Tacrolimus Metabolite M-III May Have Nephrotoxic and Myelotoxic Effects and Increase the Incidence of Infections in Kidney Transplant Recipients

Żegarska, Jolanta; Hryniewiecka, Ewa; Żochowska, Dorota; Samborowska, Emilia; Jaźwiec, Radosław; Borowiec, Agnieszka; Tszyrsznic, W.; Chmura, A.; Nazarewski, Sławomir; Dadlez, Michał; Pączek, Leszek

doi:10.1016/j.transproceed.2015.12.133

Cited by 23 publications

(16 citation statements)

References 10 publications

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“…Zegarska et al . found a significant negative correlation between the 15‐O‐demethyl tacrolimus (15‐DMT, also named M‐III) concentration and estimated glomerular filtration rate, which indirectly may support this hypothesis.…”

Section: Discussionmentioning

confidence: 82%

“…To our knowledge, no studies comparing demethylated metabolite concentrations and histological lesions in transplanted kidneys have been conducted. Zegarska et al [30] found a significant negative correlation between the 15-O-demethyl tacrolimus (15-DMT, also named M-III) concentration and estimated glomerular filtration rate, which indirectly may support this hypothesis.…”

Section: Discussionmentioning

confidence: 93%

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High tacrolimus clearance - a risk factor for development of interstitial fibrosis and tubular atrophy in the transplanted kidney: a retrospective single-center cohort study

et al. 2018

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Summary Patients with high tacrolimus clearance are more likely to experience transient under‐immunosuppression in case of a missed or delayed dose. We wanted to investigate the association between estimated tacrolimus clearance and development of graft interstitial fibrosis and tubular atrophy (IFTA) in kidney transplant recipients. Associations between estimated tacrolimus clearance [daily tacrolimus dose (mg)/trough concentration (μg/l)] and changes in IFTA biopsy scores from week 7 to 1‐year post‐transplantation were investigated. Data from 504 patients transplanted between 2009 and 2013 with paired protocol biopsies (7 weeks + 1‐year post‐transplant) were included. There were no differences in baseline biopsy scores (7 weeks) in patients with different estimated tacrolimus clearance. Increasing tacrolimus clearance was significantly associated with increased ci + ct score of ≥2 at 1 year, odds ratio of 1.67 (95% CI; 1.11–2.51). In patients without fibrosis (ci + ct ≤ 1) at 7 weeks (n = 233), increasing tacrolimus clearance was associated with development of de novo IFTA (i + t ≤ 1 and ci + ct ≥ 2) at 1 year, odds ratio of 2.01 (95% CI; 1.18–3.50) after adjusting for confounders. High tacrolimus clearance was significantly associated with development of IFTA the first year following renal transplantation.

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Section: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 93%

High tacrolimus clearance - a risk factor for development of interstitial fibrosis and tubular atrophy in the transplanted kidney: a retrospective single-center cohort study

et al. 2018

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“…The nephrotoxic potential of tacrolimus metabolites has not been accurately studied to date. Zegarska et al studied 81 KTRs and concluded in their study that tacrolimus metabolite M‐III may have nephrotoxic potential and that higher concentrations result in higher incidence of infections . However, tacrolimus is extensively metabolized by the CYP3A4 isoenzyme, the most abundant of the CYP enzymes, constituting approximately one‐third of the CYP enzymes found in the intestinal lining and the liver.…”

Section: Introductionmentioning

confidence: 99%

Tacrolimus: 20 years of use in adult kidney transplantation. What we should know about its nephrotoxicity

Bentata

2019

Artificial Organs

104

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Tacrolimus (or FK506), a calcineurin inhibitor (CNI) introduced in field of transplantation in the 1990s, is the cornerstone of most immunosuppressive regi mens in solid organ transplantation. Its use has revolutionized the future of kidney transplantation (KT) and has been associated with better graft survival, a lower in cidence of rejection, and improved drug tolerance with fewer side effects compared to cyclosporine. However, its monitoring remains complicated and underexposure increases the risk of rejection, whereas overexposure increases the risk of adverse effects, primarily nephrotoxicity, neurotoxicity, infections, malignancies, diabetes, and gastrointestinal complaints. Tacrolimus nephrotoxicity can be nonreversible and can lead to kidney graft loss, and its diagnosis is therefore best made with reference to the clinical context and after exclusion of other causes of graft dysfunction. Many factors contribute to its development including: systemic levels of tacrolimus; local renal exposure to tacrolimus; exposure to metabolites of tacrolimus; local susceptibil ity factors for CNI nephrotoxicity independent of systemic or local tacrolimus levels, such as the age of a kidney; local renal P-glycoprotein, local intestinal and hepatic cytochrome P450A3, and renin angiotensin system activation. The aim of this review is to describe the pharmacokinetics, pharmacodynamics, and mechanisms of acute and chronic tacrolimus nephrotoxicity in adult KT. K E Y W O R D Sacute,

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“…The 13-O-demethyl-tacrolimus possesses some immunosuppressive effect; however, it is about one tenth as active as tacrolimus, whereas the 31-O-demethyl metabolite displays an immunosuppressive activity comparable to tacrolimus [37,38]. On the other hand, high blood concentration of 15-O-demethyl-tacrolimus metabolite has been reported to be associated with nephrotoxicity and myelotoxicity and with higher incidence of infections [39]. Similarly to ciclosporin, tacrolimus is metabolized by CYP3A enzymes, anticipating great interindividual and intraindividual differences in pharmacokinetics of tacrolimus: (1) CYP3A activity of enterocytes contributes to the first-pass metabolism of tacrolimus;…”

Section: Calcineurin Inhibitorsmentioning

confidence: 99%

Metabolic Drug Interactions with Immunosuppressants

Monostory¹

2018

Organ Donation and Transplantation - Current Status and Future Challenges

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Organ transplantation has become a routine clinical practice for patients with endstage disease of liver, kidney, heart, or lung. Although improved immunosuppressant therapy substantially contributes to the success of transplantation, clinicians continue to face challenges because of wide interindividual variations in blood concentrations resulting in subtherapeutic or supratherapeutic levels. Many undesired side-effects or therapeutic failure of immunosuppressants as a consequence are the results of differences or changes in drug metabolism. Considering genetic and nongenetic factors, such as co-medication, can refine the immunosuppressant therapy, facilitating personalized treatments to individual recipients. This review provides an up-to-date summary of functional polymorphisms of enzymes involved in the metabolism of immunosuppressants with low molecular weight and of the clinical significance of metabolic drug interactions between immunosuppressive agents and other drugs in therapeutic regimens of transplant recipients.

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Tacrolimus Metabolite M-III May Have Nephrotoxic and Myelotoxic Effects and Increase the Incidence of Infections in Kidney Transplant Recipients

Cited by 23 publications

References 10 publications

High tacrolimus clearance - a risk factor for development of interstitial fibrosis and tubular atrophy in the transplanted kidney: a retrospective single-center cohort study

High tacrolimus clearance - a risk factor for development of interstitial fibrosis and tubular atrophy in the transplanted kidney: a retrospective single-center cohort study

Tacrolimus: 20 years of use in adult kidney transplantation. What we should know about its nephrotoxicity

Metabolic Drug Interactions with Immunosuppressants

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