| IgA Nephropathy |
Most common immune-mediated GN worldwide. Mean age 34–45 yr. ~60% incidental hematuria/proteinuria; ~30% synpharyngitic gross hematuria (concurrent with URI/GI infection). 5% nephrotic syndrome; 5% RPGN. |
Serum IgA elevated in ~50% (nonspecific). C3/C4 typically normal. Serologies to exclude secondary causes (ANA, ANCA, anti-GBM, HBV/HCV, SPEP). Proteinuria quantification (UPCR or 24-hr). |
LM: Mesangial hypercellularity ± endocapillary proliferation, crescents. IF: IgA-dominant or codominant mesangial deposits (with C3). EM: Mesangial electron-dense deposits. Classified by MEST-C score (Oxford). |
Supportive care: RAS inhibitor (or sparsentan), SGLT2i, BP <120/70, Na <2 g/d, smoking cessation. If proteinuria ≥0.5 g/d despite 3–6 mo supportive care: targeted-release budesonide (Nefecon), systemic glucocorticoids, or iptacopan (complement factor B inhibitor). |
1–4 |
| Membranous Nephropathy |
Leading cause of nephrotic syndrome in white adults. 80% present with nephrotic syndrome; 20% sub-nephrotic proteinuria. Peak age 50–60 yr. Must screen for secondary causes (malignancy, SLE, HBV, drugs). |
Anti-PLA2R antibody positive in ~70–80% (primary MN); anti-THSD7A in ~3%. C3/C4 normal. ANA, HBV/HCV/HIV, SPEP to exclude secondary causes. Age-appropriate cancer screening. |
LM: Thickened GBM, “spike and dome” pattern on silver stain. IF: Granular IgG4 and C3 along capillary walls. EM: Subepithelial electron-dense deposits. PLA2R staining on biopsy in ~85%. |
Supportive care for 6 mo (ACEi/ARB, lipid control, anticoagulation if albumin <2.5). Immunosuppression if persistent nephrotic syndrome: rituximab (first-line per MENTOR trial), cyclophosphamide + steroids (Ponticelli regimen), or CNI. Anti-PLA2R titer guides treatment response. |
5–9 |
| Minimal Change Disease (MCD) |
Most common cause of nephrotic syndrome in children (70–90%); ~10–17% in adults. Abrupt-onset nephrotic syndrome with severe edema. AKI in 18–33% of adults. Microscopic hematuria in 30–47% of adults. |
No specific serologic marker. Complement normal. Exclude secondary causes (NSAIDs, lymphoma, atopy). |
LM: Normal glomeruli (or minimal mesangial prominence). IF: Negative or low-intensity IgM/C3. EM: Diffuse podocyte foot process effacement without deposits. |
Prednisone 1 mg/kg/d (max 80 mg) for 4–16 wk, then taper. ~80–90% steroid-responsive. For frequent relapsers/steroid-dependent: cyclophosphamide, CNI (cyclosporine/tacrolimus), MMF, or rituximab. |
2, 10–13 |
| Focal Segmental Glomerulosclerosis (FSGS) |
Leading cause of nephrotic syndrome in Black adults in the US. 50–60% of adults present with nephrotic syndrome; remainder with sub-nephrotic proteinuria ± hematuria. Often with hypertension and reduced eGFR at diagnosis. Primary (idiopathic ~80%), secondary (adaptive, genetic, viral), or APOL1-associated. |
No specific serologic marker. Exclude secondary causes (HIV, obesity, reflux, reduced nephron mass). Genetic testing (APOL1, podocin, nephrin) if familial or steroid-resistant. |
LM: Segmental sclerosis of glomerular tuft (focal = some glomeruli, segmental = part of tuft). Variants: tip, perihilar, cellular, collapsing, NOS. IF: IgM/C3 trapping in sclerotic segments. EM: Foot process effacement (diffuse in primary; patchy in secondary). |
Primary FSGS: Prednisone (similar to MCD, but lower response ~40–60%). Steroid-resistant: CNI (cyclosporine/tacrolimus) ± low-dose prednisone. Rituximab for relapsing disease. Secondary FSGS: Treat underlying cause (weight loss, HIV treatment, etc.). RAS inhibition for all. |
2, 10, 13–14 |
| Lupus Nephritis |
Occurs in ~50% of SLE patients. Higher incidence in Black, Hispanic, Asian populations. Presentation ranges from silent proteinuria/hematuria to nephrotic syndrome to RPGN. Classified ISN/RPS Class I–VI. |
ANA (>95% sensitive), anti-dsDNA (specific, correlates with activity), low C3/C4 (both consumed). Anti-Smith Ab (specific). UPCR, CBC, Coombs test. Anti-phospholipid antibodies. |
LM: Varies by class — mesangial (I/II), focal proliferative (III), diffuse proliferative (IV), membranous (V), sclerotic (VI). “Full house” IF: IgG, IgA, IgM, C3, C4, C1q all positive. EM: Subendothelial (III/IV), subepithelial (V), mesangial deposits; tubuloreticular inclusions. |
Class III/IV: Pulse IV steroids → MMF or IV cyclophosphamide (Euro-Lupus or NIH protocol) for induction; MMF or AZA for maintenance. Add voclosporin or belimumab to MMF for enhanced response (triple therapy). Class V (pure): MMF + steroids. HCQ for all. RAS inhibitor for proteinuria. |
4, 15–18 |
| ANCA-Associated Vasculitis (GPA, MPA, EGPA) |
Pauci-immune NCGN. Renal involvement in >75%. Typically RPGN with rapid decline in GFR over days–weeks. Pulmonary-renal syndrome in ~10%. Extrarenal: sinusitis, pulmonary nodules/hemorrhage, skin, neuropathy. Peak age 65–75 yr. |
PR3-ANCA (c-ANCA): associated with GPA. MPO-ANCA (p-ANCA): associated with MPA. ~10% ANCA-negative. CRP elevated. Complement normal. Check anti-GBM (dual positivity in ~5–30%). |
LM: Focal segmental necrotizing and crescentic GN. IF: Pauci-immune (little or no Ig/complement). EM: No or scant immune deposits. Berden classification: focal, crescentic, mixed, sclerotic. |
Do not delay treatment for biopsy if ANCA+. Induction: Glucocorticoids + rituximab (preferred) or cyclophosphamide. Avacopan (C5a receptor inhibitor) as steroid-sparing adjunct. PLEX for severe AKI or DAH (debated post-PEXIVAS). Maintenance: Rituximab (superior to AZA) for ≥2 yr. |
19–22 |
| Anti-GBM Disease (Goodpasture Syndrome) |
Rare (~0.5–1/million). Bimodal age: young men (20–30 yr) with pulmonary-renal syndrome; older adults (60–70 yr) with renal-limited disease. RPGN ± diffuse alveolar hemorrhage (40–60%). Smoking/hydrocarbon exposure triggers pulmonary involvement. |
Anti-GBM antibody (ELISA; ~90% sensitive). May be negative in ~10% (biopsy required). Check ANCA — dual positivity (anti-GBM + ANCA) in 30–40%. Complement normal. |
LM: Crescentic GN (>80% of glomeruli with crescents in most cases). IF: Linear IgG along GBM (pathognomonic). EM: No discrete deposits; GBM disruption. |
Medical emergency. Plasmapheresis (daily for 2–3 wk to remove anti-GBM Ab) + cyclophosphamide + glucocorticoids. Imlifidase (IgG-degrading enzyme) under investigation. Dialysis-dependent patients with 100% crescents: poor renal prognosis; treatment individualized. Relapses rare (unlike AAV). No maintenance immunosuppression needed unless dual ANCA+. |
2, 23–26 |
| Post-Infectious (Post-Streptococcal) GN |
Classic nephritic syndrome: hematuria, edema, hypertension, oliguria. Occurs 1–3 wk after pharyngitis or 3–6 wk after impetigo. Most common in children (5–12 yr). IgA-dominant variant increasingly recognized in elderly/diabetics (staph-associated). |
Low C3 (normal C4) — alternate pathway activation; C3 normalizes in 6–8 wk. ASO titer (pharyngitis) or anti-DNase B (impetigo) elevated. Blood cultures if endocarditis suspected. ANA negative, ANCA negative. |
LM: Diffuse endocapillary proliferative GN with neutrophil infiltration. IF: Granular “starry sky” pattern of C3 and IgG along capillary walls and mesangium. EM: Subepithelial “humps” (electron-dense deposits). |
Primarily supportive: salt/fluid restriction, loop diuretics, antihypertensives. Antibiotics (penicillin) to eradicate residual streptococcal infection. Biopsy rarely needed if classic presentation. Prognosis excellent in children (>95% full recovery). Adults and IgA-dominant variant have worse outcomes. Steroids only for severe crescentic disease (anecdotal). |
2, 27–30 |
| C3 Glomerulopathy (C3GN / DDD) |
Rare. Presents with hematuria, proteinuria (often nephrotic), hypertension, reduced GFR. MPGN pattern on biopsy. ~50% progress to ESKD within 10 yr. May recur aggressively post-transplant. Young adults and children predominantly. |
Low C3 (in ~50%); C4 typically normal (alternative pathway). C3 nephritic factor (C3NeF) positive in many. Complement factor H, I, B levels and genetic testing. Exclude monoclonal gammopathy (SPEP, FLC). |
LM: MPGN pattern (mesangial proliferation, GBM duplication/“tram-tracking”) or mesangial proliferative. IF: C3-dominant (≥2 orders of magnitude > any Ig). DDD: dense intramembranous “sausage-shaped” deposits on EM. C3GN: mesangial/subendothelial deposits of lesser density. |
Supportive care (RAS inhibitor, SGLT2i). MMF + glucocorticoids for moderate–severe disease. Iptacopan (factor B inhibitor) and pegcetacoplan (C3 inhibitor) now FDA-approved for C3G. Eculizumab (anti-C5) with mixed results. Treat underlying monoclonal gammopathy if present. |
2, 4, 31–33 |
| Immune Complex MPGN (IC-MPGN) |
Historically “MPGN Type I/III.” Presents with nephrotic or nephritic syndrome, hypertension, hematuria, hypocomplementemia. Must exclude secondary causes: HCV, cryoglobulinemia, autoimmune disease, monoclonal gammopathy. |
Low C3 ± low C4 (depends on pathway). HCV, cryoglobulins, RF, ANA, SPEP/FLC. Complement pathway testing (C3NeF, factor H). |
LM: MPGN pattern — mesangial proliferation, GBM duplication, lobular appearance. IF: Ig + C3 positive (polyclonal or monoclonal). EM: Subendothelial ± mesangial deposits. |
Treat underlying cause (HCV: DAA therapy; cryoglobulinemia: rituximab; monoclonal gammopathy: clone-directed therapy). If primary/idiopathic: supportive care, MMF + steroids. Pegcetacoplan FDA-approved for primary IC-MPGN. |
4, 22, 31–33 |
| Cryoglobulinemic GN |
Associated with HCV (~90%), lymphoproliferative disorders, autoimmune disease. Presents with purpura, arthralgias, neuropathy, nephritic/nephrotic syndrome. Type II (mixed) most common. |
Cryoglobulins positive, RF positive, low C4 (classic pathway), C3 normal or low. HCV Ab/RNA. Monoclonal Ig studies. |
LM: MPGN pattern with intraluminal “hyaline thrombi” (cryoglobulin deposits). IF: IgG, IgM, C3 in capillary walls. EM: Organized subendothelial deposits with microtubular structure. |
Treat underlying cause: HCV → DAA therapy. Severe/life-threatening: rituximab + plasmapheresis ± glucocorticoids. Avoid cyclophosphamide if HCV+. |
22, 28 |
| Amyloidosis (AL, AA) |
AL: plasma cell dyscrasia; nephrotic syndrome most common renal presentation; may have cardiac, hepatic, neuropathic involvement. AA: chronic inflammation (RA, FMF, chronic infections); progressive proteinuria → nephrotic syndrome → ESKD. |
AL: Abnormal SPEP/UPEP, serum free light chains (κ or λ), bone marrow biopsy. AA: Elevated SAA (serum amyloid A). Both: normal complement, negative autoimmune serologies. |
LM: Amorphous eosinophilic deposits in mesangium/capillary walls. Congo red positive with apple-green birefringence under polarized light. EM: Randomly arranged 7–12 nm fibrils. Mass spectrometry for definitive typing. |
AL: Clone-directed chemotherapy (bortezomib-based, daratumumab-VCd); autologous SCT in eligible patients. AA: Treat underlying inflammation (anti-IL-1, anti-IL-6, anti-TNF). Supportive: RAS inhibitor, diuretics, anticoagulation if nephrotic. |
34–37 |
| Fibrillary GN |
Rare (1% of biopsies). Middle-aged adults. Nephrotic syndrome and/or hematuria with renal insufficiency. ~50% have underlying autoimmune disease, malignancy, or monoclonal gammopathy. |
No specific serologic marker. SPEP/FLC to exclude monoclonal gammopathy. Complement may be low. DNAJB9 is a highly sensitive and specific tissue biomarker. |
LM: MPGN or mesangial proliferative pattern. IF: Polyclonal IgG (usually IgG4), C3, κ and λ. EM: Randomly arranged fibrils 16–24 nm (larger than amyloid, smaller than immunotactoid). Congo red negative. DNAJB9 positive on IHC. |
No established therapy. Supportive care. Rituximab has shown partial responses in case series. Treat underlying condition if identified. Prognosis generally poor (~50% progress to ESKD within 2–4 yr). |
22, 28 |
| Thin Basement Membrane Disease |
Persistent isolated microscopic hematuria, often familial. Benign prognosis in most. May represent heterozygous carrier state for Alport syndrome (COL4A3/A4 mutations). |
Normal complement, negative serologies, minimal or no proteinuria. Genetic testing for COL4A3/A4/A5 if family history or progressive disease. |
LM: Normal. IF: Normal. EM: Diffuse thinning of GBM (<250 nm in adults; normal ~300–400 nm). No deposits. |
Observation and monitoring. Annual BP, urinalysis, proteinuria quantification. Genetic counseling if COL4A mutation confirmed. RAS inhibitor if proteinuria develops. |
10, 13 |
| Alport Syndrome |
X-linked (most common; COL4A5), autosomal recessive, or autosomal dominant. Progressive hematuria → proteinuria → ESKD (typically by 20s–30s in X-linked males). Sensorineural hearing loss, anterior lenticonus, dot-and-fleck retinopathy. |
No specific serologic marker. Genetic testing (COL4A3/A4/A5) is diagnostic standard. Absent α5(IV) chain on skin biopsy (X-linked). |
LM: Early — normal; late — FSGS pattern, interstitial fibrosis. IF: Absent or interrupted α3/α4/α5(IV) collagen staining on GBM. EM: GBM splitting, lamellation, and basket-weave appearance with variable thinning and thickening. |
No disease-specific therapy. RAS inhibitor (ACEi) started early delays ESKD (strong evidence). SGLT2i as adjunct. Avoid nephrotoxins. Renal transplantation is definitive; ~3–5% risk of post-transplant anti-GBM disease (de novo antibodies to α5 chain). |
2, 10, 13 |
| Diabetic Nephropathy |
Most common cause of ESKD globally. Progressive albuminuria (A2 → A3) → declining GFR over years. Typically in setting of long-standing DM (>10 yr), retinopathy, neuropathy. Biopsy usually not required if classic presentation. |
HbA1c, UACR (screening annually from diagnosis in T2DM, after 5 yr in T1DM). No autoimmune serologies needed unless atypical features (rapid decline, active sediment, no retinopathy). |
LM: Mesangial expansion, Kimmelstiel-Wilson nodules (nodular glomerulosclerosis), GBM thickening, arteriolar hyalinosis. IF: Linear IgG/albumin trapping (nonspecific). EM: GBM thickening, mesangial matrix expansion. |
RAS inhibitor (ACEi/ARB) for all with albuminuria. SGLT2 inhibitor (empagliflozin, dapagliflozin) — cornerstone of renoprotection. Finerenone (nsMRA) for additional CKD/CV risk reduction. GLP-1 RA. Glycemic control (HbA1c <7%). BP <130/80. |
10, 28 |