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

Abstract

Abbreviations: CI, confidence interval; CTS, Collaborative Transplant Study; DSA, donorspecific HLA antibodies; HR, hazard ratio; IPV, intra-patient variability.Intra-patient variability (IPV) of tacrolimus trough level has been associated with poor outcome after kidney transplantation. These findings were derived from singlecenter analyses and restricted mainly to measurements early after transplantation.We analyzed in a multicenter effort whether high IPV of tacrolimus levels at posttransplant years 1, 2, and 3 was associated with impaired clinical outcome. More than 6600 patients who received a deceased donor kidney transplant during 2000-2014 and had a functioning graft for >3 years were studied. Graft survival was significantly impaired with increasing IPV (P < 0.001). As compared to patients with a low IPV of <30%, the risk of graft loss during years 4-6 increased 32% in patients with an IPV of 30% to 44% and 66% in patients with an IPV of ≥45% (P = 0.002 and P < 0.001).About one-third of patients showed an IPV of ≥30% with substantially impaired outcome. Even in patients with good outcome during the first 3 posttransplant years, a high IPV was associated with inferior graft survival. Our data indicate that a fluctuating tacrolimus trough level at years 1, 2, and 3 posttransplant is a major problem in kidney transplantation. K E Y W O R D Sclinical research/practice, immunosuppressant -calcineurin inhibitor: tacrolimus, kidney (allograft) function/dysfunction, kidney transplantation/nephrology, pharmacokinetics/ pharmacodynamics

Evidence for the alloimmune basis and prognostic significance of Borderline T cell–mediated rejection

“…48 In the current study tacrolimus coefficient of variation was a significant independent correlate of any Banff Borderline or greater TCMR (P = .018) after adjusting for other covariates confirming previous work and extending it to Banff Borderline TCMR. 48,[50][51][52][53] Younger recipient age has been correlated with the risk of TCMR, dnDSA, and ABMR in the past independent of donor age and nonadherence. [16][17]54,55 Age-dependent metabolic and immunosuppressive effects of tacrolimus have been demonstrated in murine and human CD4 + T cells.…”

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

“…Using a better statistical framework, Sapir Pichhadze et al also demonstrated that a higher standard deviation in tacrolimus levels resulted in a higher hazard ratio for a composite endpoint that included late allograft rejection, transplant glomerulopathy or total graft loss [29]. Several other studies have confirmed that a high IPV is associated with poor long-term outcomes after kidney transplantation, late allograft rejection, and reduced renal allograft survival [30][31][32][33]. In a recent study by Sablik et al it was shown that a high tacrolimus IPV was not associated with the incidence of chronic active ABMR.…”

Efficacy and safety of tacrolimus in de novo pediatric transplant recipients randomized to receive immediate‐ or prolonged‐release tacrolimus

“…High IPV in tacrolimus trough levels has been linked to adverse transplant outcomes, and is a significant risk factor for poor long‐term graft survival in pediatric solid organ transplant patients . A study of more than 6600 kidney transplant patients with a functioning graft at least 3 years post‐transplantation also showed that graft survival was significantly reduced with higher IPV . Impact of IPV on graft survival was particularly strong in adolescents 12‐17 years of age.…”