What is nephrotic syndrome?

What is Nephrotic Syndrome?

Nephrotic syndrome is a clinical disorder defined by the triad of heavy proteinuria (≥3.5 g/24 hours in adults), hypoalbuminemia (<3.0 g/dL in adults), and edema, often accompanied by hyperlipidemia. 1

Core Diagnostic Criteria

The diagnosis requires three essential features:

• Proteinuria: ≥3.5 g/24 hours in adults (or protein-to-creatinine ratio >300-350 mg/mmol), which represents massive urinary protein loss 1, 2
• Hypoalbuminemia: Serum albumin <3.0 g/dL in adults (note: children use a lower threshold of ≤2.5 g/dL) 1
• Edema: Typically presents as periorbital swelling (most noticeable in the morning) or dependent pitting edema (more prominent later in the day) 2, 3

Important caveat: The albumin assay method matters—bromocresol green (BCG) reads approximately 0.5 g/dL higher than bromocresol purple (BCP) or immunonephelometry, so a BCG value of 2.5 g/dL equals roughly 2.0 g/dL by other methods. 1

Associated Features

Beyond the diagnostic triad, nephrotic syndrome characteristically includes:

• Hyperlipidemia: Occurs as a compensatory hepatic response to hypoalbuminemia, with elevated total cholesterol, LDL, and triglycerides 4, 5
• Lipiduria: Presence of lipids in urine 1

Underlying Pathophysiology

The fundamental defect is increased glomerular permeability to proteins due to podocyte dysfunction. 4 The podocytes are specialized epithelial cells that, together with endothelial cells and the glomerular basement membrane, form a filtration barrier that normally retains plasma proteins in circulation. 6

The mechanisms vary by disease type:

• Minimal change disease and FSGS: A T-cell-driven circulating "glomerular permeability factor" interferes with albumin selectivity 4, 7
• Membranous nephropathy: Autoimmune mechanism with pathogenic autoantibodies targeting podocyte antigens (such as anti-phospholipase A2 receptor) 4, 7
• Genetic forms: Mutations in podocyte genes (NPHS1, NPHS2, WT1, PLCE1) cause congenital nephrotic syndrome 4

The albumin loss decreases oncotic pressure, causing fluid shift from intravascular to interstitial spaces, producing edema. 4

Major Causes

Primary (Idiopathic) Causes

The most common primary glomerular diseases causing nephrotic syndrome vary by age and ethnicity:

• Children: Minimal change disease is most common 1, 7
• White adults: Membranous nephropathy predominates 2, 3
• Adults of African ancestry: Focal segmental glomerulosclerosis (FSGS) is most frequent 2

The three major histologic variants are minimal change disease, focal segmental glomerulosclerosis, and membranous nephropathy. 7

Secondary Causes

Nephrotic syndrome can result from systemic diseases:

• Diabetes mellitus: The most common multisystem disease causing nephrotic syndrome 2
• Systemic lupus erythematosus: Particularly Class V membranous lupus nephritis 7
• Infections: HIV, hepatitis B and C, and other viral infections 4, 7
• Malignancy: Solid tumors with paraneoplastic glomerular disease 7
• Medications: Drug-induced glomerular injury, anti-angiogenesis drugs, immune checkpoint inhibitors 4, 7
• Amyloidosis 2

Genetic Causes

In adults with steroid-resistant nephrotic syndrome and FSGS on biopsy, 11-24% have disease-causing variants in type IV collagen or podocyte genes. 4 Genetic testing is recommended for patients with familial kidney disease, syndromic features, or steroid-resistant FSGS. 4, 7

Serious Complications

Nephrotic syndrome carries substantial morbidity and mortality risks:

Thromboembolism

This is the most critical acute complication, particularly when serum albumin falls below 2.9 g/dL. 1 The risk stems from urinary loss of anticoagulant proteins (antithrombin III, protein C, protein S) combined with increased hepatic synthesis of procoagulant factors:

• Renal vein thrombosis: 29% risk 4, 7
• Pulmonary embolism: 17-28% risk 4
• Membranous nephropathy carries higher thrombotic risk than other causes 1

Infections

Increased susceptibility results from urinary loss of immunoglobulins and complement factors, with particular risk for:

• Cellulitis 7
• Spontaneous bacterial peritonitis 7
• Encapsulated organism infections 4

Cardiovascular Disease

Patients face four times greater risk of accelerated coronary heart disease due to hyperlipidemia, hypertension, and hypercoagulability. 1, 7

Progressive Kidney Disease

Patients with proteinuria >3.8 g/day have a 35% risk of end-stage renal disease within 2 years, regardless of underlying histology. 4, 7 Prolonged nephrotic proteinuria leads to renal scarring and eventual renal failure. 7

Acute Kidney Injury

Can occur from hypovolemia, renal vein thrombosis, or the underlying glomerular disease itself. 3, 8

Nutritional Deficiencies

Vitamin D deficiency occurs from urinary loss of vitamin D-binding protein. 8

Clinical Presentation

Patients typically present with:

• Fatigue and generalized weakness 5, 3
• Periorbital edema (morning) or dependent pitting edema (evening) 2, 3
• Frothy urine (from proteinuria) 5
• Absence of heart failure or severe liver disease (key distinguishing feature) 3

Diagnostic Evaluation

Initial Laboratory Assessment

• Quantitative proteinuria measurement: 24-hour urine collection or spot urine protein-to-creatinine ratio 2, 3
• Serum albumin (specify assay method) 1
• Complete blood count 1
• Comprehensive metabolic panel (electrolytes, kidney function) 9
• Lipid profile (total cholesterol, LDL, HDL, triglycerides) 1
• Serum and urine immunoelectrophoresis/immunofixation plus serum free light chains (to exclude paraprotein-related disease in adults) 1

Secondary Cause Evaluation

• Hepatitis B and C serologies 1
• HIV testing (particularly in high-risk populations) 1
• Antinuclear antibody (ANA), anti-dsDNA, complement levels (C3, C4) if lupus suspected 1, 7
• Fasting glucose or hemoglobin A1c (diabetes screening) 3
• Medication review for nephrotoxic agents 1

Imaging

• Renal ultrasound to assess kidney size and echogenicity 9, 1
• Abdominal ultrasound for ascites 9
• Cardiac ultrasound for effusions and left ventricular mass 9

Kidney Biopsy

Kidney biopsy should be performed in adults to determine the underlying cause and guide treatment, ideally within the first month after onset and before starting immunosuppression. 1 The biopsy is particularly useful in suspected systemic lupus erythematosus or other renal disorders where histology guides management and prognosis. 3

Biopsy requirements:

• At least 8 glomeruli for light microscopy (H&E, PAS, Masson's trichrome, silver stain) 1
• Immunofluorescence for IgG, C3, IgA, IgM, C1q, κ and λ light chains 1
• Electron microscopy to identify proliferative and membranous lesions 1

Exception: Biopsy may be deferred in adults with positive serum anti-phospholipase A2 receptor antibodies, which is diagnostic of membranous nephropathy. 1

In children <12 years, initial treatment with glucocorticoids without biopsy is standard, as minimal change disease is most common; biopsy is reserved for steroid resistance. 1

Management Principles

Supportive Care (All Patients)

• Sodium restriction: <2 g/day 3
• Fluid restriction if significant edema 3
• Loop diuretics: Furosemide 0.5-2 mg/kg per dose (up to 6 times daily, maximum 10 mg/kg/day) for edema with preserved kidney function 9, 3
• RAS inhibition: ACE inhibitors or ARBs to reduce proteinuria and blood pressure 1
• Statin therapy: For persistent hyperlipidemia, particularly with cardiovascular risk factors 1

Anticoagulation

Consider prophylactic full-dose anticoagulation when serum albumin is <20-25 g/L (2.0-2.5 g/dL) AND additional risk factors exist (proteinuria >10 g/day, membranous nephropathy, BMI >35 kg/m², immobilization). 1

• Warfarin is the anticoagulant of choice with target INR 2-3, requiring frequent monitoring due to fluctuating albumin-protein binding 1
• Avoid factor Xa inhibitors and direct thrombin inhibitors due to significant albumin binding and unpredictable urinary losses 1

Disease-Specific Immunosuppression

Treatment depends on biopsy findings:

• Minimal change disease: High-dose corticosteroids (prednisone 1 mg/kg/day); cyclosporin as alternative 1, 4
• FSGS (primary): Prednisone 1 mg/kg/day (maximum 80 mg) for minimum 4 weeks up to 16 weeks, then slow taper over 6 months after remission 9, 4
• Membranous nephropathy: Varies based on risk stratification and anti-PLA2R antibody status 1

Critical distinction: Immunosuppression should NOT be used in secondary FSGS (from obesity, reduced nephron mass, drug toxicity), as it provides no benefit and causes harm. 4 Genetic testing helps identify patients unlikely to respond to immunosuppression. 4

Adjunctive Therapy in CKD

For patients with eGFR ≥20 mL/min/1.73 m² and persistent proteinuria despite maximal RAS inhibition, SGLT2 inhibitors (such as dapagliflozin) provide kidney protection as part of comprehensive CKD management—but are adjunctive, not replacements for disease-specific therapy. 4

Common Pitfalls

• Albumin infusion is NOT recommended as standard management; focus instead on diuretics, RAS inhibition, and disease-specific immunosuppression 1
• Failing to distinguish primary from secondary FSGS leads to inappropriate immunosuppression 4
• Underestimating thrombotic risk: Assess beyond albumin level alone—consider proteinuria severity, underlying histology (membranous nephropathy highest risk), BMI, and immobility 1
• Delaying biopsy until after immunosuppression obscures histologic diagnosis 1
• Using direct oral anticoagulants instead of warfarin in nephrotic syndrome leads to unpredictable anticoagulation 1