Glomerulonephritis (GN) - Comprehensive Overview

Definition

• National Kidneys Foundation Primer on Kidney Diseases, 8e, p. 192
• Comprehensive Clinical Nephrology, 7th Edition

Clinical Syndromes

1. Nephrotic Syndrome

• Proteinuria >3.5 g/24 hr, serum albumin <3.5 g/dL, hyperlipidemia, edema
• Onset is insidious; heavy pitting edema, normal blood pressure (initially)
• No red cell casts; serum albumin markedly low
• Complications: hypercoagulability (loss of protein C, S, antithrombin III), renal vein thrombosis (risk when proteinuria >10 g/24 hr + albumin <2 g/dL), iron deficiency anemia (loss of transferrin), vitamin D deficiency, and hypogammaglobulinemia
• Common causes: Minimal Change Disease (MCD), FSGS, Membranous Nephropathy, Diabetic Nephropathy, Amyloidosis

2. Nephritic Syndrome

• Glomerular hematuria (dysmorphic RBCs, RBC casts), hypertension, oliguria, elevated creatinine, non-nephrotic proteinuria
• Onset is abrupt; raised jugular venous pressure, raised blood pressure
• Reflects active glomerular inflammation with proliferation and leukocyte infiltration
• Reduced GFR from capillary wall injury; hypertension from fluid retention + renin release

• Comprehensive Clinical Nephrology, 7th Edition, Table 16.4

3. Rapidly Progressive GN (RPGN)

• Rapid loss of kidney function over days to weeks in the setting of nephritic syndrome - may present as a uremic emergency
• The histopathologic equivalent is crescentic glomerulonephritis (proliferative cells in Bowman's space forming a crescent shape)
• Can co-present with pulmonary hemorrhage as pulmonary-renal syndrome (ANCA-associated GN, anti-GBM/Goodpasture syndrome)
• Harrison's Principles of Internal Medicine 22E, p. 2458

Etiology-Based Classification

A. Immune Complex-Mediated GN

• Occurs 1-4 weeks after streptococcal pharyngitis or impetigo (Group A beta-hemolytic strep, types 1, 4, 12)
• Most common in children aged 6-10 years
• Mechanism: deposition of immune complexes containing streptococcal pyogenic exotoxin B (SpeB) activates complement
• Low serum C3, elevated ASO/anti-DNase B titers
• Light microscopy: diffuse endocapillary proliferative GN with neutrophils in capillaries
• Immunofluorescence: granular IgG + C3
• Electron microscopy: subepithelial "humps" (pathognomonic)
• Treatment: supportive (treat underlying infection); generally self-limiting in children; worse prognosis in adults

• Most common primary glomerulopathy worldwide
• Pathogenesis: deposition of galactose-deficient IgA1 immune complexes in the mesangium, triggered by upper respiratory infections (synpharyngitic hematuria)
• Presents with recurrent macroscopic or microscopic hematuria ± proteinuria
• Systemic form: IgA vasculitis (Henoch-Schönlein Purpura) - skin, joint, intestinal manifestations
• Light microscopy: MEST-C score (Mesangial proliferation, Endocapillary proliferation, Segmental sclerosis, Tubular atrophy/interstitial fibrosis, Crescents)
• Immunofluorescence: mesangial IgA deposits (hallmark)
• Prognosis: 60% benign; ~40% progress to ESKD over 10-20 years
• Predictors of progression: renal insufficiency, hypertension, proteinuria >1 g/24 hr at diagnosis; T score most reliable for ESKD

• ISN/RPS classification: Classes I-VI based on biopsy
• Classes III/IV (focal/diffuse proliferative) carry worst prognosis; Class V = membranous
• Low C3, C4; positive anti-dsDNA, ANA

• "Tram-track" appearance on light microscopy (GBM duplication)
• Can present as nephrotic, nephritic, or mixed syndrome

B. ANCA-Associated (Pauci-Immune) GN

• Absence of significant immune deposits on immunofluorescence
• Three entities:
  • Microscopic polyangiitis (pANCA/MPO-ANCA)
  • Granulomatosis with Polyangiitis (Wegener's) (cANCA/PR3-ANCA)
  • Eosinophilic Granulomatosis with Polyangiitis (Churg-Strauss)
• Histology: necrotizing crescentic GN with few/no immune deposits
• Frequently presents as RPGN; can cause pulmonary-renal syndrome

C. Anti-GBM Disease (Type II RPGN)

• Autoantibodies against alpha-3 chain of type IV collagen (NC1 domain of GBM)
• Goodpasture disease = anti-GBM antibodies + RPGN + pulmonary hemorrhage
• Linear IgG deposits on immunofluorescence (distinctive pattern)
• Treatment: plasma exchange + high-dose steroids + cyclophosphamide

D. C3 Glomerulopathy

• Dysregulation of the alternative complement pathway
• Two subtypes: C3 glomerulonephritis and Dense Deposit Disease (DDD)
• Immunofluorescence: dominant C3 staining without significant immunoglobulin

E. Monoclonal Immunoglobulin-Associated GN

• Includes MIDD (monoclonal Ig deposition disease), PGNMID, immunotactoid GN, fibrillary GN (monotypic)

Diagnostic Work-Up

• Dysmorphic RBCs, RBC casts, granular casts - hallmarks of glomerular disease
• Proteinuria quantification (spot urine protein:creatinine or 24-hour urine)

• ASO, anti-DNase B (post-infectious)
• ANA, anti-dsDNA, C3, C4 (lupus)
• ANCA (MPO, PR3)
• Anti-GBM antibodies
• Cryoglobulins, hepatitis B/C serology
• Serum protein electrophoresis/free light chains (monoclonal)
• Complement (C3/C4 low in immune complex GN, normal in pauci-immune)

Management Principles

General (disease-nonspecific):

• Low-salt, protein-restricted diet (0.8-1 g/kg/day)
• ACE inhibitor or ARB for anti-proteinuric effect and blood pressure control
• Diuretics for edema
• Statins for hyperlipidemia (nephrotic syndrome)
• Anticoagulation for high thrombotic risk (nephrotic, especially membranous/amyloidosis)
• SGLT-2 inhibitors - now have strong evidence for diabetic kidney disease and proteinuric GN
• National Kidneys Foundation Primer on Kidney Diseases, 8e

Disease-Specific:

Key Distinguishing Features (Quick Reference)

Recent Evidence (2024-2026)

• A 2026 meta-analysis on IgA nephropathy (PMID: 41385286) found that even low-grade proteinuria is associated with adverse kidney outcomes, reinforcing aggressive proteinuria management.
• A 2025 systematic review on IgA nephropathy prevalence in China (PMID: 40138167) highlights growing global burden.
• A 2024 meta-analysis on lupus nephritis glucocorticoid dosing (PMID: 38766897) shows that lower glucocorticoid doses achieve comparable complete response rates with fewer serious infections.