Early cyclosporine a withdrawal in kidney-transplant recipients receiving sirolimus prevents progression of chronic pathologic allograft lesions

BACKGROUND: Nephrotoxicity of calcineurin inhibitors (CNIs) is partially responsible for the development of chronic allograft nephropathy (CAN). Sirolimus has demonstrated its potential to substitute for CNIs because it lacks significant nephrotoxicity and shows a short-term immunosuppressive capacity comparable with that of cyclosporine. This results in the maintenance of better renal function when cyclosporine is eliminated, but it has not been demonstrated whether this benefit is associated with an improvement in the pathologic substrate and a reduction in CAN. METHODS: We analyzed pretransplant and 1-year renal-allograft biopsies from 64 patients enrolled in a multicenter trial. Patients received cyclosporine and sirolimus during the first 3 months after transplant and were then randomly assigned to continue with cyclosporine or have it withdrawn. Histologic chronic allograft lesions were compared between groups. RESULTS: The percentage of patients in whom chronic pathologic lesions progressed was lower in the group of cyclosporine elimination. Significant differences were observed in chronic interstitial and tubular lesions (70% vs. 40.9% [P<0.05] and 70% vs. 47.8% [P<0.05], respectively), whereas no differences were observed in acute lesions (subclinical rejection). Prevalence of CAN at 1 year was lower in this group, as was the severity and incidence of new cases (P<0.05). CONCLUSIONS: Early cyclosporine withdrawal associated with sirolimus administration is followed by an improvement in renal function, a reduction in the progression of chronic pathologic allograft lesions, and a lower incidence of new cases and severity of CAN during the first year after transplantation. This benefit may result in better long-term graft outcome

Strategy to achieve biomarker-driven immunosuppression after solid organ transplantation by an academic-industry partnership within the European BIO-DrIM consortium

Solid organ transplantation has emerged as the “gold standard” therapy for end-stage organ failure as it improves both quality of life and survival. Despite the progress in short-term graft survival, that is closely associated with the impressive reduction of acute rejections within the first year, long-term graft and patient survival remain almost un-changed and unsatisfactory. Incomplete control of chronic allograft injury but particularly the adverse effects of long-term immunosuppression, such as graft toxicity, diabetes, cardiovascular events, infections, and tumours continue to challenge the long-term success. In general, immunosuppression is applied as one-size-fits-all strategy. This can result in over- and under-immunosuppression of patients with low and high alloresponsiveness, respectively. Trial- and -error strategies to minimize or even completely wean of immunosuppression have a high failure rate. Consequently, there is an unmet medical need to develop biomarkers allowing objective risk stratification of transplant patients. To achieve this goal, we engaged in an academic-industrial partnership. The central focus of the European-wide BIO-DrIM consortium (BIOmarker-Driven IMmmunosuppression) is the implementation of biomarker-guided strategies for personalizing immunosuppression to improve the long-term outcome and to decrease the adverse effects and costs of chronic immunosuppression in solid organ transplant patients. The concept includes four innovative investigator-driven clinical trials designed by the consortium

Cross-validation of IFN-γ Elispot assay for measuring alloreactive memory/effector T cell responses in renal transplant recipients.

Assessment of donor-specific alloreactive memory/effector T cell responses using an IFN-γ Elispot assay has been suggested to be a novel immune-monitoring tool for evaluating the cellular immune risk in renal transplantation. Here, we report the cross-validation data of the IFN-γ Elispot assay performed within different European laboratories taking part of the EU RISET consortium. For this purpose, development of a standard operating procedure (SOP), comparisons of lectures of IFN-γ plates assessing intra- and interlaboratory assay variability of allogeneic or peptide stimuli in both healthy and kidney transplant individuals have been the main objectives. We show that the use of a same SOP and count-settings of the Elispot bioreader allow low coefficient variation between laboratories. Frozen and shipped samples display slightly lower detectable IFN-γ frequencies than fresh samples. Importantly, a close correlation between different laboratories is obtained when measuring high frequencies of antigen-specific primed/memory T cell alloresponses. Interestingly, significant high donor-specific alloreactive T cell responses can be similarly detected among different laboratories in kidney transplant patients displaying histological patterns of acute T cell mediated rejection. In conclusion, assessment of circulating alloreactive memory/effector T cells using an INF-γ Elispot assay can be accurately achieved using the same SOP, Elispot bioreader and experienced technicians in kidney transplantation

Long-Term Outcomes in Belatacept-Treated vs. Cyclosporine-Treated Recipients of Extended Criteria Donor Kidneys: Final Results from BENEFIT-EXT, a Phase III Randomized Study

In BENEFIT-EXT (NCT00114777), extended criteria donor kidney recipients were randomized to receive belatacept-based (more intense [MI] or less intense [LI]) or cyclosporine-based immunosuppression. In prior analyses, belatacept was associated with significantly better renal function versus cyclosporine. In this prospective analysis of the intent-to-treat population, efficacy and safety were compared across regimens at 7 years posttransplant. Overall, 128/184 belatacept MI-treated, 138/175 belatacept LI-treated, and 108/184 cyclosporine-treated patients contributed data to these analyses. Hazard ratios comparing time to death/graft loss were 0.915 (95% CI: 0.625, 1.339; P=0.65) for belatacept MI versus cyclosporine and 0.927 (95% CI: 0.634, 1.356; P=0.70) for belatacept LI versus cyclosporine. Estimated mean GFR±standard error at 7 years was 53.9±1.9, 54.2±1.9, and 35.3±2.0 mL/min/1.73 m(2) for belatacept MI, belatacept LI, and cyclosporine, respectively (P<0.001 for overall treatment effect). Hazard ratios comparing freedom from death, graft loss, or estimated GFR <20 mL/min/1.73 m(2) were 0.754 (95% CI: 0.536, 1.061; P=0.10) for belatacept MI versus cyclosporine and 0.706 (95% CI: 0.499, 0.998; P=0.05) for belatacept LI versus cyclosporine. Acute rejection rates and the safety profiles of belatacept-based and cyclosporine-based treatment were similar. De novo donor-specific antibody incidence was lower for belatacept (P≤0.0001). Relative to cyclosporine, belatacept was associated with similar death/graft loss and improved renal function at 7 years posttransplant, with a safety profile consistent with previous reports. This article is protected by copyright. All rights reserved.status: publishe

Gorgonian and black coral assemblages in deep coastal bottoms and continental shelves of the Mediterranean Sea

Coral gardens are increasingly being reported at 40\u2013200 m depth in the Mediterranean Sea. These coral assemblages are composed of gorgonians from shallow coastal rocky bottoms extending their distribution to deeper areas, as well as by gorgonians and black corals with distribution restricted to the continental shelf and upper slope. Gorgonians and black corals are among the main structural species in deep benthic ecosystems, providing shelter and reproductive grounds for a highly diverse associated fauna. Due to their branching morphology and erect position, these deep coral gardens are extremely vulnerable to several fishing activities (bottom trawling, long-lines and trammel net fishing) and should consequently be protected through an ecosystem-based fishery management

Animal Forests in Deep Coastal Bottoms and Continental Shelves of the Mediterranean Sea.

Several studies using Remotely Operated Vehicles and manned submersibles have recently provided quantitative information on animal forests dominated by gorgonians, black corals, and sponges dwelling at 40\u2013200 m depth in the Mediterranean Sea. These assemblages have received relatively little attention during the last decades due to the fact that they are found below scuba diving depths, and most submersible-based research has been traditionally conducted below 200 m depth. However, these communities are among the most threatened by the impact of fishing pressure, since the larger proportion of fishing activities, especially bottom trawling on soft bottoms and passive gears on hard grounds, concentrate between 50 and 200 m depth. This chapter reviews the recent advances in the study of the spatial and bathymetric distribution patterns of these animal forests, their species composition, ecology, and conservation status