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Ergun Velidedeoglu, Marc W Cavaillé-Coll, Shukal Bala, Ozlem A Belen, Yan Wang, Renata Albrecht
BACKGROUND: Despite major advances in understanding the pathophysiology of antibody mediated rejection (AMR); prevention, diagnosis and treatment remain unmet medical needs. It appears that early T-cell mediated rejection (TCMR), de novo donor specific antibody (dnDSA) formation and AMR result from patient or physician initiated suboptimal immunosuppression, and represent landmarks in an ongoing process rather than separate events. METHODS: On April 12-13, 2017, the Food and Drug Administration (FDA) sponsored a public workshop on AMR in kidney transplantation to discuss new advances, importance of immunosuppressive medication nonadherence in dnDSA formation, associations between AMR, cellular rejection, changes in GFR, and challenges of clinical trial design for the prevention and treatment of AMR...
February 20, 2018: Transplantation
C Wiebe, V Kosmoliaptsis, D Pochinco, C Taylor, P Nickerson
BACKGROUND: Antibody-mediated rejection is a major cause of premature graft loss in kidney transplantation. Multiple scoring systems are available to assess the HLA mismatch between donors and recipients at the molecular level, however, their correlation with the development of de novo donor-specific antibody (dnDSA) has not been compared in recipients on active immunosuppression. METHODS: HLA-DRβ1/3/4/5/DQα1β1 molecular mismatch was determined using eplet analysis, amino acid mismatch, and electrostatic mismatch for 596 renal transplant recipients and correlated with HLA-DR/DQ dnDSA development...
February 13, 2018: Transplantation
Olga Charnaya, Shamir Tuchman, Asha Moudgil
The development of dnDSA anti-HLA antibodies has been shown to be a significant risk factor for graft failure. In 2008, we instituted a routine protocol of standardized monitoring and treatment of dnDSA in pediatric kidney transplant recipients. Of 67 first-time pediatric kidney transplant recipients, 26 (38%) developed dnDSA after 1.36 (IQ 1-2.14) years. Coefficient of variance of tacrolimus, a surrogate marker of non-adherence, was found to be the single most important risk factor for dnDSA development. Overall, there was a significant reduction in dnDSA with treatment in 19 (76%) children...
March 2018: Pediatric Transplantation
Claire Leibler, Allan Thiolat, Carole Hénique, Chloé Samson, Caroline Pilon, Marie Tamagne, France Pirenne, Benoit Vingert, José L Cohen, Philippe Grimbert
Generation of de novo donor-specific antibodies (dnDSAs) after renal transplant is recognized as the leading cause of late transplant failure. Hence, the optimal immunosuppressive strategies to limit dnDSA development need to be defined. Recent clinical trials using the novel costimulatory blockade agent CTLA4-Ig (Belatacept) have shown that kidney transplant recipients (KTRs) treated with Belatacept have better graft survival and function and a lower proportion of dnDSAs than control-treated KTRs. Mechanisms involved in the control of humoral responses by Belatacept remain to be investigated...
January 10, 2018: Journal of the American Society of Nephrology: JASN
Wisit Cheungpasitporn, Walter K Kremers, Elizabeth Lorenz, Hatem Amer, Fernando G Cosio, Mark D Stegall, Manish J Gandhi, Carrie A Schinstock
BACKGROUND AND OBJECTIVES: The risk of de novo donor-specific antibody (dnDSA) development following BK viremia (BKV) or nephropathy (BKN) after kidney transplant remains unclear. We aimed to evaluate the relationships among dnDSA, BKV (BK blood PCR >15,000 copies), BKN, antibody mediated rejection (AMR) and allograft loss. PATIENTS AND METHODS: We performed a retrospective cohort study of 904 solitary kidney transplant recipients transplanted between 10/2007 and 5/2014...
January 8, 2018: Clinical Transplantation
Alison J Gareau, Chris Wiebe, Denise Pochinco, Ian W Gibson, Julie Ho, David N Rush, Peter W Nickerson
Studies investigating the potential pathogenic effects of non-HLA antibodies (Ab) have identified Ab against the angiotensin II type 1 receptor (AT1 R-Ab) as a risk factor for rejection and kidney graft loss. This study sought to validate the risk of AT1 R-Ab for acute rejection and to explore the role of other non-HLA Abs in this capacity. Pre- and post-transplant sera from a cohort of 101 patients (n=453 samples total) were tested for AT1 R-Ab and other non-HLA Ab using a commercially available ELISA kit and the Luminex platform, respectively...
February 2018: Transplant Immunology
Robert Townsend Cole, Jonathan Gandhi, Robert A Bray, Howard M Gebel, Michael Yin, Nikolaz Shekiladze, An Young, Aubrey Grant, Ian Mahoney, S Raja Laskar, Divya Gupta, Kunal Bhatt, Wendy Book, Andrew Smith, Duc Nguyen, J David Vega, Alanna A Morris
BACKGROUND: Despite improvements in outcomes after heart transplantation, black recipients have worse survival compared with non-black recipients. The source of such disparate outcomes remains largely unknown. We hypothesize that a propensity to generate de-novo donor-specific antibodies (dnDSA) and subsequent antibody-mediated rejection (AMR) may account for racial differences in sub-optimal outcomes after heart transplant. In this study we aimed to determine the role of dnDSA and AMR in racial disparities in post-transplant outcomes...
November 4, 2017: Journal of Heart and Lung Transplantation
A Courtwright, J M Diamond, I Wood, I Guleria, E Milford, S El-Chemaly, H J Goldberg
There is significant variability in lung transplant centers' approach to HLA antibodies, creating heterogeneity regarding their clinical significance. Some institutions use beads coated with multiple HLA to screen candidate sera and then use single antigen bead (SAB) to determine antibody identity if the pre-screen is positive. Other centers do not pre-screen, using SAB alone, which may detect low-level antibodies of unknown significance. The primary objective of this study was to review the current literature to identify sources of heterogeneity in the identification of pre- and post-lung transplant HLA antibodies, particularly regarding antibody-detection methods...
February 2018: HLA
Justin A Steggerda, Irene K Kim, Mark Haas, Xiaohai Zhang, Alexis Kang, Helen Pizzo, Elaine Kamil, Stanley Jordan, Dechu Puliyanda
Preformed and de novo donor specific antibodies (pDSA and dnDSA) are risk factors for ABMR. This study compares the effects of pDSA vs dnDSA in pediatric kidney transplant recipients. Sixteen pediatric patients with biopsy-proven ABMR were evaluated. Strong DSA (MFI >10 000) was recorded at transplant, rejection, and follow-up. DSAs with the highest MFI were termed iDSAs. Allograft biopsies were scored according to Banff 2013 criteria. Seven of 16 (44%) patients had pDSA at transplant; 9 (56%) developed dnDSA...
December 2017: Pediatric Transplantation
Annemarie Weissenbacher, Georgios Vrakas, Mian Chen, Srikanth Reddy, Philip Allan, Henk Giele, Martin Cnm Barnardo, Anil Vaidya, Peter J Friend, Susan V Fuggle
Combining vascularised composite allotransplantation (VCA) with intestinal transplantation to achieve primary abdominal closure has become a feasible procedure. Besides facilitating closure, the abdominal wall can be used to monitor intestinal rejection. As the inclusion of a VCA raises the possibility of an enhanced alloimmune response, we investigated the incidence and clinical effect of de novo donor specific HLA antibodies (dnDSA) in a cohort of patients receiving an intestinal transplant with or without a VCA...
November 18, 2017: Transplant International: Official Journal of the European Society for Organ Transplantation
Scott Davis, Jane Gralla, Patrick Klem, Suhong Tong, Gina Wedermyer, Brian Freed, Alexander Wiseman, James E Cooper
De novo donor-specific antibodies (dnDSAs) have been associated with reduced graft survival. Tacrolimus (TAC)-based regimens are the most common among immunosuppressive approaches used in in clinical practice today, yet an optimal therapeutic dose to prevent dnDSAs has not been established. We evaluated mean TAC C0 (tacrolimus trough concentration) and TAC time in therapeutic range for the risk of dnDSAs in a cohort of 538 patients in the first year after kidney transplantation. A mean TAC C0  < 8 ng/mL was associated with dnDSAs by 6 months (odds ratio [OR] 2...
September 19, 2017: American Journal of Transplantation
Sandesh Parajuli, Patrick K Reville, Thomas M Ellis, Arjang Djamali, Didier A Mandelbrot
There is limited information about the role of protocol kidney biopsies for de novo donor-specific antibodies (dnDSA) in kidney transplant recipients, especially in those with stable graft function. We initiated a routine posttransplant DSA monitoring and surveillance biopsy program for dnDSA since 2014. We identified 45 kidney transplant recipients with dnDSA detected between January 2014 and February 2017 who underwent kidney biopsy within 60 days of detection of dnDSA. Twenty-nine (64%) had stable graft function and 16 (36%) had impaired graft function at the time of dnDSA detection...
December 2017: American Journal of Transplantation
A Castro, J Malheiro, S Tafulo, L Dias, L S Martins, I Fonseca, I Beirão, A Castro-Henriques, A Cabrita
The role of de novo donor-specific anti-human leukocyte antigen (anti-HLA) antibodies (dnDSA) within the pathways leading to graft failure remains not fully understood. We investigated 56 patients who were transplanted between 2002 and 2014 with kidney graft failure (cases), for a possible association of development of dnDSA with graft failure. The 56 patients with failed transplants were matched with 56 patients with a functioning graft at present for the variables deceased or living donor, transplant number, transplant year, recipient age and gender, donor age and gender, dialysis vintage time, transplant induction therapy...
August 4, 2017: HLA
Chris Wiebe, David N Rush, Thomas E Nevins, Patricia E Birk, Tom Blydt-Hansen, Ian W Gibson, Aviva Goldberg, Julie Ho, Martin Karpinski, Denise Pochinco, Atul Sharma, Leroy Storsley, Arthur J Matas, Peter W Nickerson
Despite more than two decades of use, the optimal maintenance dose of tacrolimus for kidney transplant recipients is unknown. We hypothesized that HLA class II de novo donor-specific antibody ( dn DSA) development correlates with tacrolimus trough levels and the recipient's individualized alloimmune risk determined by HLA-DR/DQ epitope mismatch. A cohort of 596 renal transplant recipients with 50,011 serial tacrolimus trough levels had HLA-DR/DQ eplet mismatch determined using HLAMatchmaker software. We analyzed the frequency of tacrolimus trough levels below a series of thresholds <6 ng/ml and the mean tacrolimus levels before dn DSA development in the context of HLA-DR/DQ eplet mismatch...
November 2017: Journal of the American Society of Nephrology: JASN
Ana K Islam, Neeraj Sinha, Jennifer M DeVos, Thomas S Kaleekal, Soma S Jyothula, Larry D Teeter, Duc T M Nguyen, Todd N Eagar, Linda W Moore, Mamta Puppala, Stephen T C Wong, Richard J Knight, Adaani E Frost, Edward A Graviss, A Osama Gaber
BACKGROUND: The natural history of de novo donor-specific antibodies (dnDSA) after lung transplantation is not well-described. We sought to determine the incidence and risk factors associated with dnDSA and compare outcomes between recipients with transient (or isolated) vs persistent dnDSA after transplantation. METHODS: A single-center review of all lung transplants from 1/2009-7/2013. DSAs were tested eight times in the first year and every 4 months thereafter...
June 28, 2017: Clinical Transplantation
Marie Matignon, Caroline Pilon, Morgane Commereuc, Cynthia Grondin, Claire Leibler, Tomek Kofman, Vincent Audard, José Cohen, Florence Canoui-Poitrine, Philippe Grimbert
BACKGROUND: Approximately 25% of kidney transplant recipients develop de novo anti-HLA donor-specific antibodies (dnDSA) leading to acute antibody-mediated rejection (ABMR) in 30% of patients. Preemptive therapeutic strategies are not available. METHODS: We conducted a prospective observational study including 11 kidney transplant recipients. Inclusion criteria were dnDSA occurring within the first year after transplant and normal allograft biopsy. All patients were treated with high-dose IVIG (2 g/kg 0, 1 and 2 months post-dnDSA)...
2017: PloS One
N Lachmann, M Niemann, P Reinke, K Budde, D Schmidt, F Halleck, A Pruß, C Schönemann, E Spierings, O Staeck
De novo donor-specific HLA antibodies (dnDSA) are recognized as a risk factor for premature allograft failure. Determinants of DSA specificity are generated via the indirect allorecognition pathway. Here, we present supportive data for the relevance of predicted indirectly recognizable HLA epitopes (PIRCHE) to predict dnDSA following kidney transplantation. A total of 2787 consecutive kidney transplants performed between 1995 and 2015 without preformed DSA have been analyzed. De novo DSA were detected by single antigen bead assay...
December 2017: American Journal of Transplantation
Jennifer M Loucks-DeVos, Todd N Eagar, A Osama Gaber, Samir J Patel, Larry D Teeter, Edward A Graviss, Richard J Knight
BACKGROUND: De novo donor-specific antibodies (dnDSA) after renal transplant are associated with acute rejection (AR) and graft loss, yet most recipients with dnDSA have stable function and no AR. We assessed whether the persistence of dnDSA increased the risk of a detrimental outcome. METHODS: A single-center review of renal transplant recipients monitored for dnDSA at multiple time points post-transplant. An Isolated dnDSA was defined as one positive dnDSA and no additional positive tests, whereas ≥2 positive dnDSA was defined as persistent dnDSA...
June 5, 2017: Clinical Transplantation
Hilda E Fernandez
PURPOSE OF REVIEW: Advances in technology to assess immunologic risk in solid organ transplant offer an opportunity to optimize the approach to pediatric deceased donor kidney transplant in the setting of a new allocation system in the United States. RECENT FINDINGS: Degree of human leukocyte antigen (HLA) mismatch, class II HLA mismatch, unacceptable antigens and donor-specific antibody (DSA) detected by solid-phase assays, and epitope matching pretransplant affect pediatric kidney transplant outcomes...
August 2017: Current Opinion in Organ Transplantation
Philippe Grimbert, Olivier Thaunat
Antibody-mediated rejection (AMR) usually starts with generation of donor-specific anti-HLA antibodies (DSAs), arising from a B-cell response to antigen recognition. In vitro and preclinical data demonstrate that mammalian target of rapamycin (mTOR) inhibition attenuates the mTOR-mediated intracellular signaling pathway involved in AMR-related kidney damage. The limited available data from immunological studies in kidney transplant patients, however, have not shown such effects in vivo. In terms of clinical immunosuppression, the overriding influence on rates of de novo DSA (dnDSA) or AMR-regardless of the type of regimen-is patient adherence...
July 2017: Transplant International: Official Journal of the European Society for Organ Transplantation
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