Nephritic Syndrome

Definition

• Hematuria - dysmorphic red blood cells (RBCs) and RBC casts in urine (pathognomonic)
• Proteinuria - typically in the subnephrotic range (<3.5 g/day)
• Azotemia (elevated BUN/creatinine, reduced GFR)
• Hypertension (from fluid retention and renin release from ischemic kidneys)
• Oliguria and edema (moderate, less severe than nephrotic)

• Robbins, Cotran & Kumar Pathologic Basis of Disease
• Comprehensive Clinical Nephrology, 7th Edition

Nephritic vs. Nephrotic Syndrome: Key Comparison

• Comprehensive Clinical Nephrology, 7th Edition, Table 16.4

Pathophysiology

1. Injures capillary walls, allowing RBCs to pass into urine (hematuria)
2. Reduces GFR, causing oliguria, fluid retention, and azotemia
3. Induces hypertension through fluid retention and renin release from ischemic kidneys

Etiology / Classification

• National Kidneys Foundation Primer on Kidney Diseases, 8e

Serum Complement in Nephritic Syndrome

• Postinfectious GN (streptococcal, endocarditis, shunt infections)
• Systemic lupus erythematosus
• Cryoglobulinemia
• C3 glomerulopathies

• IgA nephropathy / IgA vasculitis (Henoch-Schönlein purpura)
• Anti-GBM disease (Goodpasture syndrome)
• Pauci-immune RPGN (GPA, MPA)
• Goldman-Cecil Medicine, Table 107-4

Key Causes in Detail

1. Poststreptococcal GN (PSGN) - Prototype

• Latent period: 1-4 weeks after group A beta-hemolytic streptococcal infection (pharyngitis or skin infection/impetigo)
• Nephritogenic strains: types 1, 4, 12 (identified by M protein typing)
• Antigen: Streptococcal pyogenic exotoxin B (SpeB) - localizes in characteristic subepithelial "hump" deposits
• Serology: elevated ASO titer (pharyngitis), anti-DNase B (skin infection), low C3, low CH50
• Most common in children 6-10 years
• Biopsy: diffuse endocapillary proliferation and neutrophil infiltration; "hump-shaped" subepithelial deposits on EM; granular IgG and C3 on immunofluorescence
• Prognosis: excellent in children; adults may have residual impairment

2. IgA Nephropathy

• Most common primary glomerulopathy worldwide
• Pathogenesis: deposition of galactose-deficient IgA1 and anti-glycan antibodies in the mesangium
• Presentation: macroscopic hematuria concurrent with upper respiratory infection ("synpharyngitic" hematuria - occurs within 1-2 days, unlike PSGN's 1-4 weeks), or asymptomatic microscopic hematuria
• Normal complement
• Biopsy scoring: MEST-C score (mesangial proliferation, endocapillary proliferation, segmental sclerosis, tubulointerstitial fibrosis, crescents)
• 40% progress to ESKD over 10-20 years; predictors: renal insufficiency, hypertension, >1 g/24h proteinuria

3. Rapidly Progressive GN (RPGN) / Crescentic GN

• Defined as rapid loss of kidney function over days to weeks in the context of nephritic syndrome
• Histology: crescents (extracapillary proliferation in Bowman's space)
• Three immunopathologic types:
  • Type I: Anti-GBM antibody - linear IgG on IF; Goodpasture if also pulmonary hemorrhage
  • Type II: Immune complex - granular IF; granulomatous with polyangiitis, lupus
  • Type III: Pauci-immune (ANCA-associated) - no/sparse deposits on IF; GPA, MPA

4. Lupus Nephritis (ISN/RPS Classification)

• Class III (focal) and Class IV (diffuse) present with nephritic syndrome
• Serology: positive ANA, anti-dsDNA, anti-Smith; low C3/C4
• Class IV involves ≥50% of glomeruli with endocapillary proliferation and subendothelial deposits

5. Membranoproliferative GN (MPGN)

• Can present with nephritic syndrome, nephrotic syndrome, or both
• Low complement levels common
• May be immune complex-mediated or complement-mediated (C3 glomerulopathy)

Diagnostic Workup

Urinalysis and Urine Microscopy

• RBC casts - hallmark (though their absence does not exclude nephritic syndrome)
• Dysmorphic RBCs (acanthocytes)
• Subnephrotic proteinuria

Serology Panel

Renal Biopsy

• Required in most cases to determine specific diagnosis and guide treatment
• Three modalities: light microscopy, immunofluorescence, electron microscopy
• Essential for classification, prognosis, and treatment decisions

Treatment

Supportive Management (all nephritic syndrome)

• Fluid and sodium restriction
• Loop diuretics (for edema and fluid overload)
• Antihypertensives - oral long-acting calcium channel blocker usually sufficient; IV medications for hypertensive emergency
• Dialysis (hemodialysis or peritoneal dialysis) if needed - required in 25-30% of adults with PSGN but rarely in children

Postinfectious GN (PSGN)

• Treat underlying infection: penicillin (1.2 million units IM benzathine penicillin for adults), or erythromycin (if penicillin-allergic), or cephalosporins for 7-10 days
• Treatment is primarily supportive - recovery typically occurs in 2-4 weeks with infection resolution
• Crescentic PSGN: consider pulse methylprednisolone

RPGN/Crescentic GN

• Urgent treatment - often inpatient evaluation
• Immunosuppression: high-dose corticosteroids (IV methylprednisolone pulses) + cyclophosphamide
• Anti-GBM disease: plasmapheresis to remove pathogenic antibodies
• ANCA-associated: rituximab is an alternative to cyclophosphamide for induction

IgA Nephropathy

• ACE inhibitors/ARBs for proteinuria >1 g/day and hypertension
• Corticosteroids for progressive disease with proteinuria >1 g/day despite RAS blockade
• Newer therapy: sparsentan, budesonide (targeted-release formulation for IgAN)

Lupus Nephritis (Class III/IV)

• Induction: high-dose corticosteroids + mycophenolate mofetil or cyclophosphamide
• Maintenance: mycophenolate mofetil or azathioprine
• Adjunct: hydroxychloroquine

Rapidly Progressive GN (RPGN) - Special Emphasis

• May present as a uremic emergency
• May have concomitant pulmonary hemorrhage (pulmonary-renal syndrome) - seen with ANCA-associated GN and anti-GBM disease
• Histologic hallmark: crescents in Bowman's space (extracapillary proliferation)
• Early biopsy and aggressive immunosuppression are essential
• National Kidneys Foundation Primer on Kidney Diseases, 8e
• Comprehensive Clinical Nephrology, 7th Edition

Prognosis