Kidney paired donation (KPD) enables kidney transplant candidates with willing but incompatible living donors (LDs) to join a registry of other incompatible pairs to find compatible transplant solutions to overcome the barrier of ABO incompatibility or pre-existing donor-specific HLA antibodies.1 Even in large KPD programs, highly sensitized patients tend to accumulate.1 To assist these patients, several enhancements have been introduced; these comprise combining KPD with desensitization and including nondirected anonymous donors (NDADs) or compatible pairs.2-4 More recently, incorporation of advanced donation and utilization of deceased donor (DD) kidneys to initiate LD chains have been proposed.5
In this issue, Furian et al6 report the first actual case of a chain involving one DD, one incompatible pair, and one waitlist recipient, demonstrating that a DD kidney can be used to initiate a chain of crossover transplants. The authors describe the ethical considerations that preceded the actual chain of transplants, the protocols to allocate the chain initiating DD kidney and the kidney from the last donor in chain and other aspects.6 The authors ought to be commended for succeeding in demonstrating the feasibility of this approach; however, the wider uptake of this strategy outside countries where kidney donation by NDAD is either prohibited by law or culturally not widely accepted still faces some practical, logistical, and ethical challenges.
A key principle for KPD chains is that the recipient receives an LD kidney of equivalent quality that is better-matched than from its incompatible LD. However, it is hard to imagine that it will be easy to find chain-initiating DD kidneys of better or equal quality compared with LD kidneys, because low-kidney donor profile index (KDPI) DDs, as in the present case,6 are becoming increasingly rare.7 Although the index patient was not broadly sensitized, there were still 8 HLA mismatches with the DD donor compared with 10 with the intended LD.6 Because he was young and sensitized from a previous transplant, the predicted high eplet mismatch places him at risk for antibody-mediated rejection from de novo HLA antibodies,8 in turn reducing the chance for a subsequent transplant. The improvement from 2 to 1 DQ mismatches6 may not be relevant because some donor-recipient pairs with a conventional HLA-DQ mismatch of 2 have fewer eplet mismatches compared with other pairs with a conventional mismatch of one.9 Because the survival of DD-matched grafts is twice that for mismatched grafts, to convince that this strategy has a tangible benefit for DD kidney recipients, the algorithm used to assign the chain-initiating DD needs to be sophisticated enough to prioritize allocation to high-calculated panel reactive antibody patients and ensure good HLA matching.
While it is possible to create longer DD-initiated chains with large KPD pools, they are logistically very challenging: the time between the recipient receiving the DD kidney and their intended donor donating to the next link in the chain would have to be as short as possible to minimize the risk of donor reneging, and the same applies for the pairs downstream from the first pair. The advantages that NDADs bring into a KPD program have been extensively described,1 and it is undeniable that it is much better to work toward NDAD-initiated chains for a number of reasons. In NDAD chains, all patients receive an LD kidney, and eventually a waitlist patient will benefit from an LD transplant that he/she would not get. They are logistically easier to plan; the lead time between computer matching, performing crossmatches, and transplant surgery provides sufficient time to carefully evaluate the complex immunological aspects at stake, particularly when highly sensitized recipients are matched. Finally, they allow scheduling simultaneous donor surgeries even for relatively long chains involving up to 6–8 pairs, thus removing the risk of each donor reneging. In the end, more transplants can be performed with domino NDAD chains compared with DD-initiated chains.
There are some ethical concerns that may limit a broad uptake of this strategy. First, adopting this strategy into the organ allocation algorithms will change which patient is at the top of the allocation list. The kidney returned to a patient on the waitlist will unlikely go to the person who would have been the top ranked without this strategy. This introduces an element of inequity, denying a fair opportunity for everyone in need to receive a transplant, in favor of utility. The utility arguments supporting DD-initiated chains are that there is a net zero balance of kidneys leaving and returning to the DD waitlist and that because it can facilitate multiple transplants, including some patients on the DD waitlist, the removal of more patients from the waitlist decreases competition among those who remain on it. The biggest ethical concern about using DD kidneys to initiate KPD chains is that it disadvantages vulnerable populations, such as blood group O or elderly recipients. Blood group O patients traditionally wait longer on the DD waitlist because they can only source blood group O donors, who are most in demand. Because KPD registries have generally a greater proportion of blood group O candidates, a larger number of blood group O DD will be diverted from the waitlist, while nonblood group O kidneys will be returned to a waitlist patient. Furthermore, the diversion of low-KDPI kidneys, in an attempt to match LD organ quality, removes an even greater number of good quality organs from primarily elderly transplant candidates, in addition to those that are already directed to recipients with longest estimated posttransplant survival or to pediatric patients. As their KDPI increases, recipients of DD kidneys experience an increase in the rate of delayed graft function, which in turn is associated with shorter graft survival when compared with recipients that did not experience delayed graft function.10
Furian et al6 demonstrated that DD-initiated chains, with a great deal of effort, can work. The broader uptake of the proposed strategy in other jurisdictions will likely face some degree of resistance. Efforts to change the low rate of nondirected live donation in one’s country are as important as creating a KPD program that is much more complicated than it would be.
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3. Blumberg JM, Gritsch HA, Reed EF, et al. Kidney paired donation in the presence of donor-specific antibodies.Kidney Int2013841009–1016
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8. Kishikawa H, Kinoshita T, Hashimoto M, et al. Class II HLA eplet mismatch is a risk factor for de novo donor-specific antibody development and antibody-mediated rejection in kidney transplantation recipients.Transplant Proc2018502388–2391
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10. Zens TJ, Danobeitia JS, Leverson G, et al. The impact of kidney donor profile index on delayed graft function and transplant outcomes: a single-center analysis.Clin Transplant201832e13190