Is the treatment regimen of high‑dose prednisone, rituximab, and tacrolimus appropriate for a 62‑year‑old man with primary membranous nephropathy, high anti‑phospholipase A2 receptor antibody level, normal renal function, low urine protein‑to‑creatinine ratio, and marked B‑cell depletion?

Treatment Review for Anti-PLA2R Positive Membranous Nephropathy

Overall Assessment

The treatment regimen is problematic because tacrolimus was added after rituximab had already achieved B-cell depletion, which contradicts guideline-recommended sequencing and represents unnecessary polypharmacy in a patient who has already achieved excellent immunologic and clinical response. 1

Current Clinical Status Analysis

Your patient has achieved excellent outcomes with the following parameters:

• Urine PCR 0.63 g/g = Complete remission (target <0.3 g/g is nearly achieved) 2
• CD19 0.03% = Successful B-cell depletion 1
• Normal creatinine = Stable kidney function 1
• Anti-PLA2R antibody trajectory: The initial level of 111.79 RU/mL was moderate-to-high risk, and monitoring the trend is more important than any single value 1

Critical Problems with the Treatment Sequence

Problem 1: Inappropriate Addition of Tacrolimus

Tacrolimus should NOT have been added after rituximab in this clinical scenario. 1

• KDIGO guidelines specifically state that calcineurin inhibitors (CNIs) like tacrolimus are unlikely to induce late immunologic remission and should only be combined with rituximab when anti-PLA2R antibodies persist after initial CNI therapy 1
• The correct sequence is: CNI first → if antibodies persist at 6 months → add rituximab 1
• Your patient received the reverse sequence: rituximab first → then tacrolimus was added inappropriately 1

Problem 2: Timing and Indication Issues

The patient already achieved B-cell depletion (CD19 0.03%) from rituximab, making tacrolimus addition unnecessary. 1

• When rituximab achieves B-cell depletion and proteinuria is improving, no additional immunosuppression is indicated 1
• The guidelines explicitly state to stop additional therapy when anti-PLA2R antibodies disappear or decrease to low levels (<50 RU/mL) 1
• Adding tacrolimus exposes the patient to unnecessary CNI toxicity (nephrotoxicity, hypertension, diabetes, infections) without additional benefit 1

Problem 3: Prednisone Dosing

High-dose prednisone (1 mg/kg) as monotherapy before rituximab is not guideline-recommended. 1

• Glucocorticoids should be used in alternate-month regimens combined with cyclophosphamide (modified Ponticelli protocol), not as monotherapy 1
• Rituximab monotherapy or with minimal steroids is the preferred first-line approach for patients with stable eGFR 3, 4

What Should Have Been Done

Correct Treatment Algorithm

For a 62-year-old with anti-PLA2R 111.79 RU/mL, normal creatinine, and nephrotic-range proteinuria:

1. Risk stratification: Moderate-to-high risk based on anti-PLA2R >50 RU/mL 1
2. First-line therapy: Rituximab 1 gram on days 1 and 15 (or 375 mg/m² weekly × 4) 3, 4
3. Monitoring at 3 months: Check proteinuria, albumin, and anti-PLA2R antibodies 3, 4
4. Decision at 6 months based on antibody levels: 1
   • If antibodies absent: Stop all immunosuppression, taper tacrolimus if started 1
   • If antibodies present but decreased to <50 RU/mL: Watch carefully, continue supportive care only 1
   • If antibodies persistently elevated: Consider additional rituximab dose 1

Recommended Actions Now

Immediate Management

Taper and discontinue tacrolimus as soon as possible. 1

• The patient has achieved the therapeutic goal with rituximab alone 2
• Continuing tacrolimus provides no additional benefit and only adds toxicity risk 1
• CNIs have high relapse rates after discontinuation and don't achieve durable immunologic remission 1

Essential Monitoring

Measure anti-PLA2R antibody levels immediately to guide further decisions. 1, 5

• If antibodies are absent or <2 RU/mL: Complete immunologic remission achieved, no further immunosuppression needed 1, 5
• If antibodies are <50 RU/mL but detectable: Watch carefully, continue supportive care, recheck in 3 months 1
• If antibodies are ≥50 RU/mL or rising: Consider additional rituximab (though unlikely given excellent clinical response) 1, 5

The 50% reduction in anti-PLA2R antibody titer precedes equivalent proteinuria reduction by approximately 10 months, so immunologic remission occurs before clinical remission 5

Ongoing Surveillance

Monitor for relapse after B-cell reconstitution. 2

• Relapse risk is 10% at 2 years after B-cell reconstitution following rituximab 2
• Re-emergence of anti-PLA2R antibodies predicts relapse (hazard ratio 6.54) before proteinuria increases 5
• Check anti-PLA2R antibodies every 3-6 months after B-cell recovery 1, 3

Essential Supportive Care (Often Overlooked)

All patients require optimal supportive therapy regardless of immunosuppression status. 1, 3

• RAS blockade: ACE inhibitor or ARB with blood pressure target <130/80 mmHg 3, 4
• Statin therapy: For nephrotic dyslipidemia 3
• Anticoagulation assessment: With current PCR 0.63 and normal albumin, prophylactic anticoagulation is likely not needed, but reassess if albumin was <25 g/L during active disease 1, 3
• Infection prophylaxis: If continuing any immunosuppression, consider trimethoprim-sulfamethoxazole for Pneumocystis prophylaxis 3, 4

Common Pitfalls to Avoid

Do not interpret persistent mild proteinuria (PCR 0.63) as treatment failure. 4

• Complete remission (<0.3 g/g) can take 12-24 months after immunologic remission 2, 5
• Clinical response lags behind antibody depletion by many months 1, 5

Do not rely solely on B-cell depletion (CD19 levels) to judge rituximab efficacy. 1, 4

• Anti-PLA2R antibody levels are the key biomarker, not B-cell counts 1, 5
• Additional rituximab doses may be needed even with complete B-cell depletion if antibodies persist 1

Do not continue tacrolimus long-term after rituximab-induced remission. 1

• This combination is only indicated when CNI is started first and antibodies persist at 6 months 1
• Prolonged CNI exposure increases nephrotoxicity risk without improving outcomes 1