Overview
IgA Nephropathy
1. Overview
IgA Nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. It is characterized by predominant IgA deposits in the glomerular mesangium and has a highly variable clinical course - ranging from benign isolated haematuria to progressive renal failure.
Key Features
- Most common GN globally: Accounts for 30-40% of all GN in Asian populations
- Hallmark: Synpharyngitic haematuria (haematuria concurrent with upper respiratory infection)
- Diagnosis: Renal biopsy showing mesangial IgA deposits
- Prognosis: 20-40% progress to ESRD over 20 years
Epidemiology
| Factor | Details |
|---|---|
| Incidence | 2.5 per 100,000/year (higher in Asia) |
| Peak age | 20-30 years |
| Gender | Male predominance (2:1) |
| Geographic | Most common in Asia-Pacific, less common in Africa |
Classic Presentation
"Synpharyngitic haematuria" - Macroscopic haematuria occurring within 1-2 days of an upper respiratory tract infection (vs. post-streptococcal GN which occurs 1-2 weeks after infection)
2. Pathophysiology
┌─────────────────────────────────────────────────────────────────────────────┐
│ IgA NEPHROPATHY PATHOPHYSIOLOGY │
├─────────────────────────────────────────────────────────────────────────────┤
│ │
│ ┌─────────────────────────────────────────────────────────────────────┐ │
│ │ HIT 1: GALACTOSE-DEFICIENT IgA1 │ │
│ │ • Abnormal O-glycosylation of IgA1 hinge region │ │
│ │ • Galactose-deficient IgA1 (Gd-IgA1) produced │ │
│ │ • Genetic susceptibility + Environmental triggers │ │
│ └─────────────────────────────────────────────────────────────────────┘ │
│ ↓ │
│ ┌─────────────────────────────────────────────────────────────────────┐ │
│ │ HIT 2: AUTO-ANTIBODY FORMATION │ │
│ │ • IgG (or IgA) antibodies recognize Gd-IgA1 │ │
│ │ • Immune complex formation in circulation │ │
│ └─────────────────────────────────────────────────────────────────────┘ │
│ ↓ │
│ ┌─────────────────────────────────────────────────────────────────────┐ │
│ │ HIT 3: IMMUNE COMPLEX DEPOSITION │ │
│ │ • Circulating immune complexes deposit in mesangium │ │
│ │ • IgA predominant deposits on immunofluorescence │ │
│ └─────────────────────────────────────────────────────────────────────┘ │
│ ↓ │
│ ┌─────────────────────────────────────────────────────────────────────┐ │
│ │ HIT 4: GLOMERULAR INJURY │ │
│ │ • Mesangial cell activation and proliferation │ │
│ │ • Complement activation (alternative and lectin pathways) │ │
│ │ • Cytokine release and matrix expansion │ │
│ │ • Podocyte injury and proteinuria │ │
│ └─────────────────────────────────────────────────────────────────────┘ │
│ ↓ │
│ ┌──────────────────────┬──────────────────┬────────────────────┐ │
│ ↓ ↓ ↓ │ │
│ ┌─────────┐ ┌─────────────┐ ┌───────────────┐ │ │
│ │HAEMATURIA│ │ PROTEINURIA │ │ PROGRESSIVE │ │ │
│ │(GBM leak)│ │(podocyte │ │ CKD/ESRD │ │ │
│ │ │ │ injury) │ │ │ │ │
│ └─────────┘ └─────────────┘ └───────────────┘ │ │
│ │ │
└─────────────────────────────────────────────────────────────────────────────┘
The Multi-Hit Hypothesis
- Hit 1: Genetic predisposition to produce galactose-deficient IgA1 (Gd-IgA1)
- Hit 2: Generation of autoantibodies against Gd-IgA1
- Hit 3: Formation and deposition of immune complexes in mesangium
- Hit 4: Glomerular injury leading to clinical disease
Complement Activation
- Alternative and lectin pathways activated
- C3 commonly co-deposited with IgA
- Emerging therapeutic target (complement inhibition)
3. Clinical Features
History Taking
Essential Questions:
- Episode of macroscopic haematuria? (Timing relative to infection?)
- Known microscopic haematuria or proteinuria?
- Family history of kidney disease or haematuria?
- History of IgA vasculitis (Henoch-Schönlein purpura)?
- Prior URTI, GI infection, or exercise preceding haematuria?
Clinical Presentations
| Presentation | Frequency | Characteristics |
|---|---|---|
| Synpharyngitic haematuria | 40-50% | Macroscopic haematuria 1-2 days after URTI |
| Asymptomatic haematuria | 30-40% | Microscopic haematuria ± proteinuria on screening |
| Nephrotic syndrome | 5% | Heavy proteinuria, edema |
| Acute kidney injury | 5% | Crescentic GN, rapid decline |
| Chronic kidney disease | Variable | Slow progression with HTN |
Timing of Haematuria
Key Differentiator:
| Condition | Timing After URTI |
|---|---|
| IgA Nephropathy | 1-2 days (synpharyngitic) |
| Post-streptococcal GN | 1-2 weeks (post-infectious) |
Physical Examination
- Often unremarkable
- May have hypertension
- Edema if nephrotic-range proteinuria
- Check for purpura, joint pain (IgA vasculitis)
4. Diagnosis
Diagnostic Approach
Clinical Suspicion:
- Recurrent macroscopic haematuria with URTIs
- Persistent microscopic haematuria + proteinuria
- Young adult with unexplained CKD
Laboratory Investigations
| Test | Findings | Notes |
|---|---|---|
| Urinalysis | RBCs, dysmorphic RBCs, proteinuria | Glomerular pattern |
| Urine protein | Variable (0.5-3 g/day typical) | >g/day = higher risk |
| Serum creatinine | Variable | Assess baseline eGFR |
| Serum IgA | Elevated in 50% | Not diagnostic |
| C3, C4 | Usually normal | Low C3 suggests other GN |
| ANA, ANCA | Negative | Exclude other causes |
Renal Biopsy (Diagnostic Gold Standard)
Indications for Biopsy:
- Persistent proteinuria >0.5-1 g/day
- Declining renal function
- Active sediment with proteinuria
Histological Findings:
| Stain | Finding |
|---|---|
| Light microscopy | Mesangial hypercellularity, matrix expansion |
| Immunofluorescence | Dominant or co-dominant IgA in mesangium |
| Electron microscopy | Mesangial electron-dense deposits |
Oxford Classification (MEST-C)
| Score | Pathology | Prognostic Value |
|---|---|---|
| M | Mesangial hypercellularity | M1 = >0% of glomeruli |
| E | Endocapillary hypercellularity | E1 = present |
| S | Segmental sclerosis | S1 = present |
| T | Tubular atrophy/interstitial fibrosis | T0 = <25%, T1 = 25-50%, T2 = >0% |
| C | Crescents | C0 = 0%, C1 = <25%, C2 = >5% |
Differential Diagnosis
| Condition | Key Differentiators |
|---|---|
| Thin basement membrane disease | Family history, no proteinuria, benign course |
| Alport syndrome | Family history, hearing loss, eye findings |
| Post-streptococcal GN | 1-2 weeks post-URTI, low C3 |
| IgA vasculitis | Purpura, arthritis, GI involvement |
| Lupus nephritis | ANA positive, multi-system involvement |
5. Management Algorithm
┌─────────────────────────────────────────────────────────────────────────────┐
│ IgA NEPHROPATHY MANAGEMENT ALGORITHM │
├─────────────────────────────────────────────────────────────────────────────┤
│ │
│ CONFIRMED IgA NEPHROPATHY (Biopsy-proven) │
│ ↓ │
│ ┌─────────────────────────────────────────────────────────────────────┐ │
│ │ RISK STRATIFICATION │ │
│ │ • Proteinuria: <0.5g, 0.5-1g, >1g/day │ │
│ │ • eGFR: >60, 30-60, <30 mL/min/1.73m² │ │
│ │ • Blood pressure: Controlled vs uncontrolled │ │
│ │ • Biopsy: MEST-C scoring │ │
│ │ • Consider PRIME-IgAN risk calculator │ │
│ └─────────────────────────────────────────────────────────────────────┘ │
│ ↓ │
│ ┌─────────────────────────────────────────────────────────────────────┐ │
│ │ ALL PATIENTS: SUPPORTIVE CARE │ │
│ │ • ACEi/ARB: Target proteinuria <0.5-1 g/day │ │
│ │ • BP target: <120/80 mmHg │ │
│ │ • Lifestyle: Low sodium diet, smoking cessation │ │
│ │ • Monitor: Proteinuria, eGFR every 3-6 months │ │
│ └─────────────────────────────────────────────────────────────────────┘ │
│ ↓ │
│ ┌─────────────────────────────────────────────────────────────────────┐ │
│ │ SGLT2 INHIBITOR (Second-line) │ │
│ │ • Evidence: DAPA-CKD, EMPA-KIDNEY trials │ │
│ │ • Benefit: Reduces proteinuria and CKD progression │ │
│ │ • Consider if proteinuria persists despite ACEi/ARB │ │
│ └─────────────────────────────────────────────────────────────────────┘ │
│ ↓ │
│ ┌──────────────────────────────────────┐ │
│ │ PERSISTENT PROTEINURIA >1 g/day? │ │
│ │ (After 3-6 months optimal RAS-i) │ │
│ └──────────────────────────────────────┘ │
│ ↓ YES ↓ NO │
│ ┌──────────────────────────┐ ┌──────────────────────────────────────┐ │
│ │ HIGH-RISK: CONSIDER │ │ LOW-RISK: CONTINUE SUPPORTIVE │ │
│ │ IMMUNOSUPPRESSION │ │ • Monitor every 6-12 months │ │
│ │ │ │ • Maintain ACEi/ARB + SGLT2i │ │
│ │ Options: │ │ • Lifestyle optimization │ │
│ │ • Steroids (TESTING) │ │ │ │
│ │ • MMF (if steroid CI) │ │ │ │
│ │ • Targeted steroids │ │ │ │
│ └──────────────────────────┘ └──────────────────────────────────────┘ │
│ ↓ │
│ ┌─────────────────────────────────────────────────────────────────────┐ │
│ │ RAPIDLY PROGRESSIVE GN / CRESCENTIC │ │
│ │ • High-dose IV steroids ± Cyclophosphamide │ │
│ │ • Plasma exchange in selected cases │ │
│ │ • Urgent nephrology review │ │
│ └─────────────────────────────────────────────────────────────────────┘ │
│ ↓ │
│ ┌─────────────────────────────────────────────────────────────────────┐ │
│ │ ESRD MANAGEMENT │ │
│ │ • Dialysis (HD or PD) │ │
│ │ • Kidney transplantation (disease recurs in ~30-50% of grafts) │ │
│ │ • Pre-emptive transplant if candidate │ │
│ └─────────────────────────────────────────────────────────────────────┘ │
│ │
└─────────────────────────────────────────────────────────────────────────────┘
First-Line: RAS Blockade
ACEi/ARB:
- Foundation of therapy for ALL patients with proteinuria
- Target: Proteinuria <0.5-1 g/day
- Titrate to maximum tolerated dose
- Monitor creatinine and potassium
Blood Pressure Target:
- <120/80 mmHg per KDIGO 2021
- Lower targets associated with better outcomes
Second-Line: SGLT2 Inhibitors
Emerging Evidence:
- DAPA-CKD: Dapagliflozin reduced CKD progression by 39%
- EMPA-KIDNEY: Empagliflozin showed similar benefits
- KDIGO 2021 recommends for CKD with proteinuria
Dosing:
- Dapagliflozin 10 mg daily
- Empagliflozin 10 mg daily
- Can use with eGFR as low as 20-25 mL/min
Immunosuppression
TESTING Trial Regimen (Targeted Steroids):
- Methylprednisolone 0.6-0.8 mg/kg/day for 2 months
- Then taper over 6-9 months
- Use if proteinuria >1 g/day despite 3-6 months RAS-i
Considerations:
- Significant side effects (diabetes, infection, osteoporosis)
- Benefits most clear in high-risk patients
- Individualize based on risk-benefit
Novel Therapies (Emerging)
| Agent | Mechanism | Status |
|---|---|---|
| Sparsentan | Dual ET/AT1 receptor blocker | FDA approved 2023 |
| Budesonide (Tarpeyo) | Targeted release corticosteroid | FDA approved 2021 |
| Complement inhibitors | Block complement activation | Clinical trials |
6. Risk Stratification
Predictors of Progression to ESRD
| Risk Factor | Impact |
|---|---|
| Proteinuria > g/day | Strongest predictor |
| Hypertension | Accelerates progression |
| Reduced eGFR at diagnosis | Higher risk |
| Severe histology (MEST-C) | T2, S1 = worse prognosis |
| Male gender | Higher risk |
| Persistent haematuria | Ongoing injury |
Risk Calculators
PRIME-IgAN Score:
- Uses clinical and pathological data
- Predicts 5-10 year risk of ESRD
- Available online
KDIGO Risk Categories:
- Low risk: Proteinuria <0.5 g/day, eGFR >60
- Intermediate: Proteinuria 0.5-1 g/day
- High risk: Proteinuria >1 g/day or eGFR <60
7. Prognosis
Natural History
| Outcome | Time Frame | Proportion |
|---|---|---|
| Complete remission | Variable | 5-10% |
| Stable/Mild disease | Long-term | 40-50% |
| Slow progression | 10-20 years | 30-40% |
| ESRD | 20 years | 20-40% |
Factors Associated with Better Prognosis
- Minimal proteinuria (<0.5 g/day)
- Normal eGFR at diagnosis
- Good blood pressure control
- Favorable biopsy (M0, E0, S0, T0, C0)
- Response to therapy
8. Complications
Renal Complications
| Complication | Management |
|---|---|
| Progressive CKD | Optimize ACEi/ARB, SGLT2i, BP control |
| AKI with macroscopic haematuria | Supportive care, usually recovers |
| Rapidly progressive GN | Urgent immunosuppression |
| ESRD | Dialysis or transplantation |
Extra-Renal Associations
- IgA vasculitis (Henoch-Schönlein purpura)
- Celiac disease (consider screening)
- Liver cirrhosis (secondary IgA nephropathy)
- HIV infection (secondary IgA nephropathy)
Treatment Complications
| Treatment | Complications |
|---|---|
| ACEi/ARB | Hyperkalemia, AKI, cough (ACEi) |
| Steroids | Diabetes, osteoporosis, infection, weight gain |
| SGLT2i | UTI, genital mycotic infections, DKA (rare) |
9. Special Considerations
Pregnancy
- Plan pregnancy when disease is stable
- Switch from ACEi/ARB (teratogenic) to hydralazine/labetalol
- Monitor for pre-eclampsia
- May have transient worsening post-partum
Transplantation
- IgA nephropathy recurs histologically in 30-50% of grafts
- Clinically significant recurrence in 10-20%
- Graft loss from recurrence: 5-10% at 10 years
- Living related donation: Generally acceptable
Secondary IgA Nephropathy
Conditions Associated with Secondary IgAN:
- Liver cirrhosis (impaired IgA clearance)
- HIV infection
- Celiac disease
- Inflammatory bowel disease
- Ankylosing spondylitis
10. Key Clinical Pearls
Exam-Focused Points
- Synpharyngitic Haematuria: Occurs 1-2 days after URTI (vs. post-strep = 1-2 weeks)
- Most Common Primary GN: Worldwide, especially in Asia
- Biopsy = Gold Standard: Mesangial IgA deposits on immunofluorescence
- Serum IgA: Elevated in 50% but NOT diagnostic
- Complement Usually Normal: Distinguish from post-strep and lupus
- ACEi/ARB First-Line: Target proteinuria <0.5-1 g/day
- SGLT2 Inhibitors: Now recommended for CKD with proteinuria
- Proteinuria = Key Prognostic Factor: >1 g/day = high risk
Common Exam Scenarios
- Young adult with macroscopic haematuria during a cold
- Microscopic haematuria and proteinuria on screening
- Biopsy showing mesangial IgA - distinguish from other GN
- Management of high-risk IgAN with persistent proteinuria
11. Patient Explanation
What is IgA Nephropathy?
"IgA nephropathy is a kidney condition where a type of antibody called IgA gets deposited in the tiny filters (glomeruli) in your kidneys. This causes inflammation and, over time, can damage the filters.
It's often called 'Berger's disease' after the doctor who first described it. It's the most common type of kidney inflammation (glomerulonephritis) worldwide."
Why Does This Happen?
"In IgA nephropathy, your immune system produces IgA antibodies that are slightly abnormal. These abnormal antibodies form clumps that get stuck in your kidney filters.
When these clumps accumulate, they trigger inflammation. This is why you might notice blood in your urine after a cold or sore throat - the inflammation is temporarily increased."
What Are the Symptoms?
"Many people have no symptoms at all. The condition is often found on routine testing. You might experience:
- Blood in the urine - especially after a cold (can look like tea or cola)
- Protein in the urine - found on testing
- High blood pressure - sometimes the first sign
- Swelling - if protein loss is significant"
How is it Treated?
"Treatment aims to protect your kidneys from further damage:
-
Blood pressure medications (ACE inhibitors/ARBs) - These are the most important. They reduce pressure on your kidneys and decrease protein leakage.
-
SGLT2 inhibitors - Newer medications that also protect the kidneys.
-
Lifestyle changes - Low salt diet, healthy weight, no smoking.
-
For high-risk cases - Sometimes steroid medications are needed.
With good treatment, many people maintain stable kidney function for decades."
12. Evidence & Guidelines
Key Guidelines
| Guideline | Organization | Year | Key Points |
|---|---|---|---|
| KDIGO Glomerulonephritis | KDIGO | 2021 | ACEi/ARB first-line, SGLT2i, steroids for high-risk |
| KDIGO CKD Management | KDIGO | 2024 | SGLT2i recommendations, BP targets |
| UK RA Guidelines | Renal Association | 2021 | Biopsy indications, management |
Landmark Trials
TESTING Trial (2022):
- Methylprednisolone vs placebo in high-risk IgAN
- 55% reduction in composite renal endpoint
- Increased infection risk with steroids
- Supports steroids in high-risk, carefully selected patients
DAPA-CKD Trial (2020):
- Dapagliflozin in CKD (including IgAN subgroup)
- 39% reduction in CKD progression
- Supports SGLT2i in IgAN with proteinuria
NEFIGAN Trial (2017):
- Targeted release budesonide (Tarpeyo)
- Reduced proteinuria in IgAN
- Led to FDA approval in 2021
PROTECT Trial (2023):
- Sparsentan (dual ET/AT1 blocker) vs irbesartan
- Superior proteinuria reduction
- FDA approved for IgAN in 2023
Evidence-Based Recommendations
| Recommendation | Evidence Level |
|---|---|
| ACEi/ARB for all with proteinuria | Strong |
| SGLT2i for proteinuric CKD | Strong |
| BP target <120/80 | Moderate |
| Steroids for high-risk refractory | Moderate |
| Tonsillectomy | Weak/insufficient |
13. References
-
KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int. 2021;100(4S):S1-S276.
-
Wyatt RJ, Julian BA. IgA nephropathy. N Engl J Med. 2013;368(25):2402-2414.
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Lv J, et al. Effect of Oral Methylprednisolone on Clinical Outcomes in Patients With IgA Nephropathy: The TESTING Randomized Clinical Trial. JAMA. 2017;318(5):432-442.
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Heerspink HJL, et al. Dapagliflozin in Patients with Chronic Kidney Disease (DAPA-CKD). N Engl J Med. 2020;383(15):1436-1446.
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Trimarchi H, et al. Oxford Classification of IgA nephropathy 2016: an update from the IgA Nephropathy Classification Working Group. Kidney Int. 2017;91(5):1014-1021.
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Rovin BH, et al. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int. 2021;100(4):S1-S276.
-
Fellström BC, et al. Targeted-release budesonide versus placebo in patients with IgA nephropathy (NEFIGAN). Lancet. 2017;389(10084):2117-2127.
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Heerspink HJL, et al. Sparsentan in patients with IgA nephropathy: a prespecified interim analysis from a randomised, double-blind, active-controlled clinical trial. Lancet. 2023;401(10388):1584-1594.