Summary of FDA Workshop on Ischemia Reperfusion Injury in Kidney Transplantation

Abstract

The Food and Drug Administration (FDA) held an open public workshop in September 2011 to discuss the current state of science related to the effects of ischemia reperfusion injury (IRI) on outcomes in kidney transplantation. Topics included the development of IRI and delayed graft function (DGF), histology and biomarkers, donor factors, recipient factors, organ quality and organ preservation by means of cold storage solutions or machine perfusion. Various mechanisms of injury and maladaptive response to IRI were discussed as potential targets of intervention. Animal models evaluating specific pathophysiological pathways were presented, as were the limitations of extrapolating animal results to humans. Clinical trials of various drug products administered in the peritransplant period were summarized; a few demonstrated early improvements in DGF, but none demonstrated an improvement in late graft function. Clinical trial design for IRI and DGF were also discussed.

Defective postreperfusion metabolic recovery directly associates with incident delayed graft function

“…A range of pharmaceutical interventions that target I/R such as antioxidants and anti-inflammatory and immune-modulatory drugs successfully quench I/R injury in preclinical models, but efforts to translate these experimental findings to the human situation have been unsuccessful. 5,7 Therefore, there is currently no intervention that alleviates DGF and other forms of clinical I/R injury, a notion that points to an impaired translatability of preclinical findings. 5 Although DGF is common in deceased donor grafts, it is rare in the context of living donor kidney transplantation.…”

“…5,7 Therefore, there is currently no intervention that alleviates DGF and other forms of clinical I/R injury, a notion that points to an impaired translatability of preclinical findings. 5 Although DGF is common in deceased donor grafts, it is rare in the context of living donor kidney transplantation. This is a notable observation, because these grafts are also exposed to several hours of ischemia prior to reperfusion.…”

The diverging roles of dendritic cells in kidney allotransplantation

“…Among them, caspases can mediate apoptosis in a significant number of sub-lethally injured cells. In addition to endothelial cells, proximal tubular epithelial cells are particularly vulnerable to the toxic effects of reperfusion and tend to undergo more necrosis in comparison with the less sensitive segments, because they have higher metabolic demands [35,36]. The dying cells release in the extra-cellular space endogenous molecules that are recognized as DAMPs from the pattern recognition receptors of the innate immunity.…”

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“…1 After renal artery anastomosis, blood flow in the transplanted kidney is associated with tissue damage called reperfusion injury. 2 Reperfusion injury includes release of inflammatory cytokines, accumulation of leukocytes, and expression of adhesion molecules on endothelial cells, which consequently predispose the recipient with acute rejection. Hypoxia-induced endothelial swelling decreases the capillary diameter and deteriorates the reperfusion injury, even when the main vessel circulation is restored.…”

“…3 There are some other factors like anemia and acidosis that may exacerbate reperfusion injury. 2 Although reperfusion injury in kidney transplant is quite well defined, no indicators are presently known for this injury. In this study, we investigated whether transplanted kidney vein blood oxygenation after anastomosis can be an indicator for reperfusion injury and a predictor of postoperative renal failure.…”