Embracing Complexity to Better Serve Pediatric Kidney Transplant Recipients

Although kidney transplantation is the treatment of choice for almost all patients with kidney failure, timely transplantation is uniquely beneficial for pediatric patients. In addition to survival and quality-of-life advantages of transplantation shared by their adult counterparts, children with kidney failure who receive a transplant avoid the long-term deleterious impacts of dialysis exposure on growth and neurocognitive development.^1–3 Importantly, pediatric transplant recipients also have a longer expected post-transplant lifespan and are therefore more likely to experience allograft failure during their lifetime. Thus, recipient optimization and careful donor selection are essential to maximize graft survival and minimize the total number of transplants a pediatric recipient may eventually need.

In this issue of CJASN, Coens and colleagues used European transplant registry data to elucidate how recipient, donor, and transplant characteristics differentially affect the risk of graft failure in the short-term, intermediate-term, and long-term post-transplant periods.⁴ Analyzing 4528 pediatric kidney transplant recipients from 1990 to 2020, they reassuringly found that graft survival improved throughout the study period. The overall risk of graft failure was highest in the first post-transplant month, likely related to technical issues, emphasizing the value of pediatric transplantation at experienced, high-volume centers. Surprisingly, the association between recipient pretransplant dialysis time and graft failure dissipated by 5 years post-transplant. Important donor considerations include the finding that just two or more donor–recipient HLA mismatches were associated with an increased risk of graft failure throughout the follow-up period. Furthermore, both low donor age and high donor age were associated with inferior graft survival, with an apparent ideal donor age range of 12–36 years to minimize the risk of graft survival in both the short-term (donor age 12–45) and long-term (donor age 2–36) post-transplant periods.

This study's limitations include that follow-up was censored at 15 years after transplant, a period that is somewhat short given the young age of recipients included in the study. This limitation is especially important given a median follow-up time of <8 years and that the analysis of long-term outcomes was reliant on the outcomes of older transplants whose management may not be comparable with those of transplants today. Key data not included in the analysis include the presence and type of pretransplant donor-specific antibodies. Nevertheless, by advancing our understanding of donor characteristics associated with the best outcomes for pediatric kidney transplant recipients, these important data can inform updated deceased donor kidney allocation policies that better prioritize pediatric candidates for the organs from which they will derive greatest benefit.

Internationally, pediatric allocation priority is heterogeneously structured but clinically simplistic.⁵ Donor age is commonly used as the primary mechanism to identify organs for prioritized pediatric sequences. Many systems, including EuroTransplant, Brazil, and South Africa, prioritize pediatric donor organs (younger than 18 years) for pediatric recipients, although thresholds for prioritization range from donor age younger than 16 (India) to younger than 50 years (Scandinavia). Some systems (e.g., Australia, New Zealand, and Saudi Arabia) award pediatric candidates additional points as a primary or supplemental means of prioritization, but these bonuses convey pediatric priority for all available organs without consideration for which organs are best suited for pediatric recipients. In many places, pediatric priority is overridden by other prioritized candidates, including multiorgan or highly sensitized patients.

In the United States, which performs the highest number of pediatric kidney transplants globally, pediatric prioritization comes primarily from preferential allocation of kidneys from donors with a kidney donor profile index (KDPI) of <35% to candidates waitlisted before age 18 years, albeit with multiorgan transplant candidates and highly sensitized candidates prioritized still higher than pediatric candidates for all organs. This system was implemented in 2014 as part of the kidney allocation system, replacing a prior system (SHARE35) that used donor age younger than 35 years as the criteria for pediatric prioritization. This change was followed by an increase in delayed graft function, decreased access to pediatric donor kidneys, and longer pretransplant dialysis time for pediatric kidney transplant recipients.^6–9

It is evident that donor KDPI or age alone may not be adequate to appropriately identify organs most suitable for pediatric prioritization. In the United States, for example, among donors with ≥1 kidney recovered for the purpose of transplant between 2015 and 2022 with available data, approximately 30% of deceased donors age 12–36 years—the optimal donor age for pediatric recipients—had KDPI ≥35% and therefore were not prioritized for pediatric recipients. Furthermore, 18% of donors had discrepant age younger than 35 versus KDPI <35 designation, and both groups—age younger than 35 and KDPI <35—included many donors whose age confers an increased risk of graft failure (Figure 1A). In fact, the Organ Procurement and Transplantation Network's own guide to using the KDPI states, “[T]he KDPI was developed using graft outcomes from strictly adult transplant recipients; pediatric recipients were not included in the modeling process. Consequently, KDPI should be used with caution when assessing donor quality from the perspective of a pediatric candidate.”¹⁰ The consequences of these discrepancies may be significant: On the basis of data from Coens et al. in this issue of CJASN, at 8 years post-transplant, a pediatric recipient has a three-fold higher risk of graft failure for a kidney from a 50-year-old donor with five HLA mismatches compared with a 25-year-old donor with one HLA mismatch, despite both potentially having KDPI <35%. The full implications of this change in the donor pool for allograft longevity may therefore not yet be apparent given that kidney allocation system was only implemented in December 2014. The historical use of age alone also insufficiently assessed donor quality: From 2015 to 2022, US KDPI <35% donors were less likely than age younger than 35 years donors to have hypertension, diabetes, or donation after cardiac death (DCD) status; furthermore, kidneys from very young donors have a higher risk of graft failure. Maximizing pediatric transplant outcomes therefore requires a more complex allocation system using a combination of donor characteristics to prioritize organs for pediatric candidates.

Figure 1.

Past, present, and alternative criteria for deceased donors prioritized for pediatric kidney transplant recipients in the United States. (A) Donor age versus KDPI among donors with ≥1 kidney recovered for the purpose of transplant in the United States from 2015 to 2022, with notations indicating donors prioritized for pediatric kidney transplant candidates after the December 2014 implementation of KDPI <35%-based prioritization under the KAS versus pre-KAS prioritization on the basis of donor age younger than 35 years (SHARE35). (B) Transplants from IDPC by age of recipient during this period, where the green line indicates recipient age of 18 years. IDPC, ideal donors for pediatric candidates; KAS, kidney allocation system; KDPI, kidney donor profile index.

Given the relatively small number of pediatric transplant candidates, allocation schemes can focus on prioritizing pediatric candidates above all others for kidneys best suited for them without sacrificing access for other candidates. Donor age, size, comorbidities, and HLA mismatches could be used together to identify a subset of ideal donors for pediatric candidates (IDPC) for which pediatric candidates are prioritized. For example, IDPC might be defined as any donor with (1) age 12–17 years, (2) 18–35 years with height <160 cm, given that smaller kidneys may be more appropriate for transplantation into the smallest pediatric recipients, (3) donor age 18–35 years with creatinine ≤0.7 mg/dl and no medical risk factors (hypertension, diabetes, donation after cardiac death, hepatitis C, proteinuria, or >20 pack-year smoking history), or (4) age 18–35 years with 0–1 ABDR HLA mismatches with any pediatric candidate. Although the last clause is challenging to quantify, only 8% of deceased donors meet the first three IDPC criteria. Nevertheless, 90% of transplanted kidneys from such donors since 2014 were used for adult recipients, while accounting for only 9% of adult transplants but 31% of pediatric transplants (Figure 1B).

While pediatric prioritization for deceased donor kidneys has been successful in minimizing time to transplant for children, these systems do not adequately prioritize the organs that are most suitable for pediatric recipients. Allocation schemes drawing on our growing understanding of pediatric transplantation would benefit the transplant system by reducing post-transplant graft failure and burden of retransplantation while optimizing short-term and long-term outcomes for pediatric patients.

Disclosures

All authors have nothing to disclose.

Funding

S.A. Husain: NIDDK (K23DK133729) and Nelson Family Faculty Development Award.

Author Contributions

Conceptualization: S. Ali Husain, Lindsey M. Maclay.

Formal analysis: S. Ali Husain.

Writing – original draft: S. Ali Husain, Lindsey M. Maclay.

Writing – review & editing: S. Ali Husain, Lindsey Maclay.