Abstract
BackgroundChronic active antibody mediated rejection (c-aABMR) is a major cause of long-term kidney allograft loss. It is hypothesized that frequent sub-therapeutic exposure to immunosuppressive drugs, in particular tacrolimus (Tac), is a risk factor for the development of c-aABMR. The intra-patient variability (IPV) in Tac exposure may serve as a substitute biomarker for underexposure and/or non-adherence. In this study, the association between Tac IPV and the development of c-aABMR was investigated.MethodsWe retrospectively included 59 patients diagnosed with c-aABMR and compared them to 189 control patients matched for age, year of transplantation and type of kidney donor. The Tac IPV was calculated from pre-dose tacrolimus concentrations measured over a 3 year period preceding the diagnosis of c-aABMR. The mean Tac predose concentrations (C0), Tac IPV, renal allograft function and graft survival were compared between the groups.ResultsTac IPV was 24.4% for the cases versus 23.6% for the controls (p = 0.47). The mean Tac C0 was comparable for the cases (5.8 ng/mL) and control patients (6.1 ng/mL, p = 0.08). Only in the c-aABMR group a significant decline in both mean Tac C0 and allograft function over the timespan of 3 years was observed (p = 0.03 and p<0.001). Additionally, in the group of c-aABMR patients a high IPV was associated with inferior graft survival (p = 0.03).ConclusionsA high Tac IPV per se does not predispose to the development of c-aABMR but is associated with inferior graft survival once c-aABMR is diagnosed.
Highlights
Despite a significant improvement in short-term kidney allograft survival in the past decade, long-term kidney allograft survival has remained relatively unchanged[1]
It is hypothesized that frequent sub-therapeutic exposure to immunosuppressive drugs, in particular tacrolimus (Tac), is a risk factor for the development of Chronic active antibody mediated rejection (c-aABMR)
In the group of c-aABMR patients a high intra-patient variability (IPV) was associated with inferior graft survival (p = 0.03)
Summary
Despite a significant improvement in short-term kidney allograft survival in the past decade, long-term kidney allograft survival has remained relatively unchanged[1]. Patients with more variability in Tac exposure were more likely to develop donor-specific anti-HLA antibodies, lose their grafts and develop chronic histological lesions[3, 11,12,13,14,15,16,17]. In these studies, allograft failure was often defined as a composite endpoint which included the diagnosis of c-aABMR[3, 6, 11, 12, 15, 18]. The association between Tac IPV and the development of c-aABMR was investigated.
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