Glomerular Disease Pathology — Nephritic and Nephrotic

Key Mechanism 1: Immune Complex-Mediated Glomerulonephritis (Type III Hypersensitivity)

• Circulating or in situ-formed immune complexes (antigen-antibody) deposit in the glomerulus, activating the classical complement pathway
• Subendothelial immune complex deposition (most common in lupus and membranoproliferative GN) leads to endocapillary proliferation and glomerular injury
• Subepithelial immune complex deposition (as in membranous nephropathy) creates "spike-and-dome" ultrastructural appearance on electron microscopy
• Complement activation generates chemotactic fragments (C5a), recruiting inflammatory cells (neutrophils, macrophages) into the glomerulus
• Results in glomerular inflammation, basement membrane disruption, and loss of epithelial-endothelial barrier function

Key Mechanism 2: Anti-GBM Disease (Type II Hypersensitivity)

• Linear IgG and C3 deposition along the basement membrane in a continuous pattern (pathognomonic)
• Autoantibodies directed against the NC1 domain of type IV collagen (Goodpasture antigen)
• Direct cytotoxic injury to GBM with severe and rapidly progressive glomerulonephritis
• Often pulmonary involvement (pulmonary-renal syndrome) with alveolar hemorrhage and hemoptysis
• Results in crescent formation with fibrinoid necrosis of Bowman's capsule

Key Mechanism 3: ANCA-Associated Vasculitis (Pauci-Immune GN)

• Antineutrophil cytoplasmic antibodies (ANCA) (c-ANCA/PR3 or p-ANCA/MPO) activate neutrophils and monocytes
• Minimal or absent immune complex deposition ("pauci-immune") despite significant glomerular injury
• Neutrophils degranulate within glomeruli, releasing proteolytic enzymes and reactive oxygen species
• Results in necrotizing vasculitis of small vessels with characteristic segmental fibrinoid necrosis
• Crescent formation from Bowman's capsule rupture and proliferation of parietal epithelial cells

Key Mechanism 4: Podocyte-Mediated Injury (Primary Nephrotic Syndromes)

• Foot process effacement (fusion) of podocytes, visible on electron microscopy, reducing filtration slit area
• Loss of negative charge on the GBM (especially in minimal change disease and focal segmental glomerulosclerosis)
• Podocyte cytoskeletal proteins (nephrin, podocin) disruption leads to impaired filtration barrier integrity
• Results in selective proteinuria (primarily albumin) without structural glomerular damage
• Can progress to global glomerulosclerosis with irreversible renal insufficiency

Key Mechanism 5: Basement Membrane Structural Defects

• Thin GBM disease (hereditary nephritis): defective type IV collagen architecture
• Alport syndrome: mutations in genes encoding type IV collagen (COL4A3, COL4A4, COL4A5)
• Split basement membrane appearance ("basket-weave" on EM) pathognomonic for Alport syndrome
• Results in progressive proteinuria and hematuria with eventual hearing loss and ocular abnormalities

Nephritic Syndromes (Proliferative GN)

• Post-infectious GN (most common cause globally in children; often post-streptococcal): granular immune complex deposition, subepithelial "humps" on EM, follows Group A β-hemolytic streptococcal skin/pharyngeal infection by 1-3 weeks
• IgA nephropathy (most common primary GN worldwide): IgA-dominant immune complexes in mesangium, associated with Henoch-Schönlein purpura (HSP/IgAV), predilection for Asian and Mediterranean populations
• Lupus nephritis (SLE with glomerulonephritis in ~50% of patients): subendothelial immune complexes, "wire-loop" capillary wall appearance, full house immunofluorescence pattern (IgG, IgA, IgM, C3, C1q)
• Membranoproliferative GN (MPGN): subdivided into immune complex-mediated (post-infectious, lupus, cryoglobulinemia) and complement-mediated C3GN
• Anti-GBM disease (Goodpasture syndrome): alloimmunization or autoimmunity to type IV collagen; rapidly progressive; pulmonary-renal syndrome
• ANCA-associated vasculitis: granulomatosis with polyangiitis (GPA/Wegener), microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA/Churg-Strauss)

Nephrotic Syndromes (Non-Proliferative or Minimal Glomerular Abnormality)

• Minimal change disease (MCD) (most common cause of nephrotic syndrome in children): selective foot process effacement, normal light microscopy, accounts for ~90% of childhood nephrotic syndrome
• Focal segmental glomerulosclerosis (FSGS): segmental sclerosis in some glomeruli, progressive disease, associated with HIV, heroin, obesity, sickle cell disease
• Membranous nephropathy (MN): subepithelial immune complex deposition, spike-and-dome appearance, associated with malignancy (25% of adults), hepatitis B and C, SLE, NSAIDs
• Diabetic nephropathy (leading cause of ESRD in developed countries): nodular Kimmelstiel-Wilson lesions, basement membrane thickening, mesangial expansion
• Amyloidosis (AL and AA types): birefringent amyloid deposits under polarized light, can present with nephrotic syndrome
• Secondary causes: medications (NSAIDs, ACE inhibitors paradoxically), infections (hepatitis B and C, syphilis, malaria), malignancy, systemic diseases

Risk Factors and Predisposing Conditions

• Genetic predisposition (Alport syndrome, familial FSGS, hereditary nephritis)
• Infection (post-streptococcal, viral hepatitis, endocarditis)
• Autoimmune disease (SLE, vasculitis)
• Metabolic/systemic disease (diabetes, amyloidosis, obesity)
• Medications (NSAIDs, ACE inhibitors, penicillamine, gold)
• Malignancy-associated glomerulonephritis

Nephritic Syndrome (Acute Glomerulonephritis)

• Hematuria (often gross, tea or cola-colored urine): due to breach of GBM with egress of RBCs into Bowman's space and tubules
• RBC casts on urine microscopy: pathognomonic for glomerulonephritis, indicating RBCs trapped in Tamm-Horsfall protein matrix within tubules
• Mild-to-moderate proteinuria (typically <3-4 g/day; often <1 g/day): selective proteinuria reflects GBM permeability change
• Azotemia and elevated creatinine: reflects reduced GFR from inflamed, proliferative glomeruli narrowing capillary lumens
• Hypertension: from sodium retention and fluid overload due to reduced GFR; activation of RAAS; cytokine-mediated vasoconstriction
• Edema (periorbital and lower extremity): from sodium retention and hypervolemia; typically mild compared to nephrotic syndrome
• Oliguria (in severe cases): from marked reduction in filtration surface area

Nephrotic Syndrome (Non-Proliferative Disease)

• Heavy proteinuria (>3.5 g/day; often >10 g/day in membranous disease): from podocyte foot process effacement and loss of charge barrier
• Hypoalbuminemia (serum albumin <2.5 g/dL): from massive urinary protein loss exceeding hepatic synthesis
• Edema (often massive, anasarca): from reduced plasma oncotic pressure secondary to hypoalbuminemia and sodium retention
• Hyperlipidemia (elevated cholesterol and triglycerides): from increased hepatic synthesis of lipoproteins in response to hypoalbuminemia; also impaired lipoprotein catabolism
• Lipiduria (oval fat bodies and fatty casts on urinalysis): from glomerular permeability to lipoproteins and their uptake by tubular epithelium
• Minimal hematuria (if present): distinguishes from nephritic syndromes
• Normal or near-normal renal function (initially): reflects minimal structural glomerular damage
• Hypercoagulability and thromboembolic complications: from urinary loss of anticoagulants (antithrombin III, protein C), elevation of prothrombotic factors, hemoconcentration
• Susceptibility to infection (especially bacterial peritonitis in ascitic patients): from urinary loss of immunoglobulins and complement

Overlap Syndromes (Mixed Features)

• Moderate proteinuria (1-3.5 g/day): seen in lupus nephritis, MPGN
• Hematuria with significant proteinuria: suggestive of proliferative lesion with podocyte involvement
• Acute renal insufficiency with nephrotic features: indicates aggressive disease requiring urgent treatment

Urinalysis and Microscopy

• Active urinary sediment: RBC casts (hallmark of glomerulonephritis), WBC casts (suggest inflammation/infection), granular casts, waxy casts (signify chronic kidney disease)
• Dysmorphic RBCs (morphologically distorted from passage through damaged glomeruli): indicates glomerular bleeding
• Proteinuria quantification: 24-hour urine protein or spot urine protein-to-creatinine ratio (UPCR); nephrotic range ≥3.5 g/24 hours
• Lipiduria: oval fat bodies (lipid-laden tubular epithelial cells), fatty casts under light microscopy; confirmed with Sudan black or Oil Red O staining

Serum Chemistry and Immunology

• Elevated creatinine and BUN: reflects reduced GFR; severity correlates with glomerular proliferation/necrosis
• Hypoalbuminemia: characteristic of nephrotic syndrome; <2.5 g/dL indicates significant disease
• Hyperlipidemia: elevated total cholesterol and LDL; hypertriglyceridemia; pattern reflects altered lipoprotein metabolism
• Complement levels: low C3 and C4 in immune complex disease (lupus, post-infectious GN, cryoglobulinemia); normal in IgA nephropathy, pauci-immune ANCA disease (distinguishing feature)
• ANA, anti-dsDNA, anti-Smith antibodies: for lupus nephritis (SLE diagnosis)
• ANCA serologies: c-ANCA (PR3) for GPA; p-ANCA (MPO) for MPA or EGPA
• Anti-GBM antibodies: present in Goodpasture syndrome; rare (<1% of GN cases) but highly specific
• Cryoglobulins: in cryoglobulinemia-associated GN
• IgA level: elevated in IgA nephropathy but not diagnostic
• Hepatitis B and C serologies: to exclude secondary MN

Renal Biopsy and Histopathology

Light Microscopy (LM) Findings

• Minimal Change Disease: normal glomeruli on LM; diagnosis by exclusion and EM findings; absence of proliferation is key
• Post-Infectious GN (PSGN): diffuse endocapillary proliferation (increased cellularity within capillary lumens); crescent formation variable; lobular pattern to mesangial proliferation
• IgA Nephropathy: dominant IgA immune complex deposition in mesangium on IF; mesangial proliferation on LM; capillary wall involvement variable; segmental sclerosis in advanced disease
• Lupus Nephritis: Class I (minimal mesangial), Class II (mesangial proliferation), Class III (focal proliferative; endocapillary or extracapillary), Class IV (diffuse proliferative; most severe; endocapillary or extracapillary), Class V (membranous), Class VI (advanced sclerotic)
• Wire-loop lesions: subendothelial immune complex deposits creating capillary wall thickening
• Hyaline thrombi (platelet-fibrin thrombi): another classic lupus finding
• Fibrinoid necrosis in severe lupus GN
• MPGN: endocapillary proliferation with double contours or ribbon-like appearance of capillary walls on LM; tram-track sign on EM (electron-dense deposits within GBM)
• Anti-GBM Disease: crescents (fibrin, proliferating parietal epithelium, mononuclear cells) involving multiple glomeruli; fibrinoid necrosis of Bowman's capsule; minimal immune complex deposition (pauci-immune pattern)
• ANCA-Associated GN (Pauci-Immune): segmental fibrinoid necrosis, crescents (often cellular and/or fibrous), minimal or absent immune complex deposition; can show necrotizing vasculitis in arterioles
• Membranous Nephropathy: thickened capillary walls with spike-and-dome appearance (subepithelial projections); no proliferation; granular immune complex deposition on IF
• FSGS: segmental sclerosis in some (not all) glomeruli; hyalinosis; podocyte hypertrophy; progressive to global sclerosis
• Diabetic Nephropathy: Kimmelstiel-Wilson nodules (mesangial expansion with peripheral glomerular capillary loops spared); capsular drops (PAS-positive hyaline material); GBM thickening

Immunofluorescence (IF) Microscopy

• Linear IF pattern (continuous IgG and C3 along GBM): pathognomonic for anti-GBM disease
• Granular IF pattern (IgG, IgA, IgM, C3, ±C1q): characteristic of immune complex disease
• Full house pattern (all 5 antibodies positive): highly specific for lupus
• IgA-dominant (with IgG, C3): IgA nephropathy
• IgA and IgM dominant (without IgG): HSP-IgAV
• Negative IF ("pauci-immune"): ANCA-associated GN; confirms diagnosis in appropriate clinical context

Electron Microscopy (EM)

• Foot process effacement: hallmark of nephrotic syndrome and minimal change disease
• **Subepithelial

Immediate stabilisation (nephritic/RPGN)

• Volume and blood pressure control: loop diuretic (furosemide) plus sodium restriction for the hypervolemic hypertension of acute nephritic syndrome; hypertensive encephalopathy or pulmonary edema is an emergency requiring IV therapy and consideration of urgent dialysis for refractory volume overload, hyperkalemia, or uremia.
• Empiric pulse glucocorticoids (IV methylprednisolone) when biopsy or serology suggests crescentic GN — KDIGO's 2021 glomerular disease guideline stresses that treatment of rapidly progressive GN should not wait for a definitive histologic diagnosis.

Disease-specific first-line therapy (KDIGO 2021)

• Anti-GBM disease: plasmapheresis to remove circulating anti-NC1 antibody, plus corticosteroids and cyclophosphamide. Start before dialysis dependence — recovery is unlikely once oligoanuric.
• ANCA-associated GN: glucocorticoids plus either cyclophosphamide or rituximab for induction, then maintenance rituximab or azathioprine. Plasma exchange is reserved for severe renal failure or diffuse alveolar hemorrhage.
• Lupus nephritis (class III/IV): glucocorticoids plus mycophenolate mofetil or low-dose cyclophosphamide; hydroxychloroquine for all patients. Belimumab or a calcineurin inhibitor may be added.
• Minimal change disease: corticosteroids (prednisone) — in a child 2–10 years with classic nephrotic syndrome, treat empirically without biopsy.
• Membranous nephropathy: supportive care for low-risk disease; rituximab or cyclophosphamide-based regimens for moderate-to-high risk with persistent proteinuria.
• IgA nephropathy: maximally tolerated RAS blockade and BP control first; glucocorticoids only if proteinuria persists despite optimized supportive care.
• Post-streptococcal GN: supportive only — antibiotics treat the infection but do not alter the nephritis.

Universal supportive therapy

• RAS blockade (ACE inhibitor or ARB) for antiproteinuric effect via efferent arteriolar dilation; statin for nephrotic hyperlipidemia; SGLT2 inhibitor for proteinuric CKD, and in diabetic kidney disease the ADA Standards of Care add finerenone and GLP-1 receptor agonists.

Contraindicated/cautioned

• ACE inhibitors and ARBs in pregnancy (fetal renal dysgenesis) and combined ACEI+ARB (hyperkalemia, AKI); NSAIDs; live vaccines during immunosuppression. Screen for hepatitis B before rituximab and give PCP prophylaxis with cyclophosphamide/high-dose steroids.

Emergencies

• Hypertensive encephalopathy and pulmonary edema (classically in post-streptococcal GN in children): salt and water retention behind a low GFR expands the intravascular volume. Signals: headache, seizure, papilledema, hypoxemia with bilateral infiltrates.
• Diffuse alveolar hemorrhage in anti-GBM disease and ANCA vasculitis: shared type IV collagen epitope or capillaritis in the alveolus. Signals: hemoptysis, dropping hemoglobin with new infiltrates, and a rising DLCO.
• Life-threatening hyperkalemia and uremia from oliguric AKI — indications for urgent dialysis.
• Renal vein thrombosis / pulmonary embolism: urinary loss of antithrombin III (and protein C/S) with increased hepatic fibrinogen creates hypercoagulability, greatest in membranous nephropathy and when albumin is markedly low. Signal: abrupt flank pain, gross hematuria, and a sudden rise in proteinuria or creatinine.
• Spontaneous bacterial peritonitis in nephrotic children with ascites: loss of IgG and complement factor B impairs opsonization; Streptococcus pneumoniae and E. coli predominate. Signal: fever and abdominal tenderness with ascites.

Disease complications

• Progression to ESRD: crescents, interstitial fibrosis, and tubular atrophy on biopsy are the strongest histologic predictors; signaled by falling GFR and shrunken echogenic kidneys.
• Protein-loss syndromes: iron-refractory anemia (transferrin loss), vitamin D deficiency with secondary hyperparathyroidism (loss of vitamin D–binding protein), and hypothyroidism (thyroxine-binding globulin loss).
• Accelerated atherosclerosis from chronic nephrotic hyperlipidemia.

Treatment complications

• Glucocorticoids: hyperglycemia, osteoporosis, avascular necrosis, adrenal suppression, opportunistic infection.
• Cyclophosphamide: hemorrhagic cystitis from acrolein (prevent with mesna and hydration), later urothelial carcinoma, infertility, myelosuppression.
• Calcineurin inhibitors: dose-dependent nephrotoxicity from afferent arteriolar vasoconstriction — a rising creatinine that mimics disease relapse.
• Rituximab: hepatitis B reactivation, hypogammaglobulinemia, rarely PML.
• RAS blockade and MRAs: hyperkalemia and an expected early creatinine bump; SGLT2 inhibitors: euglycemic ketoacidosis and genital mycotic infection.

• Timing separates the two hematurias: gross hematuria during an upper respiratory infection (1–3 days, synpharyngitic) is IgA nephropathy; cola-colored urine 1–3 weeks after pharyngitis or impetigo is post-streptococcal GN. This is the single most tested nephritic discriminator.
• Complement is the branch point: low C3 suggests PSGN, lupus nephritis, MPGN/C3 glomerulopathy, or cryoglobulinemia; normal C3 suggests IgA nephropathy, anti-GBM disease, and ANCA-associated GN. In PSGN the C3 should normalize within roughly two months — persistently low C3 should redirect you to C3 glomerulopathy.
• Best next step in a 2–10 year old with nephrotic syndrome: empiric corticosteroids, not biopsy. Biopsy is reserved for steroid resistance, age outside that window, hematuria/hypertension, low complement, or renal insufficiency.
• Best next step in suspected anti-GBM disease (hemoptysis plus RPGN, linear IgG on IF): urgent plasmapheresis with steroids and cyclophosphamide — do not simply await biopsy.
• Adult membranous nephropathy: think anti-PLA2R antibody (primary) and screen for malignancy, hepatitis B, SLE, and NSAIDs (secondary). Its classic complication is renal vein thrombosis.
• The EM buzzwords: subepithelial humps = PSGN; spike-and-dome = membranous; tram-track/double contours = MPGN; diffuse foot process effacement with normal LM = minimal change; basket-weave GBM splitting = Alport.
• The association examiners love: HIV → collapsing FSGS; also heroin, obesity, and sickle cell for FSGS generally.
• Common distractors: RBC casts and dysmorphic RBCs mean nephritic, while oval fat bodies and Maltese crosses mean nephrotic — do not accept isolated hematuria with a normal biopsy as nephritis (that is thin basement membrane disease, benign, and must be distinguished from Alport, which adds sensorineural hearing loss and lenticonus). Also, pauci-immune means negative IF, not negative ANCA.