Acute Nephritic Syndrome

1. Clinical Overview

Summary

Acute Nephritic Syndrome is a clinical constellation resulting from inflammatory injury to the glomerulus. It is characterized by the classic tetrad of hematuria (typically with dysmorphic red blood cells and red cell casts), hypertension, edema, and azotemia (acute kidney injury with oliguria). [1] Unlike nephrotic syndrome, which results from podocyte injury causing massive proteinuria, nephritic syndrome reflects glomerular basement membrane damage with inflammatory cell infiltration, leading to capillary rupture and bleeding into the urinary space.

The clinical significance of acute nephritic syndrome lies in its potential for rapid progression to irreversible kidney failure. Rapidly progressive glomerulonephritis (RPGN), defined as loss of > 50% of kidney function within 3 months, represents the most severe end of the spectrum and constitutes a medical emergency requiring immediate immunosuppressive therapy. [2] Early recognition and appropriate serological workup can identify the underlying cause in over 90% of cases, enabling targeted treatment that can preserve renal function.

The epidemiology varies significantly by etiology. Post-streptococcal glomerulonephritis (PSGN) remains the most common cause of acute nephritis in children worldwide, with an estimated incidence of 9.3-28.5 per 100,000 person-years in developing countries. [3] In adults, IgA nephropathy is the most prevalent primary glomerulonephritis globally, while ANCA-associated vasculitis and lupus nephritis represent important secondary causes that require immunosuppressive therapy.

Key Facts

• The Classic Tetrad:

  1. Hematuria: Red blood cell casts and dysmorphic (acanthocytic) RBCs are pathognomonic for glomerular bleeding
  2. Hypertension: Results from sodium and water retention plus renin-angiotensin-aldosterone system (RAAS) activation
  3. Edema: Typically periorbital and pedal; less severe than nephrotic syndrome
  4. Azotemia/Oliguria: Rising creatinine with reduced urine output (less than 400 mL/day)

• Proteinuria: Characteristically "sub-nephrotic" (less than 3.5 g/day), though overlap syndromes exist

• Global Prevalence: IgA nephropathy is the most common primary glomerulonephritis worldwide, accounting for 25-50% of cases in Asia and 10-20% in Europe and North America [4]

• Pediatric Predominance: Post-streptococcal GN peaks between ages 5-12 years with male predominance (2:1)

• The Critical Emergency: RPGN (crescentic GN) can progress to dialysis-dependent renal failure within weeks without treatment

Clinical Pearls

"Coca-Cola Urine": The classic description of glomerular hematuria reflects metabolized hemoglobin producing brown/tea-colored urine. Fresh red blood (suggesting bladder or prostatic origin) indicates non-glomerular bleeding.

Synpharyngitic vs Post-infectious Timing:

• IgA Nephropathy: Hematuria occurs during or within 1-2 days of upper respiratory infection (synpharyngitic)
• Post-Streptococcal GN: Hematuria appears 1-3 weeks after streptococcal pharyngitis or 3-6 weeks after skin infection (latent period for immune complex formation)

Pulmonary-Renal Syndrome: Any patient presenting with hemoptysis and acute kidney injury should be presumed to have Goodpasture disease (anti-GBM) or ANCA-associated vasculitis until proven otherwise. This is a medical emergency requiring immediate plasma exchange and immunosuppression. [5]

Complement Levels as a Diagnostic Clue: Low C3 with normal C4 suggests alternative pathway activation (PSGN, C3 glomerulopathy), while low C3 AND C4 suggests classical pathway activation (lupus nephritis, cryoglobulinemia). [6]

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2. Nephritic vs Nephrotic Syndrome

The two poles of glomerular disease. Mixed pictures exist (e.g., membranoproliferative GN, lupus nephritis).

Mixed Nephritic-Nephrotic Syndrome

Several conditions present with features of both syndromes:

• Membranoproliferative GN (MPGN): Nephrotic-range proteinuria with active sediment
• Lupus Nephritis (Class III/IV/V): Variable presentation based on class
• IgA Nephropathy: May present with nephrotic-range proteinuria in severe cases
• Diabetic Nephropathy with superimposed GN: Particularly common in Asian populations

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3. Epidemiology

Global Burden

Risk Factors

Infection-Related GN:

• Recent streptococcal pharyngitis or impetigo
• Post-infectious GN from staphylococcal or gram-negative infections (especially in elderly)
• Hepatitis B (membranous nephropathy, PAN)
• Hepatitis C (cryoglobulinemic GN, MPGN)
• HIV (collapsing FSGS, immune complex GN)

Autoimmune GN:

• Female sex (lupus nephritis)
• African or Asian ancestry (lupus, IgA)
• HLA-DR2, HLA-B8 associations (anti-GBM disease)
• Smoking (anti-GBM disease - pulmonary hemorrhage risk) [5]
• Hydrocarbon exposure (anti-GBM disease)

Drug-Induced GN:

• Hydralazine, propylthiouracil (drug-induced ANCA vasculitis)
• Cocaine contaminated with levamisole (ANCA-positive GN)
• NSAIDs (membranous nephropathy)
• Penicillamine, gold (membranous nephropathy)

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4. Pathophysiology

Mechanisms of Glomerular Injury

The glomerulus can be injured through three principal immune mechanisms: [8]

1. Immune Complex Deposition

Circulating antigen-antibody complexes deposit in the glomerulus based on size, charge, and mesangial clearance capacity.

Subepithelial deposits (between podocytes and GBM):

• Mechanism: In situ immune complex formation or deposition of small complexes
• Appearance: "Spike and dome" pattern (membranous nephropathy)
• Example: Membranous nephropathy, post-infectious GN (hump)

Subendothelial deposits (between endothelium and GBM):

• Mechanism: Deposition of larger circulating complexes
• Appearance: "Wire loop" lesions
• Example: Lupus nephritis (Class IV), cryoglobulinemic GN

Mesangial deposits:

• Mechanism: Mesangial trapping of immune complexes
• Appearance: Mesangial expansion and hypercellularity
• Example: IgA nephropathy, Henoch-Schonlein purpura, lupus nephritis (Class I/II)

2. Direct Antibody Attack (Anti-GBM Disease)

Autoantibodies target the non-collagenous (NC1) domain of the alpha-3 chain of type IV collagen, found in glomerular and alveolar basement membranes. [5]

• Pathogenesis: The alpha-3(IV)NC1 epitope is normally cryptic (hidden within the collagen network). Pulmonary injury (smoking, hydrocarbons, infection) exposes the epitope in alveoli, triggering autoimmunity
• Immunofluorescence: Linear IgG deposition along GBM (pathognomonic)
• Clinical: Goodpasture syndrome (pulmonary hemorrhage + RPGN) or renal-limited anti-GBM disease

3. Pauci-Immune Glomerulonephritis

No significant immune complex deposition; injury is mediated by neutrophil activation via ANCA (anti-neutrophil cytoplasmic antibodies). [9]

• MPO-ANCA (p-ANCA): Anti-myeloperoxidase antibodies
• PR3-ANCA (c-ANCA): Anti-proteinase 3 antibodies
• Mechanism: ANCA bind to neutrophil surface antigens, causing activation, degranulation, and vascular injury

The Complement System in GN

Complement activation is central to many forms of glomerulonephritis. [6]

Classical Pathway Activation (Low C3 AND Low C4):

• Triggered by immune complexes (antigen-antibody)
• Conditions: Lupus nephritis, cryoglobulinemic GN, post-infectious GN (early)
• C1q, C4, C2 consumed first, then C3

Alternative Pathway Activation (Low C3, Normal C4):

• Triggered by microbial surfaces or C3 nephritic factor (C3NeF)
• Conditions: Post-streptococcal GN (late), C3 glomerulopathy, atypical HUS
• Factor H deficiency or C3NeF removes normal pathway regulation

Complement in PSGN:

• Streptococcal antigens (nephritis-associated plasmin receptor/NAPlr, streptococcal pyrogenic exotoxin B/SpeB) activate complement
• C3 is typically low during acute phase (returns to normal in 6-8 weeks)
• Persistently low C3 beyond 8 weeks suggests MPGN or C3 glomerulopathy

The "Crescent" and RPGN

Crescentic glomerulonephritis represents the most severe form of glomerular injury. [2]

Formation:

1. Severe capillary wall injury causes fibrin to leak into Bowman's space
2. Fibrin triggers proliferation of parietal epithelial cells and infiltration of monocytes/macrophages
3. These cells form a "crescent" shape that compresses the glomerular tuft
4. Without treatment, crescents become fibrotic (irreversible)

Classification of RPGN by Immunofluorescence:

Prognostic Significance of Crescents:

• less than 50% crescents: Better prognosis with treatment
• 50-80% crescents: Moderate prognosis, dialysis often required initially

• 80% crescents: Poor renal prognosis even with treatment

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5. Etiology Classification

A. Classification by Complement Levels

The complement profile provides a rapid, clinically useful framework for differential diagnosis. [6]

Low C3, Normal C4 (Alternative Pathway)

Low C3 AND Low C4 (Classical Pathway)

Normal Complement

B. Major Disease Categories

Post-Streptococcal Glomerulonephritis (PSGN)

The prototype of acute nephritic syndrome and the most common cause in children. [3]

Pathogenesis:

• Group A beta-hemolytic streptococci (Streptococcus pyogenes) cause pharyngitis or skin infection
• Nephritogenic strains express specific M proteins (M types 1, 4, 12 for pharyngitis; types 49, 55, 57 for pyoderma)
• Streptococcal antigens (NAPlr, SpeB) deposit in glomeruli and activate complement
• Latent period allows immune complex formation: 1-3 weeks (pharyngitis), 3-6 weeks (pyoderma)

Clinical Features:

• Gross hematuria ("cola/tea-colored urine")
• Periorbital edema (most prominent in mornings)
• Hypertension (may cause hypertensive encephalopathy in severe cases)
• Oliguria with acute kidney injury
• Fever and malaise (often resolved by time of nephritis)

Prognosis:

• Children: Excellent (> 95% complete recovery)
• Adults: Higher risk of persistent proteinuria and CKD (25-30%)
• Abnormal urinalysis may persist for 1-2 years but typically resolves

IgA Nephropathy (Berger Disease)

The most common primary glomerulonephritis worldwide. [4]

Pathogenesis:

• Galactose-deficient IgA1 (Gd-IgA1) is produced, particularly at mucosal surfaces
• Autoantibodies recognize the abnormal glycosylation, forming immune complexes
• Complexes deposit in the mesangium, activating mesangial cells and complement
• "Multi-hit" hypothesis: Genetic susceptibility + mucosal triggers + immune dysregulation

Clinical Spectrum:

• Episodic gross hematuria with URIs (classic synpharyngitic presentation)
• Persistent microscopic hematuria with mild proteinuria
• Nephrotic-range proteinuria (poor prognosis)
• RPGN (rare but aggressive)

Henoch-Schonlein Purpura (IgA Vasculitis):

• Systemic form of IgA nephropathy
• Tetrad: Palpable purpura (legs/buttocks), arthralgia, abdominal pain, nephritis
• Renal biopsy shows identical mesangial IgA deposits
• Self-limited in most children; adults have higher risk of CKD

ANCA-Associated Vasculitis

Small vessel vasculitis with necrotizing glomerulonephritis. [9]

Pulmonary-Renal Syndrome:

• Definition: Concurrent diffuse alveolar hemorrhage and glomerulonephritis
• Causes: GPA, MPA, anti-GBM disease, SLE, cryoglobulinemia
• Management: Emergency plasma exchange + high-dose corticosteroids + cyclophosphamide/rituximab

Anti-GBM Disease (Goodpasture Disease)

Autoantibodies against type IV collagen causing RPGN with or without pulmonary hemorrhage. [5]

Clinical Presentation:

• Young males (20-30 years): Often pulmonary-renal syndrome with hemoptysis, dyspnea, and RPGN
• Older females (60-70 years): Often renal-limited disease without pulmonary involvement
• Smoking or hydrocarbon exposure: Major risk factor for pulmonary hemorrhage

Diagnosis:

• Anti-GBM antibodies: Serum ELISA (> 90% sensitive and specific)
• Renal biopsy: Linear IgG deposition along GBM (100% specific)
• Note: 10-30% have concurrent ANCA positivity ("double-positive" disease)

Prognosis:

• Dependent on creatinine at presentation and percentage of crescents
• Patients presenting with dialysis-dependence rarely recover renal function
• Early treatment (before Cr > 500 umol/L or dialysis) associated with better outcomes

Lupus Nephritis

Renal manifestation of systemic lupus erythematosus, occurring in 40-70% of SLE patients. [7]

ISN/RPS Classification (2003/2018):

"Full House" Immunofluorescence:

• Positive staining for IgG, IgM, IgA, C3, C1q
• Pathognomonic for lupus nephritis
• Reflects multiple immune complex pathways activated

Activity and Chronicity Indices:

• Activity index: Scores reversible, inflammatory lesions (cellular crescents, fibrinoid necrosis)
• Chronicity index: Scores irreversible, scarred lesions (glomerulosclerosis, tubular atrophy)
• High chronicity predicts poor response to immunosuppression

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6. Clinical Presentation

Symptoms

Signs

General Inspection:

• Facial puffiness (periorbital edema most prominent in mornings)
• Pallor (if anemic from chronic disease or hemolysis)
• Skin rash: Malar rash (SLE), palpable purpura (HSP, vasculitis), impetigo (PSGN)

Cardiovascular:

• Hypertension (may be severe)
• Elevated JVP (fluid overload)
• S3 gallop (if cardiac failure)
• Pulmonary crackles (pulmonary edema)

Abdominal:

• Hepatosplenomegaly (SLE, cryoglobulinemia)
• Renal angle tenderness (rare in GN)

Extremities:

• Peripheral edema (pitting)
• Purpuric rash (vasculitis, HSP)
• Nail fold infarcts (vasculitis)
• Digital ischemia (cryoglobulinemia)

ENT (ANCA Vasculitis - GPA):

• Nasal crusting, epistaxis
• Saddle nose deformity
• Hearing loss
• Orbital pseudotumor

Red Flag Presentations

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7. Investigations

First-Line Investigations

Urinalysis and Microscopy

The "liquid biopsy"

• most important initial test. [8]

Dipstick:

• Blood: Positive (hematuria)
• Protein: 1-2+ (sub-nephrotic)
• Leukocyte esterase: May be positive (sterile pyuria in GN)

Microscopy (Fresh Spun Urine):

Urine Protein:Creatinine Ratio (uPCR):

• less than 50 mg/mmol: Normal
• 50-350 mg/mmol: Sub-nephrotic (typical for nephritic syndrome)

• 350 mg/mmol: Nephrotic-range (suggests mixed picture or RPGN)

Blood Tests

Renal Function:

• Urea and creatinine: Elevated in AKI
• eGFR: Calculate to quantify kidney function loss
• Electrolytes: Hyperkalemia, hyperphosphatemia, metabolic acidosis

Full Blood Count:

• Anemia: Dilutional (fluid overload), hemolytic (TMA), or chronic disease
• Thrombocytopenia: TTP/HUS, DIC, SLE
• Leukocytosis or eosinophilia: Infection, drug reaction, EGPA

Serological Panel ("Glomerular Screen")

Essential for identifying underlying cause before biopsy. [6]

Imaging

Renal Ultrasound:

• Kidney size: Normal or enlarged in acute GN; small kidneys suggest CKD
• Echogenicity: Increased in renal parenchymal disease
• Obstruction: Exclude hydronephrosis (not a cause of nephritic syndrome)
• Pre-biopsy assessment: Confirms two kidneys, adequate size for biopsy

Chest X-Ray:

• Pulmonary edema (fluid overload)
• Pulmonary hemorrhage (bilateral alveolar infiltrates in pulmonary-renal syndrome)
• Cavitating nodules (GPA)

Renal Biopsy

The gold standard for diagnosis of glomerulonephritis. [10]

Indications:

• Unexplained AKI with active urine sediment
• Nephrotic syndrome in adults
• Suspected systemic disease (lupus, vasculitis)
• Rapidly progressive renal failure (urgent indication)
• Atypical clinical course of presumed PSGN (no recovery, persisting low C3)
• Significant proteinuria (> 1 g/day) with hematuria

Relative Contraindications:

• Small kidneys (less than 9 cm) indicating CKD
• Solitary kidney (relative - may still biopsy with caution)
• Uncontrolled hypertension (BP > 160/100 mmHg)
• Bleeding diathesis (correct coagulopathy, hold anticoagulants)
• Active UTI (treat first)
• Uncooperative patient

Procedure:

• Typically ultrasound-guided percutaneous biopsy of left kidney
• Patient prone, local anesthesia, 16-18G automated needle
• Minimum 10 glomeruli for adequate diagnosis; 20+ ideal

Complications:

Biopsy Interpretation (Three Techniques):

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8. Classification Systems

Oxford Classification (MEST-C) for IgA Nephropathy

Validated prognostic scoring system for IgA nephropathy. [11]

ANCA Vasculitis Activity Scores

Birmingham Vasculitis Activity Score (BVAS):

• Comprehensive assessment of disease activity across 9 organ systems
• Scores range from 0-63
• Used for clinical trial endpoints and treatment decisions

Five Factor Score (FFS) for Prognosis:

• Age > 65 years
• Cardiac involvement
• GI involvement
• Creatinine > 150 umol/L (> 1.7 mg/dL)
• No ENT involvement (in GPA/EGPA)
• Higher scores predict higher mortality

Chapel Hill Consensus Nomenclature (2012)

Standard nomenclature for systemic vasculitis. [12]

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9. Management

Acute Management Principles

Initial Stabilization

ABCDE Assessment:

• Airway: Protect if encephalopathic
• Breathing: Assess for pulmonary edema, hemoptysis (pulmonary-renal syndrome)
• Circulation: IV access, fluid restriction if oliguric, BP control
• Disability: Assess for hypertensive encephalopathy
• Exposure: Look for rashes, purpura, signs of systemic disease

Immediate Actions:

1. Strict fluid balance: Restrict to 500 mL + previous day's output
2. Daily weights: Most accurate fluid assessment
3. Blood pressure control: Target less than 130/80 mmHg
4. Avoid nephrotoxins: Stop NSAIDs, contrast, aminoglycosides
5. Potassium management: ECG monitoring if K+ > 6.0 mmol/L

Blood Pressure Control

First-Line Agents:

• ACE Inhibitors/ARBs: Ramipril, losartan

  • Preferred for renoprotection and proteinuria reduction
  • "Mechanism: Dilate efferent arteriole, reducing intraglomerular pressure"
  • "Caution: May worsen AKI initially; monitor creatinine and potassium"
  • Accept up to 30% rise in creatinine if stable

• Calcium Channel Blockers: Amlodipine, nifedipine

  • Safe in AKI, no hyperkalemia risk
  • Add if ACEi/ARB insufficient

Hypertensive Emergency:

• IV labetalol or sodium nitroprusside
• Target: 25% reduction in MAP in first 1-2 hours
• Avoid rapid drops (risk of watershed infarcts)

Fluid Management

Diuretics:

• Loop diuretics (furosemide) are mainstay
• Higher doses needed in AKI (80-200 mg IV bolus, or infusion 5-20 mg/hr)
• Add thiazide (metolazone 5-10 mg) for diuretic resistance

Fluid Restriction:

• Typical: 1L/day + insensible losses
• More restrictive if anuric: 500 mL/day
• Low sodium diet: less than 2g/day (less than 80 mmol/day)

Indications for Urgent Dialysis (AEIOU)

Hyperkalemia Management Protocol

Step 1 - Cardiac Membrane Stabilization:

• Calcium gluconate 10%: 10 mL IV over 5-10 minutes
• Does NOT lower potassium; protects heart from arrhythmia
• Repeat if ECG changes persist

Step 2 - Intracellular Shift:

• Insulin 10 units + Glucose 50 mL of 50% dextrose
• Onset: 15-30 minutes; Duration: 4-6 hours
• Salbutamol nebulized: 10-20 mg (drives K+ intracellularly)

Step 3 - Potassium Elimination:

• Furosemide: If patient making urine
• Sodium zirconium cyclosilicate (Lokelma) or patiromer: Oral K+ binders
• Dialysis: Definitive treatment for refractory hyperkalemia

Plasma Exchange (Plasmapheresis)

Critical intervention for anti-GBM disease and severe ANCA vasculitis with pulmonary hemorrhage. [13]

Mechanism:

• Centrifugation separates plasma from cellular components
• Plasma (containing pathogenic antibodies) is discarded
• Cells returned with replacement fluid (albumin or FFP)

Indications:

• Anti-GBM disease (Grade 1A recommendation)
• ANCA vasculitis with diffuse alveolar hemorrhage
• ANCA vasculitis with severe renal failure (creatinine > 500 umol/L) - debated
• Cryoglobulinemic vasculitis

Protocol:

• 60 mL/kg plasma exchange (typically 4L per session)
• Daily or alternate days for 7-14 sessions
• Replacement: 5% albumin (or FFP if bleeding risk or post-biopsy)

Complications:

• Coagulopathy (clotting factors removed)
• Hypocalcemia (citrate anticoagulation)
• Allergic reactions
• Infection risk
• Line-related complications

Immunosuppressive Therapy

General Principles

Induction Phase:

• High-intensity therapy to control active inflammation
• Duration: 3-6 months
• Agents: High-dose corticosteroids ± cyclophosphamide or rituximab

Maintenance Phase:

• Lower-intensity therapy to prevent relapse
• Duration: 12-24 months (longer in high-risk patients)
• Agents: Low-dose steroids, azathioprine, mycophenolate

Corticosteroids

Pulse Therapy:

• IV methylprednisolone: 500-1000 mg daily for 3 days
• Indication: RPGN, severe lupus nephritis, ANCA vasculitis

Oral Prednisone:

• Initial: 1 mg/kg/day (max 60-80 mg)
• Taper: Over 3-6 months to lowest effective dose
• Goal: less than 10 mg/day by 6 months; ideally steroid-free

Side Effects of Long-term Steroids:

• Infection (PJP prophylaxis with co-trimoxazole)
• Diabetes, hypertension, weight gain
• Osteoporosis (add calcium, vitamin D, bisphosphonate)
• Cataracts, glaucoma
• Avascular necrosis
• Adrenal suppression

Cyclophosphamide

The "gold standard" cytotoxic agent for severe GN. [14]

Indications:

• ANCA vasculitis (induction)
• Lupus nephritis (Class III/IV)
• Anti-GBM disease
• Severe crescentic IgA nephropathy

Routes:

• IV pulse (preferred): 15 mg/kg (max 1.2g) every 2-3 weeks x 6 doses
• Oral (less common): 2 mg/kg/day for 3 months
• IV pulses have equal efficacy with lower cumulative dose and fewer side effects

Toxicity (The "Red Devil"):

Rituximab

Anti-CD20 monoclonal antibody depleting B lymphocytes. [15]

Evidence:

• RAVE and RITUXVAS trials: Non-inferior to cyclophosphamide for ANCA vasculitis induction
• Preferred in relapsing disease, young patients (fertility preservation), contraindications to cyclophosphamide

Dosing:

• Rheumatoid arthritis protocol: 1g IV at weeks 0 and 2
• Lymphoma protocol: 375 mg/m² weekly x 4 weeks

Monitoring:

• CD19/CD20 B cell counts: Target depletion
• Immunoglobulins: Risk of hypogammaglobulinemia with repeated courses
• Hepatitis B screening: Risk of reactivation (give prophylaxis if HBcAb+)

Side Effects:

• Infusion reactions (premedicate with antihistamine, hydrocortisone)
• Hypogammaglobulinemia (check IgG; may need IVIG replacement)
• Progressive multifocal leukoencephalopathy (PML) - rare but serious
• Late-onset neutropenia

Mycophenolate Mofetil (MMF)

Inhibits de novo purine synthesis in lymphocytes.

Indications:

• Lupus nephritis: Induction (non-inferior to cyclophosphamide for Class III/IV) and maintenance
• IgA nephropathy: Alternative to steroids (less evidence)
• ANCA vasculitis: Maintenance (after induction with cyclophosphamide or rituximab)

Dosing:

• Lupus nephritis: 2-3 g/day in divided doses
• Maintenance: 1-2 g/day

Side Effects:

• GI (nausea, diarrhea) - dose-limiting
• Bone marrow suppression
• Teratogenic (mandatory contraception)
• Infection risk

Disease-Specific Management

Post-Streptococcal GN

Primarily supportive treatment. [3]

Approach:

• Fluid and sodium restriction
• Loop diuretics for edema
• Antihypertensives for BP control
• No role for immunosuppression (self-limited disease)
• Antibiotics: Penicillin to eradicate persistent strep (does not change nephritis course but prevents transmission)

When to Suspect NOT PSGN:

• No improvement at 2 weeks
• C3 persistently low beyond 6-8 weeks
• Nephrotic-range proteinuria
• Family history of kidney disease
• Age less than 4 or > 12 years
• Indication for biopsy to exclude C3 glomerulopathy, MPGN, or other diagnosis

IgA Nephropathy

Risk-stratified management approach. [4,16]

Low Risk (Isolated hematuria, proteinuria less than 0.5 g/day, normal eGFR):

• Lifestyle: BP control, smoking cessation, weight management
• ACEi/ARB: Titrate to maximum tolerated dose
• Monitor: 6-monthly urinalysis, BP, eGFR

Moderate Risk (Proteinuria 0.5-1 g/day after ACEi/ARB optimization):

• SGLT2 inhibitor: Dapagliflozin (DAPA-CKD evidence) [17]
• Consider: Targeted-release budesonide (NEFECON - gut-directed steroid)

High Risk (Proteinuria > 1 g/day, declining eGFR, crescents on biopsy):

• Immunosuppression: Consider corticosteroids (6-12 months)
• Crescentic IgAN: Treat as RPGN (pulse steroids ± cyclophosphamide)

ANCA-Associated Vasculitis

Induction (3-6 months): [9,14,15]

• Pulse methylprednisolone (500-1000 mg x 3 days) then oral prednisone taper
• PLUS cyclophosphamide OR rituximab (equally effective per RAVE/RITUXVAS trials)
• Plasma exchange: If creatinine > 500 umol/L or pulmonary hemorrhage (PEXIVAS data showed reduced need for dialysis) [13]

Maintenance (2+ years):

• Low-dose prednisone (5-10 mg/day, eventually discontinue)
• PLUS azathioprine, methotrexate, or rituximab maintenance

Avacopan:

• C5a receptor antagonist
• ADVOCATE trial: Non-inferior to prednisone for induction, superior for sustained remission
• May allow steroid-free or steroid-minimal regimens

Anti-GBM Disease

Medical emergency requiring immediate treatment. [5]

Standard Regimen:

1. Plasma exchange: Daily for 14 days or until antibody negative
2. Cyclophosphamide: 2-3 mg/kg/day for 2-3 months
3. High-dose prednisone: 1 mg/kg/day with taper

Prognosis:

• Dialysis-dependent at presentation: less than 10% renal recovery
• Creatinine less than 500 umol/L at presentation: ~80% renal recovery with treatment
• Early treatment is critical

Post-Transplant:

• Wait 6-12 months after antibody clearance
• Low recurrence risk (less than 5%) if transplanted when antibody negative

Lupus Nephritis

Class-based treatment approach. [7,18]

Class I/II:

• Treat underlying SLE
• ACEi/ARB for proteinuria
• Monitor for progression

Class III/IV (Proliferative):

• Induction: Pulse methylprednisolone + (cyclophosphamide OR mycophenolate)
• ALMS and EURO-LUPUS trials support MMF as non-inferior to cyclophosphamide
• Maintenance: Mycophenolate or azathioprine + low-dose steroids

Class V (Membranous):

• If subnephrotic proteinuria: ACEi/ARB, monitor
• If nephrotic-range proteinuria: Add immunosuppression (mycophenolate, rituximab, calcineurin inhibitors)

Newer Agents:

• Voclosporin (calcineurin inhibitor): AURORA trial - added benefit with MMF for lupus nephritis
• Belimumab (anti-BLyS): BLISS-LN trial - improved renal response when added to standard therapy

SGLT2 Inhibitors: Paradigm Shift in GN Management

Sodium-glucose cotransporter 2 inhibitors have transformed CKD management. [17]

Mechanism:

• Block glucose and sodium reabsorption in proximal tubule
• Increased sodium delivery to macula densa triggers tubuloglomerular feedback
• Afferent arteriolar vasoconstriction reduces intraglomerular pressure
• Additional: Reduced oxidative stress, inflammation, and fibrosis

Evidence:

• DAPA-CKD: 39% reduction in composite kidney outcome (including GN patients)
• EMPA-KIDNEY: Benefit across CKD etiologies
• SGLT2 inhibitors now recommended for proteinuric CKD including IgA nephropathy

Prescribing:

• Dapagliflozin 10 mg daily or empagliflozin 10-25 mg daily
• Safe to initiate with eGFR ≥20-25 mL/min/1.73m²
• Accept initial eGFR dip of 10-20% (hemodynamic, reversible)

Side Effects:

• Genital mycotic infections (counsel on hygiene)
• Euglycemic diabetic ketoacidosis (rare; pause if unwell, fasting, or surgery)
• Volume depletion (caution with diuretics)

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10. Complications

Acute Complications

Chronic Complications

Cardiovascular Disease in GN

The #1 cause of death in GN patients is cardiovascular disease, not kidney failure. [19]

Mechanisms:

• Chronic inflammation accelerates atherosclerosis
• Hypertension causes left ventricular hypertrophy
• CKD-mineral bone disorder causes vascular calcification
• Proteinuria associated with endothelial dysfunction

Risk Reduction:

• Statin therapy (atorvastatin 20-40 mg)
• Aspirin for secondary prevention (primary prevention controversial in CKD)
• Optimal BP control (less than 130/80 mmHg)
• Smoking cessation
• SGLT2 inhibitors (cardiovascular benefit)

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11. Differential Diagnosis

Distinguishing GN from Other Causes of AKI

IgA Nephropathy vs PSGN

Alport Syndrome vs Thin Basement Membrane Nephropathy

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12. Prognosis and Outcomes

Disease-Specific Prognosis

Predictors of Poor Outcome in GN

Clinical:

• Higher creatinine at presentation
• Nephrotic-range proteinuria
• Hypertension
• Delay in immunosuppressive treatment
• Older age
• Male sex (IgA nephropathy)
• African American or Hispanic ethnicity (lupus nephritis)

Histological:

• Percentage of crescents (> 50% = poor prognosis)
• Tubular atrophy and interstitial fibrosis (chronicity)
• Glomerulosclerosis
• High chronicity index (lupus nephritis)

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13. Special Populations

Pediatric Considerations

PSGN in Children:

• Most common cause of acute nephritis in children
• Generally excellent prognosis
• Hospitalization for moderate-severe cases (BP control, fluid management)
• Avoid routine biopsy (only if atypical features)

When to Refer/Biopsy in Pediatric GN:

• Age less than 4 or > 12 years (atypical for PSGN)
• Normal C3 (suggests IgA or other diagnosis)
• Persistent low C3 beyond 6-8 weeks
• Nephrotic-range proteinuria
• RPGN picture
• Systemic symptoms (HSP, vasculitis features)

HSP Nephritis in Children:

• Usually self-limited with supportive care
• Predictors of CKD: Persistent proteinuria, crescents on biopsy
• Consider immunosuppression if crescentic or nephrotic

Pregnancy and GN

General Principles:

• Pre-existing GN increases risk of: Pre-eclampsia, IUGR, preterm delivery, CKD progression
• Stable disease with eGFR > 60 and controlled BP: Reasonable pregnancy outcomes
• Active disease: High risk; recommend remission before conception

Medication Safety:

Lupus Nephritis and Pregnancy:

• Requires remission for ≥6 months before conception
• Continue hydroxychloroquine (reduces flare risk)
• Switch from MMF to azathioprine before conception
• High-risk obstetric care mandatory
• Anti-Ro/La positive: Risk of neonatal lupus, congenital heart block

Elderly Patients

Considerations:

• Higher incidence of ANCA vasculitis in elderly (peak 65-75 years)
• Post-infectious GN from non-streptococcal sources (staph endocarditis, gram-negative)
• Greater frailty: Modify immunosuppressive doses
• Competing mortality: Cardiovascular disease often more threatening than CKD
• Lower cyclophosphamide doses; consider rituximab (less infection risk)

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14. Prevention and Screening

Primary Prevention

Post-Streptococcal GN:

• Prompt treatment of streptococcal pharyngitis (antibiotics)
• Treatment of impetigo
• Improved hygiene and living conditions

Drug-Induced GN:

• Awareness of hydralazine, PTU, levamisole-contaminated cocaine
• Monitor urinalysis in patients on high-risk medications

Secondary Prevention (Preventing CKD Progression)

Universal Measures:

• BP control less than 130/80 mmHg
• ACEi/ARB: Maximum tolerated dose
• SGLT2 inhibitors: For proteinuric CKD
• Smoking cessation
• Weight management
• Low sodium diet (less than 2g/day)
• Avoid nephrotoxins (NSAIDs, aminoglycosides, IV contrast)

Immunosuppression:

• Appropriate maintenance therapy prevents relapse
• Regular monitoring of inflammatory markers (ANCA levels, complement, dsDNA)

Screening Recommendations

First-Degree Relatives of Alport Syndrome:

• Genetic testing and/or renal biopsy
• Annual urinalysis and BP

Lupus Patients:

• Regular urinalysis (every 3-6 months)
• Renal function monitoring
• Early biopsy if new proteinuria/hematuria

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15. Key Guidelines

KDIGO Clinical Practice Guideline for Glomerulonephritis (2021) [1]

Key Recommendations:

• IgA Nephropathy: ACEi/ARB for all; consider corticosteroids for high-risk (proteinuria > 1g despite optimal supportive care)
• ANCA Vasculitis: Rituximab or cyclophosphamide equally effective for induction; plasma exchange for severe disease
• Lupus Nephritis: Mycophenolate or cyclophosphamide for induction of Class III/IV; maintenance with mycophenolate or azathioprine
• Anti-GBM: Plasma exchange + cyclophosphamide + corticosteroids

ACR/EULAR Guidelines for Lupus Nephritis (2019) [18]

Key Points:

• Hydroxychloroquine for all lupus nephritis patients (unless contraindicated)
• Mycophenolate preferred over cyclophosphamide for most patients (equivalent efficacy, better safety)
• Voclosporin and belimumab as add-on therapies in refractory cases

BSR/BHPR Guidelines for ANCA Vasculitis (2014, updated 2022) [9]

Key Points:

• Cyclophosphamide or rituximab for induction
• Plasma exchange for severe renal involvement or pulmonary hemorrhage
• Maintenance: At least 2 years after remission
• PJP prophylaxis mandatory with cyclophosphamide

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16. Exam Focus and Viva Points

Common Exam Questions

1. "What are the causes of acute nephritic syndrome? How do you classify them?"
2. "A patient presents with hemoptysis and acute kidney injury. What is your approach?"
3. "Describe the immunofluorescence patterns in glomerulonephritis."
4. "When would you perform a renal biopsy in a patient with hematuria?"
5. "How do you manage ANCA-associated vasculitis?"
6. "What is the role of plasma exchange in glomerulonephritis?"
7. "Describe the Oxford classification for IgA nephropathy."
8. "How do complement levels help differentiate causes of GN?"

Viva Opening Statements

Acute Nephritic Syndrome:

"Acute nephritic syndrome is a clinical presentation of glomerular inflammation characterized by the tetrad of hematuria with dysmorphic RBCs and RBC casts, hypertension, edema, and azotemia with oliguria. The causes can be classified by complement levels: low C3 with normal C4 suggests post-infectious or C3 glomerulopathy, low C3 and C4 suggests lupus or cryoglobulinemia, and normal complement suggests IgA nephropathy or ANCA-associated vasculitis."

Pulmonary-Renal Syndrome:

"Pulmonary-renal syndrome refers to the combination of diffuse alveolar hemorrhage and rapidly progressive glomerulonephritis. The two main causes are anti-GBM disease and ANCA-associated vasculitis, particularly MPA. This is a medical emergency requiring immediate high-dose corticosteroids, plasma exchange, and cyclophosphamide or rituximab."

Key Facts to Quote in Exams

• IgA nephropathy is the most common primary GN worldwide (25-50% in Asia)
• "Full house" immunofluorescence is pathognomonic for lupus nephritis
• RAVE trial: Rituximab is non-inferior to cyclophosphamide for ANCA vasculitis induction
• DAPA-CKD: 39% reduction in renal endpoints with dapagliflozin in CKD including GN
• Anti-GBM patients with creatinine > 500 umol/L at presentation rarely recover renal function

Common Mistakes to Avoid

• Confusing synpharyngitic (IgA) vs post-infectious (PSGN) timing
• Not checking complement levels in acute nephritis workup
• Delaying immunosuppression in RPGN while awaiting biopsy results
• Missing pulmonary-renal syndrome (always ask about hemoptysis)
• Not using PJP prophylaxis with cyclophosphamide
• Forgetting fertility counseling before cytotoxic therapy
• Using ACEi/ARB in hyperkalemic, oliguric patient with rapidly rising creatinine

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17. Patient Education

Understanding Your Condition

What is happening in my kidneys? Your kidneys filter blood through tiny units called glomeruli. In nephritic syndrome, your immune system is causing inflammation in these filters. This leads to blood leaking into your urine, high blood pressure, swelling, and reduced kidney function.

Will I need dialysis? Most patients with mild nephritic syndrome do not need dialysis. However, if inflammation is severe (RPGN), temporary dialysis may be needed to support the kidneys while treatment works.

Is this contagious? No. Even in post-streptococcal GN, the kidney problem is an immune reaction after the infection has cleared. You cannot pass kidney disease to others.

Dietary Advice (The "Renal Diet")

• Salt: less than 2g sodium/day (approximately 1 teaspoon of salt)
• Potassium (if levels high): Limit bananas, oranges, tomatoes, potatoes, chocolate, nuts
• Fluid: Typically 1-1.5L/day if oliguric; follow your doctor's advice
• Protein: Moderate intake (0.8g/kg/day) unless otherwise advised

Medication Adherence

Why is it important to take immunosuppressive medications? These medications control the immune system that is attacking your kidneys. Missing doses can lead to disease relapse and permanent kidney damage. However, they also suppress your infection-fighting ability, so report any fever, cough, or unusual symptoms to your doctor immediately.

Follow-Up Checklist

• BP monitoring at home (target less than 130/80)
• Daily weight (report weight gain > 1kg in 24 hours)
• Watch for warning signs: Reduced urine, increasing swelling, blood in urine
• Attend all clinic appointments
• Get flu and pneumococcal vaccines (if on immunosuppression)
• Avoid NSAIDs (ibuprofen, naproxen)

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18. References

1. KDIGO 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. Jennette JC, Thomas DB. Crescentic glomerulonephritis. Nephrol Dial Transplant. 2001;16(Suppl 6):80-82. doi:10.1093/ndt/16.suppl_6.80

3. Carapetis JR, Steer AC, Mulholland EK, Weber M. The global burden of group A streptococcal diseases. Lancet Infect Dis. 2005;5(11):685-694. doi:10.1016/S1473-3099(05)70267-X

4. Rodrigues JC, Haas M, Reich HN. IgA Nephropathy. Clin J Am Soc Nephrol. 2017;12(4):677-686. doi:10.2215/CJN.07420716

5. McAdoo SP, Pusey CD. Anti-Glomerular Basement Membrane Disease. Clin J Am Soc Nephrol. 2017;12(7):1162-1172. doi:10.2215/CJN.01380217

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

7. Fanouriakis A, Kostopoulou M, Cheema K, et al. 2019 Update of the Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of lupus nephritis. Ann Rheum Dis. 2020;79(6):713-723. doi:10.1136/annrheumdis-2020-216924

8. Floege J, Amann K. Primary glomerulonephritides. Lancet. 2016;387(10032):2036-2048. doi:10.1016/S0140-6736(16)00272-5

9. Ntatsaki E, Carruthers D, Chakravarty K, et al. BSR and BHPR guideline for the management of adults with ANCA-associated vasculitis. Rheumatology. 2014;53(12):2306-2309. doi:10.1093/rheumatology/keu358

10. Hogan JJ, Mocanu M, Berns JS. The Native Kidney Biopsy: Update and Evidence for Best Practice. Clin J Am Soc Nephrol. 2016;11(2):354-362. doi:10.2215/CJN.05750515

11. Trimarchi H, Barratt J, Cattran DC, et al. Oxford Classification of IgA nephropathy 2016: an update from the IgA Nephropathy Classification Working Group. Kidney Int. 2017;91(5):1014-1021. doi:10.1016/j.kint.2017.02.003

12. 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

13. 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

14. de Groot K, Harper L, Jayne DR, et al. Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized trial. Ann Intern Med. 2009;150(10):670-680. doi:10.7326/0003-4819-150-10-200905190-00004

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. Rovin BH, Caster DJ, Engel R, et al. Management of IgA nephropathy in 2023. Nat Rev Nephrol. 2023;19(11):673-688. doi:10.1038/s41581-023-00760-5

17. 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

18. Rovin BH, Teng YKO, Ginzler EM, et al. Efficacy and safety of voclosporin versus placebo for lupus nephritis (AURORA 1): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2021;397(10289):2070-2080. doi:10.1016/S0140-6736(21)00578-X

19. Thompson S, James M, Wiebe N, et al. Cause of Death in Patients with Reduced Kidney Function. J Am Soc Nephrol. 2015;26(10):2504-2511. doi:10.1681/ASN.2014070714

20. Wheeler DC, Stefánsson BV, Jongs N, et al. Effects of dapagliflozin on major adverse kidney and cardiovascular events in patients with diabetic and non-diabetic chronic kidney disease: a prespecified analysis from the DAPA-CKD trial. Lancet Diabetes Endocrinol. 2021;9(1):22-31. doi:10.1016/S2213-8587(20)30369-7

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