Glomerulonephritis (Nephritic Syndrome)

1. Clinical Overview

Glomerulonephritis (GN) represents a heterogeneous group of immune-mediated disorders characterized by inflammation of the glomeruli, the microscopic filtration units of the kidney. The condition classically presents as nephritic syndrome, a clinical constellation that distinguishes it from the more proteinuric nephrotic syndrome. The nephritic syndrome comprises four cardinal features: (1) haematuria with dysmorphic red blood cells and red cell casts, (2) hypertension secondary to sodium and water retention, (3) oliguria with acute kidney injury (AKI) due to reduced glomerular filtration rate (GFR), and (4) mild-to-moderate proteinuria (typically less than 3 g/24 hours). [1,2]

The clinical spectrum of glomerulonephritis ranges from benign, self-limiting disease (such as post-streptococcal GN in children) to aggressive, life-threatening conditions (such as anti-GBM disease or ANCA-associated vasculitis) that can progress to irreversible end-stage renal disease (ESRD) within weeks if untreated. The global burden of glomerulonephritis is substantial, with IgA nephropathy alone accounting for up to 40% of primary glomerulonephritis cases worldwide and representing the leading cause of ESRD in young adults in East Asia. [3] Early recognition, accurate diagnosis through immunological screening and renal biopsy, and prompt initiation of appropriate therapy are essential to preserve renal function and prevent progression to dialysis dependence.

The importance of glomerulonephritis extends beyond nephrology. Many forms of GN are manifestations of systemic autoimmune diseases (lupus nephritis, ANCA vasculitis), infections (post-infectious GN, hepatitis-associated cryoglobulinaemia), or represent pulmonary-renal syndromes requiring urgent multidisciplinary management. The concept of "time equals nephrons" underpins the emergency nature of rapidly progressive glomerulonephritis (RPGN), where irreversible glomerular scarring can occur within days, making urgent nephrology referral and expedited biopsy critical to salvaging renal function. [4]

Clinical Pearls

Synpharyngitic vs Post-Infectious Timing: The temporal relationship between upper respiratory tract infection and haematuria is a crucial diagnostic discriminator in young adults presenting with macroscopic haematuria.

• IgA Nephropathy (Berger's Disease): Haematuria occurs 1-2 days after pharyngitis or upper respiratory tract infection (synpharyngitic haematuria). This immediate timing reflects mucosal immune activation with rapid IgA complex deposition in glomeruli.
• Post-Streptococcal GN: Haematuria occurs 10-21 days after Group A Streptococcal pharyngitis or 3-6 weeks after skin infection (post-infectious pattern). This latency period represents the time required for immune complex formation and glomerular deposition.

Pulmonary-Renal Syndrome: The simultaneous presentation of acute kidney injury with pulmonary haemorrhage (haemoptysis, alveolar infiltrates on chest imaging, falling haemoglobin) is a medical emergency that narrows the differential to two life-threatening conditions until proven otherwise:

• Goodpasture's Disease (Anti-GBM Disease): Linear IgG deposition on immunofluorescence, anti-GBM antibodies targeting α3 chain of type IV collagen in basement membranes.
• ANCA-Associated Vasculitis (particularly Granulomatosis with Polyangiitis): Pauci-immune necrotizing crescentic GN with cANCA (PR3) positivity and systemic features (sinusitis, epistaxis, orbital inflammation). Both require urgent plasma exchange, high-dose corticosteroids, and cyclophosphamide or rituximab to prevent irreversible organ damage. [5]

Red Cell Casts: The pathognomonic finding on urine microscopy that confirms glomerular origin of haematuria. Red blood cells are forced through the damaged glomerular basement membrane (GBM), undergo morphological distortion (acanthocytes, dysmorphic RBCs), and become trapped and cemented together by Tamm-Horsfall protein (uromodulin) within the renal tubules, forming cylindrical casts. Their presence definitively localizes bleeding to the glomerulus rather than the bladder, ureters, or urethra, and is highly specific for glomerulonephritis. [6]

Complement as a Diagnostic Tool: Serum complement levels (C3, C4) provide crucial mechanistic insight into the type of glomerulonephritis:

• Low C3 and C4: Post-infectious GN, lupus nephritis (activation of both classical and alternative pathways)
• Low C3, Normal C4: Membranoproliferative GN, C3 glomerulopathy (alternative pathway dysregulation)
• Normal C3 and C4: IgA nephropathy, ANCA vasculitis, anti-GBM disease (pauci-immune or non-complement-mediated mechanisms)

---

2. Epidemiology

Global and Regional Patterns

Glomerulonephritis represents a significant global health burden with marked geographic and ethnic variation in disease prevalence and etiology. The epidemiology of specific glomerulonephritis subtypes reflects environmental exposures, genetic predisposition, and access to healthcare.

Temporal Trends

The epidemiology of glomerulonephritis has evolved significantly over recent decades:

1. Declining Post-Infectious GN: Improved socioeconomic conditions, antibiotic availability, and better hygiene have dramatically reduced post-streptococcal GN in high-income countries, though it remains a significant cause of AKI in low- and middle-income countries, particularly following skin infections in tropical climates. [9]

2. Rising ANCA Vasculitis: The incidence of ANCA-associated vasculitis has increased, likely reflecting improved diagnostic capabilities (ANCA testing availability), heightened awareness, and aging populations, with the highest incidence rates now observed in individuals > 65 years. [7]

3. Shifting Infection-Associated GN: While post-streptococcal GN has declined, other infection-related glomerulonephritis patterns have emerged, particularly Hepatitis C-associated cryoglobulinaemic GN (declining with direct-acting antivirals) and staphylococcal-associated GN in elderly patients with comorbidities.

4. Geographic Persistence of IgA Nephropathy: IgA nephropathy remains the most common primary GN globally, with particularly high prevalence in Asia. Population-based screening programs in Japan and Korea have revealed asymptomatic IgA nephropathy in up to 5% of individuals with isolated microscopic haematuria. [10]

Risk Factors

Modifiable Risk Factors:

• Streptococcal infections: Group A β-haemolytic streptococcus (pharyngitis, pyoderma)
• Chronic viral infections: Hepatitis B, Hepatitis C (cryoglobulinaemia, membranous nephropathy)
• Bacterial endocarditis: Immune complex-mediated GN
• Environmental exposures: Silica exposure (increased risk of ANCA vasculitis)
• Medications: Hydralazine, propylthiouracil, allopurinol, penicillamine (drug-induced ANCA vasculitis)

Non-Modifiable Risk Factors:

• Genetic predisposition: HLA-DR4 (Goodpasture's), HLA-DQ variants (IgA nephropathy), complement factor H mutations (C3 glomerulopathy)
• Family history: First-degree relatives have 4-9 fold increased risk of IgA nephropathy
• Ethnicity: Asian ancestry (IgA nephropathy), African ancestry (APOL1-associated collapsing glomerulopathy in lupus)
• Sex: Male (IgA nephropathy, Goodpasture's), Female (lupus nephritis)
• Age: Elderly at higher risk for ANCA vasculitis and crescentic GN

---

3. Aetiology and Pathophysiology

Classification by Pathogenic Mechanism

Glomerulonephritis can be classified into three fundamental pathogenic mechanisms based on the immunological process driving glomerular injury:

1. Immune Complex-Mediated Glomerulonephritis

Mechanism: Circulating or in situ immune complexes (antigen-antibody combinations) deposit in glomerular structures, activating complement cascades and recruiting inflammatory cells.

Patterns of Deposition:

• Mesangial: IgA nephropathy, IgA vasculitis
• Subendothelial (between GBM and endothelium): Lupus nephritis, post-infectious GN, MPGN
• Subepithelial (between GBM and podocytes): Post-streptococcal GN (classically), membranous nephropathy
• Intramembranous: Dense deposit disease, C3 glomerulopathy

Immunofluorescence Pattern: Granular ("lumpy-bumpy") IgG, IgM, IgA, and/or C3 deposition

Clinical Examples:

• Post-Streptococcal GN: Streptococcal antigen-antibody complexes deposit subepithelially; complement consumption (low C3, low C4 in acute phase) drives inflammation
• IgA Nephropathy: Galactose-deficient IgA1 (Gd-IgA1) forms circulating complexes that deposit in mesangium; predominantly mesangial IgA deposition with co-dominant C3
• Lupus Nephritis: DNA-anti-DNA complexes deposit in various locations (mesangial, subendothelial, subepithelial) depending on lupus nephritis class; consumption of both C3 and C4 via classical pathway
• Cryoglobulinaemic GN: Mixed cryoglobulins (often IgM-IgG rheumatoid factor complexes associated with Hepatitis C) deposit in glomeruli and small vessels

2. Anti-Glomerular Basement Membrane (Anti-GBM) Antibody Disease

Mechanism: Autoantibodies directed against the α3 chain of type IV collagen (specifically the NC1 domain) in glomerular and alveolar basement membranes cause direct antibody-mediated injury.

Immunofluorescence Pattern: Linear IgG deposition along GBM (pathognomonic)

Clinical Features:

• Goodpasture Syndrome: Pulmonary-renal syndrome with pulmonary haemorrhage and rapidly progressive GN
• Renal-Limited Disease: 40% present without pulmonary involvement
• Triggers: Smoking, hydrocarbon exposure, viral infections may expose cryptic epitopes
• Genetic Association: HLA-DR15 (increased susceptibility), HLA-DR1 (protection)

Prognostic Factors:

• Degree of renal failure at presentation: Dialysis-dependent at diagnosis carries less than 10% chance of renal recovery [11]
• Percentage of crescents on biopsy: > 50% crescents indicates poor prognosis
• Timing of treatment: Plasma exchange within 14 days of diagnosis improves outcomes

3. Pauci-Immune Glomerulonephritis (ANCA-Associated)

Mechanism: Neutrophil activation by anti-neutrophil cytoplasmic antibodies (ANCA) leads to necrotizing vasculitis and glomerulonephritis without significant immune complex deposition.

Immunofluorescence Pattern: Negative or minimal ("pauci-immune") staining for immunoglobulins and complement

ANCA Types and Clinical Associations:

Pathophysiology: ANCA antibodies bind to PR3 or MPO expressed on primed neutrophil surfaces, causing neutrophil degranulation, oxidative burst, and release of lytic enzymes. This leads to endothelial injury, fibrinoid necrosis, and crescent formation. [12]

Molecular Mechanisms of Glomerular Injury

Complement Activation:

• Classical pathway (C1q, C4, C2, C3) in immune complex disease with IgG/IgM
• Alternative pathway (Factor B, Factor D, Properdin) in IgA nephropathy and C3 glomerulopathy
• Membrane attack complex (C5b-9) formation causes direct podocyte and endothelial cell injury
• Anaphylatoxins (C3a, C5a) recruit inflammatory cells

Cellular Infiltration:

• Macrophages: Release oxidative stress mediators, proteases, and profibrotic cytokines
• T lymphocytes: Th1 (IFN-γ), Th17 (IL-17) drive inflammation; regulatory T cells are deficient
• Neutrophils: Predominant in acute proliferative and crescentic GN; release NETs (neutrophil extracellular traps)

Crescent Formation (Hallmark of RPGN):

• Rupture of GBM allows fibrin, inflammatory cells, and plasma proteins to enter Bowman's space
• Parietal epithelial cells proliferate and transform to myofibroblasts
• Crescents compress glomerular tuft, causing ischaemia and irreversible sclerosis
• Cellular crescents: Acute, potentially reversible with immunosuppression
• Fibrocellular crescents: Subacute, partially reversible
• Fibrous crescents: Chronic, irreversible scarring

Podocyte Injury and Proteinuria:

• Podocytes undergo foot process effacement in response to inflammatory mediators
• Slit diaphragm protein disruption (nephrin, podocin) increases glomerular permeability
• Proteinuria is typically sub-nephrotic in pure nephritic syndrome but may overlap in severe disease

---

4. Classification of Glomerulonephritis

Serological Classification (Clinical Approach)

The initial serological workup provides a practical framework for differential diagnosis:

Low Complement (C3 ± C4) Glomerulonephritis

(Suggests immune complex consumption via complement activation)

Clinical Pearl: The degree and duration of complement depression provide diagnostic clues. Post-infectious GN shows normalization of C3 within 6-8 weeks, while persistent hypocomplementaemia suggests lupus, cryoglobulinaemia, or C3 glomerulopathy.

Normal Complement (C3 and C4) Glomerulonephritis

(Pauci-immune or non-complement-activating immune mechanisms)

Histological Classification

Based on Light Microscopy Pattern:

1. Proliferative GN: Increased cellularity within glomeruli

   • Mesangial proliferative: IgA nephropathy, early lupus (Class II)
   • Endocapillary proliferative: Post-infectious GN, lupus (Class III)
   • Diffuse proliferative: Severe lupus (Class IV)

2. Crescentic GN (RPGN): > 50% glomeruli with crescents

   • Type I: Anti-GBM disease (linear IF)
   • Type II: Immune complex-mediated (granular IF)
   • Type III: Pauci-immune ANCA-associated (negative IF)

3. Sclerosing GN: Chronic, irreversible scarring

   • Focal segmental glomerulosclerosis (FSGS)
   • Global glomerulosclerosis (burnt-out GN)

4. Membranoproliferative Pattern: GBM thickening + mesangial proliferation

   • MPGN Type I (immune complex)
   • Dense deposit disease (C3 glomerulopathy)

Rapidly Progressive Glomerulonephritis (RPGN)

Definition: Rapid decline in renal function (doubling of creatinine within 3 months) with histological evidence of extensive crescent formation (> 50% of glomeruli).

Clinical Presentation:

• Acute nephritic syndrome with severe oliguria
• Rapid progression to dialysis-dependence if untreated (days to weeks)
• Systemic features depending on etiology (pulmonary haemorrhage, rash, arthritis)

Causes by Frequency in Adults:

1. ANCA-associated vasculitis (50-60%): GPA, MPA
2. Anti-GBM disease (10-20%): Goodpasture syndrome
3. Immune complex disease (20-30%): Lupus nephritis, IgA nephropathy with crescents, post-infectious GN

Prognostic Factors:

• Percentage of crescents: > 80% carries very poor prognosis
• Glomerular sclerosis: Indicates irreversible damage
• Severity of AKI: Dialysis-dependence at presentation predicts ESRD
• Timing of treatment: Early immunosuppression improves outcomes

---

5. Clinical Presentation

Cardinal Features of Nephritic Syndrome

The nephritic syndrome is a clinical diagnosis characterized by:

1. Haematuria

• Macroscopic ("Visible") Haematuria: Urine appears "smoky," "tea-coloured," "cola-coloured," or "rusty"
  • Caused by oxidation of haemoglobin to methaemoglobin in acidic urine
  • Suggests active glomerular inflammation
  • Frightening presentation that prompts medical attention
• Microscopic Haematuria: Detected only on dipstick or microscopy
  • More common presentation, especially in chronic GN
  • May be persistent or intermittent (episodic in IgA nephropathy)
• Dysmorphic Red Blood Cells: RBCs distorted by passage through damaged GBM
  • Acanthocytes (RBCs with membrane blebs) are highly specific for glomerular bleeding

  • 40% dysmorphic RBCs or > 5% acanthocytes indicate glomerular origin

• Red Blood Cell Casts: Pathognomonic for glomerulonephritis
  • RBCs agglutinated by Tamm-Horsfall protein in renal tubules
  • Confirm intrarenal (glomerular) source of bleeding
  • May be missed if urine sample is not fresh or examined by trained microscopist

2. Hypertension

• Mechanism: Sodium and water retention due to reduced GFR and activation of renin-angiotensin-aldosterone system (RAAS)
• Often acute-onset and severe (may present with hypertensive emergency)
• Can cause:
  • "Hypertensive encephalopathy: Headache, confusion, seizures, visual disturbances"
  • "Pulmonary oedema: Orthopnoea, paroxysmal nocturnal dyspnoea"
  • "Left ventricular strain: Chest pain, dyspnoea"
• Blood pressure > 180/120 mmHg requires urgent management

3. Oliguria and Acute Kidney Injury

• Oliguria: Urine output less than 400 mL/24 hours (or less than 0.5 mL/kg/hour)
• Reflects reduced GFR from glomerular inflammation and crescent formation
• Rising creatinine (doubling within days to weeks in RPGN)
• May progress to anuria and dialysis-dependence in severe cases
• Uraemic symptoms in advanced AKI: Nausea, vomiting, confusion, pericarditis, seizures

4. Proteinuria

• Mild to Moderate: Typically less than 3 g/24 hours (sub-nephrotic range)
  • Distinguishes nephritic from nephrotic syndrome
  • Reflects podocyte injury and increased glomerular permeability
• Frothy/Foamy Urine: Visible manifestation of proteinuria
• May reach nephrotic range (> 3.5 g/24 hours) in severe proliferative or crescentic GN
• Proteinuria severity correlates with disease activity and prognosis

Disease-Specific Presentations

IgA Nephropathy (Berger's Disease)

Classic Presentation:

• Synpharyngitic Haematuria: Macroscopic haematuria within 1-2 days of upper respiratory tract infection
• Young adult male (peak 20s-30s) with recurrent episodes of visible haematuria during viral illnesses
• Persistent microscopic haematuria between episodes
• Mild proteinuria; nephrotic syndrome rare except in severe cases
• Normal complement levels

Variants:

• Asymptomatic microscopic haematuria and proteinuria (most common, detected on screening)
• Acute nephritic syndrome
• Rapidly progressive GN with crescents (10-15% of biopsies)
• Chronic kidney disease with minimal symptoms (late presentation)

Post-Streptococcal Glomerulonephritis

Classic Presentation:

• Child (5-12 years) with acute nephritic syndrome
• History of Group A Streptococcal pharyngitis (10-21 days prior) or impetigo (3-6 weeks prior)
• Abrupt onset of macroscopic haematuria, periorbital oedema, hypertension
• Oliguria with rising creatinine
• Low C3 (normalizes within 6-8 weeks); positive ASO titre, anti-DNase B

Adult Presentation (increasing recognition):

• Elderly patients, diabetics, those with chronic diseases
• May present with RPGN and require dialysis
• Higher mortality than paediatric cases

ANCA-Associated Vasculitis (AAV)

Granulomatosis with Polyangiitis (GPA/Wegener's):

• Upper Respiratory: Chronic rhinosinusitis, nasal crusting, epistaxis, septal perforation, saddle-nose deformity
• Lower Respiratory: Pulmonary nodules (may cavitate), pulmonary haemorrhage, pleural effusions
• Renal: Rapidly progressive GN (focal necrotizing crescentic)
• Ocular: Scleritis, uveitis, orbital pseudotumor
• Other: Cutaneous vasculitis, peripheral neuropathy (mononeuritis multiplex)
• cANCA (PR3) positive in 80-90%

Microscopic Polyangiitis (MPA):

• Renal: Rapidly progressive GN (predominant feature, often renal-limited)
• Pulmonary: Pulmonary capillaritis with haemorrhage
• Systemic: Weight loss, fever, arthralgias, myalgias
• Peripheral Neuropathy: Mononeuritis multiplex or symmetric polyneuropathy
• pANCA (MPO) positive in 60-70%
• Less upper airway involvement than GPA

Anti-GBM Disease (Goodpasture Syndrome)

Classic Triad:

1. Pulmonary Haemorrhage: Haemoptysis, dyspnoea, falling haemoglobin, diffuse alveolar infiltrates on chest imaging
2. Rapidly Progressive Glomerulonephritis: Oliguria, rising creatinine, nephritic syndrome
3. Anti-GBM Antibodies: Circulating antibodies to α3(IV)NC1; linear IgG on renal biopsy IF

Epidemiology:

• Bimodal age distribution: Young men (20-30 years, smokers) and elderly (60-70 years)
• Male predominance or equal sex distribution
• Triggers: Smoking (increased alveolar permeability), hydrocarbon exposure, viral infections

Renal-Limited Disease: 40% present without pulmonary involvement (isolated anti-GBM nephritis)

Prognosis: Dialysis-dependence at presentation predicts renal non-recovery; pulmonary haemorrhage is life-threatening

Lupus Nephritis

Presentation Patterns (depends on histological class):

• Class I-II (Mesangial): Mild haematuria and proteinuria; normal renal function
• Class III-IV (Proliferative): Nephritic or nephrotic syndrome; AKI; low complement; high anti-dsDNA
• Class V (Membranous): Nephrotic syndrome; normal complement
• Class VI (Sclerotic): Chronic kidney disease; burnt-out disease

Systemic Features: Malar rash, photosensitivity, oral ulcers, arthritis, serositis (pleuritis, pericarditis), cytopenias, neuropsychiatric features

Serology: ANA (> 95%), anti-dsDNA (70%, correlates with disease activity), anti-Smith (30%), low C3 and C4

Physical Examination Findings

General Inspection:

• Volume Overload: Periorbital oedema (especially in children), peripheral oedema (ankles, sacral), ascites, pleural effusions
• Pallor: Anaemia of chronic disease or acute blood loss (pulmonary haemorrhage)
• Uraemia: Confusion, asterixis (metabolic encephalopathy), uraemic frost (rare, advanced ESRD)

Cardiovascular:

• Hypertension: Elevated blood pressure; may have hypertensive retinopathy (flame haemorrhages, papilloedema)
• Volume Overload: Elevated JVP, S3 gallop, pulmonary crepitations (pulmonary oedema)
• Pericarditis: Pericardial rub (uraemic or lupus-related)

Respiratory:

• Pulmonary Haemorrhage: Tachypnoea, hypoxia, haemoptysis, diffuse crepitations
• Pulmonary Oedema: Orthopnoea, bilateral basal crepitations, hypoxia

Skin:

• Palpable Purpura: Vasculitis (IgA vasculitis, cryoglobulinaemia, ANCA vasculitis) - non-blanching, raised, typically lower limbs
• Malar Rash: Lupus (butterfly distribution, photosensitive)
• Livedo Reticularis: Vasculitis, cryoglobulinaemia

ENT/Head and Neck:

• Nasal Examination: Crusting, septal perforation, saddle-nose deformity (GPA)
• Epistaxis: GPA, vasculitis
• Oral Ulcers: Lupus (typically painless, palate)

Neurological:

• Mononeuritis Multiplex: Foot drop, wrist drop (vasculitis affecting vasa nervorum)
• Peripheral Neuropathy: Glove-and-stocking sensory loss (cryoglobulinaemia, ANCA vasculitis)
• Encephalopathy: Confusion, seizures (hypertensive, uraemic, or lupus cerebritis)

---

6. Differential Diagnosis

The differential diagnosis of acute kidney injury with haematuria and/or proteinuria is broad. Key diagnostic discriminators include urinalysis findings, serological markers, and clinical context.

Primary Differential: Nephritic vs Nephrotic Syndrome

Note: Some glomerular diseases can present with features of both syndromes (e.g., severe lupus nephritis, membranoproliferative GN).

Differential Diagnosis by Presentation

Acute Kidney Injury with Haematuria

Must Not Miss (Life-Threatening):

1. Rapidly Progressive Glomerulonephritis (RPGN): ANCA vasculitis, anti-GBM disease, crescentic lupus nephritis
   • Key Features: Rapid rise in creatinine (days to weeks), oliguria, systemic features
   • Urgency: Requires emergency nephrology referral and renal biopsy
2. Pulmonary-Renal Syndrome: Anti-GBM, ANCA vasculitis
   • Key Features: AKI + haemoptysis + pulmonary infiltrates
   • Urgency: Immediate ICU/nephrology/rheumatology involvement; plasma exchange
3. Acute Tubulointerstitial Nephritis (AIN): Drug-induced, infection-related
   • Key Features: Recent medication exposure (NSAIDs, PPIs, antibiotics), fever, rash, eosinophilia
   • Urine: White cell casts, eosinophiluria (inconsistent)

Common Differentials: 4. Acute Tubular Necrosis (ATN): Ischaemic or nephrotoxic

• Key Features: Muddy brown casts, epithelial cell casts; no RBC casts or dysmorphic RBCs
• Context: Hypotension, sepsis, nephrotoxin exposure (aminoglycosides, contrast)

5. Urological Haematuria: Bladder cancer, renal calculi, trauma
   • Key Features: Painful haematuria (calculi), risk factors for malignancy (smoking, age > 50), normal renal function
   • Urine: Isomorphic RBCs (not dysmorphic), no RBC casts
   • Imaging: CT KUB (calculi), cystoscopy (bladder pathology)

Isolated Haematuria (Normal Renal Function)

Nephritic Syndrome with Systemic Features

---

7. Investigations

Early and comprehensive investigation is critical in glomerulonephritis to establish the diagnosis, identify the underlying cause, assess disease severity, and guide treatment decisions. The diagnostic approach follows a structured pathway from initial screening to definitive tissue diagnosis.

Initial Assessment

Urinalysis (Essential First-Line Test):

• Urine Dipstick:
  • "Blood: +++ (indicates haematuria)"
  • "Protein: ++ to +++ (sub-nephrotic to nephrotic range)"
  • "Leukocyte esterase and nitrites: Usually negative (if positive, consider UTI or interstitial nephritis)"
  • "Specific gravity: May be fixed in severe renal impairment"

Urine Microscopy (Critical - Must Be Fresh Sample less than 2 Hours):

• Dysmorphic Red Blood Cells: > 40% dysmorphic RBCs suggests glomerular bleeding
  • "Acanthocytes (RBCs with membrane blebs): > 5% highly specific for glomerular disease"
• Red Blood Cell Casts: Pathognomonic for glomerulonephritis
  • Formed in distal tubules when RBCs are agglutinated by Tamm-Horsfall protein
  • Confirm glomerular origin of haematuria
• White Blood Cell Casts: Suggest inflammatory process (pyelonephritis, interstitial nephritis, proliferative GN)
• Granular/Muddy Brown Casts: Acute tubular necrosis
• Fatty Casts, Oval Fat Bodies: Nephrotic syndrome

Urine Protein Quantification:

• Spot Urine Protein:Creatinine Ratio (PCR):
  • "Normal: less than 15 mg/mmol"
  • "Nephritic range: 15-300 mg/mmol"
  • "Nephrotic range: > 300 mg/mmol (equivalent to > 3.5 g/24 hours)"
• 24-Hour Urine Collection: More accurate but less convenient; gold standard for nephrotic syndrome diagnosis

Blood Tests

Renal Function:

• Serum Creatinine: Elevated in AKI; trend more important than single value
  • Doubling of creatinine within 3 months defines RPGN
• Estimated GFR (eGFR): Calculated from creatinine, age, sex, ethnicity
  • less than 60 mL/min/1.73m²: Chronic kidney disease
  • less than 15 mL/min/1.73m²: Stage 5 CKD (kidney failure)
• Urea (BUN): Elevated in AKI; Urea:Creatinine ratio > 100:1 suggests prerenal AKI or GI bleeding

Complete Blood Count:

• Haemoglobin: Anaemia (chronic disease, pulmonary haemorrhage, uraemia)
• White Cell Count: Leukocytosis (infection, vasculitis), leukopenia (lupus)
• Eosinophilia: Drug-induced interstitial nephritis, eosinophilic GPA
• Thrombocytopenia: Lupus, TTP/HUS (microangiopathic process)

Inflammatory Markers:

• ESR/CRP: Elevated in vasculitis, infection, lupus (ESR elevated, CRP often normal in lupus)

Immunological Screen ("GN Screen")

The comprehensive immunological workup aims to identify the specific etiology of glomerulonephritis:

Complement Levels:

• C3:
  • "Low in: Post-infectious GN, lupus, cryoglobulinaemia, C3 glomerulopathy, MPGN"
  • "Normal in: IgA nephropathy, ANCA vasculitis, anti-GBM disease"
• C4:
  • "Low in: Lupus (classical pathway), cryoglobulinaemia, MPGN"
  • "Normal in: Post-infectious GN (often), C3 glomerulopathy (alternative pathway)"

Autoantibodies:

• Anti-Nuclear Antibody (ANA):
  • Positive in > 95% of SLE; pattern guides further testing
  • "Homogeneous pattern: Anti-dsDNA (lupus)"
  • "Speckled pattern: Anti-Ro, Anti-La (Sjögren's, subacute cutaneous lupus)"
• Anti-Double Stranded DNA (anti-dsDNA):
  • 70% sensitive for lupus; highly specific
  • Titres correlate with lupus nephritis activity
• Anti-Smith Antibody:
  • 30% of lupus patients; highly specific but less sensitive
• Anti-Neutrophil Cytoplasmic Antibody (ANCA):
  • "cANCA (Cytoplasmic pattern): "
    • Antigen: Proteinase 3 (PR3)
    • Disease: Granulomatosis with Polyangiitis (80-90% sensitivity)
  • "pANCA (Perinuclear pattern):"
    • Antigen: Myeloperoxidase (MPO)
    • Disease: Microscopic Polyangiitis (60-70%), EGPA (40%)
  • "Note: 10-30% of patients may be ANCA-negative despite clinical vasculitis"
• Anti-GBM Antibodies (Anti-α3(IV)NC1):
  • Diagnostic for anti-GBM disease (Goodpasture syndrome)
  • Titre correlates with disease severity
  • 10-30% of anti-GBM patients are also ANCA-positive ("double-positive")

Immunoglobulins:

• Serum IgA: Elevated in 50% of IgA nephropathy patients (non-specific)
• Serum IgG, IgM: Low in primary immunodeficiency; paraprotein spike in myeloma

Infectious Serology:

• Anti-Streptolysin O (ASO): Post-streptococcal GN (pharyngitis); rises at 1-3 weeks, peaks at 3-5 weeks
• Anti-DNase B: More sensitive for post-streptococcal impetigo
• Anti-Hyaluronidase: Alternative streptococcal antibody
• Hepatitis B Surface Antigen (HBsAg): Membranous nephropathy, MPGN
• Hepatitis C Antibody/RNA: Cryoglobulinaemic GN, MPGN
• HIV Serology: HIV-associated nephropathy (HIVAN), collapsing FSGS

Cryoglobulins:

• Must be collected in pre-warmed tubes and transported at 37°C
• Type II (mixed IgM-IgG): Associated with Hepatitis C

Rheumatoid Factor:

• Present in cryoglobulinaemia
• May be positive in ANCA vasculitis

Renal Imaging

Renal Ultrasound:

• Indications: All patients with AKI to assess kidney size, exclude obstruction, guide biopsy
• Findings:
  • "Normal or enlarged kidneys: Acute process (GN, AIN)"
  • "Small kidneys (less than 9 cm): Chronic kidney disease (suggests poor reversibility)"
  • "Hydronephrosis: Obstructive uropathy (not GN)"
  • "Increased echogenicity: Chronic parenchymal disease"

Chest X-Ray:

• Indications: All patients with suspected pulmonary-renal syndrome or volume overload
• Findings:
  • "Pulmonary oedema: Bilateral perihilar alveolar infiltrates"
  • "Pulmonary haemorrhage: Diffuse bilateral airspace opacification"
  • "Cavitating nodules: GPA"
  • "Pleural effusions: Lupus (serositis), volume overload"

CT Chest (High-Resolution):

• Indications: Suspected GPA (pulmonary nodules), pulmonary haemorrhage, staging of AAV
• Findings: Cavitating nodules, ground-glass opacification (haemorrhage), bronchial wall thickening

CT Sinuses:

• Indications: Suspected GPA with upper respiratory symptoms
• Findings: Mucosal thickening, bone destruction, septal perforation

Renal Biopsy (Gold Standard)

Indications:

• Unexplained AKI with active urinary sediment (haematuria, proteinuria, casts)
• Nephritic syndrome
• Nephrotic syndrome (except in diabetics with typical diabetic nephropathy)
• Suspected glomerulonephritis based on serological findings
• Progressive CKD with unclear etiology
• Systemic disease with renal involvement (lupus, vasculitis)

Contraindications (Relative):

• Uncontrolled hypertension (> 160/100 mmHg)
• Bleeding diathesis (coagulopathy, thrombocytopenia less than 50,000, anticoagulation)
• Small kidneys (less than 9 cm) - increased bleeding risk and low diagnostic yield
• Solitary kidney (relative)
• Uncooperative patient unable to follow instructions

Technique:

• Ultrasound-guided percutaneous core biopsy (16-18 gauge needle)
• Typically performed under local anaesthesia with conscious sedation
• 2-3 cores obtained to ensure adequate glomerular sampling (minimum 8-10 glomeruli)

Processing:

1. Light Microscopy (H&E, PAS, Trichrome, Silver stains):
   • Assess glomerular cellularity, crescent formation, sclerosis
   • Evaluate tubular atrophy, interstitial fibrosis (chronic damage)
   • Identify patterns: Proliferative, crescentic, sclerosing, membranoproliferative
2. Immunofluorescence Microscopy (Fresh frozen tissue):
   • Stain for IgG, IgA, IgM, C3, C4, C1q, kappa, lambda
   • Pattern Classification:
     • Linear IgG: Anti-GBM disease (diagnostic)
     • Granular IgG, IgM, C3: Immune complex GN (lupus, post-infectious)
     • Mesangial IgA: IgA nephropathy (diagnostic)
     • Negative (pauci-immune): ANCA vasculitis
3. Electron Microscopy (Glutaraldehyde-fixed tissue):
   • Assess GBM thickness and structure
   • Identify location of electron-dense deposits:
     • Subendothelial: Lupus, MPGN
     • Subepithelial: Post-infectious GN, membranous
     • Mesangial: IgA nephropathy
   • Diagnose thin basement membrane disease, Alport syndrome

Interpretation - Key Histological Features:

Prognostic Features on Biopsy:

• Percentage of crescents: > 50% defines RPGN; > 80% very poor prognosis
• Type of crescents: Cellular (acute, reversible) vs fibrous (chronic, irreversible)
• Glomerular sclerosis: Percentage of globally sclerotic glomeruli predicts irreversible damage
• Tubular atrophy and interstitial fibrosis: Indicates chronic damage; > 50% predicts poor renal recovery
• Vascular changes: Arteriosclerosis, thrombotic microangiopathy

Complications (occur in 5-10% of biopsies):

• Macroscopic haematuria: Common (30%), self-limiting
• Perirenal haematoma: 5-10%, most small and asymptomatic
• Significant bleeding requiring transfusion: less than 1%
• Arteriovenous fistula: Rare, usually asymptomatic
• Need for nephrectomy: less than 0.1%

---

8. Management

The management of glomerulonephritis is highly dependent on the specific etiology, severity of presentation, and degree of renal impairment. The overarching principles are: (1) early diagnosis and treatment to prevent irreversible nephron loss, (2) immunosuppression for immune-mediated disease, (3) supportive care to manage complications (hypertension, volume overload, uraemia), and (4) long-term monitoring to detect relapse and progression.

General Principles

Time-Critical Nature of RPGN:

• Rapidly progressive glomerulonephritis represents a medical emergency where "time equals nephrons"
• Delay in diagnosis and treatment by even days to weeks can result in irreversible glomerulosclerosis and dialysis-dependence
• Urgent nephrology referral is mandatory for all patients with:
  • Suspected RPGN (rapidly rising creatinine, oliguria, active sediment)
  • Pulmonary-renal syndrome (AKI + haemoptysis)
  • Severe nephritic syndrome with AKI
• Expedited renal biopsy within 24-48 hours should be the goal in RPGN

Acute/Supportive Management

Supportive care addresses the complications of nephritic syndrome and AKI, regardless of etiology.

1. Hypertension Management

• Target: less than 130/80 mmHg; lower in acute phase if tolerated
• First-Line Agents:
  • "ACE Inhibitors (Ramipril, Enalapril) or Angiotensin Receptor Blockers (ARBs) (Losartan, Irbesartan):"
    • Reduce intraglomerular pressure by dilating efferent arteriole
    • Reduce proteinuria (renoprotective)
    • Contraindicated in bilateral renal artery stenosis, pregnancy
    • Monitor potassium and creatinine (acceptable rise less than 30% within 2 weeks)
  • "Calcium Channel Blockers (Amlodipine, Nifedipine): For additional BP control"
  • "Loop Diuretics (Furosemide): Essential for volume overload management"
• Avoid: NSAIDs (nephrotoxic, reduce GFR, exacerbate hypertension)

2. Volume Overload Management

• Fluid Restriction: 1-1.5 L/day in oliguria
• Sodium Restriction: less than 2 g/day
• Loop Diuretics: Furosemide 40-80 mg PO/IV (may require high doses in AKI; maximum 250 mg IV bolus or continuous infusion)
• Monitoring: Daily weights, fluid balance, clinical examination (JVP, pulmonary crepitations, peripheral oedema)
• Refractory Volume Overload: Consider ultrafiltration or haemodialysis

3. Acute Kidney Injury Management

• Monitor: Daily U&E, fluid balance, urine output
• Avoid Nephrotoxins: NSAIDs, aminoglycosides, contrast agents, ACE inhibitors if AKI worsening
• Adjust Drug Dosing: Renally excreted drugs (antibiotics, metformin, digoxin)
• Nutrition: Adequate protein intake (0.8-1.0 g/kg/day) unless uraemic; avoid excessive protein in uraemia

4. Indications for Dialysis (AEIOU mnemonic):

• A: Acidosis (severe metabolic acidosis pH less than 7.1 unresponsive to bicarbonate)
• E: Electrolyte abnormalities (hyperkalaemia > 6.5 mmol/L refractory to medical management)
• I: Intoxication (dialyzable toxins, though rare in GN)
• O: Volume overload (refractory pulmonary oedema)
• U: Uraemia (encephalopathy, pericarditis, bleeding diathesis)

5. Hyperkalaemia Management

• Acute (K > 6.5 mmol/L or ECG changes):
  • 10 mL 10% calcium gluconate IV (cardiac membrane stabilization)
  • 10 units insulin + 50 mL 50% dextrose IV (shift K intracellularly)
  • Salbutamol 10-20 mg nebulized (shift K intracellularly)
  • Sodium bicarbonate 50-100 mmol IV if acidotic
• Ongoing Management:
  • Dietary potassium restriction (less than 2 g/day)
  • Avoid ACE inhibitors/ARBs, potassium-sparing diuretics, NSAIDs
  • Oral potassium binders (Patiromer, Sodium Zirconium Cyclosilicate)
  • Loop diuretics (promote K excretion)
• Dialysis: If refractory despite medical management

6. Anaemia Management

• Iron Replacement: Oral or IV iron if deficient
• Erythropoiesis-Stimulating Agents (ESA): Consider if Hb less than 100 g/L and chronic kidney disease
• Blood Transfusion: If Hb less than 70 g/L symptomatic or active bleeding (pulmonary haemorrhage)

Disease-Specific Immunosuppressive Treatment

IgA Nephropathy

Risk Stratification (MEST-C Score on Biopsy):

• M: Mesangial hypercellularity
• E: Endocapillular hypercellularity
• S: Segmental glomerulosclerosis
• T: Tubular atrophy/interstitial fibrosis
• C: Crescents

Management Strategy:

1. All Patients (Baseline Therapy):

   • ACE Inhibitors or ARBs:
     • Titrate to maximum tolerated dose
     • Goal: Reduce proteinuria to less than 0.5 g/day
     • Renoprotective regardless of blood pressure
   • SGLT2 Inhibitors (Dapagliflozin, Empagliflozin):
     • Emerging evidence for renoprotection in IgA nephropathy [13]
     • Reduce proteinuria, slow eGFR decline
   • Blood Pressure Control: Target less than 130/80 mmHg
   • Lifestyle: Smoking cessation, healthy diet, weight loss

2. High-Risk Patients (Persistent proteinuria > 1 g/day despite 3-6 months optimal supportive care, eGFR > 30 mL/min):

   • Corticosteroids:
     • Methylprednisolone 0.6-0.8 mg/kg/day (max 48 mg/day) for 2 months, then taper over 4-6 months
     • Alternative: Pulsed methylprednisolone 1 g IV for 3 days, then oral prednisolone
     • Benefits: Reduce proteinuria, slow progression to ESRD [14]
     • Risks: Infection, hyperglycaemia, weight gain, osteoporosis
     • STOP-IgAN Trial: Suggested immunosuppression did not add benefit beyond RAS blockade, but included additional immunosuppressants beyond steroids
     • TESTING Trial: Showed benefit of corticosteroids but high infection rate in Chinese population [14]

3. Crescentic IgA Nephropathy (RPGN):

   • High-dose corticosteroids (as for ANCA vasculitis)
   • Consider cyclophosphamide or rituximab
   • Plasma exchange: Role unclear, consider in severe cases

Prognosis: "Rule of Thirds"

• 1/3 spontaneous remission or stable disease
• 1/3 persistent proteinuria and slowly progressive CKD
• 1/3 progression to ESRD within 20 years

Post-Streptococcal Glomerulonephritis

Management:

1. Supportive Care Only (in most cases):
   • Blood pressure control
   • Volume management with diuretics
   • Sodium restriction
2. Antibiotics:
   • If active infection: Penicillin V or amoxicillin for 10 days (eradicate streptococcus)
   • Prophylaxis for contacts: Not routinely recommended unless outbreak setting
3. Immunosuppression: NOT indicated (self-limiting disease)
4. Monitoring:
   • Daily U&E until improvement
   • Repeat C3 at 6-8 weeks (should normalize; persistent low C3 suggests alternative diagnosis)
   • Urinalysis at 6 weeks and 6 months (haematuria may persist for months; proteinuria should resolve)

Prognosis:

• Children: Excellent (95% complete recovery)
• Adults: Less favourable (up to 50% develop chronic kidney disease or hypertension)

ANCA-Associated Vasculitis (GPA, MPA)

Treatment follows a two-phase approach: induction of remission (suppress acute inflammation) followed by maintenance therapy (prevent relapse).

Induction Therapy (3-6 Months):

Severe/Organ-Threatening Disease (Creatinine > 500 µmol/L, pulmonary haemorrhage, cerebral vasculitis):

1. Corticosteroids:

   • Methylprednisolone 500-1000 mg IV daily for 3 days (pulse therapy)
   • Followed by Prednisolone 1 mg/kg/day PO (maximum 60-80 mg) for 4 weeks
   • Taper gradually over 3-6 months to 5-10 mg/day maintenance

2. Plus ONE of:

   • Rituximab (preferred, especially for relapsing disease):
     • 375 mg/m² IV weekly for 4 weeks, OR
     • 1000 mg IV on days 1 and 15
     • RAVE Trial: Rituximab non-inferior to cyclophosphamide for induction; superior for relapsing disease [15]
   • Cyclophosphamide:
     • 15 mg/kg IV every 2-3 weeks (adjust for age and renal function), OR
     • 2 mg/kg/day PO (reduce dose if age > 60 or eGFR less than 30)
     • Duration: 3-6 months
     • Risks: Haemorrhagic cystitis (give Mesna), infertility, infection, malignancy (bladder cancer, lymphoma)
     • Cumulative dose less than 36 g reduces malignancy risk

3. Plasma Exchange (PLEX):

   • Indications: Dialysis-dependent AKI, pulmonary haemorrhage requiring ventilation, anti-GBM disease
   • PEXIVAS Trial: Did not reduce mortality or ESRD risk in AAV [16]
   • Regimen: 7 exchanges of 60 mL/kg plasma over 14 days (alternate days)
   • Removes circulating ANCA antibodies and inflammatory mediators
   • Evidence weaker than previously thought; consider on case-by-case basis

Non-Severe Disease (Creatinine less than 500 µmol/L, no organ-threatening features):

• Prednisolone 1 mg/kg/day PO + Methotrexate 20-25 mg weekly PO/SC, OR
• Prednisolone + Mycophenolate Mofetil 2-3 g/day PO

Maintenance Therapy (18-24 months minimum, up to 5 years in relapsing disease):

• Rituximab (preferred):
  • 500 mg IV every 6 months, OR
  • Titrated based on CD19/CD20 B-cell counts or ANCA levels
  • "MAINRITSAN Trial: Rituximab superior to azathioprine for preventing relapse [17]"
• Azathioprine: 2 mg/kg/day PO (traditional agent, higher relapse rates than rituximab)
• Methotrexate: 20-25 mg weekly (alternative if intolerant to rituximab/azathioprine)
• Prednisolone: Continue low-dose 5-10 mg/day throughout maintenance

Adjunctive Therapy:

• Pneumocystis Jirovecii Prophylaxis: Co-trimoxazole 480-960 mg daily during immunosuppression
• Bone Protection: Bisphosphonates, calcium, vitamin D (on long-term corticosteroids)
• Gastric Protection: Proton pump inhibitor (PPI)

Monitoring:

• Monthly U&E, FBC, urinalysis during induction
• ANCA titres (rising levels may predict relapse, but do not treat based solely on serology)
• Monitor for infection, cytopenias, drug toxicity

Relapse Management:

• Define relapse: Recurrence of active vasculitis with rising creatinine, active urine sediment, or extra-renal features
• Treatment: Repeat induction therapy (rituximab preferred)

Anti-GBM Disease (Goodpasture Syndrome)

Emergency Treatment (mortality high without urgent treatment):

1. Plasma Exchange:

   • URGENT: Start within 24-48 hours of diagnosis
   • Removes circulating anti-GBM antibodies
   • Regimen: Daily plasma exchanges (60 mL/kg) for 14 days until anti-GBM antibodies undetectable
   • Continue until anti-GBM titre negative on two consecutive measurements
   • Evidence: Plasma exchange is standard of care based on observational data; RCT evidence limited

2. Immunosuppression:

   • Cyclophosphamide: 2-3 mg/kg/day PO (adjust for age/renal function) for 2-3 months
   • Prednisolone: 1 mg/kg/day PO (max 60-80 mg), taper after 6-8 weeks
   • Prevents new antibody formation

3. Maintenance (6-12 months):

   • Azathioprine 2 mg/kg/day PO
   • Prednisolone taper to 5-10 mg/day

Prognostic Factors:

• Dialysis-Dependent at Presentation: less than 10% renal recovery; consider kidney transplantation after 6-12 months (when anti-GBM antibodies negative)
• Creatinine less than 500 µmol/L: 80-90% avoid dialysis with treatment
• Pulmonary Haemorrhage: Life-threatening; requires ICU, mechanical ventilation, aggressive treatment

Monitoring:

• Daily anti-GBM antibody titres during plasma exchange
• Continue PLEX until undetectable
• Monitor for infection (intensive immunosuppression)

Lupus Nephritis

Management is guided by histological class on renal biopsy (ISN/RPS 2003 classification):

Class I (Minimal Mesangial) and Class II (Mesangial Proliferative):

• No specific renal therapy required
• Treat extra-renal lupus manifestations as appropriate
• Monitor urinalysis, proteinuria, renal function

Class III (Focal Proliferative) and Class IV (Diffuse Proliferative): These are the most severe forms requiring aggressive immunosuppression.

Induction Therapy (6 months):

1. Corticosteroids:

   • Methylprednisolone 500-1000 mg IV daily for 3 days (pulse)
   • Prednisolone 0.5-1 mg/kg/day PO, taper to 5-7.5 mg/day by 6 months

2. Plus ONE of:

   • Mycophenolate Mofetil (MMF): 2-3 g/day PO in divided doses
     • Preferred in many centres, especially for Black and Hispanic patients [18]
     • Better tolerated than cyclophosphamide
   • Cyclophosphamide:
     • Euro-Lupus protocol: 500 mg IV every 2 weeks for 6 doses (lower dose, fewer side effects)
     • NIH protocol: 0.5-1 g/m² IV monthly for 6 months (higher dose, more toxic)
     • Reserved for severe disease, inferior fertility outcomes

Maintenance Therapy (minimum 3 years):

• Mycophenolate Mofetil: 1-2 g/day PO, OR
• Azathioprine: 2 mg/kg/day PO
• Prednisolone: 5-7.5 mg/day long-term

Adjunctive Therapy:

• Hydroxychloroquine: 200-400 mg/day (all lupus patients; reduces flares, improves survival)
• Calcineurin Inhibitors (Tacrolimus, Cyclosporine): Consider in refractory disease
• Rituximab: Reserved for refractory cases (not first-line based on LUNAR trial)
• Belimumab: Anti-BLyS antibody, add-on for refractory lupus

Class V (Membranous Lupus Nephritis):

• If nephrotic syndrome: Treat similarly to Class III/IV (MMF or cyclophosphamide + corticosteroids)
• If sub-nephrotic proteinuria: ACE inhibitors, ARBs, conservative management

Class VI (Advanced Sclerosing):

• No immunosuppression (irreversible scarring)
• Manage as chronic kidney disease
• Consider renal replacement therapy planning

Monitoring:

• Monthly anti-dsDNA, C3, C4 (correlate with disease activity)
• Urinalysis, proteinuria, renal function
• Repeat biopsy if clinical flare or inadequate response to treatment

Cryoglobulinaemic Glomerulonephritis

Underlying Cause Treatment:

• Hepatitis C-Associated:
  • "Direct-acting antivirals (DAAs): Sofosbuvir/Velpatasvir, Glecaprevir/Pibrentasvir"
  • Achieve sustained virological response (SVR) → resolution of cryoglobulinaemia in 70-80%
• Hepatitis B-Associated: Tenofovir or Entecavir
• Lymphoproliferative Disorders: Treat underlying haematological malignancy

Immunosuppression (severe disease with RPGN, extensive vasculitis):

• Rituximab: 375 mg/m² IV weekly for 4 weeks (depletes B-cells producing cryoglobulins)
• Corticosteroids: Prednisolone 1 mg/kg/day, taper
• Plasma Exchange: Consider for severe rapidly progressive disease

---

9. Complications

Glomerulonephritis can result in acute, life-threatening complications as well as chronic sequelae that impact long-term morbidity and mortality.

Acute Complications

1. Rapidly Progressive Glomerulonephritis (RPGN)

• Definition: Rapid loss of renal function (doubling of creatinine within 3 months) with histological crescents in > 50% of glomeruli
• Pathophysiology: Severe glomerular injury with GBM rupture, fibrin exudation into Bowman's space, and proliferation of parietal epithelial cells forming crescents that compress glomerular tuft
• Clinical: Oliguria, anuria, rapid rise in creatinine, uraemic symptoms
• Outcome: Irreversible ESRD if untreated within days to weeks
• Management: Medical emergency requiring urgent renal biopsy and immunosuppression

2. Pulmonary-Renal Syndrome

• Definition: Combination of glomerulonephritis and pulmonary haemorrhage
• Causes: Anti-GBM disease (Goodpasture syndrome), ANCA vasculitis
• Clinical: Haemoptysis, dyspnoea, hypoxia, falling haemoglobin, bilateral pulmonary infiltrates on CXR
• Management: ICU admission, mechanical ventilation if severe, urgent plasma exchange + immunosuppression
• Mortality: High (up to 50%) if severe pulmonary haemorrhage

3. Hypertensive Emergency

• Definition: Severe hypertension (> 180/120 mmHg) with acute end-organ damage
• Manifestations:
  • "Hypertensive encephalopathy: Headache, confusion, seizures, visual disturbances, papilloedema"
  • "Acute heart failure: Pulmonary oedema, dyspnoea"
  • "Posterior reversible encephalopathy syndrome (PRES): Seizures, visual changes, MRI shows vasogenic oedema"
• Management: IV antihypertensives (labetalol, hydralazine, nitroprusside), reduce BP by 10-20% in first hour, avoid rapid reduction (risk of cerebral hypoperfusion)

4. Acute Pulmonary Oedema

• Cause: Volume overload from sodium retention and reduced GFR
• Clinical: Orthopnoea, paroxysmal nocturnal dyspnoea, bilateral crepitations, hypoxia
• Management: Furosemide IV (high dose may be required), oxygen, sitting upright, fluid restriction; dialysis if refractory

5. Hyperkalaemia

• Cause: Reduced renal potassium excretion in AKI
• Clinical: Often asymptomatic until severe; ECG changes (peaked T waves, widened QRS, bradycardia, VF)
• Management: See Acute Management section; urgent dialysis if refractory

6. Uraemia

• Manifestations:
  • "Uraemic encephalopathy: Confusion, asterixis, seizures, coma"
  • "Uraemic pericarditis: Pericardial rub, chest pain, risk of tamponade"
  • "Bleeding diathesis: Platelet dysfunction, bruising, GI bleeding"
  • "Uraemic frost (rare, severe ESRD): Urea crystallization on skin"
• Management: Urgent dialysis

7. Infection (Immunosuppression-Related)

• Opportunistic Infections:
  • "Pneumocystis jirovecii pneumonia (PCP): Dry cough, dyspnoea, hypoxia; diagnose with BAL; treat with high-dose co-trimoxazole + corticosteroids"
  • "CMV reactivation: Fever, leukopenia, colitis, pneumonitis"
  • "Fungal infections: Aspergillus, Candida in severely immunosuppressed"
• Prevention: Co-trimoxazole prophylaxis during cyclophosphamide, rituximab, high-dose corticosteroids

Chronic Complications

1. Chronic Kidney Disease (CKD)

• Epidemiology: 20-40% of glomerulonephritis patients progress to CKD over 10-20 years
• Risk Factors: Degree of proteinuria, hypertension, baseline renal function, histological chronicity features (tubular atrophy, interstitial fibrosis, glomerulosclerosis)
• Management: CKD-specific care (BP control, proteinuria reduction, anaemia management, bone mineral disease treatment, cardiovascular risk reduction)

2. End-Stage Renal Disease (ESRD)

• Definition: eGFR less than 15 mL/min/1.73m², requiring renal replacement therapy (dialysis or transplantation)
• Causes: RPGN without treatment, severe crescentic GN, inadequate immunosuppression, relapsing disease
• Outcomes:
  • "Haemodialysis: 3 times per week, vascular access (AV fistula, graft)"
  • "Peritoneal dialysis: Continuous or automated"
  • "Kidney Transplantation: Best long-term outcome; risk of recurrent GN in allograft (especially IgA nephropathy, FSGS)"

3. Relapsing Disease

• ANCA Vasculitis: 50% relapse within 5 years despite maintenance therapy [17]
  • "Triggers: Infections, medication non-adherence"
  • "Monitoring: ANCA titres, urinalysis, clinical symptoms"
• Lupus Nephritis: 25-30% flare rate despite maintenance immunosuppression
  • Monitor anti-dsDNA, complement levels

4. Cardiovascular Disease

• Increased Risk: CKD is independent cardiovascular risk factor; inflammation, endothelial dysfunction, hypertension
• Management: Statin therapy, antiplatelet agents (if no bleeding risk), BP control, smoking cessation

5. Malignancy

• Cyclophosphamide-Related: Bladder cancer (haemorrhagic cystitis → dysplasia), lymphoma
  • Risk increases with cumulative dose > 36 g
  • "Surveillance: Urinalysis, cystoscopy if haematuria"
• General Immunosuppression: Increased risk of skin cancers (SCC, BCC), lymphoproliferative disorders

6. Infertility

• Cyclophosphamide: Dose-dependent gonadotoxicity; higher risk in women > 30 years
• Preservation: Sperm banking (men), GnRH agonists during treatment (women, modest benefit), oocyte/embryo cryopreservation
• Alternatives: Rituximab has no known fertility effects

---

10. Prognosis and Outcomes

Prognosis in glomerulonephritis varies widely depending on the specific disease entity, severity at presentation, and response to treatment.

Disease-Specific Prognosis

Prognostic Scores and Predictive Tools

IgA Nephropathy - Oxford Classification (MEST-C Score):

• Each positive feature (M, E, S, T, C) independently predicts worse renal outcomes
• Used to guide treatment intensity (high MEST-C score → consider corticosteroids)

ANCA Vasculitis - Renal Risk Score:

• Based on: Percentage of normal glomeruli, percentage of sclerotic glomeruli, degree of tubulointerstitial fibrosis
• Predicts renal recovery in patients requiring dialysis at diagnosis

International Society of Nephrology/Renal Pathology Society (ISN/RPS) Classification for Lupus:

• Class I-II: Excellent prognosis, no renal therapy
• Class III: 80-85% renal survival at 10 years
• Class IV: 75-80% renal survival, highest risk of ESRD
• Class V: 90-95% renal survival if sub-nephrotic
• Class VI: Poor prognosis, advanced sclerosis

Mortality

Excess Mortality in Glomerulonephritis:

• ANCA Vasculitis: 5-year mortality 20-30%, primarily from infection (immunosuppression) and cardiovascular disease [7]
• Lupus Nephritis: Standardized mortality ratio 3-5 times general population
• Anti-GBM Disease: Mortality 10-20% in acute phase (pulmonary haemorrhage)

Causes of Death:

1. Infection: Leading cause in immunosuppressed patients (PCP, CMV, bacterial sepsis)
2. Cardiovascular Disease: MI, stroke, heart failure (CKD-related risk)
3. Pulmonary Haemorrhage: Goodpasture syndrome, severe AAV
4. Uraemia: Delayed diagnosis, treatment refusal
5. Malignancy: Long-term immunosuppression

---

11. Prevention and Screening

Primary Prevention

Infection Prevention:

• Prompt Treatment of Streptococcal Infections: Prevents post-streptococcal GN (antibiotic therapy for pharyngitis, impetigo)
• Vaccination: Hepatitis B vaccination (prevents HBV-associated membranous nephropathy), annual influenza and pneumococcal vaccination in CKD patients

Avoidance of Triggers:

• Smoking Cessation: Reduces risk of Goodpasture disease, slows CKD progression
• Avoid Nephrotoxins: NSAIDs, aminoglycosides, contrast agents in at-risk individuals
• Occupational Exposure: Minimize silica and hydrocarbon exposure (ANCA vasculitis, anti-GBM risk)

Secondary Prevention (Early Detection)

Screening Recommendations:

• Routine Urinalysis:
  • Annual urinalysis in high-risk populations (family history of kidney disease, diabetes, hypertension, autoimmune disease)
  • School-based screening in Japan and Korea has identified asymptomatic IgA nephropathy
• SLE Patients:
  • 6-monthly urinalysis, proteinuria quantification, renal function
  • Early detection of lupus nephritis allows prompt treatment
• ANCA Vasculitis in Remission:
  • 3-monthly urinalysis, ANCA titres (rising levels may predict relapse)

Family Screening:

• IgA Nephropathy: First-degree relatives have 4-9 times increased risk; consider urinalysis screening
• Alport Syndrome: Genetic counselling, screening of family members (audiometry, ophthalmology, urinalysis)

Tertiary Prevention (Preventing Progression)

Optimal Medical Management of CKD:

• Blood Pressure Control: Target less than 130/80 mmHg; less than 120/80 mmHg if proteinuria
• RAS Blockade: ACE inhibitor or ARB, titrate to maximum tolerated dose
• SGLT2 Inhibitors: Dapagliflozin, empagliflozin (CKD progression reduction)
• Proteinuria Reduction: Goal less than 0.5 g/day in IgA nephropathy, less than 0.5-1 g/day in other GN
• Cardiovascular Risk Reduction: Statin, antiplatelet agent, lifestyle modification
• Avoid Nephrotoxins: NSAIDs, contrast, aminoglycosides

Monitoring for Relapse:

• Regular urinalysis (detect haematuria, proteinuria)
• Renal function monitoring (creatinine, eGFR)
• Disease-specific markers (ANCA, anti-dsDNA, complement)

---

12. Key Guidelines and Evidence Base

Major Guidelines

Landmark Trials and Evidence

1. RAVE Trial (Rituximab vs Cyclophosphamide for ANCA Vasculitis) - N Engl J Med 2010 [15]

• Design: RCT comparing rituximab vs cyclophosphamide for induction in AAV
• Results: Rituximab non-inferior to cyclophosphamide for remission induction; superior in relapsing disease
• Impact: Established rituximab as first-line therapy for ANCA vasculitis

2. PEXIVAS Trial (Plasma Exchange in ANCA Vasculitis) - N Engl J Med 2020 [16]

• Design: RCT of plasma exchange vs no plasma exchange in severe AAV (dialysis-dependent or pulmonary haemorrhage)
• Results: No difference in composite outcome of death or ESRD at 12 months
• Impact: Reduced use of plasma exchange; now reserved for severe cases or anti-GBM disease

3. MAINRITSAN Trial (Rituximab vs Azathioprine for AAV Maintenance) - N Engl J Med 2014 [17]

• Design: RCT comparing rituximab vs azathioprine for maintenance therapy in AAV
• Results: Rituximab superior to azathioprine for preventing major relapse (5% vs 29% at 28 months)
• Impact: Rituximab now preferred agent for maintenance in AAV

4. TESTING Trial (Corticosteroids in IgA Nephropathy) - JAMA 2017 [14]

• Design: RCT of methylprednisolone vs placebo in IgA nephropathy with proteinuria > 1 g/day and eGFR 20-120 mL/min
• Results: Reduced risk of composite renal endpoint (40% reduction in ESRD, death, or 50% eGFR decline); high infection rate led to early termination and protocol modification
• Impact: Supports use of corticosteroids in high-risk IgA nephropathy, but highlights infection risk; debate continues

5. Euro-Lupus Nephritis Trial - Arthritis Rheum 2002

• Design: RCT comparing low-dose IV cyclophosphamide (Euro-Lupus protocol: 500 mg every 2 weeks x 6) vs high-dose NIH protocol in lupus nephritis
• Results: Non-inferior efficacy with lower toxicity
• Impact: Low-dose cyclophosphamide regimen widely adopted; shift toward MMF in many centres

6. ALMS Trial (Mycophenolate vs Cyclophosphamide in Lupus Nephritis) - N Engl J Med 2005 [18]

• Design: RCT comparing MMF vs IV cyclophosphamide for induction in lupus nephritis
• Results: MMF non-inferior to cyclophosphamide; better efficacy in Black and Hispanic patients
• Impact: MMF now first-line for lupus nephritis induction in many centres

7. Goodpasture Syndrome Management - Observational Data

• Evidence: No RCTs; management based on observational cohorts and case series [11]
• Consensus: Plasma exchange + immunosuppression is standard of care despite lack of RCT evidence
• Key Finding: Dialysis-dependence at presentation predicts renal non-recovery

---

13. Patient and Layperson Explanation

What is Glomerulonephritis?

Your kidneys contain millions of tiny filtering units called glomeruli. Think of them like very fine sieves that clean your blood by filtering out waste products while keeping important proteins and blood cells inside your body.

In glomerulonephritis (say "glom-er-you-low-nef-RYE-tis"), your immune system makes a mistake and attacks these tiny filters, causing them to become inflamed and damaged. When the filters are damaged, they start to leak things they shouldn't (like blood and protein into your urine) and stop working properly at cleaning your blood.

What Causes It?

There are many different causes:

• After an infection: Sometimes after a throat infection (like strep throat), your immune system continues fighting even after the infection is gone, and accidentally attacks your kidneys.
• Autoimmune diseases: Conditions like lupus or vasculitis, where your immune system is overactive.
• Unknown reasons: In many cases (like IgA nephropathy), we don't know exactly why it starts.

What Are the Symptoms?

• Smoky or tea-coloured urine: Blood leaking through damaged filters makes your urine look dark or "cola-coloured"
• Swelling (especially around your eyes in the morning, or in your ankles): Your kidneys aren't removing water properly
• High blood pressure: Often severe and may cause headaches
• Feeling tired: Your kidneys aren't cleaning your blood well
• Foamy urine: Protein leaking into urine makes it frothy (like beer)
• Passing less urine than normal

Is It Dangerous?

It can be, which is why early diagnosis and treatment are so important.

• Mild forms (like the kind children get after strep throat) often get better on their own with just blood pressure medication and fluid management.
• Aggressive forms (like certain types of vasculitis or rapidly progressive GN) can cause permanent kidney damage within days to weeks if not treated urgently with strong immune-suppressing medications.
• The most serious complication is kidney failure, which would require dialysis (a machine to clean your blood) or a kidney transplant.

How Is It Diagnosed?

1. Urine tests: Looking for blood and protein in your urine under a microscope
2. Blood tests: Checking kidney function and looking for antibodies (immune system markers) that can tell us what type of glomerulonephritis you have
3. Kidney biopsy: Taking a tiny sample of kidney tissue with a needle (done under local anaesthetic) to look at under a microscope. This is the gold standard test that tells us exactly what type you have and how best to treat it.

How Is It Treated?

Treatment depends on the type and severity:

Supportive Care (All Types):

• Blood pressure tablets: To control high blood pressure and protect your kidneys
• Water tablets (diuretics): To remove excess fluid and reduce swelling
• Low-salt diet: Helps control blood pressure and fluid retention

Immunosuppression (Aggressive Types):

• Steroid tablets or infusions: Dampen down the overactive immune system
• Stronger immune-suppressing drugs: Cyclophosphamide, rituximab, mycophenolate - used for severe disease
• Plasma exchange: A bit like dialysis, but instead removes harmful antibodies from your blood (used for the most aggressive types like Goodpasture syndrome)

For Mild Types (like post-strep GN in children):

• Often just supportive care with blood pressure control and monitoring
• Most children recover completely

What Is the Outlook (Prognosis)?

This depends entirely on the type of glomerulonephritis:

• Post-strep GN in children: 95% make a full recovery
• IgA nephropathy: Variable - about 1/3 improve, 1/3 stay stable, 1/3 slowly progress over many years
• ANCA vasculitis or Goodpasture syndrome: If caught early and treated aggressively, most people avoid dialysis; if treatment is delayed, there is a high risk of permanent kidney failure
• Lupus nephritis: With modern treatment, 80-85% maintain good kidney function long-term

What Can I Do to Help Myself?

• Take all medications exactly as prescribed - especially immune-suppressing drugs; stopping early can cause the disease to come back
• Attend all follow-up appointments - regular urine and blood tests catch problems early
• Low-salt diet (less than 2 g/day) - helps control blood pressure and swelling
• Stop smoking - smoking worsens kidney disease and increases risk of Goodpasture syndrome
• Avoid anti-inflammatory painkillers (NSAIDs) like ibuprofen - these can damage kidneys further
• Stay hydrated but don't overdo fluids if you have swelling
• Promptly treat infections - report fever, cough, or urinary symptoms to your doctor

Important Warning Signs (When to Seek Urgent Help)

• Worsening swelling (face, legs, abdomen)
• Severe headache or visual disturbances (may indicate very high blood pressure)
• Coughing up blood (may indicate pulmonary-renal syndrome - medical emergency)
• Passing very little or no urine
• Confusion or drowsiness (may indicate uraemia - waste products building up in blood)
• Chest pain or severe shortness of breath

Will I Need Dialysis or a Transplant?

• Most people with glomerulonephritis will NOT need dialysis if diagnosed and treated early
• Dialysis is only needed if:
  • The disease is very aggressive (rapidly progressive GN) and diagnosed late
  • Treatment doesn't work
  • The disease progresses to end-stage kidney failure despite treatment
• Kidney transplantation is an option for those who reach end-stage kidney disease; many types of glomerulonephritis can come back in the transplanted kidney (especially IgA nephropathy), but modern immunosuppression significantly reduces this risk

---

14. Examination Focus (MRCP, FRACP, USMLE)

High-Yield Exam Topics

Pattern Recognition Questions (Most Common in Written Exams):

1. Timing of Haematuria Post-Infection:

   • Question: "A 25-year-old male develops macroscopic haematuria 24 hours after a sore throat. What is the most likely diagnosis?"
   • Answer: IgA Nephropathy (synpharyngitic haematuria)
   • Differentiator: Post-streptococcal GN occurs 10-21 days post-pharyngitis (post-infectious pattern)

2. Pulmonary-Renal Syndrome:

   • Question: "A 28-year-old smoker presents with haemoptysis, dyspnoea, and acute kidney injury. Urinalysis shows haematuria and proteinuria. Chest X-ray shows bilateral infiltrates. What is the most likely diagnosis?"
   • Answer: Goodpasture Syndrome (Anti-GBM Disease)
   • Key Test: Anti-GBM antibodies, renal biopsy shows linear IgG on immunofluorescence
   • Alternative: ANCA vasculitis (cANCA/PR3 if GPA, pauci-immune on biopsy)

3. Complement Patterns:

   • Low C3 and C4: Post-infectious GN, Lupus nephritis
   • Low C3, Normal C4: C3 glomerulopathy, MPGN (alternative pathway)
   • Normal C3 and C4: IgA nephropathy, ANCA vasculitis, Anti-GBM disease

4. ANCA Patterns:

   • cANCA (PR3): Granulomatosis with Polyangiitis (upper and lower respiratory + renal involvement)
   • pANCA (MPO): Microscopic Polyangiitis (predominantly renal-limited)

5. Crescents on Biopsy:

   • Question: "Renal biopsy shows > 50% of glomeruli with crescents. What is this called?"
   • Answer: Rapidly Progressive Glomerulonephritis (RPGN)
   • Management: Medical emergency, urgent immunosuppression

6. Post-Streptococcal GN:

   • Question: "An 8-year-old child develops periorbital oedema, hypertension, and smoky urine 2 weeks after a sore throat. C3 is low. What is the management?"
   • Answer: Supportive care only (BP control, diuretics, salt restriction); antibiotics if active infection; NO immunosuppression needed

7. Red Cell Casts:

   • Question: "What is the pathognomonic finding on urine microscopy for glomerulonephritis?"
   • Answer: Red blood cell casts (prove glomerular origin of haematuria)

Viva Voce Points

Opening Statement for Glomerulonephritis: "Glomerulonephritis is a group of immune-mediated disorders characterized by inflammation of the glomeruli, presenting classically as nephritic syndrome with haematuria, hypertension, oliguria, and sub-nephrotic proteinuria. The most common cause worldwide is IgA nephropathy, accounting for up to 40% of primary glomerulonephritis. Rapidly progressive forms represent a medical emergency requiring urgent diagnosis via renal biopsy and immunosuppression to prevent irreversible kidney failure."

Structured Approach to Nephritic Syndrome: "I would approach a patient with suspected nephritic syndrome systematically:

1. Confirm the diagnosis: Urinalysis with microscopy (looking for dysmorphic RBCs and red cell casts), quantify proteinuria (typically sub-nephrotic less than 3 g/day), assess renal function (U&E, creatinine)
2. Determine the etiology: Immunological screen including complement levels (C3, C4), ANCA, anti-GBM antibodies, ANA, anti-dsDNA, infectious serology (ASO, Hepatitis B/C)
3. Assess severity: Rate of creatinine rise (RPGN if doubling within 3 months), presence of oliguria, systemic features (pulmonary haemorrhage, rash, arthritis)
4. Definitive diagnosis: Renal biopsy with light microscopy, immunofluorescence, and electron microscopy
5. Initiate management: Supportive care for all (BP control with ACE inhibitors, diuretics for volume overload); disease-specific immunosuppression for aggressive forms (corticosteroids + cyclophosphamide or rituximab for ANCA vasculitis, plasma exchange for anti-GBM disease)"

Key Differentiators Examiners Want:

• Nephritic vs Nephrotic Syndrome: Haematuria + hypertension vs heavy proteinuria + hypoalbuminaemia
• Synpharyngitic (IgA) vs Post-Infectious (Post-Strep): Timing of haematuria (1-2 days vs 10-21 days)
• Anti-GBM vs ANCA Vasculitis: Linear IgG IF vs pauci-immune; anti-GBM antibodies vs ANCA
• When to Use Plasma Exchange: Anti-GBM disease (definite), severe ANCA vasculitis with dialysis-dependence or pulmonary haemorrhage (controversial post-PEXIVAS)
• Rituximab vs Cyclophosphamide: Rituximab now first-line for ANCA vasculitis (RAVE trial); cyclophosphamide reserved for anti-GBM or severe refractory cases

Common Exam Mistakes

❌ Mistake 1: Treating post-streptococcal GN with immunosuppression

• Correction: Supportive care only; self-limiting disease

❌ Mistake 2: Confusing IgA nephropathy with IgA vasculitis (Henoch-Schönlein Purpura)

• Correction: IgA nephropathy is renal-limited; IgA vasculitis is systemic (palpable purpura, abdominal pain, arthritis)

❌ Mistake 3: Ordering ANCA or anti-GBM in a child with post-strep GN

• Correction: Clinical diagnosis based on timing, low C3, positive ASO; biopsy only if atypical features

❌ Mistake 4: Missing pulmonary-renal syndrome

• Correction: Always ask about respiratory symptoms (haemoptysis, dyspnoea) in glomerulonephritis; always get chest X-ray

❌ Mistake 5: Delaying renal biopsy in RPGN

• Correction: RPGN is a medical emergency; biopsy should be performed within 24-48 hours

Model Answer: "How Would You Investigate a Patient with Suspected Glomerulonephritis?"

"I would take a systematic approach to investigating suspected glomerulonephritis:

Initial Assessment:

• Urinalysis with microscopy: Essential to look for dysmorphic red blood cells and red cell casts, which are pathognomonic for glomerular bleeding
• Urine protein quantification: Spot PCR or 24-hour collection to quantify proteinuria (typically sub-nephrotic less than 3 g/day in nephritic syndrome)
• Renal function: U&E, creatinine, eGFR to assess severity of kidney injury
• Blood tests: FBC (anaemia, thrombocytopenia), CRP/ESR (inflammation), albumin

Immunological Screen ('GN Screen'):

• Complement levels: C3 and C4 (low in post-infectious GN, lupus, cryoglobulinaemia; normal in IgA nephropathy, ANCA vasculitis, anti-GBM)
• Autoantibodies:
  • ANCA (PR3 and MPO) for vasculitis
  • Anti-GBM antibodies for Goodpasture syndrome
  • ANA and anti-dsDNA for lupus nephritis
• Infectious serology: ASO titre (post-streptococcal), Hepatitis B and C (MPGN, cryoglobulinaemia)
• Immunoglobulins: Serum IgA (often elevated in IgA nephropathy, though non-specific)

Imaging:

• Renal ultrasound: Assess kidney size (small kidneys suggest chronic disease), exclude obstruction, guide biopsy
• Chest X-ray: Essential if any respiratory symptoms or to assess for pulmonary oedema/haemorrhage

Definitive Investigation:

• Renal biopsy: Gold standard for diagnosis
  • "Light microscopy: Pattern of injury (proliferative, crescentic, sclerosing)"
  • "Immunofluorescence: Linear IgG (anti-GBM), granular (immune complex), mesangial IgA (IgA nephropathy), pauci-immune (ANCA vasculitis)"
  • "Electron microscopy: Location of deposits (subendothelial, subepithelial, mesangial)"

This structured approach allows me to determine the etiology, assess disease severity, and guide appropriate management."

---

15. References

1. Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int. 2021;100(4S):S1-S276. doi:10.1016/j.kint.2021.05.021

2. Sethi S, Fervenza FC. Standardized classification and reporting of glomerulonephritis. Nephrol Dial Transplant. 2019;34(2):193-199. doi:10.1093/ndt/gfy220

3. Wyatt RJ, Julian BA. IgA nephropathy. N Engl J Med. 2013;368(25):2402-2414. doi:10.1056/NEJMra1206793

4. Jennette JC. Rapidly progressive crescentic glomerulonephritis. Kidney Int. 2003;63(3):1164-1177. doi:10.1046/j.1523-1755.2003.00843.x

5. Greco A, Rizzo MI, De Virgilio A, et al. Goodpasture's syndrome: a clinical update. Autoimmun Rev. 2015;14(3):246-253. doi:10.1016/j.autrev.2014.11.006

6. Fogazzi GB, Verdesca S, Garigali G. Urinalysis: core curriculum 2008. Am J Kidney Dis. 2008;51(6):1052-1067. doi:10.1053/j.ajkd.2007.11.039

7. Jennette JC, Falk RJ, Bacon PA, et al. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum. 2013;65(1):1-11. doi:10.1002/art.37715

8. Almaani S, Meara A, Rovin BH. Update on lupus nephritis. Clin J Am Soc Nephrol. 2017;12(5):825-835. doi:10.2215/CJN.05780616

9. Rodriguez-Iturbe B, Musser JM. The current state of poststreptococcal glomerulonephritis. J Am Soc Nephrol. 2008;19(10):1855-1864. doi:10.1681/ASN.2008010092

10. Lai KN, Tang SC, Schena FP, et al. IgA nephropathy. Nat Rev Dis Primers. 2016;2:16001. doi:10.1038/nrdp.2016.1

11. McAdoo SP, Pusey CD. Anti-glomerular basement membrane disease. Clin J Am Soc Nephrol. 2017;12(7):1162-1172. doi:10.2215/CJN.01380217

12. Jennette JC, Falk RJ. Pathogenesis of antineutrophil cytoplasmic autoantibody-mediated disease. Nat Rev Rheumatol. 2014;10(8):463-473. doi:10.1038/nrrheum.2014.103

13. Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al. Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2020;383(15):1436-1446. doi:10.1056/NEJMoa2024816

14. Lv J, Zhang H, Wong MG, et al. Effect of Oral Methylprednisolone on Clinical Outcomes in Patients With IgA Nephropathy: The TESTING Randomized Clinical Trial. JAMA. 2017;318(5):432-442. doi:10.1001/jama.2017.9362

15. Stone JH, Merkel PA, Spiera R, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010;363(3):221-232. doi:10.1056/NEJMoa0909905

16. Walsh M, Merkel PA, Peh CA, et al. Plasma Exchange and Glucocorticoids in Severe ANCA-Associated Vasculitis. N Engl J Med. 2020;382(7):622-631. doi:10.1056/NEJMoa1803537

17. Guillevin L, Pagnoux C, Karras A, et al. Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis. N Engl J Med. 2014;371(19):1771-1780. doi:10.1056/NEJMoa1404231

18. Appel GB, Contreras G, Dooley MA, et al. Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis. J Am Soc Nephrol. 2009;20(5):1103-1112. doi:10.1681/ASN.2008101028

19. Rovin BH, Furie R, Latinis K, et al. Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab study. Arthritis Rheum. 2012;64(4):1215-1226. doi:10.1002/art.34359

20. Berden AE, Ferrario F, Hagen EC, et al. Histopathologic classification of ANCA-associated glomerulonephritis. J Am Soc Nephrol. 2010;21(10):1628-1636. doi:10.1681/ASN.2010050477

---

Medical Disclaimer: MedVellum content is for educational purposes and clinical reference. Clinical decisions should account for individual patient circumstances, local guidelines, and specialist input. Always consult appropriate specialists for complex cases. This topic is current as of January 2026.