Ischaemia-reperfusion injury (IRI) is afrequent event in kidney transplantation, particularly when the kidney comes from a deceased donor. The brain death is usually associated with generalized ischaemia due to a hyperactivity of the sympathetic system. In spite of this, most donors have profound hypotension and require administration of vasoconstrictor agents. Warm ischaemia after kidney vessels clamping and the cold ischaemia after refrigeration also reduce oxygen and nutrients supply to tissues. The reperfusion further aggravates the state of oxidation and inflammation created by ischaemia. IRI first attacks endothelial cells and tubular epithelial cells. The lesions may be so severe that they lead to acute kidney injury (AKI) and delayed graft function (DGF), which can impair the graft survival. The unfavourable impact of DGF is worse when DGF is associated with acute rejection. Another consequence of IRI is the activation of the innate immunity. Danger signals released by dying cells alarm Toll-like receptors that, through adapter molecules and a chain of kinases, transmit the signal to transcription factors which encode the genes regulating inflammatory cells and mediators. In the inflammatory environment, dendritic cells (DCs) intercept the antigen, migrate to lymph nodes and present the antigen to immunocompetent cells, so activating the adaptive immunity and favouring rejection. Attempts to prevent IRI include optimal management of donor and recipient. Calcium-channel blockers, L-arginine and N-acetylcysteine could obtain a small reduction in the incidence of post-transplant DGF. Fenoldopam, Atrial Natriuretic Peptide, Brain Natriuretic Peptide and Dopamine proved to be helpful in reducing the risk of AKI in experimental models, but there is no controlled evidence that these agents may be of benefit in preventing DGF in kidney transplant recipients. Other antioxidants have been successfully used in experimental models of AKI but only a few studies of poor quality have been made in clinical transplantation with a few of these agents and we still lack of unambiguous demonstration that pre-treatment with these antioxidants can attenuate the impact of IRI in kidney transplantation. Interference with the signals leading to activation of innate immunity, inactivation of complement or manipulation of DCs is a promising therapeutic option for the near future.Keywords: acute kidney injury, delayed graft function, dendritic cells, innate immunity, ischaemia reperfusion

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Ischaemia-reperfusion injury: a major protagonist in kidney transplantation

Purpose of reviewDelayed graft function (DGF) has several long-term graft implications in the field of kidney transplantation and remains a challenge. The incidence of DGF is on the rise because of an increasing use of marginal kidneys in an era of organ shortage. Risk factors for DGF are numerous a

Delayed graft function in kidney transplantation.

AKI is a complex clinical condition associated with high mortality, morbidity, and health care costs. Despite improvements in methodology and design of clinical trials, and advances in understanding the underlying pathophysiology of rodent AKI, no pharmacologic agent exists for the prevention or treatment of AKI in humans. To address the barriers that affect successful clinical translation of drug targets identified and validated in preclinical animal models of AKI in this patient population, the National Institute of Diabetes and Digestive and Kidney Diseases convened the “AKI Outcomes: Overcoming Barriers in AKI” workshop on February 10–12, 2015. The workshop used a reverse translational medicine approach to identify steps necessary to achieve clinical success. During the workshop, breakout groups were charged first to design feasible, phase 2, proof-of-concept clinical trials for delayed transplant graft function, prevention of AKI (primary prevention), and treatment of AKI (secondary prevention and recovery). Breakout groups then were responsible for identification of preclinical animal models that would replicate the pathophysiology of the phase 2 proof-of-concept patient population, including primary and secondary end points. Breakout groups identified considerable gaps in knowledge regarding human AKI, our understanding of the pathophysiology of AKI in preclinical animal models, and the fidelity of cellular and molecular targets that have been evaluated preclinically to provide information regarding human AKI of various etiologies. The workshop concluded with attendees defining a new path forward to a better understanding of the etiology, pathology, and pathophysiology of human AKI.

Overcoming Translational Barriers in Acute Kidney Injury: A Report from an NIDDK Workshop.

Ischemia-reperfusion injury to the kidney is a complex pathophysiological process that has importance during transplantation as it affects graft function and survival. It starts with the physiological changes associated with the death of the donor, including the direct effects of hypoxia and metabolic stress. The injury continues through the organ procurement and preservation procedures. Upon reperfusion, the organ is then further damaged by a reactive inflammatory process which had been primed during the earlier injuries. Clinically, the damage from microvascular dysfunction and cytotoxic agents contributed by the immunologic response results in impaired graft function or graft loss. Recent advances in understanding the specific pathways involved in this injury have helped identify novel therapies. Nevertheless, ischemia-reperfusion injury continues to be a daunting problem even as these treatment strategies are being evaluated for clinical use.

Ischemia-reperfusion injury in kidney transplantation

Emerging biomarkers of delayed graft function in kidney transplantation

Background The traditional definition of delayed graft function (DGF) rests on dialysis requirement during the first postoperative week. Subsequently, a more objective and "functional" definition of DGF (fDGF) has been proposed as an alternative to this dialysis-based definition of DGF (dDGF) and defined as a failure of the serum creatinine to decrease by at least 10% daily on 3 successive days during the first week posttransplantation, irrespective of dialysis requirement. However, an association between fDGF and long-term graft failure has not been fully established, and it is unknown whether fDGF is a better marker of subsequent outcomes than dDGF. Methods We studied 750 adult deceased donor kidney transplant recipients (1996-2006) and analyzed the association between these two DGF definitions and long-term graft outcome. Results Univariable associations with death-censored graft failure were seen for both dDGF and fDGF (hazard ratio [HR] 1.59; 95% confidence interval [CI] 1.16-2.18; P=0.004 and HR 1.72; 95% CI 1.26-2.36; P=0.001, respectively). On bivariable analysis (dDGF vs. fDGF), dDGF lost significance, whereas the effect of fDGF persisted (HR 1.52; 95%CI 1.03-2.25; P=0.04). This was also the case in a multivariable model, where fDGF but not dDGF was significantly associated with graft failure (HR 1.47; 95%CI 1.06-2.03; P=0.02). Results were similar for overall graft failure. Conclusions This study confirms the utility of fDGF as an early marker of subsequent inferior allograft outcomes, suggesting superiority over the traditional (often subjective) dialysis-based definition. Wider adoption of the fDGF definition should be considered, both as a risk-stratification tool in clinical practice and a clinical trial endpoint.

Assessing and Comparing Rival Definitions of Delayed Renal Allograft Function for Predicting Subsequent Graft Failure

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Assessing and Comparing Rival Definitions of Delayed Renal Allograft Function for Predicting Subsequent Graft Failure