Seeking Standardized Definitions for HLA-incompatible Kidney Transplants: A Systematic Review.

BACKGROUND: There is no standard definition for "HLA incompatible" transplants. For the first time, we systematically assessed how HLA incompatibility was defined in contemporary peer-reviewed publications and its prognostic implication to transplant outcomes. METHODS: We combined 2 independent searches of MEDLINE, EMBASE, and the Cochrane Library from 2015 to 2019. Content-expert reviewers screened for original research on outcomes of HLA-incompatible transplants (defined as allele or molecular mismatch and solid-phase or cell-based assays). We ascertained the completeness of reporting on a predefined set of variables assessing HLA incompatibility, therapies, and outcomes. Given significant heterogeneity, we conducted narrative synthesis and assessed risk of bias in studies examining the association between death-censored graft failure and HLA incompatibility. RESULTS: Of 6656 screened articles, 163 evaluated transplant outcomes by HLA incompatibility. Most articles reported on cytotoxic/flow T-cell crossmatches (n = 98). Molecular genotypes were reported for selected loci at the allele-group level. Sixteen articles reported on epitope compatibility. Pretransplant donor-specific HLA antibodies were often considered (n = 143); yet there was heterogeneity in sample handling, assay procedure, and incomplete reporting on donor-specific HLA antibodies assignment. Induction (n = 129) and maintenance immunosuppression (n = 140) were frequently mentioned but less so rejection treatment (n = 72) and desensitization (n = 70). Studies assessing death-censored graft failure risk by HLA incompatibility were vulnerable to bias in the participant, predictor, and analysis domains. CONCLUSIONS: Optimization of transplant outcomes and personalized care depends on accurate HLA compatibility assessment. Reporting on a standard set of variables will help assess generalizability of research, allow knowledge synthesis, and facilitate international collaboration in clinical trials.

Donor-Recipient Non-HLA Variants, Mismatches and Renal Allograft Outcomes: Evolving Paradigms.

Despite significant improvement in the rates of acute allograft rejection, proportionate improvements in kidney allograft longevity have not been realized, and are a source of intense research efforts. Emerging translational data and natural history studies suggest a role for anti-donor immune mechanisms in a majority of cases of allograft loss without patient death, even when overt evidence of acute rejection is not identified. At the level of the donor and recipient genome, differences in highly polymorphic HLA genes are routinely evaluated between donor and recipient pairs as part of organ allocation process, and utilized for patient-tailored induction and maintenance immunosuppression. However, a growing body of data have characterized specific variants in donor and recipient genes, outside of HLA loci, that induce phenotypic changes in donor organs or the recipient immune system, impacting transplant outcomes. Newer mechanisms for "mismatches" in these non-HLA loci have also been proposed during donor-recipient genome interactions with transplantation. Here, we review important recent data evaluating the role of non-HLA genetic loci and genome-wide donor-recipient mismatches in kidney allograft outcomes.

A 2020 Banff Antibody-mediatedInjury Working Group examination of international practices for diagnosing antibody-mediated rejection in kidney transplantation - a cohort study.

The Banff antibody-mediated rejection (ABMR) classification is vulnerable to misinterpretation, but the reasons are unclear. To better understand this vulnerability, we evaluated how ABMR is diagnosed in practice. To do this, the Banff Antibody-Mediated Injury Workgroup electronically surveyed an international cohort of nephrologists/surgeons (n = 133) and renal pathologists (n = 99). Most providers (97%) responded that they use the Banff ABMR classification at least sometimes, but DSA information is often not readily available. Only 41.1% (55/133) of nephrologists/surgeons and 19.2% (19/99) of pathologists reported that they always have DSA results when the biopsy is available. Additionally, only 19.6% (26/133) of nephrologists/surgeons responded that non-HLA antibody or molecular transcripts are obtained when ABMR histologic features are present but DSA is undetected. Several respondents agreed that histologic features concerning for ABMR in the absence of DSA and/or C4d are not well accounted for in the current classification [31.3% (31/99) pathologists and 37.6% (50/133) nephrologist/surgeons]. The Banff ABMR classification appears widely accepted, but efforts to improve the accessibility of DSA information for the multidisciplinary care team are needed. Further clarity is also needed in Banff ABMR nomenclature to account for the spectrum of ABMR and for histologic features suspicious for ABMR when DSA is absent.

Differential Impact of Class I and Class II Panel Reactive Antibodies on Post-Heart Transplant Outcomes.

BACKGROUND: Sensitized patients awaiting heart transplantation spend a longer time on the waitlist and have higher mortality. We are now able to further characterize sensitization by discriminating antibodies against class I and II, but the differential impact of these has not been assessed systematically. METHODS AND RESULTS: Using United Network for Organ Sharing data (2004-2015), we analyzed 17,361 adult heart transplant patients whose class I and II panel reactive antibodies were reported. Patients were divided into 4 groups: class I and II ≤25% (group 1); class I ≤25% and class II ˃25% (group 2); class II ≤25% and class I >25% (group 3); and both class I and II >25% (group 4). Outcomes assessed were treated rejection at 1-year mortality, all-cause mortality, and rejection-related mortality. Compared with group 1, only group 4 was associated with a higher risk of treated rejection at 1 year (odds ratio 1.31, 95% confidence interval [CI] 1.05-1.64), all-cause mortality (hazard ratio 1.24, 95% CI 1.06-1.46), and mortality owing to rejection (subhazard ratio 1.84, 95% CI 1.18-2.85), whereas groups 2 and 3 were not (P > .05). CONCLUSIONS: Combined elevation in class I and II panel reactive antibodies seem to increase the risk of treated rejection and all-cause mortality, whereas risk with isolated elevation is unclear.

Cardiac Inotropes Offer Protection of Renal Function in Patients with Kidney Transplantation.

INTRODUCTION: Impaired cardiac function is one of the most concomitant symptoms in patients with kidney failure after long-term dialysis. In addition, the preservation of adequate perfusion pressure to the graft plays a significant role in the intraoperative management during kidney transplantation, but the use of positive inotropic drugs in kidney transplant patients has been studied less. We investigated the protective effects of renal function by means of cardiac inotropes in kidney transplant patients. METHODS: Eighty-nine patients that received kidney transplantation between April 2014 and December 2016 at Qilu Hospital were included and randomly divided into the treatment group receiving levosimendan and a control group. All kidney recipients received ABO-compatible donors. A poor outcome was defined as one of the following: delayed graft function, graft hemorrhage, or nephrectomy. RESULTS: The treatment group had a better composite outcome and the level of neutrophil gelatinase-associated lipocalin was also lower than in the control group. CONCLUSION: Inotropic drugs may play a protective role in renal function in kidney transplantation.

The protective effect and mechanism of rapamycin in the rat model of IgA nephropathy.

BACKGROUND: The pathogenesis of the development of IgA nephropathy has not been clear up to now. At present, some studies revealed that the mTOR pathway may participate in IgA nephropathy; however, the mechanism has not been systematically studied. In this study, we established an IgAN rat model to investigate the protective effects of rapamycin as a new type of immunosuppressant, as well as its therapeutic mechanisms. METHODS: After the establishment of IgA nephropathy model, rats were treated with different concentrations of rapamycin, and the protective effect of different concentrations of rapamycin on renal function of the rats was observed. The deposition of IgA was observed by immunofluorescence. The kidney expression of Akt and p70S6k proteins in mTOR pathway was examined using the western blot assay after rapamycin treatment. RESULTS: Morphology and immunofluorescence confirmed that the rat model of IgA nephropathy was successfully established. In particular, the level of proteinuria decreased with the increase of the dose of rapamycin, as well as the deposition of IgA in glomeruli. Moreover, the western blot analysis indicated that the expression of p70S6K in the downstream of mTOR pathway decreased and the upstream protein AKT of the mTOR pathway was overexpressed in the rats model. CONCLUSION: We found that rapamycin has protective effects in the IgA nephropathy rat model in a dose-dependent manner. In addition, the result of western blot assay suggested that rapamycin may display its therapeutic effects through interfering the AKT-mTOR-p70S6K signaling pathway.

HLA, Non-HLA Antibodies, and Eplet Mismatches in Pediatric Liver Transplantation: Observations From a Small, Single-Center Cohort.

OBJECTIVES: To identify the risk of developing acute rejection, allograft fibrosis, and antibody-mediated rejection, a retrospective review of pediatric patients who underwent liver transplant between July 31, 1998 and February 29, 2016 and had donor-specific antibodies measured at time of liver biopsy was undertaken. MATERIALS AND METHODS: HLAMatchmaker Software (http://www.hlamatchmaker.net) was used to define epitope mismatches between donors and recipients and to predict de novo donor-specific antibody risk. Epitope mismatches were evaluated for their immunogenicity. RESULTS: In our group of 42 recipients, 20 (48%) had donor-specific antibodies. Having an antibody against HLA-DQB1*02 was associated with acute rejection (66.6% vs 36%; P = .024). We found that DQ epitope mismatch load was greater in recipients with class II donor-specific antibodies (9.7 vs 3.6; P = .001). HLA-DQ (7.4 vs 3.6; P = .04) and HLA-DR (8.8 vs 3.8; P = .04) epitope mismatch loads were higher in recipients with DQ + DR donor-specific antibodies. A high portal fibrosis score was associated with higher mismatch load at the DQ locus (P = .005) and DQ + DR loci (P = .03). Having > 5 or > 6 epitope mismatch loads at the DQ locus identified a threshold above which development of DQ donor-specific antibodies would occur (area under the curve = 0.878). Mismatches for eplet 4Q, 45GE, 52PQ, and 52PL, thought to be immunodominant epitopes, were observed for several recipients. CONCLUSIONS: Knowledge of epitope mismatches between recipients and donors may aid transplant physicians in devising immunosuppression strategies.

Banff survey on antibody-mediated rejection clinical practices in kidney transplantation: Diagnostic misinterpretation has potential therapeutic implications.

The aim of this study was to determine how the Banff antibody-mediated rejection (ABMR) classification for kidney transplantation is interpreted in practice and affects therapy. The Banff Antibody-Mediated Injury Workgroup electronically surveyed clinicians and pathologists worldwide regarding diagnosis and treatment for 6 case-based scenarios. The participants' (95 clinicians and 72 renal pathologists) assigned diagnoses were compared to the Banff intended diagnoses (reference standard). The assigned diagnoses and reference standard differed by 26.1% (SD 28.1%) for pathologists and 34.5% (SD 23.3%) for clinicians. The greatest discordance between the reference standard and clinicians' diagnosis was when histologic features of ABMR were present but donor-specific antibody was undetected (49.4% [43/87]). For pathologists, the greatest discordance was in the case of acute/active ABMR C4d staining negative in a positive crossmatch transplant recipient (33.8% [23/68]). Treatment approaches were heterogeneous but linked to the assigned diagnosis. When acute/active ABMR was diagnosed by the clinician, treatment was recommended 95.3% (SD 18.4%) of the time vs only 77.7% (SD 39.2%) of the time when chronic active ABMR was diagnosed (P < .0001). In conclusion, the Banff ABMR classification is vulnerable to misinterpretation, which potentially has patient management implications. Continued efforts are needed to improve the understanding and standardized application of ABMR classification in the transplant community.

Pre-transplant low level HLA antibody shows a composite poor outcome in long-term outcome of renal transplant recipients.

To determine the significance of low-level DSA (donor specific antibody) in patients transplanted with negative cytotoxicity AHG (antihuman immunoglobulin) crossmatch, data from 279 patients who received a kidney transplant between July 1999 and March 2006 were collected. All kidney recipients received ABO-compatible donors. A poor outcome was defined as any one of the following: death, Cr>2.0 mmol/L, occurrence of a rejection episode. Luminex Screening and Single Antigen assays from Tepnel Life Codes were used to detect human leukocyte antigen antibodies on pre-transplant sera retrospectively. Twenty-four out of 279 recipients demonstrated the presence of solid-phase DSA (MFI>1000) present pre-transplant. In DSA+ group, the accumulated good versus poor outcome rate was 0.30 versus 0.70, respectively. These rates were 0.49 and 0.51, respectively, in the DSA- group. The difference in composite poor outcome between DSA+ versus DSA- group was significant (p=0.030). The DSA- group had no difference in patient survival as compared to the DSA+ group (p=0.061). There is no statistically significant difference for either mortality or outcome results between high MFI (>2000) and low MFI (≤2000) groups. Our data suggest that solid-phase antibodies which are not strong enough to elicit a positive T-AHG crossmatch may influence long-term graft outcome.

Organ procurement and transplantation network/united network for organ sharing histocompatibility committee collaborative study to evaluate prediction of crossmatch results in highly sensitized patients.

BACKGROUND: The requirement for a prospective crossmatch limits some organ allocation to local areas. The delay necessitated by the crossmatch restricts the distance across which offers can be made without unduly increasing the ischemia time. A collaborative study involving 14 transplant centers was undertaken by the Organ Procurement and Transplantation Network/United Network for Organ Sharing (OPTN/UNOS) Histocompatibility Committee to evaluate the accuracy with which the detection of unacceptable human leukocyte antigen (HLA) antigens by most advanced solid phase immunoassays can predict crossmatch results. In addition, using actual patients' unacceptable HLA antigens, the number of compatible donors that would have been available from the OPTN deceased kidney donors during 2002 to 2004 were investigated. METHODS: Panel reactive antibodies were performed by conventional or solid phase assays, and crossmatches were performed by cytotoxicity or flow cytometry. Analyses were stratified for T and B cell and by method of identifying unacceptable HLA antigens and crossmatch techniques. RESULTS: Combination of solid phase immunoassays and flow cytometry crossmatches resulted in a higher prediction rates of positive T cell (86.1%-93.5%) and B-cell crossmatches (91%-97.8%). Prediction of negative crossmatches based on different combination of panel reactive antibodies and crossmatch techniques varied from 14.3% to 57.1%. Furthermore, numerous potential compatible donors were identified for each patient, regardless of their ethnicity, in the OPTN database, when predicted incompatible ones were excluded. CONCLUSIONS: The above results showed that with the advent of solid phase immunoassays, HLA antibodies can now be accurately detected resulting in prediction of crossmatch outcome. This should facilitate organ allocation and prevents shipment of organs to distant incompatible recipients.

The Connecticut Center of Excellence for Eliminating Health Disparities among Latinos (CEHDL).

CEHDL's mission is to contribute to the elimination of health disparities among Latino(a)s through the formation of human resources, community-based research, and culturally appropriate outreach/extension. CEHDL is structured as a consortium led by the University of Connecticut (UConn) in close partnership with the Hispanic Health Council (HHC), a community health agency located in inner-city Hartford, and Hartford Hospital (HH). Demonstrating best practice and culturally skilled, evidence-based outreach, and bringing the best of academic, community, and health institutions to socioeconomically disadvantaged communities, CEHDL fosters scientific-community interactions and supports training of undergraduate, graduate, and medical students. Building capacity in other agencies is one method through which CEDHDL seeks to accomplish its goals. Thus far, CEHDL has made substantial progress demonstrating that interdisciplinary community-academic-hospital partnerships are essential for addressing health inequities in our country.

Decellularized cadaver vein allografts used for hemodialysis access do not cause allosensitization or preclude kidney transplantation.

BACKGROUND: Dimethyl sulfoxide-cryopreserved (CRY) cadaver vein allografts used for hemodialysis access in patients with renal failure recently have been shown to cause broad recipient allosensitization, measured by panel reactive antibody (PRA) assay. Synergraft (SYN) processing is a novel method of treating tissue that decellularizes the graft (including mismatched major histocompatibility antigens) and potentially should prevent allosensitization. METHODS: Twenty hemodialysis patients underwent placement of an SYN-processed cadaver vein allograft. PRA assay was used prospectively to assess allosensitization in these patients at baseline and 1-month intervals after engraftment. These results were compared with our historic series of CRY allograft recipients. RESULTS: There was no significant difference in baseline PRA values for SYN and CRY patients (2.8% versus 2.6%, respectively). None of the SYN patients became allosensitized at 3 months postengraftment (mean PRA, 3.2%), whereas all CRY recipients became highly sensitized at a mean of 3.1 months (mean PRA, 84.1%). This result was highly significant (P < 0.0001). CONCLUSION: SYN processing of cadaver vein allografts successfully removes antigenic material. The use of SYN allografts in patients with renal failure for hemodialysis access does not cause allosensitization and therefore should not preclude kidney transplantation.