Dataset Information

Kidney Transplant With Low Levels of DSA or Low Positive B-Flow Crossmatch: An Underappreciated Option for Highly Sensitized Transplant Candidates.

ABSTRACT: BACKGROUND:Avoiding donor-specific antibody (DSA) is difficult for sensitized patients. Improved understanding of the risk of low level DSA is needed. METHODS:We retrospectively compared the outcomes of 954 patients transplanted with varied levels of baseline DSA detected by single antigen beads and B flow cytometric crossmatch (XM). Patients were grouped as follows: -DSA/-XM, +DSA/-XM, +DSA/low +XM, +DSA/high +XM, and -DSA/+XM and followed up for a mean of 4.1 ± 1.9 years (similar among groups, P = 0.49). RESULTS:Death-censored allograft survival was similar in all groups except the +DSA/high +XM group, which was lower at 79.1% versus 96.2% in the -DSA/-XM group (P < 0.01). The incidence of chronic antibody-mediated rejection (CAMR) based on surveillance biopsy was higher with increasing DSA (8.2% -DSA/-XM, 17.0% +DSA/-XM, 30.6% +DSA/low +XM, and 51.2% +DSA/high +XM, P < 0.01), but similar in groups without baseline DSA (8.1% -DSA/-XM vs 15.4% -DSA/+XM, P = 0.19). Having a calculated panel-reactive antibody (cPRA) of 80% or greater was independently associated with CAMR (hazard ratio, 5.2; P = 0.03) even when DSA was undetected at baseline. By 2 years posttransplant, the incidence of CAMR was 19.4% in patients with cPRA of 80% or greater and undetected DSA and negative XM at baseline. CONCLUSIONS:Kidney transplantation with low-level DSA with or without a low positive XM is a reasonable option for highly sensitized patients and may be advantageous compared with waiting for a negative XM deceased donor. The risk for CAMR is low in patients with no DSA even if the XM is positive. Patients with cPRA of 80% or greater are at risk for CAMR even if no DSA is detected.

SUBMITTER: Schinstock CA

PROVIDER: S-EPMC5481511 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Publications

Kidney Transplant With Low Levels of DSA or Low Positive B-Flow Crossmatch: An Underappreciated Option for Highly Sensitized Transplant Candidates.

Schinstock Carrie A CA Gandhi Manish M Cheungpasitporn Wisit W Mitema Donald D Prieto Mikel M Dean Patrick P Cornell Lynn L Cosio Fernando F Stegall Mark M

Transplantation 20171001 10

<h4>Background</h4>Avoiding donor-specific antibody (DSA) is difficult for sensitized patients. Improved understanding of the risk of low level DSA is needed.<h4>Methods</h4>We retrospectively compared the outcomes of 954 patients transplanted with varied levels of baseline DSA detected by single antigen beads and B flow cytometric crossmatch (XM). Patients were grouped as follows: -DSA/-XM, +DSA/-XM, +DSA/low +XM, +DSA/high +XM, and -DSA/+XM and followed up for a mean of 4.1 ± 1.9 years (simila ...[more]

PMID: 28009780

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Project description:Kidney transplantation is the most effective treatment for end-stage kidney disease. Sensitization, the formation of human leukocyte antigen (HLA) antibodies, remains a major barrier to successful kidney transplantation. Despite the implementation of desensitization strategies, many candidates fail to respond. Current progress is hindered by the lack of biomarkers to predict response and to guide therapy. Our objective was to determine whether differences in immune and gene profiles may help identify which candidates will respond to desensitization therapy.Single-cell mass cytometry by time-of-flight (CyTOF) phenotyping, gene arrays, and phosphoepitope flow cytometry were performed in a study of 20 highly sensitized kidney transplant candidates undergoing desensitization therapy. Responders to desensitization therapy were defined as 5% or greater decrease in cumulative calculated panel reactive antibody (cPRA) levels, and non-responders had 0% decrease in cPRA. Using a decision tree analysis, we found that a combination of transitional B cell and regulatory T cell (Treg) frequencies at baseline before initiation of desensitization therapy could distinguish responders from non-responders. Using a support vector machine (SVM) and longitudinal data, TRAF3IP3 transcripts and HLA-DR-CD38+CD4+ T cells could also distinguish responders from non-responders. Combining all assays in a multivariate analysis and elastic net regression model with 72 analytes, we identified seven that were highly interrelated and eleven that predicted response to desensitization therapy.Measuring baseline and longitudinal immune and gene profiles could provide a useful strategy to distinguish responders from non-responders to desensitization therapy. This study presents the integration of novel translational studies including CyTOF immunophenotyping in a multivariate analysis model that has potential applications to predict response to desensitization, select candidates, and personalize medicine to ultimately improve overall outcomes in highly sensitized kidney transplant candidates.

Project description:BackgroundPatients with broad HLA sensitization have poor access to donor organs, high mortality while waiting for kidney transplant, and inferior graft survival. Although desensitization strategies permit transplantation via lowering of donor-specific antibodies, the B cell-response axis from germinal center activation to plasma cell differentiation remains intact.MethodsTo investigate targeting the germinal center response and plasma cells as a desensitization strategy, we sensitized maximally MHC-mismatched rhesus pairs with two sequential skin transplants. We administered a proteasome inhibitor (carfilzomib) and costimulation blockade agent (belatacept) to six animals weekly for 1 month; four controls received no treatment. We analyzed blood, lymph node, bone marrow cells, and serum before desensitization, after desensitization, and after kidney transplantation.ResultsThe group receiving carfilzomib and belatacept exhibited significantly reduced levels of donor-specific antibodies (P=0.05) and bone marrow plasma cells (P=0.02) compared with controls, with a trend toward reduced lymph node T follicular helper cells (P=0.06). Compared with controls, carfilzomib- and belatacept-treated animals had significantly prolonged graft survival (P=0.02), and renal biopsy at 1 month showed significantly reduced antibody-mediated rejection scores (P=0.02). However, four of five animals with long-term graft survival showed gradual rebound of donor-specific antibodies and antibody-mediated rejection.ConclusionsDesensitization using proteasome inhibition and costimulation blockade reduces bone marrow plasma cells, disorganizes germinal center responses, reduces donor-specific antibody levels, and prolongs allograft survival in highly sensitized nonhuman primates. Most animals experienced antibody-mediated rejection with humoral-response rebound, suggesting desensitization must be maintained after transplantation using ongoing suppression of the B cell response.

Dataset Information

Kidney Transplant With Low Levels of DSA or Low Positive B-Flow Crossmatch: An Underappreciated Option for Highly Sensitized Transplant Candidates.

Publications

Kidney Transplant With Low Levels of DSA or Low Positive B-Flow Crossmatch: An Underappreciated Option for Highly Sensitized Transplant Candidates.

Similar Datasets

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