Digestive Diseases News
Spring/Summer 2007

Explore Improving Long-term Outlook for Children With Liver Transplants

Children who undergo liver transplantation have an excellent outlook for long-term survival, thanks to advances in surgery and drugs to prevent organ rejection. But many challenges may threaten their quality of life along the way, including damage to other organs, post-transplant malignancies, and growth and development difficulties. Improving long-term health outcomes for these children was the subject of a daylong meeting organized by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) in February.

An ongoing concern for researchers and physicians is the effect of immunosuppressive drugs on children. A major challenge of liver transplantation is how to minimize immunosuppression without sacrificing graft function.

The most serious complications of long-term immunosuppression, according to Sue V. McDiarmid, M.D., director of pediatric liver transplantation at the David Geffen School of Medicine, University of California at Los Angeles Medical Center, are

• renal dysfunction due to the use of calcineurin inhibitors
• delays in growth, development, and cognitive function
• new-onset malignancy
• development of increased cardiovascular risk factors
• infection

McDiarmid said the most significant way to improve outcomes after pediatric liver transplantation is to improve immunosuppression. “It would be great to figure out how to withdraw all immunosuppression,” said McDiarmid, who recommended that innovative multicenter trials focus on the least amount of immunosuppression necessary to achieve good graft function with minimal side effects.

Nonadherence

Nonadherence to immunosuppressive drug regimens because of drug side effects is a research concern that also warrants study. The pediatric liver transplant community is in a unique position to spearhead the study of nonadherence to medical recommendations, the most important risk factor for poor, long-term, pediatric post-transplant outcomes, according to Eyal Shemesh, M.D., assistant professor in the Department of Psychiatry, Pediatrics Division, at Mount Sinai Medical Center.

The most important attribute of the pediatric liver transplantation population is that transplant centers routinely monitor medication blood levels, according to Shemesh. “Looking at fluctuations in these levels over time provides a powerful, objective, ready-to-use measure of adherence that is unique to this setting.” Other unique attributes, said Shemesh, are that

• pediatric liver transplant centers have agreed on several outcome measures that are routinely collected by most centers, making a multicenter study relatively easy
• specific pilot data about the measurement of adherence, consequences of nonadherence, and even treatment of nonadherence, are available in this population

Positive Outcome Measures

Researchers also should develop more positive diagnostic criteria to measure how well children who receive transplants are doing, rather than using death as the primary measurement, recommended Jay Hoofnagle, M.D., director of the NIDDK’s Liver Diseases Research Branch. Examples of other measures, said Hoofnagle, would be whether the children are going to school, participating in activities, and are later employable.

One of the research goals laid out in the National Institutes of Health (NIH) Action Plan for Liver Disease Research is “to define factors associated with successful liver transplantation in terms of growth and development, school performance, and social and intellectual development through a careful prospective and long-term assessment.”

The NIH-funded Studies of Pediatric Liver Transplantation (SPLIT) is a research network comprising 44 pediatric liver transplant centers in the United States and Canada. The network seeks to register and prospectively follow 80 percent of all children receiving a liver transplant to advance clinical research and trials about long-term outcomes, complications, and tolerance.

In addition, the Immune Tolerance Network (ITN) maintains a database and funds many studies on immune tolerance and tolerance-inducing regimens of therapy for kidney, liver, and islet transplantation; autoimmune diseases; and allergies and asthma. The ITN is a joint research network that conducts clinical trials and tolerance assay studies in the areas of kidney, liver, and islet transplantation, autoimmune diseases, and allergies and asthma.

The NIH Action Plan also calls for identifying ways to avoid liver transplantation. For instance, children with biliary atresia—the most common cause of liver transplantation in children—may be able to avoid or delay a transplant through early diagnosis, a successful operation known as the Kasai procedure, and effective anti-cholestatic and anti-fibrotic therapies.

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NIH Publication No. 07–4552
May 2007