Julie A. Houp

Domino paired kidney donation: a strategy to make best use of live non-directed donation

Current models for allocation of kidneys from living non-directed donors Living non-directed (LND) donors, also known as altruistic, good Samaritan, anonymous, or benevolent community donors, are a new and rapidly growing source of solid organs for transplantation. The willingness of individuals to donate organs without a designated recipient has been unexpected, but has probably developed as a societal response to the growing crisis in organ availability. In the context of this shortage, health professionals have attempted to make the best use of kidneys from LND donors. We present a novel application of paired donation that has the potential to multiply the number of recipients who can benefi t from each LND donation. At present, there is no universally accepted system for allocation of organs from LND donors. Selection of recipients has been at the discretion of the transplant centres where LND donors have presented and has generally been guided by one of three models: donorcentric, recipient-centric, or sociocentric allocation. Each of these models is supported by valid ethical arguments. The main goal of donor-centric allocation is to ensure a successful outcome for the recipient. A good outcome provides justifi cation for medical professionals to assist a person who is not ill to put themselves in harm’s way to aid another. A positive result also gives an LND donor a sense that their eff ort was fruitful and worthwhile. However, this model dictates allocation to the healthiest patient on the transplant waiting list. These recipients are the most likely to have good outcomes on dialysis or with organs from deceased donors, and therefore are arguably the least in need. Recipient-centric allocation is based on the belief that society has a responsibility to protect its most vulnerable and disadvantaged members. Under this model, organs from LND donors are given to those patients in the greatest need, those for whom a kidney transplant might be truly life saving, or those disadvantaged under the existing system for allocation of kidneys from deceased donors. This model mainly benefi ts children, patients who have no vascular access, highly sensitised patients, and those with life-threatening medical illnesses related to dialysis. However, because the recipient-centric model accords priority to such patients, it tends to yield unacceptably poor transplant outcomes, and could lead to a negative public perception of LND donation. Under the third model, of sociocentric allocation, the LND donated organ is treated as a public resource that should be allocated in the fairest and most equitable way, irrespective of outcome or need. This rationale dictates that the recipient should be the patient at the top of the transplant waiting list administered by the United Network of Organ Sharing (UNOS). UNOS oversees the allocation of deceased donor organs in the USA, using a so-called match run algorithm that ranks potential recipients according to agreed criteria. The limitations of this model are that a patient at the top of the list will probably receive a kidney from a deceased donor in the near future, and that they will have already incurred the costs, and exposure to comorbidity, that result from a long period on dialysis. The waiting list for deceased donor kidneys can be circumvented by patients who fi nd a willing live donor. But direct donation might be complicated by diff erences in blood type and by HLA sensitivity. Some incompatible donor-recipient pairs enter into programmes that facilitate paired donation, also known as kidney paired donation. A donor and recipient who have incompatible blood groups or HLA sensitivity can be matched with another incompatible pair, to result in two compatible transplants (fi gure). Although there are many ways to match up a pool of incompatible pairs, the mathematical technique of optimisation helps to fi nd out which matches will yield the best results. Nevertheless, even in paired-donation programmes in which mathematical optimisation is applied, more than 50% of the incompatible pairs in the pool remain unmatched. In many cases, pools of incompatible donor-recipient pairs have a high proportion of patients with blood types that are hard to match and those with HLA sensitisation.

Using real data for a virtual crossmatch

Virtual crossmatches have been performed for more than 40 years under the guise of unacceptable antigens. Today, solid-phase assays provide the opportunity for more accurate identification and more precise measurement of the strength of donor-specific antibodies. The process of performing a virtual crossmatch begins with establishing a correlation between the antibody testing assay and the results of actual crossmatches. We provide here data indicating that the identity and strength of DSA defined with solid-phase phenotype panels correlates significantly with the outcome of both cytotoxic (CDC; r = 0.83) and flow cytometric (r = 0.85) crossmatches. Based on the threshold established from these correlations, we were able to correctly predict the results of CDC and flow cytometric crossmatches in 92.8 and 92.4% of cases, respectively. The correlations with single antigen panels were substantially lower (82.6-47.9%) and may be caused by a variety of factors, including variability in the amount and condition of different antigens and extremely high sensitivity, which may make the test less robust. We demonstrate that adding additional information to the solid-phase results can increase the frequency of correct crossmatch prediction. We also present data demonstrating an additional use of the virtual crossmatch in posttransplant monitoring.

Proinflammatory Events Are Associated with Significant Increases in Breadth and Strength of HLA-Specific Antibody

Identification of factors responsible for an increase in the breadth or strength of HLA‐specific antibody (HSA) is critical to the continued successful management and transplantation of sensitized patients. A retrospective review of our HLA registry identified 107 patients with known HSA and sufficient information in their electronic patient record to determine the presence or absence of a proinflammatory event. The patients were stratified according to transplant status [sensitized and on the transplant waitlist (n = 65); immunosuppressed recipients of a positive crossmatch (+XM) transplant (n = 42)]. Eighty‐three percent of waitlist candidates and 55% of sensitized kidney transplant recipients with a documented proinflammatory event had an associated increase in HSA. Interestingly, among patients with a culture‐proven infection, 97% of the waitlist patients and 54.8% of +XM recipients had an associated rise in HSA. Overall, proinflammatory events were associated with a greater increase among waitlist patients than +XM recipients, 5.3‐fold [IRR 5.25, (95% CI 4.03–6.85), p < 0.001] versus 2.5‐fold [IRR 2.54, (95% CI 1.64–3.95), p < 0.001] increase in HSA. Therefore, sensitized patients known to have an infection or undergoing surgery should be monitored for expansion of HSA.

A Computer Match Program for Paired and Unconventional Kidney Exchanges

The number of renal transplants can be increased by implementing an exchange program involving donor‐recipient pairs for whom the donors are each incompatible with their original patient but compatible with each others patient. The number can be further increased if the exchanges are not limited to ABO incompatible pairs or combinations of two donor‐recipient pairs. However, as the number of donor‐recipient pairs willing to participate in such a program increases, there is a substantial increase in both the time taken to identify such matches and the potential for error. We have developed a computer program that accounts for ABO and HLA compatibility and is not limited to two‐way exchanges. With our database of 60 patients and 83 donors, we have been able to identify 122 two‐way and 1230 three‐way exchanges with an average run time of 30 s.

Prevalence of HLA antibodies in transfused patients with and without red cell antibodies

BACKGROUND:  Multiply transfused patients are at increased risk of developing red cell (RBC) antibodies, as well as antibodies to HLA. Although pretransfusion testing screens for RBC antibodies, no such testing is routinely performed for HLA antibodies. Determining which patients are more likely to make HLA antibodies may be important for patients undergoing elective surgery where platelets (PLTs) may be required. It is hypothesized that patients with RBC alloantibodies may be more likely to have HLA antibodies than previously transfused patients without RBC antibodies.

Casting a smaller net into a bigger donor pool: A single center’s experience with the new kidney allocation system

The new kidney allocation system (KAS) provides additional allocation points for candidates with broad HLA sensitization in an effort to increase transplant rates for this underserved population. Following the implementation of KAS, our center lowered the HLA antibody threshold for listing unacceptable antigens from a cytotoxicity crossmatch level to a flow cytometric crossmatch level increasing Calculated Panel Reactive Antibody (CPRA) values and allocation points, yet restricting acceptable donor HLA phenotypes. As a result, many sensitized candidates were transitioned from 50% to 98% CPRA categories into the 99% CPRA regional share and 100% CPRA national share categories. Exposure to these larger donor pools significantly increased transplantation with compatible donors for 100% CPRA candidates, but regional sharing was not sufficient to increase transplantation rates for our 99% CPRA candidates. Competition within the 100% CPRA cohort identified inequities for 99.99-100.0% CPRA candidates and highlighted the continued need for desensitization therapies to reduce immunological barriers and provide transplant opportunities for the most highly sensitized candidates.