Comparison of the effects of standard vs low-dose prolonged-release tacrolimus with or without ACEi/ARB on the histology and function of renal allografts

• Published in: American journal of transplantation Vol. 19; no. 6; pp. 1730 - 1744
• Main Authors: Cockfield, Sandra M., Wilson, Sam, Campbell, Patricia M., Cantarovich, Marcelo, Gangji, Azim, Houde, Isabelle, Jevnikar, Anthony M., Keough-Ryan, Tammy M., Monroy-Cuadros, Felix-Mauricio, Nickerson, Peter W., Pâquet, Michel R., Ramesh Prasad, G.V., Senécal, Lynne, Shoker, Ahmed, Wolff, Jean-Luc, Howell, John, Schwartz, Jason J., Rush, David N.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.06.2019; Elsevier Limited; John Wiley and Sons Inc
• Subjects: Adult; Allografts; Angiotensin; Angiotensin II; Angiotensin II Type 1 Receptor Blockers - administration & dosage; Angiotensin-Converting Enzyme Inhibitors - administration & dosage; Antihypertensives; Atrophy; clinical research/practice; clinical trial; Delayed-Action Preparations; Dosage; Drug Therapy, Combination; Female; Fibrosis; Graft rejection; Graft Rejection - etiology; Graft Rejection - immunology; graft survival; Health risk assessment; Humans; immunosuppressant - calcineurin inhibitor: tacrolimus; immunosuppression/immune modulation; Immunosuppressive Agents - administration & dosage; Kidney - pathology; Kidney - physiopathology; Kidney transplantation; Kidney Transplantation - adverse effects; Kidney Transplantation - methods; kidney transplantation/nephrology; Kidney transplants; Lymphocytes T; Male; Middle Aged; organ transplantation in general; Original; ORIGINAL ARTICLES; patient survival; Polyomavirus Infections - etiology; Prognosis; Prospective Studies; Renal function; Renin; Renin-Angiotensin System - drug effects; Renin-Angiotensin System - physiology; Tacrolimus; Tacrolimus - administration & dosage; Virus Activation; STD; patient survival; organ transplantation in general; (O)AHT; RAS; clinical research/practice; graft survival; ITT; immunosuppressant - calcineurin inhibitor: tacrolimus; IF/TA (+i); RTR; SD; cPRA; DSA; ATIIR1; clinical trial; eGFR; (m)FAS; DGF; immunosuppression/immune modulation; kidney transplantation/nephrology; AMR; CI; ECD; MMF; TCMR/B; ARB; TEAE; TCMR; LOW; Tac; ACEi; CNI
• ISSN: 1600-6135; 1600-6143; 1600-6143
• DOI: 10.1111/ajt.15225

Targeting the renin-angiotensin system and optimizing tacrolimus exposure are both postulated to improve outcomes in renal transplant recipients (RTRs) by preventing interstitial fibrosis/tubular atrophy (IF/TA). In this multicenter, prospective, open-label controlled trial, adult de novo RTRs were randomized in a 2 × 2 design to low- vs standard-dose (LOW vs STD) prolonged-release tacrolimus and to angiotensin-converting enzyme inhibitors/angiotensin II receptor 1 blockers (ACEi/ARBs) vs other antihypertensive therapy (OAHT). There were 2 coprimary endpoints: the prevalence of IF/TA at month 6 and at month 24. IF/TA prevalence was similar for LOW vs STD tacrolimus at month 6 (36.8% vs 39.5%; P = .80) and ACEi/ARBs vs OAHT at month 24 (54.8% vs 58.2%; P = .33). IF/TA progression decreased significantly with LOW vs STD tacrolimus at month 24 (mean [SD] change, +0.42 [1.477] vs +1.10 [1.577]; P = .0039). Across the 4 treatment groups, LOW + ACEi/ARB patients exhibited the lowest mean IF/TA change and, compared with LOW + OAHT patients, experienced significantly delayed time to first T cell–mediated rejection. Renal function was stable from month 1 to month 24 in all treatment groups. No unexpected safety findings were detected. Coupled with LOW tacrolimus dosing, ACEi/ARBs appear to reduce IF/TA progression and delay rejection relative to reduced tacrolimus exposure without renin-angiotensin system blockade. ClinicalTrials.gov identifier: NCT00933231.