Long-Term Impact of Cyclosporin Reduction with MMF Treatment in Chronic Allograft Dysfunction: REFERENECE Study 3-Year Follow Up

Abstract

Calcineurin inhibitor (CNI) toxicity contributes to chronic allograft nephropathy (CAN). In the 2-year, randomized, study, we showed that 50% cyclosporin (CsA) reduction in combination with mycophenolate mofetil (MMF) treatment improves kidney function without increasing the risk for graft rejection/loss. To investigate the long-term effect of this regimen, we conducted a follow up study in 70 kidney transplant patients until 5 years after REFERENCE initiation. The improvement of kidney function was confirmed in the MMF group but not in the control group (CsA group). Four graft losses occurred, 2 in each group (graft survival in the MMF group 95.8% and 90.9% in control group). One death occurred in the control group. There was no statistically significant difference in the occurrence of serious adverse events or acute graft rejections. A limitation is the weak proportion of patient still remaining within the control group. On the other hand, REFERENCE focuses on the CsA regimen while opinions about the tacrolimus ones are still debated. In conclusion, CsA reduction in the presence of MMF treatment seems to maintain kidney function and is well tolerated in the long term.

Figure 1

Study design.

Figure 2

Study flow chart.

Figure 3

(a) Evolution of inverse of creatinine (1/SeCr) over time in the randomization population (MMF group versus control group). (b) Evolution of inverse of creatinine (1/SeCr) over time in the on-treatment population (group I versus group II). The vertical, dotted line separates initial study phase and follow up phase.

Figure 4

(a) Evolution of creatinine clearance over time in the randomization population (MMF group versus control group). (b) Evolution of creatinine clearance over time in the on-treatment population (group I versus group II). The vertical, dotted line separates initial study phase and follow up phase.