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      Testing Danegaptide Effects on Kidney Function after Ischemia/Reperfusion Injury in a New Porcine Two Week Model

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          Abstract

          Introduction

          Ischemia/reperfusion injury (I/R-I) is a leading cause of acute kidney injury (AKI) and is associated with increased mortality. Danegaptide is a selective modifier of the gap junction protein connexion 43. It has cytoprotective as well as anti-arrhythmic properties and has been shown to reduce the size of myocardial infarct in pigs. The aim of this study was to investigate the ischemia-protective effect of Danegaptide in a porcine renal I/R-I model with two weeks follow up.

          Methods

          Unilateral renal I/R-I was induced in pigs by clamping the left renal artery over a two hour period. The model allowed examination of renal blood flow by magnetic resonance imaging (MRI) and the measurement of single kidney GFR two weeks after injury. Eleven animals were randomized to Danegaptide-infusion while nine animals received placebo. Kidney histology and urinary neutrophil gelatinase-associated lipocalin (NGAL) excretion were included as markers of AKI.

          Results

          Unilateral kidney I/R-I resulted in an immediate ~50% GFR reduction, associated with a four-fold increase in urinary NGAL-excretion. Fourteen days after I/R-I, the total GFR was ~75% of baseline with a significantly lower GFR in the injured left kidney compared to the right kidney. No differences in GFR were observed between the treated and non-treated animals immediately after I/R-I or at Day 14. Furthermore, no differences were observed in the urinary excretion of NGAL, renal blood flow or other markers of renal function.

          Conclusions

          As expected this porcine renal I/R-I model was associated with reduced GFR two weeks after injury. Danegaptide did not improve renal function after I/R-I.

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          Most cited references27

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          Delayed graft function in kidney transplantation.

          Delayed graft function is a form of acute renal failure resulting in post-transplantation oliguria, increased allograft immunogenicity and risk of acute rejection episodes, and decreased long-term survival. Factors related to the donor and prerenal, renal, or postrenal transplant factors related to the recipient can contribute to this condition. From experimental studies, we have learnt that both ischaemia and reinstitution of blood flow in ischaemically damaged kidneys after hypothermic preservation activate a complex sequence of events that sustain renal injury and play a pivotal part in the development of delayed graft function. Elucidation of the pathophysiology of renal ischaemia and reperfusion injury has contributed to the development of strategies to decrease the rate of delayed graft function, focusing on donor management, organ procurement and preservation techniques, recipient fluid management, and pharmacological agents (vasodilators, antioxidants, anti-inflammatory agents). Several new drugs show promise in animal studies in preventing or ameliorating ischaemia-reperfusion injury and possibly delayed graft function, but definitive clinical trials are lacking. The goal of monotherapy for the prevention or treatment of is perhaps unattainable, and multidrug approaches or single drug targeting multiple signals will be the next step to reduce post-transplantation injury and delayed graft function.
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            Tolerance of the human kidney to isolated controlled ischemia.

            Tolerance of the human kidney to ischemia is controversial. Here, we prospectively studied the renal response to clamp ischemia and reperfusion in humans, including changes in putative biomarkers of AKI. We performed renal biopsies before, during, and after surgically induced renal clamp ischemia in 40 patients undergoing partial nephrectomy. Ischemia duration was >30 minutes in 82.5% of patients. There was a mild, transient increase in serum creatinine, but serum cystatin C remained stable. Renal functional changes did not correlate with ischemia duration. Renal structural changes were much less severe than observed in animal models that used similar durations of ischemia. Other biomarkers were only mildly elevated and did not correlate with renal function or ischemia duration. In summary, these data suggest that human kidneys can safely tolerate 30-60 minutes of controlled clamp ischemia with only mild structural changes and no acute functional loss.
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              Impairment of diazoxide-induced formation of reactive oxygen species and loss of cardioprotection in connexin 43 deficient mice.

              Protection by ischemic preconditioning is lost in cardiomyocytes and hearts of heterozygous connexin 43 deficient (Cx43+/-) mice. Because connexin 43 (Cx43) is localized in cardiomyocyte mitochondria and mitochondrial Cx43 content is increased with ischemic preconditioning, we now tried to identify a functional defect at the level of the mitochondria in Cx43+/- mice by use of diazoxide and menadione. Diazoxide stimulates the mitochondrial formation of reactive oxygen species (ROS) and menadione generates superoxide at multiple intracellular sites; both substances elicit cardioprotection through increased ROS formation. ROS formation in response to the potassium ionophore valinomycin was also measured for comparison. Menadione (2 micromol/L) and valinomycin (10 nmol/L) induced similar ROS formation in wild-type (WT) and Cx43+/- cardiomyocytes. In contrast, diazoxide (200 micromol/L) increased ROS formation by 43+/-10% versus vehicle in WT, but only by 18+/-4% in Cx43+/- cardiomyoctes (P<0.05). Two hour-simulated ischemia and oxygenated, hypo-osmolar reperfusion reduced viability as compared with normoxia (WT: 7+/-1% versus 39+/-2%, (Cx43+/-): 8+/-1% versus 40+/-3%, P<0.01). Although menadione protected WT and Cx43+/- cardiomyocytes, diazoxide increased viability (17+/-2%, P<0.01) in WT, but not in Cx43+/- (9+/-1%). Menadione (37 microg/kg i.v.) before 30 minutes coronary occlusion and 2 hour reperfusion reduced infarct size in WT and Cx43+/- mice (24+/-4% versus 24+/-5%). In contrast, diazoxide (5 mg/kg i.v.) reduced infarct size in WT (35+/-4% versus 55+/-3% of area at risk, P<0.01), but not in Cx43+/- mice (56+/-2% versus 54+/-3%). Cardiomyocytes of Cx43+/- mice have a specific functional deficit in ROS formation in response to diazoxide and accordingly less protection.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                19 October 2016
                2016
                : 11
                : 10
                : e0164109
                Affiliations
                [1 ]Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark
                [2 ]Department of Renal Medicine. Aarhus University Hospital, Aarhus, Denmark
                [3 ]Department of Urology, Aarhus University Hospital, Aarhus, Denmark
                [4 ]Zealand Pharma A/S, Glostrup, Denmark
                [5 ]Department of Pathology, Aarhus University Hospital, Aarhus, Denmark
                [6 ]Comparative Medicines Lab, Aarhus University, Aarhus, Denmark
                [7 ]Department of Biomedicine, Aarhus University, Aarhus, Denmark
                University of Sao Paulo Medical School, BRAZIL
                Author notes

                Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Rie Schultz Hansen is an employee of Zealand Pharma. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

                • Conceptualization: CA AKK RSH RN UM MP BJ HB.

                • Formal analysis: CA AKK HB.

                • Funding acquisition: BJ RSH.

                • Investigation: CA UM AKK.

                • Methodology: CA AKK RSH RN SPK UM MP BJ HB.

                • Project administration: CA.

                • Supervision: BJ AKK HB.

                • Validation: RSH RN BJ HB.

                • Writing – original draft: CA.

                • Writing – review & editing: CA AKK RSH RN UM MP BJ HB.

                Author information
                http://orcid.org/0000-0003-3262-8524
                Article
                PONE-D-16-15862
                10.1371/journal.pone.0164109
                5070773
                27760220
                81dc8134-bf67-4e74-8d14-cb9d9b738c2e
                © 2016 Amdisen et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 19 April 2016
                : 20 September 2016
                Page count
                Figures: 6, Tables: 2, Pages: 13
                Funding
                Funded by: Zealand Pharma A/S
                Award Recipient :
                Zealand Pharma A/S, Glostrup Denmark funded the study. They participated in the study design (dose of Danegaptide) and preparation of the manuscript. They had no role in the data collection, analysis or decision to publish.
                Categories
                Research Article
                Biology and Life Sciences
                Anatomy
                Renal System
                Kidneys
                Medicine and Health Sciences
                Anatomy
                Renal System
                Kidneys
                Biology and Life Sciences
                Physiology
                Renal Physiology
                Glomerular Filtration Rate
                Medicine and Health Sciences
                Physiology
                Renal Physiology
                Glomerular Filtration Rate
                Medicine and Health Sciences
                Critical Care and Emergency Medicine
                Reperfusion
                Medicine and Health Sciences
                Vascular Medicine
                Ischemia
                Renal Ischemia
                Medicine and Health Sciences
                Vascular Medicine
                Ischemia
                Biology and Life Sciences
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