INTRODUCTION
Living donor renal transplantation is the most promising solution for closing the gap between organ supply and demand. Despite growing efforts to adopt this option for patients with end-stage renal disease (ESRD), the percentage of living donations has decreased in the United States, from 50.1% in 2000 to 38.2% in 2017 of the total number of kidney transplants.1
The figures vary in European countries, where living donor transplantation programs are still expanding. ABO-incompatible or kidney paired donation (KPD) programs have yet to be fully and uniformly developed; while the Dutch and UK programs have already optimized these processes, other European countries such as Spain, France, Italy, the Czech Republic, Austria, Belgium, Switzerland, Poland, and Scandinavia have only just started such programs or are still striving to implement one.
In Italy, 2221 kidney transplants were undertaken in 2017, and 310 of them were from living donors. This meant 61% more than in 2012 and a 1.7-fold increase over 2007.2 Desensitization techniques for ABO incompatibility are now applied at the highest-volume transplant centers. KPD programs have only been implemented in a few cases, however, due mainly to the small number of patients enrolled in such programs. KPD nonetheless seems to be the best option for candidates with circulating HLA antibodies directed against their willing donors.
Several ways to expand the use of KPD have been proposed in recent years, with dissimilar applicability, including (1) national and international KPD registries and match runs, using optimization algorithms to match pairs, including 3-way matches; (2) altruistic donors to initiate chains of KPD; (3) combining KPD with desensitization to relax the requirement for a negative crossmatch for highly sensitized patients; (4) including compatible pairs in small, single-center pools to achieve match rates that might even surpass those attainable with a nationwide list comprising only incompatible pairs; and (5) list exchanges and nondirected donations, so that incompatible living donors can provide a kidney for a candidate on the deceased donor (DD) list and, in return, their intended recipients take priority on the DD waiting list (WL).3-5
More recently, it has been suggested that DD kidneys could be used to initiate living donor chains,6,7 hypothesizing that a pilot program would show a positive impact on patients on the DD WL too, as well as improving the quality of kidneys allocated to patients on the WL, irrespective of ethnicity and blood type. There are important issues to consider when implementing such program, however, that may raise ethical and logistical concerns. These include (1) the parameters for prioritizing the chain-initiating kidney (CIK) recipient on the WL, (2) the acceptable quality and risk characteristics of the CIK donors, (3) the number of DD kidneys that might be used as CIKs, (4) the chain-ending kidney allocation strategies, (5) how to compare the quality of the living donor’s kidney with that of a DD kidney, (6) the risk of living donors reneging due to the nonsimultaneity of the procedures, and (7) the impact of cold ischemia time on chains in large regions.
As previously stated by Wall et al,7 for such an innovation to be implemented, we need to consider all these challenges. Here we describe how the ethical and logistical concerns were addressed to complete our first DD-initiated chain.
MATERIALS AND METHODS
Quantifying the Benefit
To measure the potential gain of the program and establish the number of DD-CIK that could ideally be diverted from the standard WL, we used retrospective data on the pool of incompatible donor/recipient pairs at a single center. We simulated the gain of implementing KPD transplants at a local level, starting KPD chains from a DD organ, continuing with consecutive donations involving incompatible pairs of living donors and recipients, and ending with a transplant for a patient on the WL for a DD organ who had no willing donor.
Our sequential algorithm has already been described,8 and details of the population studied are available in Supplemental Document S1 (SDC, https://links.lww.com/TP/B690).
In our simulation, the recipient of the DD organ could be any of the ESRD patients (n = 16) with an incompatible living donor who did not receive a transplant during the period considered. Receiving a transplant, even from a DD, would certainly represent a gain for these patients, but it might be argued that this policy would subtract organs from the pool available for candidates on the WL. It should be emphasized, however, that the organ provided by the living donor of the last pair in the chain would be transplanted into a patient on the DD WL. Therefore, in theory at least, patients on the WL without a potential living donor would not suffer from the introduction of this allocation procedure—also because the expected graft survival of a living donor kidney is better than that of a DD kidney.9 There nonetheless has to be some equity granted to candidates on the WL less likely to find a compatible organ. We identified 2 categories of candidates on the WL who deserve special consideration, that is, those unlikely to be transplantable (UT) for immunological reasons and those with blood type O.
UT were defined on the basis of the Nord Italia Transplant program (NITp) classification, which considers UT as patients on the WL for >5 years, or on dialysis for >7 years due to immunological issues (panel-reactive antibody [PRA] >80%, referred to either class I or class II HLA antigens). During the study period, 35 UT were listed at our center and considered available for running the algorithm. UT deserve to be protected at all costs against any detrimental effect of the procedure, and of receiving preferential treatment to increase their chances of receiving a transplant because they have already been waiting a long time. Patients with blood type O should not be at a disadvantage either, as they may have to wait longer than other candidates on the WL due to the unbalanced distribution of blood type O donors. We therefore added 3 constraints to our algorithm. First, DD organs allocated directly to UT were excluded from the algorithm, and we only considered organs allocated to patients on the standard WL. Second, whenever there was >1 living donor chain of maximal length, we selected the one (if any) that ended with a UT. Third, if a blood type O organ was used to start the chain, then it had to either end with a UT or return a blood type O organ to the standard WL.
Allocation Policy and Characteristics of CIK
For a proper allocation of the CIK, the following immunological variables of donors and recipients were taken into account: ABO identity; HLA typing for both class I (A, B, C) and class II (DP, DQ, DR) antigens; the unacceptable antigens were those with a demonstrated single antigen bead assay (Luminex) with mean fluorescence intensity (MFI) >3000.
Using DD kidneys to initiate a chain by incorporating this program into the allocation algorithms would change patient selection. Even if the kidney at the end of the chain were returned to a patient on the DD WL, it probably would not be allocated to the patient who would have been at the top of the match list if this program had not been implemented. Taking into account such a potential flaw, for patients on the DEC-K (ie, KPD starting from a DD kidney) program, we established a DD allocation strategy that would not put specific patient categories with a higher allocation priority at a disadvantage. In the interregional NITp program, which covers an area with a population of >19 million, DD kidneys are allocated to a single WL with about 2800 patients in all. Candidates in the DEC-K program could be selected for any given organ becoming available in the NITp area. Such an allocation only takes place if it does not compete with higher priority national programs, such as the urgency program (ESRD patients lacking a vascular access for dialysis), the PNI (Italian national program for hyperimmunized patients), or the kidney-pancreas program, or other interregional programs (for 0–1 HLA mismatches [MM] or UT).
The quality of the CIK was calculated with the Kidney Donor Risk Index (KDRI) and the Kidney Donor Profile Index (KDPI), and the score was expected to be comparable with the Living Kidney Donor Profile Index (LKDPI) of their willing living donor. The DDs were also defined as standard in terms of infectious or neoplastic risk.
The living donor kidney ending the chain was assigned according to Italian allocation policies: in the absence of a candidate on the emergency list or compatible PNI patients, the graft was allocated with the NITK4 algorithm, which takes into account blood type, HLA matches, and time on dialysis.10
Logistical and Ethical Issues
To keep the cold ischemia time of the CIK as short as possible, the pilot program was limited to a single center (Padua University Hospital) and its procurement area (the Veneto region). A complement-dependent cytotoxicity (CDC) crossmatch was performed with a candidate current serum.
The ethical implications were clearly and extensively exposed to the Veneto Regional Authority’s Bioethical Committee (making further institutional review board approval unnecessary). A favorable opinion was obtained in November 2017, and the program was defined as conforming to the principle of benevolence, with a high social and healthcare value. A specific information and consent form for patients and their willing donors was prepared with the collaboration of psychologists and bioethical and legal medicine experts. It was explained to the parties involved by 2 physicians on the transplant team (a surgeon and a nephrologist). When the CIK became available, and before starting the surgical procedures, confirmation of consent was required from both parties to avoid the risk of the living donor’s withdrawal.
RESULTS
Quantification of Benefit
The results of the retrospective simulation are summarized in Table 1. Given a cohort of 16 incompatible pairs, and a pool of 69 standard DDs allocated to the Padua Transplant Center, it emerged that, by using 7 grafts from DDs to start a chain, it was theoretically possible to transplant 50% of the patients who would not have otherwise been able to receive a transplant over a period of 3 years. This means that only 10% of the whole pool of standard grafts available was used for the DEC-K program.
;)
TABLE 1.: Results of the retrospective analysis
In most cases (6 out of 7), the chains ended with a UT receiving a kidney from a living donor instead of a DD organ.
Report of the First Case
The recipient was a 53-year-old male with ESRD due to IgA nephropathy, who had received the first kidney transplant from a DD in 2003, and his graft had subsequently ceased to function due to chronic damage. He started on hemodialysis again in May 2017. His blood type was A negative, and he had a history of blood transfusions. His pretransplant workup revealed no contraindications to a second kidney transplant. His 53-year-old wife (blood type A positive) wished to donate him a kidney and presented no clinical or psychological contraindications to donation. Although the patient was not broadly sensitized (PRA class I: 50%; PRA class II: 65%), the couple had a CDC-positive crossmatch, and the Luminex single bead assay revealed donor-specific antibodies (anti-A2, MFI: 20.185; DQ06:03, MFI: 1.368). Moreover, HLA-A2 was a repeat MM with the patient’s previous transplant. The couple was enrolled in the crossover national KPD program in October 2017, and the patient was actively on the WL for a DD from then on. The couple was offered the chance to enter the DEC-K program in February 2018 and completed the psychological and immunological workup on March 9, 2018.
Four days later, the patient was offered a CIK from a DD. The donor was a 28-year-old white male, 183 cm tall, weighing 94 kg, a donor after brain death due to a head trauma, with no history of hypertension or diabetes, hepatitis C virus negative, serum creatinine 0.57 mg/dL (KDRI 0.61, KDPI 3%), 2 HLA-A, 2 HLA-B, 1 HLA-DR, 1 HLA-DQ, and 2 HLA-DP MMs.
The kidney transplant was performed the next day using the standard technique. The cold ischemia time was 6 hours, and the postoperative course was uneventful, with an immediate recovery of renal function. The patient was discharged on postoperative day 9 with serum creatinine 0.9 mg/dL.
Two days after her husband’s transplant, the wife underwent laparoscopic left nephrectomy, with no complications, and she was discharged on postoperative day 3.
The living donor kidney was allocated according to the NITp algorithm to a recipient on the WL (male, aged 47 y, blood group A positive). This chain-ending patient was at his first transplant, on dialysis since April 2013, suffering from Schoenlein Henoch purpura, height 165 cm, and weight 62 kg. The LKDPI calculated for the pair was 2 because the donor was not hypertensive, a nonsmoker, with estimated glomerular filtration rate 102 mL/min, body mass index 20.5 kg/m2, 2 HLA-B MMs, and 1 DR MM. The living donor kidney transplant procedure was performed with a cold ischemia time of 1 hour and 45 minutes, and renal function recovered promptly. The CIK recipient had no complications and was discharged on postoperative day 10 with serum creatinine 1.0 mg/dL.
DISCUSSION
It had already been suggested that DD grafts could be used as a source of CIK to start chains.6,7 The underlying ethical issues, as detailed above, briefly concern (1) the proper strategy for allocating a CIK from a DD and the chain-ending kidney, (2) the pros and cons of exchanging a living donor kidney for a DD kidney, (3) the risk of living donor withdrawal, and (4) the consent of all parties.
The precedent for using a DD organ in kidney exchanges was reported by Delmonico et al.11 Their experience can be better described as a list exchange procedure, however, because “following transplant of the kidney from the living donor to the highest ranking appropriate individual identified by the transplant center’s list, the incompatible patient for whom the donor kidney was originally intended receives the right of first refusal for the next ABO identical (crossmatch negative) DD kidney available within the Region.” Unlike the case of the present report, in a list exchange donors would donate an organ before their intended recipient receives one from a DD. The degree of uncertainty regarding prioritization on the WL, especially in the case of highly sensitized patients such as those involved in our program, would also become an ethical issue when asking donors to anticipate their donation. The strategy for allocating the chain-ending kidney was according to the rules of the authors’ match run, however, and a similar approach was used in our experience, on the basis of the allocation strategy of the NITp (NITK4 algorithm).
More challenging, in our opinion, is the selection of an adequate CIK from a DD. The decision should take into account the expected graft survival and the risk of disease being transmitted from a DD kidney compared with a living donor kidney. Our protocol therefore considers the KDRI and KDPI scores for the DD kidney and compares them with the LKDPI12 of the subsequent matches. It also excludes donors carrying a risk of transmissible disease. The predictive value of the LKDPI, compared with the KDPI of DD, has recently been validated in a European cohort; based on these findings, corresponding subgroups of LKDPI and KDPI showed comparable graft survivals.13 Nevertheless, each CIK and living donor should be thoroughly assessed, taking into account several clinical aspects that are not currently (or only partially) included in these indexes, such as male/female sex, donor/recipient weight ratio, MM, preemptive status of recipients, and specific comorbidities of donors. In the reported case, the HLA match was not very good, though it was better than with the intended living donor (8 MM for the CIK versus 10 MM for the intended living donor), but the patient was sensitized against the living donor’s HLA antigens to such an extent that even the CDC crossmatch was positive. When applying the immunological analysis to the conventionally considered HLA antigens (HLA loci A, B, and DR), the recipient had 5 MM with the CIK donor, as opposed to 6 MM with the intended living donor. Although the difference in outcome between a 5 and a 6 MM is probably not substantial, it has to be said that (1) class II DR mismatches are known to be associated with worse outcomes14; (2) the DQ mismatch was 1 with the CIK donor as opposed to 2 of the original living donor, and this is also quite relevant considering that sensitization against DQ antigens is the most common following transplantation; (3) though imperfect, the KDPI and LKDPI scores include and lend weight to HLA MM, so the importance of the HLA match is already taken into account when the scores are calculated; and (4) finally, the need for a greater degree of HLA compatibility would have unavoidably had a negative impact on the waiting time, which would certainly have exceeded the “4-day” wait that we were able to offer our patient. A shorter waiting time and period on dialysis is known to significantly affect graft and patient survival, and transplantation outcome, and this should be borne in mind, as well as the degree of HLA match.
One further issue to address is how many kidneys are diverted from patients on the WL. The CIK may be allocated to any candidate with an incompatible living donor, irrespective of their PRA. Even patients with a low PRA may have an incompatible living donor. In our simulation, in the retrospective population of DD and incompatible pairs, only 10% of the standard DD kidneys (7 grafts) would have been diverted from the WL, enabling 50% of the patients in incompatible pairs to receive a transplant. Our approach would also have returned 7 additional high-quality grafts (from living donors) to the donor pool, which would have been transplanted into UT or blood group O patients. The chain-ending kidney (from a living donor) would be allocated to a candidate on the WL, preferably a UT, applying the abovementioned NITK4 allocation policy. The same allocation policy is also applied to the chain-ending kidney in chains starting from donors. The usefulness of the proposed program seems undeniable because it increases the overall number of kidneys available for transplantation and consequently the aggregate quality and quantity of life for ESRD patients.
One last important question to consider is how to manage the consent process for all the parties involved. The key points to cover, to ensure that these parties all receive adequate information, must make sure prospective living donors and CIK recipients understand the level of prioritization afforded by the program, the quality of the DD grafts considered, and the respect for their freedom to withdraw from the program at any time. It is of paramount importance to avoid donor reneging because performing several surgical procedures simultaneously would be logistically very difficult within the DEC-K program. To minimize the risk of donors reneging, each pair of donors and candidate recipients goes through a thorough educational process with 2 very experienced transplant physicians (a surgeon and a nephrologist) to ensure that they fully understand and appreciate how the DEC-K program works. The educational process therefore needs to be very thorough and can take an amount of time that is impossible to predict and difficult to standardize, even at the same center, as it depends on the psychological and attitudinal features of the patients and physicians concerned. We believe that there should be dedicated and experienced surgeons and nephrologists to explain the program to the potential pairs and answer any questions they may have. Such a procedure can hardly be standardized, but—in our opinion—the essential requirements of such a process should include at least:
- a 2-step psychological assessment, the commitment of 2 experienced physicians to explain the program,
- a third party or committee to assist the pair in their decision-making process, the ultimate goal of which is to assess their degree of understanding of the program and their willingness to participate.
It is noteworthy, however, that—unlike the case of list exchanges—patients in a chain of donations receive a kidney before their own donor relinquishes an organ to another patient. In addition, for each incompatible pair who can start a chain of donations, the optimal chain to complete can be established in advance, which makes the logistics easier. Real crossmatches can be performed as soon as the results of the virtual crossmatch are available. In this way, whenever a DD-CIK becomes available, there is no need to perform the crossmatch. In agreement with existing national policy, sera from potential recipients are collected every 3 months, and an updated assessment of the immunological profile is undertaken as soon as new samples are available. Although maximum flexibility is applied within the protocol in terms of logistics, the most likely scenario is that the kidney will travel. This is not expected to be associated with detrimental consequences in terms of cold ischemia injury (depending on the extent of the territory involved in the program, of course). In this first case, we opted to use the local pool of DD to minimize the cold ischemia time (which was 6 h in the case reported here), while the transplant from the living donor could be organized in much the same way as when the chain starts with an altruistic donor.15
It has to be acknowledged that using kidneys from unspecified living donors to initiate exchange programs has several advantages over a program of DD-initiated chains, as well as fewer (or at least different) ethical dilemmas, for various reasons: all patients receive a graft from a living donor, patients on the WL will always benefit, and the procedures are logistically easier to plan. There are several differences between the legislation adopted by different European Union countries that should be taken into consideration, however. For instance, donation is prohibited by law in some countries (such as Germany). In others (such as Italy), incentives to prompt donations, that is, soliciting donations through social media or emphasizing a given patient’s need for a kidney transplant, is illegal and living donations are only permitted in the context of a long-standing emotional relationship or in the frame of anonymity.
In our case, the motivation to explore further options to expand domino chains between incompatible pairs stemmed from the scarcity of unspecified living donors and the abovementioned Italian legal constraints. Nevertheless, the opportunity to include DD when implementing KPD may supplement and complement (rather than replace) an established KPD program through kidney paired exchanges and donors.16
To the best of our knowledge, the present report describes the first case of a chain of kidney transplants initiated with a DD kidney. Unlike previous experiences,17 this case was deliberate and programmed, following a straightforward process designed to address ethical and logistical issues. We are confident that extending the program to a national scale will enable us to optimize the allocation strategies and obtain longer chains, thus minimizing waiting times for highly immunized candidates with incompatible willing donors.
ACKNOWLEDGMENTS
The authors acknowledge Alessandro Nanni Costa, MD, and Massimo Cardillo, MD, for their contribution to the development of the project as Directors of the National Transplant Center and the NITp, respectively.
REFERENCES
1. Organ Procurement and Transplantation NetworkNational data2018Available at
https://optn.transplant.hrsa.gov/data/view-data-reports/national-data. Accessed January 12, 2018
2. Centro Nazionale TrapiantiAttivitá di donazione2018Available at
http://www.trapianti.salute.gov.it/imgs/C_17_pubblicazioni_2591_allegato.pdf. Accessed January 12, 2018
3. Roth AE, Sönmez T, Unver MU, et al. Utilizing list exchange and nondirected donation through ‘chain’ paired kidney donations.Am J Transplant200662694–2705
4. Veale JL, Capron AM, Nassiri N, et al. Vouchers for future kidney transplants to overcome “chronological incompatibility” between living donors and recipients.Transplantation20171012115–2119
5. Liu W, Treat E, Veale JL, et al. Identifying opportunities to increase the throughput of kidney paired donation.Transplantation2015991410–1415
6. Melcher ML, Roberts JP, Leichtman AB, et al. Utilization of deceased donor kidneys to initiate living donor chains.Am J Transplant2016161367–1370
7. Wall AE, Veale JL, Melcher ML. Advanced donation programs and deceased donor-initiated chains-2 innovations in kidney paired donation.Transplantation20171012818–2824
8. Silvestre C, Nicolò A, Cornelio C, et al. Potential gain of utilizing kidneys from deceased donors to initiate “chain” kidney paired donations: quantification of benefit through a real-world retrospective analysis.Transplant Int201730Suppl 282
9. Hart A, Smith JM, Skeans MA, et al. Kidney.Am J Transplant201616Suppl 211–46
10. Poli F, Cardillo M, Scalamogna M. Clinical relevance of human leukocyte antigen antibodies in kidney transplantation from deceased donors: the north Italy transplant program approach.Hum Immunol200970631–635
11. Delmonico FL, Morrissey PE, Lipkowitz GS, et al. Donor kidney exchanges.Am J Transplant200441628–1634
12. Massie AB, Leanza J, Fahmy LM, et al. A risk index for living donor kidney transplantation.Am J Transplant2016162077–2084
13. Rehse G, Halleck F, Khadzhynov D, et al. Validation of the Living Kidney Donor Profile Index in a European cohort and comparison of long-term outcomes with US results.Nephrol Dial TransplantMay 9, 2018[Epub ahead of print]. doi: 10.1093/ndt/gfy118
14. Shi X, Lv J, Han W, et al. What is the impact of human leukocyte antigen mismatching on graft survival and mortality in renal transplantation? A meta-analysis of 23 cohort studies involving 486,608 recipients.BMC Nephrol201819116
15. Bofill M, Calderon M, Castro F, et al. The Spanish Kidney Exchange Model: study of computation-based alternatives to the current procedure.In: Lecture Notes in Computer Science201710259Cham, SwitzerlandSpringer
16. Flechner SM, Thomas AG, Ronin M, et al. The first 9 years of kidney paired donation through the national kidney registry: characteristics of donors and recipients compared with national live donor transplant registries.Am J Transplant2018182730–2738
17. Flechner SM, Leeser D, Pelletier R, et al. The incorporation of an advanced donation program into kidney paired exchange: initial experience of the national kidney registry.Am J Transplant2015152712–2717
