IgA Nephropathy (Berger’s Disease) Clinical Overview
I. The "On-Call" Snapshot
Clinical Significance in Malaysia: This isn't just some academic entity. IgA Nephropathy (IgAN) is the single most common primary glomerulonephritis (GN) worldwide and a leading cause of end-stage renal disease (ESRD) in our Malaysian population. You will see this. You need to know how to identify and risk-stratify it.
High-Yield Definition: IgAN is an immune-complex-mediated GN defined by the pathognomonic finding of diffuse IgA deposits, predominantly in the glomerular mesangium, on immunofluorescence microscopy of a renal biopsy.
Clinical One-Liner: This is the classic "GN that presents with gross haematuria at the same time as a 'flu' or sore throat."
II. Etiology & Risk Factors
Etiology: The exact cause is unknown, but it's understood via a "multi-hit" hypothesis:
Hit 1: Patient (often with a genetic predisposition) produces abnormal, galactose-deficient IgA1 (gd-IgA1), likely from mucosal sites (gut, tonsils).
Hit 2: The immune system recognizes this gd-IgA1 as foreign and produces IgG autoantibodies against it.
Hit 3: These IgA1-IgG immune complexes circulate and deposit in the glomerular mesangium.
Hit 4: The deposits activate complement (alternative and lectin pathways) and trigger local inflammation, mesangial cell proliferation, and cytokine release, leading to glomerular injury.
Risk Factors:
Demographics: Male sex (2:1 to 3:1 ratio), Asian ethnicity (highest prevalence).
Genetics: Familial clustering exists.
Triggers: Mucosal infections (URTI, gastroenteritis) can precipitate episodes.
Associated Conditions: IgA vasculitis (HSP), inflammatory bowel disease, coeliac disease, chronic liver disease.
III. Quick Pathophysiology
The key is mesangial deposition. When those IgA-IgG complexes get stuck in the mesangium, they act as an inflammatory trigger. This causes mesangial cells to proliferate and lay down excess matrix (glomerulosclerosis). This inflammatory cascade damages the glomerular filtration barrier, allowing RBCs (haematuria) and protein (proteinuria) to leak into the urine. This process, over years, leads to irreversible scarring (interstitial fibrosis, tubular atrophy), loss of nephrons, and progressive CKD.
IV. Classification
The key classification system is the Oxford Classification (MEST-C Score). This is a histological score from the renal biopsy that predicts the risk of progression. It does not tell you what to treat with, but it tells you how worried to be.
Mesangial hypercellularity (M0: <50% of glomeruli, M1: >50%)
Endocapillary hypercellularity (E0: absent, E1: present)
Segmental glomerulosclerosis (S0: absent, S1: present)
Tubular atrophy/interstitial fibrosis (T0: 0-25%, T1: 26-50%, T2: >50%)
Crescents (C0: none, C1: 1-25%, C2: >25%)
Clinical Relevance: 'S' and 'T' scores are powerful predictors of GFR decline. 'E' and 'C' lesions may predict a better response to immunosuppression but also signify more active, aggressive disease.
V. Clinical Assessment
🚩 Red Flags & Immediate Actions:
Rapidly rising creatinine / AKI: (Action: Urgent VBG, BUSE, alert senior/nephrology). Reason: Suspect crescentic, rapidly progressive GN (RPGN) variant. Needs urgent biopsy and pulse steroids.
Nephrotic-range proteinuria (UPCR > 350mg/mmol or >3.5g/day) + Anasarca: (Action: Assess fluid status, check albumin, start gentle diuresis). Reason: High risk for complications (VTE, infection) and disease progression.
Hypertensive Emergency (BP > 180/120 with end-organ damage): (Action: Manage as per HTN emergency protocol, e.g., IV labetalol). Reason: Uncontrolled BP is the engine of progression in all CKD.
History:
Key Diagnostic Clue (Classic): Synpharyngitic haematuria. This is your key. The patient reports gross, "tea-coloured" or "Coca-Cola" urine 1-2 days after the onset of an URTI or gastroenteritis. This timing is crucial.
Symptom Breakdown:
Common (>50%): Asymptomatic microscopic haematuria with or without mild proteinuria, found incidentally on a UFEME for another reason (e.g., medical check-up).
Less Common (10-50%): The classic episodic gross haematuria described above. May also present with established CKD features (fatigue, nocturia, poorly controlled HTN).
Rare (<10%): Full-blown nephrotic syndrome (heavy edema, frothy urine) or the RPGN picture (oligoanuria, rapid decline in function).
Pertinent Negatives:
Ask about the timing of haematuria post-infection. If it's 1-3 weeks later, think Post-Streptococcal GN (PSGN), not IgAN.
Ask about systemic symptoms: No fever, no joint pain, no rashes (argues against Lupus Nephritis or Vasculitis).
Ask about hearing loss or visual problems (argues against Alport Syndrome).
Physical Examination (OSCE Approach):
General Inspection: Often entirely normal. May see peripheral or periorbital edema if significant proteinuria is present.
Vitals: BP is critical. Hypertension is both a symptom and a major driver of progression.
Disease-Specific Examination (System-based):
Assess fluid status: JVP, lung bases (crackles), pedal and sacral edema.
Abdominal exam: Check for hepatosplenomegaly (rules out liver disease as a secondary cause).
Skin: Look for purpuric rashes on lower limbs (to rule out IgA Vasculitis/HSP, which is the same disease spectrum).
Pertinent Negatives: No palpable purpura, no joint swelling, no malar rash.
Differentiating Disease Stage:
Early / Mild: Normal BP, normal eGFR, asymptomatic microscopic haematuria.
Intermediate / Moderate: New-onset HTN, persistent proteinuria > 0.5-1g/day, eGFR may be normal or slightly reduced.
Late / Severe: Established CKD (eGFR < 60), difficult-to-control HTN, proteinuria, +/- features of uremia.
Clinical Pearl: The most common presentation is no presentation. It's the asymptomatic patient with a dipstick finding. Your job is to not ignore that dipstick.
VI. Diagnostic Workflow
Differential Diagnosis:
Post-Streptococcal GN (PSGN):
Points For: Haematuria, proteinuria, post-infectious.
Points Against: Latent period is 1-3 weeks (post-pharyngitic), not 1-2 days (synpharyngitic).
How to Differentiate: Serum C3 will be low (it's normal in IgAN). ASO titre will be high.
Alport Syndrome (Hereditary Nephritis):
Points For: Haematuria (often microscopic), progressive CKD, family history.
Points Against: Lacks the synpharyngitic pattern.
How to Differentiate: Look for extra-renal signs: sensorineural hearing loss and ocular defects (e.g., anterior lenticonus). Biopsy (EM shows lamellated "basket-weave" GBM) is definitive.
Lupus Nephritis (Class III/IV):
Points For: Haematuria, proteinuria, renal impairment.
Points Against: Usually female, prominent systemic features (arthritis, malar rash, serositis).
How to Differentiate: Serology (ANA, anti-dsDNA will be positive; C3/C4 will be low).
Thin Basement Membrane Disease (Benign Familial Haematuria):
Points For: Persistent microscopic haematuria, often familial.
Points Against: Proteinuria and HTN are rare. Does not progress to renal failure.
How to Differentiate: Clinical course (non-progressive) is key. Biopsy (EM shows uniformly thinned GBM) is definitive.
Investigations Plan:
Bedside / Initial (First 15 Mins):
UFEME: This is your screen. Look for dysmorphic RBCs and RBC casts (confirms glomerular source of bleeding). Check for proteinuria.
BP: Must be done.
First-Line Labs & Imaging:
BUSE/Renal Profile: To establish baseline eGFR and creatinine.
Urine Protein-to-Creatinine Ratio (UPCR): To quantify proteinuria. This is your main tool for monitoring and risk stratification.
Autoimmune Screen: ANA, anti-dsDNA, C3, C4 (to rule out lupus and PSGN). Complements are typically normal in IgAN.
Hepatitis Screen: Hep B/C serology (can cause secondary membranoproliferative GN).
Ultrasound KUB: To assess kidney size, echotexture, and rule out structural causes (e.g., stones, masses).
Confirmatory / Gold Standard:
Renal Biopsy: This is the only definitive diagnosis. Indicated if there is persistent proteinuria > 0.5-1g/day, rising creatinine, or significant haematuria.
Findings:
Light Microscopy: Mesangial proliferation and matrix expansion (basis for 'M' score).
Immunofluorescence (IF): This is the diagnostic finding. Granular mesangial deposits of IgA (dominant) and C3.
Electron Microscopy (EM): Confirms electron-dense deposits located in the mesangium.
VII. Staging & Severity Assessment
This is clinical risk stratification (based on KDIGO guidelines) and is what decides management.
Low Risk: Normal GFR, normal BP, proteinuria < 0.5g/day.
Moderate Risk: Normal or stable GFR, controlled BP, but proteinuria is 0.5-1g/day.
High Risk: Persistent proteinuria > 1g/day despite 3-6 months of maximised supportive care.
Highest Risk: High risk features + declining eGFR (>5ml/min/1.73m2 per year), or RPGN picture.
VIII. Management Plan
A. Principle of Management:
Optimise Supportive Care: This is the non-negotiable foundation.
Control BP: Target < 130/80 mmHg (or <120/80 if tolerated).
Reduce Proteinuria: Target < 1g/day, ideally < 0.5g/day.
Selective Immunosuppression: Only for high-risk patients who fail supportive care.
B. Immediate Stabilisation (The ABCDE Plan):
This is typically a chronic outpatient condition and this section is not relevant unless the patient presents with an AKI from crescentic GN or a hypertensive emergency.
In that rare case: Manage ABCs, IV access, manage hyperkalemia, obtain urgent nephrology consult for consideration of pulse methylprednisolone and urgent biopsy.
C. Definitive Treatment (The Ward Round Plan):
Phase 1: Supportive Care (FOR ALL with Proteinuria > 0.5g/day)
RAAS Blockade: ACE inhibitors or ARBs (e.g., Perindopril, Losartan). This is first-line. Start and titrate to maximum tolerated dose. This is both anti-hypertensive and anti-proteinuric.
BP Control: Add other agents (e.g., CCBs, diuretics) as needed to reach target BP < 130/80.
SGLT2 Inhibitors: (e.g., Dapagliflozin 10mg OD). Following the DAPA-CKD trial, this is now standard of care for CKD (including IgAN) with eGFR > 25 and proteinuria. Add this on top of the ACEi/ARB.
Lifestyle: Crucial. Low-salt diet (< 2g sodium/day), smoking cessation, weight control.
Follow-up: Monitor BP, BUSE, and UPCR. Give this supportive care regimen at least 3-6 months to work.
Phase 2: Immunosuppression (FOR HIGH-RISK PATIENTS ONLY)
Indication: Patient still has proteinuria > 1g/day despite 3-6 months of maximised supportive care (max-dose ACEi/ARB + SGLT2i + BP control).
First-Line: Corticosteroids. (Based on the TESTING trial).
Regimen: (e.g., Oral Prednisolone 0.5-0.8mg/kg/day, max 40-60mg, or pulsed IV methylprednisolone) tapered slowly over 6 months.
Cautions: This is a major decision. You must counsel the patient on side effects (diabetes, gastritis, infections, osteoporosis). Screen for Hep B/C, TB before starting. Give gastric and bone protection.
Phase 3: Refractory Disease (Specialist Territory)
If patient fails steroids or has crescentic GN, other agents like Mycophenolate Mofetil (MMF), Cyclophosphamide, or Rituximab may be considered. This is a tertiary centre nephrology decision.
D. Long-Term & Discharge Plan:
Lifelong follow-up is mandatory, likely under nephrology.
Monitoring: 3-6 monthly checks of BP, eGFR, and UPCR.
Patient Education: Low-salt diet, sick-day rules (hold ACEi/ARB, SGLT2i, diuretics during acute illness/dehydration to prevent AKI), avoidance of nephrotoxins (especially NSAIDs).
IX. Complications
Immediate: AKI (from crescentic GN or tubular obstruction from gross haematuria), complications of nephrotic syndrome (VTE).
Short-Term (from treatment): Steroid-induced hyperglycemia, infections, cushingoid features, gastritis.
Long-Term: Progressive CKD leading to ESRD (this is the main one; 20-40% of patients progress to ESRD over 20 years). Cardiovascular disease (accelerated by CKD and HTN).
X. Prognosis
Highly variable. A "rule of thirds" is sometimes quoted: ~1/3 achieve remission, 1/3 have stable CKD, 1/3 progress to ESRD.
Key Poor Prognostic Factors:
Persistent Proteinuria > 1g/day (the strongest, most modifiable factor).
Hypertension (uncontrolled).
Reduced eGFR at time of diagnosis.
Histology (Oxford Score): 'S1', 'T1/T2', 'C1/C2' lesions all predict worse outcomes.
XI. How to Present to Your Senior
"Sir/Madam, I am calling to discuss (Patient Name/IC), a (Age)-year-old (Sex) in (Ward), who is a new referral for evaluation of persistent haematuria and proteinuria."
S: "The patient was found to have 3+ protein and 3+ blood on UFEME during a pre-employment screen. UPCR is (Value) g/day. eGFR is (Value). BP is (Value) on no medication."
B: "He is asymptomatic. No edema, no systemic symptoms. No family history of renal disease. Clinical exam is unremarkable. Autoimmune screen and complements are normal."
A: "My assessment is that this is likely a primary glomerulonephritis, with IgA Nephropathy being the top differential given his demographic and the asymptomatic presentation. He has high-risk features given the proteinuria > 1g/day."
R: "My plan is to:
Start supportive care with Perindopril 2mg OD, titrated up, and Dapagliflozin 10mg OD.
Counsel on a low-salt diet.
Consent and schedule for an ultrasound-guided renal biopsy to confirm the diagnosis and for histological staging.
See him back in clinic in 4 weeks to review BP and labs."
XII. Summary & Further Reading
Top 3 Takeaways:
IgAN is the most common primary GN. The classic, but not most common, presentation is synpharyngitic haematuria (1-2 days post-URTI).
Diagnosis is histological (renal biopsy showing mesangial IgA). Management is guided by clinical risk stratification (BP, eGFR, and especially proteinuria).
Supportive care is the cornerstone (ACEi/ARB + SGLT2i + BP control). Steroids are reserved only for high-risk patients (proteinuria > 1g/day) who fail 3-6 months of optimised supportive care.
Key Resources:
KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases (Chapter on IgA Nephropathy)
UpToDate: "Treatment and prognosis of IgA nephropathy"
Amboss: "IgA nephropathy"
