Historical vs. Current Epidemiology

Classic PSGN (decades past): - Predominantly children (age 3-12 years) and adolescents - Post-streptococcal pharyngitis (β-hemolytic Group A Streptococcus—GAS) - Endemic in developed countries with good sanitation - Sporadic cases in developed nations; endemic in tropical/developing regions

Modern Epidemiology (last 20-30 years): - Significant shift to adults, particularly elderly - Non-streptococcal etiologies predominant (55-85% in adult series) - Staphylococcal infection most common overall (S. aureus accounting for 30-80% of adult cases) - IgA-dominant IRGN now recognized as major subset in elderly (17% of IRGN cases) - Associated with: - Diabetes mellitus - Chronic kidney disease - Intravenous drug use (infected heart valves → chronic staphylococcal infection) - Healthcare-associated infections - Immunocompromised states

This epidemiologic transition has profound prognostic implications: adult-onset IRGN carries much worse prognosis than childhood PSGN [1][2].

Immune Mechanisms

Post-infectious GN results from immune complex deposition triggered by bacterial antigens:

1. Antigen-antibody complex formation:
   • Bacterial antigens (streptococcal M protein, staphylococcal proteins) presented
   • IgG antibodies produced (anti-streptococcal, anti-staphylococcal)
   • Circulating immune complexes formed
2. Immune complex deposition:
   • Complexes circulate; deposit in glomeruli
   • Primarily subepithelial (in PSGN): “bumpy” appearance on IF
   • Subendothelial/mesangial (in non-streptococcal IRGN)
3. Complement activation:
   • Classical pathway activated (via IgG-antigen-C1q)
   • Alternative pathway also activated (particularly IRGN)
   • Leads to C3/C5 cleavage → chemotaxis → neutrophil/macrophage influx
   • Characteristic C3 deposition on immunofluorescence (low C3 serum levels)
4. Glomerular injury:
   • C3/C5 components insert into glomerular basement membrane (GBM)
   • Membrane attack complex (C5b-9) formation → cellular lysis
   • Neutrophil infiltration → protease release → GBM/mesangial damage
   • Mesangial proliferation (most cells); minimal GBM damage (subepithelial deposits don’t affect GBM integrity)

Kidney Biopsy Findings

Light microscopy: - Endocapillary proliferation — most characteristic (increased mesangial and endothelial cells) - Increased mesangial cellularity and matrix - Glomerular hypercellularity (endothelial, mesangial; not epithelial crescents typically) - Exudative lesions: Neutrophil-rich infiltration - Necrosis: Minimal (unlike RPGN) - Tubular atrophy, interstitial inflammation (severity varies)

Immunofluorescence (Gold standard—pathognomonic pattern): - C3-dominant staining (brightest) — hallmark of post-infectious GN - IgG, IgA, IgM also present (usually less intense than C3) - IgA-dominant pattern in IRGN subset (instead of C3-dominant); changing classification paradigm - Minimal fibrinogen (unlike RPGN with crescents)

Electron microscopy: - Subepithelial “humps” — PSGN classic finding (not always present; “post-infectious humps”) - Large, electron-dense deposits in subepithelial space; can be mesangial/subendothelial in IRGN - GBM intact (no disruption)

Classic PSGN Presentation (Children)

Prodrome: - Recent β-hemolytic streptococcal infection, 1-3 weeks prior - Pharyngitis (sore throat, fever, exudate) - OR skin infection (impetigo, infected cuts/sores) - Pyoderma more common in tropics; pharyngitis in temperate zones

Acute phase presentation: - Hematuria: Gross hematuria (cola or tea-colored urine) in ~50%; microscopic in remainder - Proteinuria: Usually <3.5 g/day (non-nephrotic range); nephrotic-range (<20%) possible - Hypertension: ~50% of children; reflects volume expansion - Edema: Periorbital (most common), lower extremity (less common than HTN) - AKI: Variable; Cr elevation mild-moderate in most; severe in minority - Systemic signs: Fever, malaise, nausea (uremia if severe) - Pulmonary edema: Possible if severe fluid overload

Classic triad (though not all present): 1. Hematuria/RBC casts 2. Proteinuria (usually <3.5 g/day) 3. Hypertension + edema

Adult-Onset IRGN Presentation (Often Indolent)

Clinical context: - Preceding infection often non-apparent or asymptomatic (chronic staphylococcal infection) - Diabetes, CKD, or immunocompromised often present - Infection source: skin/soft tissue, respiratory, urinary, intravenous lines

Presentation: - Hematuria (may be asymptomatic microscopic) - Nephrotic-range proteinuria (30-50% of cases) — more common than PSGN - Hypertension: Present in 60-84% at presentation - AKI: Present in ~98% but may be mild - Systemic features (fever, rash, eosinophilia) rare (<10%) - Slow insidious course (weeks to months)

Serologic Markers

Anti-Streptococcal antibodies (PSGN): - ASO titer (Anti-Streptolysin O): Elevated in ~80% of PSGN; peaks 3-5 weeks post-infection - Anti-DNase B: Elevated in ~60-70% of streptococcal skin infection (pyoderma); more sensitive than ASO for skin disease - Streptokinase: Alternative marker if ASO/anti-DNase B negative - Interpretation: Single elevated titer less useful than rising titer; serial titers (2-week interval) more diagnostic - Timing: Peak ~3 weeks post-infection; may normalize by 6-12 months

Anti-Staphylococcal antibodies (IRGN): - Antibodies to staphylococcal antigens (less standardized; not routine) - Serologies less reliable for IRGN; diagnosis more dependent on kidney biopsy

Complement Levels

C3 and C4 levels: - Classic low C3, normal C4 in PSGN (alternative pathway activation) - Normalization: C3 normalizes over 6-8 weeks in ~90% of cases - Persistent low C3 (>12 weeks): Suggests alternative diagnosis (lupus, MPGN, ANCA vasculitis, post-infectious GN with alternative pathway dysregulation)

Clinical pearl: Low C3 that normalizes is reassuring for PSGN prognosis; persistent low C3 warrants additional evaluation [1].

Urinalysis

• Hematuria: RBC casts (pathognomonic for glomerulonephritis)
• Proteinuria: May be heavy (>3.5 g/day in nephrotic presentations)
• WBC, bacteria: Absent (helps rule out UTI/pyelonephritis)

Kidney Biopsy (Gold Standard)

Indications for biopsy: - Atypical presentation (no preceding infection identified, rapid progression, prolonged renal dysfunction) - Nephrotic-range proteinuria (consider biopsy to assess for alternate GN) - Rapidly progressive AKI with crescent formation (assess for RPGN, which requires immunosuppression) - Persistent low C3 >12 weeks (suggests C3 glomerulopathy or alternate diagnosis) - Diagnostic uncertainty after serologic workup

Biopsy findings distinguish PSGN from other GN (see Pathology section above) [1].

Childhood PSGN (Excellent Prognosis)

• Complete recovery: >95% of children achieve full renal recovery
• Renal function: Most return to baseline creatinine within 2-4 weeks
• Proteinuria: Usually resolves within 3-6 months
• Hematuria: May persist for months but gradually clears
• Hypertension: Resolves as edema mobilizes (usually weeks)
• Long-term follow-up: CKD/ESRD development in <1% of childhood PSGN survivors [1]

Adult-Onset IRGN (Guarded Prognosis)

In stark contrast to children:

• Complete recovery: ~40-50% of adults achieve return to baseline creatinine
• Partial recovery: ~25-30% with persistent mild Cr elevation
• Progression to CKD: ~20-30% develop stage 3-5 CKD
• ESRD: ~5-15% require dialysis within 5-10 years

Risk factors for poor outcome: - Older age (>65 years) - Diabetes mellitus - Baseline CKD (eGFR <30 at presentation) - Nephrotic-range proteinuria - Severe AKI at presentation (Cr >3 mg/dL) - IgA-dominant IRGN (vs. immune-complex PSGN) - Delayed diagnosis/treatment of underlying infection

Treatment of Underlying Infection (Critical First Step)

Streptococcal infection: - Penicillin G or amoxicillin × 10 days (eradicate organism; reduce antigen load) - Erythromycin if penicillin-allergic - Complete course even if PSGN already presenting

Staphylococcal infection: - Nafcillin or oxacillin (or vancomycin if MRSA) - Duration: 4-6 weeks (endocarditis treatment if involved); identify source (infected line, abscess)

Importance: Removing the antigen source is the most important intervention. Some reports suggest earlier antibiotic treatment may reduce severity of GN, though not definitively proven [1].

Supportive Care (Mainstay of Treatment)

No specific immunotherapy proven beneficial for PSGN or IRGN (unlike RPGN or lupus GN).

Hypertension/volume management: - Sodium restriction (goal <2 g/day) - Diuretics: Furosemide if edematous/hypertensive; target euvolemia - Antihypertensive agents: ACE-I/ARB first-line (reduce proteinuria, slow CKD progression) - Target BP <130/80 (KDIGO guidelines)

Proteinuria reduction: - ACE-I/ARB blocks efferent arteriolar vasoconstriction; reduces proteinuria by ~20-30% - Aim to reduce proteinuria as much as tolerated

Renal function support: - Avoid nephrotoxins (NSAIDs, aminoglycosides, contrast if avoidable) - Maintain euvolemia; avoid aggressive diuresis (may worsen AKI) - Restrict potassium/phosphate if CKD-MBD present

Anticoagulation: - Reserved for nephrotic syndrome with proteinuria >3.5 g/day + thrombotic risk - Typically low-molecular-weight heparin or warfarin for VTE prophylaxis (controversial; not routine)

Immunosuppression (Controversial; Not Routine)

Role of steroids/immunosuppression: - Pediatric PSGN: NOT recommended (excellent prognosis with supportive care alone) - Adult IRGN: Individualized; not established as standard - Rapidly progressive form (with crescents, RPGN features): Some experts treat with steroids ± cyclophosphamide (similar to RPGN protocol)

Rare indications for steroids: - Severe AKI with rapidly declining GFR (Cr rising >0.5 mg/dL/day despite supportive care) - Biopsy-proven RPGN with crescent formation - Evidence of systemic vasculitis (rare in IRGN)

Lack of RCT evidence: No rigorous trial shows immunosuppression improves outcomes in post-infectious GN; most experts recommend avoiding steroids in uncomplicated PSGN/IRGN [1][2].

Dialysis Indication

RRT needed in ~5-10% of adults with severe AKI: - Criteria: K >6.5 with ECG changes, severe acidosis, pulmonary edema, uremic symptoms - Most patients recover sufficient renal function to discontinue dialysis within weeks-months - Some adults may progress to permanent dialysis dependence (especially those with baseline CKD or diabetes)

Pediatric PSGN Follow-Up

• Urine dipstick/urinalysis: Monthly × 3 months, then q 3 months × 1 year
• Creatinine/eGFR: Baseline, 2 weeks, then q 3 months × 1 year
• Blood pressure: At each visit; goal normalization
• Expected course: Most improvements by 3 months; full resolution by 12 months

Adult IRGN Follow-Up (More Intensive)

• Urine dipstick/UACR: Baseline, 2 weeks, 1 month, then q 3 months × 1 year
• Serum creatinine/eGFR: Baseline, 2 weeks, 1 month, then q 3 months × 1 year
• Blood pressure: At each visit
• Complement levels (C3, C4): Baseline, 6 weeks, 12 weeks (normalization reassuring; persistent low C3 concerning)
• Serologies: Repeat ASO/anti-DNase B at 4-6 weeks if initial positive (should trend down)
• Longer follow-up: Some recommend 2-5 year follow-up to assess CKD trajectory; consider repeat biopsy if persistent proteinuria/GFR decline at 6-12 months [1]