Tacrolimus dose, blood concentrations and acute nephrotoxicity, but not CYP3A5/ABCB1 genetics, are associated with allograft tacrolimus concentrations in renal transplant recipients

Abstract

Aims Long‐term use of the immunosuppressant tacrolimus is limited by nephrotoxicity. Following renal transplantation, the risk of nephrotoxicity may be determined more by allograft than by blood tacrolimus concentrations, and thus may be affected by donor CYP3A5 and ABCB1 genetics. Little is known regarding factors that determine tacrolimus intrarenal exposure. Methods This study investigated the relationship between trough blood (C0Blood) and allograft (CGraft) tacrolimus concentrations and tacrolimus dose, haematocrit, genetics, acute nephrotoxicity, rejection status, delayed graft function, and time post‐transplant. C0Blood and CGraft were quantified in 132 renal transplant recipients together with recipient and donor CYP3A5 (rs776746) and ABCB1 3435 (rs1045642) genotypes. Results C0Blood ranged from 2.6 to 52.3 ng/mL and CGraft from 33 to 828 pg/mg tissue. Adjusting for dose, recipients who were CYP3A5 expressors had lower C0Blood compared to nonexpressors, whilst delayed graft function was associated with higher C0Blood. Linear regression showed that the significant predictors of CGraft were C0Blood (point‐wise P = 7 × 10−10), dose (P = .004) acute nephrotoxicity (P = .002) and an interaction between C0Blood and acute tacrolimus nephrotoxicity (P = .0002), with an adjusted r2 = 0.35 and no contribution from donor or recipient CYP3A5 or ABCB1 genotype. The association between CGraft and acute nephrotoxicity depended on one very high CGraft (828 pg/mg tissue). Conclusions Recipient and donor CYP3A5 and ABCB1 3435C>T genotypes are not determinants of allograft tacrolimus exposure in kidney transplant recipients. However, tacrolimus dose and C0Blood were significant predictors of CGraft, and the relationship between C0Blood and CGraft appeared to differ in the presence or absence of acute nephrotoxicity.

Kidney and Liver Tissue Tacrolimus Concentrations in Adult Transplant Recipients—The Influence of the Whole Blood and Tissue Concentrations on Efficiency of Treatment during Immunosuppressive Therapy

“…In contrast to recently published results [27], we have observed no significant correlation between daily doses of tacrolimus and graft concentration (p = 0.457 and p = 0.424, respectively). Similarly, a weak correlation between C 0 blood and tissue concentration was displayed both in kidney and in liver organs (p = 0.151; p = 0.391).…”

“…By assessing the results obtained in this study with previous ones sparingly found in the literature, excluding cases of isolation from other matrices [21][22][23][24][25][26][27][28], it has to be stated that a low value of TAC concentrations in the tissue of transplanted organs may favor the risk of occurrence the acute rejection episodes. We are convinced that other matrices used in TAC concentration determination could be more complicated, for example, bile [29] or urine.…”

“…A similar concentration range was observed in the tissues of patients: 5-387 pg/mg in liver tissue of 146 patients, and the tissue TAC concentration is less than 30 pg/mg. It was a cut-off point to discriminate clinically significant cellular rejection [5]: 119-285 pg/mg in kidney biopsies of two patients, and TAC concentrations were measured over 16-300 days post-transplantation [10]; 43.7 pg/mg and 62.6 pg/mg in renal core biopsies in only two patients [28]; and 33-828 pg/mg in renal biopsies from 132 renal transplant recipients [27].…”

Case Report: Low Hematocrit Leading to Tacrolimus Toxicity

“…The ABCB1 CT c.3435 predicts reduced P-gp functionality at the graft level and thus could theoretically have participated in the intraparenchymal accumulation of tacrolimus (Hauser et al, 2005). Although still controversial in the literature, this variant has been associated with decreased renal function at 1, 3 and 6 months and 1 year after transplantation (p < 0.01) when the graft carries the CT or TT genotypes compared with CC (Tavira et al, 2015;Sallustio et al, 2021).…”

Monitoring Intra-cellular Tacrolimus Concentrations in Solid Organ Transplantation: Use of Peripheral Blood Mononuclear Cells and Graft Biopsy Tissue

“…Two studies ( Table 1A ) have recently investigated potential relationships between renal graft tacrolimus concentrations and clinical outcomes ( Zhang et al, 2020 ; Sallustio et al, 2021 ). In 52 renal transplant recipients there was no difference in renal tacrolimus concentrations between patients with or without histologically classified subclinical acute rejection at 3 months or 1 year post transplantation ( Zhang et al, 2020 ).…”