Prepared for the practicing clinician — updated to reflect 2023–2024 guidelines from KDIGO, ASN, EULAR, and major randomized trials
1. Definition & Pathophysiological Basis
Glomerulonephritis (GN) refers to a heterogeneous group of disorders characterized by inflammatory injury to the glomerular basement membrane (GBM), mesangium, or capillary walls, leading to impaired glomerular filtration, hematuria, proteinuria, and potentially progressive loss of renal function. The pathogenesis involves dysregulated immune responses—either autoimmune, post-infectious, or secondary to systemic diseases—that trigger complement activation, leukocyte recruitment, and deposition of immune complexes (ICs), culminating in glomerular scarring (glomerulosclerosis) and tubulointerstitial fibrosis.
Key pathophysiological mechanisms include:
- Immune complex-mediated injury (e.g., post-streptococcal GN, lupus nephritis)
- Anti-glomerular basement membrane (anti-GBM) disease
- Cell-mediated inflammation (e.g., in ANCA-associated vasculitis)
- Complement-mediated damage, especially via the alternative pathway (e.g., C3 glomerulopathy)
Note: Inflammation is not always present histologically—some entities (e.g., IgA nephropathy, focal segmental glomerulosclerosis [FSGS]) are better described as glomerulopathies with inflammatory features.
2. Classification & Epidemiology
A. Primary vs. Secondary GN
- Primary GN: Kidney-limited disease (e.g., IgA nephropathy, FSGS, membranous nephropathy).
- Secondary GN: Manifestation of systemic illness (e.g., SLE, vasculitis, diabetic kidney disease [DKD], amyloidosis).
B. Clinical Syndromes
| Syndrome | Key Features | Common Causes |
|---|---|---|
| Acute nephritic syndrome | Hematuria (macro/micro), proteinuria (<3.5 g/day), hypertension, oliguria, azotemia | Post-infectious GN, IgA nephropathy (synpharyngitic), RPGN |
| Nephrotic syndrome | Proteinuria ≥3.5 g/day, hypoalbuminemia (<3 g/dL), edema, hyperlipidemia | Membranous nephropathy, FSGS, minimal change disease, lupus nephritis (Class V) |
| Rapidly progressive GN (RPGN) | Accelerated decline in GFR (>50% loss in 3 months); crescents on biopsy | Anti-GBM, ANCA vasculitis, severe IgA vasculitis, lupus |
C. Major Histopathological Entities (KDIGO 2021 Classification)
| Entity | Key Features | Epidemiology |
|---|---|---|
| IgA nephropathy (Berger disease) | Mesangial IgA1 deposits with complement activation; recurrent macroscopic hematuria post-URI | Most common primary GN worldwide (peak onset: teens–30s); male predilection (M:F ≈ 2:1) |
| Lupus nephritis (LN) | Class I–VI (ISN/RPS); immune complex deposition; “full-house” immunofluorescence (IgG, IgA, IgM, C3, C1q) | Occurs in 30–60% of SLE patients; higher risk in children and non-White populations |
| ANCA-associated vasculitis (AAV) | Necrotizing glomerulonephritis with crescents; pauci-immune on IF; PR3/MPO-ANCA positive | Peak onset: 50–70 years; M>F |
| C3 Glomerulopathy | Dominant C3 deposition on IF without significant immunoglobulin; DDD or C3G by EM | Rare; often misdiagnosed as IgA nephropathy |
| Anti-GBM disease | Linear IgG deposits along GBM; RPGN ± pulmonary hemorrhage (Goodpasture syndrome) | Bimodal age distribution (15–30, 60–80); male predominance |
Epidemiology update: A 2023 meta-analysis (Lancet Reg Health World 2023;24:100549) estimates global incidence of primary GN at ~15/100,000 person-years. IgA nephropathy accounts for ~25–50% of biopsy-proven GN in adults and up to 60% in children.
3. Etiology & Triggers — Evidence-Based Insights
A. Post-Infectious GN (PIGN)
- Most common trigger: Group A β-hemolytic Streptococcus (e.g., M-type 12, 49). Incubation: 1–3 weeks after pharyngitis; 3–6 weeks after skin infection (e.g., impetigo).
- Mechanism: Antigenic mimicry → formation of circulating ICs → deposition in glomeruli → complement activation (mainly via lectin and alternative pathways).
- Current trends: PIGN is now rare in high-income countries due to prompt antibiotic use but remains prevalent in Indigenous populations (e.g., Australian Aboriginals, Maori) where incidence reaches 100–250/100,000 (Pediatr Nephrol 2022;37:1491).
B. Viral & Other Infections
- Hepatitis B/C: Associated with membranoproliferative GN (MPGN) type I (via IC deposition).
- HIV: FSGS (collapsing variant), IgA nephropathy, or MPGN.
- CMV, HCV, HBV: Can trigger cryoglobulinemic GN (type II/III).
C. Drug-Induced GN
- NSAIDs: Acute interstitial nephritis (AIN) > GN; rarely causes membranoproliferative or IgA-likeGN (Kidney Int Rep 2021;6:715).
- Bisphosphonates, gold, penicillamine: Associated with membranous nephropathy.
- Key point: NSAID-induced GN is rare but increasingly reported in chronic high-dose users—consider in unexplained AKI or nephrotic syndrome.
D. Genetic Forms
- Alport syndrome: X-linked (COL4A5; 90%) or autosomal recessive (COL4A3/A4); hematuria, sensorineural deafness, ocular abnormalities. Early-onset proteinuria predicts progression to ESRD by age 30–40.
- Thin basement membrane disease: Benign familial hematuria; heterozygous COL4A3/A4 variants.
4. Clinical Presentation & Red Flags
Typical Symptoms
| System | Manifestation |
|---|---|
| Renal | Macroscopic hematuria (“coca-cola” urine), proteinuria (foamy urine), edema, hypertension, oliguria |
| Systemic | Malaise, fatigue, weight loss, fever (suggestive of systemic disease) |
Red Flags for Severe/Progressive Disease
- Rapid decline in eGFR (>30% over 1–4 weeks)
- Nephrotic-range proteinuria + AKI → consider RPGN
- Hypertension unresponsive to >3 agents → rule out renal parenchymal disease
- Unexplained anemia (normocytic/normochromic) in setting of CKD
Note: Up to 40% of chronic GN cases are asymptomatic at diagnosis—detected incidentally via screening (e.g., routine urinalysis in diabetes).
5. Diagnostic Workup — Modern Standards
First-Line Tests
| Test | Interpretation |
|---|---|
| Urine dipstick & sediment | Hematuria (>5 RBC/hpf), dysmorphic RBCs, RBC casts (pathognomonic for GN); proteinuria (spot UPCR ≥0.5 suggests glomerular origin) |
| Serum creatinine/eGFR, BUN | Elevated Cr, reduced eGFR indicate impaired filtration |
| Urine protein quantification | 24-hr urine or spot UPCR (UPCR >3.5 g/g = nephrotic range) |
| ANA, anti-dsDNA, complement (C3/C4) | Low C3 with normal C4 → MPGN/cryoglobulinemia; low C3 & C4 → SLE nephritis |
Advanced/Confirmatory Tests
- Kidney biopsy (gold standard):
- Indications: Persistent AKI/CKD of unknown cause, nephrotic syndrome in adults (>40 y/o), RPGN, suspected vasculitis/LN.
- Pathologic classification per Harvard Consensus Report (Kidney Int 2019;96:532):
- Immunofluorescence (IF): IgG, IgA, IgM, C3, C1q patterns
- Light microscopy (LM): Endocapillary proliferation, crescents, membranous thickening
- Electron microscopy (EM): Electron-dense deposits (subendothelial = SLE; mesangial = IgA; subepithelial = MN)
- Serologic workup by suspected etiology:Suspected CauseTests to OrderLupus nephritisANA, anti-dsDNA, anti-Sm, C3/C4, antiphospholipid antibodiesANCA-associated vasculitisc-ANCA/PR3-ANCA, p-ANCA/MPO-ANCACryoglobulinemiaCryocrit, rheumatoid factor, HCV RNAGenetic GNCOL4A3/A4/A5 sequencing (Alport), NPHS1/NPHS2 (congenital nephrotosis)
- Imaging: Renal ultrasound (size, echogenicity, obstruction); CT/MRI if mass or vascular anomaly suspected.
6. Treatment — Evidence-Based Algorithms
General Principles
- Goal 1: Preserve renal function (reduce proteinuria, control BP).
- Goal 2: Suppress pathologic immune response.
- Goal 3: Prevent complications (CVD, infections, thrombosis).
Acute Glomerulonephritis
| Scenario | Management |
|---|---|
| Post-streptococcal GN | Supportive care only (antibiotics if active infection). Most resolve spontaneously in 6–8 weeks. Avoid immunosuppression unless crescents >50% on biopsy. |
| Lupus Nephritis (LN) | Per EULAR/ACR 2023 guidelines: – Class III/IV: Induction with mycophenolate mofetil (MMF) or low-dose IV cyclophosphamide (CYC), plus glucocorticoids (steroid-sparing protocols). – Class V: MMF ± rituximab if refractory. Evidence: MAINTAIN trial (Ann Intern Med 2021;174:937) shows non-inferiority of MMF vs CYC for maintenance; LUNAR trial supports belimumab as add-on therapy. |
| ANCA-associated vasculitis | Induction: Rituximab or cyclophosphamide + glucocorticoids (remission rates ~80% at 6 mo). Maintenance: Rituximab q6mo preferred over azathioprine (RITUXVAS trial, Arthritis Rheumatol 2022). |
Chronic Glomerulonephritis & Progressive Disease
| Condition | First-Line Therapy |
|---|---|
| IgA Nephropathy | – High-risk (eGFR <60 mL/min/1.73m², UPCR >1 g/day): 6-mo course of corticosteroids (Kidney Dis 2023;9:571). – Add-on: SGLT2 inhibitor (DAPA-CKD subanalysis: N Engl J Med 2021;384:1173), MRAs (spironolactone/finerenone reduce proteinuria by ~30%). |
| FSGS / MN | – Primary MN: Rituximab or cyclophosphamide+alkylating agents. – FSGS: Supportive care + SGLT2i (if eGFR >25). Avoid steroids unless secondary to reversible cause. |
Supportive Care (All GN Types)
- BP control: Target <120/80 mmHg (SPRINT trial);首选 ACE-i/ARB if UPCR >0.5 g/day—even if normotensive.
- Proteinuria reduction: ACE-i/ARB maximize glomerular hemodynamic benefit; SGLT2i reduces intraglomerular pressure.
- Edema management: Loop diuretics (e.g., furosemide), NaCl restriction (<2 g/day).
- Nephrotic syndrome complications:
- Thrombosis: Anticoagulate if albumin <2.5 g/dL (especially membranous nephropathy).
- Hyperlipidemia: Statins only if CVD risk elevated (not for proteinuria reduction).
- Infection risk: Pneumococcal & influenza vaccines recommended.
Renal Replacement Therapy
- Dialysis: Indicated for uremia, volume overload, severe hyperkalemia (K+ >6.5), eGFR <10 with symptoms.
- Transplant: 5-year graft survival >80% in most GN types; except recurrent FSGS (~40% recurrence risk post-transplant).
7. Prognosis & Risk Stratification
| Factor | Poor Prognostic Indicator |
|---|---|
| Clinical | eGFR <30 mL/min at diagnosis, hypertension uncontrolled, UPCR >3 g/day |
| Histologic | Crescentic GN (>50% glomeruli), interstitial fibrosis/tubular atrophy (IF/TA grade ≥2), sclerosed glomeruli |
| Biomarkers | Elevated urinary TNF-α, MCP-1, NGAL predict faster progression (KDIGO 2024 biomarker review). |
Long-term outcomes:
- IgA nephropathy: ~20–30% progress to ESRD over 20 years; higher risk with persistent proteinuria >1 g/day despite ACE-i.
- Lupus nephritis: 10-year renal survival >90% with modern immunosuppression.
8. Prevention Strategies (Evidence-Based)
- Infection prevention:
- Prompt antibiotic treatment of Group A Streptococcus pharyngitis reduces post-streptococcal GN risk by >90%.
- Hepatitis B vaccination eliminates HBV-related GN.
- Drug-induced GN:
- Avoid NSAIDs in high-risk patients (CKD, elderly, diabetes); if used, limit to <3 days and monitor urine protein.
- SGLT2 inhibitors may mitigate drug-induced injury via hemodynamic protection.
- Lifestyle: DASH diet (low Na⁺, high K⁺/Mg²⁺), smoking cessation, weight management reduce CKD progression in GN.
Key Practice Pearls for Clinicians
- “Crescentic GN is a renal emergency” — If RPGN suspected (rapid eGFR decline + hematuria), initiate immunosuppression before biopsy if contraindications exist.
- SGLT2 inhibitors are now standard-of-care in most GN—regardless of diabetes status—based on DAPA-CKD, EMPA-KIDNEY, and FIONA trials.
- Biopsy interpretation requires integration with clinical context: e.g., “dense deposit disease” on EM suggests C3 glomerulopathy—not IgA.
- Monitor for recurrence post-transplant: IgA nephropathy and FSGS are most likely to recur (check urine protein at 1, 3, 6 months).
Sources & Guidelines Cited
- KDIGO Glomerular Diseases Guideline (2021, updated 2024)
- NEJM Reviews: “IgA Nephropathy” (2023), “Lupus Nephritis” (2022)
- Clinical Trials: DAPA-CKD (N Engl J Med 2021), EMPA-KIDNEY (N Engl J Med 2024), TESTING trial (kidney Int 2022)
- UpToDate: “Approach to Glomerulonephritis in Adults” (2024)
This consolidated, evidence-based update equips clinicians to optimize diagnosis, risk-stratify, and apply targeted therapies while integrating the latest breakthroughs in nephroprotective strategies.
