Tall Order

Steroid-free transplant treatment a growing success

By Krista Conger
Photographs by Leslie Williamson


	Minnie Sarwal and Oscar Salvatierra test a way to make post-transplant life more normal.

Kids who undergo kidney transplants are tough. They have to be. After all, many would not have survived until their transplant without enduring a grueling regimen of regular dialysis and, in some cases, surgery. But even they struggle with the unavoidable and nasty side effects of the drugs they must take after surgery to avoid rejecting a new organ. Corticosteroids have been the cornerstone of anti-rejection therapy since the 1950s. Their ability to suppress the immune system allowed the first successful kidney transplants and saved the lives of countless children and adults. But this gift had a cost. Steroids severely stunt children’s growth, leaving them as much as 12 inches shy of their expected adult height. They also cause high blood pressure and rapid weight gain.

Even more serious, at least in the eyes of a teenager, the steroids cause puffy, moon-shaped faces peppered with acne. Nausea, vision problems and body disfigurement round out the witches’ brew of bad medical and social karma these kids must endure for a lifetime. Any seasoned parent can predict the next problem: Some despairing kids will stop taking their medication. The fallout of this misguided effort to be more like their peers can include organ rejection, kidney failure and re-transplantation or death.

"The steroids are such a burden on children,” says Lucile Packard Children’s Hospital pediatric nephrologist Minnie Sarwal, MD, PhD. "Non-compliance is one of the leading causes of organ rejection.”
The kids aren’t alone in their frustrations. Sarwal and her colleague, Oscar Salvatierra, MD, director of the pediatric transplantation program at Packard Hospital, struggled daily with the fact that the life-saving medications they were doling out also cause irrevocable harm. But attempts to wean patients off steroids after transplant always increased the chance of acute rejection.

Undeterred by long odds, Sarwal and Salvatierra hatched a two-pronged plan to solve the problem: leave steroids out of the mix entirely and extend treatment with a newer anti-rejection drug from the standard two months after transplant to six. It was a risk, but previous studies in adults suggested that their plan might work.

The results have been nothing short of amazing. In their wake, Salvatierra and Sarwal received a $5 million grant from the National Institutes of Health this year and an additional $1 million from Fujisawa Healthcare Inc. to conduct a nationwide multicenter trial comparing the steroid-free protocol with a low-dose steroid treatment. Success would mark the end of the use of steroids in pediatric transplantation and liberate thousands of children each year from the side effects that can make post-transplantation life miserable. .

A Quiet Revolution

The seeds were sown in May 1998 when Sarwal, an assistant professor of pediatrics at the School of Medicine, attended the annual meeting of the American Society of Transplantation. In one session, researchers presented preliminary data about a steroid-free treatment protocol in adults. Although it had only been about three months since transplantation, the rates of acute organ rejection were similar in groups on and off steroids.

“The data showed that is was doable in adults,” says Sarwal, “but nobody wanted to try it in children, who can experience stronger rejection episodes. I came back from the meeting all fired up and spent the whole weekend reading about steroid minimization and withdrawal in children.”

Sarwal learned that it was difficult to predict which patients would withstand steroid weaning and which would reject their kidney. She and Salvatierra, professor of surgery (transplantation) and of pediatrics, put their heads together to figure out why patients differ in their reactions to steroid withdrawal.

“Our hypothesis was that many of the patients had become steroid-dependent,” says Salvatierra, “and withdrawal opened the window for expression of the immune response. If we were going to surmount this problem, the only option was to eliminate the use of steroids from the very beginning.”

Sarwal and Salvatierra’s radical notion flew in the face of conventional wisdom, which holds that steroids are absolutely required during the surgery and in the delicate weeks immediately following. Although steroids are currently tapered to the lowest possible dose after about four months, higher levels are held in reserve to treat guerilla attacks by the immune system, which usually occur during the first six months after transplantation.

Eliminating this reliable weapon in their anti-rejection arsenal meant that Salvatierra and Sarwal had to rely more heavily on other, more recently discovered immunosuppressants, particularly in the first critical months. Many of these either inhibit the cell division necessary to form an immune-cell army large enough to tackle the transplanted kidney or block interleukin-2 (IL-2) — a molecule that summons immune cells to battle. Most kidney transplant patients currently receive a combination of old and new: steroids coupled with two or more other immunosuppressants.

But then Salvatierra and Sarwal heard that a group of patients with an autoimmune disease that can cause blindness were safely weaned from the standard steroid treatment by substituting daclizumab — an immunosuppressant used in pediatric transplant patients. Daclizumab is an antibody that binds to and inactivates the IL-2 receptor on the immune cell surface.

“They had gotten these patients off steroids without compromising vision,” says Salvatierra. “So we thought it might also be a good replacement for kidney transplant recipients.” The physicians decided to maximize the chances that their steroid-free protocol would work by simultaneously upping the period of daclizumab treatment from two to six months — when acute rejection is most likely to occur. But one thing was still missing.

“For this new protocol to become a success, we needed the buy-in of kids and their families,” says Sarwal. Enter 13-year-old Keith Ericksen and his family. Keith’s kidneys had never developed normally; he needed a transplant. His kidney dysfunction had also left him very small. The day before the surgery, Sarwal and Salvatierra talked with Keith’s parents about the new treatment plan.

“It sounded very positive, but my first question was ‘how have the other kids responded to it?’ ” says Keith’s mother, Mary. “That’s when we realized he was the first kid.” But after discussing the pros and cons with Sarwal and Salvatierra, they decided to go ahead. “We knew steroids would stunt his growth; and he was already short,” says Mary Ericksen. “It just felt like the right thing to do. All the possible positives far outweighed the chance of a rejection episode.” So, as Salvatierra performed the surgery, Sarwal waited anxiously outside, receiving minute-by-minute reports of the new kidney’s function.

“It was very scary,” she says. “You’re essentially putting a kidney in without the big, immediate doses of steroids that had been the standard treatment for decades. You don’t want to do harm when you’re trying to do good.”

Steroids on Trial

Sarwal and Salvatierra set the bar high, and not just for Keith. “We’re looking for the perfect transplant for all kids,” says Salvatierra. “We want better kidney function and less rejection, we want no drug complications and we want normal-looking kids — no, strike that — we want normal kids, period.”

But not even they expected the results they got with Keith and nine other children in the first round of testing: Not only did they not reject their organs, they grew more and stayed healthier than similar transplant patients who were receiving steroids. Their new organs thrived in the steroid-free environment, performing even better than the kidneys of children receiving steroids. Their blood pressures also remained normal and none developed the unpleasant cosmetic side effects associated with steroids.

“The fact that the kidneys were functioning better was a big surprise,” says Sarwal, who has since worked with Salvatierra and the other transplant program physicians to implement the steroid-free protocol in more than 60 other children. “It seemed that somehow steroid treatment may actually inhibit acceptance of the new organ.” As if in confirmation, the test group has experienced an unprecedented low rate of acute rejection: 6 percent versus about 25 percent of children receiving a steroid-based treatment at Packard Children’s Hospital. Nationwide about 30 percent of pediatric kidney transplant patients experience acute rejection.

Remarkably, some of these children have even grown taller than their classmates who have never had transplants. Keith, who weighed in at about 70 pounds before his transplant, shot up from 4 feet 9 inches to nearly 5 feet 4 inches in the following year. He’s now a little over 5 feet 9 inches and weighs about 125 pounds.

“There was a period when he was growing an inch a month,” says his mother.

“The growth in these children is astonishing,” says Sarwal. “We have never seen transplantation patients growing better than their peers. Now we can see how much we were really suppressing growth with these steroids.”

Salvatierra and Sarwal’s multicenter trial will allow them to compare large numbers of kids on and off steroids to confirm that the absence of steroids enhances kidney function and reduces the chance of acute rejection.

Behind the Scenes

In addition to the clinical trial, Sarwal and Salvatierra are interested in the molecular minutiae of transplant rejection.

They’ve found that the expression of T cell activation molecules – harbingers of an up-and-coming rejection episode in patients receiving steroids – increases immediately after transplant even in perfectly healthy steroid-free patients, suggesting that the mechanism of rejection varies according to the presence or absence of steroids. They’ve also found that B cells, immune cells previously cleared of wrongdoing in transplant rejection, are actually prime troublemakers. Finally, they’ve identified at least three separate types of rejection that may merit different types of treatment responses. Their findings appear in the July 11, 2003, issue of the New England Journal of Medicine.

Each new finding increases the understanding of how rejection occurs and what can be done to stop it.

“Our quest for the perfect transplant has taken us from the patient, to the bench, to the patient again,” says Salvatierra. “We ask questions at the bedside, research and pose a hypothesis, devise protocols and adjust our treatment accordingly.”

The cycle of question-and-answer has also allowed them to significantly decrease the dose of the other immunosuppressants in the steroid-free protocol, leaving low doses of just two medicines twice a day. Keith’s mother couldn’t be happier.

“It took a little bit of blind faith,” says Mary Ericksen. “But we would do it again in a heartbeat.” And that’s what makes both physicians smile.

“All along we’ve only wanted normal-looking, normal-functioning kids,” says Salvatierra. “This is the closest anyone has gotten to this goal in the entire history of transplantation. And that is a fact. You can’t ask for much more.”

Indeed not.

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