What is the best course of treatment for a 3-year and 4-month-old child with Secondary Steroid-Resistant Nephrotic Syndrome (SRNS) and Stage 2 Hypertension (HTN), who has not responded to steroids, mycophenolate mofetil (MMF), and cyclosporin, and is currently on rituximab, frusemide (Lasix) (furosemide), enalapril, and has presented with abdominal swelling, fever, and respiratory distress?

Management of Secondary SRNS with Respiratory Distress and Severe Edema

This child requires immediate stabilization of respiratory distress and fluid overload, continuation of rituximab therapy (having received 2 doses already), aggressive diuresis with albumin support, and close monitoring for infection, while avoiding further CNI therapy given the prior cyclosporin failure and current critical state. 1, 2

Immediate Stabilization (Next 24-48 Hours)

Respiratory Management

• Continue oxygen support to maintain SpO2 >92% and consider escalation to CPAP or mechanical ventilation if work of breathing worsens, given the current tachypnea (RR 38) and recent pleural effusions. 2
• Perform therapeutic pleural tap if respiratory distress worsens, as you've already done successfully 4 times during this admission. 2
• Monitor for pulmonary edema with serial chest examinations and consider chest X-ray if clinical deterioration occurs. 2

Fluid and Diuretic Management

• Resume furosemide at 5.5 mg/kg/day in divided doses (the dose that previously achieved 1.6 ml/kg/day urine output) given the recurrent edema and respiratory compromise. 2
• Administer 20% albumin 0.5-1 g/kg IV over 2-4 hours immediately before each furosemide dose to enhance diuretic response in this severely hypoalbuminemic child. 2
• Restrict fluid intake to insensible losses plus urine output to prevent further volume overload. 2
• Monitor strict intake/output, daily weights, and abdominal girth measurements. 2

Infection Surveillance

• Complete the septic workup immediately (blood culture, urine culture) given the new fever and prior history of fever with abdominal pain. 2
• Hold rituximab dose until infection is ruled out, as immunosuppression increases infection risk. 1
• Consider empiric broad-spectrum antibiotics if fever persists or clinical deterioration occurs while awaiting culture results. 2

Immunosuppressive Strategy

Rituximab Continuation

• Proceed with the 3rd dose of rituximab once infection is excluded, as this is the appropriate first-line steroid-sparing agent for SRNS after CNI failure. 1, 3
• The KDIGO 2021 guidelines recommend rituximab for steroid-dependent and frequently relapsing disease, though evidence in SRNS is more limited. 1, 4
• Plan for a 4th dose if edema persists after the 3rd dose, as you've appropriately outlined, since some children require the full 4-dose course (375 mg/m² per dose). 1, 3

Corticosteroid Management

• Continue hydrocortisone stress dosing during acute illness rather than prednisolone, as you've appropriately done. 1
• Once stabilized, consider low-dose alternate-day prednisone (0.3-0.5 mg/kg on alternate days) as adjunctive therapy, though avoid high-dose steroids given the 2-month failure initially. 1

Avoid Further CNI Therapy

• Do not restart cyclosporin given the prior availability issues and the fact that this child has already failed both steroids and MMF, making rituximab the more appropriate next step. 1, 4
• CNIs remain first-line for SRNS, but this child's treatment course has moved beyond that option. 1, 5

Supportive Management

Cardiovascular and Renal Protection

• Continue enalapril 10 mg morning and 5 mg evening for antiproteinuric effect and blood pressure control, monitoring for hypotension (current BP 90/50 is borderline low). 1, 4
• Monitor serum creatinine and electrolytes daily given the aggressive diuresis and risk of acute kidney injury. 2
• Correct hypokalemia aggressively as you've been doing, as loop diuretics cause significant potassium wasting. 2

Metabolic Abnormalities

• Continue levothyroxine for hypothyroidism (likely secondary to nephrotic syndrome). 2
• Address the severe dyslipidemia (total cholesterol 600.7, triglycerides 818.0) with dietary modification once acute phase resolves; consider statin therapy if persistent. 5

Nutritional Support

• Provide adequate protein intake (2-3 g/kg/day) to compensate for urinary losses while avoiding excessive intake that worsens proteinuria. 2
• Ensure adequate caloric intake despite poor appetite. 2

Monitoring and Assessment for Remission

Define Treatment Response

• Monitor urine protein daily with dipstick looking for trace/negative proteinuria for 3 consecutive days to define remission. 1, 2
• Measure spot urine protein/creatinine ratio weekly to quantify response (partial remission = 50% reduction in proteinuria; complete remission = protein/creatinine <0.2). 1, 2
• Check serum albumin weekly to assess for improvement. 2

Timeline for Response Assessment

• Assess response to rituximab at 3-6 months after completing the course, as B-cell depletion takes time to translate into clinical improvement. 1, 3
• If no response after 6 months of rituximab, consider genetic testing (if not already done) to identify monogenic causes that won't respond to immunosuppression. 1, 6

Critical Pitfalls to Avoid

Infection Risk

• Do not give rituximab during active infection - this child's fever and respiratory symptoms must be fully evaluated first. 3
• Monitor for opportunistic infections given the multiple immunosuppressive agents. 3

Diuretic Management

• Do not use diuretics alone without albumin supplementation in severely hypoalbuminemic patients, as efficacy is markedly reduced. 2
• Avoid excessive diuresis that could precipitate acute kidney injury or thrombotic complications (note the elevated platelet count of 877). 2

Steroid Toxicity

• Avoid restarting high-dose daily steroids given the prior 2-month failure and significant steroid-related complications this child has already experienced. 1

Premature Treatment Discontinuation

• Do not stop rituximab after 2 doses - complete at least 3-4 doses before assessing efficacy. 1, 3
• Do not discontinue MMF abruptly - continue current dose (500 mg morning, 250 mg evening) as adjunctive therapy. 1

Prognosis and Next Steps

If Rituximab Fails

• Consider mycophenolate mofetil dose escalation to 1200 mg/m²/day in divided doses (currently underdosed at 750 mg total daily). 1, 3
• Pursue genetic testing urgently if not already done, as monogenic SRNS (likely given age <5 years and steroid resistance) won't respond to immunosuppression. 1, 6
• Refer for consideration of novel therapies or clinical trials. 4

Renal Biopsy Consideration

• Kidney biopsy should have been performed at diagnosis of steroid resistance (after 8 weeks of steroid failure) to guide therapy and assess for FSGS vs. other pathology. 1
• If not yet done, consider biopsy once stabilized to confirm histology and rule out secondary causes. 1, 5

Long-term Planning

• Counsel family about risk of progression to ESRD given the severity and treatment resistance, and begin discussing renal replacement therapy options. 4, 7
• Note that genetic SRNS has lower recurrence risk post-transplant than immune-mediated SRNS. 6