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

Am J Transplant. 2019 Jun;19(6):1730-1744. doi: 10.1111/ajt.15225. Epub 2019 Feb 1.

Abstract

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.

Keywords: clinical research/practice; clinical trial; graft survival; immunosuppressant - calcineurin inhibitor: tacrolimus; immunosuppression/immune modulation; kidney transplantation/nephrology; organ transplantation in general; patient survival.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Allografts
  • Angiotensin II Type 1 Receptor Blockers / administration & dosage*
  • Angiotensin-Converting Enzyme Inhibitors / administration & dosage*
  • Atrophy
  • Delayed-Action Preparations
  • Drug Therapy, Combination
  • Female
  • Fibrosis
  • Graft Rejection / etiology
  • Graft Rejection / immunology
  • Humans
  • Immunosuppressive Agents / administration & dosage
  • Kidney / pathology
  • Kidney / physiopathology
  • Kidney Transplantation / adverse effects
  • Kidney Transplantation / methods*
  • Male
  • Middle Aged
  • Polyomavirus Infections / etiology
  • Prognosis
  • Prospective Studies
  • Renin-Angiotensin System / drug effects
  • Renin-Angiotensin System / physiology
  • Tacrolimus / administration & dosage*
  • Virus Activation

Substances

  • Angiotensin II Type 1 Receptor Blockers
  • Angiotensin-Converting Enzyme Inhibitors
  • Delayed-Action Preparations
  • Immunosuppressive Agents
  • Tacrolimus

Associated data

  • ClinicalTrials.gov/NCT00933231