Effects of anti-adhesive therapy on kidney biomarkers of ischemia reperfusion injury in human deceased donor kidney allografts
ABSTRACT Molecular biomarkers validated previously in animal models are increasingly being studied in conjunction with traditional clinical endpoints in therapeutic trials.
We hypothesized that human kidneys would exhibit a brisk, gene-specific inflammatory response during ischemia reperfusion injury (IRI), which would be modified by anti-adhesive therapy. Forty deceased-donor kidneys were biopsied prior to implantation and ∼1 h after reperfusion during an intervention trial with the selectin antagonist YSPSL (recombinant P-selectin glycoprotein ligand Ig). Ten inflammatory genes were measured by RT-PCR and normalized to three housekeeping genes.
Pre-implantation kidney biopsies were already significantly inflamed relative to healthy tissue, with transcripts encoding IL-6, IL-8, and CD25 > 10-fold elevated. After reperfusion, IL-6 and IL-8 increased additional 60- and 120-fold (p < 0.05), while already elevated CD25-levels remained stable. Furthermore, transcripts encoding MCP-1, E-selectin, and TNFα were also induced significantly upon reperfusion (p < 0.0005). Systemic treatment of the recipient with YSPSL pre-reperfusion, with or without pre-implantation YSPSL flush of the donor organ, attenuated the post-reperfusion increase in MCP-1 and TGFβ (p < 0.05), E-selectin and hemoxygenase 1 transcripts (p < 0.1).
Our data in humans demonstrate a robust increase in inflammatory gene transcript levels during kidney transplantation IRI and reduction thereof by inhibition of leukocyte adhesion.
- SourceAvailable from: David D Roberts[Show abstract] [Hide abstract]
ABSTRACT: CD47 is a widely expressed cell surface receptor that serves as a counter-receptor for signal regulatory protein-α and as a receptor for the secreted matricellular protein thrombospondin-1. Thrombospondin-1 signaling through CD47 regulates cellular signaling pathways that control cell survival, growth, motility, mitochondrial biogenesis, arterial vasoactive responses to physiologic vasodilators and blood flow, and responsiveness to growth factors. Studies employing mice lacking either thrombospondin-1 or CD47 have revealed an important role for this receptor-ligand interaction in tissue responses to injury and stress. These null mice show enhanced recovery from soft tissue fixed ischemic injuries, ischemia reperfusion injuries, and radiation injuries. These studies have led to development of antisense strategies to locally or globally suppress CD47 gene expression. A translation-blocking CD47 morpholino improves tissue survival in skin flap and hindlimb fixed ischemia models, full thickness skin grafts, and a liver ischemia/reperfusion model of organ transplantation in mice. Furthermore, the benefits of morpholino treatment extend to aged mice and mice with dysregulated fat metabolism that characteristically exhibit impaired recovery from ischemic injuries. Activity of the morpholino was also demonstrated for treatment of ischemic injury in miniature pigs. Treatment with the CD47 morpholino protects mice from major effects of ionizing radiation including alopecia, deterioration of muscle function, soft tissue and cutaneous fibrosis, and loss of hematopoietic stem cells in bone marrow. Remarkably, the same treatment does not protect tumors but instead enhances their ablation by irradiation. We discuss prospects for further development of CD47 antisense therapeutics for clinical applications including reconstructive surgery, organ transplantation, angioplasty, and cancer.10/2011; 2(2).
- [Show abstract] [Hide abstract]
ABSTRACT: Optimizing kidney preservation is a primary issue in transplantation, particularly in relation to new donor sources, such as expanded criteria donors (ECDs) and donation after cardiac death (DCD). Kidneys from these donors are highly sensitive to ischemia-reperfusion injuries--the emblematic lesions encountered during transplantation. Despite years of research, static cold storage, with solutions designed in the 1980s, remains the gold standard in kidney transplantation. This kind of preservation, however, is unable to fully protect an ECD or DCD kidney, highlighting the need for novel strategies to improve kidney preservation or promote kidney recovery. This Review provides an overview of the emerging strategies to prevent ischemia-reperfusion injuries in donor kidneys and describes strategies that are aimed at the donor, organ or recipient to improve graft outcome. These approaches include management of donors, preconditioning of the kidney, improvements in organ preservation solutions, postconditioning and regenerative therapies of the kidney graft following transplantation. In addition, machine perfusion provides an interesting opportunity to evaluate kidney graft quality before transplantation. Overall, a combination of therapeutic approaches seem to provide the best outcome, but preclinical studies using relevant models are needed before these approaches can be incorporated into clinical practice.Nature Reviews Nephrology 05/2012; 8(6):339-47. DOI:10.1038/nrneph.2012.83 · 8.37 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: PURPOSE OF REVIEW: Pancreas transplantation is still hampered by a high incidence of early graft loss, and organ quality concerns result in high nonrecovery/discard rates. Demographic donor characteristics, surgical retrieval strategy, preservation fluid and ischemia time are crucial factors in the process of organ selection and are discussed in this review. RECENT FINDINGS: The donor shortage is driving an increasing utilization of nonideal organs which would previously have been identified as unsuitable. Recent literature suggests that organs from extended criteria donors - older (>45 years), BMI >30 kg/m, and donation after cardiac death (DCD) - can achieve the same graft and patient survival as those from standard criteria donors, with the proviso that the accumulation of risk factors and long ischemic times should be avoided. Visual assessment of the pancreas is advisable before declining/accepting a pancreas. University of Wisconsin represents the gold standard solution; however, histidine-tryptophan-ketoglutarate and Celsior result in equal outcomes if cold ischemia time (CIT) is less than 12 h. Currently in pancreas transplantation, there is no proven effective ischemia/reperfusion injury prophylaxis than trying to keep CIT as short as possible. SUMMARY: Demographic risk factors, inspection of the pancreas by an experienced surgeon and predicted CIT are crucial factors in deciding whether to accept a pancreas for transplantation. However, there is a need for an improved evidence base to determine where to set the 'cut-off' for unsuitable pancreatic grafts.Current opinion in organ transplantation 12/2012; 18(1). DOI:10.1097/MOT.0b013e32835c29ef · 2.38 Impact Factor