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Bortezomib antibody rejection

Jorge Carlos Garces, Sixto Giusti, Catherine Staffeld-Coit, Humberto Bohorquez, Ari J Cohen, George E Loss
BACKGROUND: Chronic antibody injury is a serious threat to allograft outcomes and is therefore the center of active research. In the continuum of allograft rejection, the development of antibodies plays a critical role. In recent years, an increased recognition of molecular and histologic changes has provided a better understanding of antibody-mediated rejection (AMR), as well as potential therapeutic interventions. However, several pathways are still unknown, which accounts for the lack of efficacy of some of the currently available agents that are used to treat rejection...
2017: Ochsner Journal
Dael Geft, Jon Kobashigawa
PURPOSE OF REVIEW: Antibody allosensitization poses a major immunologic challenge for patients awaiting heart transplantation. It is associated with significant morbidity and mortality for both pretransplant and posttransplant patients by prolonging wait times to transplant and increasing posttransplant rejection and vasculopathy. Many questions remain regarding methods and interpretation of antibody detection, the relevance of sensitization in specific patient populations such as those with mechanical circulatory support and the ideal strategies for desensitization...
March 16, 2017: Current Opinion in Organ Transplantation
Nils Lachmann, Michael Duerr, Constanze Schönemann, Axel Pruß, Klemens Budde, Johannes Waiser
Throughout the past years we stepwise modified our immunosuppressive treatment regimen for patients with antibody-mediated rejection (ABMR). Here, we describe three consecutive groups treated with different regimens. From 2005 until 2008, we treated all patients with biopsy-proven ABMR with rituximab (500 mg), low-dose (30 g) intravenous immunoglobulins (IVIG), and plasmapheresis (PPH, 6x) (group RLP, n = 12). Between 2009 and June 2010, patients received bortezomib (1.3 mg/m(2), 4x) together with low-dose IVIG and PPH (group BLP, n = 11)...
2017: Journal of Immunology Research
E Morelon, P Petruzzo, J Kanitakis, S Dakpé, O Thaunat, V Dubois, G Choukroun, S Testelin, J-M Dubernard, L Badet, B Devauchelle
Ten years after the first face transplantation, we report the partial loss of this graft. After two episodes of acute rejection (AR) occurred and completely reversed in the first posttransplantation year, at 90 months posttransplantation the patient developed de novo class II donor-specific antibodies, without clinical signs of AR. Some months later, she developed several skin rejection episodes treated with steroid pulses. Despite rapid clinical improvement, some months later the sentinel skin graft underwent necrosis...
January 31, 2017: American Journal of Transplantation
Sarah Kizilbash, Donna Claes, Isa Ashoor, Ashton Chen, Sara Jandeska, Raed Bou Matar, Jason Misurac, Joseph Sherbotie, Katherine Twombley, Priya Verghese
Antibody-mediated rejection leads to allograft loss after kidney transplantation. Bortezomib has been used in adults for the reversal of antibody-mediated rejection; however, pediatric data are limited. This retrospective study was conducted in collaboration with the Midwest Pediatric Nephrology Consortium. Pediatric kidney transplant recipients who received bortezomib for biopsy-proven antibody-mediated rejection between 2008 and 2015 were included. The objective was to characterize the use of bortezomib in pediatric kidney transplant recipients...
May 2017: Pediatric Transplantation
Mary Vacha, Godefroy Chery, Amanda Hulbert, Jennifer Byrns, Clark Benedetti, Catherine Ashley Finlen Copeland, Alice Gray, Oluwatoyosi Onwuemene, Scott M Palmer, Laurie D Snyder
BACKGROUND: Donor-specific antibodies (DSAs) after lung transplantation correlate with poor outcomes. The ideal treatment strategy for antibody-mediated rejection AMR is not defined. Our institution implemented an aggressive multimodality protocol for the treatment of suspected AMR. METHODS: Lung transplant recipients with suspected AMR were treated with a standardized protocol of plasma exchange, steroids, bortezomib, rituximab, and intravenous immune globulin...
December 17, 2016: Clinical Transplantation
Johannes Waiser, Michael Duerr, Constanze Schönemann, Birgit Rudolph, Kaiyin Wu, Fabian Halleck, Klemens Budde, Nils Lachmann
BACKGROUND: Current treatment strategies for antibody-mediated renal allograft rejection (AMR) are not sufficiently effective. In most centers, "standard of care" treatment includes plasmapheresis (PPH) and IVIG preparations. Since several years, modern therapeutics targeting B cells and plasma cells have become available. We investigated, whether combined administration of rituximab and bortezomib in addition to PPH and high-dose IVIG is useful. METHODS: Between November 2011 and January 2013, we treated 10 consecutive patients with biopsy-proven AMR with rituximab (500 mg), bortezomib (4× 1...
August 2016: Transplantation Direct
Rebecca Citrin, Jessica B Foster, David T Teachey
INTRODUCTION: Proteasome inhibitors have garnered interest as novel chemotherapeutic agents based on their ability to inhibit the growth of cancer cells by altering the balance of intracellular proteins. Initial clinical trials of this drug class focused on bortezomib, a reversible inhibitor of the 20S proteasome, with promising results for the treatment of adult hematologic malignancies, including multiple myeloma and non-Hodgkin lymphoma. AREAS COVERED: This article will review the use of bortezomib and other proteasome inhibitors in both adult and pediatric populations, with a focus on their use in pediatrics...
September 2016: Expert Review of Hematology
Philip T Thrush, Elfriede Pahl, David C Naftel, Elizabeth Pruitt, Melanie D Everitt, Heather Missler, Steven Zangwill, Michael Burch, Timothy M Hoffman, Ryan Butts, William T Mahle
BACKGROUND: Current knowledge of antibody-mediated rejection (AMR) after heart transplantation (HT) stems largely from adult data. Using the Pediatric Heart Transplant Study (PHTS) database, we report the incidence of AMR, describe treatment, and evaluate outcomes for treated AMR in children after HT. METHODS: We queried the PHTS database for patients <18 years of age undergoing primary HT between January 2010 and December 2014. An AMR episode was defined as either a biopsy consistent with pathologic AMR or a rejection event based on immunotherapy augmentation directed against antibody production...
December 2016: Journal of Heart and Lung Transplantation
Jakob Gubensek, Jadranka Buturovic-Ponikvar, Aljosa Kandus, Miha Arnol, Jelka Lindic, Damjan Kovac, Andreja Ales Rigler, Karmen Romozi, Rafael Ponikvar
Antibody-mediated rejection (AMR) is a major cause of kidney graft failure. We aimed to analyze treatment and outcome of AMR in a national cohort of 75 biopsy-proven acute (43 patients, 57%) or chronic active (32 patients, 43%) AMR episodes between 2000 and 2015. The mean patients' age was 46 ± 16 years, the majority was treated with plasma exchange, 4% received immunoadsorption and 7% received both. The majority received pulse methylprednisolone and low-dose CMV hyperimmune globulin, 20% received bortezomib and 13% rituximab...
June 2016: Therapeutic Apheresis and Dialysis
S C Jordan, J Choi, J Kahwaji, A Vo
The presence of HLA antibodies remains a significant and often impenetrable barrier to kidney transplantation, leading to increased morbidity and mortality for patients remaining on long-term dialysis. In recent years, a number of new approaches have been developed to overcome these barriers. Intravenous immunoglobulin (IVIG) remains the lynchpin of HLA desensitization therapy and has been shown in a prospective, randomized, placebo-controlled trial to improve transplantation rates. In addition, IVIG used in low doses with plasma exchange is a reliable protocol for desensitization...
April 2016: Transplantation Proceedings
Anil Chandraker, Ramon Arscott, George Murphy, Christine Lian, Ericka Bueno, Francisco Marty, Helmut Rennke, Edgar Milford, Stefan Tullius, Bodhan Pomahac
Face transplantation was performed in a highly sensitized recipient with positive preoperative crossmatch and subsequent antibody-mediated rejection. The recipient was a 45-year-old female with extensive conventional reconstructions after chemical burns over the majority of the body. Residual quality of life and facial functions were poor. Levels of circulating anti-human leukocyte antigen (HLA) antibodies were high, and panel reactive antibody score was 98%. A potential donor was identified; however, with positive T and B cell flow crossmatches...
May 2016: Military Medicine
S Fujiwara, M Wada, H Kudo, S Yamaki, F Fujishima, K Ishida, M Nakamura, H Sasaki, T Kazama, H Tanaka, M Nio
BACKGROUND: A significant association between donor-specific antibody (DSA) and graft rejection has recently been documented. However, confirmed strategy has not been established for DSA-associated rejection after intestinal transplantation (ITx). CASE REPORT: A 20-year-old male patient with chronic intestinal obstruction caused by hypoganglionosis of the entire intestine underwent cadaveric donor ITx with grafting performed on 232 cm of the small intestine, cecum, and a part of the ascending colon...
March 2016: Transplantation Proceedings
H K Chang, S Y Kim, J I Kim, S I Kim, J K Whang, J Y Choi, J M Park, E S Jung, S E Rha, D G Kim, I S Moon, M D Lee
A retrospective review of intestinal transplantation (ITx) at Seoul St. Mary's Hospital was made by collecting clinical data over the past 10 years. Fifteen consecutive cases from 2004 were analyzed. Five children and 10 adults (6 months to 69 years of age) were included. Primary diseases in adults included 4 mesenteric vessel thromboses, 2 strangulations, and 1 each of visceral myopathy, malignant gastrointestinal stromal tumor (GIST), mesenteric lymphangiectasis, and injury. Pediatric cases involved 2 Hirschsprung disease, 2 visceral myopathy, and 1 necrotizing enterocolitis...
March 2016: Transplantation Proceedings
Meghan H Pearl, Anjali B Nayak, Robert B Ettenger, Dechu Puliyanda, Miguel Fernando Palma Diaz, Qiuheng Zhang, Elaine F Reed, Eileen W Tsai
BACKGROUND: Current therapeutic strategies to effectively treat antibody-mediated rejection (AMR) are insufficient. Thus, we aimed to determine the benefit of a therapeutic protocol using bortezomib for refractory C4d + AMR in pediatric kidney transplant patients. METHODS: We examined seven patients with treatment-refractory C4d + AMR. Immunosuppression included antithymocyte globulin or anti-CD25 monoclonal antibody for induction therapy with maintenance corticosteroids, calcineurin inhibitor, and anti-metabolite...
August 2016: Pediatric Nephrology: Journal of the International Pediatric Nephrology Association
Stephen D Marks
There have been marked improvements in the short- and long-term outcomes for children after renal transplantation over the past two decades with superior quality and quantity of life. It is encouraging to see increased patient and renal allograft survival rates with initially lower acute renal allograft rejection rates due to improved matching and immunosuppressive regimens. Unfortunately, longer-term renal allograft survival remains unchanged with chronic allograft injury from both immune and non-immune causes, resulting in chronic allograft dysfunction, morbidity from chronic kidney disease, and eventual renal allograft loss...
August 2016: Pediatric Nephrology: Journal of the International Pediatric Nephrology Association
Jesmar Buttigieg, Bridson M Julie, Ajay Sharma, Ahmed Halawa
Kidney transplant remains the best type of renal replacement therapy in most patients with end-stage kidney disease, even in those with high immunologic risk. Immunosuppression in these patients is regarded as more complex, owing to the higher risk of both acute and chronic rejection. The advent of induction immunosuppression has resulted in a lower incidence of acute rejection and consequently improved short-term patient and allograft outcomes. Indeed, the use of these agents, especially in high-risk recipients, has become standard of care at most transplant centers...
August 2016: Experimental and Clinical Transplantation
Julio Pascual, Andreas Zuckermann, Arjang Djamali, Alexandre Hertig, Maarten Naesens
The mode of action of rabbit antithymocyte globulin (rATG) includes preferential inhibition of pre-existing donor-reactive memory T-cell reconstitution and possibly apoptosis of plasma cells, the source of donor specific antibodies (DSAs). In kidney transplant patients with low-strength preformed DSAs, non-comparative data have shown a low incidence of antibody-mediated rejection (ABMR) and graft survival using rATG even without desensitization procedures. For high strengths of preformed DSAs, rATG induction with more aggressive desensitization appears effective, with mixed results concerning the addition of B-cell specific agents...
April 2016: Transplantation Reviews
Jong Cheol Jeong, Enkthuya Jambaldorj, Hyuk Yong Kwon, Myung-Gyu Kim, Hye Jin Im, Hee Jung Jeon, Ji Won In, Miyeun Han, Tai Yeon Koo, Junho Chung, Eun Young Song, Curie Ahn, Jaeseok Yang
Combination therapy of intravenous immunoglobulin (IVIG) and rituximab showed a good transplant rate in highly sensitized wait-listed patients for deceased donor kidney transplantation (DDKT), but carried the risk of antibody-mediated rejection. The authors investigated the impact of a new combination therapy of bortezomib, IVIG, and rituximab on transplantation rate.This study was a prospective, open-labeled clinical trial. The desensitization regimen consisted of 2 doses of IVIG (2  g/kg), a single dose of rituximab (375  mg/m), and 4 doses of bortezomib (1...
February 2016: Medicine (Baltimore)
Kwanchai Pirojsakul, Dev Desai, Chantale Lacelle, Mouin G Seikaly
BACKGROUND: Data on renal allograft outcome in sensitized children are scarce. We report the clinical courses of four children who received desensitization therapy prior to renal transplantation in our institution. METHODS: Between 2009 and 2011, four pediatric patients with stage 5 chronic kidney disease received desensitization therapy due to: (1) positive donor-specific antibodies (DSA) and/or crossmatches with potential living donors, (2) more than three positive crossmatches with deceased donors or (3) high calculated panel-reactive antibody of >80 %...
October 2016: Pediatric Nephrology: Journal of the International Pediatric Nephrology Association
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