Pharmacogenetics and drug-induced nephrotoxicity in renal transplant recipients

Abstract

Introduction: The advent of calcineurin inhibitors (CNIs), as the leading immunosuppressive agents, not only has revolutionized the transplant medicine but also made it a better therapeutic intervention that guarantees the graft outcome and improves the survival rate of patients. However, genetic polymorphism(s) in the CNIs metabolic substrates genes (CYP3A4, CYP3A5) and their transporter such as P-glycoprotein (P-gp) can influence the CNIs metabolism and elicit some possible systemic and intra-renal exposures to drugs and/or metabolites with differential risk of nephrotoxicity, jeopardizing the transplantation. Methods: In the current study, we review the recent literatures to evaluate the effects of genetic polymorphisms of the genes involved in development of chronic calcineurin nephrotoxicity and progression of chronic allograft dysfunction (CAD) providing an extensive overview on their clinical impacts. Results: Identifying the inherited genetic basis for the inter-individual differences in terms of drug responses and determining the risk of calcineurin-mediated nephrotoxicity and CAD allow optimized personalized administration of these agents whith minimal adverse effects. Conclusion: Pharmacogenetics characteristics of CYP isoforms (CYP3A) and efflux transporters (P-gp and MRP), involved in metabolism and extracellular transportation of the immunosuppressive CNIs, can be of pivotal information in the pharmacotherapy of the renal-transplant recipients. Such information can be used for the successes clinical interventions to attain an improved drug administration strategy with reduced rates of rejection and toxicity.

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

“…A multitude of genetic and environmental factors may enhance the susceptibility of patients to develop tacrolimus‐induced nephrotoxicity and ultimately affect renal function. Furthermore, there is growing evidence that genetic polymorphisms in CYP3A5, CCR5, and efflux transporters (ie, P‐glycoprotein), may impact the tissue concentrations of tacrolimus and tacrolimus metabolites . For example, compared with control specimens, P‐glycoprotein expression was less pronounced in renal biopsy specimens with CNI‐induced nephrotoxicity .…”

Influence of ABCC2, CYP2C8, and CYP2J2 Polymorphisms on Tacrolimus and Mycophenolate Sodium–Based Treatment in Brazilian Kidney Transplant Recipients

“…The frangible equilibrium between the risks and benefits of immune system suppression makes the management of immunosuppressive therapy a challenging issue . Patient monitoring and drug level measurements are used to optimize efficacy and prevent underimmunosuppression or overimmunosuppression …”

Computerized techniques pave the way for drug-drug interaction prediction and interpretation

“…For instance, we are now aware of existence of direct relations between pharmacogenetics/pharmacogenomics and drug-induced toxicities such as nephrotoxicity in renal transplant recipients. 46 Therefore, to attain rational treatment modalities in various diseases, all possible detrimental DDIs/ADRs, drug-protein interactions, pharmacogenetics and drug metabolite interactions must be taken into consideration. However, from translational and personalized medicine viewpoints, effective standard protocols need to be codified and applied for these matters.…”