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

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.

Figure 1

Design of FKC‐014 (A) and distribution of patients across intervention and treatment groups (B). At randomization, patients were assigned to 1 of 4 possible treatments (LOW + ACEi/ARB; LOW + OAHT; STD + ACEi/ARB; and STD + OAHT), corresponding to 2 tacrolimus interventions (LOW vs STD) and 2 AHT interventions (ACEi/ARB vs OAHT). Patient numbers in (B) correspond to the FAS/SAF and mFAS6/24 populations. ACEi, angiotensin‐converting enzyme inhibitor; ARB, angiotensin II receptor 1 blocker; FAS, full analysis set; mFAS, modified full analysis set; LOW, low dose; OAHT, other antihypertensive treatment; SAF, safety set; STD, standard dose

Figure 2

Patient disposition in FKC‐014. *Multiple reasons could be given for early discontinuation. mFAS6, patients have evaluable biopsies at implant and month 6; mFAS24, patients have evaluable biopsies at implant and month 24. ITT, intent‐to‐treat set; SAF, safety set; (m)FAS, (modified) full analysis set

Figure 3

Least‐squares mean (±standard error) tacrolimus trough concentrations by time for patients randomized to standard‐dose (STD) vs low‐dose (LOW) tacrolimus (Tac). Light and dark purple shading indicate protocol‐specified target trough concentrations for patients randomized to LOW Tac and STD Tac. After month 6, no target was specified. Trough concentrations were estimated from a 4‐period mixed model

Figure 4

Prevalence of IF/TA at month 6 and month 24 (A) and progression of IF/TA from month 6 to month 24 by intervention and treatment group (B). Brackets indicate comparisons specified as coprimary or as key secondary efficacy endpoints. For treatment group comparisons, statistical significance was tested relative to the LOW + OAHT group and the STD + ACEi/ARB group. No test was performed comparing LOW + ACEi/ARB with STD + OAHT. Data in B show mean change in IF/TA from month 6 to month 24. ns, nonsignificant (P ≥ .05); ACEi, angiotensin‐converting enzyme inhibitor; AHT, antihypertensive treatment; ARB, angiotensin II receptor 1 blocker; FAS, full analysis set; IF/TA, interstitial fibrosis/tubular atrophy; LOW, low dose; OAHT, other antihypertensive treatment; SD, standard deviation; STD, standard dose; Tac, prolonged‐release tacrolimus

Figure 5

Change from baseline in IF/TA score by treatment group by month 6 and month 24. Statistical significance was tested relative to the LOW + OAHT group and the STD + ACEi/ARB group. No test was performed comparing LOW + ACEi/ARB with STD + OAHT. Data displayed show mean change in IF/TA score from month 0 to month 6 and month 24. ACEi, angiotensin‐converting enzyme inhibitor; AHT, antihypertensive treatment; ARB, angiotensin II receptor 1 blocker; IF/TA, interstitial fibrosis/tubular atrophy; LOW, low dose; OAHT, other antihypertensive treatment; SD, standard deviation; STD, standard dose

Figure 6

Prevalence of interstitial fibrosis/tubular atrophy with inflammation at month 6 and month 24

Figure 7

Time to first TCMR of Banff grade 1A or higher (Kaplan‐Meier estimation). Data derive from protocol and for‐cause biopsies, with protocol biopsies mandated at months 6 and 24

Figure 8

Prevalence of TCMR/B at months 6 and 24. Statistical significance was tested relative to the LOW + OAHT group and the STD + ACEi/ARB group. No test was performed comparing LOW + ACEi/ARB with STD + OAHT. ACEi, angiotensin‐converting enzyme inhibitor; AHT, antihypertensive treatment; ARB, angiotensin II receptor 1 blocker; LOW, low dose; OAHT, other antihypertensive treatment; STD, standard dose; TCMR/B, T cell–mediated rejection including borderline changes

Figure 9

Renal function by estimated glomerular filtration rate (eGFR; Chronic Kidney Disease Epidemiology Collaboration) over time by treatment group

Figure 10

Mean systolic blood pressure (A) and diastolic blood pressure (B) over time by treatment group. ACEi, angiotensin‐converting enzyme inhibitor; ARB, angiotensin II receptor 1 blocker; LOW, low dose; OAHT, other antihypertensive treatment; STD, standard dose