mucosal infection (URTI, gastroenteritis)
- *This is the discriminator from PSGN, which has a 10-21 day latency and a low C3*
- Or asymptomatic microscopic haematuria + proteinuria on screening
- Complement is normal despite the immune-complex mechanism
Epidemiology
- Commonest GN worldwide; up to 40% of biopsies in East Asia, ~20-30% in Australia and Europe, low in African ancestry
- Peak 2nd-4th decade; M:F ~2:1 in Western populations
- Prevalence partly reflects biopsy policy - Japan screens urine at school, so mild disease is detected
- A leading cause of ESKD in young adults
Aetiopathogenesis
The four-hit hypothesis
- Hit 1 - inc circulating galactose-deficient IgA1 (Gd-IgA1), produced by mucosal-type plasma cells (gut-associated lymphoid tissue, Peyer patches)
- Hit 2 - IgG (and IgA) autoantibodies against the exposed hinge-region GalNAc epitope
- Hit 3 - formation of circulating Gd-IgA1 immune complexes
- Hit 4 - mesangial deposition -> mesangial cell proliferation, cytokine release, alternative and lectin complement pathway activation -> glomerular injury
- APRIL and BAFF drive the mucosal plasma cells making Gd-IgA1 - the target of the newest therapies
- Gut mucosal immunity is central - hence the response to ileal-release budesonide and the association with coeliac disease and IBD
Secondary IgA deposition
- Cirrhosis/portal hypertension (commonest secondary form - impaired hepatic IgA clearance)
- Coeliac disease, IBD, HIV, ankylosing spondylitis, psoriasis, dermatitis herpetiformis
- Staphylococcal infection-related IgA-dominant GN in diabetics is a different disease with low C3
Diagnosis
Presentation
- Synpharyngitic macroscopic haematuria (~40-50%) - painless, resolves in days
- Asymptomatic microscopic haematuria + proteinuria (~30-40%)
- Nephrotic syndrome (~5%), RPGN/crescentic (~5%), or established CKD/hypertension
- Loin pain in some (loin pain-haematuria syndrome)
Bloods and urine
- Dysmorphic RBCs, RBC casts; UPCR variable
- Serum IgA raised in ~50% - neither sensitive nor specific, do not rely on it
- C3 and C4 normal - the finding that separates it from PSGN and lupus
Biopsy - the only way to diagnose it
- IF: dominant or co-dominant mesangial IgA (+ C3, often IgG/IgM)
- LM: mesangial hypercellularity and matrix expansion; segmental sclerosis, crescents in severe disease
- EM: mesangial (and sometimes subendothelial) electron-dense deposits
Oxford MEST-C score - report on every biopsy
| Lesion | Significance | |
|---|---|---|
| M | Mesangial hypercellularity (>0.5) | Progression |
| E | Endocapillary hypercellularity | May respond to immunosuppression |
| S | Segmental sclerosis | Progression; podocytopathy |
| T | Tubular atrophy/interstitial fibrosis | Strongest predictor of ESKD |
| C | Crescents (C0/C1/C2) | Rapid progression |
Risk prediction
- International IgAN Prediction Tool - combines MEST-C with eGFR, proteinuria, BP, age, ethnicity and treatment -> quantified risk of 50% eGFR decline or ESKD
- Proteinuria >0.5-1 g/day is the strongest modifiable predictor - time-averaged proteinuria over follow-up matters more than the presenting value
Management
KDIGO 2025 gave IgA nephropathy its own guideline. Two changes to know: simultaneous rather than sequential therapy, and much tighter proteinuria targets.
Treatment targets
- Proteinuria <0.5 g/day, ideally <0.3 g/day
- eGFR decline <1 mL/min/1.73m2 per year
- BP <120 systolic (standardised)
A. Supportive - every patient
- RASi (ACEi or ARB) at the maximally tolerated dose in everyone, regardless of blood pressure (1B)
- SGLT2i - add for persistent proteinuria, particularly high-risk patients (DAPA-CKD and EMPA-KIDNEY non-diabetic CKD data)
- Sodium restriction <2 g/day, smoking cessation, weight, cardiovascular risk
- *The old approach of 3-6 months of RASi alone before considering anything else has been abandoned - start disease-modifying therapy alongside supportive care in high-risk patients*
B. Persisting high risk despite optimised supportive care (proteinuria >0.75-1 g/day)
- Targeted-release budesonide (Nefecon) 16 mg daily for 9 months (2B)
- Ileal release -> acts on Peyer patch B cells producing Gd-IgA1; largely first-pass metabolised, so limited systemic steroid exposure (NefIgArd)
- If unavailable: systemic corticosteroids - methylprednisolone 0.4 mg/kg/day for 2 months, then reduce by 4 mg/day monthly (6-9 months total)
- *High-dose corticosteroids cause serious infection (TESTING: excess serious adverse events at full dose) - use the reduced-dose regimen, with PJP prophylaxis, and avoid if eGFR <30, diabetes, obesity, active infection*
- Sparsentan (dual endothelin-A and AT1 receptor antagonist) - replaces the RASi
- PROTECT: proteinuria -49.8% vs -15% with irbesartan; slower eGFR decline (-6.1 vs -9.9 mL/min/1.73m2)
- Monitor LFTs and fluid retention
C. Special situations
- Crescentic IgAN with rapidly rising creatinine -> treat as RPGN: pulsed corticosteroid + cyclophosphamide
- Nephrotic syndrome with diffuse foot process effacement -> treat as minimal change disease (steroid-responsive podocytopathy)
- IgA vasculitis with severe extrarenal disease -> corticosteroids
- Secondary IgAN -> treat the cause (cirrhosis, coeliac, IBD, HIV)
- *Tonsillectomy is used in Japan; not recommended outside that setting*
- Fish oil: weak and inconsistent evidence
D. On the horizon
- APRIL/BAFF inhibitors (sibeprenlimab, atacicept, telitacicept), complement inhibitors (iptacopan - factor B; narsoplimab - MASP-2; ravulizumab), atrasentan
- The guideline explicitly anticipates practice moving beyond it
Monitoring
- eGFR, UPCR, BP 3-6 monthly; re-risk-stratify with the prediction tool
Associations
- Cirrhosis and portal hypertension - commonest secondary cause
- Coeliac disease, IBD (Crohn > UC), dermatitis herpetiformis - shared gut mucosal immunity
- Ankylosing spondylitis, psoriasis, reactive arthritis, HIV
- IgA vasculitis (HSP) - the systemic form; purpura, arthritis, abdominal pain, identical renal lesion
- Alcoholic liver disease, chronic respiratory disease
- Familial clustering in ~5-10%; GWAS loci in MHC, complement factor H (CFHR3-1 deletion is protective), and mucosal immunity genes
- Malignancy (rare paraneoplastic association)
Natural history & complications
- Slowly progressive: ~20-40% reach ESKD at 20 years - a benign-looking disease with a bad long-term outcome
- Highly variable: some remit entirely, some progress in <5 years
- Recurs in ~30% of transplants and causes graft loss in ~5-10%; recurrence risk higher with rapid native ESKD and living related donors
Poor prognostic factors
- Persistent proteinuria >1 g/day - the strongest modifiable predictor (time-averaged)
- eGFR at presentation and the slope
- Hypertension
- Tubular atrophy/interstitial fibrosis (T score) - the strongest histological predictor; crescents (C score)
- Male sex, obesity, hyperuricaemia
Good prognostic factors
- Isolated recurrent macroscopic haematuria with normal eGFR, no hypertension and proteinuria <0.5 g/day
- These patients need surveillance only - annual BP, eGFR and UPCR - not treatment
Complications
- AKI during an episode of macroscopic haematuria - tubular injury from red cell casts; usually recovers
- Crescentic transformation; malignant hypertension
- Progressive CKD, cardiovascular disease
- Corticosteroid-related infection - the main treatment harm, and the reason for targeted-release budesonide
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