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Glomerulonephritis — Diagnosis & Investigations
Definition & Clinical Presentation
Glomerulonephritis (GN) refers to a group of immune-mediated inflammatory conditions of the glomerulus. The classic clinical presentation is nephritic syndrome, defined as:
- Glomerular hematuria — dysmorphic RBCs and/or RBC casts in urine
- Hypertension
- Edema
- Reduced GFR (with or without oliguria)
- Non-nephrotic-range proteinuria
When GFR declines rapidly over days to weeks in this setting, it is termed Rapidly Progressive Glomerulonephritis (RPGN).
— National Kidney Foundation Primer on Kidney Diseases, 8e
Classification (Etiology-Based)
| Category | Examples |
|---|
| Immune complex-mediated | Post-infectious GN, lupus nephritis, IgA nephropathy, cryoglobulinemia, MPGN |
| Pauci-immune / ANCA-associated | Microscopic polyangiitis (MPO-ANCA), Granulomatosis with Polyangiitis (PR3-ANCA) |
| Anti-GBM antibody-mediated | Goodpasture disease/syndrome |
| Complement-mediated | C3 glomerulopathy |
| Monoclonal gammopathy-associated | MIDD, cryoglobulinemic GN |
— National Kidney Foundation Primer on Kidney Diseases, 8e; Smith & Tanagho's General Urology, 19e
Diagnosis
History & Physical Exam
- Recent throat/skin infection (1–4 weeks prior) → post-streptococcal GN
- Concurrent infection (active) → infection-associated GN
- Systemic symptoms (joints, skin, lungs) → vasculitis, lupus
- Family history → hereditary nephritis (Alport syndrome)
- Drugs (gold, penicillamine, NSAIDs) → secondary membranous nephropathy
Investigations
1. Urinalysis & Urine Microscopy
- Dysmorphic RBCs (acanthocytes) and RBC casts — pathognomonic for glomerular origin of hematuria
- Proteinuria — usually sub-nephrotic in nephritis; nephrotic range warrants evaluation for podocytopathy
- Urine culture — to exclude infection
"In glomerulonephritis, the urinalysis demonstrates macroscopic or microscopic hematuria, RBC casts, and proteinuria. Microscopic examination of urinary sediment shows dysmorphic RBCs and RBC casts."
— Tintinalli's Emergency Medicine
2. Blood Tests
Basic Panel
| Test | Relevance |
|---|
| Serum creatinine / eGFR | Assess degree of renal impairment |
| BUN | Elevated in renal failure |
| Electrolytes | Metabolic acidosis, hyperkalemia |
| CBC | Anemia of chronic disease |
| ESR / CRP | Elevated in vasculitis, infection |
Serological Panel (Key to Subtype Diagnosis)
| Test | Positive In |
|---|
| ASO titre, anti-DNAse B | Post-streptococcal GN |
| ANA, anti-dsDNA, extractable nuclear antigens (Ro, Sm, RNP) | Lupus nephritis |
| Serum complement (C3, C4) | Low in immune complex-mediated GN (see below) |
| ANCA (MPO/P-ANCA; PR3/C-ANCA) | ANCA-associated pauci-immune GN |
| Anti-GBM antibodies | Goodpasture disease/RPGN type I |
| Anti-PLA2R, anti-THSD7A | Idiopathic membranous nephropathy |
| Rheumatoid factor, cryoglobulins | Cryoglobulinemic GN (especially with HCV) |
| Hepatitis B & C serology | HBV → membranous nephropathy/MPGN; HCV → cryoglobulinemic GN |
| HIV serology | HIVAN (collapsing FSGS) |
| Serum protein electrophoresis (SPEP), urine immunofixation (UIEP) | Monoclonal gammopathy-related GN |
| SFLC (serum free light chain) | Monoclonal gammopathy |
— National Kidney Foundation Primer on Kidney Diseases, 8e
3. Complement — A Key Diagnostic Discriminator
| Complement Level | Conditions |
|---|
| Low C3 & C4 | Lupus nephritis, cryoglobulinemic GN |
| Low C3, normal C4 | Post-infectious GN, MPGN type I/II, C3 glomerulopathy, cholesterol emboli, aHUS |
| Normal complement | ANCA-associated GN, anti-GBM GN, IgA nephropathy, HSP |
"When hematuria accompanies AKI, acute glomerulonephritis should be suspected and can diagnostically be divided into low-complement GN (immune complex-mediated lesions such as lupus nephritis, postinfectious GN, and cryoglobulinemic GN) and normocomplementemic GN (classically seen in RPGN due to ANCA and anti-GBM antibody)."
— Goldman-Cecil Medicine
4. Urine Quantification
- 24-hour urine protein — nephrotic range (>3.5 g/day) vs. nephritic range (<3.5 g/day)
- Urine protein:creatinine ratio (PCR) — practical alternative to 24-hour collection
- Split urine collection — to exclude orthostatic proteinuria (supine vs. upright)
5. Imaging
- Renal ultrasound — assess kidney size, echogenicity, hydronephrosis, structural abnormalities; guides biopsy safety
- Chest CT — in suspected pulmonary-renal syndrome (ANCA vasculitis, anti-GBM disease); shows lung nodules, infiltrates, cavities, or alveolar hemorrhage
6. Renal Biopsy — Definitive Investigation
Indications:
- Proteinuria with declining GFR
- Nephrotic-range proteinuria (>3.5 g/day)
- Proteinuria + features of glomerular source (albuminuria, acanthocytes, RBC casts)
- Persistent proteinuria with SLE or other rheumatologic condition
- Unexplained hematuria with proteinuria
Three modalities are required:
| Modality | What It Shows |
|---|
| Light microscopy | Architecture — mesangial proliferation, endocapillary proliferation, crescents, sclerosis, necrosis |
| Immunofluorescence (IF) | Pattern and class of immune deposits — granular (immune complex), linear (anti-GBM), pauci-immune (ANCA) |
| Electron microscopy (EM) | Location of deposits — subepithelial "humps" (post-infectious), subendothelial, mesangial, intramembranous |
"Specific diagnoses of renal disease require targeted immunofluorescent techniques for demonstrating a variety of antigens, antibodies, and complement fractions. Electron microscopy has complemented these immunologic methods."
— Smith & Tanagho's General Urology, 19e
Immunofluorescence Patterns by GN Type
| IF Pattern | GN Type |
|---|
| Linear IgG along GBM | Anti-GBM disease / Goodpasture |
| Granular IgG + C3 (subepithelial/subendothelial) | Post-infectious GN, lupus nephritis |
| Mesangial IgA | IgA nephropathy, HSP |
| Granular IgG + C3 (subepithelial "spikes") | Membranous nephropathy |
| Pauci-immune (few/no deposits) | ANCA-associated GN |
| Mesangial IgA + C3 + IgM (schistosomal) | Schistosomal GN |
Diagnostic Algorithm Summary
Hematuria + AKI
│
├─ Low complement ──► Immune complex GN
│ (Lupus, PSGN, Cryo)
│
└─ Normal complement ──► ANCA-associated GN (check MPO/PR3)
Anti-GBM disease (check anti-GBM Ab)
IgA nephropathy
Hematuria WITHOUT AKI ──► Chronic GN (IgA, thin GBM disease)
Proteinuria > 3.5 g/day ──► Nephrotic syndrome
(Biopsy if ANA, anti-PLA2R, viral serologies)
— Goldman-Cecil Medicine; National Kidney Foundation Primer on Kidney Diseases, 8e
Specific Types at a Glance
| Type | Key Diagnostic Feature |
|---|
| Post-streptococcal GN | ↑ASO titre, ↓C3, "subepithelial humps" on EM |
| IgA nephropathy | Mesangial IgA on IF; synpharyngitic hematuria |
| Lupus nephritis | ANA+, anti-dsDNA+, ↓C3/C4; WHO class I–VI |
| ANCA-associated GN | C-ANCA (PR3) or P-ANCA (MPO); pauci-immune on IF; crescentic GN |
| Anti-GBM (Goodpasture) | Anti-GBM Ab+; linear IgG on IF; pulmonary hemorrhage + RPGN |
| Membranous nephropathy | Anti-PLA2R+; subepithelial "spike and dome" deposits |
| Cryoglobulinemic GN | RF+, ↓C3/C4, HCV+; "intraluminal thrombi" on LM |
| MPGN | ↓C3; mesangial and endocapillary proliferation; "tram-tracking" |