Limits...
Pharmacogenetics and drug-induced nephrotoxicity in renal transplant recipients.

Zununi Vahed S, Ardalan M, Samadi N, Omidi Y - Bioimpacts (2015)

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Research Center for Pharmaceutical Nanotechnology, School of Advanced Biomedical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran ; Chronic Kidney Disease Research Center, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran ; Research Center for Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.

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.

No MeSH data available.


Related in: MedlinePlus

© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4401167&req=5

Mentions: A cascade of events have been shown to impose somewhat implications in the development of chronic CsA nephrotoxicity, including (a) stimulation of inflammatory mediators, (b) an elevation in endothelin, thromboxane and angiotensin II, (c) a decrease in prostacyclin and nitric oxid, (d) an upregulation of TGF-β1, (e) enhanced immunogenicity and (f) inappropriate apoptosis.15 Further, CsA was reported to induce an imbalance in the vasodilator/vasoconstrictor ratio leading to a minimized generation of vasodilators (prostaglandins and nitric oxide) and maximized liberation of vasoconstrictors (endothelin and thromboxane), which ultimately can enhance the renal vasoconstriction.16 In addition, CsA leads to the activation of renin–angiotensin system (RAS),17 whose functionality promotes the renal interstitial fibrosis and the chronic CNI nephrotoxicity directly through (a) stimulation of tubular transport, (b) possible activation of pro-inflammatory phenomena, (c) release of aldosterone, and (d) augmented activity of profibrogenic and growth stimulatory functions. These effects are mediated through angiotensin receptors and also the induction of TGF-β.18 Further, angiotensin II-induced aldosterone secretion participates in the development of IF/TA through increased renal vasoconstriction, TGF-β expression and apoptosis ( Fig. 1). Interstitial fibrosis in CsA nephropathy is also associated with the infiltration of macrophages as well as the expression of osteopontin and TGF-β in the tubulointerstitium,19 which seem to be caused by angiotensin II-dependent and independent mechanisms.20 Furthermore, it should be pinpointed that the CNIs may increase the hypoxia in the kidney.21 Local hypoxia or ischemia of the tubulointerstitial compartment causes the formation of free radicals or reactive oxygen species (ROS) that leads to apoptosis and tubular interstitial fibrosis.22 The inhibition of calcineurin may directly activate the apoptosis-related genes23 and/or augment the apoptosis phenomenon in the tubular and interstitial cells, resulting in tubular atrophy to some extend.24


Pharmacogenetics and drug-induced nephrotoxicity in renal transplant recipients.

Zununi Vahed S, Ardalan M, Samadi N, Omidi Y - Bioimpacts (2015)

© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4401167&req=5

Mentions: A cascade of events have been shown to impose somewhat implications in the development of chronic CsA nephrotoxicity, including (a) stimulation of inflammatory mediators, (b) an elevation in endothelin, thromboxane and angiotensin II, (c) a decrease in prostacyclin and nitric oxid, (d) an upregulation of TGF-β1, (e) enhanced immunogenicity and (f) inappropriate apoptosis.15 Further, CsA was reported to induce an imbalance in the vasodilator/vasoconstrictor ratio leading to a minimized generation of vasodilators (prostaglandins and nitric oxide) and maximized liberation of vasoconstrictors (endothelin and thromboxane), which ultimately can enhance the renal vasoconstriction.16 In addition, CsA leads to the activation of renin–angiotensin system (RAS),17 whose functionality promotes the renal interstitial fibrosis and the chronic CNI nephrotoxicity directly through (a) stimulation of tubular transport, (b) possible activation of pro-inflammatory phenomena, (c) release of aldosterone, and (d) augmented activity of profibrogenic and growth stimulatory functions. These effects are mediated through angiotensin receptors and also the induction of TGF-β.18 Further, angiotensin II-induced aldosterone secretion participates in the development of IF/TA through increased renal vasoconstriction, TGF-β expression and apoptosis ( Fig. 1). Interstitial fibrosis in CsA nephropathy is also associated with the infiltration of macrophages as well as the expression of osteopontin and TGF-β in the tubulointerstitium,19 which seem to be caused by angiotensin II-dependent and independent mechanisms.20 Furthermore, it should be pinpointed that the CNIs may increase the hypoxia in the kidney.21 Local hypoxia or ischemia of the tubulointerstitial compartment causes the formation of free radicals or reactive oxygen species (ROS) that leads to apoptosis and tubular interstitial fibrosis.22 The inhibition of calcineurin may directly activate the apoptosis-related genes23 and/or augment the apoptosis phenomenon in the tubular and interstitial cells, resulting in tubular atrophy to some extend.24

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Research Center for Pharmaceutical Nanotechnology, School of Advanced Biomedical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran ; Chronic Kidney Disease Research Center, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran ; Research Center for Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.

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.

No MeSH data available.


Related in: MedlinePlus