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Describe all types of primary glomerulonephritis

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I now have extensive, detailed content from Harrison's 22E, Robbins Pathologic Basis of Disease, and Comprehensive Clinical Nephrology 7th Ed. I have enough to write a thorough, well-organized answer covering all major primary GN types.

Primary Glomerulonephritis - Complete Overview

Primary (idiopathic) glomerulonephritis refers to glomerular disease where the kidney itself is the primary target, not secondary to a systemic illness. The major types are grouped below.

Overview & Classification

Primary GN presents as either:
  • Nephrotic syndrome - massive proteinuria (>3.5 g/day), hypoalbuminemia, edema, hyperlipidemia, lipiduria
  • Nephritic syndrome - hematuria (dysmorphic RBCs, RBC casts), hypertension, oliguria, variable proteinuria
  • Rapidly progressive (crescentic) pattern - acute loss of renal function over days to weeks

1. Minimal Change Disease (MCD)

Minimal Change Disease schematic - glomerulus appears normal with no deposits
Epidemiology: Most common cause of nephrotic syndrome in children (70-90%); accounts for only 10-15% in adults. Peak incidence at 2-6 years.
Pathogenesis: Formerly attributed solely to T-cell dysfunction causing circulating permeability factors (IL-13, IL-4) and increased CD80 on podocytes. Recent evidence identifies circulating anti-nephrin antibodies (nephrin is a key slit-diaphragm protein), causing podocyte injury and breakdown of the filtration barrier. B-cell involvement is supported by responsiveness to rituximab (anti-CD20).
Morphology:
  • Light microscopy: Normal-appearing glomeruli (hence "nil lesion")
  • Electron microscopy: Diffuse effacement (flattening/retraction) of podocyte foot processes - the hallmark lesion. No electron-dense deposits; GBM appears normal
  • Immunofluorescence: Negative, or subtle mesangial IgM; occasionally fine punctate IgG on podocytes (anti-nephrin antibody binding)
  • Proximal tubular cells are loaded with lipid and protein (historical name: lipid nephrosis)
Clinical Features:
  • Abrupt onset of nephrotic syndrome; average 24-h urine protein ~10 g; severe hypoalbuminemia
  • Acellular urinary sediment (no hematuria, no casts)
  • Hypertension in 30% of children, 20-50% of adults
  • Selective proteinuria (mainly albumin, especially in children)
  • Renal function usually preserved
Treatment & Prognosis:
  • Dramatic response to corticosteroids (>90% of children achieve complete remission after 8 weeks); adults respond more slowly but 80-90% achieve remission
  • Relapses occur in 70-75% of children after first remission
  • Steroid-dependent and frequently relapsing disease responds to rituximab
  • Excellent long-term prognosis; even steroid-dependent disease may resolve at puberty
- Harrison's Principles of Internal Medicine 22E; Robbins, Cotran & Kumar Pathologic Basis of Disease

2. Focal Segmental Glomerulosclerosis (FSGS)

Epidemiology: Most common cause of nephrotic syndrome in adults in the United States, particularly in individuals of Hispanic and African descent. Accounts for ~10% of nephrotic syndrome in children and ~35% in adults.
Pathogenesis: Primary FSGS is a diffuse podocytopathy considered to be on the same spectrum as MCD but more severe. Key mechanism involves a circulating permeability factor (possibly suPAR or others not yet fully identified) that injures podocytes diffusely, leading to focal and segmental scarring. High-risk APOL1 alleles (common in those of African ancestry) are a major genetic risk factor, causing more rapid progression to ESKD.
Morphology:
  • Sclerosis involves only a segment (not the whole) of only a subset (focal, not all) of glomeruli
  • Sclerotic lesions tend to start in the juxtamedullary glomeruli - therefore superficial biopsies may miss the diagnosis
  • Podocyte foot process effacement is diffuse (like MCD) even in unaffected glomeruli
  • On IF: IgM and C3 in sclerotic segments (non-specific, trapped)
FSGS Variants (Columbia Classification):
VariantKey Feature
Not Otherwise Specified (NOS)Most common; generic sclerosis
Tip lesionSclerosis near tubular pole; best prognosis
PerihilarSclerosis near vascular pole; often adaptive/secondary
CellularEndocapillary hypercellularity; aggressive
CollapsingGlobal capillary collapse; worst prognosis; associated with HIV, APOL1 variants
Clinical Features:
  • Nephrotic syndrome with non-selective proteinuria
  • Hypertension, microscopic hematuria, and azotemia are common at presentation
  • Unlike MCD: poor response to corticosteroids, progressive course
  • At least 50% progress to ESKD over 10 years
  • Recurs in ~30% of kidney transplants (primary FSGS much more likely to recur than secondary)
Treatment: Corticosteroids are first-line for primary FSGS; steroid-resistant disease treated with calcineurin inhibitors (cyclosporine, tacrolimus). No role for immunosuppression in secondary, adaptive, or genetic FSGS.
- Harrison's Principles of Internal Medicine 22E; Robbins, Cotran & Kumar Pathologic Basis of Disease

3. Membranous Nephropathy (Membranous GN, MGN)

Epidemiology: Accounts for ~25% of nephrotic syndrome in adults; peak incidence 30-50 years; male:female ratio 2:1. It is the most common cause of nephrotic syndrome in white adults over 40.
Pathogenesis: Chronic immune complex-mediated disease with subepithelial deposits. Major advances:
  • PLA2R (M-type phospholipase A2 receptor): Autoantibodies against this podocyte antigen cause ~60% of primary MGN. Anti-PLA2R IgG4 (poor classical complement activator) binds the basal surface of podocytes, complexes are shed to form subepithelial deposits, complement is activated (predominantly alternative pathway)
  • Other target antigens in primary MGN: NELL1, THSD7A, EXT1/EXT2 (associated with autoimmune disease), NCAM1, Sema3B, PCDH7, HTRA1
  • 20-30% is secondary (malignancy, hepatitis B, syphilis, malaria, lupus, drugs - gold, penicillamine, NSAIDs, anti-TNF agents)
Morphology:
  • LM: Uniform, diffuse thickening of the glomerular capillary wall (GBM). Normal cellularity. Silver stain shows characteristic "spikes" of GBM material projecting between subepithelial deposits
  • EM: Electron-dense deposits on the subepithelial (outer) surface of the GBM, with podocyte foot process effacement. Basement membrane material is deposited between deposits (spikes), eventually burying them
  • IF: Granular IgG and C3 deposits along peripheral capillary loops (the classic "full-house" granular staining along GBM)
Stages (Ehrenreich-Churg):
  • Stage I: Small subepithelial deposits, normal GBM
  • Stage II: GBM spikes between deposits
  • Stage III: Deposits enclosed within GBM
  • Stage IV: Irregular thickened GBM, deposits being resorbed
Clinical Features:
  • Insidious onset of nephrotic syndrome (edema, hypoalbuminemia, hyperlipidemia)
  • 15% present with sub-nephrotic proteinuria
  • Microscopic hematuria in up to 50%; hypertension in advanced disease
  • Risk of thrombosis (especially renal vein thrombosis) is higher than in any other nephrotic syndrome
  • "Rule of thirds": 1/3 spontaneous remission, 1/3 remain proteinuric but stable, 1/3 progress to ESKD
Treatment: Anti-PLA2R antibody titer guides management. Mild disease: conservative (RAAS blockade, statins). Progressive disease: immunosuppression - the Ponticelli regimen (alternating months of corticosteroids and chlorambucil/cyclophosphamide) or rituximab (now preferred first-line in many guidelines).
- Harrison's Principles of Internal Medicine 22E; Robbins, Cotran & Kumar Pathologic Basis of Disease

4. IgA Nephropathy (Berger's Disease)

Epidemiology: Most common primary GN worldwide; leading cause of renal failure globally. Particularly prevalent in Asia and among those of African ancestry carrying high-risk APOL1 alleles.
Pathogenesis: The "4-hit hypothesis":
  1. Elevated circulating galactose-deficient IgA-1 (Gd-IgA1) - the initiating event
  2. Anti-glycan autoantibodies form against the deficient hinge-region O-glycans
  3. Immune complexes form between Gd-IgA1 and anti-Gd-IgA1 IgG/IgA antibodies
  4. Complexes deposit in the mesangium, activating complement (lectin and alternative pathways) and triggering mesangial cell proliferation and injury
Morphology:
  • LM: Mesangial hypercellularity and matrix expansion (focal or diffuse); may progress to segmental sclerosis or crescents
  • IF: Dominant IgA deposits in the mesangium (hallmark); C3 co-deposition; IgG and IgM may also be present
  • EM: Mesangial electron-dense deposits; subendothelial deposits in more severe cases
  • The Oxford MEST-C score grades pathology: Mesangial hypercellularity (M), Endocapillary hypercellularity (E), Segmental sclerosis (S), Tubular atrophy/interstitial fibrosis (T), Crescents (C)
Clinical Features:
  • Classic presentation: synpharyngitic (synpneumonic) gross hematuria - hematuria appearing 1-3 days into a viral URTI (distinguishes it from postinfectious GN where hematuria is 10-21 days after infection)
  • Asymptomatic microscopic hematuria ± proteinuria (incidental finding)
  • Proteinuria >1.5 g/g protein-to-creatinine ratio with decreased GFR indicates higher risk
  • Complement levels are normal (distinguishes from PIGN)
  • May progress to ESKD; patients with high-risk APOL1 alleles progress faster
Treatment: All patients need blood pressure control (target <130/80 mmHg) and maximal RAAS blockade with ACEi/ARB. Patients with proteinuria >1 g/day despite supportive care: consider systemic corticosteroids; new therapies targeting the complement system (iptacopan, sparsentan, budesonide for targeted intestinal mucosal IgA suppression) are under investigation or recently approved.
- Harrison's Principles of Internal Medicine 22E; Comprehensive Clinical Nephrology 7th Ed

5. Membranoproliferative GN (MPGN)

MPGN glomerular schematic showing widened mesangial area, mesangial interposition, subendothelial deposits, and macrophage infiltration creating double-contour GBM
Concept: MPGN is now understood as a pattern of injury rather than a single disease. It is defined by mesangial and endocapillary hypercellularity plus GBM double-contours ("tram-tracking") due to mesangial interposition between the endothelium and GBM. It has three mechanistic subtypes:

A. Immune Complex-Mediated MPGN

Caused by chronic antigenemia with immune complex deposition:
  • Infections: Hepatitis C (most common; associated with cryoglobulinemia), hepatitis B, HIV, SBE, infected shunts
  • Autoimmune: SLE, Sjögren's syndrome, rheumatoid arthritis
  • Monoclonal immunoglobulin deposition
  • IF shows C3, IgG, IgM deposits; EM shows subendothelial ± mesangial deposits

B. Complement-Mediated MPGN (C3 Glomerulopathy)

Caused by dysregulation of the alternative complement pathway:
  • Dense Deposit Disease (DDD): Formerly MPGN type II. Defined by dense osmiophilic deposits forming ribbons within the GBM on EM (pathognomonic). Primarily affects children/young adults. C3 nephritic factor (C3NeF) stabilizes the C3 convertase. Associated with partial lipodystrophy and retinal drusen. 50% progress to ESKD. Poor prognosis
  • C3 Glomerulonephritis (C3GN): No dense ribbon deposits on EM but otherwise similar mechanism - mutations in complement factor H regulatory (CFHR) genes, C3NeF. Older average age (~30 years). Low serum C3 with normal C4. Staining: dominant C3 with little/no immunoglobulin on IF
  • Both are managed with eculizumab (anti-C5 monoclonal antibody), steroids, and RAAS blockade

C. Monoclonal Immunoglobulin-Mediated

Seen in plasma cell dyscrasias, lymphoplasmacytic lymphoma; monoclonal light/heavy chains mediate injury
General MPGN Clinical Features:
  • Presents as nephrotic syndrome, nephritic syndrome, or mixed
  • Hypocomplementemia (low C3; low C4 in immune complex types)
  • Indolent but progressive course; 50% develop ESKD within 10 years
- Harrison's Principles of Internal Medicine 22E; Comprehensive Clinical Nephrology 7th Ed

6. Postinfectious (Post-Streptococcal) GN

Epidemiology: Incidence has decreased markedly in developed countries due to antibiotic availability; still common in developing regions. Classic in children 5-12 years; can occur in adults.
Pathogenesis: Immune response to specific nephritogenic strains of group A beta-hemolytic streptococci (pharyngitis or skin/impetigo). Antibody-antigen immune complexes form in the circulation 10 days to 3 weeks after infection (latent period is critical - 1-3 weeks post-pharyngitis, 3-6 weeks post-impetigo). These complexes deposit subendothelially and activate complement (classical pathway), causing intense proliferative GN. Bacterial antigens involved include nephritis-associated plasmin receptor (NAPlr) and streptococcal pyrogenic exotoxin B (SpeB).
Morphology:
  • LM: Diffuse endocapillary proliferation with "bloodless capillaries" - infiltration by neutrophils and monocytes fills capillary lumens; mesangial expansion
  • EM: Large, hump-shaped subepithelial deposits (the "humps") - pathognomonic when present; also subendothelial deposits
  • IF: Granular "starry sky" IgG and C3 along capillary walls and mesangium; the "full-house" pattern involves both C3 and IgG
Clinical Features:
  • Acute nephritic syndrome: hematuria (tea- or cola-colored urine), oliguria, edema, hypertension
  • Oliguria and sometimes anuria; low urine Na, concentrated urine (prerenal physiology)
  • Elevated ASO titers, anti-DNase B titers, streptozyme
  • Hypocomplementemia (low C3, normal C4 - alternative pathway activation) - key diagnostic finding; C3 normalizes within 8-12 weeks
  • At time of presentation, infection may have resolved (no active infection)
Prognosis: Excellent in children - nearly complete recovery; adults have higher risk of persistent proteinuria, hypertension, and progression to CKD. Treatment is primarily supportive (salt/fluid restriction, antihypertensives, diuretics).
- Harrison's Principles of Internal Medicine 22E

7. Rapidly Progressive GN (RPGN) / Crescentic GN

Classification of RPGN: ANCA-positive vasculitis, anti-GBM disease, and low-C3 immune complex disorders
RPGN is defined clinically (rapid loss of renal function over days-weeks) and pathologically by crescents (proliferation of parietal epithelial cells and inflammatory cells surrounding and compressing glomerular capillaries) in >50% of glomeruli. There are three major immunopathologic types:

Type I: Anti-GBM Disease (Goodpasture's Disease)

  • Mechanism: Autoantibodies against type IV collagen alpha-3 chain (the Goodpasture antigen) in the GBM
  • IF: Linear IgG staining along GBM - pathognomonic pattern
  • Clinical: When confined to kidneys only = anti-GBM nephritis; when associated with pulmonary hemorrhage = Goodpasture syndrome. Young males who smoke or have inhaled hydrocarbons are at highest risk. Fulminant presentation. Anti-GBM antibodies are diagnostic
  • Treatment: Emergency plasmapheresis + cyclophosphamide/rituximab + corticosteroids. This is a single-episode disease - does not usually recur (unlike ANCA vasculitis)

Type II: Immune Complex-Mediated RPGN

  • Mechanism: Immune complex deposition with complement activation (lupus nephritis, postinfectious GN, IgAN, cryoglobulinemia, Henoch-Schönlein purpura)
  • Serology: Low C3 (complement consumption)
  • IF: Granular deposits of IgG and complement
  • Associated with: SLE, postinfectious GN, hepatitis B/C, SBE, cryoglobulinemia

Type III: Pauci-Immune RPGN (ANCA-Associated)

  • Mechanism: ANCA (antineutrophil cytoplasmic antibodies) target neutrophil granule proteins - most destructive form
    • c-ANCA (anti-PR3): Granulomatosis with polyangiitis (formerly Wegener's)
    • p-ANCA (anti-MPO): Microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis (Churg-Strauss)
  • IF: Sparse or absent deposits ("pauci-immune") - distinguishes from Types I and II
  • Clinical: Can present with pulmonary-renal syndrome (hemoptysis, epistaxis, sinusitis, nasal congestion). ANCA vasculitides may recur over time
  • Treatment: Induction with cyclophosphamide or rituximab + high-dose steroids; maintenance with rituximab or azathioprine; anti-complement therapy (avacopan) is now incorporated in guidelines
Note: Sometimes both anti-GBM and ANCA are simultaneously positive ("double-positive disease"), which has intermediate prognosis.
- Harrison's Principles of Internal Medicine 22E

8. Fibrillary GN and Immunotactoid GN

These are rare, distinct entities with organized deposits:
  • Fibrillary GN: Glomerular deposits composed of randomly arranged fibrils 10-30 nm in diameter (larger than amyloid fibrils of ~10 nm), non-congophilic (Congo red negative). Often associated with autoimmune disease or dysproteinemia
  • Immunotactoid GN: Organized microtubular deposits >30 nm, often with parallel arrangement, almost always associated with monoclonal gammopathy or lymphoplasmacytic lymphoma
Both present with proteinuria (often nephrotic range), hematuria, and hypertension, and have a poor prognosis.
- Brenner and Rector's The Kidney

Summary Table

TypePrimary SyndromeKey PathologyHallmark FindingComplementTreatment
Minimal Change DiseaseNephroticFoot process effacement on EM; normal LMAnti-nephrin antibodies; normal LMNormalCorticosteroids
FSGSNephroticFocal/segmental sclerosis; podocytopathyNon-selective proteinuria; poor steroid responseNormalSteroids, CNI; treat underlying cause
Membranous NephropathyNephroticSubepithelial deposits; GBM spikes on silver stainAnti-PLA2R antibodies; granular IF on GBMNormalRituximab; Ponticelli regimen
IgA NephropathyHematuria ± nephritic/nephroticMesangial IgA depositsSynpharyngitic hematuria; mesangial IgA on IFNormalRAAS blockade; steroids if proteinuria >1 g/day
MPGN / C3GMixed nephritic-nephroticDouble-contour GBM; mesangial proliferationTram-tracking; low C3Low C3Treat underlying cause; eculizumab for C3G
Postinfectious GNAcute nephriticSubepithelial humps on EM; endocapillary proliferationLow C3; elevated ASO titersLow C3Supportive; antihypertensives
RPGN (Crescentic)Rapidly progressiveCrescents >50% glomeruliType I: linear IF; Type II: granular IF; Type III: pauci-immune IFLow C3 (Types I, II)Plasmapheresis; cyclophosphamide/rituximab
Fibrillary/ImmunotactoidNephrotic/mixedOrganized fibrillar deposits on EM; Congo red negativeMicrotubular deposits >10 nm; non-amyloidVariableImmunosuppression; treat dysproteinemia
Sources: Harrison's Principles of Internal Medicine 22E (2025); Robbins, Cotran & Kumar Pathologic Basis of Disease; Comprehensive Clinical Nephrology 7th Ed; Brenner and Rector's The Kidney
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