Advances in Hypothermic and Normothermic Perfusion in Kidney Transplantation

Hypothermic and normothermic machine perfusion in kidney transplantation are purported to exert a beneficial effect on post-transplant outcomes compared to the traditionally used method of static cold storage. Kidney perfusion techniques provide a window for organ reconditioning and quality assessment. However, how best to deliver these preservation methods or improve organ quality has not yet been conclusively defined. This review summarises the promising advances in machine perfusion science in recent years, which have the potential to further improve early graft function and prolong graft survival.

Adipose-derived cellular therapies prolong graft survival in an allogenic hind limb transplantation model

Background The long-term survival after vascularized composite allotransplantation (VCA) is often limited by systemic rejection as well as the adverse effects of immunosuppressants. The stromal vascular fraction (SVF) can be expanded to produce adipose-derived stem cells (ADSC) which represents a combination of endothelial cells, preadipocytes, immune cells, and ADSC. It has been demonstrated that ADSC possess consistently reliable clinical results. However, literature is scarce regarding SVF in VCA. This study seeks to determine the impact of ex vivo allograft pretreatment in combination with SVF cells in the ability to promote composite tissue allotransplantation immunotolerance. Methods A rat hind limb allotransplant model was used to investigate the influence of ex vivo pretreatment of SVF and ADSC on VCA survival. Intravascular cell-free saline, ADSC, or SVF was infused into the models with immunosuppressants. The histopathological examination and duration that the allografts went without displaying symptoms of rejection was documented. Peripheral T lymphocytes and Tregs were quantified with flow cytometry while allotissue expressions of CD31 were quantified with immunohistochemical staining (IHC). ELISA was used to detect vascular endothelial growth factor (VEGF)-A as well as anti- and pro-inflammatory cytokines. Results We demonstrated that ex vivo treatment of allografts with SVF or ADSC prolonged allograft survival in contrast to medium control cohorts. There were also enhanced levels of immunomodulatory cytokines and increased VEGF-A and CD31 expression as well as reduced infiltration and proliferation of T lymphocytes along with raised Treg expressions. Conclusion These studies demonstrated that adipose-derived cellular therapies prolong graft survival in an allogenic hind limb transplantation model and have the potential to establish immunotolerance.

Renal allograft nephropathy in patient with type 1 diabetes mellitus

Renal allotransplantation is the most effective and safest mode of renal replacement therapy in patients with diabetes mellitus (DM),and currently is recognized as method of choice for patients with end-stage renal disease. Due to variety of factors damaging transplantedkidney in patients with DM, issues of long-term survival of the graft constitute a serious problem. Therefore, special attentionshould be directed at correction of rejection risk factors in order to prolong graft survival - and prevent development and progressionof chronic allograft nephropathy.

Abstract 1128: The Leukocyte Integrin Mac-1 Promotes Acute Cardiac Allograft Rejection

Background: In allograft rejection, donor endothelial cells (EC) are the principal early targets of host leukocytes and alloantibodies. Although the leukocyte integrin Mac-1(αmβ2, CD11b/ CD18) facilitates leukocyte-leukocyte as well as leukocyte-EC interactions, its roles in allograft survival and vasculopathy remains unclear. This study used murine cardiac transplantation to test the hypothesis that Mac-1 deficiency in the recipient reduces accumulation of graft infiltrating cells and attenuates cardiac allograft rejection. Results: In total-allomismatched murine cardiac allografts (BALB/c donor hearts and C57BL/6 recipients), survival averaged 13.8 ± 2.3 days (n=6) for allografts in Mac-1-deficient (Mac-1−/−) recipients compared to 8.3 ± 1.3 days (n = 18, p<0.0001) in wild-type (WT) recipients. At 7 d post-transplantation, allografts in Mac-1−/− recipients had significantly lower parenchymal rejection (PR) scores (2.3 ± 0.4) than WT recipients (3.0 ± 0.4, p<0.01). Allograft accumulation of neutrophils, T cells, and macrophages (Mϕ) significantly diminished in Mac-1−/− compared to WT recipients. To determine the cell type involved in acute graft dysfunction, we performed adoptive transfer experiments. Adoptive transfer of WT, but not Mac-1−/−, Mϕ exacerbated parenchymal rejection of 7-day allografts placed into Mac-1−/− recipients (PR score: 2.3 ± 0.4 for WT vs. 1.5 ± 0.5 for Mac1−/− Mϕ; p < 0.05), and significantly reduced graft survival (8.0 ± 1.4 vs. 13.5 ± 2.6 days, p<0.01). Neither WT nor Mac-1−/− neutrophil adoptive transfer affected graft survival in Mac-1−/− recipients. Mac-1−/− Mϕ co-cultured with allo-EC (BALB/c) expressed significantly lower levels of the co-stimulatory molecules CD40 and CD80, and mixed leukocyte reaction using allo-EC-primed Mac-1−/− Mϕ showed significantly lower antigen-presenting function than WT Mϕ. Despite attenuating acute rejection, recipient Mac-1-deficiency did not prevent graft arterial disease. Conclusion: These studies demonstrate that Mac-1 contributes to acute allograft rejection by modulating macrophage recruitment, antigen presentation, and T cell priming. These observations establish a molecular target for modulating recipient responses to prolong graft survival.