Impact of CYP3A5 genomic variances on clinical outcomes among African American kidney transplant recipients

Abstract

Little is known about the impact of CYP3A5 polymorphisms on transplantation outcomes among African American (AA) kidney transplant recipients (KTRs). To assess this issue, clinical outcomes were compared between AA CYP3A5*1 expressers and nonexpressers. This retrospective cohort study analyzed AA KTRs. Biopsy-proven acute rejection (BPAR), delayed graft function (DGF), glomerular filtration rate (GFR), infections, and tacrolimus dosing requirements were examined in 106 immunologically high-risk AA kidney transplant patients over a 2-year follow-up period. In CYP3A5*1 expressers compared to nonexpressers, the incidence of BPAR was significantly higher in the first 6 months (13% vs 0%; P = .016) compared to 24 months (13% vs 7%; P = .521). Tacrolimus total daily dose at first therapeutic level was significantly higher in CYP3A5*1 expressers (12 mg/day) compared to nonexpressers (8 mg/day; P < .001). Compared to CYP3A5*1 nonexpressers, DGF incidence was significantly higher among CYP3A5*1 expressers (27.6% vs 6.7%; P = .006). By contrast, median GFR was significantly higher in CYP3A5*1 expressers compared to nonexpressers (54.5 mL/min vs 50.0 mL/min; P = .003) at 24 months. The findings from this retrospective study suggest that AAs with CYP3A5*1 expression require 50% more tacrolimus and have an increased incidence of DGF and acute rejection.

Tacrolimus troughs and genetic determinants of metabolism in kidney transplant recipients: A comparison of four ancestry groups

“…46 In another study of 24 adult Native American kidney transplant recipients, CYP3A5*3 had a higher AF (0.94). 7 CYP3A5*3 is the most-studied CYP3A5 variant in association with tacrolimus and has been evaluated in Europeans, 18,21,[47][48][49][50][51][52] African Americans, 5,24,35,53 Asians, 52,[54][55][56][57][58][59][60] and Native Americans. Allele Frequency…”

“…2 Tacrolimus has high inter-individual pharmacokinetic variability. [4][5][6] Little is known about tacrolimus trough and dose requirements in other populations, although some data suggest that Native American transplant recipients require lower tacrolimus doses possibly due to decreased oral clearance, 7,8 others found that there were no difference between tacrolimus doses between European Americans and Native Americans. [4][5][6] Little is known about tacrolimus trough and dose requirements in other populations, although some data suggest that Native American transplant recipients require lower tacrolimus doses possibly due to decreased oral clearance, 7,8 others found that there were no difference between tacrolimus doses between European Americans and Native Americans.…”

“…3 It is well known that tacrolimus troughs and dose requirements vary between recipients of European and African ancestry, African Americans have significantly lower tacrolimus trough concentrations in comparison with European Americans and require higher tacrolimus doses to achieve similar trough concentrations. [4][5][6] Little is known about tacrolimus trough and dose requirements in other populations, although some data suggest that Native American transplant recipients require lower tacrolimus doses possibly due to decreased oral clearance, 7,8 others found that there were no difference between tacrolimus doses between European Americans and Native Americans. 9 Cytochromes P450 (CYP) 3A4 and 5 are the main drug metabolizing enzymes for tacrolimus and the genes encoding for these proteins contain important genetic variants.…”

Protocol‐based nurse coordinator management of ambulatory tacrolimus dosing in de novo renal transplant recipients—A single‐center experience with a large African American population

“…Metabolism of tacrolimus takes place by the CYP3A system . There are established differences in tacrolimus dosage requirements to achieve goal levels between African Americans (AAs) and non‐African Americans (non‐AAs) stemming from differences in CYP3A5 polymorphisms, as CYP3A5 polymorphisms have been shown to be more prevalent in AAs .…”

“…Metabolism of tacrolimus takes place by the CYP3A system . There are established differences in tacrolimus dosage requirements to achieve goal levels between African Americans (AAs) and non‐African Americans (non‐AAs) stemming from differences in CYP3A5 polymorphisms, as CYP3A5 polymorphisms have been shown to be more prevalent in AAs . These polymorphisms have caused differences in the pharmacotherapeutic consideration of tacrolimus dosing, as AAs presenting with this polymorphism tend to need more aggressive dosing to reach therapeutic levels .…”