Personalized immunosuppression after kidney transplantation

Abstract

With advances in immunosuppressive therapy, there have been significant improvements in acute rejection rates and short-term allograft survival in kidney transplant recipients.However, this success has not been translated into long-term benefits by the same magnitude. Optimization of immunosuppression is important to improve the clinical outcome of transplant recipients. It is important to note that each patient has unique attributes and immunosuppression management should not be a one-size-fits-all approach. Elderly transplant patients are less likely to develop acute rejection but more likely to die from infectious and cardiovascular causes than younger patients. For those with posttransplant cancers and BK polyomavirus-associated nephropathy, reduction of immunosuppression can increase the risk of rejection. Therapeutic drug monitoring (TDM) is routinely used for dosage adjustment of several immunosuppressive drugs. It has been hoped that pharmacogenetics can be used to complement TDM in optimizing drug exposure. Among the various drug-genotype pairs being investigated, tacrolimus and CYP3A5 gives the most promising results. Different studies have consistently shown that CYP3A5 expressers require a higher tacrolimus dose and take longer time to achieve target blood tacrolimus levels than nonexpressers. However, for pharmacogenetics to be widely used clinically, further trials are necessary to demonstrate the clinical benefits of genotypeguided dosing such as reduction of rejection and drug-related toxicities. The development of different biomarkers in recent years may help to achieve true personalized therapy in transplant patients.

Use of Pharmacogenetics to Optimize Immunosuppressant Therapy in Kidney-Transplanted Patients

“…Moreover, high cyclosporine blood levels were related to the presence of the CYP3A4*22 allele, ABCB1 2677 T/T and ABCB1 3435 T/T genotypes, as well as at ABCB1 1236TT-2677TT-3435TT haplotype ( Table 2 ). In accordance with our findings, a recent review by Cheung and Tang highlighted that CYP3A5 expressers needed a higher tacrolimus dose, while the presence of CYP3A4*22 was associated with a lower tacrolimus dose requirement, and the combined CYP3A4 and CYP3A5 genotype can have a major influence on the tacrolimus dose required to reach the target exposure in kidney transplant recipients [ 90 ]. However, the authors did not assess the influence of several important SNPs on genes involved in immunosuppressant’s pharmacokinetics (ABCB1, UGT1A9, UGT2B7, MRP2).…”

Age associations with tacrolimus and mycophenolic acid pharmacokinetics in stable Black and White kidney transplant recipients: Implications for health inequities

“…The increase in neurologic AE may contribute to increased morbidity post-transplant, which impacts the quality of life in the elderly. [10][11][12] In regard to MPA pharmacokinetic alterations over age, reduced EHR was found in the elderly compared to the younger counterparts that was quantitated by the increased ratio of the metabolite MPAG AUC 0-12h to the active moiety, MPA AUC 0-12h , and further substantiated by the reduced ratio of MPA AUC 0-6h to MPA AUC 0-12h . Minimal pharmacologic investigations into the age-associated changes in enterohepatic circulation and glucuronidation have been published and the general overviews summarize that no important changes occur with phase II metabolism over adult ages.…”

“…[19][20][21][22] Therefore, age-adjusted comparisons of immunosuppressive pharmacokinetic and AE responses in stable KTRs can address this knowledge gap and provide key insight into development of customized immunosuppression and reduce health disparities post-transplant. 10,23 The primary objective for this report was to conduct a secondary analysis of TAC and MPA pharmacokinetics in young, middle aged, and elderly stable Black and White KTRs from a published prospective, observational 12-h pharmacokinetic study of these immunosuppressives that investigated the impact of race and sex. 24,25 For the primary objective of this report, the pharmacokinetic parameters determined for TAC and MPA were AUC 0-12h , AUC 0-4h , 0-h trough (C 0h ), maximum concentration (C max ), oral clearance (CL) with body mass index (BMI)adjusted CL (CL/BMI) and inclusion of MPA AUC 6-12h , ratio of MPA AUC 6-12h to MPA AUC 0-12h and ratio of the metabolite, MPA glucuronide (MPAG) AUC 0-12h to MPA AUC 0-12h .…”

“…7 However, greater than 50% of mortality in older recipients is associated with cardiovascular disease, infections and malignancies, possibly related to empiric prescribing of immunosuppressive regimens that lacks individualization and age-adjusted dosing recommendations. [8][9][10] Increased age was found to be an independent risk for chronic allograft failure suggesting the need for age-adjusted dosing regimens during minimization of calcineurin inhibitors or glucocorticoids and to avoid drug-associated nephrotoxicity. 7,8 In addition, overimmunosuppression and severe adverse effects (AEs) commonly result in elderly recipients receiving medications with no age adjustment for declining hepatic and/ or renal function.…”

“…Elderly kidney transplant recipients (KTRs), who were rarely transplanted 30 years ago, may receive older, less functional organs but have improved long‐term survival compared to age‐matched counterparts on dialysis 7 . However, greater than 50% of mortality in older recipients is associated with cardiovascular disease, infections and malignancies, possibly related to empiric prescribing of immunosuppressive regimens that lacks individualization and age‐adjusted dosing recommendations 8–10 . Increased age was found to be an independent risk for chronic allograft failure suggesting the need for age‐adjusted dosing regimens during minimization of calcineurin inhibitors or glucocorticoids and to avoid drug‐associated nephrotoxicity 7,8 .…”