The proportion of patients with 02 HLA mismatches was 7.1% (8/113), 34 HLA mismatches was 39.8% (45/113), and 56 mismatches was 53.1% (27/113). 56.0)] and mixed rejection [HR 7.4(95% CI 2.2, 24.8)] were associated with allograft failure. We conclude that patient Rabbit Polyclonal to PEX14 factors, including a history of viral contamination requiring immunosuppression reduction or medication nonadherence, combined with DSA and histologic parameters must be considered to understand the risk of allograft failure in patients with dnDSA. == Introduction: == De novo donor specific antibody (dnDSA) is usually a major risk factor for chronic active antibody mediated rejection (ABMR) and subsequent renal allograft loss13, Sildenafil yet many patients with dnDSA have stable allograft function for years.47A clear understanding of the patient characteristics and biomarkers at the time of dnDSA detection predictive of allograft loss is needed to inform management decisions. More importantly this information can be used to effectively design clinical trials and define inclusion criteria to enrich study populations with subjects most likely to reach meaningful clinical end-points. Previous studies have shown that allograft dysfunction and histologic features of rejection help predict allograft loss4,6, but this information is not always apparent at the time of initial dnDSA detection. The patients who develop dnDSA are also heterogeneous. The main precursors to de novo DSA include patient medication nonadherence and provider initiated immunosuppression reduction (ie. for contamination)1,4,5,8, but it remains unclear whether these factors are important in predicting early allograft loss. One important biomarker of allograft loss is usually DSA. The routine single antigen bead (SAB) assay for anti-HLA antibody detection provides valuable semi-quantitative information about immunoglobulin G (IgG) directed towards class I and/or class II HLA. However, other dnDSA information may also have prognostic value such as the specific IgG subclass profile or complement binding ability of the dnDSA. The different IgG subclasses have distinct effector functions, notably a differential ability to bind complement and the Fc receptor. These factors likely influence allograft histology and allograft loss9,10,11. Previous studies have suggested that IgG3 positive DSA, C1q binding positivity, quantity of DSA as measured by mean fluorescence intensity (MFI) or titer, and the HLA class of DSA are predictive of allograft failure4,1220in single center cohorts; but these factors have not been systematically studied in a diverse multicenter cohort in the context of other important predictors of allograft failure. The objective of our project was two-fold. First, we aimed to determine the death-censored allograft survival and allograft histology following the identification of dnDSA in Sildenafil a well- characterized multicenter cohort of kidney transplant recipients. Second, we aimed to identify unique patient, histological, and dnDSA characteristics associated with early allograft failure. Patient factors studied included baseline demographics, nonadherence, or prior viral contamination requiring immunosuppression reduction. De novo DSA characteristics included IgG subclasses and C1q binding positivity. == Methods: == == Study Design == This was a retrospective observational multicenter study of solitary kidney transplant recipients transplanted from 1998 Sildenafil to 2015 [Mayo Clinic, Rochester, MN (Center A) ; New York Presbyterian Weill Cornell Medical College [NYP-WCM (Center B)], New York, NY; and University of Michigan, Ann Arbor, MI (Center C)] with dnDSA. A chart review was performed to identify patients meeting the following inclusion criteria: 1) no DSA at the time of transplant, 2) development of dnDSA with MFI > 1000 post-transplantation verified on two impartial assessments and 3) the availability of banked sera collected at the time of dnDSA detection to allow for Sildenafil additional DSA characterization at a central lab (Terasaki Research Institute, Los Angeles, CA). The overall aim of the study was to determine the factors identified at initial dnDSA detection that were associated with allograft loss. This study was approved by the Institutional Review Boards at Mayo Clinic, NYP-WCM, and University of Michigan. Clinical data were collected by chart review. == De novo Donor Specific Antibody Assessment == Donor specific antibody testing was performed using the SAB solid phase assay (LABscreen, One Lambda, Canoga Park, CA, USA)]. An MFI cut-off of 1000 was considered positive. All patients were unfavorable for DSA pretransplant and had at least one SAB test unfavorable for DSA post-transplant. Donor specific antibody testing and testing was performed for monitoring reasons at least annually post-transplant so that as indicated during allograft dysfunction. The kept sera acquired when dnDSA was detected was delivered to the Terasaki Study Institute for do it again tests using a regular protocol to verify the current presence of dnDSA and perform IgG subclass and C1q tests. Skillet IgG DSA tests was completed via the SAB assay also. The dnDSA with the best MFI at demonstration was regarded as the Dominant DSA. The strategy.