Favorable Outcomes of Kidney Exchange Program Live Donor Transplants

The only gift is a portion of thyself—Ralph Emerson

The prevalence of CKD continues to increase, driven by population expansion; aging; and the growing burden of diabetes, cardiovascular disease, and hypertension. Caring for patients with advanced stage CKD has a significant global effect because of the health care, societal, economic, and environmental costs involved. In 2017, the number of people worldwide with ESKD treated with KRT was estimated at 3.9 million and continues to grow annually.¹ Kidney transplantation offers the optimal treatment of ESKD, with lower mortality and improved quality of life compared with lifelong dialysis. For health care professionals, kidney transplantation reduces both resource burden and financial costs, regardless of donor quality.² Living donor kidney transplantation is associated with superior outcomes compared with deceased donor transplantation, providing extended transplant survival because of better donor organ quality after rigorous evaluation, strategic immunological matching, and the capacity to minimize the effect of cold ischemia time (CIT).

Kidney paired donation or kidney exchange programs (KEPs) facilitate living donor transplantation occurring despite barriers to direct live donor transplant encountered when potential donor–recipient pairs experience blood group or immunological incompatibilities. Following conceptualization of kidney paired donation by Felix Rapaport in 1986, the first exchange was performed in South Korea in 1991.³ In 1999, the practice began in Europe and soon after in the United States, with the first national KEP commencing in The Netherlands in 2004.⁴ National and international KEPs are established throughout the world and are now considered part of routine clinical practice.

In this issue of CJASN, van de Laar et al.⁵ have used data collected by the Dutch Transplant Foundation to define and compare 1-, 5-, and 10-year outcomes after ABO-compatible living donor kidney transplants (LDKTs) in KEP and non-KEP participants. More than 7500 recipients undergoing ABO-compatible LDKTs in The Netherlands from 2004 to 2021 were included in the analysis. Only 9% of all living donor transplants were performed through the KEP, and median follow-up time was 98 months. Patients receiving KEP transplants were more likely to be female and older, have longer dialysis vintage, be receiving repeat transplantation, have higher HLA mismatches and sensitization levels, as well as were more likely to receive kidneys from older, male donors. A propensity score-matching model was also generated to account for these baseline differences between KEP and non-KEP recipients. In the model, 547 recipients in the KEP group were matched with 1573 recipients in the non-KEP group, allowing the authors to mitigate the effect of baseline characteristic differences as confounding variables, affording a more robust comparison of long-term outcomes between the groups.

The authors identified no differences in 1-, 5-, and 10-year death-censored graft survival (DCGS) or kidney function measured by eGFR between those receiving KEP or non-KEP transplants. These findings were replicated in the propensity score-matched cohort. Significant differences in the rates of rejection and patient survival were identified in the KEP versus non-KEP groups, with KEP recipients experiencing more rejection episodes and lower survival, although not reproducible with propensity score matching. Delayed graft function (DGF) rates were higher than expected, and differences in DGF rates were identified in both the original and propensity-matched datasets.

Collectively, the findings by van de Laar et al. suggest that although patients entering KEPs are typically at higher immunological risk with more comorbidity, they experience comparable transplant outcomes with those who receive directed LDKTs. Using propensity score-matched modeling, van de Laar et al. have elegantly demonstrated that differences in rejection rates and patient survival in KEP recipients result from the elevated risk profile of KEP recipients, including increased comorbidity, longer dialysis vintage, higher levels of sensitization, and more frequent repeat transplantation.

Interestingly, the authors identified that an elevated risk of DGF is directly associated with KEP transplantation. Those experiencing DGF were less often preemptively transplanted and had longer dialysis vintage, higher panel reactive antibody, and a higher incidence of nephrotic syndrome as the cause of ESKD, in addition to more than three times greater hazard of death-censored transplant failure compared with recipients with immediate transplant function. Surprisingly, despite more frequent DGF in KEP transplants, CIT was comparable between KEP and non-KEP recipients and rarely exceeded 4 hours. This similarity in CIT is primarily a reflection of the Dutch National Living Kidney Donor KEP requirement for donors to travel to the recipient hospital where both the donor nephrectomy and recipient implantation surgeries are performed.

Van de Laar et al. additionally compared the results of the Dutch National Living Kidney Donor KEP with their analysis of the United Kingdom Living Kidney Sharing Scheme (UKLKSS), the largest KEP in Europe. In the UKLKSS, like most KEP programs, donated organs travel to the recipient rather than the donor, leading to longer CITs and higher attendant risk of DGF.⁶ Unexpectedly, DGF was more frequent in The Netherlands in both KEP and non-KEP transplants than the UKLKSS, despite longer median CIT in KEP transplants in the UKLKSS. In contrast to The Netherlands KEP, significant differences in eGFR at 1 year and 5 years were identified, but no difference in rejection rates were found between KEP and non-KEP transplants in the UKLKSS. Five-year DCGS rates were comparable between the two countries and were higher when compared with the United States and Europe overall.⁷ The comparable DCGS rates suggest that the transport of donor kidneys to the recipient center does not adversely affect transplant outcomes despite transport-related increases in CIT.

The methodological strengths of this study are the analysis of a large nationwide KEP cohort, including the longest median follow-up of a KEP cohort published to date, the rigorous statistical analysis, and the implementation of a propensity score-matching approach to address differences in baseline characteristics between KEP and non-KEP patients in assessing DCGS and patient survival. In addition, by assessing long-term outcomes after KEP transplants across multiple centers with comparable results, the authors have further highlighted the substantial benefits of KEPs.

The results from The Netherlands replicate similar benefits of KEPs that have been demonstrated internationally in other (predominantly) White populations, supporting the notion that such findings are generalizable to this demographic. Leeser et al. reviewed US data from more than 2300 National Kidney Registry recipients with median follow-up of 3.7 years, demonstrating similar recipient characteristics: female, older, longer dialysis vintage, greater sensitization, and higher proportion requiring retransplantation, but equivalent outcomes.⁸ DGF rates were higher in the KEP, but this did not seem to affect 7-year outcomes, and the variability of these findings reflects the literature in deceased donation. Several transnational KEPs exist including the Australian and New Zealand Paired Kidney Exchange (Australia and New Zealand), CAI (Czech Republic, Austria, and Israel), KEP South Transplant Alliance (Spain, Italy, and Portugal), and Scandiatransplant Exchange Program (STEP) (Denmark, Estonia, Finland, Iceland, Norway, and Sweden). The Scandiatransplant Exchange Program, established in 2019, provides a multinational KEP for 29 million people and includes ABO-incompatible pair participation.⁹ Although no direct comparisons were available with directed LDKTs, median CIT was longer (>300 minutes) and the DGF rate was 4%. A much smaller program has been established in Nepal with similar success but significant sex-based differences between donors and recipients.¹⁰

Importantly, this study provides evidence of a correlation between KEP transplantation and favorable post-transplant outcomes, but, because of the observational nature of the data, there are residual limitations in the ability to attribute direct causation between KEP transplantation and outcomes. Despite these constraints, the authors highlight the benefits of KEP-based transplantation success, using propensity matching to undertake a balanced comparison between KEP and non-KEP recipients, accounting for potential confounding factors related to baseline demographic, comorbidity, immunologic, and transplant-related variables. This study supports KEP transplantation as a comparable and appropriate option to directed LDKT within hierarchical treatment decision making for patients with ESKD and supports the development and expansion of KEPs to increase national and transnational live donor transplant rates.

The benefits of living kidney donation are evident, and although much of the literature reflects recipient outcomes, the effect on donors must be considered. Unspecified donation has been the subject of ethical debate, but studies have shown return to baseline health and positive psychological outcomes with limited long-term negative sequelae. KEPs remain a crucial innovation which assuages—but does not solve—challenges around scarcity of donor organs that so clearly improve long-term outcomes for those with CKD.

Supplementary Material

cjasn-20-317-s001.pdf ^{(1.3MB, pdf)}

Disclosures

Disclosure forms, as provided by each author, are available with the online version of the article at http://links.lww.com/CJN/C155.

Funding

None.

Author Contributions

Conceptualization: Sharon L. Ford, Natasha M. Rogers.

Writing – original draft: Sharon L. Ford, Natasha M. Rogers.

Writing – review & editing: Sharon L. Ford, Natasha M. Rogers.