Reduction of Extended-Release Tacrolimus Dose in Low-Immunological-Risk Kidney Transplant Recipients Increases Risk of Rejection and Appearance of Donor-Specific Antibodies: A Randomized Study

Abstract

The aim of this study (ClinicalTrials.gov, NCT01744470) was to determine the efficacy and safety of two different doses of extended-release tacrolimus (TacER) in kidney transplant recipients (KTRs) between 4 and 12 mo after transplantation. Stable steroid-free KTRs were randomized (1:1) after 4 mo: Group A had a 50% reduction in TacER dose with a targeted TacER trough level (C ) >3 μg/L; group B had no change in TacER dose (TacER C 7-12 μg/L). The primary outcome was estimated GFR at 1 year. Of 300 patients, the intent-to-treat analysis included 186 patients (group A, n = 87; group B, n = 99). TacER C was lower in group A than in group B at 6 mo (4.1 ± 2.7 vs. 6.7 ± 3.9 μg/L, p < 0.0001) and 12 mo (5.6 ± 2.0 vs. 7.4 ± 2.1 μg/L, p < 0.0001). Estimated GFR was similar in both groups at 12 mo (group A, 56.0 ± 17.5 mL/min per 1.73 m²; group B, 56.0 ± 22.1 mL/min per 1.73 m²). More rejection episodes occurred in group A than group B (11 vs. 3; p = 0.016). At 1 year, subclinical inflammation occurred more frequently in group A than group B (inflammation score [i] >0: 21.4% vs. 8.8%, p = 0.047; tubulitis score [t] >0: 19.6% vs. 8.7%, p = 0.076; i + t: 1.14 ± 1.21 vs. 0.72 ± 1.01, p = 0.038). Anti-HLA donor-specific antibodies appeared only in group A (6 vs. 0 patients, p = 0.008). TacER C should be maintained >7 μg/L during the first year after transplantation in low-immunological-risk, steroid-free KTRs receiving a moderate dose of mycophenolic acid.

Once‐daily vs twice‐daily tacrolimus for de novo living kidney transplantation patients including ABO/HLA compatible and incompatible: A randomized trial

“…Although it was not a significant difference, the TAC‐QD group had a considerably higher BPAR rate (HR: 1.87) and a relatively lower trough level in the early period than the TAC‐BID group (Figures and ). This is consistent with other studies that investigated optimal TAC exposure …”

Persistence of de novo donor‐specific HLA‐antibodies after lung transplantation: A potential marker of decreased patient survival

“…It is possible that insufficient transient drug levels of the calcineurin inhibitor tacrolimus may pave the way for the induction of DSA. A possible correlation of low tacrolimus levels with the development of DSA was recently shown in patients after kidney transplantation . That raises the question of how to handle patients with intolerance to tacrolimus early after transplantation.…”

Lower tacrolimus exposure and time in therapeutic range increase the risk of de novo donor-specific antibodies in the first year of kidney transplantation

“…In the CTOT-09 study, 14 of 21 immunologically low risk patients were randomized to TAC withdrawal before the study was terminated due to high rates of acute rejection and 5 patients developing dnDSA (30). More recently, Gatault et al randomized 186 immunologically low risk but steroid-free kidney transplant recipients on extended-release TAC and mycophenolate to two different TAC doses between months 4 and 12, with one group receiving a 50% reduction in TAC with a target C 0 of > 3 ng/ml compared to a target C 0 of 7 – 12 ng/ml (31). At 12 months, 6 of 87 patients in the lower dose TAC group (mean TAC C 0 5.6 ± 2.0 ng/ml) had developed dnDSA compared to 0 of 99 patients in the higher dose TAC group (mean TAC C 0 7.4 ± 2.1).…”