Chapter 5 - Acute Glomerulonephritis

A comprehensive guide to pathophysiology, classification, immune mechanisms, diagnosis, and evidence-based management of acute glomerular diseases.

📚 Nephrology · Glomerular Diseases🎓 Medical Education📅 Updated April 2026⏱ 45–60 min read

Section 1

Overview and Clinical Significance

Acute glomerulonephritis (AGN) represents a group of kidney diseases that develop rapidly over days to weeks, characterized by inflammation of the glomeruli — the functional filtering units of the kidney. This condition stands as a medical emergency requiring prompt recognition and intervention, as delayed treatment can result in permanent loss of kidney function and progression to end-stage renal disease (ESRD) requiring lifelong dialysis or transplantation.

The hallmark clinical presentation is the acute nephritic syndrome, a distinctive constellation of findings that reflects sudden glomerular injury: visible blood in the urine (hematuria), facial and extremity swelling (edema), elevated blood pressure (hypertension), and declining kidney function (azotemia). The condition affects both children and adults, though the underlying causes and prognosis vary significantly by age and etiology.

Globally, acute GN remains a significant cause of acute kidney injury, particularly in developing nations where post-infectious forms predominate. In developed countries, the spectrum has shifted toward autoimmune and vasculitic forms. Understanding the diverse etiologies, recognizing the clinical presentation, and implementing timely treatment are essential skills for all clinicians managing patients with suspected acute glomerulonephritis.

Clinical Importance: Acute GN can progress to end-stage renal disease within weeks if untreated. Early recognition of the acute nephritic syndrome and urgent diagnostic workup are critical determinants of renal outcomes.

Understanding Glomerular Structure and Function

To comprehend how acute glomerulonephritis develops, it is essential to understand normal glomerular anatomy and physiology. The glomerulus consists of several key components working in concert to filter blood while retaining essential proteins and cells.

The glomerular filtration barrier comprises three layers: the fenestrated endothelial cells lining the capillaries, the glomerular basement membrane (GBM) providing structural support, and the podocytes — specialized epithelial cells forming the final filtration barrier with their characteristic foot processes and slit diaphragms. This three-layered structure creates a size- and charge-selective filter that permits passage of water and small solutes while preventing loss of large proteins and blood cells.

When inflammation damages any component of this barrier, selective permeability is compromised. Red blood cells escape into the urine (hematuria), proteins leak across the damaged barrier (proteinuria), and the reduced filtering surface area leads to accumulation of waste products in the blood (azotemia). Inflammatory mediators simultaneously trigger changes in blood vessel tone and fluid handling, resulting in sodium and water retention that manifests as hypertension and edema.

**Figure 1.** The glomerular filtration barrier under normal conditions (left) versus acute glomerulonephritis (right). Note the immune complex deposits, GBM disruption, and escape of red blood cells and proteins in the injured state. The three-layered barrier — endothelium, GBM, and podocytes — is disrupted at multiple levels during acute inflammation.

Classification of Acute Glomerulonephritis

Acute glomerulonephritis is organized into distinct categories based on the underlying immunological mechanism driving glomerular injury. This classification is crucial because it guides diagnostic testing, predicts prognosis, and determines treatment strategies. The three principal immunopathological mechanisms are immune complex deposition, pauci-immune neutrophil-mediated injury, and direct anti-GBM antibody binding.

Immune Complex-Mediated Acute GN

In this category, the primary pathogenic mechanism involves deposition of immune complexes — aggregates of antibodies bound to antigens — within the glomerulus. These complexes activate the complement system, triggering an inflammatory cascade that damages glomerular structures. Immunofluorescence reveals a granular pattern of IgG, IgM, and/or IgA with complement deposition.

Post-Streptococcal Glomerulonephritis (PSGN)

PSGN represents the most common form of acute GN worldwide, particularly in pediatric populations. This disease follows infection with specific nephritogenic strains of Group A Streptococcus, typically from pharyngitis or impetigo. The characteristic feature is a latency period of 1–3 weeks (pharyngeal) or 3–6 weeks (skin) between the initial infection and onset of kidney disease. During this interval, the immune system generates antibodies against streptococcal antigens — particularly nephritis-associated plasmin receptor (NAPlr) and streptococcal pyrogenic exotoxin B (SPEB) — and these antibodies form complexes that deposit in the glomerulus. The alternative complement pathway becomes activated, recruiting inflammatory cells and triggering glomerular damage.

IgA Nephropathy (IgAN)

IgA nephropathy is the most frequently diagnosed primary glomerulonephritis worldwide. The disease is characterized by predominant deposition of immunoglobulin A (IgA) in the glomerular mesangium. Patients produce abnormal, galactose-deficient IgA1 (Gd-IgA1) molecules that are prone to aggregation and complex formation. A distinctive clinical feature is synpharyngitic hematuria — gross hematuria occurring concurrently with (not weeks after) upper respiratory tract infections — because the IgA response is triggered directly by mucosal antigens encountered during the infection.

Figure 4. The four-hit pathogenesis of IgA Nephropathy: (1) abnormal galactose-deficient IgA1 (Gd-IgA1) production by mucosal plasma cells; (2) autoantibody formation against Gd-IgA1; (3) mesangial immune complex deposition with alternative complement pathway activation; (4) mesangial cell proliferation and cytokine-driven injury. The lower panel illustrates the critical clinical distinction between synpharyngitic hematuria in IgAN (concurrent with infection) versus the delayed hematuria of PSGN (1–3 weeks after infection).Download

Lupus Nephritis (Class III/IV)

Lupus nephritis occurs in the context of systemic lupus erythematosus (SLE), an autoimmune disease affecting multiple organ systems. In acute lupus nephritis, circulating immune complexes containing anti-dsDNA antibodies deposit throughout the glomerulus — in the mesangium, subendothelial, and subepithelial spaces — triggering complement activation via the classical pathway. The acute proliferative forms (Class III: focal, and Class IV: diffuse) present with features of the acute nephritic syndrome and carry the greatest risk of progression to ESRD.

Membranoproliferative GN (MPGN)

MPGN is characterized by mesangial proliferation and thickening of the glomerular basement membrane, resulting from complement dysregulation or immune complex deposition. It can present acutely with nephritic features and is associated with low C3 levels due to persistent complement activation.

Pauci-Immune GN — ANCA-Associated Vasculitis (AAV)

This category encompasses diseases driven by anti-neutrophil cytoplasmic antibodies (ANCA) that bind to antigens on the surface of activated neutrophils, triggering their activation and degranulation. The release of toxic enzymes and reactive oxygen species causes direct glomerular damage, often resulting in crescent formation and rapidly progressive kidney failure. Immunofluorescence reveals a pauci-immune pattern — minimal or absent immunoglobulin and complement deposition — distinguishing this category from immune complex-mediated disease.

ANCA Vasculitis Mechanism — **Figure 5.** Mechanism of glomerular injury in ANCA-associated vasculitis. ANCA antibodies (PR3-ANCA in GPA, MPO-ANCA in MPA) bind to surface antigens on cytokine-primed neutrophils, triggering degranulation with release of serine proteases, reactive oxygen species (ROS), and neutrophil extracellular traps (NETs). The resulting necrotizing glomerulonephritis with crescent formation occurs in the absence of significant immune complex deposition — the defining feature of pauci-immune GN.

Granulomatosis with Polyangiitis (GPA)

Associated with PR3-ANCA (c-ANCA pattern). Characteristic involvement of upper respiratory tract (sinusitis, nasal granulomas), lungs (pulmonary nodules, hemorrhage), and kidneys. Formerly known as Wegener’s granulomatosis.

Microscopic Polyangiitis (MPA)

Associated with MPO-ANCA (p-ANCA pattern). Typically presents with pulmonary-renal syndrome — simultaneous pulmonary hemorrhage and glomerulonephritis — without upper respiratory granulomas.

Eosinophilic GPA (EGPA)

Combines asthma, peripheral eosinophilia, and systemic vasculitis. MPO-ANCA is frequently present. Cardiac involvement is a major cause of morbidity. Formerly known as Churg-Strauss syndrome.

Anti-Glomerular Basement Membrane (Anti-GBM) Disease

This rare but severe form of acute GN results from autoantibodies directed against the non-collagenous domain (NC1) of the alpha-3 chain of type IV collagen — a major structural component of the GBM. These antibodies bind directly to the basement membrane in a linear pattern along its entire length, which is pathognomonic for this disease. When anti-GBM antibodies also bind to the alveolar basement membrane in the lungs, the condition is termed Goodpasture’s syndrome, presenting with pulmonary hemorrhage simultaneously with rapidly progressive glomerulonephritis — a true medical emergency.

Anti-GBM Disease and Goodpasture Syndrome — **Figure 6.** Mechanism of anti-GBM disease and Goodpasture syndrome. Anti-GBM antibodies target the alpha-3(IV)NC1 domain of type IV collagen, producing linear IgG deposition along the entire GBM — the pathognomonic immunofluorescence finding. Classical complement pathway activation leads to necrotizing GN with extensive crescents (>80% of glomeruli). When anti-GBM antibodies cross-react with the alveolar basement membrane, pulmonary hemorrhage (Goodpasture syndrome) results. The urgency of treatment cannot be overstated: hours matter.

Other Forms of Acute GN

C3 Glomerulopathy results from dysregulation of the alternative complement pathway, often due to genetic mutations affecting complement regulatory proteins (e.g., Factor H, Factor I, C3 convertase mutations) or acquired inhibitors (e.g., C3 nephritic factor). This leads to uncontrolled complement activation and C3-dominant deposition in the glomerulus with minimal immunoglobulin deposition — distinguishing it from immune complex-mediated disease.

Infection-Associated GN can follow various infections beyond streptococci, including bacterial endocarditis (often staphylococcal), hepatitis B and C, HIV infection, syphilis, and malaria. In each case, microbial antigens or host antigens modified by infection trigger immune complex formation and glomerular deposition. Unlike PSGN, the infection is often still active at the time of GN presentation.

Disease	Mechanism	IF Pattern	C3	C4	Key Antibody
PSGN	Immune complex	Granular (C3-dominant)	↓↓	Normal	ASO, Anti-DNase B
IgA Nephropathy	Immune complex	Mesangial IgA-dominant	Normal	Normal	Elevated serum IgA (50%)
Lupus Nephritis	Immune complex	Granular “full house”	↓↓	↓↓	ANA, Anti-dsDNA
ANCA Vasculitis	Pauci-immune	Pauci-immune (minimal)	Normal	Normal	PR3-ANCA or MPO-ANCA
Anti-GBM Disease	Anti-GBM antibody	Linear IgG along GBM	Normal	Normal	Anti-GBM antibody
C3 Glomerulopathy	Complement dysregulation	C3-dominant, minimal Ig	↓↓	Normal	C3 nephritic factor

Section 4

Pathophysiology of Acute Glomerulonephritis

Mechanisms of Glomerular Injury

Antigen Presentation and Immune Activation

The initial event in most forms of acute GN involves presentation of foreign or self-antigens to the immune system. In PSGN, streptococcal antigens are presented to B cells and T cells, triggering antibody production and T cell-mediated immunity. In IgA nephropathy, abnormally glycosylated IgA1 molecules are recognized as antigenic. In ANCA-associated vasculitis, the immune system produces antibodies against neutrophil cytoplasmic antigens (PR3 and MPO). In anti-GBM disease, the immune system generates antibodies against basement membrane type IV collagen.

Immune Complex Formation and Deposition

In immune complex-mediated diseases, circulating antibodies bind to antigens, forming immune complexes that circulate in the bloodstream and eventually deposit in the glomerulus. Deposition occurs through passive trapping as complexes pass through glomerular capillaries, or through active mechanisms involving interactions with glomerular structures. In some diseases, antigens deposit first in the glomerulus, and antibodies subsequently bind to these “planted” antigens, forming immune complexes in situ. The size and composition of immune complexes influence their deposition pattern: large complexes tend to deposit in the subepithelial space (producing the characteristic “humps” of PSGN), while smaller complexes deposit subendothelially or in the mesangium.

Complement Activation Cascades

Immune complex deposition triggers activation of the complement system, a cascade of plasma proteins that amplify inflammation. Three pathways converge on a common effector mechanism:

The classical pathway is activated when IgG or IgM antibodies bind to antigens. C1q recognizes the antibody-antigen complex and initiates a proteolytic cascade generating C3 and C5 convertases. The alternative pathway is activated directly by certain microbial surfaces and IgA-containing immune complexes, bypassing early components and directly amplifying C3 activation. The lectin pathway is activated when mannose-binding lectin (MBL) recognizes carbohydrate patterns on pathogen surfaces, converging with the classical pathway at C3 activation.

Regardless of the initiating pathway, complement activation generates critical mediators: C3a and C5a act as potent chemoattractants drawing neutrophils and macrophages into the glomerulus; the C5b-9 membrane attack complex forms pores in the GBM; and C3b fragments mark glomerular structures for destruction by cells bearing complement receptors.

**Figure 7.** The three complement activation pathways (classical, lectin, and alternative) and their convergence at C3 cleavage, leading to glomerular injury through C5a-mediated cellular recruitment and membrane attack complex (MAC) formation. The alternative pathway is particularly important in PSGN and C3 glomerulopathy; the classical pathway predominates in lupus nephritis; the lectin pathway contributes in infection-associated forms.

Cellular Infiltration and Mediator Release

Chemoattractant fragments generated by complement activation recruit inflammatory cells into the glomerulus. Neutrophils and macrophages accumulate within glomerular capillaries and surrounding tissue. These cells release numerous harmful mediators including proteases (elastase, cathepsin G), reactive oxygen species (ROS), and cytokines (IL-1β, TNF-α, IL-6). In ANCA-associated vasculitis, this mechanism is the primary driver of injury: ANCA antibodies bind to surface antigens on primed neutrophils, triggering massive degranulation and neutrophil extracellular trap (NET) formation, causing severe glomerular damage in the absence of immune complex deposition.

Crescent Formation and Glomerular Scarring

In severe acute GN, particularly in rapidly progressive forms, intense inflammation causes necrosis of glomerular structures. The parietal epithelial cells lining Bowman’s capsule respond by proliferating, forming crescents — crescent-shaped accumulations of cells that compress the glomerular tuft and obliterate the capillary lumen. In the most severe cases, these crescents undergo fibrosis, leading to permanent scarring and irreversible loss of glomerular function. Crescents in more than 50% of glomeruli define rapidly progressive glomerulonephritis (RPGN) and predict poor renal outcomes without urgent treatment.

Systemic Consequences of Glomerular Injury

Reduction in Glomerular Filtration Rate

The inflammatory process reduces the surface area available for filtration through several mechanisms: proliferation of glomerular cells increases cellularity and reduces capillary lumen; crescent formation physically compresses the glomerular tuft; and swelling of endothelial cells narrows capillary lumens. Serum creatinine and blood urea nitrogen rise as waste products accumulate. In severe cases, GFR falls so dramatically that patients develop oliguria (<400 mL/day) or anuria.

Sodium and Water Retention

Despite reduced GFR, the kidneys retain sodium and water excessively in acute GN. Reduced GFR means less sodium is filtered and excreted. Inflammatory mediators and reduced renal perfusion activate the renin-angiotensin-aldosterone system (RAAS), increasing sodium reabsorption. Sympathetic nervous system activation further enhances sodium reabsorption. The result is positive sodium and water balance, leading to extracellular fluid volume expansion that manifests as hypertension and edema.

Electrolyte Abnormalities

The reduced GFR impairs excretion of potassium, leading to potentially life-threatening hyperkalemia. Phosphate retention leads to hyperphosphatemia, triggering secondary hyperparathyroidism and hypocalcemia. Metabolic acidosis develops as the kidneys fail to excrete hydrogen ions and regenerate bicarbonate — all consequences of the acute reduction in functional nephron mass.Section 5

Clinical Presentation

The Acute Nephritic Syndrome

The classic presentation of acute GN is the acute nephritic syndrome, a distinctive clinical pattern that should immediately alert clinicians to the possibility of glomerular disease. Recognition of this constellation is the essential first step in the diagnostic pathway.

Hematuria

Hematuria is the most common presenting symptom. Patients may report gross hematuria — visible blood in the urine appearing tea-colored, cola-colored, or frankly red — or hematuria may be detected only on urinalysis. The presence of red blood cell casts in the urine is highly specific for glomerular hematuria and is pathognomonic for glomerulonephritis. These casts form when red blood cells become trapped in a protein matrix (Tamm-Horsfall protein) within the renal tubules. Dysmorphic red blood cells — with irregular shapes caused by passage through damaged glomeruli — are another marker of glomerular bleeding.

Proteinuria

Protein loss typically ranges from 0.5 to 3 grams per day in acute GN — significant but usually below the nephrotic range (>3.5 g/day). The proteinuria results from increased glomerular permeability due to inflammatory damage. Patients may notice foamy urine from the high protein content creating surface tension. Nephrotic-range proteinuria can occur in severe forms, particularly lupus nephritis Class IV.

Hypertension

Elevated blood pressure is present in 50–80% of patients with acute GN, developing over days to weeks as sodium and water retention progresses. In some patients, hypertension is mild and asymptomatic. In others, particularly those with severe glomerular injury, blood pressure elevation can be dramatic and lead to hypertensive emergencies with encephalopathy, seizures, or acute heart failure.

Edema

Swelling develops as fluid accumulates in the interstitial space. Periorbital edema — puffiness around the eyes — is particularly characteristic and often the first sign that prompts patients to seek medical attention, especially in children. Peripheral edema affecting the hands, feet, and legs also develops. In severe cases, ascites and pleural effusions may occur.

Azotemia

Elevated serum creatinine and blood urea nitrogen reflect reduced GFR. The degree of azotemia correlates with the severity of glomerular injury. In mild cases, creatinine may be only mildly elevated. In severe cases with extensive crescent formation, creatinine can rise rapidly over days to weeks — the hallmark of rapidly progressive glomerulonephritis (RPGN), which demands urgent evaluation and treatment.

Etiology-Specific Clinical Features

Post-Streptococcal GN

Typically children 5–12 years. History of recent pharyngitis or impetigo. Latency period 1–3 weeks (pharyngeal) or 3–6 weeks (skin). Full nephritic syndrome. Excellent prognosis in children (>95% complete recovery).

IgA Nephropathy

Synpharyngitic hematuria (concurrent with URI, not delayed). Recurrent episodes of gross hematuria. Can present at any age. Slow progression over years to decades. No specific serological marker — biopsy required.

Lupus Nephritis

Young women of childbearing age. Systemic features: malar rash, arthritis, serositis, photosensitivity. Low C3 and C4. ANA and anti-dsDNA positive. Class III/IV presents with acute nephritic syndrome.

ANCA Vasculitis

Systemic symptoms: fever, weight loss, arthralgias. GPA: sinusitis, nasal granulomas, saddle-nose deformity. MPA: pulmonary hemorrhage. Rapidly progressive course — creatinine rising daily. ANCA positive in ~90%.

Anti-GBM Disease

Dramatic presentation. Rapidly progressive GN — creatinine doubling over days. Goodpasture syndrome: hemoptysis + rapidly progressive GN. Bimodal age distribution (20s and 60s). Medical emergency.Section 6

Diagnostic Evaluation

The diagnostic evaluation of suspected acute GN follows a systematic approach, beginning with clinical assessment and urinalysis, proceeding to targeted serological testing guided by complement levels, and culminating in kidney biopsy for definitive diagnosis and histological characterization.

**Figure 9.** Systematic diagnostic approach to acute glomerulonephritis, using serum complement levels (C3 and C4) as the initial branch point, followed by targeted serological testing for each disease category. This algorithm guides efficient and cost-effective workup. Kidney biopsy remains the gold standard for definitive diagnosis in all forms.

Urinalysis and Urine Microscopy

Urinalysis is the most important initial test for suspected glomerulonephritis. The presence of hematuria with red blood cell casts is highly specific for glomerular disease. Urine should be examined microscopically to identify casts, dysmorphic red blood cells, and white blood cells. Quantification of proteinuria through spot urine protein-to-creatinine ratio or 24-hour urine collection provides information about the degree of protein loss.

Complement Studies

Measurement of serum C3 and C4 levels is essential for differential diagnosis and serves as the initial branch point in the diagnostic algorithm:

Low C3, Normal C4: Alternative pathway activation — suggests PSGN, C3 glomerulopathy, or MPGN
Low C3 AND Low C4: Classical pathway activation — suggests lupus nephritis
Normal C3 and C4: Minimal complement involvement — suggests IgAN, ANCA vasculitis, or anti-GBM disease

Serological Testing

Disease	Key Serological Tests	Sensitivity	Specificity
PSGN	ASO titer, Anti-DNase B, Throat culture	ASO: 70–80%	High for recent strep infection
Lupus Nephritis	ANA, Anti-dsDNA, Anti-nucleosome, C3, C4	ANA: >95%	Anti-dsDNA: high specificity
ANCA Vasculitis	PR3-ANCA (c-ANCA), MPO-ANCA (p-ANCA)	~90% systemic, 50–80% renal-limited	High when combined with clinical features
Anti-GBM Disease	Anti-GBM antibody (ELISA or RIA)	>90% active disease	Very high
IgA Nephropathy	Serum IgA (elevated in 50%)	Low — biopsy required	Non-specific

Kidney Biopsy

Kidney biopsy provides definitive diagnosis and assessment of disease severity. Three modalities are used in combination: light microscopy reveals the pattern of glomerular injury (proliferative, necrotizing, crescent formation); immunofluorescence microscopy identifies the pattern of immunoglobulin and complement deposition, which is pathognomonic for specific diseases; and electron microscopy reveals the ultrastructure of immune deposits and glomerular damage at the nanometer level.

Section 7

Management of Acute Glomerulonephritis

Universal Supportive Care

Fluid and Sodium Restriction

Sodium intake should be restricted to 1–2 grams per day to minimize sodium retention and reduce blood pressure elevation. Fluid intake should be restricted to approximately 800–1000 mL per day plus ongoing urine output losses. Daily weights provide the most accurate assessment of fluid status — a weight gain exceeding 2–3 pounds per day suggests excessive fluid retention requiring more aggressive diuretic therapy.

Diuretic Therapy

Loop diuretics such as furosemide are the first-line agents for managing fluid overload and edema. These agents inhibit sodium reabsorption in the thick ascending limb of the loop of Henle and remain effective even when GFR is reduced. Thiazide diuretics are less effective in advanced renal dysfunction and should generally be avoided as monotherapy.

Blood Pressure Management

Target blood pressure should be less than 130/80 mmHg. ACE inhibitors and angiotensin receptor blockers (ARBs) are preferred first-line agents because they provide renal protection through hemodynamic effects (dilation of the efferent arteriole, reducing intraglomerular pressure) and anti-inflammatory effects. NSAIDs should be avoided as they can worsen renal function. For hypertensive emergencies, intravenous agents such as labetalol, hydralazine, or nicardipine should be used with careful blood pressure monitoring.

Dietary Modifications

Protein intake should be restricted to 0.6–0.8 g/kg/day when azotemia is present, reducing the nitrogen load the kidneys must excrete. Potassium restriction is necessary if serum potassium is elevated. Phosphate restriction may be required if hyperphosphatemia develops. Adequate caloric intake must be maintained to prevent catabolism.