High tacrolimus intra-patient variability is associated with graft rejection, and de novo donor-specific antibodies occurrence after liver transplantation

Abstract

AIMTo investigate the role of tacrolimus intra-patient variability (IPV) in adult liver-transplant recipients.METHODSWe retrospectively assessed tacrolimus variability in a cohort of liver-transplant recipients and analyzed its effect on the occurrence of graft rejection and de novo donor-specific antibodies (dnDSAs), as well as graft survival during the first 2 years posttransplantation. Between 02/08 and 06/2015, 116 patients that received tacrolimus plus mycophenolate mofetil (with or without steroids) were included.RESULTSTwenty-two patients (18.5%) experienced at least one acute-rejection episode (BPAR). Predictive factors for a BPAR were a tacrolimus IPV of > 35% [OR = 3.07 95%CI (1.14-8.24), P = 0.03] or > 40% [OR = 4.16 (1.38-12.50), P = 0.01), and a tacrolimus trough level of < 5 ng/mL [OR=3.68 (1.3-10.4), P =0.014]. Thirteen patients (11.2%) developed at least one dnDSA during the follow-up. Tacrolimus IPV [coded as a continuous variable: OR = 1.1, 95%CI (1.0-1.12), P = 0.006] of > 35% [OR = 4.83, 95%CI (1.39-16.72), P = 0.01] and > 40% [OR = 9.73, 95%CI (2.65-35.76), P = 0.001] were identified as predictors to detect dnDSAs. IPV did not impact on patient- or graft-survival rates during the follow-up.CONCLUSIONTacrolimus-IPV could be a useful tool to identify patients with a greater risk of graft rejection and of developing a de novo DSA after liver transplantation

Late intra-patient tacrolimus trough level variability as a major problem in kidney transplantation: A Collaborative Transplant Study Report

“…parameters were used due to low incidence of graft loss in small collectives. 4,[10][11][12][13][14]17 With the help of the information obtained from 71 different transplant centers, we could demonstrate that the IPV of tacrolimus trough levels at posttransplant years 1, 2, and 3 is a strong predictor of kidney graft loss during the posttransplant years 4-6 ( Figure 4). Our findings from a large collective of 6638 deceased donor cases indicate that trough level fluctuations during the later phases of transplantation have a major influence on the hard outcome measure "graft loss."…”

“…In the majority of previous studies, the impact of tacrolimus IPV on kidney graft outcome was demonstrated with measurements performed during the early phase after transplantation and to demonstrate this effect, composite outcome parameters were used due to low incidence of graft loss in small collectives 4,[10][11][12][13][14]17. In the majority of previous studies, the impact of tacrolimus IPV on kidney graft outcome was demonstrated with measurements performed during the early phase after transplantation and to demonstrate this effect, composite outcome parameters were used due to low incidence of graft loss in small collectives 4,[10][11][12][13][14]17.…”

Impact of low tacrolimus exposure and high tacrolimus intra-patient variability on the development of de novo anti-HLA donor-specific antibodies in kidney transplant recipients

“…Kaneku et al analyzed factors associated with dnDSA formation in 749 liver transplant patients and they found that patients with low CNI predose concentrations (tacrolimus <3 ng/mL or CsA <75 ng/mL) were at increased risk of developing dnDSA (OR 2.66; 95% CI, 1.2-5.84; p = 0.015) [78]. More recently, Del Bello et al described that at a cutoff CV of >35% the odds ratio for developing dnDSA within the first 2 years posttransplantation was 4.83 (p = 0.01) and at a cutoff CV of >40% the odds ratio increased to 9.73 (p = 0.01) [79]. However, dnDSA and a high tacrolimus IPV seem to have a limited overall impact on graft and patient outcome after liver transplantation [80,81].…”

“…Wiebe et al reported a 2.7 fold higher incidence of dnDSA development in recipients treated with CsA versus those treated with tacrolimus [65]. Despite these findings, dnDSA is still commonly found in SOT patients treated with standard-dose tacrolimus [61,63,78,79,82]. It is likely that differences in induction therapy and overall immunosuppression regimen contribute to the individual and/or patient cohort risk profile for developing dnDSA.…”

Acute Cellular Rejection in Paediatric Liver Transplants: Does a Living Donor Ameliorate the Risk of Rejection in Our Patients? A Retrospective Review at Wits Donald Gordon Medical Centre, South Africa

“…The risk of ACR is thought to be highest in the early post-transplant period, and this risk declines over time with development of tolerance for the liver allograft. (10) In published studies, the incidence of ACR is reported between 7% (11) and 20%, (8,12) and even up to half of all recipients (3,4,13) although the time period over which 'acute rejection' can be diagnosed varies between studies, ranging between 3 (3,12,14) and 12 months. (11) The incidence of ACR of 22% in our cohort at 3 months is in keeping with extant literature, and on par with international standards.…”