What is the recommended step‑by‑step management for a child with steroid‑resistant nephrotic syndrome (SRNS)?

Management of Steroid-Resistant Nephrotic Syndrome (SRNS) in Children

Calcineurin inhibitors (cyclosporine or tacrolimus) are the first-line immunosuppressive therapy for pediatric SRNS after confirming the diagnosis with at least 8 weeks of corticosteroid failure, and should be continued for a minimum of 12 months if partial or complete remission is achieved by 6 months. 1, 2

Step 1: Confirm the Diagnosis of SRNS

• Define steroid resistance as failure to achieve remission after 8 weeks of corticosteroid therapy (prednisone 60 mg/m²/day for 4–6 weeks followed by alternate-day dosing). 1, 2
• Quantify proteinuria using spot urine protein-to-creatinine ratio (UPCR) before defining SRNS; a first-morning UPCR ≥ 2 g/g confirms nephrotic-range proteinuria. 1, 2
• Confirm diagnosis by 6 weeks if no remission is evident, though the formal definition requires 8 weeks of treatment. 1

Step 2: Perform Essential Baseline Evaluations

Kidney biopsy is mandatory in all children with SRNS except when infection, malignancy-associated disease, or a confirmed genetic/familial cause is already identified (Grade A, strong recommendation). 1, 2

• Evaluate kidney function by measuring GFR or eGFR to establish baseline renal function before starting calcineurin inhibitors. 1
• Obtain genetic testing as soon as possible, ideally within the 2-week confirmation period, because monogenic SRNS will not respond to immunosuppression (Grade B, moderate recommendation). 1, 2
• Measure baseline serum creatinine to monitor for subsequent CNI nephrotoxicity. 1

Critical Pitfall: Resource-Limited Settings

• In low-resource countries where biopsy or genetic testing is unavailable, start calcineurin inhibitor therapy immediately rather than delaying treatment. 1
• If CNIs are unavailable, intravenous or oral cyclophosphamide may be initiated as an alternative. 1

Step 3: Initiate First-Line Immunosuppression with Calcineurin Inhibitors

Cyclosporine is dosed at 4–5 mg/kg/day divided twice daily, targeting trough levels of 60–150 ng/mL. 2, 3

Tacrolimus is dosed at 0.1 mg/kg/day divided twice daily, targeting trough levels of 5–10 ng/mL. 2, 3

• Continue CNI therapy for a minimum of 6 months and stop if no partial or complete remission of proteinuria is achieved by that time. 1, 2
• Extend CNI therapy for 12–24 months when at least partial remission is achieved by 6 months. 1, 2
• Reduce CNI dosage to the lowest level required to maintain remission once complete remission is achieved. 1
• Consider discontinuation after 12–24 months in patients with complete remission to reduce the risk of nephrotoxicity (Grade C, weak recommendation). 1

Monitoring During CNI Therapy

• Measure CNI trough levels regularly to maintain therapeutic range and avoid toxicity. 2, 3
• Monitor serum creatinine weekly during the first month, then monthly to detect nephrotoxicity early. 1
• Perform kidney biopsy if renal function declines to assess for CNI nephrotoxicity versus disease progression. 1, 2, 3
• Check spot UPCR weekly to quantify proteinuria response; partial remission is defined as ≥50% reduction in proteinuria, and complete remission as UPCR <0.2 g/g. 2, 4
• Measure serum albumin weekly to assess for improvement. 2, 4

Step 4: Define Treatment Response

• Complete remission: Urine dipstick trace or negative for protein for at least 3 consecutive days, or UPCR <0.2 g/g. 2, 4
• Partial remission: ≥50% reduction in proteinuria from baseline. 2, 4
• No response: Failure to achieve partial or complete remission after 6 months of CNI therapy. 1

Step 5: Second-Line Therapy if CNIs Fail

If no remission is achieved after 6 months of CNI therapy, consider the following second-line agents:

Mycophenolate Mofetil (MMF)

• Dose: 1200 mg/m²/day divided twice daily, targeting mycophenolic acid (MPA) area-under-curve (AUC) >50 µg·h/mL. 2, 3
• Duration: Continue for a minimum of 12 months. 2, 3
• Switch to sodium mycophenolate if significant abdominal pain develops. 2, 3
• Evidence from sequential therapy studies shows MMF can maintain remission after initial CNI response, with improved renal function and blood pressure control. 5

Rituximab

• Dose: 375 mg/m² IV for 1–4 doses. 2, 3, 4
• Reserve for children with persistent frequent relapses despite optimal prednisone plus other steroid-sparing agents, or those with serious adverse effects from other therapies. 2, 3
• Screen for hepatitis B (HBsAg, anti-HBc) and latent tuberculosis (QuantiFERON) before infusion. 2, 3, 4
• Monitor CD20 and IgG levels; hold dosing during active infection. 2, 3, 4
• Complete at least 3–4 doses before assessing efficacy, as B-cell depletion takes time to translate into clinical improvement. 4

Cyclophosphamide (if CNIs unavailable)

• Oral dose: 2 mg/kg/day for 12 weeks (cumulative maximum 168 mg/kg). 2, 3
• Never repeat cyclophosphamide due to irreversible cumulative gonadal toxicity. 2, 3
• Initiate only after achieving remission with glucocorticoids; do not start during active relapse. 2, 3
• Monitor weekly CBC for leukopenia. 2, 3
• Some studies report effectiveness in SRNS, though calcineurin inhibitors appear superior. 6, 7

Step 6: Supportive Care Throughout Treatment

• Daily urine dipstick testing by caregivers to detect early relapse or monitor response. 2
• Daily weight and blood pressure measurements during active disease. 2
• Fluid restriction to insensible losses plus urine output during severe edema/oliguria to avoid volume overload. 2, 4
• Diuretics (furosemide) for severe edema after correcting hypovolemia; consider IV albumin 0.5–1 g/kg before diuretic administration in markedly hypoalbuminemic patients to enhance diuretic response. 2, 4
• Pneumococcal vaccination is recommended due to heightened infection risk. 2
• ACE inhibitors and/or angiotensin receptor blockers for blood pressure control and antiproteinuric effect. 5

Critical Pitfalls to Avoid

• Do not start immunosuppression during active infection; complete septic workup (blood culture, urine culture) and hold therapy until infection is excluded. 4
• Do not stop CNI therapy prematurely before 6 months; inadequate treatment duration leads to higher relapse rates. 1, 2
• Do not restart high-dose daily steroids after 8 weeks of failure; this increases toxicity without benefit. 4
• Do not repeat cyclophosphamide courses due to cumulative gonadal toxicity; use alternative agents for subsequent treatment needs. 2, 3
• Do not use diuretics alone without albumin supplementation in severely hypoalbuminemic patients, as efficacy is markedly reduced. 4
• Do not delay kidney biopsy beyond 8 weeks of steroid resistance; histopathology guides therapy and prognosis. 1, 2
• Do not ignore declining renal function on CNIs; perform kidney biopsy to assess for nephrotoxicity. 1, 2, 3

Special Considerations for Genetic SRNS

• Monogenic SRNS (likely in children <5 years with steroid resistance) will not respond to immunosuppression. 4
• Pursue genetic testing urgently if not already done; positive results should prompt discontinuation of immunosuppressive therapy. 1, 2, 4
• Refer for novel therapies or clinical trials if genetic cause is confirmed. 4

Prognosis and Long-Term Management

• Most children achieving remission with CNI therapy can maintain sustained remission with sequential therapy (CNI followed by MMF monotherapy), preserving renal function long-term. 5
• Some patients may develop steroid-dependent patterns after initial SRNS treatment, requiring ongoing steroid-sparing agents. 7
• End-stage renal failure occurs in non-responders, particularly those with genetic mutations. 8, 7