Secular Trends in Survival Outcomes of Kidney Transplantation for Children

In this issue of CJASN, Francis et al. (1) examine secular trends in cause-specific mortality among transplanted children in the Australian and New Zealand Dialysis and Transplant (ANZDATA) registry. Patients were observed from time of transplant through follow-up, regardless of transplant function. The authors report 75% lower mortality risk (adjusted hazard ratio [aHR], 0.28; 95% confidence interval [95% CI], 0.18 to 0.69) among youth <20 years of age who were transplanted between 2005 and 2015 versus those transplanted in 1970–1985. These findings are consistent with results from the United States (2). In ANZDATA, Francis et al. also found that improvements in mortality risk over time were largely attributed to reductions in death from cardiovascular disease (aHR, 0.25; 95% CI, 0.08 to 0.68) and infections (aHR, 0.16; 95% CI, 0.04 to 0.70). Prior studies have not found changes in cause-specific mortality over time; however, those studies may have been limited by higher proportions of patients with unknown or missing cause of death (3,4). In the ANZDATA cohort of 1810 youth, 431 died; 174 (40%) died from cardiovascular cause, 74 (17%) died from infection, 50 (12%) died from cancer, and the remaining 31% died from other causes. The most common type of cancers were post-transplant lymphoproliferative disease and cancer of the digestive tract; cancer-related deaths were relatively stable over time. Francis et al. hypothesize that improved mortality risk is attributable to numerous factors, including improvements in immunosuppression, improved protocols to prevent and treat infections, and greater attention to cardiovascular risks. The study by Francis et al. had excellent data capture for both immunosuppressive regimens and causes of death.

Although the study by Francis et al. reassures the pediatric community that there has been progress over the past 50 years, there is much work left to be done to secure optimal outcomes for youth with ESKD. A recent US Renal Data System Annual Data Report included a disheartening table estimating remaining life expectancy among children and young adults with ESKD, reporting that, on average, youths with ESKD have a life expectancy at least 15–20 years shorter than a similar-aged youth in the general population (5). In the study by Francis et al., 81% of the time under observation was spent with a functioning transplant, and 608 youths (33.6%) received more than one transplant during a median follow-up time of 13.4 years (interquartile range [IQR], 5.5–24 years). Even with only 19% of the time of observation spent in dialysis, the median time to death was 10 years (IQR, 4–20) and median age at death was 24 years (IQR, 18–35). As a pediatric provider, parents and caregivers frequently ask me what lies ahead for their child with ESKD. Although a life expectancy of 65 years may sound favorable compared with outcomes in the 1980s, for parents in 2020, this is not good enough. Certainly, no one is guaranteed to live to reach 80 years of age, but what can we glean from the study by Francis et al. and others to help us optimize the lives of our pediatric patients with ESKD?

This study highlights the critical need for post-transplant care for children to be grounded in a CKD framework, with specific attention to BP, in addition to the usual primary focus on immunosuppression management and infection monitoring and prevention. There have been several retrospective cohort studies demonstrating that cardiovascular risks, particularly hypertension, are frequently underdiagnosed and consequently undertreated in youth with kidney transplants, despite widespread knowledge that cardiovascular disease is the leading cause of morbidity and mortality in pediatric ESKD (6,7). The Improving Renal Outcomes Collaborative (IROC), a multicenter, learning health system–based, quality improvement collaborative in the United States, may provide some infrastructure for future rigorous research in this arena (8). IROC’s first quality improvement initiative has specifically focused on improving BP control for transplanted youth by developing clinical pathways and processes for BP measurement and assessment.

In looking more closely at the study by Francis et al., three additional key findings shine light on critical targets for intervention. Besides transplant era, other significant correlates of cardiovascular and infection-related mortality included (1) deceased donor status, (2) failed transplant, and (3) adolescent age at time of transplant. Not surprisingly, being on dialysis after a failed transplant was associated with a three-fold higher risk of death (aHR, 2.9; 95% CI, 2.3 to 2.8) and crude incidence rates of death from cardiovascular or infectious causes were higher among youth on dialysis versus those with a functioning transplant. Despite different populations and methodologies, the majority of studies examining mortality risk in children with ESKD have similarly found the greatest mortality risk among deceased donor recipients, those with failed grafts, and adolescents.

First, we must promote living donation for children. In the United States, living donation rates for children have declined over the past 20 years. Although some of this decline has been attributed to changes in allocation policies, we have very poor understanding of how many pediatric patients have had potential donor candidates deemed ineligible. Further, we know nearly nothing about why potential pediatric donor candidates are ruled out. In general, pediatric donor candidates are younger than adult donor candidates, given they are often parents of young children, so, in theory, they may be healthier. Yet, younger donors also have more future time at risk to develop CKD, which may increase scrutiny among evaluating providers. Parents may be ABO incompatible. There may also be unique psychosocial barriers to donation for pediatric caregivers, such as being a single parent with other children and being unable to afford childcare while undergoing evaluation. Without an understanding of specific barriers, we are ill-equipped to effectively promote living donation. If ABO incompatibility is the issue, greater participation for kidney exchange programs, such as the National Kidney Registry, would be an appropriate target. If childcare expenses or time off work pose a substantial barrier, advocacy for public policy changes to offset the costs of living donation would be critical.

Second, we must make efforts to prevent transplant failure and sensitization, particularly for those children who do not have a suitable living donor. We need to start with donor selection, by creating a milieu of lower immunologic risk. Over time, allocation policies have moved away from prioritizing HLA matching. As opposed to adults, children are nearly guaranteed to need another transplant during their lifetime, so optimizing allocation strategies to reduce future sensitization is critical. Yet, we know that not all mismatches are created equal. To improve long-term outcomes, we need greater characterization and understanding of the expression and contribution of mismatches to development of de novo donor-specific antibody and sensitization so that we may make better informed decisions regarding donor-recipient matching (9). We also need advancements in technology to provide information about immunologic risk between potential donor-recipient pairs quickly and cost-effectively.

In addition, once a child is transplanted, we need to focus on strategies to prevent their allograft failure. We need to identify allograft injury with innovative biomarker profiles that detect early histologic sequelae so that we can change treatment regimens before there is chronic and irreversible damage. Biomarkers could also help us identify those patients who are more tolerant and in whom we can safely wean immunosuppression to minimize adverse effects such as infections. Concurrently, we must advocate for the inclusion of children in research on tolerance regimens and drug trials to establish safety and efficacy. Of note, belatacept, which was approved by the Federal Drug Administration in the United States in 2011 for adults, remains off-label with limited safety data in children.

We also need better markers to detect indiscretions in adherence early and in real time to enable us to provide timely and targeted interventions. We need institutional support and investment to provide multidisciplinary care, including the incorporation of pharmacists, psychologists, and social workers to assess adherence barriers and create targeted intervention strategies. Although adolescent age is consistently found to be a risk factor for mortality and graft loss, the majority of adolescents do survive their youth with functioning grafts. We need a better understanding of protective factors for success across stakeholders, from the patient and caregiver to the health care system. To this end, the majority of studies on pediatric and young adult transplant outcomes have focused on the “hard” outcomes of mortality and graft loss. Although we still have work to do on prolonging graft and patient survival, we must advance research by incorporating patient-centered outcomes to understand how our current treatments affect our patients’ daily lived experiences. The Standardized Outcomes in Nephrology (SONG) initiative is leading efforts to establish a set of core patient-centered outcomes across the spectrum of kidney disease for clinical trials and other forms of research (10). Our community would benefit from embracing SONG across diverse populations of children and youth to advance longitudinal progress in outcomes that matter to clinicians, patients, and caregivers.

In conclusion, Francis et al. have highlighted progress in reducing mortality among children, adolescents, and young adults, particularly with respect to cardiovascular disease and infectious causes. However, future efforts must focus on optimizing the long-term function of the first allograft, promoting living donation, and focusing on studies to advance understanding of meaningful histocompatibility, identify early allograft injury, and optimize therapeutic interventions. Future studies in children and young adults must also prioritize the inclusion of patient and caregiver stakeholders in study design, implementation, and outcomes assessment so that we truly understand that our treatments are making a difference for our patients, measured not only in the quantity of years lived, but in the quality of their daily lived experiences.

Disclosures

Dr. Amaral has nothing to disclose.

Funding

Dr. Amaral is supported by Eunice Kennedy Shriver National Institute of Child Health and Human Development grant R01HD091185 and National Institute of Diabetes and Digestive and Kidney Diseases grants R01DK120886 and R01DK110749.