INTRODUCTION — Following the first successful kidney transplant between identical twin siblings in 1954, the importance of matching for human leukocyte antigens (HLA) in kidney transplantation was demonstrated in studies that showed better graft survival in HLA identical kidney transplants compared with HLA mismatched transplants . Graft survival was superior in sibling pairs having both the same serologically defined HLA antigens and a nonreactive in vitro mixed lymphocyte proliferative response (MLR) when compared with recipients of randomly matched, deceased donors treated with the same immunosuppressive drugs. There was an intermediate level of graft survival in haploidentical parent-to-child or sibling-to-sibling transplants in which one but not both of the haplotypes matched.
Several databases, representing pooled information from a large number of collaborating centers, have accumulated additional evidence for the importance of HLA matching in kidney transplantation. Although such pooled data may suffer from variations in protocols and undocumented selection factors, the power of univariate analyses becomes compelling when thousands of patients are included. These large databases include the United Network for Organ Sharing (UNOS); the Collaborative Transplant Study (CTS); the Scientific Registry of Transplant Recipients (SRTR); the American Foundation for Donation and Transplantation (AFDT), previously known as the South-Eastern Organ Procurement Foundation (SEOPF); the United Kingdom Transplant Service; Eurotransplant; the Australian and New Zealand Dialysis and Transplant Registry (ANZDATA); and others.
Despite a decline in HLA matching following improved immunosuppression treatments, transplant agencies in Europe and the United States maintain policies that encourage HLA matching while increasing access to transplantation. European systems assign weights to A, B, C, DR matching, and in the United States, additional scores are allocated to pediatric kidney transplant candidates who are 0-ABDR mismatched with a donor, and 1 to 2 points are allocated to adult kidney transplant candidates who are 0 or 1 DR mismatched with a donor [2,3]. Nevertheless, donor and patient characteristics, geography, equity, and access consideration are factors that contribute more to priority allocation.
This topic will review HLA matching and its impact on clinical outcomes among kidney transplant recipients. A general overview of HLA typing, sensitization, and crossmatch testing in kidney transplantation is presented elsewhere. (See "Kidney transplantation in adults: Overview of HLA sensitization and crossmatch testing".)
DETERMINATION OF HLA MATCHING — Human leukocyte antigen (HLA) matching between potential donors and transplant candidates is determined by comparing their HLA antigens or alleles. In the United States, Canada, and Europe, HLA typing for waitlisted kidney transplant candidates and donors is performed by low- or high-resolution molecular typing, and serologic equivalents for HLA-A, -B, -C, -Bw4, -Bw6, -DRB1, -DR51/52/53, and -DQB antigens are reported for the transplant candidate. HLA-DPB1 is often reported at the allele level. Donors are typed for HLA-A, -B, -C, -Bw4, -Bw6, -DRB1, -DR51/52/53, -DQA1, -DQB1, -DPA1, and -DPB1 antigens, which are then reported for organ sharing (serologic equivalents are reported when applicable); HLA-DPB1 is entered in UNet at the allele level. Online libraries that are routinely vetted are available for appropriate conversion of molecular typing to serologic equivalencies when necessary. A detailed discussion of the methods used for HLA typing is presented elsewhere. (See "Kidney transplantation in adults: Overview of HLA sensitization and crossmatch testing", section on 'HLA typing'.)
When matching a donor to a recipient, an HLA mismatch approach to organ allocation, as opposed to an HLA matching approach, maximizes the number of patients considered to be a match with a deceased donor. As an example, HLA-A2 is a common antigen, and homozygosity is frequent. A donor that is homozygous for HLA-A2 (ie, serologic HLA typing is HLA-A2, A2) will be a zero antigen mismatch for a patient who types as HLA-A2, A23; one who types as HLA-A2, A2; or one who types as HLA-A2, A66. By contrast, a donor that is HLA-A2, A23 will be considered a zero antigen mismatch only for the patient typed as HLA-A2, A23 but will be a one-antigen mismatch with the other two recipients. The degree of mismatch between recipient and donor is primarily determined for HLA-A, -B, and -DR antigens because of their higher expression level and high polymorphism. Thus, a zero antigen mismatch between a recipient and donor may be defined as the absence of an HLA-A, -B, or -DR antigen in the donor's phenotype that is different from the recipient's HLA-A, -B, and -DR antigens. It is worth noting that HLA typing at the molecular level may further discriminate HLA molecules at the allele level. Thus, a serologically defined zero antigen mismatch does not rule out allele-level mismatches. Conversely, a six antigen mismatch indicates that two A, two B, and two DR antigens in the donor's phenotype are different from those of the recipient. In addition to the antigens listed for transplant candidates, HLA-DQA1 and -DPB1 typing for deceased donors is submitted to the organ procurement organization (OPO) to determine whether antibodies in the transplant candidate's serum are directed against any antigens of the donor. In the United States, molecular typing results are submitted as a PDF attachment to UNet, the computer system operated by the United Network for Organ Sharing (UNOS).
Several studies have shown that HLA matching is a stronger predictor of kidney allograft survival. In a retrospective study of 96,236 deceased-donor kidney transplants between 1995 and 2012, both HLA matching and mismatching were associated with graft survival when analyzed in individual models . However, when analyzed using a combined model that considered both HLA matching and mismatching simultaneously, only the degree of HLA matching was found to be a significant predictor of delayed graft function, one-year acute rejection, and 10-year graft survival. A subsequent study used UNOS data from 1990 to 1999 to evaluate allograft survival in 76,530 kidney transplant recipients (23,914 living-donor allograft recipients and 52,616 deceased-donor allograft recipients) with varying degrees of HLA matching . On adjusted multivariable analysis, more HLA mismatches were associated with lower graft survival beyond 10 years (higher risk of graft loss with 1 versus 6 HLA mismatched antigen). The data continue to show an improvement in allograft survival with fewer HLA mismatches between donor and recipient. Certainly, using HLA matching for allocation limits access to transplantation for recipients from underrepresented groups with rare HLA antigens not present in a primarily White donor pool. (See 'Underrepresented groups' below.)
HLA MISMATCHING AND SENSITIZATION — The high polymorphism in the human leukocyte antigen (HLA) system results in multiple variations of antigens. Consequently, transplant candidates must often receive an organ from a donor with one of several HLA mismatched antigens. Exposure to an HLA antigen that is non-self can lead to development of antibodies against the mismatched HLA antigen(s). This is known as sensitization. HLA sensitization can result from prior exposures to HLA mismatched antigens through pregnancies, blood transfusions, or previous transplantation. HLA sensitization can also develop following immune activation in patients with ventricular assist devices, infections, following surgical procedures, and possibly after vaccination. (See "Kidney transplantation in adults: Overview of HLA sensitization and crossmatch testing".)
The development of antibodies against HLA antigens can lead to serious complications posttransplantation and present significant hurdles for patients who are relisted for a second transplant. Given that the presence of HLA antibody in a patient's serum constitutes an additional barrier in selecting compatible donors, assays that detect and characterize these antibodies are used to evaluate a patient's immunologic risk prior to donor selection. For a sensitized patient, donors that express HLA antigens against which the patient has preformed antibody should be avoided when possible, and these HLA antigens are reported in UNet as "unacceptable antigens." Accurately defining the anti-HLA antibody profile of a potential transplant candidate is important since this information is used to perform virtual crossmatches. The virtual crossmatch uses the results of the antibody tests along with donor and patient HLA typing to predict a candidate's compatibility with a donor of interest. At the time of transplantation, most centers perform a physical crossmatch by incubating lymphocytes from a potential donor with serum from the transplant candidate in a complement-dependent cytotoxicity (CDC) or flow cytometric crossmatch test. An overview of crossmatch testing in kidney transplantation is presented elsewhere:
HLA FACTORS ASSOCIATED WITH TRANSPLANT OUTCOMES
Number of mismatched HLA antigens — Data from large registry studies have shown that a higher degree of human leukocyte antigen (HLA) mismatching is associated with worse transplant outcomes. As examples:
●In a United Network for Organ Sharing (UNOS) registry analysis of 189,141 first, adult, kidney-alone transplants performed between January 1, 1987 and December 31, 2013, there was a 13 percent higher risk of graft failure with one HLA mismatch and a 64 percent higher risk with six HLA mismatches, with increasing risk for each level of mismatch .
●Similar findings were reported in an analysis of the Australian and New Zealand Dialysis and Transplant Registry (ANZDATA) that included 8036 living- and deceased-donor kidney transplant recipients between 1998 and 2009 . Compared with zero HLA-antigen mismatch, increasing HLA mismatches were associated with a higher risk of graft failure; there was a 7 percent higher risk of graft failure with one HLA mismatch and a 74 percent higher risk with six HLA mismatches.
●A meta-analysis of 11 cohort studies involving 289,987 adult kidney transplant recipients found that each incremental increase in HLA mismatch was associated with a higher risk of overall graft failure (hazard ratio [HR] 1.06 per mismatch, 95% CI 1.05-1.07) and death-censored graft failure (HR 1.09 per mismatch, 95% CI 1.06-1.12) .
Relative importance of specific HLA antigens — Several studies have demonstrated that mismatches at individual HLA loci do not have equal weight with regards to transplant outcomes.
HLA-A, -B, and -DR — Analyses of large transplant registries have consistently shown a strong association between HLA matching, particularly at the HLA-A, -B, and -DR loci, and patient and graft outcomes [7,9,10]. These HLA antigens have the most polymorphisms.
The initial Collaborative Transplant Study (CTS) analysis showed that the major impact on kidney allograft outcomes came from mismatches for the HLA-DR and -B antigens, with little additional effect from the HLA-A antigens [11,12]. The United Kingdom Transplant Service and Eurotransplant data were somewhat similar, with HLA-DR matching having a much greater effect than HLA-B or -A [13,14]. Another study found that HLA-DR mismatches (and the number of rejection episodes) correlated with poor long-term survival .
Mismatching for HLA-A, -B, and -DR has been associated with a higher risk of HLA sensitization in both adult and pediatric patients who are relisted for a second kidney transplant (see "Kidney transplantation in adults: Overview of HLA sensitization and crossmatch testing"). As examples:
●In an analysis of 15,980 patients from the Scientific Renal Transplant Registry (SRTR) database who were relisted after the loss of a primary kidney transplant, patients with higher HLA-A, -B, and -DR mismatching had a greater likelihood of being newly sensitized at relisting (adjusted odds ratio [OR] 2.60 and 3.84 for one and six mismatches, respectively). Only 10 percent of patients became sensitized after a zero HLA-mismatched transplant, compared with 37 percent of those with increasing HLA mismatches .
●In a study of 2704 pediatric kidney transplant recipients who were relisted after primary graft failure, an increasing number of HLA-DR mismatches at first transplantation was associated with a higher degree of sensitization . In addition, two HLA-DR mismatches at first transplant were associated with a 20 percent lower likelihood of receiving a second transplant.
Prior sensitization against HLA class II antigens has also been associated with an increased risk for major adverse cardiac and cerebrovascular events as well as all-cause mortality in kidney transplant recipients .
HLA-DQ — Although HLA-DQ is not as polymorphic as HLA-A, -B, and -DR, HLA-DQ mismatches have been associated with an increased risk of rejection and allograft loss in kidney transplant recipients [19-21]. Consequently, UNOS has amended its policy, requiring deceased-donor HLA typing to include identification of the HLA-DQ antigens before making any kidney, kidney-pancreas, pancreas, or pancreas islet offers . However, the existing UNOS kidney allocation policy does not include HLA-DQ matching in the algorithms for organ allocation.
The relative importance of HLA-DQ mismatches is illustrated in the following studies:
●A study of the ANZDATA registry of kidney recipients transplanted between 2004 and 2012 revealed that, compared with recipients of zero HLA-DQ mismatched kidneys, the adjusted HRs for rejections in recipients who had received one or two HLA-DQ-mismatched kidneys were 1.54 (95% CI 1.08-2.19) and 2.85 (95% CI 1.05-7.75), respectively . HLA-DR was an effect modifier between HLA-DQ mismatches and antibody-mediated rejection (ABMR) such that the association between HLA-DQ mismatches and ABMR was statistically significant among those who received one or two HLA-DR-mismatched kidneys, with adjusted HR of 2.50 (95% CI 1.05-5.94).
●In a study of adult kidney transplant recipients from the UNOS database, HLA-DQ mismatches, compared with no HLA-DQ mismatches, were associated with a higher risk of rejection at one year posttransplant in recipients of living- and deceased-donor transplants (adjusted OR 1.14, 95% CI 1.03-1.27, and 1.13, 95% CI 1.03-1.23, respectively) . In addition, compared with no HLA-DQ mismatches, HLA-DQ mismatches were associated with a higher risk of graft loss among recipients of a living-donor transplant (HR 1.18, 95% CI 1.07-1.30) and deceased-donor transplants with cold ischemia time ≤17 hours (HR 1.12, 95% CI 1.02-1.27).
●In one study, the incidence of preformed anti-HLA-DQ antibodies in kidney transplant recipients was 11 percent and increased to 36 percent posttransplantation . In this study, transplant recipients with de novo persistent DQ-only donor-specific antibody (DSA) or de novo DQ plus other DSAs had more acute rejection episodes, increased risk of allograft loss, and a lower five-year allograft survival compared with recipients who did not have DSA.
HLA class II mismatches, which include HLA-DQ and -DR, have been found to be a risk factor for the development of de novo DSAs. In one study of 315 consecutive kidney transplants without pretransplant DSA, 47 patients (15 percent) developed de novo DSA at a mean of 4.6 years posttransplant . Independent predictors of de novo DSA included HLA-DR mismatches (OR 5.66) and nonadherence to immunosuppression. Similarly, a second study of 189 nonsensitized, non-HLA-identical patients who received a first-kidney transplant found that HLA-DQ mismatches were an independent risk factor for the development of de novo DSA (HR 3.14, 95% CI 1.24-7.94) .
HLA-C — Few studies have addressed the impact of HLA-C mismatches. One study of 2260 deceased-donor kidney transplant recipients found that mismatching for one or both HLA-C antigens was associated with decreased graft survival among those who were presensitized (panel reactive antibodies [PRA] >10 percent) but not those who were not presensitized .
Forty to 50 percent of kidney transplant recipients may have preformed anti-HLA-C antibodies [26-28]. However, the effect of HLA-C antibodies on allograft outcome is controversial. Some studies have suggested that HLA-C antibodies are associated with the incidence of acute rejection, while others have shown some correlation with allograft loss [26,29,30]. The availability of single-antigen bead (SAB) assays has allowed better detection of antibodies against HLA-C antigens and facilitated studies that examine their effect on transplantation outcome. In a retrospective, single-center study, 608 transplant patients were assessed for DSA as defined by a mean fluorescence intensity (MFI) >500 . Of these patients, 160 (26 percent) had DSA, and 25 (4 percent) had HLA-C antibodies at the time of transplant (day 0). Among the 22 patients with HLA-C antibodies who were available for follow-up, the incidence of ABMR in the first year was 27 percent. The mean MFI among patients with HLA-C antibody who developed ABMR was significantly higher than for patients who did not have ABMR (mean MFI values = 4966 versus 981, respectively), suggesting that patients with high levels of pretransplant HLA-C DSA may be more likely to develop ABMR during the first posttransplant year.
HLA-DP — Anti-HLA-DP antibodies are less common than antibodies to HLA-DR and -DQ, occurring in 5 to 14 percent of transplant recipients [32-34]. The frequency of HLA-DP antibodies increases in patients who were previously transplanted, occurring in up to 45 percent of retransplanted subjects . Although some studies have suggested that the presence of HLA-DP antibodies does not reduce allograft survival among recipients of a first transplant , other studies have found that HLA-DP antibodies correlate with reduced allograft survival among recipients of a second transplant [35-40].
Repeated mismatched HLA antigens — Reexposure to repeated mismatched HLA antigens may trigger reactivation of memory cells and a rebound in DSA immediately posttransplant, leading to earlier graft injury and loss [41-43]. While the presence of repeated mismatched antigens associated with DSA is generally avoided in kidney transplantation, repeat mismatches alone in the absence of circulating DSA may not need to be categorically avoided, as this practice may further limit access to transplantation.
Studies evaluating the impact of repeated mismatched HLA antigens on graft outcomes have yielded mixed results. Although some studies have reported a correlation between repeated mismatches and decreased graft survival [44-47], others have showed no effect on graft outcomes [48-53]. As an example, an analysis of 13,789 recipients of a second kidney transplant between 1995 and 2011, of whom 3868 (28 percent) had one or more repeated mismatches, found no association between the presence of any repeated mismatches (either HLA class I or II) and all-cause or death-censored graft loss . In a subgroup analysis that examined the effect of HLA class I versus class II repeated mismatches, the presence of an HLA class II repeated mismatch was found to be associated with a higher risk of death-censored graft loss but only among patients who were sensitized or underwent a nephrectomy of the first allograft before the second transplant. The better outcomes in this study may have been related to the use of modern-era immunosuppression and more sensitive HLA antibody-detection assays. Because earlier studies evaluating the impact of repeated mismatches used less sensitive methods (ie, complement-dependent cytotoxicity [CDC] crossmatch testing) to test for anti-HLA antibodies, they were less likely to detect low-level antibodies against repeated mismatched antigens. Consequently, this may have led to transplants with repeated mismatched antigens in the presence of undetected antibodies and the resulting negative impact on transplant outcomes. With the use of more sensitive HLA-testing tools in the contemporary study cited above, repeated mismatches against which a patient had already produced donor-specific anti-HLA antibodies would have been avoided and not included in the cohort evaluated.
In the absence of available assays to detect memory B cells, the clinical characteristics of the patient should be assessed along with information on historical HLA antibody levels when considering a transplant across repeated mismatches.
Exposure to noninherited HLA alleles — In utero and while nursing, infants are exposed to maternal antigens that the child has not inherited. There is evidence that such exposure may result in some degree of tolerance. One study of 205 patients evaluated the long-term survival of kidney allografts transplanted from siblings with maternal or paternal HLA alleles not inherited by the recipient . Compared with the kidneys donated from siblings with paternal alleles not inherited by the recipient, a higher incidence of survival was observed among the allografts donated from siblings with noninherited maternal alleles at both 5 and 10 years posttransplantation (86 versus 67 percent and 77 versus 49 percent, respectively). Although many unrecognized factors may be confounding, these results suggest that exposure to donor antigens prior to transplantation may help induce some degree of tolerance .
STRATEGIES TO OPTIMIZE HLA MATCHING — The likelihood of finding a fully human leukocyte antigen (HLA)-matched, unrelated donor for every kidney transplant candidate is low. Alternative strategies have focused on matching based upon structural and conformational similarity between several of the HLA antigens.
HLA epitope matching — Antibodies recognize and bind to three-dimensional configurations of amino acids called epitopes (figure 1). Epitopes consist of approximately 15 to 22 amino acid residues, which may be contiguous in the peptide chain (ie, linear) or, more commonly, brought together by protein folding (ie, conformational) [56-58].
Each HLA antigen contains a unique set of epitopes (private epitopes) as well as epitopes that are present in other HLA antigens (shared or public epitopes). Previous studies demonstrated that anti-sera used in commercial assays were reactive against more than one HLA antigen. The term cross-reactive epitope groups (CREGs) was used to describe such groups of HLA antigens that shared a common epitope and would be targeted by a common anti-HLA antibody (ie, an anti-HLA antibody that binds to a public epitope will bind to all HLA antigens that share this epitope). Matching for CREGs of HLA antigens was proposed as an alternative to traditional HLA antigen matching for deceased-donor kidney transplantation [59-62]. CREG-based matching was also promoted to improve equity in organ allocation for populations from underrepresented groups who have rarer HLA antigens (see 'Underrepresented groups' below). A few early studies reported improved long-term allograft survival when donors were selected based upon CREG-matched groups rather than HLA antigen mismatches . However, a subsequent analysis of 91,917 recipients of a deceased-donor kidney transplant from the Collaborative Transplant Study (CTS) found that matching for CREGs provided no additional benefit over HLA antigen matching for long-term graft outcomes .
Although these mixed results questioned the role of CREG-based matching for donor selection in kidney transplantation, subsequent studies evaluating the effect of mismatches of smaller clusters of amino acids (eplets) on transplant outcomes have renewed interest in HLA epitope matching. (See 'HLA eplet-mismatch load' below.)
HLA eplet-mismatch load — Eplets are clusters of polymorphic amino acids, discontinuous or linear, that are located on the surface of HLA molecules (figure 1). They have been characterized based upon molecular modeling of HLA alleles and the comparison among amino acid sequences of HLA alleles. Eplets have been called "functional epitopes" since they include the two to five amino acids that are recognized by anti-HLA antibodies within the larger 15 to 22 amino acids of an HLA epitope. Because eplets, like epitopes, are shared among several HLA antigens, eplet-based matching could be used to identify acceptable matches among different HLA molecules.
The eplet-mismatch load is determined by counting the number of eplets that are mismatched between a recipient and the potential donor. The number of donor-recipient eplet mismatches can be determined using an available computer algorithm called the HLAMatchmaker. Several observational studies have shown that a higher number of mismatched eplets is associated with a higher risk of developing donor-specific antibody (DSA) posttransplantation [65-69] and a higher risk of graft loss . Eplet mismatches in HLA-DQ also appear to confer a significant risk for de novo DSA formation, rejection, and graft failure after kidney transplantation .
While eplets identified in HLAMatchmaker were found to correlate with antibody production, one study showed that HLAMatchmaker does not predict which eplets (or amino acid sequences) will elicit a T cell response . The Predicted Indirect Recognizable HLA Epitope (PIRCHE) is a novel HLA epitope matching algorithm that considers epitopes that are recognized by T helper cells as they are presented by recipient HLA molecules to recipient T cells via the indirect pathway for peptide presentation. Several studies have shown a correlation between PIRCHE scores and the subsequent development of de novo DSA. As an example, one study demonstrated that higher numbers of PIRCHE mismatches were associated with an increased risk of rejection episodes and de novo DSA production . Another study showed in a multivariate model that for a 2.7-fold increase in PIRCHE score, the risk of graft failure increased 13 percent .
The use of eplet-mismatch load for organ allocation has been reported in small studies with homogenous populations [74,75]. However, these results are preliminary, and larger studies including more heterogeneous cohorts of transplant patients are needed to validate this approach. Limitations in the use of this approach of epitope matching for donor selection include a better distinction between the use of eplet-mismatch load versus immunogenic eplets and the availability of analysis software . (See 'Immunogenicity of HLA antigens' below.)
Immunogenicity of HLA antigens — Not all epitope mismatches result in the development of alloantibody responses. Factors such as the HLA antigens of the patient and conformational structure of the epitope may determine whether exposure to an HLA antigen results in an immune response . Some studies, for example, have shown that the physiochemical properties of amino acids, including hydrophobicity and the electrostatic charges of their side chains, are important determinants of the immunogenicity of an antigen [68,78]. Avoidance of HLA antigens that are known to be more immunogenic, particularly among pediatric transplant candidates, may reduce the incidence of antibody development if retransplantation is required.
HLA MATCHING AND TRANSPLANT OUTCOMES
Long-term graft survival — Most transplants that are lost to acute rejection do so within the first year. Later graft loss is primarily due to "chronic rejection," a disorder that is more difficult to treat with existing immunosuppressive regimens. (See "Kidney transplantation in adults: Chronic allograft nephropathy".)
Multiple analyses have demonstrated that human leukocyte antigen (HLA) matching is associated with improved long-term graft survival [4,79]. In the 2008 annual report of the Scientific Registry of Transplant Recipients (SRTR), the five-year, deceased, nonextended-criteria donor allograft survival for zero versus six HLA-mismatched, deceased-donor kidneys was 75 and 66 percent, respectively .
Long-term graft survival is also best in HLA-identical, particularly living-related, kidneys and worst in randomly matched cadaver kidneys [79,81]. As an example, a report from the same United Network for Organ Sharing (UNOS) database evaluated more than 7600 HLA-matched (ie, no mismatches) and 81,000 HLA-mismatched cadaveric kidney transplants performed between 1987 and 1999 in the United States . HLA-matched transplants had longer allograft half-lives (12.5 versus 8.6 years) and increased 10-year survival (52 versus 37 percent). Similar findings have been reported in subsequent years .
Although several reports have reaffirmed the role of HLA matching in kidney transplantation [4,7,9,11,25,82-84], some studies have challenged the importance of HLA matching . As an example, one study suggested that the importance of HLA matching for allograft survival may have diminished over the last several years, with nonimmunologic factors assuming more relative significance . In this study, the factors underlying allograft survival over the period of 1994 to 1998 were evaluated among over 30,000 transplant recipients of deceased-donor kidneys. With each successive year, ever-increasing degrees of HLA mismatching were required to have a statistically significant adverse effect upon allograft failure. Thus, increased allograft failure was significantly associated with the following: three to six antigen mismatches in 1995, four to six antigen mismatches in 1996, five and six antigen mismatches in 1997, and six antigen mismatches in 1998. By comparison, peak panel reactive antibodies (PRA); donor age, sex, and cause of death; cold ischemia time; and donor and recipient body size retained their relative importance for allograft survival over this period. The administration of increasingly better immunosuppressive regimens during this period may in part underlie these observations.
Despite these conflicting reports, the weight of overall evidence suggests that HLA matching still has a significant impact on allograft survival. The main effect can be observed between a zero antigen mismatch versus a six antigen mismatch. Based upon the 2008 Organ Procurement Transplant Network/Scientific Registry of Transplant Recipient (OPTN/SRTR) database, for example, allograft survival at five years for those with zero or six total mismatches was :
●Eighty-eight and 79 percent for living-donor kidneys, respectively
●Seventy-five and 66 percent for deceased, nonextended-criteria donor kidneys, respectively
●Sixty and 55 percent for deceased, extended-criteria donor kidneys, respectively
The improved long-term graft survival observed in well-matched HLA grafts may be less apparent in transplant recipients with a primary glomerular disease. In one report of 60 patients in whom an HLA-identical, living-related-donor transplant had been performed, allograft survival was correlated with the original kidney disorder . Among the 33 patients with an underlying glomerulonephritis, the 5-, 10-, and 20-year graft survival was 88, 70, and 63 percent, respectively; by comparison, no case of graft loss was observed among the remaining patients with nonglomerular kidney disease. In this study, recurrent disease appeared to be the principal cause of graft loss.
Patient survival compared with waiting list — Although graft survival of HLA-mismatched kidneys is reduced compared with HLA-matched kidneys, patient survival of highly sensitized recipients of HLA-mismatched kidneys is higher when compared with highly sensitized transplant candidates who remain on the waiting list and are undergoing dialysis. This was suggested by a multicenter study that compared survival of 1025 recipients of HLA-incompatible, living-donor kidneys with matched, waitlisted controls who either never received a kidney or who eventually received an HLA-compatible, deceased-donor kidney . HLA-incompatible recipients were defined as those who were transplanted across an HLA barrier and underwent desensitization protocols prior to transplantation to reduce levels of donor-specific anti-HLA antibodies (DSAs) . For each recipient of a mismatched kidney, five matched, waitlisted controls who never received a transplant and five matched, waitlisted controls who eventually received a deceased-donor kidney were drawn from the SRTR waiting list. The desensitization protocol employed was defined by individual centers.
Compared with candidates on the waiting list who never received a kidney, survival was higher among recipients of HLA-mismatched kidneys at one year (89.6 versus 95 percent), three years (72.7 versus 91.7), five years (59.2 versus 86 percent), and eight years (43.9 versus 76.5 percent). Even compared with waitlisted candidates who eventually received a deceased-donor kidney, survival was higher among recipients of HLA-mismatched kidneys at one year (94 versus 95 percent), three years (83.6 versus 91.7 percent), five years, (74.4 versus 86 percent), and eight years (43.9 versus 76.5 percent).
Importantly, this survival benefit was observed at all levels of DSAs:
●At mild DSA levels (defined by a positive single antigen bead assay but negative flow cytometry crossmatch, n = 185), compared with waitlisted candidates who never received a kidney and compared with candidates who eventually received a deceased-donor kidney, survival was higher among HLA-incompatible recipients at one year (90.6 versus 94 versus 98.4 percent, respectively), three years (76.3 versus 85.2 versus 95.1 percent, respectively), five years (61.9 versus 74.6 versus 91.2 percent, respectively), and eight years (47.1 versus 65 versus 89.2 percent, respectively).
●At moderate DSA levels (defined by positive flow cytometric crossmatch but negative cytotoxic crossmatch, n = 536), compared with waitlisted candidates who never received a kidney and candidates who eventually received a deceased-donor kidney, survival was higher among HLA-incompatible recipients at one year (89.7 versus 94.5 versus 96.1 percent, respectively), three years (72.1 versus 83.8 versus 93.3 percent, respectively), five years (58.4 versus 74.9 versus 87.1 percent, respectively), and eight years (43 versus 63.3 versus 76.3 percent, respectively).
●Among patients with a positive cytotoxic crossmatch indicating a high DSA level (n = 304), survival at one year was similar among HLA-mismatched recipients (91.1 percent) compared with both control groups (93 and 88.9 percent). At three, five, and eight years, however, compared with waitlisted candidates who never received a kidney and candidates who eventually received a deceased-donor kidney, survival was higher among HLA-incompatible recipients at three years (71.8 versus 82.2 versus 86.8 percent, respectively), five years (58.8 versus 73.2 versus 80.9 percent, respectively), and eight years (43.7 versus 61.5 versus 71 percent, respectively).
These data suggest that transplantation of an HLA-incompatible kidney confers a survival benefit compared with being waitlisted and never receiving a kidney and even compared with being waitlisted and eventually receiving a compatible, deceased-donor kidney. In this study, the survival benefit persisted despite the presence of high DSA levels and was independent of the desensitization protocol utilized. The comparator group was drawn from all patients on the waiting list rather than just active patients who would be considered suitable for transplantation. Drawing the matched controls from the entire waiting list may have overestimated the apparent benefit of transplantation of an HLA-incompatible kidney. Approximately one-third of patients on the waiting list are not active, and most are inactive because of health issues.
Acute rejection — Several retrospective studies have demonstrated that HLA matching is associated with a lower risk of acute rejection among kidney transplant recipients [84,90,91]. Although most of these studies were performed in patients receiving cyclosporine-based immunosuppression [90,91], one study showed that the number of HLA mismatches was an independent risk factor for acute rejection (odds ratio [OR] 1.65 per HLA mismatch) in transplant patients receiving immunosuppression consisting of interleukin (IL)-2 receptor antibody induction, tacrolimus, mycophenolate mofetil, and glucocorticoids . Analyses of data from two large transplant registries found that the association between HLA mismatches and acute-rejection risk was independent of the transplant era and initial immunosuppressive regimen [7,9].
Other transplant outcomes
Death with a functioning graft — HLA mismatching has been associated with a higher risk of death with a functioning kidney allograft. In a study of 177,584 deceased-donor kidney transplants performed between 1990 and 2009, the incidence of death with a functioning graft was 4.8 percent during the first posttransplant year and 7.7 percent during years 2 through 5 (approximately 2 percent per year) . The number of HLA-A, -B, and -DR mismatches correlated with a higher cumulative incidence of death with a functioning graft, from any cause, during the first three years posttransplant. This association was significant for death due to cardiovascular or infectious causes but not from malignancy.
Posttransplant lymphoproliferative disorders — Several studies have shown that HLA mismatching is an independent risk factor for the development of posttransplant non-Hodgkin lymphoma among kidney transplant recipients [93-96]. As an example, in a study of 152,728 deceased-donor kidney transplant recipients from the Collaborative Transplant Study (CTS), an increased risk of posttransplant non-Hodgkin lymphoma was observed in patients with one (hazard ratio [HR] 1.21, 95% CI 1.00-1.45) and two (HR 1.56, 95% CI 1.21-1.99) HLA-DR mismatches . Similar findings were reported in an analysis of 9209 pediatric kidney transplant recipients, in which two HLA-DR mismatches were associated with a twofold higher risk of developing posttransplant non-Hodgkin lymphoma . (See "Epidemiology, clinical manifestations, and diagnosis of post-transplant lymphoproliferative disorders", section on 'Others'.)
Posttransplant bone fractures — HLA mismatches are associated with an increased risk of posttransplant bone fractures in kidney transplant recipients. In a retrospective study of 68,814 patients who were transplanted between 1988 and 1998, HLA mismatches were associated with a 9 percent increase in the risk of bone fractures within five years of transplant compared with patients with no mismatch . Similarly, an analysis of 20,509 kidney transplant recipients from the CTS reported a higher risk of posttransplant hip fractures among patients with one (HR 1.85, 95% CI 1.18-2.89) and two (HR 2.24, 95% CI 1.25-4.02) HLA-DR mismatches.
The mechanism behind this association between HLA mismatching and bone fractures is uncertain. HLA mismatches are associated with a higher risk of acute rejection, which is generally treated with more intensive immunosuppression that could adversely affect bone quality. (See "Kidney transplantation in adults: Bone disease after kidney transplantation", section on 'Pathogenesis and risk factors'.)
HLA MATCHING AND ORGAN ALLOCATION
Deceased-donor transplantation — A limitation of strictly using human leukocyte antigen (HLA) typing for organ allocation is the difficulty in finding well-matched kidneys. The United States United Network for Organ Sharing (UNOS) program mandates that six-antigen-matched grafts be given priority. Despite the large registered waiting list and relative ease of shipping kidneys around the country, only 13 percent of recipients of deceased-donor kidneys are well matched, as defined by the six antigen matching criteria .
Priority shipping of organs is not limited to six-antigen-matched grafts, as zero antigen mismatching is also given priority. This occurred following two amendments to the original ruling by UNOS: the first to allow donors and recipients that were both homozygous for one antigen to be considered phenotypically matched and the second to allow for the shipment of zero-antigen-mismatched kidneys. With zero-antigen-mismatched kidneys, the donor does not express any antigen different from the recipient, although the recipient may have an antigen that is not expressed by the donor .
From January 2009 until December 3, 2014, only patients with calculated panel reactive antibodies (cPRAs) greater than 20 percent were allowed to be considered for the zero-antigen-mismatch program (UNOS). This policy was based upon the recognition that the expense of transportation and the negative effects of prolonged cold ischemia mitigated against improved short-term graft survival.
The kidney allocation system (KAS) implemented on December 4, 2014 was designed to balance equity and utility of allocated organs and incorporated the kidney donor profile index (KDPI; measurement of organ quality) and the estimated posttransplant survival (EPTS; measurement of candidates expected longevity). In this allocation schema, zero-antigen-mismatched kidneys with KDPI scores <20 percent would be primarily allocated to patients with EPTS scores <20 percent (those expected to experience longer years of graft function) at the national, local, and regional level. Allocation points and priority are also given for HLA-DR matching. (See "Kidney transplantation in adults: Organ sharing".)
Patients who receive an organ with more than 36 hours of cold ischemia time may not benefit from HLA matching. In an analysis of the UNOS database, recipients of zero-antigen-mismatched kidneys with less than 36 hours of cold ischemia time had superior five-year graft survival than recipients with one or more mismatches (75 and 67 percent, respectively, p<0.001) . However, no survival advantage was observed if zero-antigen-mismatched kidneys were exposed to more than 36 hours of cold ischemia time.
Thus, if there were no cold-ischemia-time effects, a strategy of national allocation and shipping of all kidneys (not just zero antigen mismatches) to minimize HLA mismatches would generate the largest graft survival improvement and cost savings . However, there would be longer preservation times under a national allocation policy, and prolongation of cold ischemia time negatively affects outcome and costs. The early results of the newer KAS suggest that there is more shipping of organs, especially for highly sensitized patients .
Underrepresented groups — The distribution of HLA antigens and frequency of deceased-donor donation differs among racial groups, thereby affecting organ allocation. Until the 2009 changes in the UNOS organ allocation policy, 17 percent of all standard criteria donor (SCD), deceased-donor kidneys were transplanted into zero-antigen-mismatched recipients , of whom approximately 90 percent were White patients and only 9 percent were Black patients . Between 1987 and 1995, Black patients received only 6 percent of fully matched kidneys despite constituting approximately one-third of the national waiting list. Conversely, 30 percent of partially or fully mismatched kidneys go to recipients from underrepresented groups, approximating the frequency with which these patients appear on the waiting list.
To address this relative inequity, the national allocation policy of the United States was changed to no longer give priority points for fewer HLA-B mismatches. This was derived in part from findings of a study that addressed the effect of eliminating HLA-B matching. Based upon a Cox model analysis in which HLA-DR but not HLA-B matching was utilized, the number of transplants was calculated to decrease by 4 percent among White patients but increase by 6.3 percent in patients of other races ; this change was determined to result only in a 2 percent increase in graft loss. By comparison, removal of both HLA-B and HLA-DR would result in an 8 percent increase in graft loss. A study modeling the impact of this policy demonstrated that it would result in a detrimental effect on survival of White patients and overall increased costs .
Pediatric patients — Transplantation of pediatric patients presents additional challenges since these patients are more likely to require repeated transplantation. Thus, well-matched organs are a priority for pediatric patients and could potentially lead to longer wait times. This is in contradiction to the clinical management of pediatric patients where reducing time on dialysis is a more important objective since this impacts their neurologic development and growth. For this reason, all allocation systems (including Share 35 and the new KAS) have focused on quicker access to deceased kidney donors for pediatric transplant candidates [104,105]. These allocation changes have also allowed pediatric patients to receive the highest-quality donors (ie, those less than 35 years old and with a KDPI of 35 percent or less) . Pediatric patients also receive priority points for HLA-DR matching. (See "Kidney transplantation in children: Outcomes", section on 'Human leukocyte antigen matches'.)
Clinicians are conflicted between waiting for an HLA well-matched, deceased-donor organ or selecting a less well-matched living donor for their pediatric transplant candidates. In a study that analyzed the impact of HLA matching on outcomes among 3687 pediatric kidney transplant recipients, 10-year graft survival of kidneys from well-matched deceased donors with zero to one HLA mismatch was comparable to that of kidneys from less well-matched living donors with four to six HLA mismatches . These findings suggest that living-donor pediatric kidney transplantation should ideally be performed from donors with fewer than four HLA-A+, -B+, -DR mismatches.
HLA MATCHING AND SIMULTANEOUS ORGAN TRANSPLANTATION — When kidneys are transplanted along with another organ, human leukocyte antigen (HLA) matching may take a backseat to urgency of transplantation, as is the case for simultaneous heart-kidney (SHK) transplantation, or to evidence for a protective effect, as is the case for simultaneous liver-kidney (SLK) transplantation. The relevance of HLA mismatching in multiorgan transplantation has not been well studied, although an Organ Procurement Transplant Network/Scientific Registry of Transplant Recipient (OPTN/SRTR) report found a similar percentage of transplants with >5 HLA-A, -B, -DR mismatches when multiorgan transplantation was compared with kidney transplantation alone (KTA; >55 percent for SLK transplantation, >50 percent for SHK transplantation, and >45 percent for KTA) [108,109].
IMPACT OF NON-HLA ANTIGENS — A number of non-human leukocyte antigens (HLA) have been found to be important antibody targets and may impact transplant outcomes, as discussed below.
MICA — The major histocompatibility complex (MHC) class I-related chain A (MICA) is the product of an HLA-related, polymorphic gene . MICA is expressed on monocytes, keratinocytes, fibroblasts, and endothelial cells. Although its exact function is unclear, MICA is recognized by a subpopulation of intestinal gamma delta T cells and may play a role in the activation of a subpopulation of natural killer cells .
●Among 1920 recipients of kidney transplants, MICA antibodies were detected in 217 (11.4 percent) . Compared with those without antibodies, the presence of MICA antibodies significantly lowered one-year allograft survival among all patients (88.3 versus 93 percent), recipients of first-kidney transplants (87.8 versus 93.5 percent), and recipients who received well-matched kidneys (zero or one HLA-A plus HLA-B plus HLA-DR mismatch; 83.2 versus 95.1 percent).
●As part of the 13th International Histocompatibility Workshop, 1329 patients with functioning transplants were prospectively tested for HLA antibodies in 2002 and followed for four years . At four years, allograft survival was significantly higher among those with no identified antibodies (806 deceased-donor recipients) versus those with HLA (158 patients) or MICA antibodies (69 patients; 81 versus 58 and 72 percent, respectively).
●In a prospective trial of the 14th International Histocompatibility Workshop, one-year allograft survival of 1319 deceased-donor recipients and no HLA antibodies was 96 percent . This was significantly higher than that observed for the 344 patients with HLA antibodies (94 percent) and the 33 patients with MICA antibodies (83 percent). By comparison, 12 recipients with donor-specific antibodies (DSAs) tested by single-antigen beads had a one-year graft survival of 64 percent, and 27 patients with non-donor-specific "strong" antibodies had a 66 percent survival.
These trials provide strong evidence that HLA and MICA antibodies are associated with graft failure after one and four years posttransplant. Some authors have therefore recommended universal testing of kidney transplant patients for antibodies against HLA as well as MICA posttransplantation and careful monitoring of serum creatinine levels if antibodies are detected.
However, testing for non-HLA antibodies is not widely performed. We test for such antibodies in select patients with evidence of antibody-mediated rejection (ABMR) without the presence of circulating donor-specific HLA antibodies.
Angiotensin II type 1 receptor — The angiotensin II type 1 receptor (AT1R) is a G protein-coupled receptor and one of the main components of the renin-angiotensin system (RAS). AT1R is expressed on endothelial and vascular smooth muscle cells [117,118], podocytes, and other kidney tissue [119,120]. Through the action of its natural ligand, angiotensin II, AT1R regulates blood flow, salt and water retention, aldosterone secretion, inflammation, and vascular remodeling [121-123]. Anti-AT1R antibodies have been detected in patients who have biopsy evidence of ABMR but do not have detectable DSAs [124,125].
The presence of anti-AT1R antibodies has been associated with poor kidney transplant outcomes including acute rejection and graft loss [126-130]. In vitro studies have shown that anti-AT1R antibodies isolated from the sera of transplant recipients can induce Erk signaling in endothelial and vascular smooth muscle cells in a similar fashion as the natural ligand, angiotensin II, resulting in the increased expression of inflammatory and coagulation proteins [118,131-133]. In addition, passive transfer of anti-AT1R antibody into healthy animals and anti-AT1R antibody stimulation of cultured cells result in phenotypic changes resembling vascular diseases, providing evidence that these antibodies are not only biomarkers but also contribute to disease pathogenesis .
By contrast, a few studies have found no correlation between the presence of anti-AT1R antibodies and kidney allograft outcomes [135,136].
H-Y antigen — Due to reactivity against Y chromosome H-Y encoded gene products, transplants from a male donor to a female recipient, particularly hematopoietic cell transplants, are reportedly associated with an increased risk of rejection. However, the role of such gene products in kidney transplantation is unclear. This was indirectly evaluated in a retrospective cohort study of nearly 200,000 recipients of deceased-donor kidneys . Compared with all other sex combinations, an increased risk of allograft failure was noted in female recipients of male-donor kidneys at one year (hazard ratio [HR] 1.08, 95% CI 1.03-1.14) and between 2 and 10 years (HR 1.06, 95% CI 1.01-1.10). These findings suggest that there may be an association between adverse effects and H-Y encoded products. Further studies are required to better understand this possible association.
Other non-HLA antigens — Large-scale exome and genome sequencing technology has enabled the identification of other non-HLA genetic mismatches between kidney transplant recipients and their donors that could predict long-term graft survival [138-140]. In a genome-wide analysis of 477 pairs of deceased donors and first-kidney transplant recipients with stable graft function at three months posttransplant, genetic mismatches in non-synonymous single-nucleotide polymorphisms (nsSNPs) were quantified for genes encoding transmembrane or secreted proteins . The number of nsSNP mismatches was predictive of graft loss after adjusting for HLA eplet mismatches (HR 1.68 per unit increase in interquartile range, 95% CI 1.17-2.41). Five-year death-censored graft survival was 98 percent in the quartile with the lowest number of nsSNP mismatches, 91 percent in the second quartile, 89 percent in the third quartile, and 82 percent in the highest quartile. DSAs directed against genetically predicted mismatched epitopes for some of the transmembrane proteins were identified among an independent cohort of 25 donor-recipient pairs with chronic ABMR. Although additional studies are needed to further characterize these non-HLA antigens, these findings support the important role of non-HLA alloimmunity in kidney transplantation and its impact on long-term transplant outcomes.
Genetic variants that cause disruptions (ie, deletions) in kidney genes may predispose a kidney transplant recipient to allosensitization and rejection, particularly if the recipient is homozygous for the deletion polymorphism and receives an organ from a donor who has at least one normal allele. This scenario, referred to as "genomic collision," was evaluated in a study that screened 705 kidney transplant recipients for 50 common gene-disrupting deletion polymorphisms . Recipients who were homozygous for the specific single-nucleotide polymorphism rs893403 on chromosome 2q12.3 at the LIMS1 locus had a higher risk of acute rejection compared with recipients who did not have this genotype (HR 1.84, 95% CI 1.35-2.50). This finding was replicated in 2004 donor-recipient pairs from three independent transplant cohorts (HR 1.55, 95% 1.25-1.93). In addition, homozygosity for rs893403 was associated with the presence of serum antibodies against the LIMS1 protein. The results of this study identify LIMS1 as a potential minor histocompatibility antigen and support genomic collision at the LIMS1 locus as a potential mechanism contributing to the risk of rejection in kidney transplant recipients.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Kidney transplantation".)
●Overview – Human leukocyte antigen (HLA) matching between potential donors and transplant candidates is determined by comparing their HLA antigens. In the United States, Canada, and Europe, HLA typing for waitlisted kidney transplant candidates is performed by intermediate- or high-resolution molecular typing, and serologic equivalents for HLA-A, -B, -C, -Bw4, -Bw6, -DR, -DR51/52/53, and -DQB antigens are reported for organ sharing. (See 'Introduction' above and 'Determination of HLA matching' above.)
●Determination of HLA matching – The degree of mismatch between recipient and donor is primarily determined for HLA-A, -B, and -DR antigens. Thus, a zero antigen mismatch between a recipient and donor is defined as the absence of an HLA-A, -B, or -DR antigen in the donor's phenotype that is different from the recipient's HLA-A, -B, and -DR antigens. Conversely, a six antigen mismatch indicates that two A, two B, and two DR antigens in the donor's phenotype are different from those of the recipient. (See 'Determination of HLA matching' above.)
●HLA mismatching and sensitization – The high polymorphism in the HLA system results in multiple variations of antigens. Consequently, transplant candidates often must receive an organ from a donor with one of several HLA-mismatched antigens. Exposure to an HLA antigen that is non-self can lead to development of antibodies against the mismatched HLA antigen(s). This is known as sensitization. (See 'HLA mismatching and sensitization' above.)
●HLA factors associated with transplant outcomes – Data from large registry studies have shown that a higher degree of HLA mismatching is associated with worse transplant outcomes. In addition, several studies have demonstrated that mismatches at individual HLA loci do not have equal weight with regards to transplant outcomes. In particular, there is a strong association between HLA matching at the HLA-A, -B, and -DR loci and patient and graft outcomes. (See 'HLA factors associated with transplant outcomes' above.)
●Repeated mismatched HLA antigens – Reexposure to repeated mismatched HLA antigens may trigger reactivation of memory B cells and a rebound in donor-specific antibodies (DSA) immediately posttransplant, leading to earlier graft injury and loss. While the presence of repeated mismatched antigens associated with DSA is generally avoided in kidney transplantation, repeat mismatches alone in the absence of circulating DSA may not need to be categorically avoided, as this practice may further limit access to transplantation. (See 'Repeated mismatched HLA antigens' above.)
●Strategies to optimize HLA matching – The likelihood of finding a fully HLA-matched, unrelated donor for every kidney transplant candidate is low. Alternative strategies have focused on matching based upon structural and conformational similarity among several of the HLA antigens. (See 'Strategies to optimize HLA matching' above.)
●HLA matching and transplant outcomes – HLA matching has been associated with improved long-term graft survival and a lower risk of acute rejection among kidney transplant recipients. Although the survival of HLA-mismatched kidneys is reduced compared with HLA-matched kidneys, the survival of highly sensitized recipients of HLA-mismatched kidneys is higher when compared with highly sensitized transplant candidates who remain on the waiting list and are undergoing dialysis. HLA mismatching has been associated with an increased risk of death with a functioning graft, posttransplant lymphoproliferative disorders, and posttransplant bone fractures. (See 'HLA matching and transplant outcomes' above.)
●HLA matching and organ allocation – A limitation of strictly using HLA typing for organ allocation is the difficulty in finding well-matched kidneys. The United States United Network for Organ Sharing (UNOS) program mandates that six-antigen-matched grafts be given priority. Despite the large registered waiting list and relative ease of shipping kidneys around the country, only 13 percent of recipients of deceased-donor kidneys are well matched. (See 'HLA matching and organ allocation' above.)
●Impact of non-HLA antigens – A number of non-HLA antigens have been found to be important antibody targets and may impact transplant outcomes, including the major histocompatibility complex (MHC) class I-related chain A (MICA), angiotensin II type 1 receptor (AT1R), and the H-Y antigen. (See 'Impact of non-HLA antigens' above.)
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