High-resolution HLA genotyping improves PIRCHE-II assessment of molecular mismatching in kidney transplantation.

HLA matching in solid organ transplant is performed with the aim of assessing immunologic compatibility in order to avoid hyperacute rejection and assess the risk of future rejection events. Molecular mismatch algorithms are intended to improve granularity in histocompatibility assessment and risk stratification. PIRCHE-II uses HLA genotyping to predict indirectly presented mismatched donor HLA peptides, though most clinical validation studies rely on imputing high resolution (HR) genotypes from low resolution (LR) typing data. We hypothesized that use of bona fide HR typing could overcome limitations in imputation, improving accuracy and predictive ability for donor-specific antibody development and acute rejection. We performed a retrospective analysis of adult and pediatric kidney transplant donor/recipient pairs (N = 419) with HR typing and compared the use of imputed LR genotyping verses HR genotyping for PIRCHE-II analysis and outcomes. Imputation success was highly dependent on the reference population used, as using historic Caucasian reference populations resulted in 10 % of pairs with unsuccessful imputation while multiethnic reference populations improved successful imputation with only 1 % unable to be imputed. Comparing PIRCHE-II analysis with HR and LR genotyping produced notably different results, with 20 % of patients discrepantly classified to immunologic risk groups. These data emphasize the importance of using multiethnic reference panels when performing imputation and indicate HR HLA genotyping has clinically meaningful benefit for PIRCHE-II analysis compared to imputed LR typing.

Current approaches for risk assessment of intestinal transplant patients: A view from the histocompatibility laboratory.

Despite its recent decline in volumes, intestinal transplantation remains an important option for patients with irreversible intestinal failures. The long-term outcome of an intestinal transplant has stagnated. The major cause of graft loss is rejection, resulting from mismatches in human leukocyte antigens (HLA) and the presence of antibodies to mismatched donor-specific HLA antigens (DSA). Literature has reported that DSAs, either preformed before transplantation or developed de novo after transplantation, are harmful to intestinal grafts, especially for those without combined liver grafts. A comprehensive assessment of DSA by the histocompatibility laboratory is critical for successful intestinal transplantation and its long-term survival. This paper briefly reviews the history and current status of different methods for detecting DSA and their clinical applications in intestinal transplantation. The focus is on applying different antibody assays to manage immunologically challenging intestinal transplant patients before and after transplantation. A clinical case is presented to illustrate the complexity of HLA tests and the necessity of multiple assays. The review of risk assessment by the histocompatibility laboratory also highlights the need for close interaction between the laboratory and the intestinal transplant program.

Sensitization in transplantation: Assessment of Risk 2022 Working Group Meeting Report.

The Sensitization in Transplantation: Assessment of Risk workgroup is a collaborative effort of the American Society of Transplantation and the American Society of Histocompatibility and Immunogenetics that aims at providing recommendations for clinical testing, highlights gaps in current knowledge, and proposes areas for further research to enhance histocompatibility testing in support of solid organ transplantation. This report provides updates on topics discussed by the previous Sensitization in Transplantation: Assessment of Risk working groups and introduces 2 areas of exploration: non-human leukocyte antigen antibodies and utilization of human leukocyte antigen antibody testing measurement to evaluate the efficacy of antibody-removal therapies.

Alloimmune risk assessment for antibody-mediated rejection in kidney transplantation: A practical proposal.

Kidney transplantation is the treatment of choice for patients with end-stage renal disease. Although an improvement in graft survival has been observed in the last decades with the use of different immunosuppressive drugs, this is still limited in time with antibody-mediated rejection being a main cause of graft-loss. Immune monitoring and risk assessment of antibody-mediated rejection before and after kidney transplantation with useful biomarkers is key to tailoring treatments to achieve the best outcomes. Here, we provide a review of the rationale and several accessible tools for immune monitoring, from the most classic to the modern ones. Finally, we end up discussing a practical proposal for alloimmune risk assessment in kidney transplantation, including histocompatibility leukocyte antigen (HLA) and non-HLA antibodies, HLA molecular mismatch analysis and characterization of peripheral blood immune cells.

Characterization of an advanced viable bone allograft with preserved native bone-forming cells.

Bone grafts are widely used to successfully restore structure and function to patients with a broad range of musculoskeletal ailments and bone defects. Autogenous bone grafts are historically preferred because they theoretically contain the three essential components of bone healing (ie, osteoconductivity, osteoinductivity, and osteogenicity), but they have inherent limitations. Allograft bone derived from deceased human donors is one alternative that is also capable of providing both an osteoconductive scaffold and osteoinductive potential but, until recently, lacked the osteogenic component of bone healing. Relatively new, cellular bone allografts (CBAs) were designed to address this need by preserving viable cells. Although most commercially-available CBAs feature mesenchymal stem cells (MSCs), osteogenic differentiation is time-consuming and complex. A more advanced graft, a viable bone allograft (VBA), was thus developed to preserve lineage-committed bone-forming cells, which may be more suitable than MSCs to promote bone fusion. The purpose of this paper was to present the results of preclinical research characterizing VBA. Through a comprehensive series of in vitro and in vivo assays, the present results demonstrate that VBA in its final form is capable of providing all three essential bone remodeling properties and contains viable lineage-committed bone-forming cells, which do not elicit an immune response. The results are discussed in the context of clinical evidence published to date that further supports VBA as a potential alternative to autograft without the associated drawbacks.

Histocompatibility Assessment in Precision Medicine for Transplantation: Towards a Better Match.

Human Leukocyte Antigen (HLA) diversity is the key driver of alloimmune responses. Ideally, patients would receive an allograft that is fully matched at the allelic level. However, the extensive polymorphism in the HLA loci renders this impractical. Thus, there is growing interest in determining whether HLA mismatches at the eplet/epitope level better reflects the true disparity between a donor-recipient pair, with the goal of predicting permissible mismatches versus those that should be avoided because they will elicit a strong alloimmune response. Here, we will discuss the available algorithms used to predict immunogenicity/antigenicity of mismatches and prognosticate graft outcomes.

Improve in-depth immunological risk assessment to optimize genetic-compatibility and clinical outcomes in child and adolescent recipients of parental donor kidney transplants: protocol for the INCEPTION study.

BACKGROUND: Parental donor kidney transplantation is the most common treatment option for children and adolescents with kidney failure. Emerging data from observational studies have reported improved short- and medium-term allograft outcomes in recipients of paternal compared to maternal donors. The INCEPTION study aims to identify potential differences in immunological compatibility between maternal and paternal donor kidneys and ascertain how this affects kidney allograft outcomes in children and adolescents with kidney failure. METHODS: This longitudinal observational study will recruit kidney transplant recipients aged ≤18 years who have received a parental donor kidney transplant across 4 countries (Australia, New Zealand, United Kingdom and the Netherlands) between 1990 and 2020. High resolution human leukocyte antigen (HLA) typing of both recipients and corresponding parental donors will be undertaken, to provide an in-depth assessment of immunological compatibility. The primary outcome is a composite of de novo donor-specific anti-HLA antibody (DSA), biopsy-proven acute rejection or allograft loss up to 60-months post-transplantation. Secondary outcomes are de novo DSA, biopsy-proven acute rejection, acute or chronic antibody mediated rejection or Chronic Allograft Damage Index (CADI) score of > 1 on allograft biopsy post-transplant, allograft function, proteinuria and allograft loss. Using principal component analysis and Cox proportional hazards regression modelling, we will determine the associations between defined sets of immunological and clinical parameters that may identify risk stratification for the primary and secondary outcome measures among young people accepting a parental donor kidney for transplantation. This study design will allow us to specifically investigate the relative importance of accepting a maternal compared to paternal donor, for families deciding on the best option for donation. DISCUSSION: The INCEPTION study findings will explore potentially differential immunological risks of maternal and paternal donor kidneys for transplantation among children and adolescents. Our study will provide the evidence base underpinning the selection of parental donor in order to achieve the best projected long-term kidney transplant and overall health outcomes for children and adolescents, a recognized vulnerable population. TRIAL REGISTRATION: The INCEPTION study has been registered with the Australian New Zealand Clinical Trials Registry, with the trial registration number of ACTRN12620000911998 (14th September 2020).

Humanized Mouse Model as a Novel Approach in the Assessment of Human Allogeneic Responses in Organ Transplantation.

The outcome of organ transplantation is largely dictated by selection of a well-matched donor, which results in less chance of graft rejection. An allogeneic immune response is the main immunological barrier for successful organ transplantation. Donor and recipient human leukocyte antigen (HLA) mismatching diminishes outcomes after solid organ transplantation. The current evaluation of HLA incompatibility does not provide information on the immunogenicity of individual HLA mismatches and impact of non-HLA-related alloantigens, especially in vivo. Here we demonstrate a new method for analysis of alloimmune responsiveness between donor and recipient in vivo by introducing a humanized mouse model. Using molecular, cellular, and genomic analyses, we demonstrated that a recipient's personalized humanized mouse provided the most sensitive assessment of allogeneic responsiveness to potential donors. In our study, HLA typing provided a better recipient-donor match for one donor among two related donors. In contrast, assessment of an allogeneic response by mixed lymphocyte reaction (MLR) was indistinguishable between these donors. We determined that, in the recipient's humanized mouse model, the donor selected by HLA typing induced the strongest allogeneic response with markedly increased allograft rejection markers, including activated cytotoxic Granzyme B-expressing CD8+ T cells. Moreover, the same donor induced stronger upregulation of genes involved in the allograft rejection pathway as determined by transcriptome analysis of isolated human CD45+cells. Thus, the humanized mouse model determined the lowest degree of recipient-donor alloimmune response, allowing for better selection of donor and minimized immunological risk of allograft rejection in organ transplantation. In addition, this approach could be used to evaluate the level of alloresponse in allogeneic cell-based therapies that include cell products derived from pluripotent embryonic stem cells or adult stem cells, both undifferentiated and differentiated, all of which will produce allogeneic immune responses.

Transfusion burden following reduced intensity allogeneic hematopoietic cell transplantation: Impact of donor type.

BACKGROUND: Transfusions are essential for allogeneic hematopoietic cell transplant (HCT), yet they are influenced by graft, donor, and other factors. STUDY DESIGN: We analyzed transfusions in 165 adult reduced intensity HCTs (2016-2019): HLA matched sibling donor (MSD) (n = 59), matched URD (n = 25), UCB (n = 33), and haploidentical (haplo, n = 48) detailing the cumulative incidence of platelet and RBC transfusion independence, total transfusions (day-10 to day+100) plus transfusion densities (per week) over 110 days. RESULTS: Platelet recovery to 20 × 109 /L by 6 months occurred in 39/48 (81.25%) haplo recipients (median 33 [range, 0-139]) days vs. 58/59 (98.3%) MSD (median 10 [0-37]), 21/25 (84%) matched URD (median 20 [0-153]), and 29/33 (87.87%) UCB (median 48 [29-166]) days, p < .01. Regression analysis demonstrated a lower likelihood of prompt platelet recovery in matched URD, UCB, or haplo HCTs vs. MSD. Recovery to platelet independence was quickest in MSD (median 8 days [range 0-94]), vs. URD (median 16 days [0-99]), UCB (median 57 [0-94]), or haplo (median 45 [12-97]) days, p < .01. Platelet needs were unaffected by age, conditioning, or acute GVHD. RBC transfusion independence was achieved in 78% of MSD, 64% URD, and 82% UCB, though less frequent (58%) and slowest in haplo recipients, p < .01. All haplo and UCB recipients required platelet transfusions vs. only 51% of MSD and 76% of URD. RBC needs were highest in UCB and haplo HCTs. DISCUSSION: The transplant donor influences the transfusion burden with greater platelet and RBC needs in haplo and UCB HCT which directly contributes to increased cost of care.

Better Understanding the Disparity Associated With Black Race in Heart Transplant Outcomes: A National Registry Analysis.

BACKGROUND: Black heart transplant recipients have higher risk of mortality than White recipients. Better understanding of this disparity, including subgroups most affected and timing of the highest risk, is necessary to improve care of Black recipients. We hypothesize that this disparity may be most pronounced among young recipients, as barriers to care like socioeconomic factors may be particularly salient in a younger population and lead to higher early risk of mortality. METHODS: We studied 22 997 adult heart transplant recipients using the Scientific Registry of Transplant Recipients data from January 2005 to 2017 using Cox regression models adjusted for recipient, donor, and transplant characteristics. RESULTS: Among recipients aged 18 to 30 years, Black recipients had 2.05-fold (95% CI, 1.67-2.51) higher risk of mortality compared with non-Black recipients (P<0.001, interaction P<0.001); however, the risk was significant only in the first year post-transplant (first year: adjusted hazard ratio, 2.30 [95% CI, 1.60-3.31], P<0.001; after first year: adjusted hazard ratio, 0.84 [95% CI, 0.54-1.29]; P=0.4). This association was attenuated among recipients aged 31 to 40 and 41 to 60 years, in whom Black recipients had 1.53-fold ([95% CI, 1.25-1.89] P<0.001) and 1.20-fold ([95% CI, 1.09-1.33] P<0.001) higher risk of mortality. Among recipients aged 61 to 80 years, no significant association was seen with Black race (adjusted hazard ratio, 1.12 [95% CI, 0.97-1.29]; P=0.1). CONCLUSIONS: Young Black recipients have a high risk of mortality in the first year after heart transplant, which has been masked in decades of research looking at disparities in aggregate. To reduce overall racial disparities, clinical research moving forward should focus on targeted interventions for young Black recipients during this period.

Center-level Variation in HLA-incompatible Living Donor Kidney Transplantation Outcomes.

BACKGROUND: Desensitization protocols for HLA-incompatible living donor kidney transplantation (ILDKT) vary across centers. The impact of these, as well as other practice variations, on ILDKT outcomes remains unknown. METHODS: We sought to quantify center-level variation in mortality and graft loss following ILDKT using a 25-center cohort of 1358 ILDKT recipients with linkage to Scientific Registry of Transplant Recipients for accurate outcome ascertainment. We used multilevel Cox regression with shared frailty to determine the variation in post-ILDKT outcomes attributable to between-center differences and to identify any center-level characteristics associated with improved post-ILDKT outcomes. RESULTS: After adjusting for patient-level characteristics, only 6 centers (24%) had lower mortality and 1 (4%) had higher mortality than average. Similarly, only 5 centers (20%) had higher graft loss and 2 had lower graft loss than average. Only 4.7% of the differences in mortality (P < 0.01) and 4.4% of the differences in graft loss (P < 0.01) were attributable to between-center variation. These translated to a median hazard ratio of 1.36 for mortality and 1.34 of graft loss for similar candidates at different centers. Post-ILDKT outcomes were not associated with the following center-level characteristics: ILDKT volume and transplanting a higher proportion of highly sensitized, prior transplant, preemptive, or minority candidates. CONCLUSIONS: Unlike most aspects of transplantation in which center-level variation and volume impact outcomes, we did not find substantial evidence for this in ILDKT. Our findings support the continued practice of ILDKT across these diverse centers.

Impact of HLA polymorphisms among cadaveric donors on kidney graft allocation.

This study provides data on HLA-A, -B, and -DRB1 frequencies among 861 end-stage renal disease (ESRD) patients from Croatia and estimates the benefit of the kidney exchange program by comparing HLA distribution and assessing HLA mismatches (MMs) within a group of ESRD patients who received kidney grafts from 707 cadaveric donors (422 from Croatia and 285 from Eurotransplant). Patients positive for HLA-B*07, -B*08, or -B*44 genes more often received a kidney from ET donors, while HLA-DRB1*11 and -DRB1*16 positive patients more frequently received a kidney from CRO donors. ABDR MM 000 was more frequently present in the case of transplantation from ET donors, while MM 222 was significantly more frequent when the donor was from Croatia. Sensitized patients received kidney more frequently from ET donors (P < .0001). A large pool of organ donors with different HLA gene distributions allows for a higher probability of transplantation from HLA highly matched donor.

Sensitization in transplantation: Assessment of risk (STAR) 2019 Working Group Meeting Report.

The purpose of the STAR 2019 Working Group was to build on findings from the initial STAR report to further clarify the expectations, limitations, perceptions, and utility of alloimmune assays that are currently in use or in development for risk assessment in the setting of organ transplantation. The goal was to determine the precision and clinical feasibility/utility of such assays in evaluating both memory and primary alloimmune risks. The process included a critical review of biologically driven, state-of-the-art, clinical diagnostics literature by experts in the field and an open public forum in a face-to-face meeting to promote broader engagement of the American Society of Transplantation and American Society of Histocompatibility and Immunogenetics membership. This report summarizes the literature review and the workshop discussions. Specifically, it highlights (1) available assays to evaluate the attributes of HLA antibodies and their utility both as clinical diagnostics and as research tools to evaluate the effector mechanisms driving rejection; (2) potential assays to assess the presence of alloimmune T and B cell memory; and (3) progress in the development of HLA molecular mismatch computational scores as a potential prognostic biomarker for primary alloimmunity and its application in research trial design.

Racial disparities in access to HLA-matched unrelated donor transplants: a prospective 1312-patient analysis.

Availability of 8/8 HLA-allele matched unrelated donors (URDs) is a barrier for ethnic and racial minorities. We prospectively evaluated receipt of 8/8 HLA-allele matched URD or either 7/8 URD or cord blood (CB) transplants by patient ancestry from 2005 to 2017. Matched URDs were given priority if they were available. Of 1312 patients, 723 (55%) received 8/8 URD, 219 (17%) 7/8 URD, 319 (24%) CB, and 51 (4%) had no 7/8 or 8/8 URD or CB graft. Europeans were more likely to receive an 8/8 URD transplant than non-Europeans (67% vs 33%) and less likely to have no URD or CB graft (1% vs 9%). Southern Europeans received 8/8 URD transplants (41%) at rates similar to those of Asians (34%) and white Hispanics (35%); Africans were the least likely (18%) to undergo 8/8 URD transplantation. CB and 7/8 URDs extended transplant access to all groups. In 742 recent patients, marked racial disparity in 8/8 URD access between groups observed in earlier years persisted with only a modest increase in the percentage of 8/8 URD transplants. Of 78 recent African patients, 46% received a CB transplant and 14% had no 7/8 or 8/8 URD or CB graft. Increasing registry size has not resolved the racial disparity in URD access, which emphasizes the importance of alternative graft sources.

Renal Transplant and Its Outcomes: Single-Center Experience From India.

OBJECTIVES: Improvements in early graft survival and long-term graft function have made kidney transplant a more cost-effective alternative to dialysis. We aimed to assess renal transplant outcomes over a 9-month follow-up of recipients in a cost-limited setting (a tertiary care center in India). MATERIALS AND METHODS: Included patients in this prospective observational study were those who underwent renal transplant from July 2016 to February 2017 (8 months) and followed for 9 months. RESULTS: Of 122 included patients, 20 (16.4%) were women and 102 (83.6%) were men (mean age 35.61 ± 10.64 y), with 92 (75.4%) from a lower socioeconomic status. Kidneys were from first-degree relatives for 52 patients (42.6%), from spousal donors for 34 (27.9%), from deceased donors for 24 (19.7%), and from second/third degree relative donors for 12 (9.8%). All patients underwent only complementdependent cytotoxicity crossmatch due to financial constraints. Fifty patients (41%) had history of packed red blood cell transfusion. Induction was thymoglobulin in 60 patients (49.2%), basiliximab in 8 (6.6%), and no induction in 54 (44.3%). Forty patients (30.1%) underwent biopsy for graft dysfunction, and 32 (26.2%) had graft rejection: 18 (14.8%) with antibodymediated rejection, 5 (4.1%) with T-cell-mediated rejection, and 9 (7.4%) with both. Opportunistic infections were shown in 24.5% of patients, including primarily cytomegalovirus (10.7%), tuberculosis (5.7%), and aspergillosis (3.3%). Twenty-nine patients (24%) had new-onset diabetes posttransplant. At end of follow-up, 93 patients (76.2%) had normal graft function, 21 (17.2%) had chronic graft dysfunction, 3 (2.4%) had graft loss, and 5 (4.1%) died. History of blood transfusion (P = .001) predicted the occurrence of antibody-mediated rejection, and induction used showed trend toward prediction (P = .083). CONCLUSIONS: With high rejection rates, it would be prudent to include proper immunologic testing, even in cost-limited settings, pretransplant. The high infection and death rates are also concerning.

Temporal Changes in the Impact of HLA Mismatching Among Pediatric Kidney Transplant Recipients.

BACKGROUND: Allocation for pediatric deceased-donor kidney transplantation (pDDKT) in the United States now de-emphasizes HLA matching to improve equality in access to transplantation, but other national systems still consider HLA matching due to concerns about graft survival. We hypothesized that the impact of HLA mismatching has decreased over time due to advances including improved immunosuppression. METHODS: Using Scientific Registry of Transplant Recipient data, we analyzed whether the association between the number of HLA mismatches and outcomes of first-time pDDKTs changed between 2 eras: 1995 to 2004 (N = 2854) and 2005 to 2014 (N = 4643). RESULTS: Between eras, the median number of mismatches increased from 4 to 5 (P < 0.001). Overall graft failure risk was higher among HLA-mismatched versus HLA-matched transplants (adjusted hazard ratio 1.211.431.69 for 3-6 versus 0-2 mismatches; P < 0.001), and this association was similar pre-2005 and post-2005 (Pinteraction = 0.5). Median panel-reactive antibody change at relisting increased from 79 to 85 (P = 0.01), but the association between number of HLA mismatches and panel-reactive antibody change was similar between eras (Pinteraction = 0.6). CONCLUSIONS: Our finding that increased HLA mismatching continues to impact graft survival, with 43% higher risk of graft failure, highlights the tradeoff between transplant access equity and outcomes and calls into question the deemphasis on HLA matching in pDDKT allocation in the United States.

Allocation of deceased donor kidneys: A review of international practices.

The demand for kidney transplantation continues to exceed the availability of deceased donor kidneys. Balancing the overarching principles of the optimal use of (utility) and equal access to (equity) this scarce resource requires a sophisticated allocation system. This review will examine how various factors are addressed in allocation systems around the world to strike a balance between utility and equity.

Determining the Quantitative Principles of T Cell Response to Antigenic Disparity in Stem Cell Transplantation.

Alloreactivity compromising clinical outcomes in stem cell transplantation is observed despite HLA matching of donors and recipients. This has its origin in the variation between the exomes of the two, which provides the basis for minor histocompatibility antigens (mHA). The mHA presented on the HLA class I and II molecules and the ensuing T cell response to these antigens results in graft vs. host disease. In this paper, results of a whole exome sequencing study are presented, with resulting alloreactive polymorphic peptides and their HLA class I and HLA class II (DRB1) binding affinity quantified. Large libraries of potentially alloreactive recipient peptides binding both sets of molecules were identified, with HLA-DRB1 generally presenting a greater number of peptides. These results are used to develop a quantitative framework to understand the immunobiology of transplantation. A tensor-based approach is used to derive the equations needed to determine the alloreactive donor T cell response from the mHA-HLA binding affinity and protein expression data. This approach may be used in future studies to simulate the magnitude of expected donor T cell response and determine the risk for alloreactive complications in HLA matched or mismatched hematopoietic cell and solid organ transplantation.

HLA-Epitope Matching or Eplet Risk Stratification: The Devil Is in the Details.

"Epitope matching" became a trending topic in organ transplantation. In fact, discussions on clinical implementation and utilization of this approach in organ allocation algorithms are currently on-going. More recently, the term "eplet mismatch load" was introduced in publications. While the terms are often used synonymously, they are NOT equivalent. This short overview is meant to emphasize the differences between the terms epitope matching and eplet mismatching (or mismatch load) as well as to provide perspective on different approaches for interpretation of immune compatibility between the donor of an organ transplant and the recipient. It highlights some of the less explored qualities of HLA-epitopes, and stresses the need to understand the differences between donor and recipient in terms of immunogenicity and ability to initiate an immune response. While the field of "epitope matching" shows enormous promise, it is still in its infancy. What is sorely missing is understanding of EPITOPE COMPATIBILITY rather than matching. Further work is required before new approaches can be introduced into routine clinical practice and organ allocation schemes.

Complete Chain of the First Global Kidney Exchange Transplant and 3-yr Follow-up.

BACKGROUND: Global Kidney Exchange (GKE) offers an opportunity to expand living renal transplantation internationally to patients without financial means. These international pairs are entered into a US kidney exchange program that provides long-term financial support in an effort to identify opportunities for suitable exchanges for both these international pairs and US citizens. OBJECTIVE: While the promise of GKE is significant, it has been met with ethical criticism since its inception in 2015. This paper aims to demonstrate the selection process and provide >3 yr of follow-up on the first GKE donor and recipient from the Philippines. DESIGN, SETTING, AND PARTICIPANTS: The first GKE transplant occurred with a young Filipino husband and wife who were immunologically compatible, but lacked the financial means to continue hemodialysis or undergo a kidney transplant in their home country. The pair was enrolled in the Alliance for Paired Donation matching system, several alternative kidney exchanges were identified, and the pair subsequently underwent renal transplantation and donation in the USA financed by philanthropy. The resulting nonsimultaneous extended altruistic chain provided transplantation for the Filipino husband and 11 US patients. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The Filipino donor and recipient were followed by transplant professionals in both the Philippines and the USA. Follow-up data were maintained as required by the Organ Procurement and Transplantation Network in the USA. RESULTS AND LIMITATIONS: The Filipino donor has normal blood pressure and renal function, and the Filipino recipient is doing well 3.5 yr after their donation and transplantation. CONCLUSIONS: While criticisms of GKE highlight concerns for possible exploitation of financially disadvantaged groups, these results demonstrate that these concerns did not come to fruition, and the outcome experienced by the GKE donor and recipient (and other US participants) was successful. PATIENT SUMMARY: The first Filipino Global Kidney Exchange (GKE) donor-recipient pair continues to be followed by both US and Filipino transplant centers. Both are in good health, support the GKE program, and advocate for its expansion.