Gene Mutation Increases Drug Toxicity, Rejection Risk in Pediatric Kidney Transplants
Study Suggests Genetic Approach to Personalized Screening of Anti-Rejection Drug Dosing
“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
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,
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
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SOURCE Cincinnati Children’s Hospital Medical Center