Antibody-Guided Therapy in Phospholipase A2 Receptor-Associated Membranous Nephropathy

Abstract

Introduction: A 6-month course of cyclophosphamide (CP) and steroids is effective in primary membranous nephropathy (MN), but unappealing because of long-term side effects. We evaluated efficacy of an "antibody-guided" treatment schedule.

Methods: Patients with phospholipase A2 receptor (PLA2R)-related MN and high risk of progression were treated with CP 1.5 mg/kg/d and steroids in cycles of 8 weeks. Anti-PLA2R antibodies were measured by indirect immunofluorescence (IIFT) at 8, 16, and 24 weeks, and a negative test resulted in withdrawal of CP, and rapid tapering of prednisone. In patients with persistent anti-PLA2R antibodies at 24 weeks, CP was switched to mycophenolate mofetil. Treatment was repeated in patients with a relapse.

Results: Our analysis included 65 patients (48 males, 17 females), age 61 ± 12 years, estimated glomerular filtration rate (eGFR) 46 ml/min per 1.73 m² (35-68), urine protein-to-creatinine ratio 7.7 grams/10 mmol creatinine (5.4-11.1) and serum albumin 20 g/l (16-26). Immunologic remission rate was 71% after 8 weeks, 86% after 16 weeks, 88% after 24 weeks, and 94% after 3 years. Twenty-seven patients (42%) had persistent clinical remission after only 8 weeks of therapy. Sixteen patients needed a second course of therapy because of immunologic or clinical relapse. Follow-up was 37 (26-58) months. Overall partial remission rate was 92%. One patient developed end-stage kidney disease. Antibody-guided therapy (ABG) was as effective as the standard 6-month course, whereas providing a lower cumulative dose of CP (11.1 [8.0-18.5] vs. 18.9 [14.2-23.6] grams).

Conclusion: ABG is effective, and allows individualized therapy, with many patients responding to 8 weeks of CP-based therapy.

Keywords: anti-PLA2R antibodies; cyclophosphamide; membranous nephropathy.

Graphical abstract

Figure 1

Flowchart of patients’ inclusion. PLA2R, phospholipase A2 receptor.

Figure 2

Flowchart of clinical events. In total, 52 remissions after the first course of ABG therapy are counted, of which 49 persisted >6 months. Each ∗ is 1 patient with short partial remission between additional immunosuppression and end of follow-up. ∞ in this patient additional IS was started because of slight increase in proteinuria and decrease in serum albumin, not fulfilling relapse criteria. Each † is 1 patient that died in remission. ABG, antibody-guided; aPLA2R, anti-PLA2R; CR, complete remission; ESRD, end-stage renal disease; IS, immunosuppressive therapy; PR, partial remission.

Figure 3

(a) Kaplan-Meier curves of clinical partial remission and (b) clinical relapse or second therapy.

Figure 4

(a) Kaplan-Meier curves of overall clinical remission and (b) relapse free survival in patients with ABG therapy versus patients treated with cyclophosphamide during 6 months. Relapse was defined as relapse after clinical or immunologic remission.