Glomerulonephritis — Nephritic Syndrome

• Immune complex deposition and complement activation: The cornerstone of nephritic glomerulonephritis involves deposition of circulating immune complexes (or in-situ formation) at the glomerular basement membrane (GBM) and mesangium. These deposits activate the complement cascade via classical, alternative, or lectin pathways, generating C3a and C5a (potent chemoattractants), C3b (opsonin), and the membrane attack complex (C5b-9). In post-streptococcal GN, for example, streptococcal antigens (including streptococcal pyrogenic exotoxin B, streptococcal hyaluronate, and possibly cationic streptococcal antigens) form complexes with host antibodies; these are trapped by the glomerulus where they activate complement and recruit inflammatory cells. The resulting complement-mediated cytotoxicity and activation of resident mesangial cells and infiltrating neutrophils drives the proliferative inflammatory response characteristic of nephritic syndrome. On immunofluorescence microscopy, this typically manifests as "full house" staining in lupus (IgG, IgA, IgM, C3, C1q) or dominant C3 in C3 glomerulopathy.

• Recruitment and activation of inflammatory cells: The chemotactic gradient created by complement fragments (C5a, C3a) and released cytokines (TNF-α, IL-1, IL-6) promotes infiltration of neutrophils, monocytes/macrophages, and T lymphocytes into the glomerulus. These cells amplify inflammation by releasing proteolytic enzymes (elastase, collagenase), reactive oxygen species, and additional cytokines. Neutrophil extracellular traps (NETs) released by activated neutrophils may serve as autoantigens in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, creating a self-perpetuating cycle of inflammation. Macrophage infiltration promotes M1 pro-inflammatory polarization initially, which further amplifies glomerular injury and contributes to the proliferative changes (endocapillary proliferation, crescent formation). The number of infiltrating macrophages correlates with progression to renal failure in many forms of nephritic GN.

• Glomerular cell proliferation and structural damage: The inflammatory milieu triggers proliferation of resident glomerular cells, particularly endothelial and mesangial cells, leading to endocapillary proliferation (swelling of endothelial cells and capillary lumens filled with inflammatory cells and proliferating endothelium). In more aggressive forms of nephritic syndrome, such as crescentic GN, there is circumferential or segmental proliferation of parietal epithelial cells, forming extracapillary crescent lesions that may compress the capillary lumen and lead to rapid loss of glomerular filtration. Direct immune-mediated damage to the GBM occurs through several mechanisms: complement-mediated lysis via the membrane attack complex, antibody-dependent cellular cytotoxicity (ADCC) mediated by Fc receptors on infiltrating cells, and direct injury from neutrophil serine proteases. This structural disruption permits leakage of red blood cells and proteins into the urinary space (hematuria with dysmorphic RBCs, proteinuria). The inflammatory edema and increased glomerular cellularity reduce the filtration surface area, contributing to the reduction in glomerular filtration rate (GFR) observed in acute nephritic syndrome. Over time, if inflammation is not controlled, tubular atrophy and interstitial fibrosis develop, leading to chronic kidney disease.

• Alteration of glomerular hemodynamics and permselectivity: Beyond structural damage, inflammatory cytokines alter the glomerular filtration barrier's charge and size selectivity. Cytokine-mediated endothelial activation increases production of vasoconstrictors (endothelin, angiotensin II) and decreases vasodilators (nitric oxide, prostacyclin), leading to increased glomerular capillary hydrostatic pressure initially (compensatory response), but in the setting of severe inflammation and crescent formation, capillary obliteration ensues. The loss of the GBM charge barrier (normally negatively charged, preventing filtration of anionic proteins) results in proteinuria of non-selective nature; this is typically mild-to-moderate (<3.5 g/day) in nephritic syndrome, in contrast to nephrotic-range proteinuria. The inflammatory process also induces expression of adhesion molecules (ICAM-1, VCAM-1) on endothelial cells, facilitating cell-cell interactions that perpetuate the inflammatory cascade.

• Activation of the intrinsic pathway and coagulation: Tissue factor-bearing inflammatory cells in the glomerulus can activate the extrinsic coagulation pathway, leading to microthrombi formation within capillaries. This thrombotic microangiopathy, particularly prominent in membranoproliferative GN and some cases of lupus nephritis, contributes to capillary occlusion and ischemic injury. Fibrin deposition is visible on immunofluorescence and electron microscopy, reinforcing the systemic nature of the inflammatory activation.

• Molecular mimicry and loss of immune tolerance in secondary forms: In lupus nephritis, antibodies against double-stranded DNA (anti-dsDNA) and nucleosomes form circulating immune complexes that deposit in the glomerulus. In ANCA-associated vasculitis, mutations affecting genes encoding serine protease 3 (PR3) and myeloperoxidase (MPO), combined with environmental triggers (infections, drug exposure), break immune tolerance, allowing autoreactive T and B cells to escape regulatory T cell (Treg) control. The resulting ANCAs bind to PR3 or MPO on the surface of primed neutrophils, causing neutrophil activation, degranulation, and direct vascular injury—a mechanism distinct from immune complex-mediated nephritic syndrome but producing a similar clinical phenotype of glomerulonephritis with hematuria and hypertension.

Primary (Idiopathic) Glomerulonephritis

• IgA nephropathy (IgAN): The most common primary glomerulonephritis worldwide, accounting for up to 50% of cases in Asia and 20-30% in North America and Europe. Characterized by predominant IgA deposits in the mesangium on immunofluorescence, it results from aberrant glycosylation of serum IgA (increased O-linked galactose deficiency), allowing formation of nephritogenic IgA1-IgG complexes that deposit in the glomerulus. Risk factors include younger age (peak incidence 20-40 years), male predominance (2:1), Asian and Mediterranean ethnicity, and possibly genetic predisposition. Mucosal infections (respiratory or gastrointestinal) may trigger disease flares. Hematuria (gross or microscopic) and mild proteinuria are typical, though up to 30% of patients progress to end-stage renal disease (ESRD) within 20 years.

• Post-infectious glomerulonephritis (PIGN): Post-streptococcal GN (PSGN) is the classic acute nephritic syndrome historically and remains common in developing nations, particularly in children <12 years following group A streptococcal (GAS) throat or skin infection (impetigo). PSGN typically presents 10-14 days after infection with sudden-onset gross hematuria, hypertension, and mild renal dysfunction; the prognosis is generally favorable with >95% recovery of renal function in children, though older patients and those with delayed presentation may have slower recovery. Other post-infectious forms include post-viral GN (following hepatitis B and C, HIV, EBV), post-bacterial endocarditis GN, and post-parasitic infection GN. Non-streptococcal post-infectious GN increasingly recognized in adults, sometimes associated with methicillin-resistant Staphylococcus aureus (MRSA) or other organisms. Cryoglobulinemia associated with hepatitis C presents with hematuria and hypertension in addition to systemic vasculitis.

• Membranoproliferative glomerulonephritis (MPGN): Formerly classified into types I, II, and III but reclassified based on immunofluorescence pattern (immune complex-mediated MPGN vs. non-immune complex or pauci-immune MPGN). Immune complex MPGN associates with systemic lupus erythematosus, hepatitis C, and other infections. MPGN type II (dense intramembranous deposits/membranoproliferative GN with dense intramembranous deposits [MPGN-DID], previously called membranoproliferative GN with dense intramembranous deposits) is rare and associated with partial lipodystrophy. Non-immune complex (C3) MPGN results from dysregulation of the alternative complement pathway due to mutations in complement factor H, factor I, or factor B, or autoantibodies against factor H, placing it in the spectrum of C3 glomerulopathy.

• Rapidly progressive glomerulonephritis (RPGN) / Crescentic GN: Defined by crescents (extracapillary proliferation) in >50% of glomeruli on renal biopsy and rapid decline in GFR over days to weeks. Three pathogenic mechanisms: anti-GBM disease (antibodies directed against the NC1 domain of the α3 chain of type IV collagen; ~10-15% of RPGN cases), ANCA-associated vasculitis (~50-60% of RPGN cases), and immune complex-mediated RPGN (~20-25% of RPGN cases, including lupus, PSGN, MPGN with crescent formation). Anti-GBM disease presents as Goodpasture syndrome when pulmonary hemorrhage accompanies glomerulonephritis. ANCA-associated vasculitis encompasses granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). Risk factors for RPGN include heavy smoking (particularly for anti-GBM disease), certain HLA alleles, infections (triggering ANCA-associated disease), and drug exposures (hydralazine, levamisole-contaminated cocaine can induce ANCA).

• Lupus nephritis: Occurs in 40-80% of systemic lupus erythematosus (SLE) patients, with nephritic presentation common in WHO/ISN-RPS class III (focal proliferative), IV (diffuse proliferative), and V (membranous) lupus nephritis. Risk factors include younger age at SLE onset, non-European ancestry (African descent, Hispanic, Asian), male gender, and genetic polymorphisms in complement and Fc receptor genes. Presented as secondary GN below.

• Other primary forms: Thin basement membrane disease presents with asymptomatic hematuria but generally has excellent prognosis. Alport syndrome with X-linked inheritance presents with progressive hereditary nephritis, sensorineural hearing loss, and ocular abnormalities; males affected more severely. IgM nephropathy (monoclonal IgM deposits without IgA, IgG, or IgA) is rare.

Secondary Glomerulonephritis (Systemic Disease)

• Lupus nephritis: Most common secondary glomerulonephritis in developed countries. Lupus-mediated immune complex formation (anti-dsDNA, anti-nucleosome antibodies) leads to glomerular deposition and complement activation. Nephritic presentation with hematuria, hypertension, and proteinuria often indicates more proliferative (class III-IV) disease requiring aggressive immunosuppression.

• ANCA-associated vasculitis: GPA (formerly Wegener granulomatosis), MPA, and EGPA (formerly Churg-Strauss syndrome) present with necrotizing vasculitis affecting small and medium vessels. GPA typically associates with c-ANCA/PR3 antibodies and upper respiratory tract involvement; MPA with p-ANCA/MPO antibodies; EGPA with asthma, eosinophilia, and p-ANCA/MPO antibodies. All present with rapidly progressive nephritic syndrome and systemic manifestations (constitutional symptoms, rash, arthralgias, pulmonary infiltrates, sinusitis).

• Anti-GBM disease (Goodpasture syndrome): Autoantibodies against the NC1 domain of α3(IV)NC1 collagen; presents with pulmonary-renal syndrome (hemoptysis, pulmonary infiltrates, glomerulonephritis) or isolated glomerulonephritis. Risk factors include smoking, infections, and genetic predisposition. Rapidly progressive with crescent formation; requires immediate immunosuppression to prevent ESRD.

• Systemic infections: Hepatitis B (membranous GN or MPGN), Hepatitis C (cryoglobulinemia, MPGN), Endocarditis (immune complex GN with crescents possible), Syphilis (secondary syphilis with immune complex GN), HIV (typically HIV-associated nephropathy, but also immune complex GN in some).

• Malignancy-associated GN: Membranous GN associates with adenocarcinomas (lung, gastric, colorectal), lymphomas, and melanoma. MPGN and RPGN also reported. Mechanism involves direct deposition of tumor antigens or formation of immune complexes with tumor-associated antigens.

• Drug-induced nephritic syndrome: Hydralazine and levamisole-contaminated cocaine cause ANCA-associated vasculitis with ANCA negativity possible and risk of drug-induced lupus with nephritic features. NSAIDs rarely cause acute interstitial nephritis with nephritic features. ACE inhibitor/ARB use in certain genetic backgrounds (complement dysregulation) may unmask disease.

• Other secondary causes: Sarcoidosis (granulomatous interstitial nephritis and glomerulonephritis), Inflammatory bowel disease (IgA nephropathy, vasculitis-associated GN), Rheumatoid arthritis (with secondary amyloidosis or vasculitis), Mixed cryoglobulinemia (hepatitis C-associated).

• Gross or microscopic hematuria with dysmorphic red blood cells: The hallmark sign of nephritic syndrome, resulting from disruption of the glomerular filtration barrier allowing egress of red blood cells into the urine. Gross hematuria (tea-colored or cola-colored urine) is often the presenting complaint and may be sudden in onset, particularly in PSGN. Dysmorphic RBCs (irregular shape, membrane blebs, RBC casts) on urine microscopy indicate glomerular origin rather than lower urinary tract bleeding. The presence of RBC casts (>5 per low-power field) is highly specific for glomerulonephritis. Hematuria may persist for weeks to months even as clinical disease resolves, particularly in IgAN.

• Hypertension: Present in up to 50-80% of patients with acute nephritic syndrome, resulting from sodium retention due to reduced GFR and renin-angiotensin system activation secondary to decreased renal perfusion. In

Step 1 — confirm glomerular origin

• Urinalysis with microscopy of a fresh spun sediment: the single most important initial test. Dysmorphic RBCs, acanthocytes, and especially RBC casts localize bleeding to the glomerulus; casts form because Tamm-Horsfall protein moulds extravasated erythrocytes in the tubular lumen. Isomorphic RBCs without casts point instead to a urologic source.
• Quantify proteinuria and function: spot urine protein-to-creatinine ratio (sub-nephrotic, <3.5 g/g, in pure nephritic disease) plus serum creatinine and eGFR trend. A creatinine doubling over days to weeks defines the rapidly progressive phenotype and converts the workup into an emergency.

Step 2 — serologic triage (order before biopsy)

• Complement-based sorting: low C3 suggests post-infectious GN, C3 glomerulopathy/MPGN, cryoglobulinemia, endocarditis-associated GN, or lupus (which classically lowers both C3 and C4). Normal complement favors IgA nephropathy/IgA vasculitis, anti-GBM disease, and ANCA-associated GN.
• Targeted antibodies: ANCA with PR3/MPO ELISA, anti-GBM antibody, ANA and anti-dsDNA, ASO and anti-DNase B (anti-DNase B is the better marker after pyoderma), hepatitis B and C, HIV, cryoglobulins, and blood cultures when endocarditis is plausible.

Step 3 — kidney biopsy is the gold standard

• Light, immunofluorescence, and electron microscopy together establish the pattern: linear GBM staining (anti-GBM), pauci-immune necrotizing lesions (ANCA), mesangial IgA (IgA nephropathy), "full house" staining (lupus), subepithelial humps (post-streptococcal), tram-track double contours (MPGN).
• Named classifications: the Oxford MEST-C score grades mesangial/endocapillary hypercellularity, segmental sclerosis, tubulointerstitial fibrosis, and crescents in IgA nephropathy; the ISN/RPS classes I–VI stage lupus nephritis and drive immunosuppression; crescents in more than half of glomeruli define crescentic GN.
• KDIGO's 2021 glomerular diseases guidance supports deferring biopsy in a child with textbook post-streptococcal GN and normalizing complement, but biopsying atypical, adult, or non-resolving cases.

Immediate stabilization

• Volume and blood pressure control: sodium and fluid restriction plus a loop diuretic (furosemide) for the hypervolemic hypertension of nephritic syndrome, which is volume-dependent rather than renin-driven. Treat hypertensive emergency or pulmonary edema with IV antihypertensives and consider urgent dialysis for refractory volume overload, hyperkalemia, or uremia.
• Do not wait for biopsy in suspected RPGN: pulse IV glucocorticoids (methylprednisolone) are started empirically once a rapidly rising creatinine with an active sediment is documented, since crescents fibrose within weeks.

Disease-specific therapy (KDIGO 2021 glomerular diseases guideline)

• Post-infectious GN: supportive only. Antibiotics eradicate the organism and limit spread but do not alter the established nephritis; immunosuppression is not indicated. In endocarditis- or shunt-associated GN, treating the infection is the treatment.
• IgA nephropathy: maximally tolerated RAS blockade (ACE inhibitor or ARB) with blood pressure control and lifestyle measures as optimized supportive care; an SGLT2 inhibitor is now standard for proteinuric CKD per KDIGO. Glucocorticoids — or targeted-release budesonide — are considered only for persistent proteinuria above roughly 1 g/day despite months of optimized supportive care, weighing serious infection risk.
• ANCA-associated GN: glucocorticoids plus rituximab or cyclophosphamide for induction, then maintenance rituximab or azathioprine; the C5a-receptor antagonist avacopan allows steroid sparing. Plasma exchange is reserved for selected severe disease such as diffuse alveolar hemorrhage.
• Anti-GBM disease: a true emergency — urgent plasmapheresis plus cyclophosphamide plus corticosteroids, begun before serology returns; dialysis dependence at presentation predicts non-recovery.
• Proliferative lupus nephritis (ISN/RPS III/IV): glucocorticoids with mycophenolate mofetil or low-dose IV cyclophosphamide, increasingly combined with belimumab or voclosporin, consistent with ACR and KDIGO recommendations.

Contraindicated / cautions

• Cyclophosphamide and mycophenolate are teratogenic; ACE inhibitors and ARBs — including captopril — are contraindicated in pregnancy. Azathioprine is the pregnancy-compatible option.
• Avoid live vaccines and screen for hepatitis B and latent TB before rituximab or high-dose steroids; add PJP prophylaxis.

Disease-related — emergencies first

• Hypertensive emergency and posterior reversible encephalopathy: abrupt salt and water retention outpaces cerebral autoregulation, especially in children with post-streptococcal GN. Signals are headache, seizures, and visual loss with severely elevated pressures — treat immediately.
• Acute pulmonary edema: volume overload with a low GFR; orthopnea, rales, and a widened cardiac silhouette on chest film. Requires loop diuretics and, if refractory, urgent dialysis.
• Hyperkalemia and uremia from AKI: peaked T waves or a widened QRS mandates calcium, insulin-dextrose, and dialysis.
• Diffuse alveolar hemorrhage: hemoptysis, falling hemoglobin, and diffuse infiltrates in anti-GBM disease or ANCA vasculitis — a pulmonary-renal syndrome emergency requiring plasmapheresis and immunosuppression.
• Progression to crescentic GN and ESRD: unchecked extracapillary proliferation obliterates Bowman's space; a creatinine rising over days is the tell.
• Chronic kidney disease with tubulointerstitial fibrosis: the long-term outcome in IgA nephropathy and lupus nephritis; heralded by persistent proteinuria and shrinking kidneys.

Treatment-related

• Cyclophosphamide: acrolein metabolite injures urothelium causing hemorrhagic cystitis (prevent with hydration and mesna) plus later bladder cancer, gonadal failure, and myelosuppression — watch the CBC nadir.
• Rituximab: B-cell depletion yields hypogammaglobulinemia, recurrent infection, hepatitis B reactivation (screen HBsAg and anti-HBc first), and rarely PML.
• Glucocorticoids: infection, hyperglycemia, osteoporosis, avascular necrosis, adrenal suppression; Pneumocystis jirovecii pneumonia warrants TMP-SMX prophylaxis on prolonged high-dose therapy.
• Calcineurin inhibitors (voclosporin, tacrolimus): vasoconstrictive nephrotoxicity that can be mistaken for a disease flare — check drug levels before escalating immunosuppression.
• Plasma exchange: depletion of clotting factors and immunoglobulin, citrate-induced hypocalcemia (perioral tingling), and catheter-related bloodstream infection.
• RAS blockade: acute creatinine rise and hyperkalemia from efferent arteriolar dilation.

• RBC casts are the answer to "glomerular or not": dysmorphic RBCs plus casts with sub-nephrotic proteinuria equals nephritic syndrome. Isomorphic RBCs with clots point to a urologic source instead.
• Sort by complement first: low C3 — post-streptococcal GN, C3 glomerulopathy/MPGN, cryoglobulinemia, endocarditis; low C3 and C4 — lupus; normal complement — IgA nephropathy, anti-GBM disease, ANCA vasculitis. This single branch point answers many stems.
• Timing separates PSGN from IgA nephropathy: gross hematuria 1–3 weeks after pharyngitis or impetigo with low C3 is post-streptococcal; hematuria concurrent with an upper respiratory infection (synpharyngitic) with normal C3 is IgA nephropathy (Berger disease).
• Match the immunofluorescence pattern to the disease: linear GBM = anti-GBM; pauci-immune = ANCA; starry-sky/lumpy-bumpy granular with subepithelial humps on EM = post-streptococcal; mesangial IgA = IgA nephropathy; "full house" = lupus; tram-track double contours = MPGN.
• Best next step in suspected RPGN — rising creatinine over days with an active sediment — is urgent kidney biopsy with empiric pulse methylprednisolone, not observation. Anti-GBM disease additionally gets plasmapheresis and cyclophosphamide.
• The association examiners love: hemoptysis plus hematuria is a pulmonary-renal syndrome; smoking is the classic trigger for alveolar hemorrhage in anti-GBM disease, and upper-airway destructive lesions with c-ANCA/PR3 point to granulomatosis with polyangiitis.
• Common distractor — treating PSGN with steroids: management is supportive with salt restriction and a loop diuretic; antibiotics limit transmission but do not change the nephritis, and children recover in the vast majority of cases.
• Second distractor — hematuria plus sensorineural hearing loss is Alport syndrome (type IV collagen), not IgA nephropathy; benign familial hematuria (thin basement membrane disease) has isolated hematuria and a normal creatinine.