Why is cotrimoxazole (trimethoprim/sulfamethoxazole) prescribed for a patient with nephrotic syndrome, particularly those who are immunocompromised due to immunosuppressive therapy?

Why Cotrimoxazole is Given in Nephrotic Syndrome

Cotrimoxazole (trimethoprim-sulfamethoxazole) is prescribed in nephrotic syndrome primarily as prophylaxis against Pneumocystis jirovecii pneumonia (PCP) in patients receiving immunosuppressive therapy, particularly high-dose prednisone, rituximab, or cyclophosphamide. 1

Primary Indication: PCP Prophylaxis

The 2021 KDIGO guidelines explicitly recommend prophylactic trimethoprim-sulfamethoxazole for patients with nephrotic syndrome who are receiving high-dose prednisone or other immunosuppressive agents including rituximab and cyclophosphamide. 1 This recommendation addresses the substantially elevated infection risk created by the combination of:

• Immunosuppressive medications that deplete immune function 1
• Nephrotic syndrome itself, which causes loss of immunoglobulins through urinary protein loss 1
• Uremia and malnutrition, which further impair immune responses 1

Mechanism of Increased Infection Risk

Patients with nephrotic syndrome face a dual immunocompromised state:

• Disease-related immunosuppression: Massive proteinuria leads to urinary loss of immunoglobulins, complement factors, and other immune proteins 1
• Treatment-related immunosuppression: Corticosteroids, rituximab (which depletes B cells), and cyclophosphamide all profoundly suppress cellular and humoral immunity 1

Without prophylaxis, PCP can develop as a life-threatening opportunistic infection, particularly during the first few months of immunosuppressive therapy. 2

Dosing and Duration

Standard prophylactic dosing is cotrimoxazole 480 mg (single-strength tablet) daily or 960 mg (double-strength tablet) three times weekly. 2 This differs markedly from treatment doses used for active PCP infection (120 mg/kg/day). 2

Prophylaxis should continue throughout the duration of immunosuppressive therapy and typically for several months after discontinuation, as immune reconstitution is gradual. 1

Additional Considerations Before Starting Immunosuppression

The KDIGO guidelines emphasize a comprehensive infection screening protocol before initiating immunosuppressive therapy in nephrotic syndrome patients: 1

• Screen for tuberculosis (TB) with interferon-gamma release assay or tuberculin skin test 1
• Screen for hepatitis B and C, HIV, and syphilis 1
• Evaluate for Strongyloides in patients from endemic tropical regions, particularly those with eosinophilia and elevated IgE 1
• Update vaccinations including pneumococcal, influenza, and herpes zoster (Shingrix) before starting immunosuppression 1, 3

Common Pitfalls to Avoid

Failing to prescribe prophylaxis when initiating high-dose corticosteroids or other immunosuppressive agents is a critical error that can result in preventable, life-threatening PCP. 1

Using treatment doses instead of prophylactic doses exposes patients to unnecessary toxicity including hyperkalemia, hyponatremia, and bone marrow suppression. 4, 5 Prophylactic dosing (480-960 mg daily or thrice weekly) is substantially lower than treatment dosing (120 mg/kg/day). 2

Discontinuing prophylaxis prematurely when immunosuppression is ongoing leaves patients vulnerable to opportunistic infections. 1

Monitoring During Prophylaxis

While cotrimoxazole prophylaxis is generally well-tolerated at low doses, monitor for: 6, 5

• Electrolyte abnormalities: Trimethoprim can cause hyperkalemia (acts like a potassium-sparing diuretic) and hyponatremia 4, 5
• Bone marrow suppression: Check complete blood counts periodically, particularly in patients with renal dysfunction 6, 5
• Renal function: Although cotrimoxazole can be used in renal impairment, dose adjustment may be needed when creatinine clearance falls below 30 mL/min 5

Alternative Prophylaxis Options

For patients with sulfa allergy or intolerance to cotrimoxazole, alternative PCP prophylaxis includes: 2

• Dapsone 100 mg daily (with or without pyrimethamine) 2
• Nebulized pentamidine 300 mg monthly 2
• Atovaquone 1500 mg daily 2

However, cotrimoxazole remains first-line due to superior efficacy, lower cost, and additional coverage against other bacterial pathogens. 2