Reduced Tacrolimus Trough Level Is Reflected by Estimated Glomerular Filtration Rate (eGFR) Changes in Stable Renal Transplantation Recipients: Results of the OPTIMUM Phase 3 Randomized Controlled Study

Sehoon Park, Yon Su Kim, Jungpyo Lee, Wooseong Huh, Chul Woo Yang, Young-Lim Kim, Yeong Hoon Kim, Joong Kyung Kim, Chang-Kwon Oh, Su-Kil Park, Sehoon Park, Yon Su Kim, Jungpyo Lee, Wooseong Huh, Chul Woo Yang, Young-Lim Kim, Yeong Hoon Kim, Joong Kyung Kim, Chang-Kwon Oh, Su-Kil Park

Abstract

BACKGROUND Minimizing the tacrolimus dosage in patients with stable allograft function needs further investigation. MATERIAL AND METHODS We performed an open-label, randomized, controlled study from 2010 to 2016 in 7 tertiary teaching hospitals in Korea and enrolled 345 kidney transplant recipients with a stable graft status. The study group received reduced-dose tacrolimus, 1080-1440 mg/day of enteric-coated mycophenolate sodium (EC-MPS), and corticosteroids. The control group received the standard tacrolimus dosage and 540-720 mg/day of EC-MPS with steroids. The primary endpoint was the mean estimated glomerular filtration rate (eGFR) and change in the eGFR at 12 months after randomization. RESULTS The mean tacrolimus trough level of the study group was 4.51±1.62 ng/mL, which was lower than that of the control group, at 6.75±2.82 ng/mL (P<0.001). The primary endpoint was better in the study group in terms of change in eGFR (P<0.001). The month 12 eGFRs were 73.6±28.4 and 68.3±18.1 mL/min/1.73 m² in the study and the control groups, respectively, but the difference did not reach statistical significance (P=0.07). The incidence of adverse events was similar between the study and the control groups. CONCLUSIONS Minimizing tacrolimus to a trough level below 5 ng/mL combined with conventional EC-MPS can be considered in patients with a steady follow-up, as it was associated with small benefits in the changes of the eGFR (Clinicaltrials.gov number: NCT01159080).

Conflict of interest statement

Conflicts of interest

None.

Figures

Figure 1
Figure 1
Study population. The flow diagram of the study population; MPS – mycophenolate sodium; FAS – full analysis set; PP – per protocol set.
Figure 2
Figure 2
Mean daily dosage of the study medications. Comparison of mean daily dosage of the study medications between the study and the control group. Left y-axis indicates the mean daily dosage of tacrolimus and steroid, the right y-axis shows the mean daily dosage of mycophenolate sodium.
Figure 3
Figure 3
Change of eGFR from baseline to 12 months after randomization. Both percent (%) and absolute (mL/min/1.73 m2) changes of eGFR at 12 months after randomization are shown. The y-axis indicates the mean change and the error bars show the standard error of the mean. The study group had better outcome in terms of eGFR change according to all the methods we tested; SEM – standard error of the mean.

References

    1. Pascual M, Theruvath T, Kawai T, et al. Strategies to improve long-term outcomes after renal transplantation. N Engl J Med. 2002;346:580–90.
    1. Chan L, Andres A, Bunnapradist S, et al. Renal function and NODM in de novo renal transplant recipients treated with standard and reduced levels of tacrolimus in combination with EC-MPS. J Transplant. 2012;2012:941640.
    1. Kamar N, Rostaing L, Cassuto E, et al. A multicenter, randomized trial of increased mycophenolic acid dose using enteric-coated mycophenolate sodium with reduced tacrolimus exposure in maintenance kidney transplant recipients. Clin Nephrol. 2012;77:126–36.
    1. Margreiter R. Efficacy and safety of tacrolimus compared with ciclosporin microemulsion in renal transplantation: A randomised multicentre study. Lancet. 2002;359:741–46.
    1. Burdmann EA, Andoh TF, Yu L, Bennett WM. Cyclosporine nephrotoxicity. Semin Nephrol. 2003;23:465–76.
    1. Nankivell BJ, Borrows RJ, Fung CL, et al. Calcineurin inhibitor nephrotoxicity: Longitudinal assessment by protocol histology. Transplantation. 2004;78:557–65.
    1. Hernandez D, Miquel R, Porrini E, et al. Randomized controlled study comparing reduced calcineurin inhibitors exposure versus standard cyclosporine-based immunosuppression. Transplantation. 2007;84:706–14.
    1. Moore J, Middleton L, Cockwell P, et al. Calcineurin inhibitor sparing with mycophenolate in kidney transplantation: A systematic review and meta-analysis. Transplantation. 2009;87:591–605.
    1. Sawinski D, Trofe-Clark J, Leas B, et al. Calcineurin inhibitor minimization, conversion, withdrawal, and avoidance strategies in renal transplantation: A systematic review and meta-analysis. Am J Transplant. 2016;16:2117–38.
    1. Weir MR, Ward MT, Blahut SA, et al. Long-term impact of discontinued or reduced calcineurin inhibitor in patients with chronic allograft nephropathy. Kidney Int. 2001;59:1567–73.
    1. Bolin P, Jr, Shihab FS, Mulloy L, et al. Optimizing tacrolimus therapy in the maintenance of renal allografts: 12-month results. Transplantation. 2008;86:88–95.
    1. Merville P, Berge F, Deminiere C, et al. Lower incidence of chronic allograft nephropathy at 1 year post-transplantation in patients treated with mycophenolate mofetil. Am J Transplant. 2004;4:1769–75.
    1. Placebo-controlled study of mycophenolate mofetil combined with cyclosporin and corticosteroids for prevention of acute rejection. European Mycophenolate Mofetil Cooperative Study Group. Lancet. 1995;345:1321–25.
    1. Land W, Vincenti F. Toxicity-sparing protocols using mycophenolate mofetil in renal transplantation. Transplantation. 2005;80:S221–34.
    1. Chan L, Mulgaonkar S, Walker R, et al. Patient-reported gastrointestinal symptom burden and health-related quality of life following conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium. Transplantation. 2006;81:1290–97.
    1. Behrend M. Adverse gastrointestinal effects of mycophenolate mofetil: Aetiology, incidence and management. Drug Saf. 2001;24:645–63.
    1. Budde K, Glander P, Kramer BK, et al. Conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium in maintenance renal transplant recipients receiving tacrolimus: Clinical, pharmacokinetic, and pharmacodynamic outcomes. Transplantation. 2007;83:417–24.
    1. Nankivell BJ, Gruenewald SM, Allen RD, Chapman JR. Predicting glomerular filtration rate after kidney transplantation. Transplantation. 1995;59:1683–89.
    1. Levey AS, Bosch JP, Lewis JB, et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: A new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999;130:461–70.
    1. Tang IY, Meier-Kriesche HU, Kaplan B. Immunosuppressive strategies to improve outcomes of kidney transplantation. Semin Nephrol. 2007;27:377–92.
    1. Ekberg H, Tedesco-Silva H, Demirbas A, et al. Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med. 2007;357:2562–75.
    1. Kramer BK, Montagnino G, Del Castillo D, et al. Efficacy and safety of tacrolimus compared with cyclosporin A microemulsion in renal transplantation: 2 year follow-up results. Nephrol Dial Transplant. 2005;20:968–73.
    1. Vincenti F, Jensik SC, Filo RS, et al. A long-term comparison of tacrolimus (FK506) and cyclosporine in kidney transplantation: Evidence for improved allograft survival at five years. Transplantation. 2002;73:775–82.
    1. Nankivell BJ, P’Ng CH, O’Connell PJ, Chapman JR. Calcineurin inhibitor nephrotoxicity through the lens of longitudinal histology: Comparison of cyclosporine and tacrolimus eras. Transplantation. 2016;100:1723–31.
    1. Ekberg H, Grinyo J, Nashan B, et al. Cyclosporine sparing with mycophenolate mofetil, daclizumab and corticosteroids in renal allograft recipients: The CAESAR study. Am J Transplant. 2007;7:560–70.
    1. Gaston RS, Kaplan B, Shah T, et al. Fixed- or controlled-dose mycophenolate mofetil with standard- or reduced-dose calcineurin inhibitors: The Opticept trial. Am J Transplant. 2009;9:1607–19.
    1. Pascual J, Bloom D, Torrealba J, et al. Calcineurin inhibitor withdrawal after renal transplantation with alemtuzumab: Clinical outcomes and effect on T-regulatory cells. Am J Transplant. 2008;8:1529–36.
    1. Smak Gregoor PJ, de Sevaux RG, Ligtenberg G, et al. Withdrawal of cyclosporine or prednisone six months after kidney transplantation in patients on triple drug therapy: A randomized, prospective, multicenter study. J Am Soc Nephrol. 2002;13:1365–73.
    1. Abramowicz D, Del Carmen Rial M, Vitko S, et al. Cyclosporine withdrawal from a mycophenolate mofetil-containing immunosuppressive regimen: Results of a five-year, prospective, randomized study. J Am Soc Nephrol. 2005;16:2234–40.
    1. Tonelli M, Hemmelgarn B, Gill JS, et al. Patient and allograft survival of Indo Asian and East Asian dialysis patients treated in Canada. Kidney Int. 2007;72:499–504.
    1. Rudge C, Johnson RJ, Fuggle SV, Forsythe JL. Renal transplantation in the United Kingdom for patients from ethnic minorities. Transplantation. 2007;83:1169–73.
    1. Pirsch J, Bekersky I, Vincenti F, et al. Coadministration of tacrolimus and mycophenolate mofetil in stable kidney transplant patients: Pharmacokinetics and tolerability. J Clin Pharmacol. 2000;40:527–32.

Source: PubMed

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