IgA Nephropathy (IgAN) - Comprehensive Long Note

Definition and Overview

• Comprehensive Clinical Nephrology, 7th Edition, p. 331
• NKF Primer on Kidney Diseases, 8e, p. 3054
• Robbins & Kumar Basic Pathology, p. 512

Epidemiology

• Comprehensive Clinical Nephrology, 7th Edition, p. 332

Pathogenesis - The "Four-Hit" Model

Hit 1: Elevated Galactose-Deficient IgA1 (Gd-IgA1)

• IgA1 carries O-linked sugars at its hinge region. In IgAN, these are enriched in galactose-deficient IgA1 (gd-IgA1) - where N-acetylgalactosamine is exposed instead of being capped by galactose.
• Excess mucosal IgA1 enters the systemic circulation - either directly from the mucosa-associated lymphoid tissue (MALT) or after translocation of mucosal lymphocytes to the bone marrow.
• Gd-IgA1 is elevated in >90% of patients but is also found in unaffected relatives, confirming it is necessary but not sufficient.

Hit 2: Production of Autoantibodies Against Gd-IgA1

• IgA and IgG autoantibodies form against the exposed N-acetylgalactosamine (GalNAc) residues of gd-IgA1, recognizing it as "foreign."
• These are typically cross-reactive against antigens from microorganisms involved in upper respiratory/gastrointestinal infections (explaining the synpharyngitic hematuria).

Hit 3: Formation and Deposition of Immune Complexes

• Circulating IgA1-anti-IgA1 immune complexes form, which then deposit in the mesangium.
• Deposition may also result from altered IgA1 interactions with matrix proteins, mesangial cell/monocyte Fc receptors (FcαRI), and impaired clearance via hepatic asialoglycoprotein receptors and Kupffer cell FcαR.
• Mesangial IgA1 in IgAN is also enriched for gd-IgA1.

Hit 4: Mesangial Cell Activation and Injury

• Deposited immune complexes activate complement (via alternative and lectin pathways - classical pathway components are typically absent).
• Mesangial cells are activated, producing cytokines, chemokines, and profibrotic mediators (TGF-β, PDGF), leading to mesangial proliferation and progressive fibrosis.

Genetic Factors

• Over 25% of blood relatives have elevated gd-IgA1; familial cases exist but >90% are sporadic.
• Genome-wide association studies (GWAS) have identified risk loci including: HLA-DR, -DQ, -DP, HLA-B; α-defensin (DEFA) gene cluster; complement factor H; CARD8; MYCT1; ZNF543.
• Geographic variation mirrors genetic susceptibility: highest risk in East Asia, lower in Europe/North America.

Role of Mucosal Immunity

• Close association between mucosal infections and episodes of hematuria ("synpharyngitic" hematuria - hematuria concurrent with or within 1-2 days of upper respiratory infection).
• Altered gut microbiome composition in IgAN.
• Gut bacteria modulate IgA class switching, mucosal IgA production, and IgA1 O-galactosylation.
• Risk alleles from GWAS overlap with inflammatory bowel disease susceptibility genes.
• Comprehensive Clinical Nephrology, 7th Edition, pp. 331-332
• Robbins & Kumar Basic Pathology, p. 512
• Brenner and Rector's The Kidney, p. 3378

Clinical Manifestations

1. Episodic Gross (Macroscopic) Hematuria - Most Common Presentation in Young Adults (~50%)

• Coca-cola/tea-colored urine, often concurrent with or within 24-48 hours of an upper respiratory tract infection (synpharyngitic hematuria).
• Contrasts with post-streptococcal GN where hematuria appears 1-3 weeks after infection.
• Episodes typically resolve spontaneously; interval hematuria may persist.

2. Asymptomatic Microscopic Hematuria ± Proteinuria

• More common in older adults or those identified by routine urinalysis screening.
• Persistent microscopic hematuria is the most common finding in population screening.

3. Nephrotic Syndrome (Rare)

• Nephrotic-range proteinuria occurs but is unusual; should prompt investigation for a concurrent podocytopathy (e.g., minimal change disease superimposed on IgAN).

4. Acute Kidney Injury (<5% of all cases)

• Three mechanisms:
  1. Crescentic (rapidly progressive) IgAN - necrotizing GN with crescent formation.
  2. Tubule occlusion by red blood cells from heavy glomerular hematuria.
  3. Incidental AKI superimposed on chronic IgAN (e.g., NSAID-induced AIN) - more common in elderly.
• AKI presentation carries a significantly higher risk of progression to ESKD.

5. Chronic Kidney Disease with Hypertension

• Older patients with longstanding undiagnosed disease; already have hypertension and impaired GFR at first presentation.
• Accelerated hypertension occurs in ~5% of patients.

6. IgA Vasculitis (Henoch-Schönlein Purpura / HSP)

• Systemic form of IgA-mediated disease with classic tetrad: palpable purpura (buttocks/legs), arthralgias, abdominal pain, and nephritis.
• Children have a more favorable renal prognosis than adults.

Secondary IgA Nephropathy

• Liver disease (especially alcoholic cirrhosis, hepatitis B, schistosomiasis) - due to impaired IgA clearance by hepatic asialoglycoprotein receptors and Kupffer cells.
• Inflammatory bowel disease (IBD increases risk of ESKD in IgAN).
• Celiac disease (mucosal IgA hyperresponsiveness).
• Ankylosing spondylitis
• Dermatitis herpetiformis
• HIV/AIDS (polyclonal IgA increase)

Renal Pathology

Light Microscopy

• Normal appearance (mesangial IgA found only on IF)
• Mesangial widening and hypercellularity (most common)
• Focal proliferative GN (segmental inflammation in some glomeruli)
• Diffuse mesangial proliferative GN
• Crescentic GN (rare, severe disease)

Immunofluorescence (IF) - Diagnostic Hallmark

• Dominant or codominant mesangial IgA deposition (required for diagnosis)
• Often accompanied by C3, properdin (alternative pathway)
• Smaller amounts of IgG or IgM may be present
• Early classical complement components (C1q, C4) are characteristically absent

Electron Microscopy

• Confirms mesangial electron-dense deposits
• Paramesangial deposits may extend into capillary walls in severe disease

IgA Nephropathy Histology (Robbins & Comprehensive Clinical Nephrology)

Fig. 12.12 IgA nephropathy. (A) Mesangial hypercellularity on H&E. (B) Bright mesangial IgA deposits on immunofluorescence. - Robbins & Kumar Basic Pathology

Fig. 24.4 Renal pathology panels in IgAN showing Oxford MEST-C components - Comprehensive Clinical Nephrology, 7th Ed.

The Oxford Classification (MEST-C Score)

• Comprehensive Clinical Nephrology, 7th Edition, p. 314
• NKF Primer on Kidney Diseases, 8e, p. 3060

Diagnosis

• No specific serum or urine biomarker exists for IgAN.
• Renal biopsy is required for definitive diagnosis.
• Serum IgA levels are elevated in ~50% of patients but are non-specific and not diagnostic.
• Serum gd-IgA1 levels are elevated in most IgAN patients but also in relatives without nephropathy.

Differential Diagnosis

Prognosis and Risk Stratification

Clinical Predictors of Progression (at Biopsy):

1. Reduced GFR at presentation
2. Hypertension (persistent)
3. Proteinuria >1 g/24 hours (especially time-averaged proteinuria)
4. Older age at onset

During Follow-up:

• Only persistent hypertension and time-averaged proteinuria are reliable predictors.
• Risk of progression is low when proteinuria remains <0.2 g/24h with normal BP.
• Persistent microscopic hematuria is associated with worse outcomes; hematuria remission improves outcomes in those with persistent proteinuria.
• Hyperuricemia, smoking, and increased BMI are independent risk factors.

Histologic Predictors:

• T score (tubular atrophy/interstitial fibrosis) - most consistent predictor of ESKD.
• High MEST-C scores add prognostic information beyond clinical features.

Low-Risk Features (Mostly Good 7-10 Year Prognosis):

• Isolated microhematuria
• Little or no proteinuria
• Normal BP and GFR at diagnosis
• Note: Up to 40% of these patients develop increasing proteinuria; up to 5% lose GFR over this period - necessitating regular follow-up.
• Comprehensive Clinical Nephrology, 7th Edition, pp. 309-316

Treatment

1. Supportive and Kidney-Protective Measures (All Patients)

• Renin-angiotensin system (RAS) blockade: ACE inhibitor or ARB - first-line therapy to reduce proteinuria and slow progression. Target BP <130/80 mmHg.
• SGLT2 inhibitors (e.g., dapagliflozin): Emerging role in reducing proteinuria and preserving GFR.
• Dietary salt restriction, weight loss, smoking cessation.
• Statin therapy for dyslipidemia.
• Fish oil (omega-3 fatty acids): Modest benefit shown in some trials; used in some guidelines for patients with proteinuria >1 g/day.

2. Tonsillectomy

• Tonsillectomy has been practiced in Japan for patients with frequent tonsillitis-associated flares.
• Evidence in Western populations is limited; not widely recommended.

3. Corticosteroids

• Indications: Patients with persistent proteinuria >1 g/24h despite optimal RAS blockade AND eGFR >30 mL/min/1.73m².
• STOP-IgAN trial: Intensive supportive care ± corticosteroids; corticosteroids reduced proteinuria but did not reduce rate of GFR decline, with significant infections and metabolic side effects.
• TESTING trial (2017 and extended 2022): Methylprednisolone significantly reduced risk of kidney failure compared to placebo in patients with proteinuria >1 g/day (eGFR 20-120), but with significantly increased serious adverse events (infections, deaths) at full dose; low-dose methylprednisolone protocol showed better safety.
• KDIGO 2021 guidelines: Consider steroids only in selected high-risk patients with optimal supportive care first; weigh infection risk.

4. Immunosuppression

• Cyclophosphamide + steroids: For crescentic IgAN (rapidly progressive GN presentation); analogous to treatment of ANCA vasculitis-related crescentic GN.
• Mycophenolate mofetil (MMF): Trials largely negative in Western populations; some benefit in Chinese patients.
• Rituximab: Some case reports in children with severe disease; not established standard.

5. Targeted APRIL/BAFF Pathway Therapies (Novel)

• Sparsentan (dual endothelin-angiotensin receptor antagonist): FDA-approved for IgAN.
• Budesonide (Nefecon/Tarpeyo): Targeted-release formulation delivering steroids to the Peyer's patches in the distal ileum, reducing mucosal IgA production with fewer systemic steroid side effects. FDA-approved for IgAN with proteinuria >1 g/day.
• Iptacopan (complement factor B inhibitor), Atacicept (APRIL/BAFF blocker): In clinical trials.

6. Treatment of Specific Presentations

• Crescentic IgAN (RPGN): Pulse methylprednisolone + cyclophosphamide; consider plasma exchange in severe cases (though evidence limited compared to ANCA-GN).
• AKI from hematuria-induced tubular occlusion: Supportive care; RBC casts in tubules.
• IgA vasculitis (HSP) nephritis: Corticosteroids for systemic features; immunosuppression for severe nephritis (EULAR/PRINTO/PRES guidelines).

Transplantation

• IgAN patients are ideal transplant candidates (relatively young, few comorbidities).
• Mesangial IgA deposits recur in up to 60% of transplanted kidneys.
• Recurrence may occur within days to weeks but is often clinically silent initially.
• Recurrent IgAN: 30% in living-related grafts vs. 23% in cadaveric grafts.
• Graft survival is not significantly affected in the first 10 years; thereafter, recurrent disease may accelerate graft loss.
• Transplanting kidneys with IgA deposits into non-IgAN recipients leads to rapid disappearance of deposits, confirming the disease lies in the recipient's immune system, not the kidney.
• Crescentic recurrent IgAN is rare but resistant to treatment and causes rapid graft failure.
• Comprehensive Clinical Nephrology, 7th Edition, pp. 319-322

IgAN vs. HSP (IgA Vasculitis) Nephritis

Summary Flowchart

Patient with hematuria ± proteinuria
         ↓
Urinalysis + 24h urine protein + serum creatinine/eGFR
         ↓
Persistent hematuria ± proteinuria > 0.5 g/day OR impaired eGFR
         ↓
Renal Biopsy
         ↓
Mesangial IgA on IF → IgA Nephropathy
         ↓
MEST-C scoring + Clinical risk stratification
         ↓
Low risk: Supportive (RAS blockade, BP control, lifestyle)
High risk (proteinuria >1g, reduced eGFR, M1/E1/T1-2/C1-2):
→ Optimize RAS blockade → Consider steroids/IS
→ Crescentic: Pulse steroids + cyclophosphamide

Key Points to Remember

1. Most common primary GN worldwide; highest incidence in East Asia.
2. Pathogenesis: gd-IgA1 → autoantibodies → immune complexes → mesangial deposition → complement activation → injury.
3. Classic presentation: synpharyngitic gross hematuria in a young male (vs. post-streptococcal hematuria appearing 1-3 weeks later).
4. Diagnosis requires renal biopsy - mesangial IgA dominant on immunofluorescence; no C1q or C4.
5. Oxford MEST-C score guides prognosis; T score is the most reliable predictor of ESKD.
6. 30-40% reach ESKD in 20-30 years; prognosis driven by hypertension, proteinuria, and eGFR.
7. Treatment: RAS blockade for all; steroids for high-risk (proteinuria >1g + eGFR >30); cyclophosphamide for crescentic disease; newer agents include budesonide (Nefecon) and sparsentan.
8. Transplant recurrence in up to 60% but rarely affects graft survival before 10 years.

• Comprehensive Clinical Nephrology, 7th Edition - Chapters 24 & 80
• NKF Primer on Kidney Diseases, 8th Edition - Chapter 21
• Robbins & Kumar Basic Pathology - Chapter 12
• Brenner and Rector's The Kidney, 2-Volume Set