IgA Nephropathy (Berger's Disease)

Overview

IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide, particularly prevalent in Asia (accounting for >45% of primary glomerular diseases in Chinese biopsy registries). It predominantly affects males over females (2:1 to 3:1 in White populations; near 1:1 in Asian populations), most commonly in the second to third decade of life. - Comprehensive Clinical Nephrology, 7th Ed.

Pathogenesis - The "Four-Hit" Model

The pathogenesis follows a well-established sequence: - Brenner & Rector's The Kidney

Hit 1 - Aberrant IgA1 glycosylation: B cells (especially mucosal) produce galactose-deficient IgA1 (Gd-IgA1) - the hinge-region O-linked glycans lack galactose and instead carry N-acetylgalactosamine, making the molecule immunogenic.
Hit 2 - Autoantibody formation: IgG and IgA autoantibodies recognize the exposed N-acetylgalactosamine on Gd-IgA1 as "foreign" and form immune complexes.
Hit 3 - Immune complex deposition: These large polymeric complexes deposit in the glomerular mesangium (they cannot be cleared efficiently by the liver in patients with liver disease, worsening the condition).
Hit 4 - Mesangial injury: Deposited complexes activate complement (predominantly via the alternative and lectin pathways - classical pathway components C1q/C4 are typically absent) and trigger mesangial cell proliferation, cytokine/chemokine overproduction, and progressive fibrosis.

Genetic factors: GWAS studies identify susceptibility loci in MHC, the DEFA gene cluster, and the alternative complement pathway. Familial IgAN variants have been found in DEFA4, MYCT1, CARD8, and ZNF543. More than 25% of blood relatives have elevated serum Gd-IgA1 levels.

Why mucosal infections trigger attacks: Infections increase mucosal IgA production, driving surges in Gd-IgA1 and immune complex formation - hence the "synpharyngitic hematuria" pattern.

Clinical Presentations

No single presentation is pathognomonic. The three main patterns are: - Comprehensive Clinical Nephrology, 7th Ed., p. 333

Presentation	Frequency	Features
Episodic macroscopic hematuria	40-50%	Brown urine (rarely red), loin pain, onset within 24 hours of mucosal infection (vs. 2-3 week delay in poststreptococcal GN)
Asymptomatic micro-hematuria ± proteinuria	30-40%	Detected on screening; proteinuria usually <2 g/24 h
Nephrotic/nephritic syndrome, hypertension, CKD	Less common	Older patients; worse prognosis

Macroscopic hematuria episodes typically resolve spontaneously over days; microscopic hematuria persists between attacks. Episodes may be accompanied by acute kidney injury from tubular injury, which is usually reversible.

Histology (Renal Biopsy - Required for Diagnosis)

Light microscopy: Ranges from normal to mesangial widening/hypercellularity, focal proliferative GN, diffuse mesangioproliferative GN, or (rarely) crescentic GN.

Immunofluorescence: Dominant mesangial IgA deposits (often with C3, properdin, and smaller amounts of IgG or IgM). C1q is absent. This is the diagnostic hallmark.

Electron microscopy: Electron-dense deposits in the mesangium.

IgA Nephropathy histology: (A) Light microscopy showing mesangial proliferation; (B) Immunofluorescence showing bright IgA deposits in mesangial regions

Fig. 12.12 - Robbins Basic Pathology: (A) mesangial proliferation on H&E; (B) characteristic IgA deposition (yellow/green) in mesangium on immunofluorescence.

Oxford (MEST-C) Classification (2009, updated 2016)

Biopsy scored on five features to predict progression risk: - Comprehensive Clinical Nephrology, 7th Ed.

Score	Feature	Categories
M	Mesangial hypercellularity	M0 / M1
E	Endocapillary hypercellularity	E0 / E1
S	Segmental glomerulosclerosis	S0 / S1
T	Tubular atrophy / interstitial fibrosis	T0 / T1 / T2
C	Crescents	C0 / C1 / C2

Higher T and C scores correlate strongly with worse renal outcomes.

Prognosis

~30-40% of patients reach ESRD within 20-30 years
If diagnosed very early: only ~5% develop CKD stage 4-5 at 20 years
In typical presentations: ~25% ESRD + further 20% significant GFR decline at 20 years
A Swedish study found patients with IgAN die ~6 years earlier than the general population, mostly from cardiovascular causes

Adverse prognostic markers (Box 24.2, CCN): hypertension, proteinuria >1 g/day, reduced eGFR at biopsy, older age, high MEST-C scores, male sex.

Associated Conditions

IgAN can be secondary to: - Comprehensive Clinical Nephrology, 7th Ed., p. 333

Rheumatic/autoimmune: Ankylosing spondylitis, rheumatoid arthritis, Reiter syndrome, uveitis
GI: Celiac disease, ulcerative colitis, Crohn's disease, Whipple disease
Hepatic: Alcoholic liver disease, nonalcoholic cirrhosis (impaired hepatic clearance of IgA complexes)
Skin: Dermatitis herpetiformis
IgA vasculitis (Henoch-Schonlein Purpura): Systemic counterpart with identical renal lesion plus rash, arthritis, GI involvement

Treatment

Supportive (All Patients)

RAS blockade (ACEi or ARB): First-line for proteinuria >0.5 g/day and/or hypertension; target BP <130/80 mmHg; aim to reduce proteinuria to <1 g/day (or <0.5 g/day if possible)
Optimized BP control
Fish oil (omega-3): Modest evidence; used in some centers
Tonsillectomy: Practiced widely in Japan; evidence remains limited

Immunosuppression (High-Risk Patients)

Corticosteroids: Used in patients with proteinuria >1 g/day despite optimized RAS blockade and eGFR >30 mL/min/1.73m². The TESTING trial showed benefits but also serious infection risk.
Targeted-release budesonide (TRF-budesonide / Nefecon): Delivers budesonide to the ileum (the primary site of aberrant IgA production). A 2025 meta-analysis (PMID 40721561) confirms efficacy and safety in IgAN treatment, with reduced systemic side effects versus systemic steroids.
Sparsentan: Dual endothelin/angiotensin receptor antagonist. A 2024 systematic review and meta-analysis (PMID 39333921) confirmed safety and efficacy versus irbesartan in IgAN.
A 2025 network meta-analysis (PMID 40606442) comparing multiple agents for IgAN found significant antiproteinuric effects from several newer targeted therapies.

Emerging/Novel Agents

Complement inhibitors (anti-C5, anti-factor B, anti-MASP-2): Targeting the alternative/lectin complement pathway
Atacicept, blisibimod: Anti-BAFF/APRIL agents targeting B-cell IgA production
Iptacopan: Factor B inhibitor

ESRD

Renal replacement therapy; IgAN recurs in ~30% of transplants (usually mild)

Key Differentials

Poststreptococcal GN: Hematuria 2-3 weeks after infection (vs. concurrent in IgAN); low C3; resolves completely
Thin basement membrane disease: Persistent micro-hematuria, family history, normal IgA on IF
IgA vasculitis: Systemic features (rash, joint, GI); identical renal pathology
Alport syndrome: X-linked, thinning/splitting of GBM on EM, family history of renal failure/deafness

Sources: Robbins & Kumar Basic Pathology (p. 512-513) | Comprehensive Clinical Nephrology, 7th Ed. (pp. 333-336) | Brenner & Rector's The Kidney (p. 3378) | Recent meta-analyses: PMIDs 39333921, 40606442, 40721561

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