Does HLA matching matter in the modern era of renal transplantation?

Children with end-stage kidney disease should be offered the best chance for future survival which ideally would be a well-matched pre-emptive kidney transplant. Paediatric and adult practice varies around the world depending on geography, transplant allocation schemes and different emphases on living (versus deceased) donor renal transplantation. Internationally, paediatric patients often have priority in allocation schemes and younger donors are preferentially allocated to paediatric recipients. HLA matching can be difficult and may result in longer waiting times. Additionally, with improved surgical techniques and modern immunosuppressive regimens, how important is the contribution of HLA matching to graft longevity? In this review, we discuss the relative importance of HLA matching compared with donor quality; and long-term patient outcomes including re-transplantation rates. We share empirical evidence that will be useful for clinicians and families to make decisions about best donor options. We discuss why living donation still provides the best allograft survival outcomes and what to do in the scenario of a highly mismatched living donor.

A Europe wide acceptable mismatch program will enable transplantation of long waiting highly sensitised patients with a compatible donor.

Immunisation against Human Leucocyte Antigens (HLA) can be caused by pregnancy, blood transfusion, or organ transplants. The HLA antibody status of a given patient significantly influences their access and waiting time to transplant. For some highly sensitised patients (HSP) there is hardly any suitable donor available in the deceased donor pool of their allocation organisation and therefore they wait a very long time before being offered a kidney for transplant. Especially patients with rare HLA phenotypes in relation to the actual donor pool are waiting extremely long. As HLA phenotypes are different in the various European populations, we hypothesized that extension of the donor pool outside the respective allocation system will increase the chance of receiving a compatible transplant for this subgroup of highly sensitised patients. One of the objectives of the EUROSTAM project, (a Europe-wide Strategy to enhance Transplantation of highly sensitised patients on the basis of Acceptable HLA Mismatches) was to develop a tool to compare the chance of transplanting HSP in different European populations with donor organs from within and outside their own donor pool. Information on the HLA type and ABO blood group of the actual donor population, as well as the acceptable mismatches of long waiting HSP were obtained from the EUROSTAM partner organizations i.e. Eurotransplant (ET), UK National Health Service Blood and Transplant (NHSBT), Barcelona, Prague and Athens. Results from simulations using the newly developed tool shows that 195 (27%) of the 724 long waiting highly sensitised patients registered at each partner organisation have increased chances of transplant in a different European donor pool. This makes a strong case for sharing kidneys between European countries for selected difficult to transplant patients.

Changing patterns of clinical decision making: are falling numbers of antibody incompatible transplants related to the increasing success of the UK Living Kidney Sharing Scheme? A national cohort study.

Antibody incompatibility is a barrier to living kidney transplantation; antibody incompatible transplantation (AIT) is an accepted treatment modality, albeit higher risk. This study aims to determine changes to clinical decision making and access to AIT in the UK. An electronic survey was sent to all UK renal transplant centres (n = 24), in 2014, and again in 2018. Questions focused on entry & duration in the UKLKSS for HLA and ABO-incompatible pairs, Can and provision of direct AIT transplantation within those centres. Between 2014 & 2018, the duration recommended for patients in the UKLKSS increased. In 2014, 34.8% of centres reported leaving HLA-i pairs in the UKLKSS indefinitely, or reviewing on a case by case basis, by 2018 this increased to 61%. Centres offering direct HLA-i transplantation reduced from 58% to 37%. For low titre (1:8) ABO-i recipients, 66% of centres recommended at least 9 months (3 matching runs) in the UKLKSS scheme in 2018, compared to 47% in 2014, 50% fewer units consider direct ABO-i transplantation for unsuccessful pairs with high ABO titres (>1:512). Over time, clinicians appear to be facilitating more conservative management of AIT patients, potentially limiting access to living donor transplantation.

Towards uniformity in the definition of acceptable mismatches for highly sensitized patients.

The Eurotransplant (The Eurotransplant International Foundation) acceptable mismatch programme has been shown to be a successful tool to enhance transplantation of highly sensitized patients(HSPs). However, patients with rare HLA phenotypes in relation to the Eurotransplant donor population remain on the waiting list. EUROSTAM is an European Union funded project to explore the feasibility of a Europe-wide acceptable mismatch programme enabling transplantation of HSPs with rare HLA phenotypes within their own organ exchange organization. The present study, which forms part of the EUROSTAM project, assesses the differences in the practices of the laboratories in different countries with respect to their HLA antibody profiling and risk adverseness. In the serum exchange exercises of 18 samples, a high level of variability has been shown in both assays and interpretation of results. In the data exchange exercise when all participants were given the same Luminex raw data for analysis, a high degree of consensus was reached where the median fluorescent intensity values of beads were <500 and >2000 for standard single antigen bead assays, or <500 and >5000 for assignment of acceptable mismatches. The risk adverseness analysis has showed distinct patterns of attitudes towards the perceived risks based on HLA antibody assay results, most probably influenced by the local protocols of the clinical transplant programme of each laboratory. In order to ensure fairness and maintain consistencies of organ exchange among partner transplant centres, a centralized facility will be instrumental for a uniform definition of acceptable mismatches.

Long- and short-term outcomes in renal allografts with deceased donors: A large recipient and donor genome-wide association study.

Improvements in immunosuppression have modified short-term survival of deceased-donor allografts, but not their rate of long-term failure. Mismatches between donor and recipient HLA play an important role in the acute and chronic allogeneic immune response against the graft. Perfect matching at clinically relevant HLA loci does not obviate the need for immunosuppression, suggesting that additional genetic variation plays a critical role in both short- and long-term graft outcomes. By combining patient data and samples from supranational cohorts across the United Kingdom and European Union, we performed the first large-scale genome-wide association study analyzing both donor and recipient DNA in 2094 complete renal transplant-pairs with replication in 5866 complete pairs. We studied deceased-donor grafts allocated on the basis of preferential HLA matching, which provided some control for HLA genetic effects. No strong donor or recipient genetic effects contributing to long- or short-term allograft survival were found outside the HLA region. We discuss the implications for future research and clinical application.

De novo donor-specific HLA antibodies after combined intestinal and vascularized composite allotransplantation - a retrospective study.

Combining vascularized composite allotransplantation (VCA) with intestinal transplantation to achieve primary abdominal closure has become a feasible procedure. Besides facilitating closure, the abdominal wall can be used to monitor intestinal rejection. As the inclusion of a VCA raises the possibility of an enhanced alloimmune response, we investigated the incidence and clinical effect of de novo donor-specific HLA antibodies (dnDSA) in a cohort of patients receiving an intestinal transplant with or without a VCA. The sequential clinical study includes 32 recipients of deceased donor intestinal and VCA transplants performed between 2008 and 2015; eight (25%) modified multivisceral transplants and 24 (75%) isolated small bowel transplants. A VCA was used in 18 (56.3%) cases. There were no episodes of intestinal rejection without VCA rejection. Fourteen patients (14 of 29; 48.3%) developed dnDSA. In the VCA group, fewer patients developed dnDSA; six of 16 (37.5%) VCA vs. eight of 13 (61.5%) non-VCA. There was no statistically significant difference in one- and 3-year overall graft survival stratified for the presence of dnDSA; P = 0.286. In the study, there is no evidence that the addition of a VCA increases the incidence of dnDSA formation compared to transplantation of the intestine alone.

The UK National Registry of ABO and HLA Antibody Incompatible Renal Transplantation: Pretransplant Factors Associated With Outcome in 879 Transplants.

BACKGROUND: ABO and HLA antibody incompatible (HLAi) renal transplants (AIT) now comprise around 10% of living donor kidney transplants. However, the relationship between pretransplant factors and medium-term outcomes are not fully understood, especially in relation to factors that may vary between centers. METHODS: The comprehensive national registry of AIT in the United Kingdom was investigated to describe the donor, recipient and transplant characteristics of AIT. Kaplan-Meier analysis was used to compare survival of AIT to all other compatible kidney transplants performed in the United Kingdom. Cox proportional hazards regression modeling was used to determine which pretransplant factors were associated with transplant survival in HLAi and ABOi separately. The primary outcome was transplant survival, taking account of death and graft failure. RESULTS: For 522 HLAi and 357 ABO incompatible (ABOi) transplants, 5-year transplant survival rates were 71% (95% confidence interval [CI], 66-75%) for HLAi and 83% (95% CI, 78-87%) for ABOi, compared with 88% (95% CI, 87-89%) for 7290 standard living donor transplants, and 78% (95% CI, 77-79%) for 15 322 standard deceased donor transplants (P < 0.0001). Increased chance of transplant loss in HLAi was associated with increasing number of donor specific HLA antibodies, center performing the transplant, antibody level at the time of transplant, and an interaction between donor age and dialysis status. In ABOi, transplant loss was associated with no use of IVIg, cytomegalovirus seronegative recipient, 000 HLA donor-recipient mismatch; and increasing recipient age. CONCLUSIONS: Results of AIT were acceptable, certainly in the context of a choice between living donor AIT and an antibody compatible deceased donor transplant. Several factors were associated with increased chance of transplant loss, and these can lead to testable hypotheses for further improving therapy.

Living Donation Has a Greater Impact on Renal Allograft Survival Than HLA Matching in Pediatric Renal Transplant Recipients.

BACKGROUND: Living donor (LD) kidney transplantation accounts for around half of all pediatric renal transplant recipients and results in improved renal allograft survival. The aim of this study was to determine the effect of HLA matching on deceased and LD renal allograft outcomes in pediatric recipients. METHODS: Data were obtained from the UK Transplant Registry held by NHS Blood and Transplant on all children who received a donation after brain death (DBD) or LD kidney-only transplant between 2000 and 2011. HLA-A, HLA-B and HLA-DR mismatches were categorized into 4 levels and 2 groups. Data were fully anonymized. RESULTS: One thousand three hundred seventy-eight pediatric renal transplant recipients were analyzed; 804 (58%) received a DBD donor kidney, 574 (42%) received an LD kidney. Five-year renal allograft survival was superior for children receiving a poorly HLA-matched LD kidney transplant (88%, 95% confidence interval [95% CI], 84-91%) compared with children receiving a well HLA-matched DBD kidney transplant (83%, 95% CI, 80-86%, log rank test P = 0.03). Five-year renal allograft survival was superior for children receiving an LD kidney with 1 or 2 HLA-DR mismatches (88%, 95% CI, 84-91%) compared with children receiving a DBD kidney with 0 HLA-DR mismatches (83%, 95% CI, 80-86%, log rank test P = 0.03). CONCLUSIONS: In children, poorly HLA-matched LD renal transplant outcomes are not inferior when compared with well HLA-matched DBD renal transplants. It is difficult to justify preferentially waiting for an improved HLA-matched DBD kidney when a poorer HLA-matched LD kidney transplant is available.

The Impact of Ischemia/Reperfusion Injury on Liver Allografts from Deceased after Cardiac Death versus Deceased after Brain Death Donors.

BACKGROUND AND AIMS: The shortage of organs for transplantation has led to increased use of organs procured from donors after cardiac death (DCD). The effects of cardiac death on the liver remain poorly understood, however. Using livers obtained from DCD versus donors after brain death (DBD), we aimed to understand how ischemia/reperfusion (I/R) injury alters expression of pro-inflammatory markers ceramides and influences graft leukocyte infiltration. METHODS: Hepatocyte inflammation, as assessed by ceramide expression, was evaluated in DCD (n = 13) and DBD (n = 10) livers. Allograft expression of inflammatory and cell death markers, and allograft leukocyte infiltration were evaluated from a contemporaneous independent cohort of DCD (n = 22) and DBD (n = 13) livers. RESULTS: When examining the differences between transplant stages in each group, C18, C20, C24 ceramides showed significant difference in DBD (p<0.05) and C22 ceramide (p<0.05) were more pronounced for DCD. C18 ceramide is correlated to bilirubin, INR, and creatinine after transplant in DCD. Prior to transplantation, DCD livers have reduced leukocyte infiltration compared to DBD allografts. Following reperfusion, the neutrophil infiltration and platelet deposition was less prevalent in DCD grafts while cell death and recipients levels of serum aspartate aminotransferase (AST) of DCD allografts had significantly increased. CONCLUSION: These data suggest that I/R injury generate necrosis in the absence of a strong inflammatory response in DCD livers with an appreciable effect on early graft function. The long-term consequences of increased inflammation in DBD and increased cell death in DCD allografts are unknown and warrant further investigation.

Impact of Donation Mode on the Proportion and Function of T Lymphocytes in the Liver.

BACKGROUND: Liver T-cells respond to the inflammatory insult generated during organ procurement and contribute to the injury following reperfusion. The mode of liver donation alters various metabolic and inflammatory pathways but the way it affects intrahepatic T-cells is still unclear. METHODS: We investigated the modifications occurring in the proportion and function of T-cells during liver procurement for transplantation. We isolated hepatic mononuclear cells (HMC) from liver perfusate of living donors (LD) and donors after brain death (DBD) or cardiac death (DCD) and assessed the frequency of T-cell subsets, their cytokine secretion profile and CD8 T-cell cytotoxicity function, responsiveness to a danger associated molecular pattern (High Mobility Group Box1, HMGB1) and association with donor and recipient clinical parameters and immediate graft outcome. RESULTS: We found that T-cells in healthy human livers were enriched in memory CD8 T-cells exhibiting a phenotype of non-circulating tissue-associated lymphocytes, functionally dominated by more cytotoxicity and IFN-γ-production in DBD donors, including upon activation by HMGB1 and correlating with peak of post-transplant AST. This liver-specific pattern of CD8 T-cell was prominent in DBD livers compared to DCD and LD livers suggesting that it was influenced by events surrounding brain death, prior to retrieval. CONCLUSION: Mode of liver donation can affect liver T-cells with increased liver damage in DBD donors. These findings may be relevant in designing therapeutic strategies aimed at organ optimization prior to transplantation.

Role of anti-vimentin antibodies in renal transplantation.

BACKGROUND: The role of non-HLA antibodies in rejection is not clear. We investigate whether antibodies to vimentin are made after renal transplantation and if production is associated with interstitial fibrosis and tubular atrophy (IFTA). METHODS: In this retrospective study, sera from 70 recipients of renal allografts (40 controls, 30 IFTA) were studied. The biopsy diagnosis of interstitial fibrosis and tubular atrophy (IFTA) was based on random, cause-indicating biopsies. Sera were collected pretransplant and at 3 monthly intervals up to 5 years posttransplant or diagnosis of IFTA and assayed by ELISA for IgM and IgG anti-vimentin antibodies (AVA) and HLA antibodies. RESULTS: Mean titers of IgM AVA were higher at every year after transplantation compared with pretransplant for both IFTA and controls groups (P<0.001). There was no difference in the mean level of IgM AVA achieved by IFTA and control groups. The mean pretransplant levels of IgG AVA in the IFTA and control group were 18.2±11.7 and 11.0±8.1, respectively (P=0.001). There was a significant increase between the pretransplant mean levels of IgG AVA and the levels at years 1 to 4 in the IFTA group (years 1-3, P<0.0001, year 4 P=0.003) but not in the controls. There was no significant difference between the numbers of IFTA or control patients achieving a positive value (mean+2SD of pretransplant antibody titers) of IgM AVA (50% versus 37.5%, respectively) or IgG AVA (26.6% versus 12.5%, respectively). There was no association between production of HLA and AVA antibodies. CONCLUSION: Posttransplant production of IgM AVA is not associated with IFTA. The production of IgG AVA by a minority of IFTA patients suggests that in some individuals, IgG AVA may be involved in the pathology of IFTA.

Vessel rejection secondary to human leucocyte antigen antibodies directed against the arterial conduit following pancreas transplantation from a separate donor.

Whole-organ pancreas transplantation is typically carried out using a Y-graft derived from the donor iliac vessels. We describe a case in which a 31-year-old male underwent a simultaneous pancreas-kidney transplant, but in which vessels from a different donor were used for the arterial anastomosis of the pancreas graft. Although initially there was good function, 18 months post-transplant the patient was admitted with diabetic ketoacidosis secondary to pancreas graft failure. Radiological investigations revealed complete occlusion of the vascular Y-graft, and laboratory investigations demonstrated donor-specific human leucocyte antigen (HLA) antibodies directed against HLA mismatches of the vessel donor. This case highlights the risks of using allogeneic vascular material for surgical anastomoses.

Consensus guidelines on the testing and clinical management issues associated with HLA and non-HLA antibodies in transplantation.

BACKGROUND: The introduction of solid-phase immunoassay (SPI) technology for the detection and characterization of human leukocyte antigen (HLA) antibodies in transplantation while providing greater sensitivity than was obtainable by complement-dependent lymphocytotoxicity (CDC) assays has resulted in a new paradigm with respect to the interpretation of donor-specific antibodies (DSA). Although the SPI assay performed on the Luminex instrument (hereafter referred to as the Luminex assay), in particular, has permitted the detection of antibodies not detectable by CDC, the clinical significance of these antibodies is incompletely understood. Nevertheless, the detection of these antibodies has led to changes in the clinical management of sensitized patients. In addition, SPI testing raises technical issues that require resolution and careful consideration when interpreting antibody results. METHODS: With this background, The Transplantation Society convened a group of laboratory and clinical experts in the field of transplantation to prepare a consensus report and make recommendations on the use of this new technology based on both published evidence and expert opinion. Three working groups were formed to address (a) the technical issues with respect to the use of this technology, (b) the interpretation of pretransplantation antibody testing in the context of various clinical settings and organ transplant types (kidney, heart, lung, liver, pancreas, intestinal, and islet cells), and (c) the application of antibody testing in the posttransplantation setting. The three groups were established in November 2011 and convened for a "Consensus Conference on Antibodies in Transplantation" in Rome, Italy, in May 2012. The deliberations of the three groups meeting independently and then together are the bases for this report. RESULTS: A comprehensive list of recommendations was prepared by each group. A summary of the key recommendations follows. Technical Group: (a) SPI must be used for the detection of pretransplantation HLA antibodies in solid organ transplant recipients and, in particular, the use of the single-antigen bead assay to detect antibodies to HLA loci, such as Cw, DQA, DPA, and DPB, which are not readily detected by other methods. (b) The use of SPI for antibody detection should be supplemented with cell-based assays to examine the correlations between the two types of assays and to establish the likelihood of a positive crossmatch (XM). (c) There must be an awareness of the technical factors that can influence the results and their clinical interpretation when using the Luminex bead technology, such as variation in antigen density and the presence of denatured antigen on the beads. Pretransplantation Group: (a) Risk categories should be established based on the antibody and the XM results obtained. (b) DSA detected by CDC and a positive XM should be avoided due to their strong association with antibody-mediated rejection and graft loss. (c) A renal transplantation can be performed in the absence of a prospective XM if single-antigen bead screening for antibodies to all class I and II HLA loci is negative. This decision, however, needs to be taken in agreement with local clinical programs and the relevant regulatory bodies. (d) The presence of DSA HLA antibodies should be avoided in heart and lung transplantation and considered a risk factor for liver, intestinal, and islet cell transplantation. Posttransplantation Group: (a) High-risk patients (i.e., desensitized or DSA positive/XM negative) should be monitored by measurement of DSA and protocol biopsies in the first 3 months after transplantation. (b) Intermediate-risk patients (history of DSA but currently negative) should be monitored for DSA within the first month. If DSA is present, a biopsy should be performed. (c) Low-risk patients (nonsensitized first transplantation) should be screened for DSA at least once 3 to 12 months after transplantation. If DSA is detected, a biopsy should be performed. In all three categories, the recommendations for subsequent treatment are based on the biopsy results. CONCLUSIONS: A comprehensive list of recommendations is provided covering the technical and pretransplantation and posttransplantation monitoring of HLA antibodies in solid organ transplantation. The recommendations are intended to provide state-of-the-art guidance in the use and clinical application of recently developed methods for HLA antibody detection when used in conjunction with traditional methods.

Baculovirus as delivery system for gene transfer during hypothermic organ preservation.

Concerns over the safety of conventional viral vectors have limited the translation of gene transfer from an exciting experimental procedure to a successful clinical therapy in transplantation. Baculoviruses are insect viruses, but have the ability to enter mammalian cells and deliver potential therapeutic molecules with no evidence of viral replication. This study provides evidence of the ability of recombinant baculovirus to enter mammalian kidneys and livers during cold preservation. Six kidneys and six liver lobules retrieved from large pigs were perfused with University of Wisconsin (UW) solution containing a baculovirus tagged with green fluorescent protein and preserved for 8 h. In addition, six kidneys were perfused with UW containing a baculovirus expressing red fluorescent protein and preserved for 24 h. Green fluorescent virus particles were detected within transduced kidneys and livers after 8 h standard cold storage and red fluorescent protein mRNA was detected in kidneys after 24 h of cold preservation. There were no significant differences in tissue architecture, cell morphology or ATP content between experimental organs and their controls. Ex vivo transduction of organs with recombinant baculovirus during conventional cold preservation was demonstrated with no evidence of additional injury or reduction in cell viability.

Peripheral blood sampling for the detection of allograft rejection: biomarker identification and validation.

Currently, acute allograft rejection can only be detected reliably by deterioration of graft function confirmed by allograft biopsy. A huge drawback of this method of diagnosis is that substantial organ damage has already taken place at the time that rejection is diagnosed. Discovering and validating noninvasive biomarkers that predict acute rejection, and chronic allograft dysfunction, is of great importance. Many studies have investigated changes in the peripheral blood in an attempt to find biomarkers that reflect changes in the graft directly or indirectly. Herein, we will review the promises and limitations of the peripheral blood biomarkers that have been described in the literature so far.

Analysis of factors that affect outcome after transplantation of kidneys donated after cardiac death in the UK: a cohort study.

BACKGROUND: A third of all kidneys from deceased donors in the UK are donated after cardiac death, but concerns have been raised about the long-term outcome of such transplants. We aimed to establish these outcomes for kidneys donated after controlled cardiac death versus brain death, and to identify the factors that affect graft survival and function. METHODS: We used data from the UK transplant registry to select a cohort of deceased kidney donors and the corresponding transplant recipients (aged ≥18 years) for transplantations done between Jan 1, 2000, and Dec 31, 2007. Kaplan-Meier estimates were used to assess graft survival, and multivariate analyses were used to identify factors associated with graft survival and with long-term renal function, which was measured from estimated glomerular filtration rate (eGFR). FINDINGS: 9134 kidney transplants were done in 23 centres; 8289 kidneys were donated after brain death and 845 after controlled cardiac death. First-time recipients of kidneys from cardiac-death donors (n=739) or brain-death donors (n=6759) showed no difference in graft survival up to 5 years (hazard ratio 1·01, 95% CI 0·83 to 1·19, p=0·97), or in eGFR at 1-5 years after transplantation (at 12 months -0·36 mL/min per 1·73 m(2), 95% CI -2·00 to 1·27, p=0·66). For recipients of kidneys from cardiac-death donors, increasing age of donor and recipient, repeat transplantation, and cold ischaemic time of more than 12 h were associated with worse graft survival; grafts from cardiac-death donors that were poorly matched for HLA had an association with inferior outcome that was not significant, and delayed graft function and warm ischaemic time had no effect on outcome. INTERPRETATION: Kidneys from controlled cardiac-death donors provide good graft survival and function up to 5 years in first-time recipients, and are equivalent to kidneys from brain-death donors. Allocation policy for kidneys from cardiac-death donors should reduce cold ischaemic time, avoid large age mismatches between donors and recipients, and restrict use of kidneys poorly matched for HLA in young recipients. FUNDING: UK National Health Service Blood and Transplant, and Cambridge National Institute for Health Research Biomedical Research Centre.

HLA class I amino acid sequence-based matching after interlocus subtraction and long-term outcome after deceased donor kidney transplantation.

We have shown previously that human leukocyte antigen (HLA) immunogenicity, defined by the physiochemical properties of mismatched amino acids, predicts humoral alloimmunity, and now report the effect on long-term graft survival after kidney transplantation. The influence of HLA-A and -B mismatch, number of amino acid mismatches (after interlocus subtraction) and their physiochemical (electrostatic and hydrophobic) disparity on the outcome of fully HLA matched and single HLA-A or -B mismatched deceased donor kidney transplants undertaken in the United Kingdom (1990-2005) were analyzed (n = 5,247). Grafts with a single HLA-A or -B mismatch had significantly lower survival than fully matched transplants (81.9% vs 84.2% at 5 years, p = 0.004). However, single HLA-A or -B mismatched grafts with no or one amino acid mismatch had better survival than grafts with two or more amino acid mismatches (89.3% vs 81.8% at 5 years, HR 1.5, p = 0.03). The number of mismatched amino acids was an independent predictor of transplant survival after adjusting for the underlying HLA matching effect (p = 0.02). Physiochemical disparity scores correlated closely with amino acid mismatches and provided no additional predictive value. The immunogenicity of HLA class I alloantigens defined at the level of amino acid sequence correlates more closely with outcome after renal transplantation than conventional serologic HLA matching.

Factors affecting graft and patient survival after live donor kidney transplantation in the UK.

BACKGROUND: The outcome after living donor renal transplantation is superior to that for deceased donor transplantation, but the results are not uniformly successful. The factors responsible for the variable outcome after living donor transplantation have not been well defined. METHODS: UK Transplant Registry data were analyzed to determine the outcomes of 3142 first adult kidney transplants from living donors (71% genetically related and 29% unrelated) performed between 2000 and 2007 inclusive. Kaplan-Meier survival estimates were determined, and factors that might be associated with graft and patient survival were analyzed using Cox proportional hazards regression modeling. RESULTS: Patient survival at 5 years was better for recipients of grafts from related than unrelated donors (97% vs. 93%, P=0.0002), but conversely graft survival was better in recipients of genetically unrelated grafts (93% vs. 89%, P=0.06). After adjustment for the factors found to influence graft and patient survival, these differences were no longer apparent. In contrast to the expectations, the degree of human leukocyte antigen-A, -B, and -DR mismatch did not influence graft survival. Increasing donor age (but not recipient age), recipient diabetes, and grafts from adult offspring were independently associated with poorer patient survival in the first 3 years after transplantation. Poorer graft survival was independently associated with donor age older than 59 years, and female recipients. CONCLUSIONS: Advanced donor age, but not human leukocyte antigen mismatch, is associated with poorer outcome after live donor kidney transplantation. However, the results of live donor transplantation remain superior to deceased donor kidney transplantation.

Impact of the 1998 UK National Allocation Scheme for deceased heartbeating donor kidneys.

INTRODUCTION: National and regional strategies for allocating deceased heartbeating (DHB) donor kidneys to patients awaiting transplant are of great importance and have major implications for patients and healthcare systems. We describe the rationale for the 1998 National Kidney Allocation Scheme (1998 NKAS) and its impact on renal transplantation in the United Kingdom over 5 years. METHODS: The 1998 NKAS was based on three tiers of patients defined by human leukocyte antigen (HLA) mismatch. This involved national allocation of well-matched kidneys in tiers 1 and 2, with regional allocation for less well-matched patients in tier 3. Pediatric patients (younger than 18 years) and regional patients were prioritized in tiers 1 and 2, with a points score based on six factors determining the specific priority order for allocation. RESULTS: The 1998 NKAS allocated approximately half the kidneys from DHB donors to the national transplant list and resulted in significantly improved HLA matching, more than doubling the proportion of transplants that were 000 HLA-A, -B, and -DR mismatched from 7% to 16% for adults. Pediatric patients achieved comparable levels of HLA matching to adult patients for the first time in the United Kingdom through improved access to adult donor organs. The scheme also benefited highly sensitized patients and improved equity with regard to patient blood group, rareness of HLA type, and HLA homozygosity. CONCLUSION: The 1998 NKAS represented a significant advance for the allocation of DHB donor kidneys in the United Kingdom and, while not addressing inequities in access to transplant, it did largely achieve the principal goal of improving HLA matching.

Factors influencing outcome after deceased heart beating donor kidney transplantation in the United Kingdom: an evidence base for a new national kidney allocation policy.

BACKGROUND: Outcomes after deceased heart beating donor kidney transplantation are good, but survival rates vary according to a number of donor-, recipient-, and transplant-related factors. This comprehensive analysis of transplant outcomes was undertaken to inform development of a new Kidney Allocation Scheme. METHODS: A complete case analysis of the outcome of kidney-only transplants in the United Kingdom, 1995 to 2001, was undertaken using Cox regression modeling. Seven thousand three hundred eighty-five (77%) of the 9585 transplants reported to the UK Transplant Registry were primary transplants in adults. Regrafts and pediatric patients (age <18 years) were analyzed separately. Transplant and patient survival over 5 years were investigated in addition to causes of prolonged cold ischemia time (CIT). RESULTS: A variety of factors significantly adversely influenced kidney transplant and patient outcome, including older donor age, older recipient age, waiting time to transplant over 2 years, diabetes, and earlier year of transplant. Human leukocyte antigen mismatch and CIT were significant in analyses of transplant but not in patient outcome, and an increased graft failure rate was also identified in adolescent patients. CIT was prolonged by long-distance kidney exchanges between centers (2 hr) and reallocation of kidneys for alternative patients (7 hr). CONCLUSION: This study identified a number of factors that influence transplant outcome after deceased heart beating donor kidney transplant in the United Kingdom. The findings suggest that the influences of human leukocyte antigen mismatch and CIT are most relevant in considering a revised kidney allocation scheme.