9.3 Nephritic Syndromes, RPGN & Indications for Renal Replacement Therapy

1. Nephritic Syndromes & Rapidly Progressive Glomerulonephritis (RPGN)

Nephritic conditions are characterized by inflammatory disruption of the glomerular capillary wall, leading to hematuria with dysmorphic RBCs and RBC casts, variable sub-nephrotic proteinuria, oliguria, hypertension, and azotemia.

Classification by Serum Complement Levels

Diagnostic evaluation of suspected nephritic syndrome begins with testing serum complement levels (C3 and C4):

                         ┌─────────────────────────────────────────┐
                         │       Suspected Nephritic Syndrome      │
                         └────────────────────┬────────────────────┘
                                              │
                                     Check Serum C3 & C4
                                              │
                     ┌────────────────────────┴────────────────────────┐
                     ▼                                                 ▼
        ┌─────────────────────────┐                       ┌─────────────────────────┐
        │    Low Serum C3/C4      │                       │     Normal Serum C3/C4  │
        │   (Hypocomplementemic)  │                       │    (Normocomplementemic)│
        └────────────┬────────────┘                       └────────────┬────────────┘
                     │                                                 │
       ┌─────────────┼─────────────┐                     ┌─────────────┼─────────────┐
       ▼             ▼             ▼                     ▼             ▼             ▼
   Post-Strept.    Lupus        Cryo-                  IgA           Anti-GBM       ANCA
    (PSGN)       Nephritis   globulinemia           Nephropathy    (Goodpasture)  Vasculitis
   (Low C3,      (Low C3 &   (Low C4 >> C3,         (Berger)       (Linear IgG)   (Pauci-immune)
    Norm C4)       Low C4)     Hep C +)             (Normal C3/C4) (Normal C3/C4) (Normal C3/C4)

Clinical Profiles of Major Nephritic Disorders

1. IgA Nephropathy (Berger Disease):

   • Epidemiology: The most common primary glomerulonephritis worldwide; prominent in East Asian and young adult Caucasian populations.
   • Clinical Presentation: Synpharyngitic macroscopic hematuria occurring concurrently or 1 to 2 days following an upper respiratory tract infection or vigorous exercise. Characterized by normal serum complement (C3/C4 normal).
   • Comparison with Post-Streptococcal GN (PSGN):
     • IgA Nephropathy: Hematuria occurs 1–2 days after URI; serum C3 is normal; recurrent episodic hematuria is common.
     • Post-Streptococcal GN: Hematuria occurs 1 to 3 weeks after streptococcal pharyngitis (or 3 to 6 weeks after streptococcal impetigo); serum C3 is markedly low (normalizes in 6–8 weeks); positive ASO or anti-DNase B titers; subepithelial "humps" on EM.
   • Histopathology: Mesangial proliferation with intense mesangial IgA and C3 deposition on immunofluorescence.
   • Systemic Counterpart: IgA Vasculitis (Henoch-Schönlein Purpura): IgA nephropathy plus palpable purpura (buttocks/lower extremities), non-deforming arthralgias, and colicky abdominal pain / GI bleeding.
   • Treatment:
     • Conservative First-Line: Maximum tolerated ACE inhibitor or ARB to achieve BP <120 mmHg and proteinuria <0.5–1.0 g/day; add SGLT2 inhibitor (Dapagliflozin / Empagliflozin).
     • Targeted Disease-Modifying Agents: Targeted-release oral Budesonide (Tarpeyo) 16 mg daily (acts on mucosal Peyer's patches in the terminal ileum to reduce galactose-deficient IgA1 production; NefIgArd trial); or Sparsentan (dual endothelin-angiotensin receptor antagonist; PROTECT trial).
     • Systemic Immunosuppression: Systemic corticosteroids reserved for rapidly progressive crescentic variants.

2. Anti-Glomerular Basement Membrane (Anti-GBM) Disease / Goodpasture Syndrome:

   • Pathophysiology: Circulating autoantibodies directed against the non-collagenous domain of the alpha-3 chain of Type IV collagen in the glomerular and alveolar basement membranes.
   • Clinical Presentation: Rapidly progressive glomerulonephritis (RPGN) with acute oliguric renal failure combined with diffuse alveolar hemorrhage (hemoptysis, dyspnea, new alveolar infiltrates on chest imaging, iron-deficiency anemia, elevated DLCO >130% due to intra-alveolar RBC uptake of carbon monoxide).
   • Renal Biopsy: Diagnostic hallmark is smooth, continuous, linear deposition of IgG (and C3) along the glomerular capillary loops on immunofluorescence, accompanied by extensive cellular crescent formation (>50% of glomeruli).
   • Therapeutic Emergency:
     • Immediate Plasma Exchange (Plasmapheresis) daily or every other day for 14 days to remove circulating anti-GBM antibodies.
     • High-Dose Corticosteroids: IV Methylprednisolone 500–1000 mg daily for 3 days, followed by oral Prednisone 1 mg/kg/day.
     • Cyclophosphamide: Oral (2 mg/kg/day) or IV pulsed monthly for 3 to 6 months to arrest autoantibody production.

3. ANCA-Associated Vasculitis (Pauci-Immune RPGN):

   • Definition: Necrotizing crescentic glomerulonephritis with absence or paucity of immunoglobulin and complement staining (Pauci-Immune) on immunofluorescence.
   • Phenotypes:
     • Granulomatosis with Polyangiitis (GPA, Wegener): Associated with c-ANCA (anti-proteinase 3 [PR3]). Triad of upper airway disease (chronic sinusitis, bloody nasal crusting, saddle-nose deformity, subglottic stenosis), lower respiratory involvement (pulmonary nodules with central cavitation, alveolar hemorrhage), and necrotizing crescentic GN.
     • Microscopic Polyangiitis (MPA): Associated with p-ANCA (anti-myeloperoxidase [MPO]). Rapidly progressive crescentic GN and pulmonary capillaritis without granulomatous inflammation or upper airway destructive lesions.
     • Eosinophilic Granulomatosis with Polyangiitis (EGPA, Churg-Strauss): Associated with p-ANCA (MPO) in ~40–50%; severe asthma, marked peripheral blood eosinophilia (>1500/µL or >10%), migratory pulmonary infiltrates, mononeuritis multiplex, and necrotizing vasculitis.
   • Treatment Strategy:
     • Induction Therapy: Rituximab (375 mg/m2 weekly x 4 or 1000 mg q2 weeks x 2) is preferred first-line, or IV Cyclophosphamide, combined with high-dose corticosteroids.
     • Targeted Complement Inhibition: Avacopan (oral C5a receptor antagonist, 30 mg PO BID via ADVOCATE trial) allows significant corticosteroid reduction/tapering while achieving equivalent remission rates and improved renal recovery.
     • Maintenance Therapy: Rituximab 500 mg IV every 6 months for 2 years, or Azathioprine / Mycophenolate Mofetil.

4. Lupus Nephritis (Systemic Lupus Erythematosus):

   • Pathophysiology: Deposition of circulating and in situ DNA/anti-DNA immune complexes activating classical complement pathway.
   • ISN/RPS Classification:
     • Class I: Minimal mesangial lupus nephritis.
     • Class II: Mesangial proliferative lupus nephritis.
     • Class III: Focal proliferative lupus nephritis (<50% of glomeruli involved).
     • Class IV: Diffuse proliferative lupus nephritis (>=50% of glomeruli involved). Most common and most severe form; demonstrates subendothelial deposits, "wire-loop" lesions on LM, marked endocapillary proliferation, and crescents.
     • Class V: Membranous lupus nephritis (subepithelial deposits, severe nephrotic proteinuria).
     • Class VI: Advanced sclerosing lupus nephritis (>90% global sclerosis).
   • Biopsy Hallmark: "Full-House" Immunofluorescence positive for IgG, IgA, IgM, C3, and C1q.
   • Laboratory Profile: Hypocomplementemia (profoundly low C3 and low C4), elevated anti-double-stranded DNA (anti-dsDNA) titers, positive ANA.
   • Treatment for Proliferative Lupus Nephritis (Class III / IV +/- V):
     • Induction: Mycophenolate Mofetil (MMF) (2–3 g/day; preferred in non-white patients) OR IV Cyclophosphamide (low-dose Euro-Lupus or high-dose NIH regimen), combined with pulse IV glucocorticoids tapered to low-dose oral prednisone.
     • Add-On Biologics / Novel Regimens: Belimumab (BLyS inhibitor, added to MMF/corticosteroids) OR Voclosporin (novel calcineurin inhibitor added to MMF/corticosteroids) significantly improves complete renal response rates.
     • Background Therapy: Hydroxychloroquine for all SLE patients unless strictly contraindicated (reduces flares, renal damage accrual, and thrombosis).
     • Maintenance: MMF (1–2 g/day) or Azathioprine for >=3–5 years.

2. Indications for Emergent Renal Replacement Therapy

When acute medical management fails, emergent initiation of dialysis is lifesaving. The indications are summarized by the classic mnemonic AEIOU: