What is the initial workup and treatment for a patient presenting with nephrotic syndrome?

Nephrotic Syndrome Workup

Initial Diagnostic Confirmation

Confirm nephrotic syndrome by documenting proteinuria ≥3.5 g/24 hours (or spot urine protein-to-creatinine ratio ≥3.5 g/g), serum albumin <3.0 g/dL, and edema. 1, 2

• In children, use proteinuria ≥40 mg/h/m² or first morning urine protein-to-creatinine ratio ≥2 g/g, with serum albumin ≤2.5 g/dL 2
• Note that albumin assay type matters: bromocresol green (BCG) reads approximately 0.5 g/dL higher than bromocresol purple (BCP) or immunonephelometry 2

Laboratory Workup to Exclude Secondary Causes

Perform targeted testing to identify secondary causes including diabetes mellitus, systemic lupus erythematosus, infections, and medication-induced disease. 1

Essential Initial Labs:

• Complete blood count with platelets 2
• Serum electrolytes, creatinine, and estimated GFR 1
• Fasting glucose and hemoglobin A1c to screen for diabetes 1
• Lipid profile (typically shows hyperlipidemia) 1
• Complement levels (C3, C4) to assess for immune-mediated disease 2
• Antinuclear antibody (ANA) and anti-dsDNA if lupus is suspected 2
• Hepatitis B and C serologies 2
• HIV testing in high-risk populations 2

Additional Workup:

• Serum IgG level (often low due to urinary losses) 2
• Thyroid function tests 2
• Calcium, phosphate, alkaline phosphatase, PTH, and vitamin D levels 2
• Review all medications for nephrotoxic agents 2

Imaging Studies

Obtain renal ultrasound to assess kidney size and echogenicity, particularly before potential biopsy. 2

• Abdominal ultrasound to evaluate for ascites 2
• Cardiac ultrasound to check for pericardial effusions and left ventricular mass 2

Kidney Biopsy Decision Algorithm

For Adults:

Perform kidney biopsy within the first month after onset, preferably before starting immunosuppressive treatment, to establish histologic diagnosis. 2

• Biopsy is indicated in all adults except those with positive serum anti-phospholipase A2 receptor antibodies (diagnostic of membranous nephropathy) 2
• Ensure biopsy sample includes ≥8 glomeruli for light microscopy with H&E, PAS, Masson's trichrome, and silver stain 2
• Immunofluorescence for IgG, C3, IgA, IgM, C1q, κ and λ light chains is required 2
• Electron microscopy is recommended to facilitate recognition of proliferative and membranous lesions 2
• In advanced CKD (GFR <30 mL/min/1.73 m²), biopsy may still be considered if there is evidence of active disease and kidney size >9 cm 2

For Children:

In children <12 years with typical presentation, defer biopsy and initiate empiric corticosteroid therapy. 1, 2

• Biopsy is indicated in steroid-resistant nephrotic syndrome after 4-6 weeks of treatment 1
• Biopsy is also indicated in children ≥12 years at presentation 2
• Minimal change disease is the most common cause in children <12 years 2

Genetic Testing Considerations

Consider genetic testing in patients with familial kidney disease, syndromic features, steroid-resistant FSGS, or congenital/early-onset disease. 1, 2

• Use massively parallel sequencing or whole-exome sequencing 1
• Document history of prematurity as potential etiology for reduced nephron number 2
• Assess for non-kidney manifestations including neurological status, sight, hearing, and dysmorphic features 1

Risk Stratification for Complications

Thromboembolism Risk:

Assess venous thromboembolism risk, particularly when serum albumin falls below 2.9 g/dL. 2

• Membranous nephropathy carries higher VTE risk than other causes 2
• Consider using validated risk assessment tools (e.g., http://www.med.unc.edu/gntools/) 2
• Consider prophylactic anticoagulation in high-risk patients, particularly those with membranous nephropathy and serum albumin <2.9 g/dL 2
• Use treatment doses of unfractionated or low-molecular-weight heparin or warfarin; avoid factor Xa inhibitors and direct thrombin inhibitors due to albumin binding and urinary losses 2

Infection Risk:

Administer pneumococcal and influenza vaccines to prevent infections. 1

• Consider prophylactic trimethoprim-sulfamethoxazole for patients receiving high-dose immunosuppression 1

Initial Supportive Management

Edema Management:

Restrict dietary sodium to <2.0 g/day and use loop diuretics as first-line agents for edema. 1

• Avoid intravenous fluids and saline; concentrate oral fluid intake if necessary 1
• Use albumin infusions only for clinical indicators of hypovolemia (oliguria, acute kidney injury, prolonged capillary refill time, tachycardia, hypotension), not based on serum albumin levels alone 3

Proteinuria and Blood Pressure Control:

Initiate ACE inhibitors or ARBs at maximally tolerated doses for proteinuria and blood pressure control. 1

• Target systolic blood pressure <120 mmHg in adults using standardized office BP measurement 1
• In congenital nephrotic syndrome, combined ACE inhibitor therapy may increase serum albumin levels 3

Disease-Specific Treatment Initiation

For Minimal Change Disease:

Administer prednisone at 1 mg/kg/day (maximum 80 mg) or alternate-day dose of 2 mg/kg (maximum 120 mg) for adults. 1

• In children, use prednisone at 60 mg/m² per day (maximum 80 mg/day) or 2 mg/kg/day for 4-6 weeks 1
• Continue high-dose corticosteroids for minimum 4 weeks and up to 16 weeks as tolerated or until complete remission 1
• Taper corticosteroids slowly over 6 months after achieving complete remission 1

For Focal Segmental Glomerulosclerosis:

Classify FSGS into primary, genetic, secondary, or undetermined cause to guide treatment. 2

• Confirm idiopathic FSGS before initiating immunosuppressive therapy 1
• Consider calcineurin inhibitors (cyclosporine 3-5 mg/kg/day divided into 2 doses or tacrolimus 0.1-0.2 mg/kg/day divided into 2 doses) as first-line therapy for patients with contraindications to high-dose corticosteroids 1

For Membranous Nephropathy:

Initiate therapy only when urinary protein persistently exceeds 4 g/day and remains >50% of baseline despite 6 months of conservative therapy, or severe disabling symptoms are present. 1

Special Populations

Congenital Nephrotic Syndrome:

Refer children with congenital nephrotic syndrome immediately to specialized pediatric nephrology units due to disease complexity. 3, 1

• Avoid central venous lines due to high thrombosis risk; if required, administer prophylactic anticoagulation for duration of line placement 3
• Consider ambulatory management when stable to improve quality of life and reduce nosocomial infection risk 3
• Early referral to transplant center is recommended to minimize time on dialysis 1
• Bilateral nephrectomy is recommended at time of kidney failure (CKD G5) if nephrotic syndrome persists and/or patient has WT1 pathogenic variant 3

Monitoring Protocol

Assess proteinuria and kidney function every 2-4 weeks for the first 2-4 months, then every 3-6 months. 1, 2

• Monitor for medication side effects, particularly with long-term immunosuppressive therapy 1
• Regularly evaluate for complications including thromboembolism and infections 2
• In pediatric patients, monitor growth velocity, blood pressure, weight, height, intraocular pressure, and evaluate for infection, psychosocial disturbances, thromboembolism, peptic ulcers, cataracts, and osteoporosis 4