Tacrolimus Trough Concentration Variability and Disparities in African American Kidney Transplantation

Abstract

Background Low tacrolimus concentrations have been associated with higher risk of acute rejection, particularly within African-American (AA) kidney transplant recipients; little is known about intrapatient tacrolimus variabilities impact on racial disparities. Methods Ten year, single-center, longitudinal cohort study of kidney recipients. Intrapatient tacrolimus variability was assessed using the coefficient of variation (CV) measured between 1 month posttransplant and the clinical event, with a comparable period assessed in those without events. Pediatrics, nontacrolimus/mycophenolate regimens and nonrenal transplants were excluded. Multivariable Cox regression models were used to analyze data. Results 1411 recipients were included (54.4% AA) with 39 521 concentrations utilized to assess intrapatient tacrolimus CV. Overall, intrapatient tacrolimus CV was higher in AAs vs non-AAs (39.9±19.8 % vs. 34.8±15.8% p<0.001). Tacrolimus variability was a significant risk factor for deleterious clinical outcomes. A 10% increase in tacrolimus CV augmented the risk of acute rejection by 20% (aHR 1.20, 1.13–1.28; p<0.001) and the risk of graft loss by 30% (aHR 1.30, 1.23–1.37; p<0.001), with significant effect modification by race for acute rejection, but not graft loss. High tacrolimus variability (CV >40%) was a significant explanatory variable for disparities in AAs; the crude relative risk of acute rejection in AAs was reduced by 46% when including tacrolimus variability in modeling and reduced by 40% for graft loss. Conclusions These data demonstrate that intrapatient tacrolimus variability is strongly associated with acute rejection in AAs and graft loss in all patients. Tacrolimus variability is a significant explanatory variable for disparities in AA recipients.

Tacrolimus trough and dose intra‐patient variability and CYP3A5 genotype: Effects on acute rejection and graft failure in European American and African American kidney transplant recipients

“…In comparison, our study evaluated a larger cohort and focused on early TAC troughs and doses. A more recent study by Taber et al also included earlier intra‐patient TAC trough variability starting at one month prost‐transplant in a larger cohort and showed that trough variability was higher in AA (CV 39.9%) compared to non‐AA recipients (CV 34.8%), which is consistent with our findings.…”

“…Similar studies showed association between high intra‐patient TAC trough variability and acute rejection, decline in glomerular filtration rate, graft loss, or composites thereof . A study by Taber et al of TAC troughs beginning at 1 month post‐transplant showed that high trough variability was associated with a higher risk of acute rejection and graft loss. To our knowledge, no study has previously investigated the impact of intra‐patient variability in TAC dose on kidney transplant outcomes.…”

“…Studies on the impact of TAC trough intra‐patient variability (mostly obtained in the first year post‐transplant) have not been consistent, but generally point toward worse outcomes at higher levels of variability . Older studies showed that intra‐patient variability in cyclosporine exposure and trough concentration was associated with poorer outcomes .…”

Urinary microbiome associated with chronic allograft dysfunction in kidney transplant recipients

“…Both optimizing choice of calcineurin inhibitor and therapeutic serum drug level have been associated with decreasing rates of acute rejection . With respect to ancestry, race/ethnicity impacts CYP enzymatic expression, tacrolimus dose requirements, and rates of acute rejection that disproportionately affect African‐Americans . Rates of kidney allograft survival in African‐American recipients are lower than in their Caucasian counterparts by more than 5% at 5 years (OPTN data, 2008‐2015).…”

The Advantages and Challenges of Diversity in Pharmacogenomics: Can Minority Populations Bring Us Closer to Implementation?

“…This difference in allele frequency results in a functional Cytochrome P450 3A5 isozyme (CYP3A5) enzyme in a majority of African Americans, while most Europeans do not have a functional enzyme. A recent study of tacrolimus dosing in 50 African Americans showed that the CYP3A5*1 allele is associated with normal function (also referred to as expressers), subtherapeutic concentrations, and higher dose requirements for tacrolimus compared with nonexpressers, i.e., patients with a CYP3A5*3/*3 diplotype …”