Nephritic Syndrome versus Nephrotic Syndrome
Key Distinguishing Feature
The single most reliable way to differentiate nephritic from nephrotic syndrome is the degree of proteinuria: nephrotic syndrome is defined by proteinuria ≥3.5 g/24 hours (or protein-creatinine ratio ≥3500 mg/g), whereas nephritic syndrome typically presents with sub-nephrotic proteinuria. 1
Diagnostic Criteria
Nephrotic Syndrome
- Proteinuria ≥3.5 g/24 hours in adults (≥40 mg/h/m² or UPCR ≥2 g/g in children) 2
- Hypoalbuminemia <3.0 g/dL in adults (<2.5 g/dL in children) 2
- Peripheral edema (periorbital in morning, dependent later in day) 3
- Often accompanied by hyperlipidemia and lipiduria 2
Nephritic Syndrome
- Sub-nephrotic proteinuria (typically <3.5 g/24 hours) 1
- Hematuria with dysmorphic red blood cells (>80% dysmorphic RBCs suggests glomerular origin) 4
- Red blood cell casts (virtually pathognomonic for glomerulonephritis) 4
- Hypertension (more prominent than in nephrotic syndrome) 5
- Acute kidney injury with rising creatinine 5
Pathophysiology
Nephrotic Syndrome
- Primary mechanism: podocyte dysfunction leading to increased glomerular permeability to proteins 1
- In minimal change disease and FSGS, a T-cell-driven circulating "glomerular permeability factor" interferes with glomerular permselectivity 1
- In membranous nephropathy, pathogenic autoantibodies target podocyte antigens (e.g., PLA2R) 1
- Loss of albumin decreases oncotic pressure, causing fluid shift to interstitial spaces 1
Nephritic Syndrome
- Primary mechanism: inflammatory injury to glomerular capillaries with immune complex deposition or direct antibody-mediated damage 4
- Disruption of glomerular basement membrane allows red blood cell extravasation 4
- Inflammatory response reduces GFR and causes salt/water retention 5
Common Etiologies
Nephrotic Syndrome
- Children: Minimal change disease (most common) 2
- White adults: Membranous nephropathy (most common) 3
- African ancestry populations: Focal segmental glomerulosclerosis (most common) 3
- Secondary causes: Diabetes mellitus (most common systemic cause), lupus, amyloidosis 3
Nephritic Syndrome
- Post-infectious glomerulonephritis (most common overall) 5
- IgA nephropathy 5
- Lupus nephritis 5
- ANCA-associated vasculitis 6
Clinical Presentation Algorithm
Step 1: Quantify Proteinuria
- Obtain spot urine protein-creatinine ratio or 24-hour urine collection 1
- If ≥3.5 g/24 hours (or PCR ≥3500 mg/g): Proceed with nephrotic syndrome evaluation 1
- If <3.5 g/24 hours: Evaluate for nephritic features 1
Step 2: Examine Urine Sediment
- Nephrotic pattern: Oval fat bodies, fatty casts, minimal hematuria 5
- Nephritic pattern: Dysmorphic RBCs (>80%), red cell casts, white cell casts 4
Step 3: Assess Renal Function and Blood Pressure
- Nephrotic: Usually preserved GFR initially; blood pressure normal or mildly elevated 5
- Nephritic: Acute rise in creatinine; marked hypertension common 5
Diagnostic Workup
For Nephrotic Syndrome
- Serum albumin (confirm <3.0 g/dL in adults) 2
- Lipid panel (assess hyperlipidemia) 2
- Complement levels (C3, C4) to evaluate for immune-mediated disease 2
- Autoimmune serologies (ANA, anti-dsDNA) if lupus suspected 2
- Hepatitis B/C, HIV serologies to identify secondary causes 2
- Serum and urine protein electrophoresis to exclude paraprotein-related disease 2
- Renal biopsy within first month in adults (except if PLA2R-Ab positive) 2
For Nephritic Syndrome
- Complete blood count with differential 4
- Serum creatinine and eGFR (using CKD-EPI in adults, modified Schwartz in children) 4
- Complement levels (C3, C4) (low in post-infectious GN, lupus, MPGN) 4
- ANCA serologies (MPO, PR3) if vasculitis suspected 6
- Anti-GBM antibodies if rapidly progressive GN 6
- ASO titers, throat culture if post-streptococcal GN suspected 5
- Renal biopsy (gold standard when information will alter management) 4
Management Approach
Nephrotic Syndrome
Supportive Care (All Patients)
- ACE inhibitor or ARB to reduce proteinuria and target BP ≤125/75 mmHg 2
- Dietary sodium restriction <2 g/day 1
- Loop diuretics (furosemide 0.5–2 mg/kg per dose) for edema 1
- Statin therapy for persistent hyperlipidemia (target LDL <100 mg/dL) 1
- Anticoagulation when albumin <2.0 g/dL with additional risk factors (proteinuria >10 g/day, BMI >35, immobilization) 2
- Use warfarin (target INR 2–3); avoid factor Xa inhibitors due to unpredictable pharmacokinetics 2
Disease-Specific Immunosuppression
For Minimal Change Disease:
- High-dose prednisone 1 mg/kg/day (max 80 mg) for 4–16 weeks until remission 1
- Alternative: Cyclosporine 2–3 mg/kg/day (target trough 100–175 ng/mL) for steroid-intolerant patients 2
For Primary FSGS:
- First-line: Prednisone 1 mg/kg/day (max 80 mg) for minimum 4 weeks up to 16 weeks 2
- Continue 2 weeks after complete remission, then taper over 6 months 2
- Steroid-resistant: Cyclosporine 3–5 mg/kg/day (trough 125–175 ng/mL) for ≥6 months 2
- Maintain CNI for 12 months after remission, then taper slowly over 6–12 months 2
For Membranous Nephropathy:
- Observe with supportive care for 6 months if proteinuria >4 g/day but stable renal function 1
- Initiate immunosuppression if proteinuria persists >4 g/day after 6 months or creatinine rises ≥30% 1
- Regimen: Alternating monthly cycles of corticosteroids + cyclophosphamide for 6 months 1
SGLT2 Inhibitor Adjunctive Therapy
- Add dapagliflozin if eGFR ≥20 mL/min/1.73 m² and UACR ≥200 mg/g, on top of maximal RAS inhibition 1
- Monitor for initial eGFR dip of 3–5 mL/min (reversible, not indication to stop) 1
- Hold during acute illness with vomiting/diarrhea to prevent ketoacidosis 1
Nephritic Syndrome
Supportive Care
- Blood pressure control with ACE inhibitor or ARB 4
- Diuretics (furosemide 0.5–2 mg/kg) only if fluid overload with preserved kidney function; avoid if intravascular hypovolemia 4
- Dietary sodium restriction 4
- Monitor for complications: Thromboembolism (if significant hypoalbuminemia), infection 4
Disease-Specific Immunosuppression
- Intensity based on severity and specific glomerulonephritis type 4
- Post-infectious GN: Usually supportive care only; immunosuppression not indicated 5
- IgA nephropathy: Corticosteroids if proteinuria >1 g/day despite maximal RAS inhibition 6
- Lupus nephritis: High-dose corticosteroids + cyclophosphamide or mycophenolate 6
- ANCA vasculitis: Rituximab or cyclophosphamide + corticosteroids 6
Complications and Risk Stratification
Nephrotic Syndrome
- Thromboembolism risk: 29% for renal vein thrombosis, 17–28% for pulmonary embolism 1
- Highest risk: Albumin <2.0 g/dL, proteinuria >10 g/day, membranous nephropathy 2
- Infection risk: Loss of immunoglobulins and complement factors 1
- Progression to ESRD: 35% risk within 2 years if proteinuria >3.8 g/day 1
Nephritic Syndrome
- Acute kidney injury requiring dialysis in severe cases 4
- Hypertensive emergency with end-organ damage 5
- Rapidly progressive GN if crescents on biopsy (requires urgent immunosuppression) 4
Critical Pitfalls to Avoid
In Nephrotic Syndrome
- Do not use albumin infusions routinely; reserve for severe hypovolemia with hypotension 2
- Do not use immunosuppression for secondary FSGS (obesity, drug-induced, genetic forms) 1
- Do not rapidly taper CNI after remission; taper over 6–12 months to prevent relapse 2
- Do not delay biopsy in adults; perform within first month before starting immunosuppression 2
- Do not use factor Xa inhibitors for anticoagulation due to albumin binding and urinary losses 2
In Nephritic Syndrome
- Do not delay biopsy in rapidly progressive GN; urgent diagnosis and treatment prevent irreversible damage 4
- Do not use aggressive diuresis if intravascular volume depleted despite edema 4
- Do not assume post-infectious GN without confirming low complement normalizes within 8 weeks 5
Prognosis
Nephrotic Syndrome
- Minimal change disease: >90% respond to steroids; excellent prognosis 2
- Primary FSGS: 70% respond to CNI; 50% relapse rate 2
- Membranous nephropathy: Spontaneous remission in 30%; 30% progress to ESRD 1