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 renin-angiotensin system (RAS) blockade, sodium restriction, and diuretic therapy, with immunosuppressive therapy reserved for specific indications based on the underlying cause and disease severity. 1

Initial Conservative Management

Blood Pressure and Proteinuria Control

• Initiate ACE inhibitors or ARBs as first-line therapy for blood pressure control and proteinuria reduction, targeting BP <125/80 mmHg. 1
• Consider delaying ACEi/ARB initiation in patients with podocytopathy (minimal change disease, steroid-sensitive nephrotic syndrome, FSGS) expected to respond rapidly to immunosuppression, particularly in adults without hypertension. 1
• Use potassium-wasting diuretics and/or potassium-binding agents to manage hyperkalemia and allow continuation of RAS blockade. 1
• Counsel patients to hold ACEi/ARB and diuretics during sick days or when at risk for volume depletion. 1

Dietary and Lifestyle Modifications

• Restrict dietary sodium to <2.0 g/day (<90 mmol/day) as a synergistic intervention for controlling hypertension and proteinuria. 1, 2
• Restrict fluid intake when feasible, especially in cases of hyponatremia and severe edema. 3, 2
• Encourage weight normalization, smoking cessation, and regular exercise. 1
• Intensify sodium restriction in patients who fail to achieve proteinuria reductions despite maximally tolerated medical therapy. 1

Edema Management

• 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 and preserved kidney function. 1, 3, 2
• Avoid diuretics in patients with evidence of intravascular hypovolemia (poor peripheral perfusion, hypotension). 3, 2
• Consider administering furosemide (0.5-2 mg/kg) at the end of albumin infusions unless marked hypovolemia or hyponatremia is present. 1, 3
• Exercise caution with diuretic dosing; doses >6 mg/kg per day should not be given for periods longer than 1 week. 3

Albumin Infusions

• Administer intravenous albumin only when clinically indicated for signs of hypovolemia (poor perfusion, hypotension) or failure to thrive, not based solely on serum albumin levels. 3
• The purpose of albumin infusion is to support intravascular volume and reduce edema, not to normalize serum albumin levels. 3
• Home administration of albumin infusions by trained parents/caregivers can be considered to improve quality of life and reduce hospitalization. 3

Immunosuppressive Therapy

Focal Segmental Glomerulosclerosis (FSGS)

Corticosteroid and immunosuppressive therapy should be considered only in idiopathic FSGS associated clinically with features of nephrotic syndrome. 1

First-Line Corticosteroid Therapy

• Administer prednisone or prednisolone at a daily single dose of 1 mg/kg (maximum 80 mg) or alternate-day dose of 2 mg/kg (maximum 120 mg). 1
• Continue initial high-dose corticosteroids for a minimum of 4 weeks; extend up to a maximum of 16 weeks as tolerated, or until complete remission is achieved, whichever is earlier. 1
• Taper corticosteroids slowly over 6 months after achieving complete remission. 1

Alternative First-Line Therapy

• Consider calcineurin inhibitors (CNIs) as first-line therapy for patients with relative contraindications or intolerance 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 diabetes. 1
• Approximately 70% of patients with non-genetic steroid-resistant nephrotic syndrome achieve complete or partial remission with calcineurin inhibitors. 4

Minimal Change Disease in Pediatric Patients

• Corticosteroids are the cornerstone of treatment, with steroid response being the main prognostic factor. 5
• Most children respond to a cycle of oral steroids and are defined as having steroid-sensitive nephrotic syndrome. 5
• For steroid-resistant cases, calcineurin inhibitors (ciclosporin and tacrolimus) are the standard of care. 4

Cyclophosphamide for Steroid-Resistant Disease

• The recommended dosage of cyclophosphamide is 2 mg/kg orally once daily for 8 to 12 weeks (maximum cumulative dose 168 mg/kg) in pediatric patients with biopsy-proven minimal change nephrotic syndrome who failed to respond to or are unable to tolerate corticosteroids. 6
• Treatment beyond 90 days increases the probability of sterility in males. 6
• Cyclophosphamide should be taken in the morning with adequate fluid intake to reduce urinary tract toxicity. 6

Lupus Nephritis

• Initial therapy should combine corticosteroids (1A evidence) with either cyclophosphamide (1B evidence) or mycophenolate mofetil (1B evidence). 1
• If patients show worsening lupus nephritis (rising serum creatinine, worsening proteinuria) during the first 3 months of treatment, change to an alternative recommended initial therapy or perform repeat kidney biopsy. 1

Management of Complications

Hyperlipidemia

• Consider statin therapy as first-line treatment for persistent hyperlipidemia in patients with additional cardiovascular risk factors (hypertension, diabetes). 1, 2
• Assess ASCVD risk based on LDL-C, Apo B, triglyceride and Lp(a) levels, age group, and ASCVD risk enhancers. 1
• Align statin dosage intensity to ASCVD risk. 1
• Consider non-statin therapy (bile acid sequestrants, fibrates, ezetimibe, PCSK9 inhibitors) for patients intolerant to statins or at high ASCVD risk despite maximally tolerated statin dose. 1

Thromboembolism Prevention

• Monitor for thromboembolism, especially with significant hypoalbuminemia. 2
• Consider prophylactic anticoagulation when central venous access is required. 1, 2, 7
• Venous thromboembolism is a significant risk in nephrotic syndrome with high cholesterol levels. 8

Infection Prevention

• Implement infection prophylaxis measures, especially in children with congenital nephrotic syndrome. 3
• Serious bacterial infections are possible complications requiring vigilance. 9

Nutritional Support

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

Special Considerations for Congenital Nephrotic Syndrome

Diagnostic Approach

• Genetic testing should be considered as a first-line diagnostic measure, preferably using parallel massive sequencing or whole-exome sequencing. 3, 7
• Routine kidney biopsy is not recommended but may be considered in patients with sporadic, non-syndromic disease if comprehensive genetic testing has not yielded a molecular diagnosis. 1

Management Strategy

• A stepwise approach with prolonged conservative management is appropriate; routine early nephrectomies should be avoided. 1, 3, 7
• Patients should be managed by a multidisciplinary team including specialized pediatric nephrology, neonatologists, nurses, dieticians, surgeons, psychologists, and social workers. 3, 7
• Ambulatory management should be considered when possible to improve quality of life, reduce risk of nosocomial infections, and decrease treatment costs. 1, 3

Nephrectomy Indications

• Nephrectomy should be considered only in patients with severe complications (persistent hypovolemia, thrombosis, failure to thrive) despite optimal conservative management. 3
• Bilateral nephrectomy is recommended before transplantation in patients with persisting nephrotic syndrome and/or WT1-dominant pathogenic variants. 1, 3

Critical Pitfalls to Avoid

• Do not use immunosuppressive agents for genetic forms of congenital nephrotic syndrome, as they are unlikely to respond. 1
• Avoid routine early nephrectomies in congenital nephrotic syndrome. 1, 3
• Do not administer prophylactic antibiotics or prophylactic anticoagulation routinely in adult nephrotic syndrome without specific indications. 9
• Do not use intravenous albumin prophylactically; reserve for clinical indicators of hypovolemia or failure to thrive. 3
• Recognize that approximately one-third of steroid-resistant nephrotic syndrome cases have a monogenic origin and will not respond to immunosuppression. 4, 5