A 5-year prospective, randomized, open-label study of standard versus low-dose prolonged-release tacrolimus with or without ACEi/ARB in kidney transplantation
Sandra M. Cockfield1, Patricia M. Campbell2, Marcelo Cantarovich3, Azim Gangji4, Ahmed Shoker5, Anthony M. Jevnikar6, Felix-Mauricio Monroy-Cuadros7, Peter W. Nickerson8, Michel R. Pâquet9, G. V. Ramesh Prasad10, Lynne Senécal11, Jason J. Schwartz12, Jean-Luc Wolff13, David Rush14.
1Division of Nephrology, University of Alberta, Edmonton, AB, Canada; 2Department of Laboratory Medicine and Pathology, University of Alberta Hospitals, Edmonton, AB, Canada; 3Division of Nephrology, Department of Medicine, McGill University Health Centre, Montréal, QC, Canada; 4Department of Medicine, St Joseph’s Healthcare Hamilton, Hamilton, ON, Canada; 5Department of Transplantation, University of Saskatchewan, Saskatoon, SK, Canada; 6Department of Internal Medicine, London Health Sciences Centre, London, ON, Canada; 7Division of Transplant Surgery, Foothills Medical Centre, Calgary, AB, Canada; 8Department of Internal Medicine and Immunology, Health Sciences Centre, Winnipeg, MB, Canada; 9Division of Nephrology, Hôpital Notre-Dame du CHUM, Montréal, QC, Canada; 10Division of Nephrology, St Michael’s Hospital, Toronto, ON, Canada; 11Department of Medicine, Hôpital Maisonneuve-Rosemont, Montréal, QC, Canada; 12Medical Affairs, Astellas Pharma Global Development, Northbrook, IL, United States; 13Division of Nephrology, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, Canada; 14Department of Medicine, Health Sciences Centre, Winnipeg, MB, Canada
Introduction: Optimizing tacrolimus (TAC) exposure and/or using angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARB) may modulate inflammation (i) as well as interstitial fibrosis and tubular atrophy (IFTA) after kidney transplant (KTx). Two-year data from a study in KTx patients receiving prolonged-release TAC coupled with either ACEi/ARB or other antihypertensives (OAHT) showed that low-dose TAC coupled with ACEi/ARB was associated with less IFTA severity and progression, less IFTA + i, and delayed onset of clinical rejection compared with low-dose TAC without ACEi/ARB (Cockfield et al. Am J Transplant 2019;19:1730–44). We now report 5-year results from this study.
Methods: This was a Canadian multicenter, prospective, open-label, controlled study in adult de novo KTx recipients randomized in a 2x2 design to standard dose (0.15–0.20 mg/kg) or low dose (LOW; 0.05–0.15 mg/kg) prolonged-release TAC combined with either ACEi/ARB or OAHT. All patients received basiliximab induction, mycophenolate mofetil and prednisone. Protocol biopsies were taken at implantation, 6 and 24 months. Five-year data include patient and graft survival, renal function, proteinuria, blood pressure and the incidence of Class II de novo donor-specific antibody (dnDSA).
Results: Overall, 281 patients were randomized. Between 3 and 5 years, mean TAC trough levels were ~6 ng/mL. Patient survival at 5 years was 95.7% and comparable between groups (94.2–97.2% across groups). Overall graft survival was 94.3% (89.7% in the LOW+OAHT group vs 94.4–97.1% in the other groups). Graft function, blood pressure, and proteinuria were similar in all groups. At 5 years, class II dnDSA incidence was 13.2% in the LOW+OAHT group vs 5.6–7.2% in other groups. There were no unexpected safety findings observed at 5 years.
Conclusion: KTx patients receiving low-dose prolonged-release TAC combined with ACEi/ARB have comparable outcomes to those receiving standard doses of prolonged-release TAC with or without ACEi/ARB, while treatment with low-dose prolonged release TAC without ACEi/ARB may be associated with worse outcomes.
This study was sponsored by Astellas Pharma Inc. Editorial support was provided by Cello Health MedErgy, funded by Astellas Pharma Inc.
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