How do nephritic and nephrotic syndromes differ in clinical presentation, laboratory findings, typical causes, and management?

Nephritic vs Nephrotic Syndrome: Clinical Differentiation

Nephrotic syndrome presents with massive proteinuria (>3.5 g/day), severe hypoalbuminemia (<3.0 g/dL), and edema, while nephritic syndrome manifests with hematuria, mild-to-moderate proteinuria, hypertension, and acute kidney injury—two fundamentally different glomerular injury patterns requiring distinct diagnostic and therapeutic approaches. 1, 2, 3

Clinical Presentation

Nephrotic Syndrome

• Edema dominates the presentation: periorbital swelling (most prominent in morning) progressing to dependent pitting edema and potentially anasarca 4, 5
• Proteinuria is massive: >3.5 g/24 hours in adults (>40 mg/h/m² or UPCR ≥2 g/g in children), often exceeding 10 g/day 6, 1
• Hypoalbuminemia is severe: serum albumin <3.0 g/dL in adults, <2.5 g/dL in children 6, 1
• Hyperlipidemia is characteristic: elevated total cholesterol, LDL, and triglycerides as a compensatory hepatic response 7, 2
• Hematuria is typically absent or microscopic only; macroscopic hematuria suggests alternative diagnosis 2, 8
• Blood pressure is usually normal unless secondary causes (diabetes, lupus) are present 2
• Renal function is often preserved initially, though can deteriorate with disease progression 5

Nephritic Syndrome

• Hematuria is the hallmark: gross or microscopic with dysmorphic RBCs (>80% dysmorphic) and red cell casts on urine sediment 1, 3
• Proteinuria is mild-to-moderate: typically <3.5 g/day, though overlap can occur 2, 3
• Hypertension is prominent: often acute-onset and difficult to control 2, 3
• Acute kidney injury is common: rising creatinine with oliguria reflecting inflammatory glomerular damage 3
• Edema is present but less severe: related to sodium retention and hypertension rather than oncotic pressure loss 2
• Hypoalbuminemia is mild or absent unless nephrotic-range proteinuria develops (mixed syndrome) 2

Laboratory Findings

Nephrotic Syndrome

• Urine protein-to-creatinine ratio (UPCR) >300-350 mg/mmol or 24-hour protein >3.5 g 1, 4
• Serum albumin <3.0 g/dL with corresponding hyperlipidemia 1
• Selective proteinuria (predominantly albumin) suggests minimal change disease; non-selective suggests other etiologies 8
• Normal complement levels (C3, C4) in primary causes (minimal change disease, FSGS, membranous nephropathy) 8
• Urine sediment is bland: few cells, oval fat bodies, fatty casts may be present 2
• Hypercoagulable state: loss of antithrombin III, protein C, protein S increases thromboembolism risk to 29% for renal vein thrombosis 7

Nephritic Syndrome

• Active urine sediment: dysmorphic RBCs, red cell casts (pathognomonic for glomerulonephritis), white cell casts 1, 3
• Proteinuria <3.5 g/day in most cases 2, 3
• Elevated creatinine with reduced eGFR reflecting acute glomerular inflammation 3
• Low complement levels (C3, C4) in post-infectious GN, lupus nephritis, membranoproliferative GN 2, 3
• Positive serologies: ANCA in vasculitis, anti-GBM in Goodpasture syndrome, ANA/anti-dsDNA in lupus 3

Typical Causes

Nephrotic Syndrome

Primary (Idiopathic) Causes:

• Minimal change disease: most common in children <12 years (80-90% of pediatric cases), characterized by diffuse foot process effacement on electron microscopy with normal light microscopy 6, 9
• Focal segmental glomerulosclerosis (FSGS): most common in adults of African ancestry (up to 80% of cases), classified into primary, genetic, secondary, and undetermined subtypes 7, 9
• Membranous nephropathy: most common in white adults, now proven autoimmune with anti-PLA2R antibodies in 70-80% of primary cases 6, 4

Secondary Causes:

• Diabetes mellitus: most common systemic cause overall 6, 9
• Systemic lupus erythematosus: particularly class V (membranous) lupus nephritis 9
• Amyloidosis and paraprotein-related diseases: require serum/urine immunofixation and free light chains 1
• Infections: hepatitis B, hepatitis C, HIV 9
• Medications: NSAIDs, gold, penicillamine 9

Nephritic Syndrome

• Post-infectious glomerulonephritis: most common cause, typically 1-3 weeks after streptococcal pharyngitis or skin infection 2, 3
• IgA nephropathy: most common primary GN worldwide, presents with episodic gross hematuria concurrent with upper respiratory infections 2, 3
• Lupus nephritis: particularly class III (focal proliferative) and class IV (diffuse proliferative) 6, 3
• ANCA-associated vasculitis: granulomatosis with polyangiitis, microscopic polyangiitis 3
• Anti-GBM disease (Goodpasture syndrome): rapidly progressive with pulmonary hemorrhage 6, 3
• Membranoproliferative GN: now classified by immunofluorescence pattern (immune complex, complement-mediated, or pauci-immune) rather than electron microscopy 6, 3

Management Approach

Nephrotic Syndrome Management

Supportive Care (All Patients):

• Sodium restriction to <2 g/day and fluid restriction if severe hypoalbuminemia 1
• Loop diuretics (furosemide) for edema control, often requiring high doses due to reduced tubular delivery 1
• RAS inhibition with ACE inhibitors or ARBs to reduce proteinuria and blood pressure, target BP ≤125/80 mmHg 1, 7
• Statin therapy for persistent hyperlipidemia with cardiovascular risk factors 7

Thromboprophylaxis:

• **Consider prophylactic anticoagulation when serum albumin <2.0-2.5 g/dL (20-25 g/L) AND additional risk factors** (proteinuria >10 g/day, BMI >35, immobilization, membranous nephropathy) 1, 7
• Warfarin is preferred anticoagulant with target INR 2-3; avoid direct oral anticoagulants due to unpredictable pharmacokinetics from albumin binding and urinary losses 1, 7

Disease-Specific Immunosuppression:

• Minimal change disease: prednisone 1 mg/kg/day (max 80 mg) for 4-16 weeks, then slow taper; cyclosporine 2-6 mg/kg/day is alternative for steroid-resistant/dependent cases 1, 7
• Primary FSGS: prednisone 1 mg/kg/day or alternate-day 2 mg/kg (max 120 mg) for minimum 4 weeks up to 16 weeks, then 6-month taper after remission 1, 7
• Membranous nephropathy: monitor anti-PLA2R antibodies to guide immunosuppression decisions 6
• Genetic FSGS: immunosuppression is contraindicated; focus on supportive care only 7

Adjunctive Therapy:

• SGLT2 inhibitors (e.g., dapagliflozin) for patients with eGFR ≥20 mL/min/1.73 m² and UACR ≥200 mg/g as kidney-protective therapy on top of RAS inhibition 7

Nephritic Syndrome Management

Acute Management:

• Urgent nephrology referral for suspected rapidly progressive GN (rising creatinine, oliguria) 3
• Blood pressure control: target <130/80 mmHg with ACE inhibitors/ARBs and additional agents as needed 3
• Fluid and sodium restriction to manage hypertension and edema 2
• Loop diuretics for volume overload 2

Disease-Specific Treatment:

• Post-infectious GN: supportive care only; immunosuppression is contraindicated 3
• IgA nephropathy: RAS inhibition; consider corticosteroids for persistent proteinuria >1 g/day with eGFR >50 mL/min/1.73 m² 6
• Lupus nephritis: high-dose corticosteroids plus mycophenolate mofetil or cyclophosphamide for proliferative classes 6
• ANCA vasculitis: cyclophosphamide or rituximab plus high-dose corticosteroids for induction, followed by maintenance immunosuppression 6
• Anti-GBM disease: plasmapheresis plus cyclophosphamide and corticosteroids; treatment is time-critical 6

Diagnostic Algorithm

Initial Evaluation for Both Syndromes

1. Quantify proteinuria: spot UPCR or 24-hour collection 1
2. Assess renal function: serum creatinine, eGFR 1
3. Examine urine sediment: dysmorphic RBCs and casts indicate nephritic syndrome 1
4. Measure serum albumin: <3.0 g/dL confirms nephrotic syndrome 1
5. Check complement levels (C3, C4): low levels suggest specific nephritic causes 1

When Nephrotic Syndrome is Suspected

• Screen for secondary causes: fasting glucose/HbA1c, ANA, anti-dsDNA, hepatitis B/C, HIV, serum/urine immunofixation with free light chains 1
• Kidney biopsy is indicated for all adults except when anti-PLA2R antibodies are positive (confirms membranous nephropathy) 1
• Children <12 years with typical presentation: empiric corticosteroid trial without biopsy; biopsy only if steroid-resistant 1

When Nephritic Syndrome is Suspected

• Urgent serologic workup: ANCA (MPO and PR3), anti-GBM antibodies, ANA, anti-dsDNA, ASO titers, cryoglobulins 3
• Kidney biopsy is essential to establish diagnosis and guide immunosuppression; perform within first month, ideally before starting treatment 1
• Biopsy must include: ≥8 glomeruli for light microscopy (H&E, PAS, trichrome, silver), immunofluorescence (IgG, C3, IgA, IgM, C1q, κ/λ), and electron microscopy 1

Common Pitfalls and Caveats

• Mixed nephritic-nephrotic syndrome can occur: lupus nephritis and membranoproliferative GN may present with features of both; biopsy is mandatory 2, 3
• Do not delay biopsy in nephritic syndrome: rapidly progressive GN can lead to irreversible kidney damage within days to weeks 3
• Albumin assay variability matters: bromocresol green (BCG) reads 0.5 g/dL higher than bromocresol purple (BCP); specify assay type when interpreting results 1
• Avoid immunosuppression in secondary FSGS: obesity-related, medication-induced, or genetic FSGS will not respond and may cause harm 7
• Thromboprophylaxis is not routine: individualize based on albumin level (<2.0-2.5 g/dL) plus additional risk factors, not albumin alone 1, 7
• Post-infectious GN does not require immunosuppression: supportive care only; steroids may worsen outcomes 3
• Genetic testing is now standard for steroid-resistant FSGS: 11-24% of adults have disease-causing variants in podocyte or collagen genes 7