The Kidney Foundation of Canada

Dr. Tom D. Blydt-Hansen 

Dr. Tom D. Blydt-Hansen

University of British Columbia, British Columbia
Co-Applicants:  Colin JR Ross, Bruce C. Carleton, Mara Medeiros, David Wishart, Atul K. Sharma

Pharmacometabolomics in pediatric transplant recipients and relationship to mycophenolate mofetil pharmacokinetics and pharmacogenomics


2017-2019:  $100,000  |  Biomedical Research Grant  |  Category: Transplantation

Biography

Dr. Tom Blydt-Hansen received his MD, CM from McGill University in 1992. He trained in Pediatrics and Nephrology at the Montreal Children's Hospital, and went on to receive further training in transplantation and research at the University of California, Los Angeles. He started his Nephrology career at the University of Manitoba in 2001 and went on to become Division Head of Nephrology from 2005-2014. Since 2014, he is Director of the Multi-Organ Transplant Program at BC Children’s Hospital and a Senior Scientist at the BC Children’s Hospital Research Institute.

His clinical and translational research program is focused on characterizing kidney allograft injury using urine metabolite profiling and other biomarkers. He is lead investigator in the PROBE study, a CIHR funded multi-center cohort study to identify non-invasive urine biomarkers of allograft rejection in pediatric kidney transplant recipients. Most recently, he received funding from Kidney Foundation of Canada to develop a test for mycophenolate treatment monitoring. He is also engaged in collaborations to identify urinary biomarkers (metabolomics) associated with chronic kidney disease, acute kidney injury, type 2 diabetes and cisplatin nephrotoxicity. He is co-investigator on several nationally funded transplant research studies including CKiD, iCARE, CAN-RESTORE and CNTRP.

Lay Summary

Children with end-stage kidney failure benefit greatly from kidney transplantation to return them to more normal living. In order to prevent rejection, children must continue to take medications that suppress the immune system for the rest of their lives. Because these medications can have side effects, the challenge is to give enough medication to prevent rejection but not so much that they have serious side effects.

Mycophenolate mofetil (MMF) is a medication that is difficult to use. It works very well to prevent rejection but also can cause blood and gastrointestinal toxicity (e.g. diarrhea). These side effects impact on quality of life and can result in dose reductions. Unfortunately, these dose reductions also can increase the risk of rejection.

Unlike some other medication, there are not easy tests to monitor the level of MMF in the blood, making it difficult to adjust. There are also a lot of differences in people’s metabolism, and MMF down more slowly in some people and too quickly in others. These differences are partly determined by our genes and so we are all unique in this way. But it means that it can be very hard to know what is the right dose for transplant recipients to keep their kidney safe and them feeling well.

Right now, there are two studies already taking place for children with kidney transplants, one in Canada and another in Mexico. We will work with these studies to develop a better monitoring test for MMF. Our research group will use comprehensive drug level testing (called pharmacokinetics) and urine testing for small molecules
(called metabolites) to learn how to predict the right MMF dose for children. Some of these differences are genetics, so we will include genetic information about kidney transplant recipients to develop the test. This test can be done in the future on urine samples from clinic, to screen for either risk of toxicity or low MMF drug levels that can cause rejection. There will be 80-100 children studied in Mexico, who will have pharmacokinetic testing done to see how much MMF is getting into their body on their regular dose of medication. We will first look for pattern of metabolites in urine, to see which ones are related to high or low levels of MMF. We fill find other metabolites by looking for patterns related to genes that affect MMF metabolism. This will give us the best combination of metabolite markers to develop a urine test. We will use this test to find how well this testing predicts side effects and kidney transplant failure.

More accurate testing and monitoring will permit kidney transplant doctors to adjust the dose of MMF so that children will have the benefit of blocking rejection and avoid some of the MMF side effects. Better adjustment of MMF will improve the quality of life of children after transplant, and may extend their kidney transplant function by reducing the risk of rejection.