HLA-B8, DR3: a new risk factor for graft failure after renal transplantation in patients with underlying immunoglobulin A nephropathy.

BACKGROUND: The HLA-B8, DR3 haplotype has been associated with high immune reactivity. In this study, we have tested whether this haplotype has differential effect on graft survival in patients with IgAN compared with control patients. METHODS: From the Eurotransplant Registry we analyzed graft survival of 1207 recipients with IgAN and 7935 control patients with non-glomerular diseases. Death-censored graft loss according to the HLA-B8, DR3 haplotype was calculated with Kaplan-Meier analysis and Cox-regression model was used to correct for various risk factors. RESULTS: The frequency of the HLA-B8, DR3 haplotype was significantly lower in IgAN patients compared with controls (10.3% vs. 15.4%, p < 0.001). Ten-year graft survival was identical in the control group with and without the HLA-B8, DR3 haplotype (71.1% and 70.2%, respectively), but significantly worse in IgAN patients carrying the HLA-B8, DR3 haplotype compared with patients without it (52.5% vs. 69.1%, respectively, p = 0.009). The risk of graft loss was increased by 66% (HR 1.6, 95% CI 1.14, 2.29) in IgAN with the HLA-B8, DR3 haplotype and independent of well-known risk factors. CONCLUSIONS: We have identified a new risk factor for graft loss unique to patients with IgAN. This finding emphasizes the exclusive immune characteristics of IgAN patients after transplantation.

Simpler and equitable allocation of kidneys from postmortem donors primarily based on full HLA-DR compatibility.

BACKGROUND: The introduction of human leukocyte antigen (HLA)-matching in nonliving kidney transplantation has resulted into a better graft outcome, but also in an increase of waiting time, especially for patients with rare HLA phenotypes. We addressed the question of the differential influence of HLA-DR-matching versus HLA-A,B in clinical kidney transplantation. METHODS: We used Kaplan-Meier product limit method to estimate survival rates, and Cox proportional hazard regression for the estimation of relative risks (Hazard-ratios) for different variables. RESULTS: A single center study (n=456 transplants, performed between 1985 and 1999) showed that full HLA-DR compatibility leads to a lower incidence of biopsy confirmed acute rejections in the first 180 posttransplantation days. These results were substantiated using the Eurotransplant database (n=39,205 transplants performed between 1985 and 2005) where graft survival in the full HLA-DR compatible group was significantly better than in the incompatible. An additional positive effect of HLA-A,B matching was only found in the full HLA-DR compatible group. In both studies, the introduction of a single HLA-DR incompatibility eliminates the HLA-A,B matching effect. CONCLUSIONS: We propose to allocate postmortem kidneys only to patients with full HLA-DR compatibility, and use HLA-A,B compatibility as an additional selection criterion. All patients, irrespective of their ethnic origin, will profit since the polymorphism of HLA-DR is by far lower than that of HLA-A,B. Excessive kidney travel and cold ischemia time will be significantly reduced.

Exclusive characteristics of graft survival and risk factors in recipients with immunoglobulin A nephropathy: a retrospective analysis of registry data.

BACKGROUND: Some studies have claimed that patients with immunoglobulin A (IgA) nephropathy have better graft survival than other renal graft recipients, whereas others have rejected this statement. We have addressed this paradox in the present study. METHODS: In all, 1,207 patients with IgA nephropathy who received a primary cadaveric renal graft from 1990 to 2002 were identified in the Eurotransplant database. For comparison, we analyzed 7,935 patients with nonglomerular diseases. Death-censored graft survival was calculated using Kaplan Meier estimates and a multivariable Cox regression analysis was used for risk calculations. RESULTS: Death-censored graft survival was superior in patients with IgA nephropathy in the first period after transplantation. After 3 years posttransplant, however, there was an accelerated decline in graft survival in recipients with IgA nephropathy. The fully adjusted risk of graft loss in the first year was increased by 40% in the control group compared to IgA nephropathy (hazard ratio [HR] 1.40, 95% CI 1.12-1.75), whereas the risk was significantly lower in the control group after the first year posttransplant (HR 0.75, 95% CI 0.63-0.88). Cold ischemia time, immunization and HLA-DR mismatch were risk factors for graft loss in the control group but not for IgA nephropathy, whereas HLA-AB mismatch was an independent risk factor, exclusively for the IgA nephropathy group. CONCLUSIONS: Recipients with IgA nephropathy have better 1-year graft survival, presumably due to favorable immunological behavior. This benefit was however abolished in the long-term by increased graft loss with time. Studies are needed to explain the difference in graft survival and the reason why different risk factors are involved in graft failure.

Renal allograft function in matched pediatric and adult recipient pairs of the same donor.

BACKGROUND: To study the effect of donor age on kidney function, the authors investigated matched pairs from the same kidney donor given to a pediatric or an adult recipient. METHODS: Fifteen matched pairs of an adult and a pediatric patient, selected from the Eurotransplant registry, receiving the renal graft from the same cadaveric donor were selected for analysis of graft function over 7 years. Nine matched pairs were from adult donors (mean age, 40 years; range, 23-60 years) and six from pediatric donors (mean age, 11 years; range, 4-15 years). All recipients had comparable immunosuppression with cyclosporine A, prednisolone, and azathioprine and comparable numbers of acute rejection, cytomegalovirus reactivation, and antihypertensive therapy. Mean age of pediatric and adult recipients at transplantation was 5 years (range, 1-9 years) and 38 years (range, 25-60 years), respectively. RESULTS: The calculated glomerular filtration rate (GFR) corrected to body surface area was not different in adult and pediatric recipients. Initial absolute GFR was significantly lower in pediatric recipients (27 mL/ min; range, 17-38 mL/min) than in adult recipients (54 mL/min; range, 25-74 mL/min) (P <0.05) and remained lower in the following years. Initially, pediatric donor kidneys transplanted into pediatric recipients showed a lower absolute GFR than those transplanted into adults, however, approaching the GFR in adult recipients later. Adult donor kidneys transplanted into pediatric recipients showed a persistently lower absolute GFR in children compared with those transplanted into adult recipients. CONCLUSIONS: The authors conclude that adult donor kidneys in pediatric recipients decrease GFR in the early stages and lack an increase in GFR with growth of the child.

The Eurotransplant Study on Twin Lung Transplants (ESOTWIN): 90 paired single-lung transplants from the same donor.

BACKGROUND: Despite its reduced benefit for a single recipient, the transplantation of two single-lung allografts as opposed to one bilateral lung transplant has the indisputable advantage of maximizing the number of patients that benefit from a single donor. METHODS: In the period 1997 to 1999, 90 paired single-lung transplants (SLTx) from 45 donors were performed in 16 lung centers in Eurotransplant, with a complete follow-up of 1 year. RESULTS: No significant differences between left- and right-lung allograft recipients were observed regarding age, sex, primary disease, number of human leukocyte antigen mismatches, cold ischemic time, and donor-to-recipient cytomegalovirus match. Early posttransplant outcome, as assessed by oxygenation index at 12, 24, and 48 hr, also did not differ significantly, and there were no differences in time to extubation and time spent in the intensive care unit. In the first month, six left- and three right-lung allograft recipients died. Bronchiolitis obliterans syndrome developed in 5 of 39 left-lung and 10 of 42 right-lung allograft recipients. If the retrieval team was different from the transplanting team, a significantly worse 1-year posttransplant survival rate was seen in patients who underwent left SLTx compared with those who underwent right SLTx (62% vs. 92%, respectively; P=0.04). CONCLUSIONS: More fatal posttransplant complications occur in patients undergoing left SLTx compared with right SLTx. A less optimistic assessment of the left lung by the not-implanting retrieval team is warranted.

HLAmatchmaker: a molecularly based algorithm for histocompatibility determination. III. Effect of matching at the HLA-A,B amino acid triplet level on kidney transplant survival.

BACKGROUND: HLAMatchmaker is a recently developed computer-based algorithm to determine donor-recipient HLA compatibility at the molecular level. Originally designed for highly alloimmunized patients, this algorithm is based on the concept that immunogenic epitopes are represented by amino acid triplets on exposed parts of protein sequences of HLA-A, -B, and -C chains accessible to alloantibodies. Donor HLA compatibility is determined by intralocus and interlocus comparisons of triplets in polymorphic sequence positions. For most patients, HLAMatchmaker can identify certain mismatched HLA antigens that are zero-triplet mismatches to the patient's HLA phenotype and should, therefore, be considered fully histocompatible. The present study was designed to determine how class I HLA matching at the triplet level affects kidney transplant outcome. METHODS: We analyzed two multicenter databases of zero-HLA-DR-mismatched kidneys transplanted from 1987 to 1999. One database consisted of 31,879 primary allografts registered by U.S. transplant centers in the United Network for Organ Sharing database and the other consisted of 15,872 transplants in the Eurotransplant program. RESULTS: HLA-A,B mismatched kidneys that were compatible at the triplet level exhibited almost identical graft survival rates as the zero-HLA-A,B antigen mismatches defined by conventional criteria. This beneficial effect of triplet matching was seen for both nonsensitized and sensitized patients and also for white and nonwhite patients. CONCLUSIONS: These findings suggest that the application of HLAMatchmaker will increase the number of successful transplants, at least in the HLA-DR match combinations.

The heart-allocation simulation model: a tool for comparison of transplantation allocation policies.

BACKGROUND: Numerous studies have investigated prognostic factors for the survival of transplant candidates waiting for a donor organ, but little is known about the impact of allocation policies on waiting list outcome. Simulation models would allow a comparison of different policies for allocating donor hearts on pretransplant outcome. METHODS: A model was built for the Eurotransplant waiting list for heart transplantation. Survival and delisting distributions were estimated from the Eurotransplant transplant candidate inflow between 1995 and 2000 (n=7,142). Other characteristics were obtained directly from the transplant candidate inflow of 1999 and 2000 (n=2,097) and the donor organs of 1998 and 1999 (n=1,520). Overall and subgroup waiting list mortality were estimated for allocation policies differing by ABO blood group, border, and clinical profile rules. RESULTS: The model estimated that international organ exchange reduces waiting list mortality in the different countries by 1.9% to 12.4%. An allocation policy incorporating the initial clinical profile of the transplant candidates further reduced waiting list mortality by 1.7%. Changing ABO rules toward identical matching yielded a slightly more equitable survival for the different groups, without an overall effect on mortality. The best possible allocation policy is the policy where organs are allocated to patients that are at highest risk of dying, and withholding organs from patients that would eventually delist because of improvement. CONCLUSIONS: Patients benefit from international organ exchange and by a heart allocation scheme based on clinical profiles. Timely delisting of patients who are-temporarily-too well for transplantation is the best waiting list policy.

It takes six to boogie: allocating cadaver kidneys in Eurotransplant.

In March 1996, a new allocation point system for cadaver kidneys, the Eurotransplant (ET) Kidney Allocation System (KAS), was introduced in ET, the first multinational organ exchange organization. The aims of ETKAS were to reduce average and maximum waiting time, to allow patients with rare human leukocyte antigen (HLA) phenotypes or combinations to receive an "optimal" offer, to keep the exchange rates between the participating countries balanced, and finally to keep optimal graft survival, by means of HLA matching. Elderly patients and highly sensitized patients profit in addition from special programs, the ET Senior Program and the Acceptable Mismatch Program, respectively. All kidneys are offered to the pool and are allocated according to the degree of HLA matching, mismatch probability, waiting time, distance from the donor center, and balance between the countries participating in ET. A summary of 6 years' experience with the ETKAS is presented in this article.

The acceptable mismatch program as a fast tool for highly sensitized patients awaiting a cadaveric kidney transplantation: short waiting time and excellent graft outcome.

There are many highly sensitized patients on the kidney waiting lists of organ exchange organizations because it is difficult to find a crossmatch negative cadaver kidney for these patients. Recently, several protocols have been developed to remove the donor-specific human leukocyte antigen (HLA) antibodies from the serum of these patients before transplantation. These approaches, including the use of intravenous immunoglobulins, plasmapheresis and immunoglobulins (plasmapheresis-cytomegalovirus-immunoglobulin), and immunoabsorption, seem to lead to a certain success rate, although the additional immunosuppression necessary to remove and control the production of donor-specific alloantibodies may have its impact on the short-term (infections) and long-term (incidence of cancer) immune surveillance. Furthermore, some of these therapies represent a considerable financial burden for patients and society. In the present report, we advocate selection of crossmatch negative donors on the basis of the Acceptable Mismatch Program, as the first and best option for highly sensitized patients to undergo transplantations. No additional immunosuppression is necessary, and graft survival in this group of "difficult" patients is identical to that of nonsensitized recipients. Because the nature of the HLA polymorphism does not allow all patients to profit from this approach, removal of circulating HLA antibodies can be considered as a rescue therapy for those patients for whom the Acceptable Mismatch Program does not give a solution.

A prognostic model for predicting waiting-list mortality for a total national cohort of adult heart-transplant candidates.

BACKGROUND: Current trends in medical management of advanced heart failure and transplant medicine and the enactment of a national transplant law forced a change toward allocation driven by disease severity. OBJECTIVE: The aim of this study was to create a model for predicting waiting-list survival on the basis of simple clinical parameters. METHODS: The clinical profiles of all patients registered for heart transplantation in Germany in 1997 (n=889) were used as a derivation set, and the total German 1998 cohort (n=897) was used as a validation set. The model was validated by the c statistic and by comparison of risk stratified mortality rates. The validated model was fine tuned by the appropriate calibration procedures. The data were first classified into physiologic subscores: an urgency score, a left ventricular heart failure score, a right ventricular heart failure score, and a systemic heart failure score. A stepwise modeling procedure was undertaken using these subscores as factors as well as the recipient's age, ABO blood group, and body surface area. RESULTS: The urgency and the left ventricular subscore were found to be significantly associated with waiting-list mortality. A summary index termed German Transplant Society (GTS) score was then calculated on the basis of seven parameters contained in these two subscores. The GTS score was able to predict waiting-list mortality risks for the 1998 cohort: 1-year mortality before transplantation was 71%, 34%, 11% for the high, medium, and low risk groups, respectively. CONCLUSION: The use of this continuous disease severity index may improve the selection of cardiac transplant candidates.

The number of amino acid triplet differences between patient and donor is predictive for the antibody reactivity against mismatched human leukocyte antigens.

BACKGROUND: The correlation between antibody production against mismatched donor human leukocyte antigens (HLA) and the number of amino acid sequence mismatches was analyzed in patients who rejected a kidney transplant (n=146). METHODS: A similar analysis was performed for the antibody production of women against the paternal HLA antigens of their child (n=1,397). The amino acid sequence (triplet) differences were analyzed using the HLAMatchmaker algorithm. RESULTS: In both groups, a positive correlation was found between the number of triplet mismatches and the percentage of individuals producing antibodies (P <0.0001). If zero triplet mismatches were present, no antibodies were formed in all cases. When 11 or 12 triplet mismatches were present, 94% of the transplant patients produced antibodies against the donor. In pregnancy, 11 or 12 triplet mismatches led to 27% of the women producing specific antibodies. CONCLUSIONS: These results indicate that the immunogenicity of the fetus is lower than that of a rejected kidney and that analysis of the number of triplet mismatches can predict the antibody reactivity against the mismatched HLA antigens.

Differential immunogenicity of HLA mismatches: HLA-A2 versus HLA-A28.

The immunogenicity of human leukocyte antigen (HLA)-A2 versus HLA-A28 was analyzed by antibody production, cytotoxic T-lymphocyte (CTL) induction, and graft survival. We observed that an HLA-A2 mismatched child in HLA-A28 women leads to HLA-A2 specific antibodies in 32% of the women (n=31), whereas in the case of an HLA-A28 child and HLA-A2 women (n=30), no HLA-A28 specific antibodies were found ( P<0.002). Also, the CTL precursor frequencies were significantly lower against HLA-A28 compared with CTLp frequencies against HLA-A2 ( P=0.012). Finally, the kidney graft survival was slightly better in HLA-A2 positive recipients transplanted with HLA-A28 mismatches. We can conclude that single HLA-A28 mismatches are less immunogenic in HLA-A2 individuals compared with single HLA-A2 mismatches in HLA-A28 individuals, which is probably because the mismatched epitopes on the HLA-A2 molecule are unique epitopes, whereas the mismatched epitopes on HLA-A28 are shared by other HLA-A and HLA-B molecules.

The HLA-DR phenotype of the responder is predictive of humoral response against HLA class I antigens.

Recent studies suggest that the immunogenicity of an human leukocyte antigen (HLA) incompatibility should be considered in the context of the HLA phenotype of the recipient. The HLA-DR phenotype of the responder is thought to be predictive for the strength of the alloimmune response. In order to analyze the humoral response against HLA class I antigens in the context of the HLA-DR phenotype of the responder, we selected all HLA-DR homozygous Dutch patients that were present on the Eurotransplant waiting list between 1967 and 2000 (n=1,317 patients). By logistic regression it was determined whether antibody production against a specific HLA class I antigen is associated with a particular HLA-DR antigen in the patient. Furthermore, it was analyzed whether a patient, expressing a particular HLA-DR antigen, preferentially produces antibodies against particular HLA class I antigens. The results demonstrate that patients, homozygous for a certain HLA-DR antigen, cannot be considered high or low responders when analyzing the antibody response in terms of panel reactive antibody (PRA) value. However, a correlation can be found between the HLA-DR phenotype of the patient and the specific antibody response against HLA class I antigens. For example, antibodies against HLA-A10, -A11, -A19, and -B35 are produced more frequently by HLA-DR6 positive individuals, whereas antibodies against HLA-A3, -B5, -B7, -B8, and -B12 are produced more frequently by HLA-DR4 positive individuals. These data confirm that the HLA-DR phenotype of the responder plays a determinative role in the immunogenicity of mismatched HLA antigens. The results indicate that selection of HLA class I mismatches of the donor in the context of the HLA-DR phenotype of the responder might reduce the incidence of humoral graft rejection and minimize the sensitization grade of retransplant candidates.

The crossmatch policy of the transplantation center influences graft survival in cadaver kidney transplantation.

The outcome of cadaver kidney transplantation is influenced by several independent parameters including the center effect. In this parameter is included patient management in the pre- and posttransplantation phases, as well as the policy of the transplantation center with respect to sensitized patients and crossmatching. It is generally accepted that sensitization influences the graft outcome but the complications of the crossmatch policy of the individual transplant centers have never been studied in a systematic way. Here, using the results from 24 transplantation centers, served by 22 tissue typing laboratories affiliated with Eurotransplant, we provide indirect evidence that the crossmatch policy of the transplant center has a significant influence on the graft outcome. The use of historical sera for the decisive crossmatch is beneficial for graft survival in sensitized patients.

Renal transplantation of highly sensitised patients via prioritised renal allocation programs. Shorter waiting time and above-average graft survival.

BACKGROUND: Highly sensitised renal transplant candidates (HSP) have a reduced chance of receiving a transplant. In Eurotransplant (ET), two special allocation programs have been made available for such patients: the Highly Immunised Tray (HIT) program and the Acceptable Mismatch program (AM), albeit with different inclusion and exclusion criteria (HIT, current PRA% >or=85%; AM, current and/or historical PRA% >or=85%). When a suitable kidney is available for a patient, included in these special programs, the kidney is mandatory offered. In contrast, in the point score system of the standard ET kidney allocation procedure (ETKAS), HSP (PRA >or=85%) only get a marginal bonus according to their current sensitisation. It was tested whether the allocation priority of the two special allocation programs is justified from the perspective of transplant outcome. METHODS: The post- transplant outcomes of recent consecutive cohorts of AM, HIT and HSP-ETKAS transplants were compared. The end points were initial graft function, rejection episodes during the first three months post-transplant, and 1-year kidney graft outcome. RESULTS: Between January 1, 1997 and June 30, 1998, 101 HSP received a kidney-only transplant: 29 via AM, 39 via HIT and 33 via ETKAS. HLA-A,B,DR matching was more favourable in the AM and HIT allocation groups and their waiting times till transplantation were much shorter than those of the HSP-ETKAS allocation group. The incidence of initial graft non-function was similar among the three HSP allocation groups, averaging 50%. Recovery of the initial non-function was more likely for AM and HIT transplants. No difference was present with regard to the percentage of patients who experienced at least one rejection episode during the first three months post-transplant, averaging 43%. However, the AM group had less severe and/or less recurrent rejection episodes. The 1-year kidney graft survival, censored for death with functional graft, was 96% for AM, 82% for HIT and 75% for HSP-ETKAS transplants (p = 0.04). CONCLUSIONS: The two special allocation programs for HSP do yield adequate results and offer a shorter waiting time, compared to the standard kidney allocation procedure. The AM approach might be preferred because of the smoother post-transplant management and the better graft survival, keeping the HIT approach as a back up. Since the allocation priority is justified in view of efficiency, the renal transplant community should support the incorporation of a special allocation program for HSP in their respective organ exchange program.

The role of an organ exchange organization in increasing split-liver transplantation.

Eurotransplant introduced a new allocation policy in January 2003 to increase the number of liver transplants by offering centers an incentive to split deceased donor livers for 2 recipients. Centers were granted the option of choosing a suitable recipient for the second portion of the split liver from their own waiting list and, to increase the awareness for liver splitting, centers were asked by the Eurotransplant duty officer whether they would consider splitting whenever a liver that met the 50/50 rule (donor age <50 and weight >50 kg) was available. During the first year after implementing this policy, split-liver transplants increased by 67% and again by 10% during the second year (a total of 288 transplants in the 2-year period). The number of pediatric recipients of a split liver increased from 44 in 2002 to 76 in 2004 and the pediatric waiting list decreased by 36% (73 to 47) one year after implementation of the new policy. More than 95% of the 288 split liver transplants involved one adult and one pediatric recipient. Nearly three-quarters of the split liver transplants were performed at 3 centers with both a pediatric and adult waiting list and with surgeons experienced in the procedure. We conclude that Eurotransplant's liver allocation policy has increased the number of liver transplants, particularly among children, by rewarding centers that split livers for transplantation to 2 recipients without prolonging cold ischemia time. The number of centers that could benefit from this policy will increase as more surgeons are trained in the splitting procedure.

Evaluation of the Eurotransplant Senior Program. The results of the first year.

UNLABELLED: On 4 January 1999, the Eurotransplant Senior Program (ESP) was implemented within the Eurotransplant kidney allocation scheme. PATIENTS AND METHODS: Kidneys obtained from donors aged over 65 years of age (65+) were allocated to a selected group of nonimmunized 65+ patients undergoing their first transplant. All transplants were performed locally to minimize cold-ischemic time. All transplants performed with kidneys from elderly donors that were allocated via ESP (ESP group) were compared to transplants performed with similar kidneys allocated via the standard renal allocation system (control group). Initial kidney function and 1-year graft outcome were assessed. RESULTS: In 1999, 227 ESP and 102 control transplants were performed. The duration of cold-ischemic time was 12 and 19 h for the ESP and control groups, respectively. No rejection episodes occurred in 60% and 67% of the ESP patients and controls, respectively, while a direct kidney function was observed in 59% of ESP and 49% of control patients. The 1-year graft survival rates, censoring for graft losses due to deaths in patients with functioning grafts, were 86% and 79%, respectively. CONCLUSION: An old-for-old renal allocation algorithm can be successful provided that risk factors, such as cold-ischemic time, are reduced.