Effect of HLA matching in renal transplantation]

Evaluation of HLA-matching is useful in determining graft function and survival in a recipient in cadaveric renal transplantation. The effects of HLA on graft function, which serum creatinine indicative of, and graft survival were examined in both living and cadaveric transplantation in 280 Japanese renal transplants performed at Osaka University and Osaka Prefectural Hospital between October, 1982 and December, 1991 (cadaver 68, living 212). HLA-DR mismatch had a strong effect in living transplants, whereas no disparity was found in cadaver transplants with HLA-DR mismatch. HLA-B, DR mismatch had more effect than HLA-DR in cadaver transplants, and the same effect as HLA-DR in living transplants. HLA-AB affected graft function. It can be used to predict the effect of long-term graft survival. The HLA-haplotype match had the strongest association with graft survival and function in both cases of living and cadaver transplants. HLA-haplotypes of a cadaveric donor and a recipient were presumed by means of the linkage disequilibrium. These findings showed that HLA-matching, especially of haplotype, is an essential factor in relatively low risk renal transplant survival and function. 1-haplotype-matched transplantation, determined by the family study or presumed by the linkage disequilibrium is recommended if not 2-haplotype matched.     

The role of HLA matching in transplantation

All viable human tissues transplanted from one individual to another are at risk of rejection. The extent of risk depends on the donor HLA-host T cell receptor disparity. Such disparity is now known to involve genetic products coded by both HLA and non-HLA genes. T cell responses to mismatches on transplants are graded: the greater the mismatch the greater the number of clones of T cells responding. Consequently, the more severe the rejection process. Global statistics support this view in that cumulative mismatches at HLA are associated with poorer graft survival. However such studies also suggest that mismatches at different HLA loci vary in potency. The strength of mismatch seems to increase from HLA-A, the weakest, through HLA-B to HLA-DR, the most potent. Analysis of clinical results suggests that the risk associated with HLA mismatches in kidney transplantation dwindles after the first five months post-transplant. Although graft losses tend to occur sporadically thereafter, no major risk associated with HLA mismatches can be discerned. Whether this dwindling impact of HLA mismatches with time post-transplant is a general phenomenon applicable to all transplants, or whether it suggests some form of adaptation of host to graft in kidney transplant recipients alone is a subject for further exploration. Tissues vary widely in their susceptibility to rejection through HLA mismatches.(ABSTRACT TRUNCATED AT 250 WORDS)     

Current status of HLA matching in renal transplantation

Summary The impact of HLA compatibility on the success rate of kidney transplants was studied in over 80,000 recipients of primary transplants. The transplants were done from 1982 to 1991 at over 300 transplant centers in 43 countries. The results show that matching the HLA chromosomes in related donor transplants has a striking influence. It is also important that matching for individual HLA antigens in cadaver transplants provides a highly significant improvement in graft survival (P<0.0001). After 5 years, matched grafts have a survival rate approximately 20% higher than completely mismatched grafts. The matching effect is particularly strong in presensitized and second graft recipients. There is now direct evidence that even if it is necessary to transport well-matched kidneys a long way, they have a significantly higher success rate than locally transplanted poorly matched kidneys. New data based on molecular technology show that the precise identification of HLA-DR antigens by DNA typing further improves the success rate of HLA-matched transplants.Abbreviations MM mismatched antigens - RFLP restriction fragment length polymorphism     

Clinical usefulness of HLAMatchmaker in HLA epitope matching for organ transplantation

HLAMatchmaker is a computer algorithm that determines HLA compatibility at the structural level. Donor-recipient histocompatibility is assessed with polymorphic amino acid configurations that represent structurally defined elements of HLA epitopes originally assigned as triplets and more recently as eplets. For many patients, HLAMatchmaker can identify mismatched HLA antigens that can be considered compatible at the structural level. Structurally based HLA matching reduces humoral allosensitization and correlates with good transplant outcome. Moreover, HLAMatchmaker is useful in the analysis of serum antibody reactivity and benefits the strategy of identifying acceptable mismatches for highly sensitized patients.     

The role of HLA matching in hematopoietic cell transplantation

Hematopoietic cell transplantation (HCT) can be a life-saving therapy for patients with genetic and acquired hematologic diseases. Despite major advances in supportive care during HCT, immunological complications of the alloimmune response, including graft rejection and graft-versus-host disease (GVHD), remain major impediments to successful clinical outcomes. Although graft rejection mediated by host immune cells and GVHD mediated by donor immune cells can be prevented or mediated by immune suppression therapy, genetic HLA matching remains essential for successful strategies designed to minimize the risks of transplantation. The most favorable HCT results are seen in patients with a genotypically HLA-identical sibling donor, but the limited availability of matched related donors has severely restricted the clinical application of this therapy. Fortunately, the establishment of large unrelated volunteer donor registries now provides the opportunity to identify HLA matches for many patients who lack a family donor. The criteria for unrelated donor matching, however, are poorly defined. Until recently, an analysis of matching beyond HLA-identical siblings has been limited by typing technology. The introduction within the past few years of new methods for high resolution typing and definition of HLA alleles has had a profound impact on our ability to identify and interpret the multiple nucleotide sequence polymorphisms that encode HLA antigens. Preliminary studies clearly demonstrate the importance of precise matching at the allele level for successful transplantation. There remain, however, important unanswered questions about the relative importance of different HLA loci in matching strategies, as well as incomplete information about permissible limits of mismatching in different patient populations.     

Trends in kidney transplantation rates and disparities

OBJECTIVE: To examine the likelihood of transplantation and trends over time among persons with end-stage renal disease (ESRD) in Wisconsin. METHODS: We examined the influence of patient- and community-level characteristics on the rate of kidney transplantation in Wisconsin among 22,387 patients diagnosed with ESRD between January 1, 1982 and October 30, 2005. We grouped patients by the year of ESRD onset in order to model the change in transplantation rates over time. RESULTS: After multivariate adjustment, all other racial groups were significantly less likely to be transplanted compared with whites, and the racial disparity increased over calendar time. Older patients were less likely to be transplanted in all periods. Higher community income and education level and a greater distance from patients' residence to the nearest dialysis center significantly increased the likelihood of transplantation. Males also had a significantly higher rate of transplantation than females. CONCLUSION: These results demonstrate a growing disparity in transplantation rates by demographic characteristics and a consistent disparity in transplantation by socioeconomic characteristics. Future studies should focus on identifying specific barriers to transplantation among different subpopulations in order to target effective interventions.     

The economic implications of HLA matching in cadaveric renal transplantation.

BACKGROUND: The potential economic effects of the allocation of cadaveric kidneys on the basis of tissue-matching criteria is controversial. We analyzed the economic costs associated with the transplantation of cadaveric kidneys with various numbers of HLA mismatches and examined the potential economic benefits of a local, as compared with a national, system designed to minimize HLA mismatches between donor and recipient in first cadaveric renal transplantations. METHODS: All data were supplied by the U.S. Renal Data System. Data on all payments made by Medicare from 1991 through 1997 for the care of recipients of a first cadaveric renal transplant were analyzed according to the number of HLA-A, B, and DR mismatches between donor and recipient and the duration of cold ischemia before transplantation. RESULTS: Average Medicare payments for renal transplant recipients in the three years after transplantation increased from 60,436 dollars per patient for fully HLA-matched kidneys (those with no HLA-A, B, or DR mismatches) to 80,807 dollars for kidneys with six HLA mismatches between donor and recipient, a difference of 34 percent (P<0.001). By three years after transplantation, the average Medicare payments were 64,119 dollars for transplantations of kidneys with less than 12 hours of cold ischemia time and 74,997 dollars for those with more than 36 hours (P<0.001). In simulations, the assignment of cadaveric kidneys to recipients by a method that minimized HLA mismatching within a local geographic area (i.e., within one of the approximately 50 organ-procurement organizations, which cover widely varying geographic areas) produced the largest cost savings (4,290 dollars per patient over a period of three years) and the largest improvements in the graft-survival rate (2.3 percent) when the potential costs of longer cold ischemia time were considered. CONCLUSIONS: Transplantation of better-matched cadaveric kidneys could have substantial economic advantages. In our simulations, HLA-based allocation of kidneys at the local level produced the largest estimated cost savings, when the duration of cold ischemia was taken into account. No additional savings were estimated to result from a national allocation program, because the additional costs of longer cold ischemia time were greater than the advantages of optimizing HLA matching.     

BSHI Guideline: HLA matching and donor selection for haematopoietic progenitor cell transplantation

A review of the British Society for Histocompatibility and Immunogenetics (BSHI) “Guideline for selection and HLA matching of related, adult unrelated donors and umbilical cord units for haematopoietic progenitor cell transplantation” was undertaken by a BSHI appointed writing committee. Literature searches were performed, and the data extracted were presented as recommendations according to the GRADE nomenclature.     

Impact of persistent and cleared preformed HLA DSA on kidney transplant outcomes

Preformed HLA donor-specific antibodies (DSA) only detected with Luminex have been associated with increased risk of antibody-mediated rejection (ABMR) and graft failure after kidney transplantation (KT). Their evolution after KT may modify this risk. We analyzed postransplant evolution of preformed DSA identified retrospectively and their impact on outcomes of 370 KT performed 2006–2014. Antibodies were monitored prospectively at 1-3-5?years after KT and if any dysfunction. Early acute ABMR was more frequent among patients with preformed DSA class-I or I?+?II than isolated class-II (29.4% vs 4.5%, p?=?0.02). One year post-KT, 20 of 34 patients with functioning KT had persistent DSA. Preformed DSA class-II persisted more frequently than class-I/I?+?II (66.7% vs 33.3%; p?=?0.031). The only risk factor independently associated with persistence was pretransplant MFI. Patients with de novo DSA had the highest risk of ABMR (HR 22.2 [CI 6.1–81.2]). Although recipients with persisting preformed DSA had significantly increased ABMR risk (HR 14.7 [CI 6.5–33.0]), those with cleared preformed DSA also had a higher risk than those without DSA (HR 7.01 [CI 2.2–21.8]).Preformed DSA are a very important risk factor for ABMR and graft loss. Patients who clear preformed DSA still show an increased risk of ABMR and graft loss after KT.     

造血干细胞移植受-供者HLA抗原识别部位的核苷酸匹配研究

目的 研究中国人群等待造血干细胞移植受-供者人类白细胞抗原(human leukocyte antigens,HLA)-A、-B、-Cw、-DRBl、-DQB1 5个位点的等位基因及核苷酸匹配情况,从单核苷酸水平探讨最佳供选择方案.方法 采用聚合酶链反应测序分型法(polymerase chain reaction-sequence-based typing,PCR-SBT),对537对中国人群等待造血干细胞移植受-供者HLA-A、-B、-Cw、-DRB1、-DQB1位点的等位基因进行序列分型,应用BLAST工具分析受-供者HLA核苷酸差异.结果 37对受-供者中HLA-A、-B、-Cw、-DRB1、-DQB1五位点核苷酸完全匹配占16.20%,单个等位基因错配的受-供者对分别占8.38%,0.74%,12.29%,2.42%和2.79%,两个或两个以上等位基因错配比率占42.65%.检出A*02:01-A*02:06,A*02:06-A*02:07,Cw*03:04-Cw*15:02,Cw*03:03-Cw*04:01,Cw*03:04-Cw*14:02,Cw *03:03-Cw*08:01,DRB1*04:03:01-DRB1*04:05不容许错配等位基因对.两对受-供者B*07:05:01-B*07:06,Cw*07:01:01-Cw*07:06抗原识别区外核苷酸错配.结论 在造血干细胞移植选择HLA错配的无关供者时注意受-供核苷酸匹配差异,对HLA抗原识别区内的核苷酸匹配差异和抗原识别区外的核苷酸匹配差异应当加以区别.本研究结果为优化供者选择顺序提供科学参考数据.     

The role of HLA matching in renal transplantation: experience from one center

The influence of serology-based HLA matching on the risk of acute rejection episodes and of graft loss was analyzed in a material of 678 living donor (LD) and 997 cadaveric donor (CD) renal transplantations performed in our center in the period 1989-97. In LD transplantation, recipients of HLA-identical sibling grafts had the lowest rejection risk and the best graft survival, with a half-life estimate of 30 years. One-HLA-haplotype mismatched grafts did better than two-haplotype mismatched related or unrelated donor grafts. Matching for HLA-DR significantly reduced the rejection risk of one-haplotype mismatched grafts. In CD first transplants, HLA-DR matched grafts had a lower incidence of rejection and better survival than HLA-DR mismatched grafts. Expected half-life for HLA-DR matched grafts was 12 years compared to less than 7 years for HLA-DR mismatched grafts. The effects of matching for HLA-A and -B did not reach statistical significance. In CD regrafts, a two-antigen mismatch for HLA-A or -DR led to a significantly poorer graft survival, but the panel-reactive antibody (PRA) status of the recipient was the most influential factor. In CD renal transplantation, we conclude that organ allocation based on matching for HLA-DR 1-14 is effective and not too difficult to obtain even in centers with a short patient waiting list.     

Short tandem repeats haplotyping of the HLA region in preimplantation HLA matching

Recently, preimplantation genetic diagnosis (PGD) has been considered for several indications beyond its original purpose, not only to test embryos for genetic disease but also to select embryos for a nondisease trait, such as specific human leukocyte antigen (HLA) genotypes, related to immune compatibility with an existing affected child in need of a haematopoetic stem cell (HSC) transplant. We have optimized an indirect single-cell HLA typing protocol based on a multiplex fluorescent polymerase chain reaction (PCR) of short tandem repeat (STR) markers scattered throughout the HLA complex. The assay was clinically applied in 60 cycles from 45 couples. A conclusive HLA-matching diagnosis was achieved in 483/530 (91.1%) of the embryos tested. In total, 74 (15.3%) embryos revealed an HLA match with the affected siblings, 55 (11.4%) of which resulted unaffected and 46 (9.5%) have been transferred to the patients. Nine pregnancies were achieved, five healthy HLA-matched children have already been delivered and cord blood HSCs, were transplanted to three affected siblings, resulting in a successful haematopoietic reconstruction.