Navigation Links
Gene Mutation Increases Drug Toxicity, Rejection Risk in Pediatric Kidney Transplants
Date:2/18/2009

Study Suggests Genetic Approach to Personalized Screening of Anti-Rejection Drug Dosing

CINCINNATI, Feb. 18 /PRNewswire-USNewswire/ -- Screening for mutations in a gene that helps the body metabolize a kidney transplant anti-rejection drug may predict which children are at higher risk for side effects, including compromised white blood cell count or organ rejection, according to new research.

Published online Feb. 18 by the Nature journal Clinical Pharmacology and Therapeutics, the study suggests this genetic approach could also help physicians tailor personalized anti-rejection drug doses to prevent adverse reactions, said senior investigators Alexander A. Vinks, Pharm.D., Ph.D., and Jens Goebel M.D., of Cincinnati Children's Hospital Medical Center.

"There are better ways than just giving standard doses of these drugs, and in due course these types of technologies will be available worldwide to help patients," said Dr. Vinks, director of the Division of Clinical Pharmacology and the Pediatric Pharmacology Research Unit at Cincinnati Children's. "This pilot study shows personalized and prospective MMF dosing and monitoring may be feasible to reduce the high incidence of drug toxicity in children without compromising the drug's protective effects against kidney graft rejection."

MMF, or Mycophenolate Mofetil, is an immunosuppressive agent commonly used to prevent rejection in organ transplants, particularly in kidney transplants. After taken orally, the drug is quickly processed by the body into active form. During this time, patients with a specific point mutation in the gene that helps break down the drug, UGT, metabolize the drug slower. This point mutation, called UGT1A9-331, causes overexposure and adverse side effects in the affected children, the study concluded. UGT encodes the drug's main metabolizing enzyme in the body, uridine diphosphate-glucuronosyl transferase.

Adverse side effects most commonly linked to MMF have included gastrointestinal complications (such as diarrhea) or leukopenia - a drop in white blood cell count that can put patients at higher risk for infections. In some instances, patients have to be taken off the drug or have their dosage reduced to the point where they risk rejection of the new organ.

The current study analyzed 38 children who had received kidney transplants. Sixteen of the children experienced adverse side effects from MMF therapy. In the adverse reaction group, nine children with the specific UGT point mutation developed leukopenia. The researchers found no strong association between UGT gene variants and diarrhea - the most common side effect linked to MMF - suggesting gastrointestinal reactions to the drug may be caused by other factors.

Some previous studies have linked UGT gene mutations and MMF-related side effects in kidney transplant recipients, while others have suggested a greater risk for adverse events in children. A review of earlier research combined with their current data led researchers in this study to conclude that pediatric kidney transplant recipients on MMF therapy have a significantly higher likelihood of drug-related complications than adult patients. One previous study compared 22 pediatric and 37 adult transplant recipients, all who started with the standard recommended doses of MMF. Among the children, 54.5 percent experienced adverse side effects compared to 21.6 percent of the adults.

Besides the UGT1A9-331 point mutation, other studies have also linked a second variation, called UGT2B7-900, to possible MMF overexposure and development of leukopenia, said Tsuyoshi Fukuda, Ph.D., co-author on the current study and a colleague in Dr. Vinks' division at Cincinnati Children's. The research team recently completed pharmacokinetic and biomarker studies - which analyze how the body metabolizes a drug - to solidify the connection between different variants of UGT and MMF overexposure in pediatric kidney transplant patients.

Researchers want to use data from these pharmacokinetic studies as a basis for showing whether increased MMF exposure in adults can also be linked to specific variations in the UGT gene, according to Dr. Fukuda.

The pilot study is part of the growing field of genetic-based pharmacology, or pharmacogenetics. Combining biology and information technology, researchers are developing computer-based algorithms that allow taking a few drops of blood and analyzing how quickly a person's body will break down and absorb a drug based on their genetic makeup. The goal is to reduce drug-related side affects by optimizing drug doses for individual patients.

Dr. Goebel is medical director of Kidney Transplantation Program in the Division of Nephrology and Hypertension at Cincinnati Children's. Also participating in this study were the divisions of Human Genetics and Biostatistics/Epidemiology at Cincinnati Children's, the National Institutes of Health's Pediatric Pharmacology Research Unit network, the Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, and the University of Arkansas for Medical Sciences and Arkansas Children's Hospital, Little Rock, Ark.

Funding support came from the National Institutes of Health and a translational research initiative grant from Cincinnati Children's.

Cincinnati Children's Hospital Medical Center is one of America's top three children's hospitals for general pediatrics and is highly ranked for its expertise in digestive diseases, respiratory diseases, cancer, neonatal care, heart care and neurosurgery, according to the annual ranking of best children's hospitals by U.S. News & World Report. One of the three largest children's hospitals in the U.S., Cincinnati Children's is affiliated with the University of Cincinnati College of Medicine and is one of the top two recipients of pediatric research grants from the National Institutes of Health. For its achievements in transforming healthcare, Cincinnati Children's is one of six U.S. hospitals since 2002 to be awarded the American Hospital Association-McKesson Quest for Quality Prize(R) for leadership and innovation in quality, safety and commitment to patient care. The hospital is a national and international referral center for complex cases, so that children with the most difficult-to-treat diseases and conditions receive the most advanced care leading to better outcomes. Additional information can be found at www.cincinnatichildrens.org.

    Contact: Nick Miller
    513-803-6035

'/>"/>
SOURCE Cincinnati Children's Hospital Medical Center
Copyright©2009 PR Newswire.
All rights reserved

Related medicine news :

1. Gene Mutation Tied to Majority of Cases of Mental Retardation
2. The Bachmann-Strauss Dystonia & Parkinson Foundation: New Study Identifies Gene Mutations as Cause of Dystonia in Amish-Mennonite Families
3. Gene mutations increase risk for aggressive prostate cancer
4. 60 Million Worldwide Carry Heart Disease Mutation
5. Scientists identify new congenital neutropenia syndrome and causative gene mutation
6. Gene Mutation Tied to Inherited Fatal Lung Disease
7. Yeast mimics severity of mutations leading to fatal childhood illness
8. Mutations common to cancer and developmental disorder examined in a novel disease model
9. UBC researchers discover gene mutation that causes eye cancer
10. Gene Mutation in Dalmatians Sheds Light on Kidney Stones in Humans
11. Gene Mutation May Cause Some Cases of Seasonal Affective Disorder
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:6/26/2017)... ... June 26, 2017 , ... LARKR™ , an innovative new smartphone app ... across the country to join its online treatment platform. , Launching in just ... a substantially greater number of people in need nationwide, and to supplement their traditional ...
(Date:6/26/2017)... ... June 26, 2017 , ... New patients with missing teeth ... with or without a referral. Dr. Cotey is a trusted dentist who has placed ... replacement option. , Patients with missing teeth in Fitchburg, WI, are encouraged to find ...
(Date:6/25/2017)... , ... June 25, 2017 , ... Republicans in the ... and replace Obamacare, called the Better Care Reconciliation Act. It differs significantly from the ... will need to be reconciled in committee, or the House will have to take ...
(Date:6/25/2017)... ... ... heatwave currently bearing down on Northern California pushing temperatures to the maximum, many people are ... with laser hair removal. , The process of summer waxing and constantly shaving unwanted ... want to do is get out, dive in and cool off. There is a way ...
(Date:6/24/2017)... ... June 24, 2017 , ... ... PA at the Sheraton Erie Bayfront and Erie Convention Center on June 8-10. ... experience, exhibits, a student quiz bowl, award and scholarship presentations, and professional networking. ...
Breaking Medicine News(10 mins):
(Date:5/30/2017)... CAESAREA, Israel , May 30, 2017 DarioHealth Corp. ... and big data solutions, today announced that it will be presenting ... 2017, at 8:00 AM PT. Erez Raphael , CEO, of ... The conference will be held on June 6th & 7th, ... 180 companies in the small / micro-cap space. ...
(Date:5/26/2017)... plc (NASDAQ: ENDP ) announced today that ... in a fireside chat at Goldman Sachs, 38 th ... 10:40 a.m. PT / 1:40 p.m. ET. The conference will ... Verdes, CA. A live webcast and ... Company,s website at http://www.endo.com/investors/overview . Participants should allow approximately ...
(Date:5/22/2017)... , May 22, 2017  Lilac Corp, ... Gene-Eden-VIR/Novirin, announces the launch of a new ... the results of a clinical study that showed ... treatment with Gene-Eden-VIR/Novirin in individuals suffering from HPV ... note that there are no other treatments that ...
Breaking Medicine Technology: