311.3: A 5-Year Prospective, Randomized, Open-Label Study of Standard Versus Low-Dose Prolonged-Release Tacrolimus With Or Without ACEi/ARB in Kidney Transplantation

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.