'A Lot More to Do' for Longevity of Kids Who Receive Organs

Jake Remaly

July 05, 2023

Sara Kathryn Smith, MD, knows better than most that studying pediatric organ transplant recipients in adulthood can be a challenge.

Dr Sara Kathryn Smith

Smith, the medical director of pediatric liver transplantation at Johns Hopkins Children's Center in Baltimore, is a transplant recipient herself.

"Following somebody 20, 30 years after a liver transplant when they are out there running their life and having no issues at all, it is hard to convince them to come back every month for labs," Smith said.

Long-term follow-up could identify ways to keep patients healthier longer. As another pediatric transplant hepatologist, Evelyn Hsu, MD, put it: "We want to make these kids into grandparents, not get them 1 year of life or 5 years of life."

Research shows there may be plenty of room to improve patients' long-term survival.

Risk for premature death among pediatric transplant recipients is as much as 130 times higher relative to peers matched by age, sex, and hometown during a median follow-up of 18 years after transplant, according to a study from Finland published in the March issue of Pediatric Transplantation. Cardiovascular disease, infections, and cancer were common causes of death.

The study is the first to assess the survival rate for pediatric patients two decades after surgery, the researchers say.

Groups in the United States recognize the importance of capturing similar long-term data. The Scientific Registry of Transplant Recipients (SRTR) held a conference in July 2022 to identify which sorts of data related to transplantation outcomes are of interest to patients, families, and healthcare professionals for assessing the performance of the transplantation system and informing decision-making. Attendees agreed that documenting long-term outcomes for all patients and living donors is "a moral and ethical obligation."

Hypertension, Sepsis, PTLD

In the Finnish study of long-term survival, Rebekka Salonen, with Tampere University in Finland, and colleagues studied outcomes for 233 patients who had undergone transplantation at one center between 1982 and 2015. The 20-year survival rates were 86.1% for kidney recipients, 58.5% for liver recipients, and 61.4% for heart recipients.

One quarter of patients died during a median follow-up of 18 years, compared with 0.2% of peers in the control group.

The most common causes of death among patients included cardiovascular disease (23%), infections (22%), and malignancies (17%), the researchers report.

Deaths from cardiovascular disease were largely due to hypertension-related strokes and heart attacks. Infection-related deaths were mainly due to sepsis. Cancer deaths were primarily caused by posttransplant lymphoproliferative disease (PTLD), Guido Filler, MD, PhD, notes in a commentary published with the study.

"Unfortunately, there is a lot more to do to achieve longevity of our pediatric transplant patients," Filler, professor of pediatrics at Western University in London, Ontario, Canada, told Medscape Medical News.

Need for RCTs

In 1997, Filler was the principal investigator of the first published randomized controlled clinical trial in pediatric kidney transplantation. The study showed that tacrolimus was more effective than cyclosporine microemulsion in preventing acute rejection.

"A lot of progress has been made with regards to losing solid organ transplants early from rejection," Filler said. "Nonetheless, little progress has been made over the past 20 years with regards to the baseline immunosuppression with tacrolimus, mycophenolate mofetil, and steroids."

Prophylaxis with antiviral drugs helps prevent early illness, but immunosuppression still increases the risk for cancer, he said.

"Worst of all, though, is cardiovascular disease due to cardiorenal syndrome ― the worse the kidney function, the worse the cardiac function," Filler said. "There is a very high prevalence of renal dysfunction in all solid organ transplant recipients."

Sodium and hypertension are potential modifiable risk factors. The concentration of sodium in skin correlates with risk for cardiovascular disease, and sodium accumulates faster in patients with impaired kidney function. Sodium-glucose cotransporter 2 (SGLT2) inhibitors should be studied in randomized controlled trials in pediatric solid organ recipients, Filler said.

"Unfortunately, pediatrics is lagging behind" in conducting such studies, he said. "Other strategies such as strict blood pressure control also urgently require prospective validation."

A Planned Overhaul

The US transplant system in 2022 celebrated its millionth transplant but also faced criticism from congressional investigators and the National Academies of Sciences, Engineering and Medicine. Critics noted problems with transportation glitches and life-threatening mistakes and called for efforts to reduce the number of discarded organs.

About 104,000 people, including nearly 2000 children, were on the transplant waiting list in the United States as of January 30.

In March, the Health Resources and Services Administration (HRSA), an agency of the US Department of Health and Human Services, announced an initiative to modernize and "strengthen accountability and transparency" in the Organ Procurement and Transplantation Network (OPTN). The network consists of hundreds of public and private organizations, including 251 transplant centers, 56 organ procurement organizations, and 140 histocompatibility laboratories.

One group worries that children might not be represented in the planning process.

"There is significant risk of losing ground towards the goal of eliminating pediatric waitlist mortality in this modernization effort," the Society of Pediatric Liver Transplantation said in a May 30 statement.

Providers of pediatric healthcare and patient representatives must be involved "in every step," the group said.

In 2019, among liver candidates younger than 1 year, the waitlist mortality rate exceeded that for adults, the society noted. But there have been positive developments too: Recent changes to organ allocation policies led to a substantial reduction in the rate of deaths on the pediatric liver waitlist, according to the group.

"For pediatric liver recipients, we have achieved greater than 90% patient survival rate at five years post-transplant ― but this means that transplant was available too late, or that complications were too overwhelming, to save one in 10 of these children," the society said.

As part of the modernization initiative, HRSA envisions a more competitive process to select those organizations that manage the transplant network.

United Network for Organ Sharing (UNOS) has administered the network since it was awarded the first OPTN contract in 1986. It receives approximately $6.5 million annually from the federal government.

"As always, we welcome a competitive bidding process," UNOS CEO Maureen McBride, PhD, said in a message on the organization's website. Nevertheless, it is crucial that "some portion of the contract be carried out by bidders with experience in OPTN operations, given how incredibly complex the system is and that lives are at stake."

The Chronic Disease Research Group, a division of the Hennepin Healthcare Research Institute, operates the SRTR. The registry supports any effort to improve the organ donation and transplantation system, director Jon Snyder, PhD, said.

"The success of the OPTN Modernization Initiative will depend on how the contracts are issued, who they are awarded to, and how those entities align to improve the system's performance," Snyder told Medscape. "At this stage, without more information about the intended structure, it is difficult to speculate about unintended consequences or the success of the initiative."

HRSA plans to seek contractors in fall 2023 and spring 2024.

International Collaborations

Juan C. Alejos, MD, medical director of the pediatric heart transplant program for UCLA Health in Los Angeles, expects that additional insights on long-term patient survival will come from international collaborations of organizations such as the Pediatric Heart Transplant Society.

Members of the society pool data, publish articles, and seek input from each other on difficult cases, Alejos said.

"It's such a super-subspecialized field that a lot of the work we do is collegial," he said.

Results from a single center may have limited generalizability. Salonen and colleagues noted a high incidence of congenital nephrotic syndrome of Finnish type among the kidney recipients in their study, differentiating the population from cohorts in other countries. In addition, the use of an initial immunosuppression protocol based on triple immunosuppression with cyclosporin A, azathioprine, and methylprednisolone is less common elsewhere.

A central struggle in transplantation is finding the right balance between controlling the body's response to an organ that does not belong to it and limiting harm from suppressing the immune system, Alejos said.

He discusses the lifelong risks with patients.

"When I started to do this, we would quote to families that the transplanted heart would last about 5 to 7 years, and then you'd have to get transplanted again," Alejos said.

Alejos can now tell families that, through medical advances, a transplanted heart can last 15 to 20 years.

"But it's still not going to take a baby to retirement, for instance," he said.

When UCLA Health published an article last year about its pediatric heart transplant program, it described the program's evolution and touted its survival rates. It also mentioned that Alejos had recently attended a memorial service for a former patient who had died at age 34 years.

"If we're going to celebrate our successes, we also have to mourn and learn from sad cases in which patients passed away," Alejos said.

The patient's parents told Alejos they were grateful for having had the time to watch their son grow up, graduate from high school and college, work, and get engaged.

An Intervention That Succeeds

Smith was diagnosed with autoimmune hepatitis when she was in high school. She received a liver transplant as a college student and needed additional organ transplants because of complications.

Her medical training led to fellowships in pediatric gastroenterology and pediatric transplant hepatology. Throughout her career, Smith has befriended more than 30 doctors who have had received transplants.

"I'm here showing that this is an intervention that works," she said. "It has the promise of returning you to a normal life and being able to achieve your dream if you want. We need to continue to work to improve the system overall to give every child that chance."

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