What is the treatment for a patient with nephrotic syndrome?

Treatment of Nephrotic Syndrome

The treatment of nephrotic syndrome requires a comprehensive approach starting with conservative management including sodium restriction (<2.0 g/day), RAS inhibition with ACE inhibitors or ARBs, and diuretics for edema control, followed by disease-specific immunosuppression based on the underlying etiology and steroid responsiveness. 1

Initial Conservative Management

Fluid and Edema Control

• Restrict dietary sodium to <2.0 g/day (<90 mmol/day) as the foundational intervention for edema management. 1
• Restrict fluid intake when feasible, particularly in patients with hyponatremia and severe edema. 2, 3
• Administer furosemide (0.5-2 mg/kg per dose, up to six times daily; maximum 10 mg/kg per day) for patients with intravascular fluid overload (evidenced by good peripheral perfusion, high blood pressure, and edema) and preserved kidney function. 1, 2
• Avoid diuretics in patients with evidence of intravascular hypovolemia (poor peripheral perfusion, hypotension, or signs of volume depletion). 2, 3
• When administering albumin infusions, give furosemide (0.5-2 mg/kg) at the end of each infusion unless marked hypovolemia or hyponatremia is present. 1, 2

Renin-Angiotensin System Blockade

• Initiate ACE inhibitors or ARBs for blood pressure control (target <125/80 mmHg) and proteinuria reduction, with a goal of reducing proteinuria to <1 g/day when possible. 1
• It may be reasonable to delay ACE inhibitor or ARB initiation in normotensive patients with minimal change disease or FSGS expected to respond rapidly to immunosuppression. 1
• Use potassium-wasting diuretics and/or potassium-binding agents to manage hyperkalemia and allow continuation of RAS blockade. 1
• Counsel patients to hold ACE inhibitors/ARBs and diuretics during sick days or when at risk for volume depletion. 1

Cardiovascular Risk Management

• Consider statin therapy for persistent hyperlipidemia, particularly in patients with additional cardiovascular risk factors (hypertension, diabetes). 1, 3
• Assess ASCVD risk based on LDL-C, Apo B, triglyceride, and Lp(a) levels, age, and ASCVD risk enhancers. 1
• Align statin dosage intensity to ASCVD risk; statins can be initiated in children aged >8 years with concerning family history or extremely elevated LDL-C in the context of shared decision-making. 1

Disease-Specific Immunosuppressive Therapy

Focal Segmental Glomerulosclerosis (FSGS)

• Corticosteroid therapy should be considered only in idiopathic FSGS with clinical features of nephrotic syndrome. 1
• Administer prednisone or prednisolone at 1 mg/kg/day (maximum 80 mg) or alternate-day dosing of 2 mg/kg (maximum 120 mg). 1
• Continue high-dose corticosteroids for a minimum of 4 weeks, up to a maximum of 16 weeks as tolerated, or until complete remission is achieved. 1
• Taper corticosteroids slowly over 6 months after achieving complete remission. 1
• Consider calcineurin inhibitors (cyclosporine or tacrolimus) as first-line therapy for patients with contraindications to high-dose corticosteroids (uncontrolled diabetes, psychiatric conditions, severe osteoporosis). 1
• Cyclosporine may be preferred over tacrolimus in patients at risk for diabetes due to lesser tendency to precipitate hyperglycemia. 1

Minimal Change Disease and Steroid-Sensitive Nephrotic Syndrome

• Corticosteroids are the cornerstone of treatment, with most children responding to oral steroids. 4
• For patients with frequent relapses requiring repeated steroid cycles, consider steroid-sparing agents including levamisole, mycophenolate mofetil, calcineurin inhibitors, anti-CD20 monoclonal antibodies (rituximab), or cyclophosphamide. 4

Steroid-Resistant Nephrotic Syndrome

• Calcineurin inhibitors (cyclosporine or tacrolimus) are the standard of care for non-genetic steroid-resistant nephrotic syndrome, with approximately 70% achieving complete or partial remission. 5
• Consider genetic testing, especially in congenital nephrotic syndrome or early-onset disease, as genetic forms are unlikely to respond to immunosuppression. 2, 6
• For patients not responding to calcineurin inhibitors, consider mycophenolate mofetil or rituximab. 5, 4

Pediatric Minimal Change Nephrotic Syndrome

• For biopsy-proven minimal change nephrotic syndrome in children who failed to respond to or cannot tolerate corticosteroids, cyclophosphamide 2 mg/kg orally once daily for 8-12 weeks (maximum cumulative dose 168 mg/kg) is indicated. 7
• Treatment beyond 90 days increases the probability of sterility in males. 7
• Cyclophosphamide should be taken in the morning with adequate fluid intake to reduce urinary tract toxicity. 7

Lupus Nephritis (Class IV)

• Initial therapy should combine corticosteroids (1A) with either cyclophosphamide (1B) or mycophenolate mofetil (1B). 1
• If worsening occurs during the first 3 months (rising creatinine, worsening proteinuria), change to alternative therapy or perform repeat kidney biopsy. 1

Prevention and Management of Complications

Thromboembolism

• Consider prophylactic anticoagulation when central venous access is required, given the high thrombosis risk in nephrotic syndrome. 2, 6
• Monitor for signs of venous thromboembolism, especially with significant hypoalbuminemia. 3, 8

Infection Prevention

• Implement infection prophylaxis measures, especially in children with congenital nephrotic syndrome or those on immunosuppression. 2, 3
• Monitor closely for signs of infection, as severe immunosuppression may lead to serious and sometimes fatal infections. 7

Nutritional Support

• Ensure adequate nutrition to prevent malnutrition and support growth, particularly in children. 2, 3
• Consider growth hormone substitution in children with growth impairment. 2
• Supplement with vitamin D (colecalciferol or calcifediol) and calcium (250-500 mg/day) in cases of low 25-OH-D3, low ionized calcium, or elevated PTH. 3

Special Considerations for Congenital Nephrotic Syndrome

• Manage with a multidisciplinary team in specialized pediatric nephrology centers, including nephrologists, neonatologists, nurses, dietitians, surgeons, psychologists, and social workers. 2, 6
• Do not perform routine early nephrectomies; consider nephrectomy only in patients with persistent severe complications despite optimal conservative management (persistent hypovolemia, thrombosis, failure to thrive). 1, 2
• Consider nephrectomy before transplantation in patients with persisting nephrotic syndrome and/or WT1-dominant pathogenic variants. 1, 2
• Ambulatory management should be considered when possible to improve quality of life and reduce nosocomial infection risk. 1, 2, 6
• Home administration of albumin infusions by trained parents is feasible and safe. 1, 2

Critical Pitfalls to Avoid

• Never use immunosuppressive agents for genetic forms of congenital nephrotic syndrome, as they are unlikely to respond. 1, 2
• Do not give diuretic doses >6 mg/kg per day for periods longer than 1 week due to toxicity risk. 1, 2
• Avoid routine kidney biopsy in congenital nephrotic syndrome; reserve for sporadic, non-syndromic disease when comprehensive genetic testing is non-diagnostic. 1
• Do not base albumin infusions solely on serum albumin levels; use clinical indicators of hypovolemia or failure to thrive instead. 1, 2
• Avoid central venous lines when possible due to high thrombosis risk in nephrotic syndrome. 1