TO038
TACROLIMUS WITH CORTICOSTEROIDS IS INFERIOR TO MODIFIED PONTICELLI REGIMEN IN THE MANAGEMENT OF PRIMARY MEMBRANOUS NEPHROPATHY: RESULTS AT 2 YEARS OF RANDOMIZATION

Introduction and Aims: Both cyclical steroids (GC) with cyclophosphamide (CTX) (cCTX/GC) and calcineurin inhibitors (CNIs) are recommended as first line agents in the management of primary membranous nephropathy (PMN). At the end of 1-year of randomization, both tacrolimus (TAC) with GC (TAC*) and cCTX/GC are equally effective in the management of PMN. However, the utility of CNIs in maintaining remission is limited by the risk of relapse after stopping the drug. So, the present study was undertaken to see if TAC* was non-inferior to cCTX/GC after 2 years of starting therapy.

Methods: A total of 70 (based on sample size calculation for non-inferiority of TAC* to cCTX/GC) adults (≥18 years) with persistent nephrotic syndrome (NS) inspite of 6 months of non-immunosuppressive symptomatic treatment (NIST) resistant PMN cases, randomised to receive either Modified Ponticelli Regimen (cCTX/GC) or a combination of TAC* (TAC 5-10 ng/ml for 1^st 6 months and 4-8 ng/ml for next 6 months along with oral prednisolone 0.5 mg/kg/day for 6 months) (CTRI/2013/10/004061) were prospectively followed. Serum anti m-type phospholipase A2 receptor (aPLA₂R) (ELISA, EUROMMUN, Lubeck, Germany) was done at baseline, 6, 12 months of therapy and during relapse of NS. Primary outcome: Percentage of patients achieving remission (either complete remission (Proteinuria< 500 mg/day with normal serum albumin (>3.5 g/dL) or partial remission (Proteinuria≥ 500 mg/day but <2 g/day or <50% of baseline, with normal serum albumin (> 3.5 g/dL)) at end of 24 months of starting therapy. Secondary outcome: eGFR at 24 months, association of aPLA₂R antibodies with relapse and adverse events during the course of study.

Results: PMN was aPLA₂R related in 48 (68.6%) cases. In the intention-to-treat analysis 71 vs. 77% (p-0.78), 66 vs. 89% (p-0.04), 60 vs. 86% (p-0.03) of cases were at remission at 12, 18 and 24 months in the TAC* vs. cCTX/GC groups respectively. Persistent remission (without any additional immunosuppression) at 12, 18 and 24 months was 71 vs. 77% (p-0.78), 63 vs. 83% (p-0.10) and 51 vs. 80% (p-0.02) in TAC* vs. cCTX/GC group respectively. Relapse rate after remission at 12 months was 36% and 3.7% in TAC/GC and cCTX/GC group respectively (p-0.004). Twelve cases in the TAC* arm (34%) (9 cCTX/GC and 3 rituximab) and 4 (8.5%) (3 TAC and 1 rituximab) in cCTX/GC group received secondary immunosuppressive therapy and at end of therapy, 78%, 33% and 50% achieved remission with cCTX/GC, TAC and rituximab respectively. There was a very good association of aPLA2R titer with remission and relapse. The significant decrease in eGFR at 12 months of TAC* therapy normalized at 18 and 24 months. At 24 months, patients on cCTX/GC had higher incidence of amenorrhea compared to TAC* therapy.

Conclusions: At two years of randomization, TAC* is inferior to cCTX/GC in the management of NIST refractory PMN. Relapse is higher in TAC* compared to cCTX/GC. aPLA₂R has a very good association with remission and relapse.