Chapter 18: Nephritic & Nephrotic Syndromes

Definitions and Urine Microscopy

Nephrotic Syndrome: Proteinuria >3.5 g/day, hypoalbuminemia <3.0 g/dL, edema, hyperlipidemia. Urine microscopy shows oval fat bodies and fatty casts.

Nephritic Syndrome: Hematuria with RBC casts, proteinuria <3.5 g/day, hypertension, reduced GFR. Urine microscopy is notable for dysmorphic RBCs and RBC casts.

Serological Evaluation of Nephritic Syndrome

Complement Evaluation

Measuring C3 and C4 helps identify the complement pathway activation and narrow the differential diagnosis.

Complement Pattern	Renal-Limited Diseases	Systemic Diseases
Low C3 & C4 (Classical Pathway)	Idiopathic MPGN Type I	SLE nephritis, Cryoglobulinemia, Endocarditis
Low C3, Normal C4 (Alternative Pathway)	Post-infectious GN, C3 glomerulopathy	Atypical HUS
Normal C3 & C4	IgA nephropathy, Renal-limited vasculitis, Anti-GBM nephritis	ANCA Vasculitis (GPA, MPA), Goodpasture's, HSP, Alport syndrome

Immunosuppression in Nephrotic Syndrome

Minimal Change Disease (MCD)

First-line therapy is high-dose oral corticosteroids. For frequently relapsing or steroid-dependent disease, options include cyclophosphamide, calcineurin inhibitors (cyclosporine), mycophenolate mofetil (MMF), or rituximab.

Focal Segmental Glomerulosclerosis (FSGS)

Initial treatment is also high-dose corticosteroids. For steroid-resistant cases, calcineurin inhibitors (cyclosporine, tacrolimus) are first-line. MMF can be an alternative. Blacks and patients with the collapsing variant are often unresponsive.

Membranous Nephropathy (MN)

Diagnosis can often be made non-invasively with a positive anti-PLA2R antibody test. Treatment is risk-stratified. Low-risk patients receive supportive care. Moderate to high-risk patients are treated with immunosuppression, with rituximab now considered a first-line option alongside cyclophosphamide-based regimens.

Rapidly Progressive Glomerulonephritis (RPGN)

RPGN: A Medical Emergency

RPGN is a clinical syndrome of rapid GFR decline (≥50% over days to 3 months) with extensive crescent formation on biopsy. It is classified by immunofluorescence pattern:

Type I (Linear): Anti-GBM disease. Treat with plasmapheresis, steroids, and cyclophosphamide.
Type II (Granular): Immune complex disease (e.g., Lupus, IgA). Treat the underlying cause.
Type III (Pauci-immune): ANCA-associated vasculitis. Treat with high-dose steroids and either cyclophosphamide or rituximab. Plasmapheresis is indicated for severe renal failure or pulmonary hemorrhage.

New and Emerging Treatments

Novel Therapies for Glomerular Disease

Tarpeyo (Budesonide): A gut-targeted steroid, now fully FDA-approved for IgA nephropathy.
Endothelin Receptor Antagonists: Sparsentan (dual ERA/ARB) and Atrasentan show promise in reducing proteinuria in IgAN and FSGS.
Biologics: Rituximab is established; Daratumumab (anti-CD38) is being studied.
Other FDA-Approved Options: FABHALTA® (alternative complement pathway inhibitor) and FILSPARI® (sparsentan) are available for IgA Nephropathy.

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