A critical analysis of racial difference with mycophenolate mofetil (MMF) dosing, clinical outcomes and adverse effects in pediatric kidney transplant patients

Jensen, Chelsey J.; Shrivastava, Seema; Taber, David J.; Weimert, Nicole A.; Shatat, Ibrahim F.; Orak, John K.; Chavin, K.; Baliga, P.

doi:10.1111/j.1399-0012.2010.01304.x

Cited by 3 publications

(2 citation statements)

References 12 publications

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“…Our results also indicate that African American race confers a greater risk of kidney allograft rejection, which has been shown in other adult and pediatric studies . Although this has been reported by multiple groups, the cause is uncertain and likely multifactorial.…”

Section: Discussionsupporting

confidence: 84%

Severe intellectual disability is not a contraindication to kidney transplantation in children

Chen

Farney

Russell

et al. 2017

Pediatric Transplantation

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Renal transplantation in children with ID is controversial. Acceptability of these children as candidates varies between programs. Limited outcome data in pediatric renal TXP recipients with cognitive impairment diminish their access to TXP. A retrospective chart review was performed of all children who underwent renal transplantation between January 1, 2002 and June 30, 2012 (N=72). Patients were divided into two groups, those with ID prior to transplantation (n=10) and those without (non-ID; n=62). Graft survival and BPAR episodes were compared between the two groups using Kaplan-Meier estimates. Graft survival rates at 3 years post-TXP were 100% in the ID group and 80% in the non-ID group (P=.13). Rates of BPAR at 3 years post-TXP were 10% in the ID group and 27% in the non-ID group (P=.29). Graft survival and acute rejection-free survival rates are similar between children with ID and those without. Based on midterm outcomes, there is no apparent contraindication to renal transplantation in pediatric patients with ID. Children with ID should be considered as TXP candidates provided that they have an adequate social support network.

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Section: Discussionsupporting

confidence: 84%

Severe intellectual disability is not a contraindication to kidney transplantation in children

Chen

Farney

Russell

et al. 2017

Pediatric Transplantation

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“…1 Therefore, it can reduce rejection and improve graft and recipient survival. 2,3 However, even when administrated at its recommended dose, some patients have more serious adverse effects, including diarrhea, abdominal pain, bone marrow toxicities, and infection, [4][5][6] which can vary. 7 At present, a large number of clinical investigations have shown that gene polymorphism is one of the important factors leading to MMF differences among individuals, [8][9][10] with individualized medication regimens based on different genotypes of patients effectively increasing the therapeutic efficacy and reducing adverse effects, as well as reducing the cost of treatment.…”

Section: Introductionmentioning

confidence: 99%

Untitled

Iemsupakkul

Kongchareonsombat²,

Kijvikai³

2018

Exp Clin Transplant

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Objectives: Mycophenolate mofetil is a first-line drug after organ transplant, but there are differences in metabolism of mycophenolate mofetil among individuals. The UDP glucuronosyltransferase enzyme is the key metabolic enzyme for mycophenolate mofetil, and UGT1A8 gene polymorphisms may affect the elimination of mycophenolate mofetil in patients. Here, we conducted an in vitro study to explore the relation between UGT1A8 gene polymorphisms and mycophenolate mofetil metabolism. Materials and Methods: Five mutant loci overexpression vectors (UGT1A8 128C>T, 157C>A, 431C>T, 518C>G, and 830G>A) were constructed by genetic recombination and site-directed mutagenesis. We used Lipo2000 (Invitrogen, Carlsbad, CA, USA) to transfect the vectors into HEK293 cells. Mycophenolic acid, the active ingredient of mycophenolate mofetil, was added to different groups of cells. We then used the liquid chromatography tandem-mass spectrometry technique to detect production of the metabolite 7-O-mycophenolic acid glucuronide and to evaluate activity of the UDP glucuronosyltransferase enzyme in cells with different overexpression vectors. Results: Mutations of UGT1A8 157C>A and 518C>G vectors can lead to increased activity of UDP glucuronosyltransferase enzymes and increased production of the 7-O-mycophenolic acid glucuronide metabolite, which showed 116% (P < .001) and 107% (P = .0191) production changes of 157C>A and 518C>G mutations, respectively, relative to wild-type UGT1A8. However, mutations of UGT1A8 431C>T and 830G>A loci resulted in decreased activity of UDP glucuronosyltransferase enzymes and decreased production of the metabolite, respectively showing 62.9% (P < .001) and 9.05% (P < .001) activity relative to wild-type UGT1A8. UGT1A8 128C>T had little effect on enzyme activity, with 96.8% activity relative to wild-type UGT1A8 (P = .0569). Conclusions: Our results showed that UGT1A8 gene polymorphisms can affect the activity of UDP glucuronosyltransferase enzyme, which may influence the elimination of mycophenolate mofetil in different patients.

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Pharmacology and toxicology of mycophenolate in organ transplant recipients: an update

2014

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This review aims to provide an update of the literature on the pharmacology and toxicology of mycophenolate in solid organ transplant recipients. Mycophenolate is now the antimetabolite of choice in immunosuppressant regimens in transplant recipients. The active drug moiety mycophenolic acid (MPA) is available as an ester pro-drug and an enteric-coated sodium salt. MPA is a competitive, selective and reversible inhibitor of inosine-5'-monophosphate dehydrogenase (IMPDH), an important rate-limiting enzyme in purine synthesis. MPA suppresses T and B lymphocyte proliferation; it also decreases expression of glycoproteins and adhesion molecules responsible for recruiting monocytes and lymphocytes to sites of inflammation and graft rejection; and may destroy activated lymphocytes by induction of a necrotic signal. Improved long-term allograft survival has been demonstrated for MPA and may be due to inhibition of monocyte chemoattractant protein 1 or fibroblast proliferation. Recent research also suggested a differential effect of mycophenolate on the regulatory T cell/helper T cell balance which could potentially encourage immune tolerance. Lower exposure to calcineurin inhibitors (renal sparing) appears to be possible with concomitant use of MPA in renal transplant recipients without undue risk of rejection. MPA displays large between- and within-subject pharmacokinetic variability. At least three studies have now reported that MPA exhibits nonlinear pharmacokinetics, with bioavailability decreasing significantly with increasing doses, perhaps due to saturable absorption processes or saturable enterohepatic recirculation. The role of therapeutic drug monitoring (TDM) is still controversial and the ability of routine MPA TDM to improve long-term graft survival and patient outcomes is largely unknown. MPA monitoring may be more important in high-immunological recipients, those on calcineurin-inhibitor-sparing regimens and in whom unexpected rejection or infections have occurred. The majority of pharmacodynamic data on MPA has been obtained in patients receiving MMF therapy in the first year after kidney transplantation. Low MPA area under the concentration time from 0 to 12 h post-dose (AUC0-12) is associated with increased incidence of biopsy-proven acute rejection although AUC0-12 optimal cut-off values vary across study populations. IMPDH monitoring to identify individuals at increased risk of rejection shows some promise but is still in the experimental stage. A relationship between MPA exposure and adverse events was identified in some but not all studies. Genetic variants within genes involved in MPA metabolism (UGT1A9, UGT1A8, UGT2B7), cellular transportation (SLCOB1, SLCO1B3, ABCC2) and targets (IMPDH) have been reported to effect MPA pharmacokinetics and/or response in some studies; however, larger studies across different ethnic groups that take into account genetic linkage and drug interactions that can alter a patient's phenotype are needed before any clinical recommendations based on patient genotype can b...

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A critical analysis of racial difference with mycophenolate mofetil (MMF) dosing, clinical outcomes and adverse effects in pediatric kidney transplant patients

Cited by 3 publications

References 12 publications

Severe intellectual disability is not a contraindication to kidney transplantation in children

Severe intellectual disability is not a contraindication to kidney transplantation in children

Untitled

Pharmacology and toxicology of mycophenolate in organ transplant recipients: an update

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