Predictive Factors of Acute Rejection after Early Cyclosporine Withdrawal in Renal Transplant Recipients Who Receive Mycophenolate Mofetil

Abstract

The aim of this randomized, open-labeled trial was to compare the incidence of acute rejection after an early (3 mo posttransplantation) withdrawal of cyclosporine (CsA) or mycophenolate mofetil (MMF) in renal transplantation. Among 218 eligible recipients, 108 nonsensitized, rejection-free patients who were under a triple drug regimen (CsA-MMF-prednisone) and had received a first kidney from a deceased donor were enrolled. At 3 mo after graft, they were gradually withdrawn from CsA (MMF group, n ‫؍‬ 54) or MMF (CsA group, n ‫؍‬ 54). A graft biopsy and a pharmacokinetic study of CsA and mycophenolic acid were systematically performed before the randomization. At 1 yr, graft and patient survival rates were 100% in each group. Renal function was improved in the MMF group compared with the CsA group (Cockcroft calculated clearance 64.7 ؎ 18.7 versus 56.5 ؎ 18.0 ml/min; P ‫؍‬ 0.023). However, the probability of acute rejection was higher in the MMF group (18.5 versus 5.6%; P ‫؍‬ 0.045). The 10 patients who developed acute rejection after CsA withdrawal had a significantly higher incidence of borderline changes on the randomization biopsy than the 44 rejection-free patients (five of 10 versus eight of 44; P ‫؍‬ 0.034), and they displayed a lower area under the curve of mycophenolic acid (43 ؎ 9 versus 58 ؎ 22 mg/h per L; P ‫؍‬ 0.045). Multivariate analysis confirmed that borderline changes and area under the curve of mycophenolic acid were significant risk factors of acute rejection after CsA discontinuation. It is concluded that a systematic graft biopsy and a pharmacokinetic study of mycophenolic acid are needed to reduce the risk for acute rejection after CsA withdrawal.

Cyclosporine Withdrawal from a Mycophenolate Mofetil–Containing Immunosuppressive Regimen

“…Accordingly, a 12-mo study of 77 patients found that when CsA was withdrawn at 3 mo from a triple-therapy regimen that comprised MMF ϩ steroids, a low mycophenolic acid AUC 0 to 12 at the time of CsA discontinuation was a predictor for later acute rejection (13). The hypothesis that therapeutic drug monitoring of MMF may be advantageous when CsA is withdrawn is also being investigated in an ongoing study by Dr. J. de Fijter in Leiden, Netherlands.…”

Epithelial-to-Mesenchymal Transition Predicts Cyclosporine Nephrotoxicity in Renal Transplant Recipients

“…Patients were switched from CsA to tacrolimus if they experienced a steroid-resistant acute rejection episode. The main results from this trial were as follows: (1) at 1 year, although graft function was better preserved in the MMF group, the risk of BPAR was 13% higher (it is noteworthy that patients experiencing BPAR after CsA withdrawal more frequently showed borderline changes at M3 and had a lower exposure to MMF) 9 ; the chronic allograft damage index was equivalent in the two groups 13 ; and the incidence of focal or diffuse C4d deposits was significantly higher in the MMF group; and (2) at 2 years, graft function remained better in the MMF group, but persistent CsA exposure was not an independent risk factor for a decline in graft function.…”

“…Because acute rejection is known to trigger the occurrence of EMT in grafts, 10 and because in this trial biopsy-proven acute rejection (BPAR) was more frequent in the MMF group, 9 we wanted to rule out a possible confusing effect of BPAR on the change in the EMT score. We therefore performed a subgroup analysis excluding BPAR episodes (i.e., after excluding two patients from the CsA group and eight patients from the MMF group).…”

“…The study design has been reported elsewhere, 9 and the trial is registered in the Australian New Zealand Clinical Trial Registry (http://www.anzctr. org.au/ACTRN12610000070033.aspx).…”

“…To do this, we retrospectively analyzed the sequential graft biopsies collected during a randomized controlled trial performed in Lille, France, in the early 2000s in 108 patients who were exposed to CsA for the first 3 months and then divided them into two equal groups-one in which CsA was continued and mycophenolate mofetil (MMF) was withdrawn and one in which CsA was progressively withdrawn and MMF was continued. 9 Biopsies were taken after 3 and 12 months (M3 and M12). Our findings show that in patients showing early EMT in tubular cells, the withdrawal of CsA normalized the risk of the decline in graft function over time.…”