Edward Sharples

Erythropoietin Protects the Kidney against the Injury and Dysfunction Caused by Ischemia-Reperfusion

Erythropoietin (EPO) is upregulated by hypoxia and causes proliferation and differentiation of erythroid progenitors in the bone marrow through inhibition of apoptosis. EPO receptors are expressed in many tissues, including the kidney. Here it is shown that a single systemic administration of EPO either preischemia or just before reperfusion prevents ischemia-reperfusion injury in the rat kidney. Specifically, EPO (300 U/kg) reduced glomerular dysfunction and tubular injury (biochemical and histologic assessment) and prevented caspase-3, -8, and -9 activation in vivo and reduced apoptotic cell death. In human (HK-2) proximal tubule epithelial cells, EPO attenuated cell death in response to oxidative stress and serum starvation. EPO reduced DNA fragmentation and prevented caspase-3 activation, with upregulation of Bcl-X(L) and XIAP. The antiapoptotic effects of EPO were dependent on JAK2 signaling and the phosphorylation of Akt by phosphatidylinositol 3-kinase. These findings may have major implications in the treatment of acute renal tubular damage.

Erythropoietin attenuates the tissue injury associated with hemorrhagic shock and myocardial ischemia.

Here we investigate the effects of erythropoietin (EPO) on the tissue/organ injury caused by hemorrhagic shock (HS), endotoxic shock, and regional myocardial ischemia and reperfusion in anesthetized rats. Male Wistar rats were anesthetized with thiopental sodium (85 mg/kg i.p.) and subjected to hemorrhagic shock (HS; i.e., mean arterial blood pressure reduced to 45 mmHg for 90 min, followed by resuscitation with shed blood for 4 h), endotoxemia (for 6 h), or left anterior descending coronary artery occlusion (25 min) and reperfusion (2 h). HS and endotoxemia resulted in renal dysfunction and liver injury. Administration of EPO (300 IU/kg i.v., n = 10) before resuscitation abolished the renal dysfunction and liver injury in hemorrhagic, but not endotoxic, shock. HS also resulted in significant increases in the kidney of the activities of caspases 3, 8, and 9. This increase in caspase activity was not seen in HS rats treated with EPO. In cultured human proximal tubule cells, EPO concentration-dependently reduced the cell death and increase in caspase-3 activity caused by either ATP depletion (simulated ischemia) or hydrogen peroxide (oxidative stress). In the heart, administration of EPO (300 IU/kg i.v., n = 10) before reperfusion also caused a significant reduction in infarct size. In cultured rat cardiac myoblasts (H9C2 cells), EPO also reduced the increase in DNA fragmentation caused by either serum deprivation (simulated ischemia) or hydrogen peroxide (oxidative stress). We propose that the acute administration of EPO on reperfusion and/or resuscitation will reduce the tissue injury caused by ischemia-reperfusion of the heart (and other organs) and hemorrhagic shock.

Recombinant human erythropoietin protects the liver from hepatic ischemia-reperfusion injury in the rat

Recently, erythropoietin was shown to have both hematopoietic as well as tissue‐protective properties. Erythropoietin (EPO) had a protective effect in animal models of cerebral ischemia, mechanical trauma of the nervous system, myocardial infarction, and ischemia‐reperfusion (I/R) injury of the kidney. It is not known whether EPO protects the liver against I/R injury. Using a rat model of liver I/R injury, we aimed to determine the effect of the administration of human recombinant erythropoietin (rhEPO) on liver injury. Rats were subjected to 30 min of liver ischemia followed by 2 h of reperfusion. When compared with the sham‐operated rats, I/R resulted in significant rises in the serum levels of aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, gamma‐glutamyl transferase, tissue lipid peroxidation, caspase‐3 activity and altered histology. Administration of rhEPO 5 min before ischemia was able to reduce the biochemical evidence of liver injury; however, this protection was not evident when rhEPO was administered 5 min before reperfusion. Mechanistically, early administration of rhEPO was able to reduce the oxidative stress and caspase‐3 activation, suggesting the subsequent reduction of apoptosis. This study provides the first evidence that rhEPO causes a substantial reduction of the liver injury induced by I/R in the rat.

Mechanisms of Disease: cell death in acute renal failure and emerging evidence for a protective role of erythropoietin

Acute renal failure—characterized by a sudden loss of the ability of the kidneys to excrete nitrogenous waste, and to maintain electrolyte homeostasis and fluid balance—is a frequently encountered clinical problem, particularly in the intensive care unit. Unfortunately, advances in supportive interventions have done little to reduce the high mortality associated with this condition. Might erythropoietin (EPO) have utility as a therapeutic agent in acute renal failure? This hormone mediates anti-apoptotic effects in the bone marrow, facilitating maturation and differentiation of erythroid progenitors. New evidence indicates that EPO also exerts anti-apoptotic effects in the brain, heart and vasculature, which can limit the degree of organ damage. Here, we review the emerging biological role of EPO in the kidney and the pathophysiology of ischemia–reperfusion injury in an attempt to understand the therapeutic potential of EPO in acute renal failure.

Summary of the 5th Edition of the Renal Association Clinical Practice Guidelines (2009-2012)

Robert Mactier, Simon Davies, Chris Dudley, Paul Harden, Colin Jones, Suren Kanagasundaram, Andrew Lewington, Donald Richardson, Maarten Taal, Peter Andrews Richard Baker, Cormac Breen, Neill Duncan, Ken Farrington, Richard Fluck, Colin Geddes, David Goldsmith, Nic Hoenich, Stephen Holt, Alan Jardine, Sarah Jenkins, Mick Kumwenda, Elizabeth Lindley, Mark MacGregor, Ashraf Mikhail, Edward Sharples, Badi Shrestha, Rajesh Shrivastava, Simon Steddon, Graham Warwick, Martin Wilkie, Graham Woodrow, Mark Wright

UK Renal Registry 19th Annual Report: Appendix I Acronyms and Abbreviations used in the Annual Report

AAB Academic Affairs Board (Renal Association) ACE (inhibitor) Angiotensin converting enzyme (inhibitor) AKI Acute kidney injury ANZDATA Australia and New Zealand Dialysis and Transplant Registry APD Automated peritoneal dialysis ADPKD Autosomal dominant polycystic kidney disease APKD Adult polycystic kidney disease ATTOM Access to transplant and transplant outcome measures ATTOMic Access to transplant and transplant outcome measures in children AV Arteriovenous AVF Arteriovenous fistula AVG Arteriovenous graft BAPN British Association of Paediatric Nephrology BCG Bromocresol green BCP Bromocresol purple Bicarb Bicarbonate BMD Bone mineral disease BMI Body mass index BP Blood pressure BSI Blood stream infection BTS British Transplant Society Ca Calcium CAB Clinical Affairs Board (Renal Association) CABG Coronary artery bypass grafting CAPD Continuous ambulatory peritoneal dialysis CCG Clinical Commissioning Group CCL Clinical Computing Limited CCPD Cycling peritoneal dialysis CDI Clostridium difficile infection Chol Cholesterol CHr Target reticulocyte Hb content CI Confidence interval CICR Cumulative incidence competing risk CIF Cumulative incidence function CK Creatine kinase CKD Chronic kidney disease CKD-EPI Chronic kidney disease epidemiology collaboration CK-MB Creatine kinase isoenzyme MB CKD-MBD Chronic kidney diseasemineral bone disorder COPD Chronic obstructive pulmonary disease