Kidney transplant outcomes are limited by toxicities associated with calcineurin inhibitors and steroids. This trial was conducted to determine whether a costimulation blockade (CoB)-based regimen could achieve acceptable long-term outcomes

We assessed the effectiveness of standardized protocols in decreasing postoperative mechanical ventilation time to <6 hours.Methods: In 2061 patients undergoing coronary bypass, the proportion extubated in<6 hours was calculated for 3 sequential time periods. During period 1 patients were weaned per baseline practices; during period 2, per a protocol developed by a multidisciplinary committee; and during period 3, as in period 2 but with paralytic reversal and extubation performed at lower body temperatures and an extubation reminder sheet prominently displayed. We used a c 2 test to examine differences in ventilation times among the 3 time periods and logistic regression modeling to control for independent risk factors for prolonged ventilation. As measures of patient safety, we examined rates of reintubation and rates of patient shivering following paralytic reversal.Results: Twelve percent of patients were extubated in<6 hours during period 1, 24% during period 2 (P<.01), and 38% during period 3 (P <.01 compared with both periods 1 and 2). After controlling for 12 risk factors, patients were more likely to be extubated in<6 hours during period 2 (odds ratio, 2.39; 95% confidence interval, 1.84-3.10) and period 3 (odds ratio, 5.05; 95% confidence interval, 3.65-6.99) than during period 1. There was no difference in reintubation rates across periods, and the rate of patient shivering did not increase with paralytic reversal at lower body temperature. Conclusions:The standardized protocols outlined in this article dramatically improved early extubation performance.

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Ventilator-associated pneumonia remains a major cause of morbidity and mortality in postoperative heart surgery patients. We present a systematic review of the literature on the incidence, risk factors, and prevention of this condition in a population at heightened risk.

Our understanding of the role of B cells in organ transplantation remains incomplete and continues to grow. The majority of research has focused on the detrimental role of antibodies that drive the development of pathogenesis of the transplanted organ. However, it has been shown that not all donor-specific antibodies are harmful and in some circumstances can even promote tolerance through the mechanism of accommodation. Furthermore, B cells can have effects on transplanted organs through their interaction with T cells, namely antigen presentation, cytokine production, and costimulation. More recently, the role and importance of Bregs was introduced to the field of transplantation. Due to this functional and ontogenetic heterogeneity, targeting B cells in transplantation may bring undesired immunologic side effects including increased rejection. Therefore, the selective control of B cells that contribute to the humoral response against donor antigens will continue to be an important and challenging area of research and potentially lead to improved long-term transplant outcomes.

Sensitized kidney transplant recipients experience high rates of antibody-mediated rejection due to the presence of donor-specific antibodies and immunologic memory. Here we show that transient peri-transplant treatment with the central complement component C3 inhibitor Cp40 significantly prolongs median allograft survival in a sensitized nonhuman primate model. Despite donor-specific antibody levels remaining high, fifty percent of Cp40-treated primates maintain normal kidney function beyond the last day of treatment. Interestingly, presence of antibodies of the IgM class associates with reduced median graft survival (8 vs. 40 days; p = 0.02). Cp40 does not alter lymphocyte depletion by rhesus-specific anti-thymocyte globulin, but inhibits lymphocyte activation and proliferation, resulting in reduced antibody-mediated injury and complement deposition. In summary, Cp40 prevents acute antibody-mediated rejection and prolongs graft survival in primates, and inhibits T and B cell activation and proliferation, suggesting an immunomodulatory effect beyond its direct impact on antibody-mediated injury.

Purpose of review-Manipulating costimulatory signals has been shown to alter T cell responses and prolong graft survival in solid organ transplantation. Our understanding of and ability to target various costimulation pathways continues to evolve.Recent findings-Since the approval of belatacept in kidney transplantation, many additional biologics have been developed targeting clinically relevant costimulation signaling axes including CD40-CD40L, inducible costimulator-inducible costimulator ligand (ICOS-ICOSL), and OX40-OX40L. Currently, the effects of costimulation blockade on posttransplant humoral responses, tolerance induction, and xenotransplantation are under active investigation. Here, we will discuss these pathways as well as preclinical and clinical outcomes of biologics targeting these pathways in organ transplantation.Summary-Targeting costimultion is a promising approach for not only controlling T cell but also B cell responses. Consequently, costimulation blockade shows considerable potential for improving outcomes in antibody-mediated rejection and xenotransplantation.

Background Membrane cofactor protein CD46 attenuates the complement cascade by facilitating cleavage of C3b and C4b. In solid organ xenotransplantation, organs expressing CD46 have been shown to resist hyperacute rejection. However, the incremental value of human CD46 expression for islet xenotransplantation remains poorly defined. Methods This study attempted to delineate the role of CD46 in early neonatal porcine islet engraftment by comparing Gal‐knocked out (GKO) and hCD46‐transgenic (GKO/CD46) islets in a dual transplant model. Seven rhesus macaques underwent dual transplant and were sacrificed at 1 hour (n = 4) or 24 hours (n = 3). Both hemilivers were recovered and fixed for immunohistochemistry (CD46, insulin, neutrophil elastase, platelet, IgM, IgG, C3d, C4d, CD68, Caspase 3). Quantitative immunohistochemical analysis was performed using the Aperio Imagescope. Results Within 1 hour of intraportal infusion of xenografts, no differences were observed between the two types of islets in terms of platelet, antibody, or complement deposition. Cellular infiltration and islet apoptotic activity were also similar at 1 hour. At 24 hours, GKO/CD46 islets demonstrated significantly less platelet deposition (P = 0.01) and neutrophil infiltration (P = 0.01) compared to GKO islets. In contrast, C3d (P = 0.38) and C4d (P = 0.45) deposition was equal between the two genotypes. Conclusions Our findings suggest that expression of hCD46 on NPIs potentially provides a measurable incremental survival advantage in vivo by reducing early thrombo‐inflammatory events associated with instant blood‐mediated inflammatory reaction (IBMIR) following intraportal islet infusion.