June 3, 2008 - By Krista Conger
An innovative treatment pioneered at Lucile Packard Children's Hospital that eliminates some toxic anti-rejection drugs for children with kidney transplants is safe, effective and even beneficial, according to researchers from Packard Children's and the School of Medicine.
The findings represent the largest and longest study of this treatment in pediatric transplant patients and may lead to a new standard of care for these children. The research was presented June 2 at the annual meeting of the American Transplant Congress in Toronto.
The novel approach abandons the long-held practice of using steroid drugs to tamp down the transplant recipient's immune system. Omitting the steroids in children avoids the problems of growth suppression, high blood pressure and rapid weight gain that can go hand-in-hand with long-term use of the drugs. Instead, the treatment relies on the extended use of a different type of immune-suppressing medication, called daclizumab. The effect of the change on children in the study, some of whom were followed as long as eight years, is evident on many fronts.
'We are seeing children grow as they were meant to grow,' said pediatric nephrologist Minnie Sarwal, MD, PhD, who devised the treatment in 1998. 'Not only that, their organs are performing better and are less likely to be rejected.'
Sarwal, associate professor of pediatrics at the School of Medicine, said ongoing steroid use can cut as much as 12 inches off a child's eventual adult height. In contrast, many of the 123 patients in the study actually caught up and surpassed their peers in height within a few years.
'We're very excited about the results,' said the study's first author, Li Li, MD, senior biostatistician in Sarwal's lab. Li has received the American Transplant Congress's Young Investigator Award for the research.
The study, funded by the National Institutes of Health, received additional financial support from Astellas, the company formerly called Fujisawa that manufactures one of the drugs used in both the steroid-based and steroid-free treatments. Roche Pharmaceuticals, which manufactures both daclizumab and a third drug used in both treatments, provided free extended-dosing daclizumab for use in the study.
Li and Sarwal compared 123 children with kidney transplants who did not receive steroids with 111 age-matched, transplanted peers who received the standard steroid-based treatment. They followed each child for as long as eight years and found that those undergoing the steroid-free treatment were significantly less likely than their peers to undergo acute rejection. They also grew better. Children who received their transplants at age 6 or younger showed a height gain of almost three standard deviations over their steroid-based counterparts six years after transplantation. Steroid-free children were also less likely to have high blood pressure or weight gain
Alexys Handley experienced the benefits of the steroid-free treatment first hand. The 17-year-old San Jose girl received a kidney from her father, Brian, in 2002 after being diagnosed with kidney disease when she was 11. Since then she's given several speeches to the National Kidney Foundation about her experiences and continues to serve as an educational resource for medical students and physicians.
'I've been to transplant camp and seen other kids struggling with the side effects of steroids, such as weight gain,' said Handley. 'I'm just very, very grateful I didn't have to go through with that.'
Now, nearly six years later, Handley is a healthy, active teenager who has already grown to be 5-foot-5, which is about three inches taller than would have been expected had she been on steroids. She plans to continue speaking out about what the steroid-free protocol means to her and to other pediatric kidney transplant patients.
'I am a teenager. Like all teenagers, I want to be attractive, and to not spend a lot of time in the hospital. Basically, I feel that if you have a better option, of course you go with it. Steroids are not a good option.'
Jettisoning the steroids for the first time nearly 10 years ago was a leap of faith on the part of Sarwal and pediatric transplant surgeon Oscar Salvatierra, MD, professor emeritus of pediatrics and of surgery, as well as the patients' families. Conventional wisdom held that steroid treatment was absolutely necessary during the transplant itself to prevent organ rejection, as well as throughout the following months and years. But pediatric physicians struggled with the knowledge that, although life-saving, this approach left many of their young patients battling devastating side effects. In fact, most cases of organ rejection occur when a fed-up adolescent refuses to take his or her anti-rejection medication.
'The steroids are such a big burden for children,' said Sarwal. 'But even though there were clues in adults that we could safely leave steroids out of the post-transplant treatment, we didn't expect the organs to actually be healthier and better tolerated.'
The promising preliminary results led not only to this completed Packard Children's study, but also spearheaded an ongoing $8 million grant from the NIH to conduct a randomized trial of the steroid-free treatment in children at 12 centers nationwide. Sarwal also reported on the one-year results of that trial at the same meeting.
In addition to specifically studying steroid-free anti-rejection protocols, Sarwal and her colleagues were recently awarded a $6 million grant from NIH to study whether specific patterns of gene expression can be used to predict whether a child will reject or tolerate the donated organ. Mattel Children's Hospital at UCLA, Emory University's School of Medicine and Children's Healthcare of Atlanta will also share in the grant, which is aimed at improving the long-term survival of pediatric kidney transplant recipients.
'We are developing a new standard for pediatric transplant patients,' said Sarwal. 'You should look normal. You should feel normal. You should be normal. These kids deserve that.'
Li's and Sarwal's colleagues on the current study include Salvatierra; pediatric transplant surgeon Waldo Concepcion, MD, associate professor of surgery; and pediatric nephrologists Cynthia Wong, MD, assistant professor of pediatrics; Steven Alexander, MD, professor of pediatrics; Paul Grimm, MD, professor of pediatrics and administrative associate J. Martin.
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