losartan-potassium and Acute-Kidney-Injury

Sepsis-induced acute kidney injury (SI-AKI), a common critically ill, represents one of the leading causes of global death. Emerging evidence reveals autophagy as a pivotal modulator of SI-AKI. Autophagy affects the cellular processes of renal lesions, including cell death, inflammation, and immune responses. Herein, we conducted a systematic and comprehensive review on the topic of the proposed roles of autophagy in SI-AKI. Forty-one relevant studies were finally included and further summarized and analyzed. This review revealed that a majority of included studies (24/41, 58.5%) showed an elevation of the autophagy level during SI-AKI, while 22% and 19.5% of the included studies reported an inhibition and an elevation at the early stage but a declination of renal autophagy in SI-AKI, respectively. Multiple intracellular signaling molecules and pathways targeting autophagy (e.g. mTOR, non-coding RNA, Sirtuins family, mitophagy, AMPK, ROS, NF-Kb, and Parkin) involved in the process of SI-AKI, exerting multiple biological effects on the kidney. Multiple treatment modalities (e.g. small molecule inhibitors, temsirolimus, rapamycin, polydatin, ascorbate, recombinant human erythropoietin, stem cells, Procyanidin B2, and dexmedetomidine) have been found to improve renal function, which may be attributed to the elevation of the autophagy level in SI-AKI. Though the exact roles of autophagy in SI-AKI have not been well elucidated, it may be implicated in preventing SI-AKI through various molecular pathways. Targeting the autophagy-associated proteins and pathways may hint towards a new prospective in the treatment of critically ill patients with SI-AKI, but more preclinical studies are still warranted to validate this hypothesis.

Topics: Acute Kidney Injury; Autophagy; Critical Illness; Epigenesis, Genetic; Erythropoietin; Humans; Prospective Studies; Sepsis

In addition to being a leading cause of morbidity and mortality worldwide, sepsis is also the most common cause of acute kidney injury (AKI). When sepsis leads to the development of AKI, mortality increases dramatically. Since the cardinal feature of sepsis is a dysregulated host response to infection, a disruption of kidney-immune crosstalk is likely to be contributing to worsening prognosis in sepsis with acute kidney injury. Since immune-mediated injury to the kidney could disrupt its protein manufacturing capacity, an investigation of molecules mediating this crosstalk not only helps us understand the sepsis immune response, but also suggests that their supplementation could have a therapeutic effect. Erythropoietin, vitamin D and uromodulin are known to mediate kidney-immune crosstalk and their disrupted production could impact morbidity and mortality in sepsis with acute kidney injury.

Topics: Acute Kidney Injury; Animals; Erythropoietin; Humans; Immune System; Kidney; Sepsis; Uromodulin; Vitamin D

The renoprotective effects of erythropoietin (EPO) are well-known; however, the optimal timing of EPO administration remains controversial. Red blood cell (RBC) transfusion is an independent risk factor for cardiac surgery-associated acute kidney injury (CSA-AKI). We aimed to evaluate the efficacy of EPO on CSA-AKI and RBC transfusion according to the timing of administration.. We searched the Cochrane Library, EMBASE, and MEDLINE databases for randomized controlled trials. The primary outcome was the incidence of CSA-AKI following perioperative EPO administration, and the secondary outcomes were changes in serum creatinine, S-cystatin C, S-neutrophil gelatinase-associated lipocalin, urinary neutrophil gelatinase-associated lipocalin, length of hospital and intensive care unit (ICU) stay, volume of RBC transfusion, and mortality. The subgroup analysis was stratified according to the timing of EPO administration in relation to surgery.. Eight randomized controlled trials with 610 patients were included in the study. EPO administration significantly decreased the incidence of CSA-AKI (odds ratio: 0.60, 95% confidence interval [CI]: 0.43-0.85, P = .004; I2 = 52%; P for heterogeneity = .04), intra-operative RBC transfusion (standardized mean difference: -0.30, 95% CI: -0.55 to -0.05, P = .02; I2 = 15%, P for heterogeneity = .31), and hospital length of stay (mean difference: -1.54 days, 95% CI: -2.70 to -0.39, P = .009; I2 = 75%, P for heterogeneity = .001) compared with control groups. Subgroup analyses revealed that pre-operative EPO treatment significantly reduced the incidence of CSA-AKI, intra-operative RBC transfusion, serum creatinine, and length of hospital and ICU stay.. Pre-operative administration of EPO may reduce the incidence of CSA-AKI and RBC transfusion, but not in patients administered EPO during the intra-operative or postoperative period. Therefore, pre-operative EPO treatment can be considered to improve postoperative outcomes by decreasing the length of hospital and ICU stay in patients undergoing cardiac surgery.

Topics: Acute Kidney Injury; Cardiac Surgical Procedures; Creatinine; Erythrocyte Transfusion; Erythropoietin; Humans; Lipocalin-2; Perioperative Care; Postoperative Complications; Randomized Controlled Trials as Topic

Iron is an essential element that is indispensable for life. The delicate physiological body iron balance is maintained by both systemic and cellular regulatory mechanisms. The iron-regulatory hormone hepcidin assures maintenance of adequate systemic iron levels and is regulated by circulating and stored iron levels, inflammation and erythropoiesis. The kidney has an important role in preventing iron loss from the body by means of reabsorption. Cellular iron levels are dependent on iron import, storage, utilization and export, which are mainly regulated by the iron response element-iron regulatory protein (IRE-IRP) system. In the kidney, iron transport mechanisms independent of the IRE-IRP system have been identified, suggesting additional mechanisms for iron handling in this organ. Yet, knowledge gaps on renal iron handling remain in terms of redundancy in transport mechanisms, the roles of the different tubular segments and related regulatory processes. Disturbances in cellular and systemic iron balance are recognized as causes and consequences of kidney injury. Consequently, iron metabolism has become a focus for novel therapeutic interventions for acute kidney injury and chronic kidney disease, which has fuelled interest in the molecular mechanisms of renal iron handling and renal injury, as well as the complex dynamics between systemic and local cellular iron regulation.

Topics: Acute Kidney Injury; Erythropoiesis; Erythropoietin; Homeostasis; Humans; Inflammation; Iron; Iron-Regulatory Proteins; Kidney; Kidney Tubules, Distal; Kidney Tubules, Proximal; Mitochondria; Nephrons; Oxidative Stress; Renal Insufficiency, Chronic

The renoprotection of erythropoietin (EPO) and its derivatives such as helix B surface peptide (HBSP) have attracted a great deal of attention from scientists and clinicians alike. The evolutional achievement in the dissociation of tissue protection and erythropoiesis is obtained through HBSP characterisation and synthesis. We performed a series of studies using EPO, as well as HBSP, in a variety of biological models subjected to transplant-related renal injuries such as ischemia reperfusion injury (IRI) and/or immunosuppressant nephrotoxicity. In this short review, we would like to address the effects of EPO in different formats, and its underlying mechanisms with focuses on apoptosis and inflammation in in vitro, ex vivo and in vivo renal injury models, and to further explore potential applications and challenges in humans.

Topics: Acute Kidney Injury; Animals; Anti-Inflammatory Agents; Apoptosis; Cytokine Receptor Common beta Subunit; Disease Models, Animal; Erythropoietin; Gene Expression Regulation; Humans; Kidney; Oxidative Stress; Peptide Fragments; Protective Agents; Receptors, Erythropoietin; Reperfusion Injury

The role of perioperative erythropoietin (EPO) for preventing cardiac surgery associated acute kidney injury (CSA-AKI) remains uncertain with published trials producing conflicting results. Perspective into the factors at work is needed, due to ongoing uncertainty.. We undertook the systematic review and meta-analysis of randomised-controlled trials (RCTs) using random-effects modelling. The primary outcome was safety and efficacy of perioperative EPO to prevent CSA-AKI and the secondary outcomes were change in serum creatinine, urinary neutrophil gelatinase-associated lipocalin, time in ICU, rates of postoperative transfusions, haemodialysis, and mortality. Subgroup analysis explored the effect of the timing of the EPO dose in relation to surgery, the dose response, and the impact of the preoperative risk for CSA-AKI for the patient group.. Our findings suggest that administering EPO before anaesthesia is emerging as an important factor for efficacy. Erythropoietin may have a role in preventing CSA-AKI, however, additional high-quality prospective studies are warranted, particularly aimed at describing the methodological components, such as the timing and size of the dose, which potentiate the cytoprotective effect of EPO in the clinical setting.

Topics: Acute Kidney Injury; Cardiac Surgical Procedures; Erythropoietin; Female; Humans; Male; Perioperative Care; Postoperative Complications

The effect of erythropoietin (EPO) on the prevention of cardiac surgery-associated acute kidney injury (CSA-AKI) is controversial. Therefore, we undertook the meta-analysis of randomized controlled trials (RCTs) to assess the efficacy and safety of EPO on the prevention of CSA-AKI in adult patients and to explore whether risk factors for AKI could explain the inconsistent effects. PubMed and EMbase databases were searched to identify eligible RCTs. The meta-analysis was performed with fixed- or random-effects models according to the heterogeneity, and the subgroup analysis stratified by risk factors for AKI was carried out. Five RCTs involving 423 patients were included. Overall, EPO administration was not associated with a reduced incidence of CSA-AKI [relative risk (RR): 0.64, 95% confidence interval (CI): 0.35-1.16], with a moderate heterogeneity (I(2) = 67.4%, heterogeneity P = 0.02). Subgroup analysis showed that, in patients without high risk factors for AKI, EPO administration could significantly reduce the incidence of CSA-AKI (RR: 0.38, 95% CI: 0.24-0.61), intensive care unit length of stay [standardized mean difference (SMD): -0.54, 95% CI: -1.05 to -0.04] and hospital length of stay (SMD: -0.48, 95% CI: -0.94 to -0.02). The test of heterogeneity was not significant in the two subgroups. EPO administration could significantly reduce the incidence of CSA-AKI, but not in patients with high risk factors for AKI. Substantial heterogeneity across trials could be attributed to high risk factors for AKI. However, our findings should be interpreted cautiously because of the limited studies included, and high-quality RCTs are warranted.

Topics: Acute Kidney Injury; Aged; Aged, 80 and over; Cardiac Surgical Procedures; Cardiopulmonary Bypass; Coronary Artery Bypass; Erythropoietin; Female; Humans; Male; Middle Aged; Randomized Controlled Trials as Topic

Renal hypoxia is known to play an important role in the pathophysiology of acute renal injury as well as in chronic kidney diseases. The mediators of hypoxia are the transcription factors HIF (hypoxia-inducible factors), that are highly regulated. Under normoxic conditions constitutively expressed HIF-α subunits are hydroxylated by prolyl hydroxylases (PHD1, PHD2, and PHD3) and subsequently degraded by proteasomes.. This narrative review is based on the material searched for and obtained via PubMed and MEDLINE up to January 2015.. The MAPK organizer 1 (Morg1) has been identified to act as a scaffold protein of PHD3 and suppression of Morg1 leads to the stabilization of HIF-α, which forms in the absence of oxygen a heterodimer with HIF-β, translocates to the nucleus and promotes the transcription of HIF target genes.. This review summarizes the current knowledge regarding the role of hypoxia, HIF signalling, and Morg1 in acute and chronic renal injury.

Topics: Acute Kidney Injury; Adaptor Proteins, Signal Transducing; Aryl Hydrocarbon Receptor Nuclear Translocator; Erythropoietin; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Kidney Failure, Chronic; Signal Transduction

Renal ischemia reperfusion injury (IRI) contributes to the development of acute kidney injury (AKI). Several processes are involved in the development of renal IRI with the generation of reactive oxygen species, inflammation and apoptosis. MicroRNAs (miRNAs) are endogenous, small and noncoding RNAs that repress gene expression of target mRNA in animals post-transcriptionally. miRNA-mediated gene repression is a major modulatory mechanism to regulate fundamental cellular processes such as the cell cycle, proliferation, growth, and apoptosis, which in turn have pivotal influences on pathophysiological outcomes. Recent studies have revealed the pathogenic roles played by miRNAs in many renal diseases, such as IRI, AKI and renal carcinoma. In addition, the majority of miRNAs identified appear to be differentially expressed, probably to quell the injury response by modulating inflammation, apoptosis and proliferation and may point us toward new pathways that can be targeted to regulate or prevent renal IRI. They may represent novel diagnostic biomarkers of renal IR injury.

Topics: Acute Kidney Injury; Animals; Apoptosis; Erythropoietin; Humans; Melatonin; Mice; MicroRNAs; Rats; Reactive Oxygen Species; Reperfusion Injury

The aim was to investigate the efficacy and safety of erythropoietin (EPO) to prevent acute kidney injury (AKI) in patients with critical illness or perioperative care.. Randomized controlled trials comparing EPO with placebo for AKI prevention in adult patients with critical illness or perioperative care were searched in MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, the Web of Science, and Clinical Trials.gov until October 2014. The outcomes of interest included the incidence of AKI, dialysis requirement, mortality, and adverse event. Fixed effect model was used to calculate the pooled risk ratio (RR) and 95% confidence interval (CI) for eligible studies.. Ten randomized controlled trials involving 2759 participants were identified and included in the analysis. Compared with placebo, EPO administration did not reduce the incidence of AKI (RR, 0.97; 95% CI, 0.79-1.19; P = 0.782), dialysis requirement (RR, 0.72; 95% CI, 0.31-1.70; P = 0.457), or mortality (RR, 0.96; 95% CI, 0.78-1.18; P = 0.705). Moreover, EPO had no effect on the risk of adverse events, but estimations of RR were difficult due to their relatively infrequent occurrence.. This meta-analysis suggests that prophylactic administration of EPO in patients with critical illness or perioperative care does not prevent AKI, dialysis requirement, or mortality.

Topics: Acute Kidney Injury; Adult; Aged; Critical Illness; Erythropoietin; Female; Humans; Incidence; Male; Middle Aged; Odds Ratio; Postoperative Complications; Preoperative Care; Randomized Controlled Trials as Topic; Renal Dialysis; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome

Despite extensive research, no therapeutic interventions have been shown to prevent AKI, accelerate recovery of AKI, or reduce progression of AKI to CKD in patients. This failure in translation has led investigators to speculate that the animal models being used do not predict therapeutic responses in humans. Although this issue continues to be debated, an important concern that has not been addressed is whether improvements in preclinical study design can be identified that might also increase the likelihood of translating basic AKI research into clinical practice using the current models. In this review, we have taken an evidence-based approach to identify common weaknesses in study design and reporting in preclinical AKI research that may contribute to the poor translatability of the findings. We focused on use of N-acetylcysteine or sodium bicarbonate for the prevention of contrast-induced AKI and use of erythropoietin for the prevention of AKI, two therapeutic approaches that have been extensively studied in clinical trials. On the basis of our findings, we identified five areas for improvement in preclinical study design and reporting. These suggested and preliminary guidelines may help improve the quality of preclinical research for AKI drug development.

Topics: Acetylcysteine; Acute Kidney Injury; Animals; Contrast Media; Disease Models, Animal; Erythropoietin; Free Radical Scavengers; Humans; Research Design; Sodium Bicarbonate; Translational Research, Biomedical

Renal pericytes have been neglected for many years, but recently they have become an intensively studied cell population in renal biology and pathophysiology. Pericytes are stromal cells that support vasculature, and a subset of pericytes are mesenchymal stem cells. In kidney, pericytes have been reported to play critical roles in angiogenesis, regulation of renal medullary and cortical blood flow, and serve as progenitors of interstitial myofibroblasts in renal fibrogenesis. They interact with endothelial cells through distinct signaling pathways and their activation and detachment from capillaries after acute or chronic kidney injury may be critical for driving chronic kidney disease progression. By contrast, during kidney homeostasis it is likely that pericytes serve as a local stem cell population that replenishes differentiated interstitial and vascular cells lost during aging. This review describes both the regenerative properties of pericytes as well as involvement in pathophysiologic conditions such as fibrogenesis.

Topics: Acute Kidney Injury; Erythropoietin; Fibrosis; Humans; Kidney; Mesenchymal Stem Cells; Neovascularization, Physiologic; Pericytes; Regeneration; Renal Insufficiency, Chronic

Erythropoietin is a 30.4 kDa glycoprotein produced by the kidney, which is mostly known for its physiological function in regulating red blood cell production in the bone marrow Accumulating evidence, however suggests that erythropoietin has additional organ protective effects, which may specifically be useful in protecting the brain and kidneys from injury. Experimental evidence suggests that these protective mechanisms are multi-factorial in nature and may include inhibition of apoptotic cell death, stimulation of cellular regeneration, inhibition of deleterious pathways and promotion of recovery. In this article we review the physiology of erythropoietin, assess previous work that supports the role of erythropoietin as a general tissue protective agent and explain the mechanisms by which it may achieve this tissue protective effect. We then focus on specific laboratory and clinical data that suggest that erythropoietin has a strong brain protective and kidney protective effect. In addition, we comment on the implications of these studies for clinicians at the bedside and for researchers designing controlled trials to further elucidate the true clinical utility of erythropoietin as a neuroprotective and nephroprotective agent. Finally, we describe EPO-TBI, a double-blinded multi-centre randomised controlled trial involving the authors that is being conducted to investigate the organ protective effects of erythropoietin on the brain, and also assesses its effect on the kidneys.

Topics: Acute Kidney Injury; Animals; Brain; Clinical Trials as Topic; Erythropoietin; Humans; Neuroprotective Agents; Protective Agents; Receptors, Erythropoietin

Topics: Acute Kidney Injury; Autoantigens; Darbepoetin alfa; Diabetic Nephropathies; Erythropoietin; Glomerulonephritis, Membranous; Hematinics; Humans; Immunosuppressive Agents; Kidney Diseases; Lupus Nephritis; Randomized Controlled Trials as Topic; Renal Replacement Therapy

Improving the ability of the kidney to tolerate injury through preconditioning is likely to have important clinical implications. Although a number of preconditioning strategies have been studied, ischemic preconditioning (IP) has been studied the most experimentally. The information gathered has helped us shed more light into the mechanisms responsible for this tissue adaptation that confers to tissues a more resistant status. IP is effective within minutes, suggesting that preformed mediators are involved. This is followed by delayed preconditioning, a phenomenon that is less potent but longer acting. Remote preconditioning occurs also in non-affected tissues and can be transferable. A number of mediators and transcription factors have been implicated including kinases, heat shock proteins, nitric oxide and neurogenic pathways, all of which help change the cell into a more resistant phenotype. There is evidence that IP also occurs in the human environment with lessons learned from myocardial ischemia, hepatic resection and cerebral ischemia. Because of the ethical impediment with intentionally applying organ ischemia, there has been an interest in pharmacological preconditioning lately. Exogenously administered erythropoietin was shown to benefit kidneys subjected to different insults. In addition, mesenchymal stem cells-based approaches for the prevention and treatment of acute kidney injury (AKI) are being studied. Calcineurin inhibitors may represent a viable way to reduce ischemia reperfusion injury in transplantation. Translating the experimental findings to the clinical arena remains a challenge. The discovery of new biomarkers for AKI should help initiate therapy early, when therapy could make a difference.

Topics: Acute Kidney Injury; Animals; Calcineurin Inhibitors; Erythropoietin; Humans; Ischemic Preconditioning; Mesenchymal Stem Cell Transplantation

Acute kidney injury (AKI) frequently occurs in critically ill patients and is an independent risk factor for poor outcome. The prevention of kidney injury in intensive care remains a great challenge as specific nephroprotective therapies are still lacking. The present review summarizes recent evidence for the use of erythropoietin as a promising candidate to provide protection from AKI.. Beyond the known hematopoietic actions of erythropoietin, a number of preclinical studies demonstrated that erythropoietin possesses pleiotropic, organ-protecting properties. Preconditional and postconditional erythropoietin treatment was shown to protect from ischemic, toxic and septic AKI. Despite heterogeneities in study design and dose, erythropoietin consistently ameliorated renal injury. The mechanisms of protection remain largely unclear but may involve reduction of apoptosis, induction of cellular proliferation and tissue repair as well as mobilization of stem cells.. Animal studies revealed a physiological basis for the use of erythropoietin in AKI, which may be clinically applicable to prevent AKI in critically ill patients, but clinical studies are still lacking.

Topics: Acute Kidney Injury; Adaptor Proteins, Signal Transducing; Carrier Proteins; Critical Illness; Erythropoietin; Hematopoiesis; Humans; Intracellular Signaling Peptides and Proteins; Recombinant Proteins; Ribonucleoproteins, Small Nuclear; Risk Factors; Tumor Suppressor Proteins

The kidney can achieve a structural and functional recovery after the damage induced by ischemia and reperfusion. This is due to the regeneration of epithelial tubular cells, the intervention of immature cells mainly localized in the medulla, and a small number of bone marrow-derived stem cells. In many instances, however, recovery is delayed or does not occur at all. The mechanisms allowing the renal cells to de-differentiate still need to be clarified in order to find a therapeutic approach that can amplify this ability and then stop the fibroid involution and the progression toward renal failure. Several authors have hypothesized a protective effect of EPO against ischemic and cytotoxic renal damage and observed that patients precociously treated with EPO showed a slower progression of renal failure. EPO has been demonstrated to have proliferative and anti-apoptotic effects in ischemia-reperfusion models in the brain and cell cultures. Moreover, EPO can mobilize stem cells and increase the plasmatic levels and the renal expression of VEGF. These effects seem to be dose-dependent and could be due to the activation of signal transduction systems, like Jak and STAT. In the presence of high doses of exogenous EPO or during the treatment with long-acting EPO-like molecules, non-specific receptors may be activated through a low-affinity link. Further investigations are needed to determine new therapeutic applications for EPO and other analogous hormones. Very long-acting molecules or molecules with cyto-protective but no erythropoietic effect may represent useful tools in the study of the molecular mechanisms underlying EPO's action and may have a rapid and safe therapeutic application.

Topics: Acute Kidney Injury; Animals; Cell Differentiation; Disease Models, Animal; Disease Progression; Dose-Response Relationship, Drug; Erythropoietin; Humans; Ischemia; Kidney; Recombinant Proteins; Signal Transduction

The well-established physiological function of erythropoietin (EPO) is the induction of erythropoiesis. A growing body of evidence indicates that EPO has tissue-protective effects and prevents tissue damage during ischemia and inflammation. Tissue protection after ischemia and injury has been found in the brain, heart, and kidney. It has been speculated that EPO has anti-apoptotic effects in cardiovascular cells. These novel effects of EPO seem to be independent of its erythropoietic activity. Unclear is the role of the known EPO receptor or whether other signaling pathways are involved; a novel EPO receptor might be involved in tissue protection by this hormone. This review article summarizes present knowledge of cardiovascular and renal protective effects of EPO and discusses possible underlying mechanisms.

Topics: Acute Kidney Injury; Anemia; Animals; Cardiovascular Diseases; Erythropoiesis; Erythropoietin; Humans; Recombinant Proteins; Vascular Diseases

The kidney has the ability to restore the structural and functional integrity of the proximal tubule, which undergoes extensive epithelial cell death via necrosis and apoptosis after a prolonged ischaemic insult. This review focuses on the recent advances in this area, and discusses the possible therapeutic interventions that might be derived from these insights.. Interest has recently been focused on the possible role of bone marrow originating stem cells in endogenous repair of the injured tubule, the identification of a resident population of progenitor cells in the kidney, and the potential therapeutic role of growth factors including erythropoietin and hepatocyte growth factor to stimulate these processes.. Advances in the understanding of the early processes that initiate and control the proliferation of surviving tubular epithelium and vascular structures are ready to be translated into clinical trials in acute kidney injury.

Topics: Acute Kidney Injury; Apoptosis; Epithelium; Erythropoietin; Humans; Intercellular Signaling Peptides and Proteins; Ischemia; Kidney; Kidney Tubules, Proximal; Mesoderm; Necrosis; Stem Cells

Renal ischemia-reperfusion (I-R) contributes to the development of ischemic acute renal failure (ARF). Multi-factorial processes are involved in the development and progression of renal I-R injury with the generation of reactive oxygen species, nitric oxide and peroxynitrite, and the decline of antioxidant protection playing major roles, leading to dysfunction, injury, and death of the cells of the kidney. Renal inflammation, involving cytokine/adhesion molecule cascades with recruitment, activation, and diapedesis of circulating leukocytes is also implicated. Clinically, renal I-R occurs in a variety of medical and surgical settings and is responsible for the development of acute tubular necrosis (a characteristic feature of ischemic ARF), e.g., in renal transplantation where I-R of the kidney directly influences graft and patient survival. The cellular mechanisms involved in the development of renal I-R injury have been targeted by several pharmacological interventions. However, although showing promise in experimental models of renal I-R injury and ischemic ARF, they have not proved successful in the clinical setting (e.g., atrial natriuretic peptide, low-dose dopamine). This review highlights recent pharmacological developments, which have shown particular promise against experimental renal I-R injury and ischemic ARF, including novel antioxidants and antioxidant enzyme mimetics, nitric oxide and nitric oxide synthase inhibitors, erythropoietin, peroxisome-proliferator-activated receptor agonists, inhibitors of poly(ADP-ribose) polymerase, carbon monoxide-releasing molecules, statins, and adenosine. Novel approaches such as recent research involving combination therapies and the potential of non-pharmacological strategies are also considered.

Topics: Acute Kidney Injury; Animals; Antioxidants; Erythropoietin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Kidney; Kidney Diseases; Nitric Oxide; Nitric Oxide Synthase; Peroxisome Proliferator-Activated Receptors; Poly(ADP-ribose) Polymerase Inhibitors; Purinergic P1 Receptor Agonists; Reactive Nitrogen Species; Reactive Oxygen Species; Receptors, Lysosphingolipid; Recombinant Proteins; Reperfusion Injury

Pharmacologic interventions for the prevention and therapy of acute kidney injury (AKI) can be roughly divided into 2 main strategies: Optimising renal perfusion and modulation of intrarenal pathophysiological mechanisms, i.e. formation of free oxygen radicals, inflammation, tubular cast formation and renal (tubular) regeneration. Improvement of impaired renal perfusion can be achieved by optimising systemic haemodynamics by volume expansion and the appropriate use of inotropes and/or vasopressors. Up to now prospective randomised controlled trials on selective renal vasodilatation have turned out rather unsuccessful, with the exception of the adenosine antagonist theophylline, in certain indications like drug-induced renal failure or contrast nephropathy. Studies in humans on pharmacological interventions interfering with intrarenal pathophysiological mechanisms of AKI are also sparse. Investigated compounds comprise N-acetyl-cysteine, mannitol and antioxidants like selenium or vitamin C. The results are heterogeneous and a significant beneficial effect of either substance could not yet be convincingly demonstrated.

Topics: Acute Kidney Injury; Antioxidants; Contrast Media; Diuretics; Diuretics, Osmotic; Erythropoietin; Humans; Kidney Diseases; Mannitol; Multicenter Studies as Topic; Prospective Studies; Randomized Controlled Trials as Topic; Reactive Oxygen Species; Regeneration; Renal Circulation; Theophylline; Vasoconstrictor Agents; Vasodilator Agents

The haematopoietic factor erythropoietin (EPO) has recently been recognized to play a physiological role in the brain and other tissues. The EPO receptor is present in the glomerulus, mesangial and tubular epithelial cells in the kidney. We have reviewed the experimental use of EPO in animal models of acute renal failure. EPO attenuates the dysfunction and histological changes associated with ischaemia-reperfusion injury, with a reduction in apoptotic cell death. EPO has also shown benefit in animal models of systemic shock and cisplatin-induced nephrotoxicity. In vitro studies have shown that EPO has direct effects on proliferation and cell death in proximal tubular epithelial cells. There is increasingly strong experimental evidence that EPO may be of therapeutic use in acute renal failure, and clinical trials should be undertaken to determine its clinical applications in this field.

Topics: Acute Kidney Injury; Animals; Cytoprotection; Endothelium, Vascular; Erythropoietin; Kidney; Reperfusion Injury

The hemopoietic growth factor erythropoietin (EPO) has been recognized to be a multifunctional cytokine that plays a key role in ischemic preconditioning in the brain and heart. The EPO receptor is expressed widely in the kidney, and we review the important findings from the use of EPO in experimental models of acute renal failure that show that EPO reduces tubular cell death and hence the dysfunction induced by ischemia reperfusion injury, and we explore how these observations may be translated into the clinical arena.

Topics: Acute Kidney Injury; Animals; Apoptosis; Brain Ischemia; Erythropoietin; Humans; Kidney; Kidney Tubules, Proximal; Recombinant Proteins; Reperfusion Injury

Recovery of renal function after acute renal failure is an important clinical determinant of patient morbidity. Herein, the epidemiology of renal recovery after acute renal failure will be described, along with potential predictive factors and interventions.. Renal recovery has been variably defined, most often as recovery to independence from renal replacement therapy. A recent consensus definition for acute renal failure has been published and included provisions for defining renal recovery. Renal recovery to renal replacement therapy independence occurs in the majority by hospital discharge and peaks by 90 days. All of older age, female sex, co-morbid illnesses, especially chronic kidney disease, and late initiation of renal replacement therapy or conventional intermittent renal replacement therapy have been coupled with non-recovery. Analysis of the literature suggests several interventions may influence recovery.. The prognosis is generally good for recovery after acute renal failure. Most patients will be independent of renal replacement therapy by 90 days. Additional research is necessary, however, to understand recovery rates not only to independence from renal replacement therapy, but also to complete and partial recovery. Future studies need to consider the health economic implications for survival and non-recovery. Finally, questions on the role of various interventions require characterization in randomized controlled trials to determine how they may influence renal prognosis.

Topics: Acute Kidney Injury; Erythropoietin; Humans; Hypoglycemic Agents; Insulin; Nutritional Support; Prognosis; Recovery of Function; Sodium Potassium Chloride Symporter Inhibitors

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.

Topics: Acute Kidney Injury; Animals; Apoptosis; Cell Death; Erythropoietin; Humans

Topics: Acute Kidney Injury; Animals; Biomarkers; Contrast Media; Endothelin Receptor Antagonists; Endothelin-1; Endotoxemia; Erythropoietin; Fibrosis; Glycopeptides; Heart Failure; Humans; Hypotension; Kidney Failure, Chronic; Peptides, Cyclic; Peritoneal Dialysis; Peritoneum; Prognosis; Recombinant Proteins; Renal Dialysis

Topics: Acute Kidney Injury; Conscious Sedation; Critical Care; Diuretics; Erythropoietin; Humans; Positive-Pressure Respiration; Pulmonary Disease, Chronic Obstructive

The use of recombinant human erythropoietin (rHuEpo) has revolutionized anemia management of early and late stages of chronic kidney disease. Darbopoietin is also now available for the treatment of anemia of chronic kidney disease. In addition, rHuEpo has been used for the treatment of anemia observed in critical illness. Unfortunately, the existing clinical studies of anemia in critically ill patients do not distinguish between those with and without acute renal failure (ARF). This review summarizes the existing experimental and clinical studies supporting the use of rHuEpo in ARF due to ischemic/nephrotoxic injury and conclusions are drawn on the rationale for further research into the use of this drug in ARF.

Topics: Acute Kidney Injury; Anemia; Animals; Critical Illness; Erythropoietin; Humans; Recombinant Proteins

Erythropoietin (EPO) in the renal cortex is synthesized by fibroblast-like cells that are in direct contact with capillaries and adjacent tubular cells. Prompted by this anatomical relationship, we asked whether renal cells express EPO receptors (EPORs) through which EPO could act as a renotropic cytokine. We found that all regions of human, rat and mouse kidney, mesangial and proximal and distal tubular cells express authentic EPORs. Similar EPOR expression was detected in kidney cancer cells, and in cyst epithelia from polycystic kidneys. In vitro, EPO stimulated mitogenesis in all normal and malignant cells, and cell survival and motogenesis in injured tubular cells. Since the normal kidney is essentially unresponsive to EPO, we hypothesized that EPO's cytokine effects in the kidney are revealed when tubular cells are induced to proliferate by a prior insult, as occurs in acute renal failure. Accordingly, we found that EPO treatment of rats with 'ischemic' acute renal failure afforded renoprotection and accelerated functional recovery.

Topics: Acute Kidney Injury; Animals; Cytokines; Erythropoietin; Humans; Kidney; Kidney Neoplasms; Polycystic Kidney, Autosomal Dominant; Reference Values

Recently a growing number of case reports has been published about successful pregnancy outcome of dialysed women on recombinant human erythropoietin therapy. During pregnancy the maternal demand for erythropoietin may undergo changes, with consideration of recombinant human erythropoietin therapy in the early stage of renal insufficiency, as is shown by our two reported cases. The use of recombinant human erythropoietin seems to be safe for the foetus: it does not cross the placental barrier, and therefore lacks any direct foetal effect. The treatment of anaemia with recombinant human erythropoietin carries benefits for both the mother and foetus. One of the most important preconditions for successful recombinant human erythropoietin therapy is adequate iron supplementation. Due to the increased risk of pregnancy induced hypertension or preeclampsia, there is a need for slow and gradual correction of anaemia, and an individually tailored target hematocrit. A close follow up of he patient by the obstetrical-nephrological team is essential, with the intensive monitoring of the fetuses. In some cases with normal renal function the stimulation of erythropoiesis with recombinant human erythropoietin may also be needed during the pregnancy.

Topics: Acute Kidney Injury; Adult; Erythropoietin; Female; Humans; Pregnancy; Pregnancy Complications; Pregnancy Complications, Hematologic

Experiments in laboratory animals clearly show that adenosine acts as a vasoconstrictive metabolite in the kidney. Adenosine receptor antagonists like theophylline can inhibit renal vasoconstriction in response to exogenous and endogenous adenosine. Based on these findings a number of experiments have been performed to test whether the vasoconstrictive action of adenosine in the kidney might be important also in pathophysiological states. In various animal models theophylline and other methylxanthine derivatives have been successfully employed to improve renal function after induction of acute renal failure. Clinical implications of these experimental findings comprise the prevention of acute renal failure following the administration of radio contrast media by theophylline. Another therapeutic aspect derives from experimental and clinical data showing that theophylline controls erythropoietin production in erythrocytosis after renal transplantation.

Topics: Acute Kidney Injury; Adenosine; Animals; Contrast Media; Erythropoietin; Humans; Kidney; Purinergic P1 Receptor Antagonists; Renal Circulation; Theophylline; Vasoconstriction

Topics: Acute Kidney Injury; Anti-Bacterial Agents; Drug Therapy; Erythropoietin; Humans; Kidney Failure, Chronic; Pharmacokinetics; Recombinant Proteins; Renal Dialysis

Topics: Acute Kidney Injury; Aluminum; Erythropoietin; Humans; Kidney Failure, Chronic; Kidney Transplantation; Peritoneal Dialysis, Continuous Ambulatory; Renal Dialysis

rEPO therapy provides a unique opportunity to correct anemia in end-stage renal failure patients. Complete correction of the anemia, although possible, has some obvious disadvantages over a partial correction with a target hemoglobin of 10-13 g/dl or a hematocrit of 30-35%, respectively. Unresponsiveness to rEPO seems to be rare; in most cases the predicted hemoglobin increase could be seen as soon as an underlying iron deficiency was treated adequately. Blood loss and aluminum toxicity are the next most frequent reasons for an inadequate response to rEPO. Hypertension (and its complications) as well as fistula clotting are the most important side-effects which require close attention when patients at risk for these complications are treated with rEPO.

Topics: Acute Kidney Injury; Anemia; Blood Pressure; Erythropoietin; Humans; Recombinant Proteins

The ability to produce a concentrated urine is imposed by a uniquely low ambient oxygen pressure in the renal medulla due to shunt diffusion within the vascular bundles. As the thick ascending limb of Henle's loop (TAL-segment) is able to glycolyse anaerobically, a phase of oxygen deficiency may be bridgespanned. It allows an exceptionally high oxygen extraction of 80% in this area. If oxygen capacity is reduced systematically, which can be effected in the isolated kidney model by using cell free perfusate, a typical pattern of lesions occur in TAL-segments. Segments near vascular bundles remain intact, as they take advantage from a radial oxygen diffusion originating from vascular bundles. The extent of lesions is increasing directed to the inner medulla due to the reduction of oxygen pressure, whereas lesions are not present in the inner medulla itself. Cells of TAL-segments are swelling during oxygen deficiency, when transport work surpasses the available energy necessary due to the luminal fluid inflow. Lesions could be prevented, when oxygen capacity was enhanced by adding erythrocytes or when transport was blocked by furosemide. Swollen cells in TAL-segments however are able to aggravate medullary hypoxia by an outflow block in vivo. Secondly, it can be demonstrated, that oxygen shunt diffusion is not only present in renal medulla but also within renal cortex especially as a preglomerular diffusion shunt for blood gases. Thus PCO2 has been measured to be 65 mmHg in the outermost cortical zone and thereby some 20 mmHg higher than renal venous blood.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acute Kidney Injury; Animals; Energy Metabolism; Erythropoietin; Humans; Ischemia; Kidney Concentrating Ability; Kidney Medulla; Loop of Henle; Oxygen Consumption; Rats

Topics: Acute Kidney Injury; Adaptation, Physiological; Adenine Nucleotides; Ammonia; Animals; Dogs; Energy Metabolism; Enzymes; Erythropoietin; Gluconeogenesis; Hormones; Kidney Diseases; Lipid Metabolism; Mitochondria; Nephrons; Oxygen Consumption; Prostaglandins; Rabbits; Rats

Topics: Acute Kidney Injury; Anemia; Anemia, Hemolytic; Blood Viscosity; Bone Marrow; Diphosphoglyceric Acids; Erythrocytes; Erythropoietin; Half-Life; Hematocrit; Hemoglobins; Hemolysis; Humans; Kidney Failure, Chronic; Oxygen Consumption; Pyelonephritis; Renal Dialysis; Transfusion Reaction

Pure red cell aplasia is a selective aplasia of the marrow erythroid cells. Unlike aplastic anemia, the marrow has a normal cellularity and the patients generally have normal leukocyte and platelet blood counts. The congenital form of the disease occurs in the firlst 1 1/2 years of life and is often responsive to corticosteroids. The acquired form may be secondary to infections, drugs, chemicals, or hemolytic anemia (aplastic crisis). In these cases it is often acute and self-limited with cessation of the infection or drug ingestion. It may also be secondary to systemic lupus erythematosus, rheumatoid arthritis, acute severe renal failure, severe nutritional deficiency, or diverse neoplasms, and may remit with treatment of the primary condition. When a thymoma is present, it should be resected since a remission is produced in 29 per cent of these patients. The remaining patients have an acquired primary form of the disease that tends to be chronic and in some cases may have an immune pathogenesis. A cytotoxic immunoglobulin inhibitor of the marrow erythroid cells or erythropoietin has been described and these patients may respond to prednisone and/or to cytotoxic immunosuppressive drugs such as cyclophosphamide and 6-mercaptopurine. Pure red cell aplasia appears to be more common than the literature has revealed and has stimulated much investigation into an immune pathogenesis for marrow failure.

Topics: Acute Kidney Injury; Anemia, Aplastic; Antilymphocyte Serum; Arthritis, Rheumatoid; Blood Cell Count; Blood Transfusion; Cyclophosphamide; Deficiency Diseases; Erythropoietin; Humans; Immune System Diseases; Infections; Lupus Erythematosus, Systemic; Mercaptopurine; Prednisone; Remission, Spontaneous; Splenectomy; Thymoma; Thymus Neoplasms

Topics: Acute Kidney Injury; Androgens; Anemia; Blood Transfusion; Cobalt; Erythropoietin; Female; Humans; Iron; Kidney; Kidney Failure, Chronic; Male; Nephrectomy; Renal Dialysis; Sex Factors

Acute kidney injury (AKI) and disordered fluid balance are common in premature neonates; a positive fluid balance dilutes serum creatinine, and a negative fluid balance concentrates serum creatinine, both of which complicate AKI diagnosis. Correcting serum creatinine for fluid balance may improve diagnosis and increase diagnostic accuracy for AKI.. To determine whether correcting serum creatinine for fluid balance would identify additional neonates with AKI and alter the association of AKI with short-term and long-term outcomes.. This study was a post hoc cohort analysis of the Preterm Erythropoietin Neuroprotection Trial (PENUT), a phase 3, randomized clinical trial of erythropoietin, conducted at 19 academic centers and 30 neonatal intensive care units in the US from December 2013 to September 2016. Participants included extremely premature neonates born at less than 28 weeks of gestation. Data analysis was conducted in December 2022.. Diagnosis of fluid-corrected AKI during the first 14 postnatal days, calculated using fluid-corrected serum creatinine (defined as serum creatinine multiplied by fluid balance [calculated as percentage change from birth weight] divided by total body water [estimated 80% of birth weight]).. The primary outcome was invasive mechanical ventilation on postnatal day 14. Secondary outcomes included death, hospital length of stay, and severe bronchopulmonary dysplasia (BPD). Categorical variables were analyzed by proportional differences with the χ2 test or Fisher exact test. The t test and Wilcoxon rank sums test were used to compare continuous and ordinal variables, respectively. Odds ratios (ORs) and 95% CIs for the association of exposure with outcomes of interest were estimated using unconditional logistic regression models.. A total of 923 premature neonates (479 boys [51.9%]; median [IQR] birth weight, 801 [668-940] g) were included, of whom 215 (23.3%) received a diagnosis of AKI using uncorrected serum creatinine. After fluid balance correction, 13 neonates with AKI were reclassified as not having fluid-corrected AKI, and 111 neonates previously without AKI were reclassified as having fluid-corrected AKI (ie, unveiled AKI). Therefore, fluid-corrected AKI was diagnosed in 313 neonates (33.9%). Neonates with unveiled AKI were similar in clinical characteristics to those with AKI whose diagnoses were made with uncorrected serum creatinine. Compared with those without AKI, neonates with unveiled AKI were more likely to require ventilation (81 neonates [75.0%] vs 254 neonates [44.3%] and have longer hospital stays (median [IQR], 102 [84-124] days vs 90 [71-110] days). In multivariable analysis, a diagnosis of fluid-corrected AKI was associated with increased odds of adverse clinical outcomes, including ventilation (adjusted OR, 2.23; 95% CI, 1.56-3.18) and severe BPD (adjusted OR, 2.05; 95% CI, 1.15-3.64).. In this post hoc cohort study of premature neonates, fluid correction increased the number of premature neonates with a diagnosis of AKI and was associated with increased odds of adverse clinical outcomes, including ventilation and BPD. Failing to correct serum creatinine for fluid balance underestimates the prevalence and impact of AKI in premature neonates. Future studies should consider correcting AKI for fluid balance.. ClinicalTrials.gov Identifier: NCT01378273.

Topics: Acute Kidney Injury; Birth Weight; Bronchopulmonary Dysplasia; Cohort Studies; Creatinine; Erythropoietin; Humans; Infant, Newborn; Infant, Newborn, Diseases; Male; Neuroprotection; Retrospective Studies

Treatment with erythropoietin is well established for anemia in chronic kidney disease patients but not well studied in acute kidney injury.. This is a multicenter, randomized, pragmatic controlled clinical trial. It included 134 hospitalized patients with anemia defined as hemoglobin < 11 g/dL and acute kidney injury defined as an increase of serum creatinine of ≥ 0.3 mg/dL within 48 h or 1.5 times baseline. One arm received recombinant human erythropoietin 4000 UI subcutaneously every other day (intervention; n = 67) and the second received standard of care (control; n = 67) during the hospitalization until discharge or death. The primary outcome was the need for transfusion; secondary outcomes were death, renal recovery, need for dialysis.. There was no statistically significant difference in transfusion need (RR = 1.05, 95%CI 0.65,1.68; p = 0.855), in renal recovery full or partial (RR = 0.96, 95%CI 0.81,1.15; p = 0.671), in need for dialysis (RR = 11.00, 95%CI 0.62, 195.08; p = 0.102) or in death (RR = 1.43, 95%CI 0.58,3.53; p = 0.440) between the erythropoietin and the control group.. Erythropoietin treatment had no impact on transfusions, renal recovery or mortality in acute kidney injury patients with anemia. The trial was registered on ClinicalTrials.gov (NCT03401710, 17/01/2018).

Topics: Acute Kidney Injury; Anemia; Erythropoietin; Female; Hemoglobins; Humans; Male; Recombinant Proteins; Renal Dialysis

To evaluate whether extremely low gestational age neonates (ELGANs) randomized to erythropoietin have better or worse kidney-related outcomes during hospitalization and at 22-26 months of corrected gestational age (cGA) compared with those randomized to placebo.. We performed an ancillary study to a multicenter double-blind, placebo-controlled randomized clinical trial of erythropoietin in ELGANs.. ELGANs have high rates of in-hospital AKI and kidney-related problems at 22-26 months of cGA. Recombinant erythropoietin may protect ELGANs against long-term elevated SBP but does not appear to protect from AKI, low eGFR, albuminuria, or elevated DBP at 22-26 months of cGA.

Topics: Acute Kidney Injury; Albuminuria; Double-Blind Method; Erythropoietin; Female; Gestational Age; Glomerular Filtration Rate; Humans; Hypertension; Infant, Extremely Premature; Infant, Newborn; Infant, Premature, Diseases; Male; Recombinant Proteins; Renal Insufficiency, Chronic

AKI is associated with poor short- and long-term outcomes. Questions remain about the frequency and timing of AKI, and whether AKI is a cause of death in extremely low gestational age neonates.. The Recombinant Erythropoietin for Protection of Infant Kidney Disease Study examines the kidney outcomes of extremely low gestational age neonates enrolled in the Preterm Epo Neuroprotection study, a randomized, placebo-controlled trial of recombinant human erythropoietin. We included 900 of 941 patients enrolled in Preterm Epo Neuroprotection. Baseline characteristics were compared by primary exposure (severe AKI versus none/stage 1 AKI) using unadjusted logistic regression models. Cox regression models estimated the relationship between severe AKI and death after adjustment for potential confounders. Time-dependent AKI was modeled as a binary outcome and a categorical variable by stage of AKI. We fit Cox models using time-dependent AKI status lagged by <7 days before death. Landmark analyses examined the relationship of death with development of severe AKI.. Severe AKI occurred in 168 of 900 (19%, 95% confidence interval, 17% to 20%) neonates, and stage 3 AKI occurred in 60 (7%, 95% confidence interval, 5% to 8%). Stage 3 AKI occurring 7 days before death (hazard ratio, 3.88; 95% confidence interval, 1.26 to 11.96), intraventricular hemorrhage (hazard ratio, 2.01; 95% confidence interval, 1.01 to 3.99) and sepsis (hazard ratio, 2.85; 95% confidence interval, 1.12 to 7.22) were all independently associated with death. Severe AKI occurring 7 days before death (hazard ratio, 2.21; 95% confidence interval, 0.92 to 5.26) was associated with death but not statistically significant. In a landmark analysis, after adjusting for potential confounders, late (after day 14 and before day 28) severe AKI was strongly associated with higher hazard of death (hazard ratio, 4.57; 95% confidence interval, 1.82 to 11.5).. Severe AKI occurs frequently in extremely low gestational age neonates. Stage 3 AKI is associated with mortality, and this association is present 7 days before death.

Topics: Acute Kidney Injury; Double-Blind Method; Erythropoietin; Female; Gestational Age; Humans; Infant, Extremely Premature; Infant, Newborn; Male; Prospective Studies; Recombinant Proteins; Severity of Illness Index

Contrast-induced-nephropathy (CIN) is associated with poor outcomes, thus prevention of CIN may be of clinical value. Erythropoietin (EPO) has been shown to elicit tissue-protective effects in experimental models and in clinical studies of acute kidney injury. We therefore evaluated its effectiveness for prevention of CIN after coronary angiography (CA) ± percutaneous coronary intervention (PCI) in diabetic patients with chronic kidney disease.. A prospective, randomized, controlled trial was carried out in 138 diabetic patients with eGFR <60 mL/min who underwent non-urgent CA ± PCI. Patients received normal saline and n-acetyl cysteine before CA, with or without 50,000 U of EPO administered 30 min prior to CA. CIN was defined as an increase in serum creatinine of at least 0.5 mg/dL during the first 2 days after exposure to contrast media. Primary outcome was the incidence of CIN. Secondary outcomes were the sensitivity and positive predictive value (PPV) of Cystatin C (CC) and Neutrophil-gelatinase-associated-lipocalin (NGAL) for diagnosis of CIN.. The observed incidence of CIN was 8.7%, significantly lower than the expected for such high-risk population. The administration of EPO prior to CA did not reduce the incidence of CIN (9.7% vs. 7.6%, P = 0.65). CC and NGAL demonstrated a low sensitivity (16.6%) and low PPV (6.7 and 33.3%, respectively) for detecting CIN.. The administration of EPO prior to CA did not reduce the incidence of CIN. Additional prospective research with a larger sample size and in other patient categories is essential to further define the potential protective effect of EPO on prevention of CIN.

Topics: Acetylcysteine; Acute Kidney Injury; Aged; Aged, 80 and over; Biomarkers; Contrast Media; Coronary Angiography; Cystatin C; Cytoprotection; Diabetic Nephropathies; Double-Blind Method; Drug Administration Schedule; Erythropoietin; Female; Humans; Infusions, Intravenous; Iohexol; Israel; Lipocalin-2; Male; Middle Aged; Prospective Studies; Protective Agents; Recombinant Proteins; Renal Insufficiency, Chronic; Risk Factors; Time Factors; Treatment Outcome; Triiodobenzoic Acids

Acute kidney injury (AKI) is associated with high morbidity and mortality. Recombinant human erythropoietin has been shown to exert cytoprotection against ischemia. This study examined the effect of erythropoietin in preventing AKI during thoracic aortic surgery with moderate hypothermic circulatory arrest.. In this double-blind, randomized study, 66 patients undergoing thoracic aortic surgery with moderate hypothermic circulatory arrest (target temperature, 28°C) randomly received either erythropoietin 500 IU·kg(-1) or the same amount of normal saline intravenously after anesthesia induction. The primary endpoint was incidence of AKI defined according to the RIFLE criteria during the first 7 postoperative days.. AKI occurred in 60% of all patients. The two groups did not show any differences in the incidence and severity of AKI. Also, there was no difference in the level of serum neutrophil gelatinase-associated lipocalin between the groups. The cardiac index was higher in the erythropoietin group, however, immediately after weaning from cardiopulmonary bypass (p = 0.02). Furthermore, postoperative cardiac complications and prolonged vasopressor dependence were reduced in the erythropoietin group (p = 0.04 and p = 0.049, respectively).. A single bolus administration of erythropoietin 500 IU·kg(-1) at anesthesia induction failed to provide renoprotection in patients who underwent thoracic aortic surgery with moderate hypothermic circulatory arrest. However, erythropoietin significantly reduced cardiac complications, and lowered the incidence of prolonged vasopressor dependence.

Topics: Acute Kidney Injury; Adult; Aged; Aged, 80 and over; Circulatory Arrest, Deep Hypothermia Induced; Double-Blind Method; Erythropoietin; Female; Humans; Male; Middle Aged

To date, there are no known methods for preventing acute kidney injury after cardiac surgery. Increasing evidence suggests that erythropoietin has renal antiapoptotic and tissue protective effects. However, recent human studies have shown conflicting results. The authors aimed to study the effect of a single high-dose erythropoietin preoperatively on renal function after coronary artery bypass grafting in patients with preoperative impaired renal function.. This single-center, randomized, double-blind, placebo-controlled study included 75 patients scheduled for coronary artery bypass grafting with preexisting renal impairment estimated glomerular filtration rate based on p-cystatin C (<60 and >15 ml/min). The patients either received a single high-dose erythropoietin (400 IU/kg) or placebo preoperatively. The primary endpoint was renal protection evaluated by p-cystatin C at the third postoperative day compared to the preoperative values. Incidence of acute kidney injury and other renal biomarker changes were among secondary endpoints.. There was no statistically significant difference on the third postoperative day for relative p-cystatin C level changes from baseline between the groups, 131 ± 31% (mean ± SD) for the study group and 125 ± 24% for the control group (P = 0.31; 95% CI, -0.6 to 20% for the difference). There were no statistically significant differences in other renal biomarkers or measures between the groups (p-neutrophil gelatinase-associated lipocalin, p-creatinine, p-urea, and estimated glomerular filtration rate). There were no other differences in outcome variables between the groups.. Intravenous administration of a single high-dose (400 IU/kg) erythropoietin did not have a renal protective effect on patients with reduced kidney function undergoing coronary artery bypass surgery.

Topics: Acute Kidney Injury; Aged; Coronary Artery Bypass; Double-Blind Method; Erythropoietin; Female; Humans; Male; Middle Aged; Prospective Studies; Recombinant Proteins

Cardiac surgery-associated acute kidney injury (CSA-AKI) is a common complication following coronary bypass graft (CABG) surgery. Multi-factorial causes of CSA-AKI involve oxidative stress and inflammation. Erythropoietin (EPO) has been shown from many studies to have a reno-protective effect. The present study was conducted to examine the role of EPO in preventing CSA-AKI.. This prospective, randomized, double-blind, placebo-controlled trial was conducted in the Cardiovascular and Thoracic Unit. One hundred patients randomly received either 200 U/kg of rHuEPO (n = 50) or saline (n = 50) intravenously three days before operation, and rHuEPO 100 U/kg or saline at operation time. The serum creatinine (SCr), estimated glomerular filtration rate (eGFR) and urine neutrophil gelatinase-associated lipocaline (NGAL) were measured in order to evaluate renal injury following CABG.. The incidence of CSA-AKI was significantly lower in rHuEPO group (14%) when compared with the placebo group (38%; p < 0.01). The mean intensive care unit (ICU) and hospital stays of the rHuEPO group were significantly shorter than the placebo group (p < 0.01). Postoperative increases in SCr and decreases in eGFR were significantly lower in the rHuEPO group than the placebo group (p < 0.05). The mean urine NGAL in rHuEPO group was significantly lower than the placebo group at 3 hr, 6 hr, 12 hr and 18 hr after CABG (p < 0.05), respectively.. Prophylaxis administration with intravenous rHuEPO before cardiac surgery decreased the incidence of CSA-AKI and urine NGAL with reduced days in ICU and hospital in elective CABG patients.. ClinicalTrials.gov: NCT01066351.

Topics: Acute Kidney Injury; Acute-Phase Proteins; Adult; Aged; Biomarkers; Cardiac Surgical Procedures; Double-Blind Method; Erythropoietin; Female; Humans; Lipocalin-2; Lipocalins; Male; Middle Aged; Placebo Effect; Preoperative Care; Prospective Studies; Proto-Oncogene Proteins

Recombinant human erythropoietin (EPO) is known to provide organ protection against ischemia-reperfusion injury through its pleiotropic properties. The aim of this single-site, randomized, case-controlled, and double-blind study was to investigate the effect of pre-emptive EPO administration on the incidence of postoperative acute kidney injury (AKI) in patients with risk factors for AKI undergoing complex valvular heart surgery.. We studied ninety-eight patients with preoperative risk factors for AKI. The patients were randomly allocated to either the EPO group (n = 49) or the control group (n = 49). The EPO group received 300 IU/kg of EPO intravenously after anesthetic induction. The control group received an equivalent volume of normal saline. AKI was defined as an increase in serum creatinine >0.3 mg/dl or >50% from baseline. Biomarkers of renal injury were serially measured until five days postoperatively.. Patient characteristics and operative data, including the duration of cardiopulmonary bypass, were similar between the two groups. Incidence of postoperative AKI (32.7% versus 34.7%, P = 0.831) and biomarkers of renal injury including cystatin C and neutrophil gelatinase-associated lipocalin showed no significant differences between the groups. The postoperative increase in interleukin-6 and myeloperoxidase was similar between the groups. None of the patients developed adverse complications related to EPO administration, including thromboembolic events, throughout the study period.. Intravenous administration of 300 IU/kg of EPO did not provide renal protection in patients who are at increased risk of developing AKI after undergoing complex valvular heart surgery.. Clinical Trial.gov, NCT01758861.

Topics: Acute Kidney Injury; Biomarkers; Cardiopulmonary Bypass; Case-Control Studies; Double-Blind Method; Epoetin Alfa; Erythropoietin; Female; Heart Valve Diseases; Hematinics; Hematocrit; Humans; Incidence; Kidney Function Tests; Male; Middle Aged; Postoperative Complications; Recombinant Proteins; Risk Factors; Treatment Outcome

Treatment of renal anemia with erythropoietic stimulating agents sometimes increases blood pressure. It is uncertain whether this is due to direct vasoconstriction and/or increased red blood cell mass.. We conducted a post-hoc analysis of 160 critically ill patients in the EARLYARF trial with elevated urinary γ-glutamyltranspeptidase and alkaline phosphatase, indicating acute kidney injury. Patients received 2 doses of intravenous (i.v.) epoetin (500 U/kg), 24 hours apart, or placebo, in a randomized, double-blind study design. Hourly intra-arterial mean arterial pressure (MAP), and norepinephrine equivalent dose (NED: determined using equipotency conversion factors for doses of epinephrine, vasopressin, phenlyephrine, or dopamine) were extracted from clinical records. The differences between baseline and maximum MAP and NED (ΔMAP and ΔNED) over 4, 24, 72-hour, and 30-day periods following study drug administration were compared between groups.. At baseline, MAP was 78 ± 14 mmHg in the epoetin group and 81 ± 15 mmHg in the placebo group (p = 0.22). There were no differences between groups in ΔMAP (6 ± 14 versus 7 ± 14 mmHg; p = 0.53), in ΔNED, or in ΔMAP adjusted for ΔNED at 4 hours, or at any time points. A subgroup analysis of only those patients not requiring vasopressor support (n = 71) also showed no differences between epoetin and placebo for all outcomes.. We concluded that intravenous high dose epoetin does not acutely increase blood pressure, suggesting no acute vasoconstrictor effect in this setting.

Topics: Acute Kidney Injury; Adult; Aged; Blood Pressure; Critical Illness; Double-Blind Method; Erythropoietin; Female; Humans; Male; Middle Aged; Recombinant Proteins; Retrospective Studies

Previous studies reported the beneficial effect of erythropoietin (EPO) in acute injuries. We followed patients with and without acute kidney injury (AKI) after coronary artery bypass grafting (CABG) and evaluated the effect of EPO on long-term outcome. We also assessed the efficacy of urinary neutrophil gelatinase-associated lipocalin (uNGAL) as a predictive marker of AKI. Seventy-one patients scheduled for elective CABG were randomly given either 300 U/kg of EPO or saline before CABG. The primary outcome was AKI, and the secondary outcome was the all-cause-mortality and composite of all-cause-mortality and end stage renal disease (ESRD). Twenty-one patients had AKI, 14 (66.7%) in the placebo group and 7 (33.3%) in the EPO group (P = 0.05). Also, uNGAL was higher in the patients with AKI than in those without AKI at baseline, 2, 4, 24, and 72 hr after CABG (P = 0.011). Among patients with AKI, 2-week creatinine (Cr) was not different from baseline Cr in the EPO group, but 2-week Cr was significantly higher than baseline Cr in the placebo group (P = 0.009). All-cause-mortality (P = 0.022) and the composite of all-cause-mortality and ESRD (P = 0.003) were reduced by EPO. EPO reduces all-cause-mortality and ESRD in patients with AKI, largely due to the beneficial effect of EPO on recovery after AKI.

Topics: Acute Kidney Injury; Acute-Phase Proteins; Aged; Aged, 80 and over; Biomarkers; Coronary Artery Bypass; Creatinine; Double-Blind Method; Epoetin Alfa; Erythropoietin; Female; Hematinics; Humans; Kaplan-Meier Estimate; Lipocalin-2; Lipocalins; Male; Middle Aged; Placebo Effect; Prospective Studies; Proto-Oncogene Proteins; Recombinant Proteins; Risk Factors; ROC Curve; Treatment Outcome

Erythropoietin (EPO) has been widely used for the treatment of anemia in chronic kidney disease (CKD). A growing body of evidence indicates that the therapeutic benefits of EPO could extend beyond the improvement of anemia. The aim of the present study was to determine whether EPO affects renovascular and oxidative stress biomarkers in pre-dialysis CKD patients with anemia.. The study was a single-arm prospective study. Fifteen CKD patients (9 males and 6 females, mean age 63 years) with anemia (mean Hb: 8.1 g/dL) were treated with recombinant human EPO; 12,000 U administered subcutaneously once every 2 weeks. Various parameters were measured before and 6 months after treatment. These included serum hemoglobin (Hb), creatinine, estimated glomerular filtration rate (eGFR), proteinuria, urinary liver-type fatty acid binding protein (L-FABP--a biomarker of renal injury), urinary 8-hydroxydeoxyguanosine (8-OHdG--a marker of oxidative stress), serum asymmetrical dimethylarginine (ADMA), carotid artery intima-media thickness (IMT) and brachial-ankle pulse wave velocity (baPWV) as vascular markers and plasma brain natriuretic peptide (BNP) levels and left ventricular ejection fraction (LVEF) as cardiac function markers and cardio-thoracic ratio (CTR) and inferior vena cava dimension (IVCS) as extra fluid retention markers.. After 6 months, serum Hb was significantly increased (p<0.001) and urinary levels of protein, L-FABP and 8-OHdG, carotid IMT, baPWV, plasma BNP and serum ADMA levels were significantly decreased (p<0.001). Serum creatinine, eGFR, LVEF, CTR and IVCS showed little difference throughout the experimental period.. These data suggest that recombinant human EPO may ameliorate renal injury, oxidative stress and progression of atherosclerosis in addition to improving anemia in CKD patients.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Acute Kidney Injury; Aged; Arginine; Atherosclerosis; Biomarkers; Cardiovascular System; Carotid Intima-Media Thickness; Deoxyguanosine; Dose-Response Relationship, Drug; Erythropoietin; Fatty Acid-Binding Proteins; Female; Glomerular Filtration Rate; Hemoglobins; Humans; Kidney; Kidney Failure, Chronic; Male; Middle Aged; Natriuretic Peptide, Brain; Oxidative Stress; Prospective Studies; Recombinant Proteins; Treatment Outcome

Depending on the specific definition, acute kidney injury (AKI) occurs in 7-40% of patients undergoing cardiac surgery. Even small changes in serum creatinine (SCr) levels are associated with increased mortality after cardiac surgery. However, there are no current methods for preventing AKI after cardiac surgery. Erythropoietin (EPO) has been shown to elicit tissue-protective effects in various experimental models. In this pilot trial, we evaluated the effectiveness of EPO in the prevention of AKI after coronary artery bypass grafting (CABG).. 71 patients scheduled for elective CABG randomly received either 300 U/kg of EPO or saline intravenously before surgery. AKI was defined as a 50% increase in SCr levels over baseline within the first 5 postoperative days. Estimated glomerular filtration rate (eGFR) was calculated from the Cockcroft-Gault equation.. Of 71 patients, 13 developed postoperative AKI: 3 of the 36 patients in the EPO group (8%) and 10 of the 35 patients in the placebo group (29%; p = 0.035). The increase in postoperative SCr concentration and the decline in postoperative eGFR were significantly lower in the EPO group than in the placebo group.. In our small, pilot trial, prophylactic administration of EPO prevents AKI and improves postoperative renal function. These data are preliminary and require confirmation in a larger clinical trial.

Topics: Acute Kidney Injury; Aged; Coronary Artery Bypass; Double-Blind Method; Erythropoietin; Female; Humans; Incidence; Male; Middle Aged; Pilot Projects; Postoperative Complications; Prospective Studies

In a prospective observational study, we examined the temporal relationships between serum erythropoietin (EPO) levels, haemoglobin concentration and the inflammatory response in critically ill patients with and without acute renal failure (ARF).. Twenty-five critically ill patients, from general and cardiac intensive care units (ICUs) in a university hospital, were studied. Eight had ARF and 17 had normal or mildly impaired renal function. The comparator group included 82 nonhospitalized patients with normal renal function and varying haemoglobin concentrations. In the patients, levels of haemoglobin, serum EPO, C-reactive protein, IL-1beta, IL-6, serum iron, ferritin, vitamin B12 and folate were measured, and Coombs test was performed from ICU admission until discharge or death. Concurrent EPO and haemoglobin levels were measured in the comparator group.. EPO levels were initially high in patients with ARF, falling to normal or low levels by day 3. Thereafter, almost all ICU patients demonstrated normal or low EPO levels despite progressive anaemia. IL-6 exhibited a similar initial pattern, but levels remained elevated during the chronic phase of critical illness. IL-1beta was undetectable. Critically ill patients could not be distinguished from nonhospitalized anaemic patients on the basis of EPO levels.. EPO levels are markedly elevated in the initial phase of critical illness with ARF. In the chronic phase of critical illness, EPO levels are the same for patients with and those without ARF, and cannot be distinguished from noncritically ill patients with varying haemoglobin concentrations. Exogenous EPO therapy is unlikely to be effective in the first few days of critical illness.

Topics: Acute Kidney Injury; Acute-Phase Reaction; Adult; Aged; Aged, 80 and over; Biomarkers; Blood Transfusion; Critical Illness; Erythropoietin; Female; Hemoglobins; Humans; Inflammation; Interleukin-6; Male; Middle Aged; Outpatients; Prospective Studies; Reference Values; Time

Topics: Acute Kidney Injury; Aged; Drug Resistance; Erythropoietin; Female; Humans; Inflammation; Male; Middle Aged; Recombinant Proteins; Renal Dialysis

Acute kidney injury (AKI) is one of frequent complications of sepsis with high mortality. Mitochondria is the center of energy metabolism participating in the pathogenesis of sepsis-associated AKI, and SIRT1/PGC1-α signaling pathway plays a crucial role in the modulation of energy metabolism. Erythropoietin (EPO) exerts protective functions on chronic kidney disease. We aimed to assess the effects of EPO on cell damage and energy metabolism in a cell model of septic AKI. Renal tubular epithelial cells HK-2 were treated with LPS and human recombinant erythropoietin (rhEPO). Cell viability was detected by CCK-8 and mitochondrial membrane potential was determined using JC-1 fluorescent probe. Then the content of ATP, ADP and NADPH, as well as lactic acid, were measured for the assessment of energy metabolism. Oxidative stress was evaluated by detecting the levels of ROS, MDA, SOD and GSH. Pro-inflammatory cytokines, including TNF-α, IL-6, and IL-1β, were measured with ELISA. Moreover, qRT-PCR and western blot were performed to detect mRNA and protein expressions. shSIRT1 was used to knockdown SIRT1, while EX527 and SR-18292 were applied to inhibit SIRT1 and PGC1-α, respectively, to investigate the regulatory mechanism of rhEPO on inflammatory injury and energy metabolism. In LPS-exposed HK-2 cells, rhEPO attenuated cell damage, inflammation and abnormal energy metabolism, as indicated by the elevated cell viability, the inhibited oxidative stress, cell apoptosis and inflammation, as well as the increased mitochondrial membrane potential and energy metabolism. However, these protective effects induced by rhEPO were reversed after SIRT1 or PGC1-α inhibition. EPO activated SIRT1/PGC1-α pathway to alleviate LPS-induced abnormal energy metabolism and cell damage in HK-2 cells. Our study suggested that rhEPO played a renoprotective role through SIRT1/PGC1-α pathway, which supported its therapeutic potential in septic AKI.

Topics: Acute Kidney Injury; Apoptosis; Energy Metabolism; Erythropoietin; Humans; Inflammation; Kidney; Lipopolysaccharides; Sepsis; Sirtuin 1

Acute kidney injury (AKI) survivors are at an increased risk of chronic kidney disease, end-stage kidney disease, and mortality. Little is known about the effect of erythropoietin (EPO), a kidney-producing hormone, in post-AKI setting. We aimed to investigate the role of EPO as a predictor of long-term outcomes in post-severe AKI survivors.. We performed a retrospective analysis of post-AKI cohort conducted between August 2018 and December 2021. Adults who survived severe AKI stages 2-3 were enrolled. Serum EPO was obtained at 1 month after hospital discharge. We explored whether EPO level could predict long-term kidney outcomes at 12 months including mortality, kidney replacement therapy, doubling serum creatinine, and major adverse kidney events at 365 days.. One hundred and twelve patients were enrolled. Median EPO level was significantly higher in non-survivors than survivors (28.9 [interquartile range: 16.2-50.7] versus 11.6 mU/mL [7.5-22.3], p = 0.003). The best EPO level cut-off was 16.2 mU/mL (sensitivity 77.8%, specificity 62.1%). Serum EPO predicted 12-month mortality with an area under the curve (AUC) of 0.69. Combining clinical model using age, baseline, and discharge kidney function with serum EPO improved prediction with AUC of 0.74. Multivariable analysis demonstrated that high-level of EPO group had significantly higher mortality compared with low-level EPO group (15.2% vs. 3.0%, p = 0.020). Hematocrit was significantly lower in high-level EPO group compared with low-level EPO group at 12 months (33.4 ± 1.1% vs. 36.0 ± 0.9%, p = 0.038).. Plasma EPO appears to be a useful marker for predicting long-term outcome in post-severe AKI survivors.

Topics: Acute Kidney Injury; Adult; Erythropoietin; Humans; Kidney; Kidney Failure, Chronic; Retrospective Studies

Topics: Acute Kidney Injury; Biomarkers; Critical Care; Erythropoietin; Fibroblast Growth Factor-23; Humans; Prospective Studies; Renal Insufficiency, Chronic; Sepsis

Serum creatinine (SCr) is a routine marker of kidney injury but also increases with dehydration and muscular work. This study was to elucidate whether increase in SCr is associated with more specific markers of kidney tubular and interstitial injury and function, during prolonged heat stress among workers at high risk of chronic kidney disease of non-traditional origin (CKDnt).. Urine monocyte chemoattractant protein-1 (MCP-1), kidney injury molecule-1 (KIM-1), calbindin, glutathione S-transferase-π (GST-π), clusterin, interleukin 18 and albumin, fractional excretion of potassium (FEK), blood haemoglobin, serum potassium, ferritin and erythropoietin were measured before and after harvest in a sample of 30 workers with a ≥0.3 mg/dL SCr increase across harvest (cases), and 53 workers with stable SCr (controls).. Urine MCP-1 (p for differential cross-harvest trend <0.001), KIM-1 (p=0.002), calbindin (p=0.02), GST-π (p=0.04), albumin (p=0.001) and FEK (p<0.001) increased in cases, whereas blood haemoglobin (p<0.001) and serum erythropoietin (p<0.001) decreased.. Several markers of tubular and interstitial injury and function changed as SCr increased across a harvest season, supporting the use of SCr as an indicator of kidney injury in physically active workers regularly exposed to heat stress. Repeated injury similar to that described here, and continued work under strenuous and hot conditions with similarly elevated injury markers is likely to worsen and possibly initiate CKDnt.

Topics: Acute Kidney Injury; Albumins; Biomarkers; Calbindins; Creatinine; Erythropoietin; Female; Heat Stress Disorders; Humans; Kidney; Male; Potassium; Renal Insufficiency, Chronic; Saccharum

Mannitol and hypertonic saline are used to treat raised intracerebral pressure in patients with traumatic brain injury, but their possible effects on kidney function and mortality are unknown.. A post hoc analysis of the erythropoietin trial in traumatic brain injury (ClinicalTrials.gov NCT00987454) including daily data on mannitol and hypertonic saline use.. Twenty-nine university-affiliated teaching hospitals in seven countries.. A total of 568 patients treated in the ICU for 48 hours without acute kidney injury of whom 43 (7%) received mannitol and 170 (29%) hypertonic saline.. None.. We categorized acute kidney injury stage according to the Kidney Disease Improving Global Outcome classification and defined acute kidney injury as any Kidney Disease Improving Global Outcome stage-based changes from the admission creatinine. We tested associations between early (first 2 d) mannitol and hypertonic saline and time to acute kidney injury up to ICU discharge and death up to 180 days with Cox regression analysis. Subsequently, acute kidney injury developed more often in patients receiving mannitol (35% vs 10%; p < 0.001) and hypertonic saline (23% vs 10%; p < 0.001). On competing risk analysis including factors associated with acute kidney injury, mannitol (hazard ratio, 2.3; 95% CI, 1.2-4.3; p = 0.01), but not hypertonic saline (hazard ratio, 1.6; 95% CI, 0.9-2.8; p = 0.08), was independently associated with time to acute kidney injury. In a Cox model for predicting time to death, both the use of mannitol (hazard ratio, 2.1; 95% CI, 1.1-4.1; p = 0.03) and hypertonic saline (hazard ratio, 1.8; 95% CI, 1.02-3.2; p = 0.04) were associated with time to death.. In this post hoc analysis of a randomized controlled trial, the early use of mannitol, but not hypertonic saline, was independently associated with an increase in acute kidney injury. Our findings suggest the need to further evaluate the use and choice of osmotherapy in traumatic brain injury.

Topics: Acute Kidney Injury; Brain Injuries, Traumatic; Diuretics, Osmotic; Erythropoietin; Female; Fluid Therapy; Humans; Intracranial Pressure; Male; Mannitol; Saline Solution, Hypertonic; Treatment Outcome

The high mortality rate associated with acute kidney injury (AKI) is commonly due to progressive, inflammatory multiple organ dysfunction, which often involves neurological complications. The AKI-stimulated mechanisms leading to brain dysfunction are not well understood, which hinders development of new therapeutic avenues to minimize AKI-mediated neural effects. The hippocampal CA1 area is a particularly vulnerable region during AKI but the electrophysiological and inflammatory mechanisms involved in this vulnerability remain largely unknown. Here, we used immunohistochemistry to quantitatively investigate the number of astrocytes expressing glial fibrillary acidic protein (GFAP) as an indicator of inflammation, and whole cell patch clamp to evaluate electrophysiological changes in CA1 at different time points following induction of bilateral renal ischemia (BRI) in male Wistar rats. Further we evaluated the effectiveness of erythropoietin (EPO, 1000 U/kg i.p.) in mitigating BRI-associated changes. Plasma concentrations of blood urea nitrogen (BUN) were significantly enhanced at 24 h, 72 h and 1 week, and creatinine (Cr) was increased at 24 h after reperfusion, which were changes reduced by EPO. BRI led to an increase in CA1 GFAP-positive cells 24 h and 72 h, but not 1 week, after reperfusion, and EPO reversed this effect of BRI at 24 h. Additionally, BRI caused an increase in the peak amplitude and coefficient of variation of CA1 pyramidal neuronal action potentials, which were changes not seen in presence of EPO. When taken together, altered neuronal electrophysiological properties and astrogliosis could contribute to the neurological complications induced by AKI, and EPO offers hope as a potential neuroprotective agent.

Topics: Acute Kidney Injury; Animals; Astrocytes; Blood Urea Nitrogen; CA1 Region, Hippocampal; Creatinine; Disease Models, Animal; Erythropoietin; Ischemia; Kidney; Male; Neurons; Neuroprotective Agents; Rats; Rats, Wistar

Helix B-Surface peptide (HBSP) is the latest discovered erythropoietin (EPO) analogue that can retain the activity of EPO. EPO, which is widely used for treating renal anemia, has recently been proved to have protective effects on ischemia-reperfusion injury of brain, heart and kidney. The protective effects of EPO and HBSP on cardiac function were found in rats with myocardial ischemia. However, the effect of HBSP on sepsis-induced renal injury is still unclear.. Establishment of rat kidney injury model and treated with HBSP and lipoposaccharide. Renal injury in rats was observed by hematoxylin-eosin staining and injury index score. Levels of serum creatinine (SCr), blood urea nitrogen (BUN) and Cystatin C (Cys C) were detected using fully automatic biochemical analyzer, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and IL-1β were detected by enzyme-linked immunosorbent assay. Western blot analysis was performed to determine the role of HBSP in phosphatidylinositol 3-kinase (PI3K)/Akt pathway.. Acute kidney injury (AKI) appeared after modeling, however, HBSP alleviated the pathological conditions of the kidney injury. In addition, HBSP lowered kidney injury index score in the rats, and decreased the levels of SCr, BUN, Cys C, TNF-α, IL-6 and IL-1β, moreover, HBSP also showed the effect of activating PI3K/Akt pathway.. HBSP alleviated lipoposaccharide-induced AKI and improved kidney function of the rats with sepsis. More importantly, the effects of HBSP on lipoposaccharid-induced AKI were realized via activating PI3K/Akt pathway. The findings in the current study provide new insights into the therapeutic mechanism for treating the disease.

Topics: Acute Kidney Injury; Animals; Disease Models, Animal; Erythropoietin; Kidney; Peptide Fragments; Phosphatidylinositol 3-Kinase; Protective Agents; Proto-Oncogene Proteins c-akt; Rats; Sepsis; Signal Transduction; Treatment Outcome

Acute kidney injury (AKI) is the most common condition in hospitalized patients. As ischemia/reperfusion-induced AKI (IR-AKI) is as a major contributor to end-stage disease, an effective therapeutic intervention for IR-AKI is imperative. Erythropoietin (EPO) is a potent stimulator of erythroid progenitor cells and is significantly upregulated during hypoxia. Here, we investigated the renoprotective effects of EPO in an IR-AKI mouse model. Mice were assigned to sham, EPO only, and IR only groups, and the IR group was treated with EPO prior to injury. EPO was administered twice at 30 min prior to bilateral renal artery occlusion, and 5 min before reperfusion, with all mice sacrificed 24 h after IR-AKI. The serum was harvested for renal functional measurements. The kidneys were subjected to histological evaluation, and the biochemical changes associated with renal injury were assessed. EPO significantly attenuated the renal dysfunction associated with IR-AKI, as well as tissue injury. Apoptotic cell death and oxidative stress were significantly reduced in EPO-treated mice. Macrophage infiltration and expression of ICAM-1 and MCP-1 were also significantly reduced in EPO-treated mice. Furthermore, the expression of inflammasome-related factors (NLRP1, NLRP3, and caspase-1 cleavage), via the activation of the COX-2 and NF-B signaling pathways were significantly reduced following EPO treatment. To our knowledge, this is the first study to demonstrate that inflammasome-mediated inflammation might be a potential target of EPO as a treatment for ischemic AKI.

Topics: Acute Kidney Injury; Adaptor Proteins, Signal Transducing; Animals; Apoptosis; Apoptosis Regulatory Proteins; Caspase 1; Cell Hypoxia; Cyclooxygenase 2; Disease Models, Animal; Erythroid Precursor Cells; Erythropoietin; Gene Expression Regulation; Humans; Inflammasomes; Kidney; Mice; NLR Family, Pyrin Domain-Containing 3 Protein; Reperfusion Injury

Topics: Acute Kidney Injury; Anemia; Betacoronavirus; Coronavirus Infections; COVID-19; Erythropoiesis; Erythropoietin; Hematinics; Humans; Pandemics; Pneumonia, Viral; SARS-CoV-2; Treatment Outcome

Topics: Acute Kidney Injury; Diabetes Mellitus; Diabetic Nephropathies; Erythropoietin; Humans; Kidney; Nephrology

If the kidney suddenly loses its ability to remove waste, acute kidney injury (AKI) will occur that dangerous levels of waste may accumulate, and the chemical composition of the blood may become unbalanced. AKI usually develops rapidly within a few days and is very common in hospitalized patients, especially those in urgent need of intensive care. AKI can be fatal and requires serious treatment. However, it can be reversible. The purpose of this research was to investigate the effects of recombinant human erythropoietin (rhEPO) on the expression of nuclear factor E2-related factor 2 (Nuclear factor E2, Nrf2) and Heme oxygenase (HO-1) in rats AKI and its protective effects on the kidney. For this purpose, 40 SD rats were averagely and randomly divided into 4 groups: control group, sham operation group, model group, and rhEPO group. The rhEPO group was injected with 5% glucose mixed with rhEPO to form 3000 IU/ (kg/d) rhEPO. Except for the rhEPO group, three groups were injected with 5% glucose at the same dose level as the rhEPO group respectively. Before the third administration, the renal pedicle was clamped for 60 min and then perfused for 24 hours. Changes of Serum creatinine (Scr) and Urea nitrogen (BUN) of rats in each group were detected before and after modeling. Twenty-four hours after modeling, renal tissues of rats in each group were taken, and expressions of Nrf2 and HO-1 in renal tissues were detected by qRT-PCR and Western blot methods. There were no significant differences in Scr and BUN contents in the four groups before modeling (p> 0.05). There were no significant differences in Scr and BUN contents in the control group and sham operation group after modeling compared with those before modeling (p> 0.05). Expressions of Nrf2 and HO-1 in the rhEPO group were higher than those in the model group, the sham operation group and the control group (p< 0.05), while expressions of Nrf2 and HO-1 in model group were higher than those in sham operation group and control group (p< 0.05). There were no significant differences in expressions of Nrf2 and HO-1 between the sham operation group and the control group (p> 0.05). rhEPO can induce expressions of Nrf2 and HO-1 in AKI rats. RhEPO has a protective effect on the kidney, which may be related to expressions of Nrf2 and HO-1.

Topics: Acute Kidney Injury; Animals; Blood Urea Nitrogen; Creatinine; Erythropoietin; Heme Oxygenase (Decyclizing); Humans; Kidney; Male; NF-E2-Related Factor 2; Protective Agents; Rats; Rats, Sprague-Dawley; Recombinant Proteins

The kidneys are the major organs for erythropoietin (EPO) production in adults, and thus, kidney damage results in reduced EPO levels and anemia. Inhibitors of Hypoxia-inducible factor-prolyl hydroxylase domain-containing protein (HIF-PHD) are awaited as new therapeutic options for renal anemia. It can be predicted that most patients who receive HIF-PHD inhibitors have renal dysfunction as a cause of anemia. Therefore, in the present study, we investigated the effects of the HIF-PHD inhibitor molidustat on anemia and renal dysfunction when initiated after the onset of renal anemia. Male C57BL/6J mice received adenine orally to induce nephropathy. After the onset of nephropathy, the mice were treated with either vehicle or molidustat. After 4 weeks of administration, vehicle-treated mice displayed significant anemia, and molidustat ameliorated this anemia. Vehicle-treated mice exhibited reduced creatinine clearance and body weight, increased blood urea nitrogen levels, histopathological changes, immune cell infiltration, and dehydration. Molidustat reversed immune cell infiltration, dehydration, and renal fibrosis without improving renal functional parameters. In conclusion, molidustat treatment initiated after the onset of nephropathy and renal anemia reversed anemia in mice. Molidustat improved some parameters of renal abnormality, but it did not restore renal function.

Topics: Acute Kidney Injury; Adenine; Anemia; Animals; Disease Models, Animal; Erythropoietin; Hypoxia-Inducible Factor 1; Male; Mice, Inbred C57BL; Prolyl-Hydroxylase Inhibitors; Pyrazoles; Triazoles

Substantial progress was made in acute kidney injury (AKI) over the past 10 years, but no therapeutic interventions have been shown to prevent AKI or accelerate functional recovery after injury. A large number of preclinical studies supports the use of recombinant human erythropoietin (rHuEPO) to prevent AKI, but the clinical trial data are inconclusive. To address concerns about preclinical study design and reporting in AKI, we here presented our rigorous experiments on the use of rHuEPO in a mouse model simulating the most common post-ischemic AKI in patients.. Use of saline vehicle or rHuEPO (100 or 1000 U/KgBW) in mice subjected to AKI induced by ischemia-reperfusion injury of left kidney 2 weeks after right nephrectomy (NX + IRI).. NX + IRI resulted in a reproducible AKI model. Use of rHuEPO as a pretreatment or posttreatment did not affect AKI severity, functional recovery, and mouse survival regardless of gender, injury severity, or doses of rHuEPO. Administering rHuEPO with 1000 U/KgBW did increase hematocrit and modulate AKI kidney macrophages by Nos2 downregulation and Ccl17 upregulation. Active expression of erythropoietin receptor (EPOR) was not identified in renal cells by lineage tracing study, whereas expression of colony-stimulating factor 2 receptor β (CSF2Rβ) was identified in kidney macrophages and upregulated after AKI. Both EPOR and CSF2Rβ were identified in cultured bone marrow derived macrophages, possibly mediated the robust inhibition of cytokine-induced phenotype switching by rHuEPO.. Use of rHuEPO can modulate macrophage function but not the post-ischemic AKI severity, functional recovery and survival in mice.

Topics: Acute Kidney Injury; Animals; Apoptosis; Disease Models, Animal; Erythropoietin; Female; Kidney; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nephrectomy; Recombinant Proteins; Reperfusion Injury; Signal Transduction

Backgrounds/Objectives: Elevated erythropoietin (EPO) is observed in human acute kidney injury (AKI). Whether blood EPO level is associated with mortality or other organ dysfunction in critically ill patients is unknown.. A prospective observational cohort study of 162 AKI patients requiring renal replacement therapy (RRT) was conducted in our intensive care unit (ICU) during October 2013 through October 2016. We evaluated the relation with plasma EPO at RRT initiation and 90-day mortality, hemoglobin, urine output, and sequential organ failure assessment (SOFA) score until day 7 or discharge from the ICU.. The analysis revealed that EPO was significantly associated with 90-day mortality with an adjusted hazard ratio of 2.13 (95% CI 1.11-5.78). Hemoglobin levels, RRT dependence, and daily urine output on days 1 through 7 did not differ between the high EPO group (≥56.2 mIU/mL) and low EPO groups (< 56.2 mIU/mL). As for organ dysfunction, hyperbilirubinemia patients (≥2.0 mg/dL; hepatic SOFA ≥2) were more frequent in the high EPO group (62.1 vs. 37.9%; p < 0.05), while other SOFA scores did not differ between both groups. Exacerbation of hepatic dysfunction was observed more frequently in the high EPO than the low EPO group (49.3 vs. 27.2%; p < 0.05).. Elevated EPO was not associated with anemia or RRT dependence. However, higher rates of mortality and hepatic dysfunction were observed in high EPO patients than in low EPO patients.

Topics: Acute Kidney Injury; Aged; Erythropoietin; Female; Humans; Liver; Male; Middle Aged; Prospective Studies; Renal Replacement Therapy

Nowadays, people diagnosed sepsis may develop acute kidney injury (AKI), resulting heavy burden of health care. Recombinant human erythroprotein (rhEPO) has been suggested to have multifunction and may be used in the prevention or treatment of AKI, and its underlying mechanism remains largely unknown.. In our study, cell model induced by LPS-activated cell apoptosis in vitro and AKI animal model caused by lipopolysaccharide (LPS) injection in vivo. MTT assay and Flow Cytometry were conducted to analyze cell viability and apoptosis, respectively. Western bot was used to analyze expressions of apoptosis and autophagy associated proteins, and effects on AMPK/SIRT1 pathway.. Our results suggested that rhEPO inhibited LPS-induced cell apoptosis in HK-2 and HEK-293. Moreover, we found that rhEPO activated autophagy to prevented cell apoptosis, changing the expression level of autophagy associated proteins such as LC3-I/LC3-II and P62, and AMPK/SIRT1 pathway was involved in its regulation. Additionally, both EX527 (SIRT1 inhibitor) and Compound C (AMPK inhibitor) blocked the autophagy effects caused by rhEPO and thus reversed the anti-apoptotic effects of rhEPO. Furthermore, our data demonstrated that rhEPO inhibited LPS-induced kidney tubular injury and decreased the expression level of apoptotic proteins by altering the expression level of autophagy related proteins and AMPK/SIRT1 pathway related proteins in vitro.. Collectively, rhEPO suppressed LPS-induced cell apoptosis via AMPK/SIRT1 pathway mediated autophagy, and modulating their levels may serve as potential way in preventing AKI.

Topics: Acute Kidney Injury; AMP-Activated Protein Kinases; Animals; Apoptosis; Autophagy; Erythropoietin; HEK293 Cells; Humans; Lipopolysaccharides; Male; Rats, Wistar; Recombinant Proteins; Sepsis; Signal Transduction; Sirtuin 1

The erythropoietin receptor (EpoR) is widely expressed but its renoprotective action is unexplored. To examine the role of EpoR in vivo in the kidney, we induced acute kidney injury (AKI) by ischemia-reperfusion in mice with different EpoR bioactivities in the kidney. EpoR bioactivity was reduced by knockin of wild-type human EpoR, which is hypofunctional relative to murine EpoR, and a renal tubule-specific EpoR knockout. These mice had lower EPO/EpoR activity and lower autophagy flux in renal tubules. Upon AKI induction, they exhibited worse renal function and structural damage, more apoptosis at the acute stage (<7 days), and slower recovery with more tubulointerstitial fibrosis at the subacute stage (14 days). In contrast, mice with hyperactive EpoR signaling from knockin of a constitutively active human EpoR had higher autophagic flux, milder kidney damage, and better renal function at the acute stage but, surprisingly, worse tubulointerstitial fibrosis and renal function at the subacute stage. Either excess or deficient EpoR activity in the kidney was associated with abnormal peritubular capillaries and tubular hypoxia, creating a "U-shaped" relationship. The direct effects of EpoR on tubular cells were confirmed in vitro by a hydrogen peroxide model using primary cultured proximal tubule cells with different EpoR activities. In summary, normal erythropoietin (EPO)/EpoR signaling in renal tubules provides defense against renal tubular injury maintains the autophagy-apoptosis balance and peritubular capillary integrity. High and low EPO/EpoR bioactivities both lead to vascular defect, and high EpoR activity overides the tubular protective effects in AKI recovery.

Topics: Acute Kidney Injury; Animals; Apoptosis; Autophagy; Capillaries; Cell Hypoxia; Cells, Cultured; Disease Models, Animal; Erythropoietin; Fibrosis; Humans; Kidney Tubules, Proximal; Mice, 129 Strain; Mice, Transgenic; Neovascularization, Physiologic; Receptors, Erythropoietin; Signal Transduction

It is accepted that osteoblasts/osteocytes are the major source for circulating fibroblast growth factor 23 (FGF23). However, erythropoietic cells of bone marrow also express FGF23. The modulation of FGF23 expression in bone marrow and potential contribution to circulating FGF23 has not been well studied. Moreover, recent studies show that plasma FGF23 may increase early during acute kidney injury (AKI). Erythropoietin, a kidney-derived hormone that targets erythropoietic cells, increases in AKI. Here we tested whether an acute increase of plasma erythropoietin induces FGF23 expression in erythropoietic cells of bone marrow thereby contributing to the increase of circulating FGF23 in AKI. We found that erythroid progenitor cells of bone marrow express FGF23. Erythropoietin increased FGF23 expression in vivo and in bone marrow cell cultures via the homodimeric erythropoietin receptor. In experimental AKI secondary to hemorrhagic shock or sepsis in rodents, there was a rapid increase of plasma erythropoietin, and an induction of bone marrow FGF23 expression together with a rapid increase of circulating FGF23. Blockade of the erythropoietin receptor fully prevented the induction of bone marrow FGF23 and partially suppressed the increase of circulating FGF23. Finally, there was an early increase of both circulating FGF23 and erythropoietin in a cohort of patients with severe sepsis who developed AKI within 48 hours of admission. Thus, increases in plasma erythropoietin and erythropoietin receptor activation are mechanisms implicated in the increase of plasma FGF23 in AKI.

Topics: Acute Kidney Injury; Animals; Bone Marrow Cells; Disease Models, Animal; Erythroid Precursor Cells; Erythropoietin; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Male; Mice, Inbred C57BL; Prospective Studies; Rats, Sprague-Dawley; Receptors, Erythropoietin; Recombinant Proteins; Sepsis; Shock, Hemorrhagic; Time Factors; Up-Regulation

Hemodilutional anemia is associated with acute kidney injury (AKI) and mortality in patients undergoing cardiac surgery by mechanisms that may include tissue hypoxia. Our hypothesis was to assess if changes in the potential hypoxic biomarkers, including methemoglobin and erythropoietin, correlated with a decrease in hemoglobin (Hb) concentration following hemodilution on cardiopulmonary bypass (CPB).. Arterial blood samples were taken from patients (n = 64) undergoing heart surgery and CPB at baseline, during CPB, following CPB, and in the intensive care unit (ICU). Potential hypoxic biomarkers were measured, including methemoglobin, plasma Hb, and erythropoietin. Data were analyzed by repeated measures one-way analysis of variance on ranks and linear regression.. Hemoglobin levels decreased following CPB and methemoglobin increased in the ICU (P < 0.001 for both). No correlation was observed between the change in Hb and methemoglobin (P = 0.23). By contrast, reduced Hb on CPB correlated with increased lactate, reduced pH, and increased erythropoietin levels following CPB (P ≤ 0.004 for all). Increased plasma Hb (P < 0.001) also correlated with plasma erythropoietin levels (P < 0.001).. These data support the hypothesis that erythropoietin rather than methemoglobin is a potential biomarker of anemia-induced tissue hypoxia. The observed relationships between decreased Hb during CPB and the increase in lactate, reduced pH, and increase in erythropoietin levels suggest that early changes in plasma erythropoietin may be a pragmatic early biomarker of anemia-induced renal hypoxia. Further study is required to determine if anemia-induced increases in erythropoietin may predict AKI in patients undergoing cardiac surgery.. www.clinicaltrials.gov (NCT01883713). Registered 21 June 2013.

Topics: Acute Kidney Injury; Aged; Anemia; Biomarkers; Cardiac Surgical Procedures; Cardiopulmonary Bypass; Erythropoietin; Female; Hemodilution; Hemoglobins; Humans; Hypoxia; Male; Methemoglobin; Middle Aged; Prospective Studies

Acute kidney injury (AKI) is a frequent complication of sepsis, with a high mortality. Hallmarks of septic-AKI include inflammation, endothelial injury, and tissue hypoxia. Therefore, it would be of interest to develop therapeutic approaches for improving the microvascular damage in septic-AKI. Erythropoietin (EPO) is a well-known cytoprotective multifunctional hormone. Thus, the aim of this study was to evaluate the protective effects of EPO on microvascular injury in a murine model of endotoxemic AKI. Male Balb/c mice were divided into four groups: control, LPS (8 mg/kg, ip.), EPO (3000 IU / kg, sc.) and LPS + EPO. A time course study (0-48 h) was designed. Experiments include, among others, immunohistochemistry and Western blottings of hypoxia-inducible transcription factor (HIF-1α), erythropoietin receptor (EPO-R), vascular endothelial growth factor system (VEGF/VEGFR-2), platelet and endothelial adhesion molecule-1 (PeCAM-1), inducible nitric oxide synthase (iNOS) and phosphorylated nuclear factor kappa B p65 (NF-κB). Data showed that EPO attenuates renal microvascular damage during septic-AKI progression through a) the decrease of HIF-1 alpha, iNOS, and NF-κB and b) the enhancement of EPO-R, PeCAM-1, VEGF, and VEGFR-2 expression. In summary, EPO renoprotection involves the attenuation of septic-induced renal hypoxia and inflammation as well as ameliorates the endotoxemic microvascular injury.

Topics: Acute Kidney Injury; Animals; Blotting, Western; Disease Models, Animal; Disease Progression; Endotoxemia; Erythropoietin; Immunohistochemistry; Inflammation; Lipopolysaccharides; Male; Mice; Mice, Inbred BALB C; Microvessels; Sepsis; Time Factors

Anemia is a common feature in critically ill patients. Serum soluble-Fas (sFas) levels are associated with anemia in chronic kidney disease. It is possible that sFas levels are also associated with anemia in acute kidney injury (AKI) patients. The study aims to investigate the relationship between serum levels of sFas, erythropoietin (Epo), inflammatory cytokines, and hemoglobin (Hb) concentration in critically ill patients with AKI. We studied 72 critically ill patients with AKI (AKI group; n = 53) or without AKI (non-AKI group; n = 19), and 18 healthy volunteers. Serum sFas, Epo, tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, IL-10, iron status, and Hb concentration were analyzed in all groups. We also investigated the correlation between these variables in the AKI group. Critically ill patients (AKI and non-AKI groups) had higher serum levels of Epo than healthy volunteers. Hb concentration was lower in the AKI group than in the other groups. Serum sFas, IL-6, TNF-α, and ferritin levels were higher in the AKI group. Hb concentration correlated negatively with serum IL-6 (r = -0.37, P = 0.008), sFas (r = -0.35, P = 0.01), and Epo (r = -0.27, P = 0.04), while serum sFas correlated positively with iron levels (r = 0.36, P = 0.008) and IL-6 (r = 0.28, P = 0.04) in the AKI group. In multivariate analysis, after adjusting for markers of inflammation and iron stores, only serum sFas levels (P = 0.03) correlated negatively with Hb concentration in the AKI group. Serum Epo and inflammatory cytokine levels are elevated in critically ill patients with or without AKI. Serum levels of sFas are elevated and independently associated with anemia in critically ill patients with AKI.

Topics: Acute Kidney Injury; Adult; Aged; Aged, 80 and over; Anemia; Biomarkers; Cytokines; Erythropoietin; fas Receptor; Female; Humans; Inflammation; Inflammation Mediators; Male; Middle Aged

Methods enabling kidney-specific gene transfer in adult mice are needed to develop new therapies for kidney disease. We attempted kidney-specific gene transfer following hydrodynamic tail vein injection using the kidney-specific podocin and gamma-glutamyl transferase promoters, but found expression primarily in the liver. In order to achieve kidney-specific transgene expression, we tested direct hydrodynamic injection of a DNA solution into the renal pelvis and found that luciferase expression was strong in the kidney and absent from extra-renal tissues. We observed heterogeneous, low-level transfection of the collecting duct, proximal tubule, distal tubule, interstitial cells, and rarely glomerular cells following injection. To assess renal injury, we performed the renal pelvis injections on uninephrectomised mice and found that their blood urea nitrogen was elevated at two days post-transfer but resolved within two weeks. Although luciferase expression quickly decreased following renal pelvis injection, the use of the piggyBac transposon system improved long-term expression. Immunosuppression with cyclophosphamide stabilised luciferase expression, suggesting immune clearance of the transfected cells occurs in immunocompetent animals. Injection of a transposon expressing erythropoietin raised the haematocrit, indicating that the developed injection technique can elicit a biologic effect in vivo. Hydrodynamic renal pelvis injection enables transposon mediated-kidney specific gene transfer in adult mice.

Topics: Acute Kidney Injury; Animals; DNA Transposable Elements; Erythropoietin; Gene Expression; Gene Expression Regulation; Gene Transfer Techniques; Genes, Reporter; Genetic Vectors; Hydrodynamics; Immunosuppressive Agents; Kidney; Male; Mice; Organ Specificity; Promoter Regions, Genetic; Transfection

Erythropoietin (EPO) is a well-known hormone that is clinically used for the treatment of anemia. Very recently, an increasing body of evidence showed that EPO could still regulate bioactivities of macrophages. However, the details about the immunomodulatory effect of EPO on macrophages are not fully delineated, particularly in the setting of renal damages. Therefore, in the present study, we determined whether EPO could exert an impact on the dynamics of macrophages in a well-established model of rhabdomyolysis-induced acute kidney injury and explored the potential mechanisms. EPO was found to ameliorate kidney injuries by reducing macrophages recruitment and promoting phenotype switch toward M2 macrophages in vivo. It was also confirmed that EPO could directly suppress pro-inflammatory responses of M1 macrophages and promote M2 marker expression in vitro. Data indicated the possible involvement of Jak2/STAT3/STAT6 pathway in the augmentation of EPO on M2 polarization. These results improved the understanding of the immunoregulatory capacity of EPO on macrophages, which might optimize the therapeutic modalities of EPO.

Topics: Acute Kidney Injury; Animals; Erythropoietin; Janus Kinase 2; Macrophages; Mice; Rhabdomyolysis; Signal Transduction; STAT3 Transcription Factor; STAT6 Transcription Factor

The effects of erythropoietin (EPO) alone or in conjunction with ischemic preconditioning (IPC) on nitric oxide synthase as well as comparing their effects on oxidative stress and proinflammatory cytokines are studied. Rats underwent bilateral renal ischemia of 50 min followed by 24 h reperfusion. They were administered EPO (5000 iu/kg i.p.) and/or subjected to IPC and sacrificed after 24 h, then plasma and tissue samples were obtained. Treatment of either EPO or IPC and their combination attenuates oxidative stress, decreases histological damages, inhibits proinflammatory response, and up-regulates iNOS and eNOS gene expression compared to IR group. In addition, EPO+IPC and EPO treatment produced significant up-regulation in iNOS gene expression compared to IPC group. In IPC and EPO+IPC groups, more powerful effect on up-regulation of eNOS gene expression was shown compared to EPO group. Our findings suggest that treatment with EPO or IPC and their combination improve renal function and preserve tubular damage induced by IR injury. These advantageous effects were closely related to reducing oxidative stress, suppressing proinflammatory response and enhancing generation of NO. IPC was more powerful in enhancement of eNOS gene expression compared to EPO that was more effective in increasing of iNOS gene expression.

Topics: Acute Kidney Injury; Animals; Combined Modality Therapy; Erythropoietin; Ischemic Preconditioning; Male; Nitric Oxide Synthase; Rats; Rats, Wistar; Reperfusion Injury; Treatment Outcome; Up-Regulation

Erythropoietin (EPO) is shown to exert protective effects on different tissues in haemorrhagic shock (HS) states. Nitric oxide (NO), as a multifunctional signaling molecule, is implicated in diverse physiologic and pathologic processes. In order to understand the exact mechanism of EPO protection, in this study we evaluated the role of different NOS enzymes in the EPO signaling pathway in male rats.. Rats were randomized to five groups: 1) Sham, 2) HS 3) EPO 4) L-NAME, a non-specific NOS inhibitor 5) 1400W, a specific iNOS inhibitor. HS was induced by withdrawal of 50% of total blood volume. After 2h, resuscitation was performed with the shed blood and Ringer's lactate. In group 3, rats were treated with EPO (300IU/kg, i.v.) over 10min before HS induction. In the L-NAME and 1400W groups, L-NAME (10mg/kg, i.p.) and 1400W (2mg/kg, i.p.) were administered 30min before EPO injection. Blood and kidney tissue samples were obtained 3h after resuscitation.. EPO increased the survival rate and significantly improved kidney function and histology compared to the HS group. There were less renal oxidative stress, apoptosis and systemic inflammatory responses in the EPO group. EPO increased eNOS and more abundantly iNOS mRNA expressions. L-NAME and 1400W significantly abolished all beneficial effects of EPO.. In this in vivo animal model, we showed that EPO administration prior to HS attenuates renal injury and dysfunction in rats. The protective effects of EPO may be mediated by nitric oxide and the expression of different NOS enzymes, especially iNOS isoform.

Topics: Acute Kidney Injury; Animals; Disease Models, Animal; Erythropoietin; Kidney; Male; Nitric Oxide; Nitric Oxide Synthase Type II; Oxidative Stress; Rats; Rats, Wistar; Shock, Hemorrhagic

Acute ischemia-reperfusion (I/R) injury is the most common causes of acute renal failure in daily clinical\ practice. It has been recognized that endothelial cell dysfunction and microvascular injury as the pathophysiological changes during I/R injury. Protective effects of erythropoietin (EPO) have been demonstrated in various experimental models of I/R induced injury. Therefore, the aim of the present study was to investigate whether EPO administration has renoprotective effect against acute renal failure I/R injury in rats by promotion of endothelial progenitor cells (EPCs) mobilization and\ neovascularization.. Male Sprague-Dawley rats were pretreated with EPO (1,000 IU/kg/day, ip); or the placebo for 3 days before the induction of I/R procedure. On day 4, the bilateral renal occlusion for 30 min operations to produce renal I/R injury or treatment with EPO 30 min before the initiation of I/R were done. At the end of the reperfusion period at day 1 day 2 and day 4, blood and renal tissues were collected to investigate renal function and pathohistological examination. The expression levels of CAV-1 and CD34 were determined for circulating of EPCs in blood, while CD34, CAV-1 and VEGFR-2 were investigated for mobilized EPCs in kidney, using real time PCR. The expression level of VEGF was also examined to indicate the angiogenesis in kidney using real time PCR and western blotting.. In the I/R group, the significantly increased values of serum urea and creatinine were found on Day 1 after ischemia, as compared to sham group. The development of tubular epithelial cell necrosis, peritubular capillary congestion and mild interstitial infiltration has been observed in this group. Administration of EPO in I/R rat was significantly improved renal function and significantly less the tubular damage. The treatment with EPO significantly increased in expression levels of CD34 and CAV-1 in blood, and also CAV-1, VEGFR-2 and VEGF in kidney tissue in this group, as compared to the I/R group.. These results suggest that treatment with EPO protects the kidney from ischemic acute renal injury via\ increasing the mobilization and recruitment of EPCs, resulting in the induction of expression of VEGF that might play an important role in the repair response.

Topics: Acute Kidney Injury; Animals; Blood Urea Nitrogen; Creatinine; Disease Models, Animal; Erythropoietin; Ischemia; Kidney; Male; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2

Erythropoietin (EPO) production is stimulated by hypoxia in the kidney. Ischaemic injury plays a crucial role in the pathogenesis of acute kidney injury (AKI). However, EPO concentrations in critically ill patients complicated with AKI have not been evaluated sufficiently. This study was conducted to clarify the factors associated with plasma EPO concentrations in AKI.. This study prospectively enrolled 98 critically ill adult patients treated at the adult mixed ICU. Plasma EPO, insulin-like growth factor-binding protein-1 (IGFBP-1), neutrophil gelatinase-associated lipocalin (NGAL), interleukin-6 (IL-6) and urinary N-acetyl-β-D-glucosaminidase (NAG) were measured on ICU admission.. Acute kidney injury occurred in 42 (42.9%) patients. Significantly higher plasma EPO in the AKI group was detected than in the non-AKI group (16.13 (9.87-28.47) mIU/mL versus 27.81 (10.16-106.02) mIU/mL, P < 0.05). Plasma IGFBP-1 in the AKI group was also significantly higher than in the non-AKI group (19 208 (8820-50 780) pg/mL versus 63 199 (25 289-147 489) pg/mL, P < 0.05). Plasma EPO concentration was negatively correlated with haemoglobin in the non-AKI group with statistical significance, but not in the AKI group. Multiple logistic regression analysis revealed that plasma EPO in the AKI group was associated significantly with plasma IGFBP-1 and complication of diabetes mellitus, but not the haemoglobin concentration, partial pressure of arterial oxygen (PaO2 ), and IL-6.. Not low arterial oxygen tension, haemoglobin concentration, and inflammation evaluated by IL-6 but plasma IGFBP-1 was significantly associated with plasma EPO concentration in AKI, suggesting an unknown mechanism related to systemic stress conditions for EPO regulation in AKI.

Topics: Acute Kidney Injury; Adult; Aged; Biomarkers; Case-Control Studies; Chi-Square Distribution; Critical Illness; Erythropoietin; Female; Humans; Insulin-Like Growth Factor Binding Protein 1; Logistic Models; Male; Middle Aged; Multivariate Analysis; Predictive Value of Tests; Prospective Studies; Up-Regulation

Beneficial effects of erythropoietin (EPO) have been reported in acute kidney injury (AKI) when administered prior to induction of AKI. We studied the effects of EPO administration on renal function shortly after ischemic AKI. For this purpose, rats were subjected to renal ischemia for 30 min and EPO was administered at a concentration of 500 U/kg either i.v. as a single shot directly after ischemia or with an additional i.p. dose until 3 days after surgery. The results were compared with AKI rats without EPO application and a sham-operated group. Renal function was assessed by measurement of serum biochemical markers, histological grading, and using an isolated perfused kidney (IPK) model. Furthermore, we performed flow cytometry to analyze the concentration of endothelial progenitor cells (EPCs) in the peripheral blood and renal vessels. Following EPO application, there was only a statistically non-significant tendency of serum creatinine and urea to improve, particularly after daily EPO application. Renal vascular resistance and the renal perfusion rate were not significantly altered. In the histological analysis, acute tubular necrosis was only marginally ameliorated following EPO administration. In summary, we could not demonstrate a significant improvement in renal function when EPO was applied after AKI. Interestingly, however, EPO treatment resulted in a highly significant increase in CD133- and CD34-positive EPC both in the peripheral blood and renal vessels.

Topics: AC133 Antigen; Acute Kidney Injury; Animals; Blood Vessels; Creatinine; Disease Models, Animal; Endothelial Progenitor Cells; Erythropoietin; Flow Cytometry; Glomerular Filtration Rate; Hematocrit; Ischemia; Kidney; Male; Rats; Rats, Sprague-Dawley; Urea

Topics: Acute Kidney Injury; Circulatory Arrest, Deep Hypothermia Induced; Erythropoietin; Female; Humans; Male

Septic conditions contribute to tissue hypoxia, potentially leading to multiple organ failure, including acute kidney injury. The regulation of cellular adaptation to low oxygen levels is regulated by hypoxia-inducible transcription factors (HIFs). While the role of HIFs in ischaemia/reperfusion is more studied, their function in sepsis-induced renal injury is not well characterized. In this study, we investigated whether pharmacological activation of HIFs by suppression of prolyl-hydroxylases (PHDs) protects against septic acute kidney injury.. Two models of sepsis-caecal ligation and punction and peritoneal contamination and infection-were induced on 12-week-old C57BL6/J mice. Pharmacological inhibition of PHDs, leading to HIF activation, was achieved by intraperitoneal application of 3,4-dihydroxybenzoate (3,4-DHB) before sepsis. A quantitative real-time reverse transcription polymerase chain reaction, immunohistology and enzyme-linked immunosorbent assays were utilized to detect gene expression, renal protein levels and renal functional parameters, respectively. Tissue morphology was analysed by periodic acid-Schiff reaction. Early kidney injury was estimated by kidney injury molecule-1 analyses. Apoptosis was detected in situ by terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling stain. The systemic effect of 3,4-DHB pretreatment in sepsis was analysed by 72-h survival studies.. Pharmacological activation of HIFs before sepsis induction attenuated sepsis-related vacuolization and dilation of the proximal tubules, reduced tubular apoptosis and correlated to lower T-cell infiltration in renal tissue compared with the non-treated septic animals. PHD suppression elevated the basal renal HIF-1α expression and basal plasma concentrations of HIF targets erythropoietin and vascular endothelial growth factor. Whereas it preserved renal structure in both models, it improved renal function in a model-dependent manner. Moreover, inhibition of PHDs led to increased mortality in both models. Analysis of liver function showed increased organ destruction with massive glycogen loss and hepatocyte's apoptosis due to 3,4-DHB administration before sepsis induction.. In summary, the pharmacological activation of HIFs by 3,4-DHB administration, although it showed renoprotective effects in sepsis-related kidney injury, induced more severe problems in other organs such as the liver during sepsis, leading to increased mortality.

Topics: Acute Kidney Injury; Animals; Apoptosis; Disease Models, Animal; Erythropoietin; Gene Expression; Hydroxybenzoates; Hypoxia-Inducible Factor 1, alpha Subunit; Kidney; Male; Mice; Mice, Inbred C57BL; Mortality; Prolyl Hydroxylases; Prolyl-Hydroxylase Inhibitors; Sepsis; Vascular Endothelial Growth Factor A

Erythropoietin (EPO) may be a beneficial tissue-protective cytokine. However, high doses of EPO are associate with adverse effects, including thrombosis, tumor growth, and hypertension. Carbamylated erythropoietin (CEPO) lacks both erythropoietic and vasoconstrictive actions. In this study, we compared the renoprotective, hemodynamic, and hematologic activities and survival effects of identical EPO and CEPO doses in rat models of clinically relevant AKI presentations, including ischemia-reperfusion-induced AKI superimposed on CKD (5000 U/kg EPO or CEPO; three subcutaneous injections) and ischemia-reperfusion-induced AKI in old versus young animals and male versus female animals (1000 U/kg EPO or CEPO; three subcutaneous injections). Compared with EPO therapy, CEPO therapy induced greater improvements in renal function and body weight in AKI on CKD animals, with smaller increases in hematocrit levels and similarly improved survival. Compared with EPO therapy in the other AKI groups, CEPO therapy induced greater improvements in protection and recovery of renal function and survival, with smaller increases in systolic BP and hematocrit levels. Overall, old or male animals had more severe loss in kidney function and higher mortality rates than young or female animals, respectively. Notably, mRNA and protein expression analyses confirmed the renal expression of the heterodimeric EPO receptor/CD131 complex, which is required for the tissue-protective effects of CEPO signaling. In conclusion, CEPO improves renal function, body and kidney weight, and survival in AKI models without raising hematocrit levels and BP as substantially as EPO. Thus, CEPO therapy may be superior to EPO in improving outcomes in common forms of clinical AKI.

Topics: Acute Kidney Injury; Age Factors; Animals; Erythropoietin; Female; Male; Rats; Rats, Inbred F344; Renal Insufficiency, Chronic; Sex Factors

Acute kidney injury (AKI) is common in hospitalized patients and has a poor prognosis, the severity of AKI being linked to progression to chronic kidney disease. This stresses the need to search for protective mechanisms during the acute phase. We investigated kidney repair after hypoxic injury using a rat model of renal artery branch ligation, which led to an oxygen gradient vertical to the corticomedullary axis. Three distinct zones were observed: tubular necrosis, infarction border zone and preserved normal tissue. EphA2 is a receptor tyrosine kinase with pivotal roles in cell architecture, migration and survival, upon juxtacrine contact with its membrane-bound ligand EphrinA1. Following hypoxia, EphA2 was up-regulated in cortical and medullary tubular cells, while EphrinA1 was up-regulated in interstitial cells adjacent to peritubular capillaries. Moreover, erythropoietin (EPO) messenger RNA (mRNA) was strongly expressed in the border zone of infarcted kidney within the first 6 h. To gain more insight into the biological impact of EphA2 and EphrinA1 up-regulation, we activated the signalling pathways in vitro using recombinant EphrinA1/Fc or EphA2/Fc proteins. Stimulation of EphA2 forward signalling in the proximal tubular cell line HK2 increased cell attachment and laminin secretion at the baso-lateral side. Conversely, activation of reverse signalling through EphrinA1 expressed by Hep3B cells promoted EPO production at both the transcriptional and protein level. Strikingly, in co-culture experiments, juxtacrine contact between EphA2 expressing MDCK and EphrinA1 expressing Hep3B was sufficient to induce a significant up-regulation of EPO mRNA production in the latter cells, even in the absence of hypoxic conditions. The synergistic effects of EphA2 and hypoxia led to a 15-20-fold increase of EPO expression. Collectively, our results suggest an important role of EphA2/EphrinA1 signalling in kidney repair after hypoxic injury through stimulation of (i) tubular cell attachment, (ii) secretion of basal membrane proteins and (iii) EPO production. These findings could thus pave the way to new therapeutic approaches.

Topics: Acute Kidney Injury; Animals; Cell Line, Tumor; Cells, Cultured; Coculture Techniques; Ephrin-A1; Erythropoietin; Humans; Hypoxia; Laminin; Male; Rats; Rats, Sprague-Dawley; Receptor, EphA2; RNA, Messenger; Signal Transduction; Up-Regulation

The antimicrobial β-defensin-like role of hepcidin (HEPC) has been increasingly investigated for its potential role in acute kidney injury (AKI). In sepsis-induced AKI, there is a complex interplay between positive and negative regulation of HEPC, with consequently altered distributions of iron caused by changes in HEPC levels. The aim of the current research was to assess serum HEPC levels in a cohort of septic patients with AKI and investigate the regulatory impact of hypoxia-inducing factor (HIF)-1α, erythropoietin (EPO) and inflammation on HEPC levels and related signal cascades in these patients. Baseline, higher levels of SCr (2.3-fold), blood urea nitrogen (BUN) (1.8-fold), uric acid (2.3-fold) and white blood cell (2.3-fold) were noted in septic AKI patients, along with decreased levels of albumin (15.7%), creatinine (44.7%) and BUN/creatinine ratios (23.8%), compared to in normal subjects. These hosts also had increased serum levels of TNFα (4.4-times) and TGFβ1 (3.2-times) compared to controls (p < 0.05). Further, HEPC and HIF-1α levels were also increased (8.8- and 3.6-times control levels), while EPO levels were decreased (77.8%) from control levels. After 12 weeks of antibiotic therapy, all septic AKI patients showed significant improvement of the altered markers of kidney dysfunction. In line with significant reductions in serum TNFα and TGFβ1 (25.5% and 26.2%, respectively), HEPC and HIF-1α levels were significantly decreased (31.6% and 19.3%), and EPO levels increased (1.9-fold) compared to pretreatment values. There was a significant positive correlation between HEPC levels and kidney function markers (SCr and BUN), inflammatory TNFα and TGFβ1 and serum HIF-1α and pAKT in septic AKI patients before and after treatment. Based on the results here, we conclude that HEPC, EPO and HIF-1α are involved in the pathogenesis of sepsis-induced AKI and confirm the dominating effects of inflammatory determinants over hypoxia-related complications.

Topics: Acute Kidney Injury; Cells, Cultured; Cohort Studies; Erythropoietin; Hepcidins; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Iron; Oncogene Protein v-akt; PTEN Phosphohydrolase; Sepsis; Signal Transduction; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

Sepsis remains the most important cause of acute kidney injury (AKI) and acute lung injury (ALI) in critically ill patients. The cecal ligation and puncture (CLP) model in experimental mice reproduces most of the clinical features of sepsis. Erythropoietin (EPO) is a well-known cytoprotective multifunctional hormone, which exerts anti-inflammatory, anti-oxidant, anti-apoptotic and pro-angiogenic effects in several tissues. The aim of this study was to evaluate the underlying mechanisms of EPO protection through the expression of the EPO/EPO receptor (EPO-R) and VEGF/VEF-R2 systems in kidneys and lungs of mice undergoing CLP-induced sepsis. Male inbred Balb/c mice were divided in three experimental groups: Sham, CLP, and CLP+EPO (3000IU/kg sc). Assessment of renal functional parameters, survival, histological examination, immunohistochemistry and/or Western blottings of EPO-R, VEGF and VEGF-R2 were performed at 18h post-surgery. Mice demonstrated AKI by elevation of serum creatinine and renal histologic damage. EPO treatment attenuates renal dysfunction and ameliorates kidney histopathologic changes. Additionally, EPO administration attenuates deleterious septic damage in renal cortex through the overexpression of EPO-R in tubular interstitial cells and the overexpression of the pair VEGF/VEGF-R2. Similarly CLP- induced ALI, as evidenced by parenchymal lung histopathologic alterations, was ameliorated through pulmonary EPO-R, VEGF and VEGF-R2 over expression suggesting and improvement in endothelial survival and functionality. This study demonstrates that EPO exerts protective effects in kidneys and lungs in mice with CLP-induced sepsis through the expression of EPO-R and the regulation of the VEGF/VEGF-R2 pair.

Topics: Acute Kidney Injury; Acute Lung Injury; Animals; Blood Urea Nitrogen; Cecum; Creatinine; Disease Models, Animal; Erythropoietin; Kidney; Ligation; Male; Mice, Inbred BALB C; Punctures; Receptors, Erythropoietin; Sepsis; Survival Analysis; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2

Neurologic sequelae remain a common and destructive problem in patients with acute kidney injury. The objective of this study was to evaluate the possible neuroprotective effect of erythropoietin (EPO) on motor impairments following bilateral renal ischemia (BRI) in two time points after reperfusion: short term (24 h) and long term (1 week). Male Wistar rats underwent BRI or sham surgery. EPO or saline administration was performed 30 min before surgery (1000 U/kg, i.p.). Explorative behaviors and motor function of the rats were evaluated by open field, rotarod, and wire grip tests. Plasma concentrations of blood urea nitrogen (BUN) and creatinine (Cr) were significantly enhanced in BRI rats 24 h after reperfusion. BRI group had only an increased level of BUN but not Cr 1 week after reperfusion. Impairment of balance function by BRI was not reversed by EPO 24 h after reperfusion, but counteracted 7 days after renal ischemia. Muscle strength had no significant differences between the groups. BRI group had a decrease in locomotor activity, and EPO could not reverse this reduction in both time points of the experiment. Although EPO could not be offered as a potential neuroprotective agent in the treatment of motor dysfunctions induced by BRI, it could be effective against balance dysfunction 1 week after renal ischemia.

Topics: Acute Kidney Injury; Animals; Blood Urea Nitrogen; Creatinine; Disease Models, Animal; Erythropoietin; Locomotion; Male; Motor Disorders; Muscle Strength; Neuroprotective Agents; Rats; Rats, Wistar; Reperfusion; Reperfusion Injury

Persistent alterations of the renal tissue due to maladaptive repair characterize the outcome of acute kidney injury (AKI), despite a clinical recovery. Acute damage may also limit the renal production of erythropoietin, with impairment of the hemopoietic response to ischemia and possible lack of its reno-protective action. We aimed to evaluate the effect of a cell therapy using human CD133

Topics: AC133 Antigen; Acute Kidney Injury; Animals; Disease Models, Animal; Erythropoietin; Fibrosis; Heterografts; Humans; Kidney Tubules; Mice; Mice, SCID; Stem Cell Transplantation; Stem Cells

Renal ischemia-reperfusion (IR) contributes to the development of acute renal failure (ARF). Oxygen free radicals are considered to be principal components involved in the pathophysiological tissue alterations observed during renal IR. The purpose of this study was to investigate the combination effect of melatonin (MEL) and erythropoietin (EPO), which are a potent antioxidant and anti-apoptotic agents, in IR-induced renal injury in rats. Wistar Albino rats were unilaterally nephrectomized and subjected to 45 min of renal pedicle occlusion followed by 24 h reperfusion. MEL (10 mg/kg, i.p) and EPO (5000 U/kg, i.p) were administered prior to ischemia. After 24 h reperfusion, following decapitation, blood samples were collected for the determination of superoxide dismutase (SOD), glutathione peroxidase (GPx), and malondialdehyde (MDA) levels. Also, renal samples were taken for histological evaluation and apoptosis assay. Ischemia-reperfusion increased SOD, GPx, MDA levels, and TUNEL positive cells. Histopathological findings of the IR group confirmed that there was renal impairment in the tubular epithelium. Treatment with EPO and MEL decreased SOD, GPx, and MDA levels, histopathological changes, and TUNEL positive cells. These results indicated that the combination of MEL and EPO could not exert more nephroprotective and anti-apoptotic effects than MEL treatment in renal ischemia-reperfusion injury.

Topics: Acute Kidney Injury; Animals; Antioxidants; Apoptosis; Epoetin Alfa; Erythropoietin; Glutathione Peroxidase; Male; Malondialdehyde; Melatonin; Rats; Rats, Wistar; Reperfusion Injury; Superoxide Dismutase

Renal ischaemia-reperfusion (I/R) injury, a primary cause of acute renal failure, can induce high morbidity and mortality. This study aimed to explore the effect of erythropoietin on renal I/R injury and its underlying mechanism.. Fifty male Sprague-Dawley rats were randomly allocated to three groups (n = 10): the sham group, the renal ischaemia-reperfusion-saline (IRI) group, and the IRI+-Erythropoietin (EPO) group. Erythropoietin (250, 500, 1000 U/kg) was intraperitoneally injected 30 min before inducing I/R. Renal I/R injury were induced by clamping the left renal artery for 30 min followed by reperfusion, along with a contralateral nephrectomy. Renal function and histological damage were determined after 24 h reperfusion. The expression of pro-inflammatory cytokines interleukin-6 (IL-6), interleukin-1 β (IL-1β), and tumour necrosis factor-α (TNF-α) in the serum and renal tissue were evaluated by enzyme linked immunosorbent assay (ELISA) and reverse transcription-polymerase chain reaction (RT-PCR), respectively. Further, the effects of erythropoietin on PI3K/Akt signalling, erythropoietin receptor (EPOR) and nuclear factor (NF)-κB activation were measured by Western blotting.. Erythropoietin pretreatment can significantly decrease the level of renal dysfunction in a dose-dependent manner, attenuated the renal histological changes, the expression of TNF-α, IL-1β, and IL-6, the levels of reactive oxygen species (ROS) production and NF-κB p65 phosphorylation in renal tissue upon IRI. Moreover, erythropoietin pretreatment could further activate the PI3K/Akt signalling and induced EPOR activity.. Erythropoietin pretreatment could attenuate renal I/R injury by suppressing inflammation, which was associated with activating PI3K/Akt signalling though EPOR activation. Our findings suggest that erythropoietin may be a novel practical strategy to prevent renal I/R injury.

Topics: Acute Kidney Injury; Animals; Anti-Inflammatory Agents; Biomarkers; Cytoprotection; Disease Models, Animal; Enzyme Activation; Erythropoietin; Inflammation Mediators; Interleukin-1beta; Interleukin-6; Kidney; Male; Phosphatidylinositol 3-Kinase; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats, Sprague-Dawley; Reactive Oxygen Species; Receptors, Erythropoietin; Reperfusion Injury; Signal Transduction; Transcription Factor RelA; Tumor Necrosis Factor-alpha

Understanding the mechanisms of protecting the kidneys from injury is of great importance because there are no effective therapies that promote repair and the kidneys frequently do not repair adequately. Evidence has shown that erythropoietin (EPO) has a vital renoprotective role, independent of its erythropoietic effect. However, whether EPO can contribute to kidney repair after injury and the potential mechanisms are not fully understood.. To investigate the renoprotective mechanism of EPO, a kidney ischemia/reperfusion injury (IRI) model was induced in adult male Sprague-Dawley rats. The rats were subsequently randomly treated with EPO or a vehicle 6 hours after the kidney IRI. The rats were sacrificed on Day 3, Day 5, and Day 7 post kidney IRI. Renal function and histological alterations were examined. Renal interstitial macrophage infiltration, cell proliferation, apoptosis, and angiogenesis were evaluated by immunostaining. Furthermore, the effects of EPO on the Wnt/β-catenin pathway and IRI-related micro-RNAs were investigated.. The administration of EPO significantly improved renal function and reduced tubular injury. Furthermore, EPO treatment significantly prevented tubular cell apoptosis and promoted cell proliferation after IRI. Erythropoietin significantly suppressed macrophage infiltration, compared to the vehicle. In addition, treatment with EPO markedly prevented the loss of microvasculature. We have also demonstrated that, compared to the vehicle, EPO administration enhanced the expression of Wnt7b and β-catenin, and downregulated miR-21, -214, -210, and -199a.. Erythropoietin protects the kidneys against IRI by attenuating injury of the renal microvasculature and tubule epithelial cells, by promoting Wnt/β-catenin pathway activation, and by regulating miRNA expression.

Topics: Acute Kidney Injury; Animals; Apoptosis; Disease Models, Animal; Erythropoietin; Kidney; Male; MicroRNAs; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Wnt Signaling Pathway

Topics: Acute Kidney Injury; Animals; Antineoplastic Agents; Cisplatin; Erythropoietin; Female; Kidney; Male

To investigate the prognostic value of serum endogenous erythropoietin (EPO) in patients with acute coronary syndrome (ACS), including that in the development of acute kidney injury (AKI).. Eighty-four patients (46 men, 38 women; mean age 63 ± 11 years) with ACS were examined. Twenty-one (25%) patents were diagnosed with ECG ST-segment elevation acute myocardial infarction (STSEAMI), 12 (14%) had ECG non-STSEAMI, and 51 (61%) had unstable angina. Thrombolytic therapy was performed in 10 (48%) patients with STSEAMI. The patients whom had not undergone coronarography were included in the investigation to exclude the nephrotoxic effect of X-ray contrast agents.. AKI was observed in 7 of the patients with acute myocardial infarction and in only 1 of those with unstable angina. Four (5%) patients died during hospitalization. The EPO level of > 10.5 IU/ml predicted the development of AKI in the ACS patients with a sensitivity of 71% and a specificity of 67%. That of > 13.7 IU/ml was associated with hospital death in the ACS patients with a sensitivity of 100% and a specificity of 75% (AUC = 0.93%).. High serum EPO levels in an ACS patent during his hospital stay may serve as a biomarker for a high risk for AKI and high death rates.. Цель исследования. Изучить прогностическое значение эндогенного эритропоэтина (ЭПО) сыворотки крови у больных с острым коронарным синдромом (ОКС), в том числе в развитии острого повреждения почек (ОПП). Материалы и методы. Обследовали 84 больных с ОКС (46 мужчин, 38 женщин, средний возраст 63±11 лет). У 21 (25%) пациента диагностирован острый инфаркт миокарда с подъемом сегмента ST (ОИМпST), у 12 (14%) - острый инфаркт миокарда без подъема сегмента ST (ОИМбпST) на электрокардиограмме, у 51 (61%) - нестабильная стенокардия. Тромболитическая терапия проведена 10 (48%) больным с ОИМпST. Для исключения нефротоксичного действия рентгеноконтрастных препаратов в исследование включены больные, которым коронарография не выполнялась. Результаты. Среди больных ОИМ острое повреждение почек наблюдалось у 7, а среди пациентов с нестабильной стенокардией - только у 1. Умерли во время госпитализации 4 (5%) больных. Уровень ЭПО >10,5 МЕ/мл прогнозировал развитие ОПП у больных с ОКС с чувствительностью 71% и специфичностью 67% (AUC=0,73). Уровень ЭПО >13,7 МЕ/мл был ассоциирован со смертью больных с ОКС в стационаре с чувствительностью 100% и специфичностью 75% (AUC=0,93). Заключение. Высокий уровень ЭПО в сыворотке крови у больного с ОКС во время пребывания в стационаре может служить биомаркером высокого риска развития острого повреждения почек и высокой летальности.

Topics: Acute Coronary Syndrome; Acute Kidney Injury; Biomarkers; Coronary Angiography; Electrocardiography; Erythropoietin; Female; Follow-Up Studies; Humans; Male; Middle Aged; Prognosis

We developed a novel, erythropoietin-derived, non-erythropoiesis, cyclic helix B peptide (CHBP) that displays potent renoprotection against acute kidney injury (AKI). To determine the mechanism of CHBP-mediated protection, we investigated the proteomic profile of mice treated with CHBP in a kidney ischemia-reperfusion (IR) injury model. The isobaric tags for relative and absolute quantitation (iTRAQ)-labeled samples were analyzed using a QSTAR XL LC/MS system. In total, 38 differentially expressed proteins (DEPs) were shared by all experimental groups, while 3 DEPs were detected specifically in the IR + CHBP group. Eight significant pathways were identified, and oxidative phosphorylation was shown to be the most important pathway in CHBP-mediated renoprotection. The significant DEPs in the oxidative phosphorylation pathway elicited by CHBP are NADH-ubiquinone oxidoreductase Fe-S protein 6 (NDUFS6), alpha-aminoadipic semialdehyde synthase (AASS) and ATP-binding cassette sub-family D member 3 (ABCD3). The DEPs mentioned above were verified by RT-qPCR and immunostaining in mouse kidneys. We tested 6 DEPs in human biopsy samples from kidney transplant recipients. The trend of differential expression was consistent with that in the murine model. In conclusion, this study helps to elucidate the pharmacological mechanisms of CHBP before clinical translation.

Topics: Acute Kidney Injury; Animals; Enkephalins; Erythropoietin; Kidney; Male; Mice; Mice, Inbred BALB C; NAD; Oxidative Phosphorylation; Protein Precursors; Proteome; Proteomics; Reperfusion Injury; Signal Transduction

Treatment of renal ischemia-reperfusion (IR) injury with recombinant human erythropoietin (rhEPO) reduces acute kidney injury and improves function. We aimed to investigate whether progression to chronic kidney disease associated with acute injury was also reduced by rhEPO treatment, using in vivo and in vitro models. Rats were subjected to bilateral 40-min renal ischemia, and kidneys were studied at 4, 7, and 28 days postreperfusion for renal function, tubular injury and repair, inflammation, and fibrosis. Acute injury was modulated using rhEPO (1,000 or 5,000 IU/kg, intraperitoneally) at the time of reperfusion. Renal tubular epithelial cells or fibroblasts in culture were subjected to hypoxia or oxidative stress, with or without rhEPO (200 IU/ml), and fibrogenesis was studied. The results of the in vivo model confirmed functional and structural improvement with rhEPO at 4 days post-IR (P < 0.05). At 7 days post-IR, fibrosis and myofibroblast stimulation were increased with IR with and without rhEPO (P < 0.01). However, at 28 days post-IR, renal fibrosis and myofibroblast numbers were significantly greater with IR plus rhEPO (P < 0.01) compared with IR only. Mechanistically, rhEPO stimulated profibrotic transforming growth factor-β, oxidative stress (marker 8-hydroxy-deoxyguanosine), and phosphorylation of the signal transduction protein extracellular signal-regulated kinase. In vitro, rhEPO protected tubular epithelium from apoptosis but stimulated epithelial-to-mesenchymal transition and also protected and activated fibroblasts, particularly with oxidative stress. In summary, although rhEPO was protective of renal function and structure in acute kidney injury, the supraphysiological dose needed for renoprotection contributed to fibrogenesis and stimulated chronic kidney disease in the long term.

Topics: Acute Kidney Injury; Animals; Apoptosis; Cells, Cultured; Disease Progression; Epoetin Alfa; Erythropoietin; Extracellular Signal-Regulated MAP Kinases; Fibrosis; Humans; Kidney; Kidney Diseases; Male; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Reperfusion Injury; Treatment Outcome

Renal ischemia reperfusion (IR) is an important cause of renal dysfunction. It contributes to the development of acute renal failure. Oxidative damage from reactive oxygen species is considered to be the principal component involved in the pathophysiological tissue alterations observed during IR. The purpose of this study was to evaluate the effect of a combined treatment with erythropoietin (EPO) plus melatonin (MEL), which are known anti-inflammatory and antioxidant agents, in IR-induced renal injury in rats.. Wistar Albino rats were unilaterally nephrectomized and subjected to 45 min of renal pedicle occlusion followed by 24 h of reperfusion. MEL (10 mg/kg, i.p) and EPO (5000 U/kg, i.p) were administered prior to ischemia. After 24 h of reperfusion, blood samples were collected for the determination of superoxide dismutase (SOD), glutathione peroxidase (GPx), plasma levels of total antioxidant capacity (TAC), and malondialdehyde (MDA) and serum urea level. Also, renal samples were taken for histological evaluation.. Ischemia reperfusion significantly increased urea, blood SOD, and GPx levels. Histological findings of the IR group indicated that there was increase in tubular and glomerular hyaline cast, thickening of Bowman capsule basement membrane, and renal impairment in the glomerular epithelium. Treatment with EPO and MEL significantly decreased blood SOD, GPx, and urea levels and increased TAC level. In the EPO + MEL group, while the histopathological changes were lower than those in EPO group, they were the same as MEL group.. EPO and MEL combination treatment exerted more nephroprotective effects than EPO treatment and nearly had protective effects similar to MEL treatment.

Topics: Acute Kidney Injury; Animals; Anti-Inflammatory Agents; Antioxidants; Disease Models, Animal; Drug Therapy, Combination; Erythropoietin; Glutathione Peroxidase; Kidney; Male; Malondialdehyde; Melatonin; Models, Animal; Rats; Rats, Wistar; Reactive Oxygen Species; Reperfusion Injury; Superoxide Dismutase

Acute kidney injury is common, serious with no specific treatment. Ischemia-reperfusion is a common cause of acute kidney injury (AKI). Clinical trials suggest that preoperative erythropoietin (EPO) or remote ischemic preconditioning may have a renoprotective effect. Using a porcine model of warm ischemia-reperfusion-induced AKI (40-min bilateral cross-clamping of renal arteries, 48-h reperfusion), we examined the renoprotective efficacy of EPO (1,000 iu/kg iv.) or remote ischemic preconditioning (3 cycles, 5-min inflation/deflation to 200 mmHg of a hindlimb sphygmomanometer cuff). Ischemia-reperfusion induced significant kidney injury at 24 and 48 h (χ(2), 1 degree of freedom, >10 for 6/7 histopathological features). At 2 h, a panel of biomarkers including plasma creatinine, neutrophil gelatinase-associated lipocalin, and IL-1β, and urinary albumin:creatinine could be used to predict histopathological injury. Ischemia-reperfusion increased cell proliferation and apoptosis in the renal cortex but, for pretreated groups, the apoptotic cells were predominantly intratubular rather than interstitial. At 48-h reperfusion, plasma IL-1β and the number of subcapsular cells in G2-M arrest were reduced after preoperative EPO, but not after remote ischemic preconditioning. These data suggest an intrarenal mechanism acting within cortical cells that may underpin a renoprotective function for preoperative EPO and, to a limited extent, remote ischemic preconditioning. Despite equivocal longer-term outcomes in clinical studies investigating EPO as a renoprotective agent in AKI, optimal clinical dosing and administration have not been established. Our data suggest further clinical studies on the potential renoprotective effect of EPO and remote ischemic preconditioning are justified.

Topics: Acute Kidney Injury; Animals; Creatinine; Disease Models, Animal; Epoetin Alfa; Erythropoietin; Female; Hindlimb; In Situ Nick-End Labeling; Ischemic Preconditioning; Preoperative Care; Recombinant Proteins; Reperfusion Injury; Swine

Sepsis remains the most important cause of acute kidney injury (AKI) in critically ill patients and is an independent predictor of poor outcome. The administration of lipopolysaccharide (LPS) to animals reproduces most of the clinical features of sepsis, including AKI, a condition associated with renal cellular dysfunction and apoptosis. Erythropoietin (EPO) is a well known cytoprotective multifunctional hormone, which exerts anti-inflammatory, anti-oxidant, anti-apoptotic and angiogenic effects in several tissues. The aim of this study was to evaluate the underlying mechanisms of EPO renoprotection through the expression of the EPO receptor (EPO-R) and the modulation of the intrinsic apoptotic pathway in LPS-induced AKI. Male inbred Balb/c mice were divided in four experimental groups: Control, LPS (8 mg/kg i.p.), EPO (3000 IU sc) and LPS+EPO. Assessment of renal function, histological examination, TUNEL in situ assay, immunohistochemistry and Western blottings of caspase-3, Bax, Bcl-xL, EPO-R and Cytochrome c were performed at 24h post treatment. LPS+EPO treatment significantly improved renal function and ameliorated histopathological injury when compared to the LPS treated group. Results showed that EPO treatment attenuates renal tubular apoptosis through: (a) the overexpression of EPO-R in tubular interstitial cells, (b) the reduction of Bax/Bcl-xL ratio, (c) the inhibition Cytochrome c release into the cytosol and (d) the decrease of the active caspase-3 expression. This study suggests that EPO exerts renoprotection on an experimental model of LPS-induced AKI. EPO induced renoprotection involves an anti-apoptotic effect through the expression of EPO-R and the regulation of the mitochondrial apoptotic pathway.

Topics: Acute Kidney Injury; Animals; Apoptosis; Cryoprotective Agents; Disease Models, Animal; Erythropoietin; Humans; Kidney; Lipopolysaccharides; Male; Mice; Mice, Inbred BALB C; Mitochondria; Receptors, Erythropoietin

Acute renal tubular injury is a serious complication in the postoperative period, which is associated with high mortality and increased ICU stay. We aimed to demonstrate the protective effect of rhEPO against acute tubular injury induced by ischemia-reperfusion and to explore the mechanism of canonical transient receptor potential channel-6.. Randomized laboratory animal study.. Animal research laboratory.. Male Sprague-Dawley rats were randomly divided into three groups: the sham group, the control group, and the rhEPO group. Experimental acute tubular injury was established in rats by bilateral renal arterial occlusion for 30 minutes followed by reperfusion.. Blood samples were obtained for cystatin-C and neutrophil gelatinase-associated lipocalin measurements by enzyme-linked immunosorbance assays. Seventy-two hours after reperfusion, urine samples were collected for osmolality and fractional excretion of sodium (%) assays on a chemistry analyzer. Kidneys were harvested at 24, 48, and 72 hours after reperfusion. Transient receptor potential channel-6, aquaporin-2, and Na,K-ATPase expression in collecting ducts were studied by immunofluorescence and Western blot. Coimmunoprecipitations were also performed to identify the possible signalplex relation between transient receptor potential channel-6 and aquaporin-2 or Na,K-ATPase channels. RhEPO pretreatment significantly inhibited serum cystatin-C (2 hr: 453 ± 64 μg/L vs 337 ± 28 μg/L, p < 0.01), serum neutrophil gelatinase-associated lipocalin (72 hr: 1,175 ± 107 ng/L vs 1,737 ± 402 ng/L, p < 0.05), and urinary fractional excretion of sodium (%) increase (0.9 ± 0.1 vs 2.2 ± 0.8, p < 0.05) and alleviated the decrease of urinary osmolality (1,293 ± 101 mosmol/kg H2O vs 767 ± 91 mosmol/kg H2O, p < 0.05) induced by ischemia-reperfusion injury. Meanwhile, recombinant human erythropoietin greatly improved the ischemia-reperfusion-induced attenuation of transient receptor potential channel-6 expression (48 hr: 42% ± 2% vs 67% ± 2% and 72 hr: 55% ± 2% vs 66% ± 2%), as well as aquaporin-2 and Na,K-ATPase expression in collecting ducts. Transient receptor potential channel-6 functionally interacted with Na,K-ATPase but not aquaporin-2.. Recombinant human erythropoietin pretreatment at the dose of 5,000 IU/kg potently prevented ischemia-reperfusion-induced acute tubular injury, which might be partly attributed to the restoring the effect of transient receptor potential channel-6 expression and collecting duct function.

Topics: Acute Kidney Injury; Acute-Phase Proteins; Animals; Aquaporin 2; Cystatin C; Erythropoietin; Humans; Kidney Tubules, Collecting; Lipocalin-2; Lipocalins; Male; Proto-Oncogene Proteins; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Reperfusion Injury; Sodium-Potassium-Exchanging ATPase; TRPC Cation Channels

Based on its pleiotropic effects, erythropoietin can decrease inflammation, oxidative stress, and apoptosis. Erythropoietin provides organ protection for the heart, brain, and kidney in diverse preclinical animal studies, especially models that include ischemia-reperfusion injury and/or inflammation. However, large clinical studies in coronary reperfusion, heart failure, stroke, acute kidney injury, and chronic renal disease have failed to demonstrate improved outcomes. A study in a previous issue of Critical Care examining the ability of erythropoietin to prevent or ameliorate acute kidney injury in patients undergoing complex valvular heart surgery is similarly negative. The failure of erythropoietin in clinical studies may be due to an inadequate dose, since the receptors responsible for organ protection may require higher concentrations than those responsible for erythropoiesis. However, as has occurred in studies in sepsis and acute respiratory distress syndrome, the negative studies probably reflect an inadequate understanding of the complexity of the underlying processes with multiple redundant and interacting pathways that may differ among the large number of different cell types involved. As tools to understand this complexity and integrate it on an organismal basis continue to evolve, we will develop the ability to use erythropoietin and related nonhematopoietic agents for organ protection.

Topics: Acute Kidney Injury; Erythropoietin; Female; Heart Valve Diseases; Hematinics; Humans; Male; Postoperative Complications

We investigated the effect of erythropoietin (EPO) on differentiation and secretion of bone marrow-derived mesenchymal stem cells in an acute kidney injury microenvironment. Acute kidney injury mouse models were prepared. Both renal cortices were then immediately collected to produce the ischemia/reperfusion kidney homogenate supernatant. The morphological and ultrastructural changes in the cells were observed using an inverted microscope and a transmission electron microscope. Cytokeratin-18 was detected using flow cytometry. Bone morphogenetic protein-7 levels, hepatocyte growth factor, and vascular endothelial growth factor in the culture medium were detected using an enzyme-linked immunosorbent assay. The cells had high CD29 and CD44 expression, as well as low CD34 and CD45 expression. More round and oval cells with cobble-like appearances were observed after EPO treatment. In addition, an increase in the number of rough endoplasmic reticula, lysosomes, and mitochondria was observed in the cytoplasm; the intercellular junction peculiar to epithelial cells was also seen on the cell surface. After treatment with ischemia/reperfusion kidney homogenate supernatant, cytokeratin-18 expression increased significantly and EPO could magnify its expression. Bone morphogenetic protein-7 levels, hepatocyte growth factor, and vascular endothelial growth factor levels after treatment with ischemia/reperfusion kidney homogenate supernatant significantly decreased, whereas EPO increased the cytokine secretion. The acute kidney injury microenvironment can induce the bone marrow-derived mesenchymal stem cells to partially differentiate into renal tubular epithelium-shaped cells, but weaken their secretion function. EPO intervention can boost up their differentiation function and reverse their low secretion effect.

Topics: Acute Kidney Injury; Animals; Antigens, CD34; Bone Marrow Cells; Bone Morphogenetic Protein 7; Cell Differentiation; Cells, Cultured; Erythropoietin; Hepatocyte Growth Factor; Hyaluronan Receptors; Integrin beta1; Keratin-18; Leukocyte Common Antigens; Male; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice; Mice, Inbred C57BL; Reperfusion Injury; Vascular Endothelial Growth Factor A

Acute renal injury after cardiopulmonary bypass is common and associated with high mortality. We aimed to demonstrate the glomerular protective effects of recombinant human erythropoietin using an in vivo rat cardiopulmonary bypass model and to explore the possible mechanism.. Dose-related renal protective effects of recombinant human erythropoietin were studied in phase I. Male Sprague Dawley rats were randomly divided into 5 groups: sham group, cardiopulmonary bypass group, and 3 recombinant human erythropoietin-treated cardiopulmonary bypass groups (bolus doses of 500, 3000, and 5000 U/kg 24 hours before surgery). Blood and urine samples were collected just before surgery and at 2, 4, 24, 48, and 72 hours after surgery. In phase II, rats were divided into 3 groups: sham group, cardiopulmonary bypass group, and 5000 U/kg recombinant human erythropoietin group. Kidneys were harvested at 4, 24, 48, and 72 hours after surgery. Ultra-organization of glomeruli was observed. Glomerular transient receptor potential channel 6 (TRPC6) expression was studied by immunofluorescence and Western blot. Nuclei nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1 (NFATc1) activity was analyzed by enzyme-linked immunosorbent assays and electrophoretic mobility shift assay.. Pretreatment of 5000 U/kg recombinant human erythropoietin decreased the urine protein (72 hours: 7.82 ± 1.13 g/L vs 11.28 ± 1.73 g/L), serum creatinine (72 hours: 35.0 ± 3.5 μmol/L vs 60.7 ± 7.6 μmol/L), and cystatin-C (2 hours: 336.5 ± 28.2 μg/L vs 452.6 ± 63.8 μg/L) compared with the control group (P < .01). Cardiopulmonary bypass induced morphologic abnormalities of podocyte foot processes and slit diaphragms, which was improved by recombinant human erythropoietin. Furthermore, recombinant human erythropoietin significantly relieved glomerular TRPC6 increase and NFATc1 activation induced by cardiopulmonary bypass.. Pretreatment of 5000 U/kg recombinant human erythropoietin elicited potent glomerular protection against cardiopulmonary bypass. This protection may be partly due to downregulation of glomerular TRPC6-NFATc1 pathway.

Topics: Acute Kidney Injury; Animals; Biomarkers; Cardiopulmonary Bypass; Creatinine; Cystatin C; Cytoprotection; Disease Models, Animal; Dose-Response Relationship, Drug; Erythropoietin; Humans; Kidney Glomerulus; Male; NFATC Transcription Factors; Podocytes; Protective Agents; Proteinuria; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Signal Transduction; Time Factors; Transcription Factors; TRPC Cation Channels

Topics: Acute Kidney Injury; Animals; Erythropoietin; Male; Rhabdomyolysis

The β-common receptor (βcR) plays a pivotal role in the nonhematopoietic tissue-protective effects of erythropoietin (EPO). Here we determined whether EPO reduces the acute kidney injury (AKI) caused by sepsis and whether this effect is mediated by the βcR. In young (2 months old) C57BL/6 wild-type and βcR knockout mice, lipopolysaccharide caused a significant increase in serum urea and creatinine, hence AKI. This AKI was not associated with any overt morphological alterations in the kidney and was attenuated by EPO given 1 h after lipopolysaccharide in wild-type but not in βcR knockout mice. In the kidneys of endotoxemic wild-type mice, EPO enhanced the phosphorylation of Akt, glycogen synthase kinase-3β, and endothelial nitric oxide synthase, and inhibited the activation of nuclear factor-κB. All these effects of EPO were lost in βcR knockout mice. Since sepsis is more severe in older animals or patients, we tested whether EPO was renoprotective in 8-month-old wild-type and βcR knockout mice that underwent cecal ligation and puncture. These older mice developed AKI at 24 h, which was attenuated by EPO treatment 1 h post cecal ligation and puncture in wild-type mice but not in βcR knockout mice. Thus, activation of the βcR by EPO is essential for the observed reduction in AKI in either endotoxemic young mice or older mice with polymicrobial sepsis, and for the activation of well-known signaling pathways by EPO.

Topics: Acute Kidney Injury; Animals; Caspase 3; Cecum; Cytokine Receptor Common beta Subunit; Disease Models, Animal; Erythropoietin; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Hepatitis A Virus Cellular Receptor 1; Kidney; Ligation; Lipopolysaccharides; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Phosphorylation; Proto-Oncogene Proteins c-akt; Sepsis; Signal Transduction

Bone marrow-derived mesenchymal stem cells (BMSCs) preferentially migrate to the injured tissue but with limited efficiency. Here we investigated the effect of erythropoietin (EPO) treatment on the BMSC migration to the acute kidney injury (AKI) microenvironment. The possible mechanisms were also discussed. A hypoxia/re-oxygenation (HR) model of renal tubular epithelial cells (RTECs) was established to generate AKI in vitro, and a chemotaxis experiment was conducted using the transwell chamber. EPO treatment enhanced the BMSC migration to the HR-RTEC culturing chamber in a SDF-1 level-dependent manner, which was fully inhibited by the treatment of anti-SDF-1 antibody. The BMSC migration could also be partly blocked by LY294002 (phosphoinositide 3-kinase (PI3K) inhibitor) and PD98059 (MAPK inhibitor). Western blot analysis showed that phosphorylated Akt and phosphorylated MAPK in BMSCs were enhanced by EPO treatment. In the in vivo experiment, BMSCs were transplanted into the AKI mice and EPO was subcutaneously injected. The results showed that EPO injection increased the SDF-1 protein expression and BMSC accumulation in the renal tissue, which was consistent with a decent improvement of renal function. In addition, the BMSC accumulation in the renal tissue was blocked by anti-SDF-1 antibody, LY294002 or PD98059. Our data suggest that AKI microenvironment had a directional chemotactic effect on BMSCs, which could be further enhanced by the EPO treatment. The increased SDF-1 level in the AKI microenvironment and the activations of PI3K/AKT and MAPK in BMSCs were the possible mechanisms for the effect of EPO. Therefore, BMSC transplantation combined with EPO injection can be a novel and effective approach for AKI repair.

Topics: Acute Kidney Injury; Animals; Bone Marrow Cells; Cell Movement; Cells, Cultured; Cellular Microenvironment; Drug Evaluation, Preclinical; Erythropoietin; Kidney; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice; Mice, Inbred C57BL

So far, no effective therapy is available for acute kidney injury (AKI), a common and serious complication with high morbidity and mortality. Interest has recently been focused on the potential therapeutic effect of mouse adult renal progenitor cells (MRPC), erythropoietin (EPO) and suramin in the recovery of ischemia-induced AKI. The aim of the present study is to compare MRPC with MRPC/EPO or MRPC/suramin concomitantly in the treatment of a mouse model of ischemia/reperfusion (I/R) AKI.. MRPC were isolated from adult C57BL/6-gfp mice. Male C57BL/6 mice (eight-weeks old, n = 72) were used for the I/R AKI model. Serum creatinine (Cr), blood urea nitrogen (BUN) and renal histology were detected in MRPC-, MRPC/EPO-, MRPC/suramin- and PBS-treated I/R AKI mice. E-cadherin, CD34 and GFP protein expression was assessed by immunohistochemical assay.. MRPC exhibited characteristics consistent with renal stem cells. The features of MRPC were manifested by Pax-2, Oct-4, vimentin, α-smooth muscle actin positive, and E-cadherin negative, distinguished from mesenchymal stem cells (MSC) by expression of CD34 and Sca-1. The plasticity of MRPC was shown by the ability to differentiate into osteoblasts and lipocytes in vitro. Injection of MRPC, especially MRPC/EPO and MRPC/suramin in I/R AKI mice attenuated renal damage with a decrease of the necrotic injury, peak plasma Cr and BUN. Furthermore, seven days after the injury, MRPC/EPO or MRPC/suramin formed more CD34(+) and E-cadherin+ cells than MRPC alone.. These results suggest that MRPC, in particular MRPC/EPO or MRPC/suramin, promote renal repair after injury and may be a promising therapeutic strategy.

Topics: Acute Kidney Injury; Adult Stem Cells; Animals; Antigens, CD34; Cadherins; Cell Differentiation; Cells, Cultured; Drug Therapy, Combination; Epoetin Alfa; Erythropoietin; Green Fluorescent Proteins; Hematinics; Kidney; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Octamer Transcription Factor-3; PAX2 Transcription Factor; Recombinant Proteins; Suramin; Vimentin

The protective effect of Erythropoietin (EPO) analogue rHuEPO on acute renal injury induced by exhaustive exercise had been reported. The purpose of this study is to probe into the protective effect of EPO on chronic renal injury induced by repeated exhaustive exercise for four weeks.. Eighty adult male Sprague-Dawley rats were used in this experiment. The animals were randomly allocated to one of four groups: control (C), exhaustive exercise test (ET), ET plus EPO pre-treatement (ET+EPO) and ET+EPO plus LY294002 pretreatment (ET+EPO+LY).. Compared with the rats in control group, there was considerable damage in kidney cells in rats of ET group as revealed by histological and ultrastructural examinations. However, treatment with EPO during the training, the exhaustive running distance was significant increased (P < 0.01), and the pathological changes of kidney cell were much less compared with those of rats without EPO intervention. When LY294002, a specific inhibitor of phospholipids phthalocyanine inositol 3-kinase, was added to the EPO treated rats, the injury changes of renal cell were becoming more pronounced.. The protective effect of EPO on chronic renal injury induced by repeated exhaustive exercise was demonstrated in the present study. We proposed that the effect could be due to inhibiting the cell apoptosis and blocking the formation of interstitial fibrosis via activation of the PI3K/Akt pathway, thus plays role in the endogenous protection of the kidney injury.

Topics: Acute Kidney Injury; Animals; Erythropoietin; Exercise Test; Male; Physical Exertion; Protective Agents; Random Allocation; Rats; Rats, Sprague-Dawley

Erythropoietin (EPO) is a glycoprotein hormone produced predominantly in the kidneys. The protective effect of exogenous EPO in hypoxic-ischemic brain injury has been thoroughly examined in neonates. However, the metabolism of endogenous EPO in neonates remains unclear.. We aimed to evaluate the concentration of urinary EPO (uEPO) in critically ill neonates and to identify possible clinical and laboratory variables that may be associated with uEPO levels.. The concentrations of EPO, cystatin-C, microalbumin, and α1-microglobulin in the first available urine sample during the initial 72 h of life were measured in 103 critically ill neonates. Clinical and laboratory data were collected for each neonate.. There was a positive correlation between uEPO levels and urinary levels of cystatin-C (r = 0.265, p = 0.008), microalbumin (r = 0.422, p < 0.001), and α1-microglobulin (r = 0.421, p < 0.001). The concentration of uEPO was elevated in neonates who developed acute kidney injury (AKI) during the first week of life compared with those without AKI (p = 0.002) and was also elevated in neonates with brain injury, as demonstrated by ultrasound or magnetic resonance imaging, compared to neonates without brain injury (p = 0.008). An increased log10 uEPO level was associated with the occurrence of AKI (OR 2.70, p = 0.007) and brain injury (OR 2.33, p = 0.016).. An increased urinary EPO level in the early postnatal period is significantly associated with kidney and brain injury in critically ill neonates.

Topics: Acute Kidney Injury; Albuminuria; Alpha-Globulins; Biomarkers; Brain Injuries; Critical Illness; Cystatin C; Erythropoietin; Female; Humans; Infant, Newborn; Linear Models; Logistic Models; Magnetic Resonance Imaging; Male; Multivariate Analysis; Odds Ratio; Predictive Value of Tests; Prognosis; Risk Factors; Time Factors; Ultrasonography, Doppler, Transcranial; Up-Regulation

Experimental evidence has indicated a role of adult renal progenitor cells in kidney regeneration and a protective role of the kidney by erythropoietin (EPO) and suramin in animal models and in humans after acute kidney injury (AKI). Han and colleagues analyzed different therapeutic effects between mouse renal progenitor cells (MRPCs), MRPC/EPO, or MRPC/suramin on the regeneration and protection of renal function after AKI. Their results revealed that MRPCs in combination with EPO or suramin are able to attenuate renal damage and promote renal recovery after ischemia/reperfusion injury in a mouse model. The researchers concluded that the combined approach with MRPCs and EPO or suramin could be a new therapeutic strategy for AKI.

Topics: Acute Kidney Injury; Adult Stem Cells; Animals; Erythropoietin; Hematinics; Kidney; Male; Suramin

Bone-marrow mesenchymal stem cells (BMSCs) transplantation is effective for acute kidney injury (AKI) repair but with limited efficiency. In the present study, BMSCs marked by bromodeoxyuridine (BrdU) were transplanted to the AKI mouse model with erythropoietin (EPO) being subcutaneously injected. The blood urea nitrogen (BUN) and serum creatinine (Scr) levels, pathological changes, distribution of BMSCs, expressions of the cytokeratin 18 (CK18) and the stromal cell-derived factor 1 (SDF-1) in the nephridial tissues were measured. The directional migration of BMSCs to the AKI microenvironment in vitro was also tested. The results showed that BMSCs transplantation or EPO injection alone decreased the BUN and Scr levels and the acute tubular necrosis (ATN) scoring in varied degrees. The combination of these decreased the above indicators' levels significantly. BrdU(+) cells (BMSCs) were observed in the AKI nephridial tissues, and CK18 expressed in the cytoplasm of these cells. EPO injection increased the proportion of BrdU(+) cells with the enhanced expression of SDF-1 in the AKI nephridial tissues. EPO increased the migrating number of BMSCs to the AKI microenvironment in vitro, and additional anti-SDF-1 treatment with SDF-1 antibody neutralized this effect. Our results showed that EPO increased the number of the transplanted BMSCs in the injured nephridial tissues and enhanced the AKI repair effect of BMSCs transplantation. The enhanced kidney-homing efficiency for BMSCs mediated by the SDF-1/CXCR4 pathway is one of the possible mechanisms for EPO performance.

Topics: Acute Kidney Injury; Animals; Bone Marrow; Cell Movement; Cells, Cultured; Disease Models, Animal; Erythropoietin; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice; Mice, Inbred C57BL

Cisplatin (CDDP) and mitomycin C (MMC), two alkylating agents used against various solid tumours, are a common source of acute kidney injury. Thus, strategies for minimizing CDDP and MMC toxicity are of a clinical interest. In this study, we aimed to investigate the protective role of recombinant human erythropoietin (rhEPO) against oxidative stress and genotoxicity induced by CDDP and MMC in cultured Vero cells. Three types of treatments were performed: (i) cells were treated with rhEPO 24 h before exposure to CDDP/MMC (pre-treatment), (ii) cells were treated with rhEPO and CDDP/MMC simultaneously (co-treatment), (iii) cells were treated with rhEPO 24 h after exposure to CDDP/MMC (post-treatment). Our results showed that rhEPO decreased the reactive oxygen species levels, the malondialdehyde levels and ameliorated glutathione (reduced and oxidized glutathione) modulation induced by CDDP and MMC in cultured Vero cells. Furthermore, rhEPO administration prevented alkylating agents-induced DNA damage accessed by comet test. Altogether, our results suggested a protective role of rhEPO, against CDDP- and MMC-induced oxidative stress and genotoxicity, especially in pre-treatment condition.

Topics: Acute Kidney Injury; Alkylating Agents; Animals; Antioxidants; Cells, Cultured; Chlorocebus aethiops; Cisplatin; DNA Damage; Erythropoietin; Glutathione; Humans; In Vitro Techniques; Kidney; Malondialdehyde; Mitomycin; Models, Animal; Oxidative Stress; Reactive Oxygen Species; Recombinant Proteins; Time Factors; Vero Cells

Two groups elucidate novel mechanisms of tissue protection by erythropoietin (EPO). Hu et al. demonstrate that Klotho's protective effect against oxidant-induced cytotoxicity is partially mediated by an increase in the endogenous expression of the classical EPO receptor (EpoR). While erythropoiesis is stimulated by the canonical EpoR homodimer, the tissue-protective effects of EPO are mediated through a heterodimeric 'tissue-protective' receptor. Coldewey et al. demonstrate a protective role of the 'tissue-protective' EpoR against acute kidney injury.

Topics: Acute Kidney Injury; Animals; Cytokine Receptor Common beta Subunit; Cytoprotection; Erythropoietin; Glucuronidase; Humans; Kidney; Klotho Proteins; Male; Receptors, Erythropoietin; Sepsis

The protective role of recombinant human erythropoietin (RHE) against cisplatin-induced nephrotoxicity has been reported, but the role of sex differences is not clearly known. The aim of this study was to determine the sex-based difference in the protective effect of RHE against cisplatin-induced nephrotoxicity.. Thirty-three Wistar rats were divided into 6 groups. According to protocol l, male and female rats were treated with RHE (100 IU/kg/d) for 3 days and then received a single dose of cisplatin (7 mg/kg). According to protocol 2, the rats received the same single dose of cisplatin and then were treated with RHE for 7 days. Two other groups of male and female rats received a similar regimen of protocol 2 except for saline instead of RHE. All the animals were sacrificed 1 week after cisplatin administration.. All of the experimental animals experienced weight loss. The percentage change of weight in male rats with protocol 1 was significantly less than that in male rats in protocol 2 and control groups. However, in female groups, the percentage of change in weights was slightly higher with protocol 2 than with protocol 1 and control treatment. Administration of RHE significantly decreased changes in serum creatinine, BUN, and malondialdehyde levels in male rats, but not in females. No significant difference was observed in serum nitrite level, kidney weight, and kidney damage score between the groups.. This study suggested that erythropoietin may lead to different responses against cisplatin-induced nephrotoxicity in male and female rats.

Topics: Acute Kidney Injury; Animals; Antineoplastic Agents; Blood Urea Nitrogen; Body Weight; Cisplatin; Creatinine; Disease Models, Animal; Erythropoietin; Female; Kidney; Male; Malondialdehyde; Nitrites; Organ Size; Random Allocation; Rats; Rats, Wistar; Sex Characteristics; Sex Factors

Ischemia reperfusion (IR) and cyclosporine A (CsA) injuries are unavoidable in kidney transplantation and are associated with allograft dysfunction. Herein, the effect and mechanism of a novel tissue protective peptide, helix B surface peptide (HBSP) derived from erythropoietin, were investigated in a rat model. The right kidney was subjected to 45 min ischemia, followed by left nephrectomy and 2-week reperfusion, with or without daily treatment of CsA 25 mg/kg and/or HBSP 8 nmol/kg. Blood urea nitrogen was increased by CsA but decreased by HBSP at 1 week and 2 weeks, while the same changes were revealed in urinary protein/creatinine only at 2 weeks. HBSP also significantly ameliorated tubulointerstitial damage and interstitial fibrosis, which were gradually increased by IR and CsA. In addition, apoptotic cells, infiltrated inflammatory cells, and active caspase-3+ cells were greatly reduced by HBSP in the both IR and IR + CsA groups. The 17 kD active caspase-3 protein was decreased by HBSP in the IR and IR + CsA kidneys, with decreased mRNA only in the IR + CsA kidneys. Taken together, it has been demonstrated, for the first time, that HBSP effectively improved renal function and tissue damage caused by IR and/or CsA, which might be through reducing caspase-3 activation and synthesis, apoptosis, and inflammation.

Topics: Acute Kidney Injury; Animals; Apoptosis; Caspase 3; Cyclosporine; Enzyme Activation; Erythropoietin; Fibrosis; Gene Expression; Inflammation; Kidney; Kidney Function Tests; Male; Peptide Fragments; Protective Agents; Rats; Reperfusion Injury; RNA, Messenger

Cisplatin is one of the most important chemotherapeutic agents useful in the treatment of a variety of solid tumors; however, it has several side effects such as nephrotoxicity. In the present study, the effect of rhEPO on acute kidney injury induced by i.p. injection of rats with 9.0 mg/kg cisplatin was studied. It was observed that EPO treated group showed a significantly lower rate in the extent and severity of the histological signs of kidney injury than untreated one. This is attributed to (i) a decrease in the elevated oxidative and nitrosative stress markers, (ii) reduction of the expression of VEGF, HO-1 and iNOS as well as (iii) improvement of Bcl2 immunoreaction in most tubular cells. Thus, EPO may be one of the futures therapeutic possibilities to overcome the side effects of anti-cancer drugs induced acute renal injury through various mechanisms including down regulation of vascular endothelial growth factor (VEGF), hemeoxygenase-1 (HO-1) and inducible nitric oxide synthase (iNOS) expressions in addition to stimulation of tubular cell regeneration.

Topics: Acute Kidney Injury; Animals; Antineoplastic Agents; Blood Cell Count; Cisplatin; Disease Progression; Electrophoresis, Agar Gel; Erythropoietin; Gene Expression; Kidney Function Tests; Male; Nitric Oxide Synthase Type II; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; Vascular Endothelial Growth Factor A

The aim of this study was to determine the effects of erythropoietin (EPO), moderate hypothermia, and a combination thereof on the kidneys of newborn rats damaged during perinatal asphyxia. An animal model of perinatal asphyxia (Wistar rats) was used in which after birth, newborn rats were divided into four groups of 15 animals each: G1, rats exposed only to asphyxia; G2, rats exposed to asphyxia and hypothermia (rectal temperature 32°C) and which received EPO (darbepoetin alpha) intraperitoneally; G3, rats exposed to asphyxia and hypothermia; G4, rats exposed to asphyxia and which received EPO. The rats were sacrificed on the 7th day of life and histopathological evaluation of kidneys was performed. Damage to the proximal tubules was significantly higher in group G1 rats than in groups G2, G3, and G4 rats (p < 0.01). Damage to the distal tubules was found only in group G1 rats. Histological changes in the proximal tubules were more prominent than in the distal tubules (p < 0.01). The immature glomeruli zone was less expressed in group G4 rats than in groups G1, G2, and G3 rats (p < 0.01). Based on these results, we conclude that EPO and hypothermia, as well as the combination thereof, have a protective effect on rats' kidneys damaged during perinatal asphyxia.

Topics: Acute Kidney Injury; Animals; Animals, Newborn; Asphyxia Neonatorum; Combined Modality Therapy; Cytoprotection; Darbepoetin alfa; Disease Models, Animal; Erythropoietin; Female; Humans; Hypothermia, Induced; Infant, Newborn; Kidney; Kidney Glomerulus; Kidney Tubules; Male; Protective Agents; Rats; Rats, Wistar; Time Factors

Inhibition of the HIF regulating prolyl hydroxylation domain (PHDs) proteins prior to renal injury (preconditioning) has been shown to protect the kidney via activation of hypoxia-inducible transcription factors (HIF). Application of erythropoietin (EPO), one of the HIF target genes, has also been shown to be nephroprotective, and it remains unclear to what extent the effect of HIF induction is mediated by EPO. It is also unknown whether HIF activation after the onset of ischaemia (postconditioning) is still able to protect the kidney.. Using a rat model of renal ischaemia-reperfusion injury, animals were treated with the PHD inhibitor (PHD-I) 2-(1-chloro-4-hydroxyisoquinoline-3-carboxamido) acetate (ICA), vehicle (Veh) or recombinant human EPO (300 IU/kg) 6 h (ICA or Veh) or 30 min (EPO) prior to ischaemia (preconditioning) or with ICA prior to reperfusion (postconditioning). Renal function was assessed at baseline, 24 h and 72 h. After 72 h, kidneys were processed for histology and morphometric analysis. HIF immunohistochemistry and real-time polymerase chain reaction for HIF target genes, including EPO, were performed to evaluate ICA effects.. ICA treatment resulted in stabilization of HIF-1α and -2α and up-regulation of HIF target genes in a dose-dependent manner. Preconditional activation of HIF by ICA significantly improved serum creatinine levels and renal morphology in comparison to Veh (P < 0.05), while postconditional ICA treatment was ineffective. EPO therapy improved tissue morphology but had no impact on the course of serum creatinine.. These findings are in line with the concept that PHD-Is exert their protective effects through accumulation of HIF target gene products, with time requirements for increased transcription and translation of HIF-dependent genes, and suggest that their renoprotective effect is not predominately mediated by EPO.

Topics: Acute Kidney Injury; Animals; Enzyme Inhibitors; Epoetin Alfa; Erythropoietin; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Immunoenzyme Techniques; Male; Procollagen-Proline Dioxygenase; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Recombinant Proteins; Reperfusion Injury; RNA, Messenger

Topics: Acute Kidney Injury; Adult; Blood Component Transfusion; Bone Marrow; Cell Lineage; Combined Modality Therapy; Darbepoetin alfa; Erythropoietin; Filgrastim; Granulocyte Colony-Stimulating Factor; Hematuria; Humans; Lupus Erythematosus, Systemic; Lupus Nephritis; Lymphohistiocytosis, Hemophagocytic; Male; Mycophenolic Acid; Myelodysplastic Syndromes; Pancytopenia; Pericarditis; Prednisone; Proteinuria; Recombinant Proteins

Rhabdomyolysis is one of the causes of acute renal failure. Erythropoietin (EPO) has been found to interact with its receptor (EPO-R) expressed in a large variety of non-haematopoietic tissues to induce a range of pleiotropic cytoprotective actions. In this study, we used recombinant human erythropoietin (rhEPO) to study the effects on the glycerol-induced rhabdomyolysis with acute renal failure in rats.. Twenty-four rats were divided into three groups as glycerol group, glycerol+EPO group and normal saline+EPO group. Rhabdomyolysis was induced by intramuscular injection of 10 mlkg(-1) 50% glycerol in rats. Ten minutes later, the rats received an intravenous injection of rhEPO (300 Ukg(-1)). Biochemical substances, including haemoglobin, blood urea nitrogen (BUN), creatinine (Cre), glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT) and creatine phosphokinase (CPK), were measured at 0, 1, 3, 6, 9, 12, 18, 24 and 48 h. Rats were sacrificed 48 h later after glycerol administration and the kidneys were removed immediately for pathology and immunohistochemistry (IHC).. Intramuscular injection of glycerol significantly increased blood BUN, Cre, GOT, GPT and CPK levels and induced severe histopathologic damage in the kidneys. Nuclear factor-κB (NF-κB) and inducible nitric oxide synthase (iNOS) were increased and E-cadherin was decreased after glycerol administration, as detected by IHC in the kidneys. Post-treatment with rhEPO decreased blood BUN, Cre, GOT, GPT and CPK levels, decreased markers of kidney injury and suppressed the release of NF-κB and iNOS after rhabdomyolysis.. Treatment with rhEPO suppressed the activities of NF-κB and iNOS, decreased BUN, Cre, GOT, GPT and CPK levels, and decreased the markers of kidney injury after rhabdomyolysis. These actions ameliorated rhabdomyolysis-induced acute renal failure in rats.

Topics: Acute Kidney Injury; Alanine Transaminase; Animals; Aspartate Aminotransferases; Blood Urea Nitrogen; Erythropoietin; Glycerol; Immunohistochemistry; Injections, Intravenous; Kidney; Male; NF-kappa B; Nitric Oxide Synthase Type II; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Rhabdomyolysis; Tumor Necrosis Factor-alpha

Despite advances in supportive care, sepsis-related mortality remains high, especially in patients with acute kidney injury (AKI). Erythropoietin can protect organs against ischemia and sepsis. This effect has been linked to activation of intracellular survival pathways, although the mechanism remains unclear. Continuous erythropoietin receptor activator (CERA) is an erythropoietin with a unique pharmacologic profile and long half-life. We hypothesized that pretreatment with CERA would be renoprotective in the cecal ligation and puncture (CLP) model of sepsis-induced AKI.. RATS WERE RANDOMIZED INTO THREE GROUPS: control; CLP; and CLP+CERA (5 µg/kg body weight, i.p. administered 24 h before CLP). At 24 hours after CLP, we measured creatinine clearance, biochemical variables, and hemodynamic parameters. In kidney tissue, we performed immunoblotting--to quantify expression of the Na-K-2Cl cotransporter (NKCC2), aquaporin 2 (AQP2), Toll-like receptor 4 (TLR4), erythropoietin receptor (EpoR), and nuclear factor kappa B (NF-κB)--and immunohistochemical staining for CD68 (macrophage infiltration). Plasma interleukin (IL)-2, IL-1β, IL-6, IL-10, interferon gamma, and tumor necrosis factor alpha were measured by multiplex detection.. Pretreatment with CERA preserved creatinine clearance and tubular function, as well as the expression of NKCC2 and AQP2. In addition, CERA maintained plasma lactate at normal levels, as well as preserving plasma levels of transaminases and lactate dehydrogenase. Renal expression of TLR4 and NF-κB was lower in CLP+CERA rats than in CLP rats (p<0.05 and p<0.01, respectively), as were CD68-positive cell counts (p<0.01), whereas renal EpoR expression was higher (p<0.05). Plasma levels of all measured cytokines were lower in CLP+CERA rats than in CLP rats.. CERA protects against sepsis-induced AKI. This protective effect is, in part, attributable to suppression of the inflammatory response.

Topics: Acute Kidney Injury; Animals; Cecum; Cytokines; Erythropoietin; Gene Expression Regulation; Hemodynamics; Kidney Tubules; Ligation; Macrophages; Male; Multiple Organ Failure; NF-kappa B; Polyethylene Glycols; Punctures; Rats; Rats, Wistar; Receptors, Erythropoietin; Sepsis; Toll-Like Receptor 4

The pathophysiology of sepsis involves complex cytokine and inflammatory mediator networks, a mechanism to which NF-κB activation is central. Downregulation of endothelial nitric oxide synthase (eNOS) contributes to sepsis-induced endothelial dysfunction. Erythropoietin (EPO) has emerged as a major tissue-protective cytokine in the setting of stress. We investigated the role of EPO in sepsis-related acute kidney injury using a cecal ligation and puncture (CLP) model. Wistar rats were divided into three primary groups: control (sham-operated); CLP; and CLP+EPO. EPO (4,000 IU/kg body wt ip) was administered 24 and 1 h before CLP. Another group of rats received N-nitro-l-arginine methyl ester (l-NAME) simultaneously with EPO administration (CLP+EPO+l-NAME). A fifth group (CLP+EPOtreat) received EPO at 1 and 4 h after CLP. At 48 h postprocedure, CLP+EPO rats presented significantly higher inulin clearance than did CLP and CLP+EPO+l-NAME rats; hematocrit levels, mean arterial pressure, and metabolic balance remained unchanged in the CLP+EPO rats; and inulin clearance was significantly higher in CLP+EPOtreat rats than in CLP rats. At 48 h after CLP, creatinine clearance was significantly higher in the CLP+EPO rats than in the CLP rats. In renal tissue, pre-CLP EPO administration prevented the sepsis-induced increase in macrophage infiltration, as well as preserving eNOS expression, EPO receptor (EpoR) expression, IKK-α activation, NF-κB activation, and inflammatory cytokine levels, thereby increasing survival. We conclude that this protection, which appears to be dependent on EpoR activation and on eNOS expression, is attributable, in part, to inhibition of the inflammatory response via NF-κB downregulation.

Topics: Acute Kidney Injury; Animals; Creatinine; Cytokines; Down-Regulation; Drug Therapy, Combination; Enzyme Inhibitors; Erythropoietin; I-kappa B Kinase; Inflammation; Inulin; Male; NF-kappa B; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase Type III; Rats; Rats, Wistar; Receptors, Erythropoietin; Sepsis; Up-Regulation

To explore the effects of erythropoietin (EPO) on the differentiation and secretion of cultured bone marrow-derived mesenchymal stem cells (BM-MSC) in the microenvironment of acute kidney injury (AKI).. C57BL/6 murine BM-MSC (mBM-MSC) were successfully isolated by the methods of Percoll density gradient centrifugation and adherence cultivation. The AKI murine model was induced by ischemia/reperfusion (I/R). The homogenate supernatants were prepared for normal and I/R murine kidney. P3-mBM-MSC were treated differently: Group A: low glucose DMEM medium with 10% fetal bovine serum, Group B: normal murine kidney homogenate supernatant intervention, Group C: I/R kidney homogenate supernatant intervention, Group D: I/R kidney homogenate supernatant plus different concentrations of EPO (1, 5, 10, 50 U/ml). Each group was incubated for 1, 3, 5 and 7 days. Inverted microscope was used to observe the morphological changes of these cells and their ultrastructural changes were observed by transmission electron microscope. Cytokeratin-18 was detected by flow cytometry. The levels of bone morphogenetic protein-7 (BMP-7), hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) were detected by ELISA in culture medium.. The cells yielded a high expression of CD29 and CD44 and a low expression of CD34 and CD45. Compared with Groups A and B, the cells of Group C presented oval and short fusiform shapes. After the intervention of EPO, Group D showed a cobble appearance. More organelles were also found. A trace expression of CK18 was found in Groups A and B. A positive expression of CK18 was significantly higher in Groups C and D than Groups A and B (P < 0.01). The expression of EPO 50 U/ml at Day 5 and 7 was higher than Group C of the same time (5 d: 35.22 ± 4.04 vs 8.72 ± 0.38, 7 d: 42.00 ± 5.39 vs 13.20 ± 1.14, both P < 0.01). The results of ELISA showed that the levels of BMP-7, HGF and VEGF in Group C decreased significantly (P < 0.01 or P < 0.05).. The intervention of EPO may boost the differentiation of mBM-MSC but reverse its low secretion.

Topics: Acute Kidney Injury; Animals; Bone Marrow Cells; Cell Differentiation; Cells, Cultured; Erythropoietin; Flow Cytometry; Male; Mesenchymal Stem Cells; Mice; Mice, Inbred C57BL

Interest has recently been focused on the possible role of bone marrow-originating stem cells and the therapeutic role of erythropoietin in the recovery of ischemia-induced acute kidney injury (AKI). The aim of the present study was to compare treatment with mesenchymal stem cells (MSCs) to treatment with darbepoetin-α (DPO) or both concomitantly in a rat model of ischemia/reperfusion (I/R) AKI.. Forty male Sprague-Dawley rats were included, and 28 of them were randomly assigned to controls (treated with serum physiologic) or one of the three treatment groups treated with either DPO, MSCs, or both (MSCs and DPO concomitantly) after the induction of I/R injury. Hematocrit, serum creatinine, and BUN levels were obtained at 0, 24, 48, and 72 h of surgery, and renal tissue was obtained at 72 h after nephrectomy for histological analysis. Tissue injury was quantified by standardized histological scoring systems, using light and electron microscopes.. Treatment with MSCs or DPO improved renal function compared with controls. However, the improvement observed in renal function in the MSC/DPO group was better than that in the other groups. Histological analysis demonstrated that tissue injury was significantly decreased in rats in the MSC or DPO groups compared to that of the controls; however the best recovery was observed in rats treated with MSCs and DPO concomitantly.. These results suggest that concomitant application of DPO and MSCs may be a potential novel renoprotective therapy for patients after having sustained an ischemic renal insult.

Topics: Acute Kidney Injury; Animals; Apoptosis; Blood Urea Nitrogen; Combined Modality Therapy; Creatinine; Darbepoetin alfa; Erythropoietin; Hematinics; Hematocrit; Ischemia; Kidney; Male; Mesenchymal Stem Cell Transplantation; Random Allocation; Rats; Rats, Sprague-Dawley; Reperfusion Injury

Acute renal injury is one of the most frequent complications after cardiopulmonary bypass (CPB). This study was designed to evaluate the potential protective effect of erythropoietin (EPO) on CPB-induced renal injury in a rat model. Male Sprague-Dawley rats were randomly divided into three groups, sham-operated group (sham), control CPB group (control), erythropoietin CPB group (EPO). Blood samples were collected at the beginning, at the end of CPB, and at 0.5, 1, 2 and 24 h post-operation, and the kidneys were harvested 24 h postoperatively and observed by optical microscopy. Levels of serum creatinine (Cr) and blood urea nitrogen (BUN) were assayed. Tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6(IL-6) levels in the renal tissues were evaluated by the method of enzyme linked immunosorbent assay (ELISA). Protein and mRNA levels of nuclear factor kappa B p65 (NF-κB p65), intercellular adhesion molecule-1 (ICAM-1) were also determined using western blot and real-time PCR respectively. Serum Cr and BUN levels as well as TNF-α, IL-1β and IL-6 levels in renal tissues in control group were significantly higher than those in the sham group. However, the levels of above biomarkers were markedly decreased in EPO group when comparing with control group. Furthermore, NF-κB p65, ICAM-1 protein and mRNA expression were significantly down-regulated in EPO group comparing with control group. In addition, microscopic examinations revealed that histological injury was alleviated when treated with EPO. The results indicated that EPO potently protected against CPB-induced acute renal injury and inhibited expression of NF-κB p65 and inflammatory response.

Topics: Acute Kidney Injury; Animals; Cardiopulmonary Bypass; Erythropoietin; Gene Expression Regulation; Inflammation Mediators; Male; Postoperative Complications; Random Allocation; Rats; Rats, Sprague-Dawley; Transcription Factor RelA

Acute renal failure (ARF) can be caused by injuries that induce tissue hypoxia, which in turn can trigger adaptive or inflammatory responses. We previously showed the participation of basic fibroblast growth factor (FGF-2) in renal repair. Based on this, the aim of this study was to analyze the effect of FGF-2 signaling pathway manipulation at hypoxia-induced protein levels, as well as in key proteins from the vasoactive systems of the kidney. We injected rat kidneys with FGF-2 recombinant protein (r-FGF) or FGF-2 receptor antisense oligonucleotide (FGFR2-ASO) after bilateral ischemia, and evaluated the presence of iNOS, EPO and HO-1, in representation of hypoxia-induced proteins, as well as COX-2, renin, kallikrein, and B2KR, in representation of the vasoactive systems of the kidney. A reduction in iNOS, HO-1, EPO, renin, kallikrein, B2KR, and in renal damage was observed in animals treated with r-FGF. The opposite effect was found with FGF-2 receptor down-regulation. In contrast, COX-2 protein levels were higher in kidneys treated with r-FGF and lower in those that received FGFR2-ASO, as compared to saline treated kidneys. These results suggest that the protective role of FGF-2 in the pathogenesis of ARF induced by I/R is a complex process, through which a differential regulation of metabolic pathways takes place.

Topics: Acute Kidney Injury; Animals; Cell Hypoxia; Cyclooxygenase 2; Disease Models, Animal; Erythropoietin; Fibroblast Growth Factor 2; Heme Oxygenase-1; Kallikreins; Kidney; Male; Nitric Oxide Synthase; Rats; Rats, Sprague-Dawley; Receptor, Bradykinin B2; Reperfusion Injury

There is a plethora of experimental data on the potential therapeutic benefits of recombinant human erythropoietin (rhEPO) and its synthetic derivatives in critical care medicine, in particular in ischemia/reperfusion injury. Most of the recent clinical trials have not shown clear benefits, and, in some patients, EPO-aggravated morbidity and mortality was even reported. Treatment with rhEPO has been successfully used in patients with anemia resulting from chronic kidney disease, but even a subset of this patient population does not adequately respond to rhEPO therapy. The following viewpoint uses rhEPO as an example to highlight the possible pitfalls in current practice using young healthy animals for the evaluation of therapies to treat patients of variable age and underlying chronic co-morbidity.

Topics: Acute Kidney Injury; Animals; Clinical Trials as Topic; Critical Illness; Drug Resistance; Erythropoietin; Humans; Models, Animal; Recombinant Proteins; Renal Insufficiency, Chronic; Reperfusion Injury

Erythropoietin (EPO) is a cytokine with organ-protective properties. We hypothesized that EPO could attenuate acute renal dysfunction and inflammation in a porcine model of ischemia-reperfusion (IR). Furthermore, we aimed to characterize the impact of EPO on systemic and renal hemodynamics, and renal oxygen consumption.. Twenty-four pigs were randomly assigned to three groups: (1) EPO (5000 IU/kg) administered intravenously before IR (n=9), (2) placebo administered before IR (n=9), or (3) sham group, anesthetized and operated on only (n=6). IR was induced by clamping the left renal artery for 45 min. Hemodynamics and renal blood flow (RBF) were analyzed continuously. Glomerular filtration rate (GFR), renal oxygen consumption, and plasma cytokines (IL-1β, IL-6, IL-8, IL-10, and TNF-α) were analyzed hourly. Renal biopsies were analyzed for cytokine content and apoptosis.. GFR was higher during reperfusion in the EPO group than in the placebo group (P<0.01). No differences between the IR groups were found in hemodynamics, RBF, oxygen consumption, or renal apoptosis. The levels of TNF-α in the plasma (P=0.036) and the levels of TNF-α and IL-10 in the renal cortex (P=0.04 and P=0.01, respectively) were lower in the EPO group compared with the sham group.. EPO attenuated the renal dysfunction as estimated as GFR. This effect was not related to changes in the hemodynamics. The immunomodulatory effects of EPO were manifested as decreased levels of TNF-α and IL-10 in renal biopsies and TNF-α levels in plasma.

Topics: Acute Kidney Injury; Animals; Apoptosis; Caspase 3; Cytokines; Erythropoietin; Glomerular Filtration Rate; Hemodynamics; Immunohistochemistry; Kidney; Kidney Function Tests; Oxygen Consumption; Pulmonary Gas Exchange; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Renal Circulation; Reperfusion Injury; Swine

Following our long-standing interest in the mechanisms involved in selenium toxicity, the aim of this work was to extend our previous studies to gain a better understanding of mercuric chloride (HgCl₂) + diphenyl diselenide (PhSe)₂ toxicity. Mice received one daily dose of HgCl₂ (4.6 mg kg(-1) , subcutaneously) for three consecutive days. Thirty minutes after the last injection of HgCl₂, mice received a single dose of (PhSe)₂ (31.2 mg kg(-1) , subcutaneously). Five hours after (PhSe)₂ administration, mice were euthanized and δ-aminolevulinate dehydratase, catalase (CAT), glutathione S-transferase (GST) and Na(+) , K(+) -ATPase activities as well as thiobarbituric acid-reactive substances (TBARS), ascorbic acid and mercury levels were determined in kidney and liver. Parameters in plasma (urea, creatinine, protein and erythropoietin), whole blood (hematocrit and hemoglobin) and urine (protein) were also investigated. HgCl₂ + (PhSe)₂ exposure caused a decrease in renal GST and Na(+) , K(+) -ATPase activities and an increase in renal ascorbic acid and TBARS concentrations when compared with the HgCl₂ group. (PhSe)₂ potentiated the increase in plasma urea caused by HgCl₂. HgCl₂ + (PhSe)₂ exposure caused a reduction in plasma protein levels and an increase in hemoglobin and hematocrit contents when compared with the HgCl₂ group. There was a significant reduction in hepatic CAT activity and an increase in TBARS levels in mice exposed to HgCl₂ + (PhSe)₂ when compared with the HgCl₂ group. The results demonstrated that (PhSe)₂ did not modify mercury levels in mice. In conclusion, (PhSe)₂ potentiated damage caused by HgCl₂ affecting mainly the renal tissue.

Topics: Acute Kidney Injury; Animals; Ascorbic Acid; Benzene Derivatives; Catalase; Creatinine; Erythropoietin; Glutathione Transferase; Kidney; Liver; Male; Mercuric Chloride; Mercury; Mice; Organoselenium Compounds; Oxidative Stress; Porphobilinogen Synthase; Thiobarbituric Acid Reactive Substances; Urea

Bone marrow-derived mesenchymal stromal cells (MSCs) are promising for regenerative medicine applications, such as for renoprotection and repair in acute kidney injury (AKI). Erythropoietin (Epo) can also exert cytoprotective effects on various tissues including the kidney. We hypothesized that MSCs gene-enhanced to secrete Epo may produce a significant beneficial effect in AKI. Mouse Epo-secreting MSCs were generated, tested in vitro, and then implanted by intraperitoneal injection in allogeneic mice previously administered cisplatin to induce AKI. Epo-MSCs significantly improved survival of implanted mice as compared to controls (67% survival versus 33% with Vehicle only). Also, Epo-MSCs led to significantly better kidney function as shown by lower levels of blood urea nitrogen (72 ± 9.5 mg/dl versus 131 ± 9.20 mg/dl) and creatinine (74 ± 17 µmol/l versus 148±19.4 µmol/l). Recipient mice also showed significantly decreased amylase and alanine aminotransferase blood concentrations. Kidney sections revealed significantly less apoptotic cells and more proliferating cells. Furthermore, PCR revealed the presence of implanted cells in recipient kidneys, with Epo-MSCs leading to significantly increased expression of Epo and of phosphorylated-Akt (Ser473) (P-Akt) in these kidneys. In conclusion, our study demonstrates that Epo gene-enhanced MSCs exert significant tissue protective effects in allogeneic mice with AKI, and supports the potential use of gene-enhanced cells as universal donors in acute injury.

Topics: Acute Kidney Injury; Animals; Bone Marrow Cells; Cell Survival; Cisplatin; Culture Media, Conditioned; Epithelial Cells; Erythropoietin; Kidney; Male; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Survival Analysis; Transduction, Genetic; Transplantation, Homologous

Erythropoietin (EPO) can stimulate the proliferation and protraction of endothelial progenitor cells, and plays an important role in the proliferation and differentiation of marrow-derived mesenchymal stem cells (mMSCs) under the acute kidney injury (AKI) microenvironment. In the present study, C57BL/6 mice mMSCs were isolated, and AKI mice models were prepared. The renal cortex was obtained to prepare the ischemia/reperfusion (I/R) kidney homogenate supernatant. P3-mMSCs were treated by different methods: one group was added only I/R kidney homogenate supernatant, and another contained different concentrations of EPO (1, 5, 10, 50 IU/mL) in I/R kidney homogenate supernatant. The proliferation and apoptosis of mMSCs were detected by CCK-8 and TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling), respectively. Expression of erythropoietin receptor (EPOR) and protein of the signal pathway related to proliferation/apoptosis were also examined. The results showed that the proliferation ability of mMSCs treated with I/R kidney homogenate supernatant decreased significantly, while the apoptosis percentage was significantly higher than that of the control. After intervention of EPO, their proliferation enhanced and the apoptosis percentage decreased. EPOR expression was positive in P3-mMSCs. EPO decreased the expression of caspase-3 of mMSCs under the AKI microenvironment in a dose- and time-dependent manner, but increased the Bcl-2 expression. The expression of phosphor-Janus kinase 2, phosphor-signal transducer and activator of transcription (pSTAT-5) increased significantly in 10 IU/mL EPO cultured for five days. Our results show that EPO can promote proliferation of mMSCs in vitro under the AKI microenvironment, which is mediated by EPOR and related with the proliferation/apoptosis signal pathway.

Topics: Acute Kidney Injury; Animals; Apoptosis; Blotting, Western; Caspase 3; Cell Proliferation; Erythropoietin; In Situ Nick-End Labeling; Male; Mesenchymal Stem Cells; Mice; Mice, Inbred C57BL; Receptors, Erythropoietin; Signal Transduction

The use of Cyclosporine A (CsA) as rejection prophylaxis following organ transplantation is limited by its nephrotoxicity. CsA induces renal damage that is associated with tubulo-interstitial injury and parenchymal sequestration of macrophages, perpetuating pro-inflammatory processes. Furthermore, CsA exerts a diabetogenic effect by damaging pancreatic islet cell integrity. Continuous Erythropoietin Receptor Activator (CERA) was shown to mediate tissue-protective and anti-inflammatory effects in various settings of organ injury. Here, we investigated the effect of low dose CERA in a model of CsA-induced renal and pancreatic injury. Rats were exposed to medium-dose CsA for 28 days. Low-dose CERA was given to the treatment group (CERA) (n=6) once per week vs. a CsA-treated control group (CONTROL) (n=6). The effect of CERA on renal and pancreatic injuries was analyzed by organ function, histology, immunohistochemistry (CD68(+)-macrophages, insulin), ELISA (TGF-β1) and RT-PCR (TGF-β1, Osteopontin, IL-10). CsA induced functional kidney damage. Low dose CERA did not lead to improved kidney function in the treatment group. However, low dose CERA showed a trend toward upregulation of osteopontin accompanied by increased renal macrophage-infiltration and enhanced parenchymal TGF-β1 and IL-10 when compared to controls. Moreover, CERA treated animals showed amelioration of pancreatic islet cell injury. In this model of acute CsA-mediated renal injury, low dose CERA administration was associated with anti-inflammatory effects and preservation of pancreatic islet cell viability.

Topics: Acute Kidney Injury; Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Body Weight; Cell Survival; Cyclosporine; Disease Models, Animal; Dose-Response Relationship, Drug; Erythropoietin; Gene Expression Regulation; Glucose; Hematologic Tests; Interleukin-10; Islets of Langerhans; Kidney; Macrophages; Male; Osteopontin; Polyethylene Glycols; Rats; Rats, Sprague-Dawley; Transforming Growth Factor beta1

Cisplatin (Cisp) is one of the most widely used chemotherapeutic agents for the treatment of several human malignancies. The efficacy of Cisp is dose dependent and at higher doses serious kidney injury may occur. Recombinant human erythropoietin (rhEPO) has recently been shown to exert an important cytoprotective effect in experimental brain injury and ischemic acute renal failure. The aim of the present study was to explore whether rhEPO administration is protective against Cisp-induced oxidative damage and renal injury. Our results showed that Cisp induced a marked oxidative stress and renal failure. Administration of rhEPO (pre-, co- or postadministration with regard to Cisp) decreased oxidative damage induced by Cisp. Recombinant human EPO reduced malondialdehyde and protein carbonyl levels. Recombinant human EPO also prevented glutathione depletion and ameliorated the increased catalase activity induced by Cisp treatment. Furthermore, rhEPO restored creatinine and blood urea nitrogen levels increased by Cisp. We concluded that rhEPO administration especially in pretreatment condition protected rats against Cisp-induced renal oxidative stress and nephrotoxicity.

Topics: Acute Kidney Injury; Animals; Anticarcinogenic Agents; Antioxidants; Blood Urea Nitrogen; Catalase; Cisplatin; Creatinine; Erythropoietin; Glutathione; Humans; Kidney; Lipid Peroxidation; Male; Malondialdehyde; Oxidative Stress; Protein Carbonylation; Rats; Rats, Wistar; Recombinant Proteins

Diabetic patients are at higher risk of failure to recover after acute kidney injury, however, the mechanism and therapeutic strategies remain unclear. Erythropoietin is cytoprotective in a variety of non-haematopoietic cells. The aim of the present study was to clarify the mechanism of diabetes-related acceleration of renal damage after ischaemia-reperfusion injury and to examine the therapeutic potential of asialoerythropoietin, a non-haematopoietic erythropoietin derivative, against ischaemia-reperfusion-induced acute kidney injury in diabetic mice.. C57BL/6J mice with and without streptozotocin-induced diabetes were subjected to 30 min unilateral renal ischaemia-reperfusion injury at 1 week after induction of diabetes. They were divided into four group: (i) non-diabetic plus ischaemia-reperfusion injury; (ii) non-diabetic plus ischaemia-reperfusion injury plus asialoerythropoietin (3000 IU/kg bodyweight); (iii) diabetic plus ischaemia-reperfusion injury; and (iv) diabetic plus ischemia-reperfusion injury plus asialoerythropoietin. Experiments were conducted at the indicated time periods after ischaemia-reperfusion injury.. Ischaemia-reperfusion injury of diabetic kidney resulted in significantly low protein expression levels of bcl-2, an anti-apoptotic molecule, and bone morphogenetic protein-7 (BMP-7), an anti-fibrotic and pro-regenerative factor, compared with non-diabetic kidneys. Diabetic kidney subsequently showed severe damage including increased tubular cell apoptosis, tubulointerstitial fibrosis and decreased tubular proliferation, compared with non-diabetic kidney. Treatment with asialoerythropoietin induced bcl-2 and BMP-7 expression in diabetic kidney and decreased tubular cell apoptosis, tubulointerstitial fibrosis and accelerated tubular proliferation.. Reduced induction bcl-2 and BMP-7 may play a role in the acceleration of renal damage after ischaemia-reperfusion injury in diabetic kidney. The renoprotective effects of asialoerythropoietin on acute kidney injury may be mediated through the induction of bcl-2 and BMP-7.

Topics: Acute Kidney Injury; Animals; Asialoglycoproteins; Diabetes Mellitus, Experimental; Erythropoietin; Male; Mice; Mice, Inbred C57BL; Reperfusion Injury

We investigated the protective effect of Erythropoietin (EPO) analogue rHuEPO on renal injury induced by acute exhaustive exercise in the rat. Rats were randomly allocated to one of 3 groups: normal control (C), exhaustive exercise test (ET) and EPO pre-treatment (rHuEPO 2 000 U/kg) plus ET (EPO+ET). Compared with controls, animals in the ET group had increased serum urea nitrogen, serum creatinine, urine protein, and renal tissue malondialdehyde (MDA) and decreased renal tissue nitric oxide (NO), nitric oxide synthase (NOS) and superoxide dismutase (SOD) activities. There was severe damage in renal tubular epithelial cells with a lot of cell apoptosis, and TUNEL assay revealed a remarkably high apoptotic index (p<0.01). Changes in renal function and kidney tissue were much less in the EPO+ET group (p<0.05) and the apoptotic index was much lower than in the ET group (18.45±0.32 vs. 27.55±0.49, p<0.05). EPO pretreatment thus significantly prevented renal cell apoptosis, and counteracted high MDA and low NO and NOS renal contents induced by exhaustive exercise. The data point to a potential value of EPO in preventing the acute renal injury after exhaustive exercise.

Topics: Acute Kidney Injury; Animals; Apoptosis; Erythropoietin; In Situ Nick-End Labeling; Male; Malondialdehyde; Nitric Oxide; Nitric Oxide Synthase; Physical Conditioning, Animal; Rats; Rats, Sprague-Dawley; Reperfusion Injury

Several genetic polymorphisms have been identified to play a role in the occurrence and progression of renal dysfunction after cardiac surgery with cardiopulmonary bypass (CPB). Recently, it was demonstrated that the T allele of SNP rs1617640 in the promoter of the erythropoetin (EPO) gene is significantly associated with proliferative diabetic retinopathy (PDR) and end-stage renal disease (ESRD) due to increased EPO expression. This disease risk-associated gene and its potential pathway mediating severe microvascular complications in T-allele carriers could also play a role on renal dysfunction in patients who underwent cardiac surgery with CPB. We hypothesized that the patients' ability to produce increased EPO concentrations will affect morbidity and mortality after CPB. We conducted a prospective single center study between April 2006 and May 2007. In 481 patients who underwent cardiac surgery with CPB we prospectively examined the SNP rs1617640 in the promoter of the EPO gene by DNA sequencing. The patients were grouped according to their genotype (GG, GT, and TT). The genotype distribution of SNP rs1617640 in the promoter of the EPO gene was 36% (TT), 49% (TG), and 15% (GG). There was no difference in age, body mass index, gender, CPB time, or length of stay in intensive care unit. The hospitalization was irrespective of the patients' genotypes. The baseline creatinine in the TT group was 0.2 points higher than in the other groups; however this was without statistical significance in the multivariate analysis. No significant difference was shown in Euroscore, the Simplified Acute Physiology Score II, the Acute Physiology and Chronic Health Evaluation Score II, Acute Renal Failure Score, or the Risk, Injury, Failure, Loss of Kidney Function Score. The mortality was equal across the genotypes. However, an association between the TT genotype and acute renal replacement therapy (P=0.03), intra-aortic balloon pump usage (P=0.02), and serum creatine phosphokinase-MB increase (P=0.03) were observed after cardiac surgery. Our analysis suggests that the risk allele (T) of rs1617640 plays a role in the development of renal dysfunction after cardiac surgery with CPB. Patients with the TT risk allele required more frequent acute renal replacement therapy. Since our result is close to the border of significance, this hypothesis should be investigated in larger prospective studies with long-term follow-up to emphasize this polymorphism as a potential risk factor.

Topics: Acute Kidney Injury; Aged; Biomarkers; Cardiac Surgical Procedures; Cardiopulmonary Bypass; Chi-Square Distribution; Creatine Kinase, MB Form; Creatinine; Erythropoietin; Female; Gene Frequency; Genetic Predisposition to Disease; Germany; Humans; Logistic Models; Male; Middle Aged; Odds Ratio; Phenotype; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Prospective Studies; Renal Replacement Therapy; Risk Assessment; Risk Factors

5-lipoxygenase inhibitor and human recombinant erythropoietin might accelerate renal recovery in cisplatin-induced acute renal failure rats. Male Sprague-Dawley rats were randomized into four groups: 1) normal controls; 2) Cisplatin group-cisplatin induced acute renal failure (ARF) plus vehicle treatment; 3) Cisplatin+nordihydroguaiaretic acid (NDGA) group-cisplatin induced ARF plus 5-lipoxygenase inhibitor treatment; 4) Cisplatin+erythropoietin (EPO) group-cisplatin induced ARF plus erythropoietin treatment. On day 10 (after 7 daily injections of NDGA or EPO), urea nitrogen and serum Cr concentrations were significantly lower in the Cisplatin+NDGA and Cisplatin+EPO groups than in the Cisplatin group, and 24 hr urine Cr clearances were significantly higher in the Cisplatin+EPO group than in the Cisplatin group. Semi-quantitative assessments of histological lesions did not produce any significant differences between the three treatment groups. Numbers of PCNA(+) cells were significantly higher in Cisplatin, Cisplatin+NDGA, and Cisplatin+EPO groups than in normal controls. Those PCNA(+) cells were significantly increased in Cisplatin+NDGA group. These results suggest that EPO and also NDGA accelerate renal function recovery by stimulating tubular epithelial cell regeneration.

Topics: Acute Kidney Injury; Animals; Arachidonate 5-Lipoxygenase; Blood Urea Nitrogen; Cisplatin; Creatinine; Epithelial Cells; Erythropoietin; Kidney; Kidney Tubules; Male; Masoprocol; Rats; Rats, Sprague-Dawley; Regeneration

Topics: Acute Kidney Injury; Aged; Anti-Inflammatory Agents; Biopsy; Cathartics; Colonoscopy; Creatinine; Enema; Erythropoietin; Female; Glomerular Filtration Rate; Humans; Kidney; Nephrocalcinosis; Phosphates; Prednisolone; Treatment Outcome

Topics: Acute Disease; Acute Kidney Injury; Anti-Bacterial Agents; Antimicrobial Cationic Peptides; Cholesterol; Erythropoietin; Hepcidins; Humans; Peritoneal Dialysis; Time Factors

Renal injury induced by aortic ischemia-reperfusion (IR) is an important factor in the development of postoperative acute renal failure following abdominal aortic surgery. The purpose of this study is to examine the effect of erythropoietin on renal injury induced by aortic IR in rats.. Twenty-four Wistar-Albino rats were randomized into 3 groups (8 per group). The control group underwent laparotomy and dissection of the infrarenal abdominal aorta without occlusion. The aortic IR group underwent clamping of the infrarenal abdominal aorta for 30 min followed by 60 min of reperfusion. The aortic IR + erythropoietin group underwent the same aortic IR periods and was pretreated with 1000 U/kg subcutaneous erythropoietin 5 min before ischemia. In rat kidney specimens, tissue levels of malondialdehyde (MDA), superoxide dismutase, catalase, and glutathione peroxidase were measured. Histological evaluation of the rat kidney tissues was also done.. Aortic IR significantly increased the levels of MDA and superoxide dismutase (P < 0.05 versus control). Erythropoietin significantly decreased the levels of MDA, superoxide dismutase, and catalase (P < 0.05 versus aortic IR). Histological evaluation showed that aortic IR significantly increased (P < 0.05 versus control), whereas erythropoietin significantly decreased (P < 0.05 versus aortic IR) the focal glomerular necrosis, dilation of Bowman's capsule, degeneration of tubular epithelium, necrosis in tubular epithelium, interstitial inflammatory infiltration, and congestion of blood vessels.. The results indicate that erythropoietin has protective effects on renal injury induced by aortic IR in rats.

Topics: Acute Kidney Injury; Animals; Aorta, Abdominal; Catalase; Erythropoietin; Female; Glutathione Peroxidase; Kidney; Male; Malondialdehyde; Rats; Rats, Wistar; Reperfusion Injury; Superoxide Dismutase

Recent studies have demonstrated that erythropoietin (EPO) receptors are expressed on tubular epithelial cells and that EPO can protect tubular cells from injury in vitro and in vivo. Separate studies have demonstrated that marrow stromal cells (MSCs) exert a renoprotective effect in ischemia-reperfusion and cisplatin tubular injury via the secretion of factors that reduce apoptosis and increase proliferation of tubular epithelial cells. In the present study we demonstrate that MSCs express EPO receptors and that EPO can protect MSCs from serum deprivation-induced cell death and can stimulate MSC proliferation in vitro. The administration of EPO to mice resulted in the expansion of CD45-Flk1-CD105+ MSCs in the bone marrow and in the spleen and mobilized these cells as well as CD45-Flk1+ endothelial progenitor cells into the peripheral circulation. Consistent with previous reports, the administration of EPO diminished the decline in renal function associated with cisplatin administration. This effect was partially reproduced by intraperitoneal injection of cultured EPO-mobilized cells in cisplatin-treated mice. Thus the in vivo expansion and/or activation of these cells may contribute to the renoprotective effects of EPO to protect tubular cells from toxic injury.

Topics: Acute Kidney Injury; Adipocytes; Animals; Antineoplastic Agents; Cell Division; Cell Survival; Cells, Cultured; Cisplatin; Drug Interactions; Erythropoietin; Female; Kidney Tubules; Mesenchymal Stem Cells; Mice; Mice, Inbred C57BL; Receptors, Erythropoietin; Stromal Cells

Strategies to prevent contrast-induced nephropathy (CIN) are suboptimal. Erythropoietin was recently found to be cytoprotective in a variety of nonhematopoietic cells, so it was hypothesized that the nonhematopoietic erythropoietin derivative asialoerythropoietin would prevent CIN. Nephropathy was induced in rats by injection of the radiocontrast medium Ioversol in addition to inhibition of prostaglandin and nitric oxide synthesis. Administration of a single dose of asialoerythropoietin before the induction of nephropathy significantly attenuated the resulting renal dysfunction and histologic renal tubular injury. Contrast-induced apoptosis of renal tubular cells was inhibited by asialoerythropoietin both in vivo and in vitro, and this effect was blocked by a Janus kinase 2 (JAK2) inhibitor in vitro. Furthermore, phospho-JAK2/signal transducer and activator of transcription 5 (STAT5) and heat-shock protein 70 increased after injection of asialoerythropoietin, suggesting that the effects of asialoerythropoietin may be mediated by the activation of the JAK2/STAT5 pathway. Overall, these findings suggest that asialoerythropoietin may have potential as a new therapeutic approach to prevent CIN given its ability to preserve renal function and directly protect renal tissue.

Topics: Acute Kidney Injury; Animals; Apoptosis; Asialoglycoproteins; Caspase 3; Contrast Media; Erythropoietin; Kidney Tubules, Proximal; LLC-PK1 Cells; Male; Rats; Rats, Sprague-Dawley; Signal Transduction; Swine; Triiodobenzoic Acids

Erythropoietin (Epo) induces erythrocytosis by suppressing erythroid progenitor cell apoptosis through the Janus-activated kinase-signal transducers and activators of transcription (JAK-STAT) pathway. Since apoptosis contributes to cisplatin (CP)-induced nephrotoxicity and Epo receptors (EpoR) are expressed in the kidney, we examined the role of antiapoptosis in recombinant human erythropoietin (rHuEpo)-mediated renal protection. In human renal proximal tubular epithelial (RPTE) cells in culture, rHuEpo, but not inactive rHuEpo (I-rHuEpo), the receptor-binding sites of which are mutated, caused a significant reduction in CP-induced apoptosis at > or = 100 U/ml. rHuEpo, but not I-rHuEpo, increased STAT5 and Akt/PKB phosphorylation, demonstrating functional EpoR expression on RPTE cells. Furthermore, the JAK2 inhibitor tyrphostin AG-490 attenuated rHuEpo protection, suggesting a role of the JAK-STAT pathway in rHuEpo-mediated antiapoptosis. In rats, intravenous administration of 5,000 U/kg rHuEpo, but not an equivalent peptide mass of I-rHuEpo, before a single 5.5 mg/kg iv injection of CP, significantly increased hematocrit (Hct) and reduced the CP-induced increase in serum creatinine. Serum creatinine on day 4 was 3.4 +/- 0.3, 1.9 +/- 0.3, and 3.5 +/- 0.4 mg/dl in the CP, CP + rHuEpo, and CP + I-rHuEpo groups, respectively. Similarly, darbepoietin-alpha (DA), a hyperglycosylated analog of rHuEpo with prolonged in vivo activity when injected at 25 microg/kg iv before CP, significantly increased Hct and reduced serum creatinine. Renal clearance studies based on glomerular filtration rate and renal blood flow confirmed the significant renal protection by DA against CP. Tubular apoptosis and necrosis were significantly reduced in the kidneys of the CP + DA vs. the CP + saline group. Moreover, the equalization of Hct by venesection did not abrogate the DA-mediated renal protection. Administration of DA 48 h after CP injection also conferred significant renal protection. Thus our experiments confirm a role for erythropoiesis-stimulating proteins, including the new analog DA, in limiting CP-induced nephrotoxicity and suggest that antiapoptosis via the Epo-EpoR interaction is an important mechanism for renal protection.

Topics: Acute Kidney Injury; Animals; Antineoplastic Agents; Apoptosis; Cells, Cultured; Cisplatin; Darbepoetin alfa; Disease Models, Animal; Enzyme Inhibitors; Erythropoietin; Hematinics; Hematocrit; Humans; Janus Kinase 2; Kidney; Male; Necrosis; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Receptors, Erythropoietin; Recombinant Proteins; STAT5 Transcription Factor; Tyrphostins

Topics: Acute Kidney Injury; Amlodipine; Epoetin Alfa; Erythropoietin; Female; Fibrosis; Humans; Inflammation; Middle Aged; Prednisone; Recombinant Proteins; Sarcoidosis; Treatment Outcome

Acute renal failure (ARF) is a clinical syndrome characterized by deterioration of renal function over a period of hours or days. The principal causes of ARF are ischemic and toxic insults that can induce tissue hypoxia. Transcriptional responses to hypoxia can be inflammatory or adaptive with the participation of the hypoxia-inducible factor 1alpha and the expression of specific genes related to oxidative stress. The production of peroxynitrites and protein nitrotyrosylation are sequelae of oxidative stress. In several clinical and experimental conditions, inflammatory responses have been related to cyclooxygenase (COX)-2, suggesting that its activation might play an important role in the pathogenesis and progression of nephropathies such as ARF. In the kidney, renin and bradykinin participate on the regulation of COX-2 synthesis. With the hypothesis that in ARF there is an increase in the expression of agents involved in adaptive and inflammatory responses, the distribution pattern and abundance of COX-2, its regulators renin, kallikrein, bradykinin B2 receptor, and oxidative stress elements, heme oxygenase-1 (HO-1), erythropoietin (EPO), inducible nitric oxide synthase (iNOS), and nitrotyrosylated residues were studied by immunohistochemistry and immunoblot analysis in rat kidneys after bilateral ischemia. In kidneys with ARF, important initial damage was demonstrated by periodic acid-Schiff staining and by the induction of the damage markers alpha-smooth muscle actin and ED-1. Coincident with the major damage, an increase in the abundance of EPO, HO-1, and iNOS and an increase in renin and bradykinin B2 receptor were observed. Despite the B2 receptor induction, we observed an important decrease in COX-2 in the ischemic-reperfused kidney. These results suggest that COX-2 does not participate in inflammatory responses induced by hypoxia.

Topics: Acute Kidney Injury; Animals; Cyclooxygenase 2; Erythropoietin; Heme Oxygenase-1; Ischemia; Kidney; Male; Nitric Oxide Synthase Type II; Oxidative Stress; Rats; Rats, Sprague-Dawley; Receptor, Bradykinin B2; Renin; Tissue Distribution; Tyrosine

Erythropoietin (EPO), originally identified for its critical role in promoting erythrocyte survival and differentiation, has been shown to exert multiple paracrine/autocrine functions. Protective effects of EPO have been demonstrated in various tissues and experimental models of ischaemia-induced injury. In the present study, we investigated the effect of EPO on an in vivo rat model of renal ischaemia/reperfusion (I/R) injury and the possible mechanisms implicated in the EPO-mediated anti-apoptotic action.. Male Wistar rats, subjected to renal ischaemia for 45 min, were administered either saline or EPO (500 U/kg, i.p.) 20 min prior to I/R. A sham-operated group served as the control. At 48 h of reperfusion, the renal dysfunction and injury was assessed by measurement of serum biochemical markers (urea, creatinine) and histological grading. Apoptosis was assessed by the TUNEL method and morphological criteria. Expression of Bax and NF-kappaB (p65) was also evaluated.. High levels of serum urea and creatinine were identified at 48 h after ischaemia. The EPO-treated group had significantly lower serum and creatinine levels. Semi-quantitative assessment of the histological lesions showed that rats subjected to I/R developed marked structural damage, whereas significantly less tubular damage was observed in the EPO-treated group. I/R caused an increase in TUNEL-positive cells that was accompanied by morphological evidence of apoptosis. In the EPO-treated rats only a few scattered TUNEL-positive cells were observed. Up-regulation of Bax in the tubular epithelial cells and increased expression of NF-kappaB was observed in the I/R-treated rats, while diminished expression of Bax and positive immunostaining of NF-kappaB was observed in the EPO-treated rats.. Administration of EPO as a single dose before the onset of ischaemia produced a significant reduction in tubular injury, which was accompanied by a marked amelioration of renal functional impairment. The cytoprotective action of EPO against I/R injury seems to be associated with its anti-apoptotic action. Moreover, transcription factor NF-kappaB is likely to play a pivotal role in the pathophysiology of I/R renal injury and might have a key role in EPO-mediated protective effects.

Topics: Acute Kidney Injury; Animals; Apoptosis; Disease Models, Animal; Erythropoietin; Male; NF-kappa B; Rats; Rats, Wistar; Reperfusion Injury

Administration of human recombinant erythropoietin (EPO) at time of acute ischemic renal injury (IRI) inhibits apoptosis, enhances tubular epithelial regeneration, and promotes renal functional recovery. The present study aimed to determine whether darbepoetin-alfa (DPO) exhibits comparable renoprotection to that afforded by EPO, whether pro or antiapoptotic Bcl-2 proteins are involved, and whether delayed administration of EPO or DPO 6 h following IRI ameliorates renal dysfunction. The model of IRI involved bilateral renal artery occlusion for 45 min in rats (N = 4 per group), followed by reperfusion for 1-7 days. Controls were sham-operated. Rats were treated at time of ischemia or sham operation (T0), or post-treated (6 h after the onset of reperfusion, T6) with EPO (5000 IU/kg), DPO (25 mug/kg), or appropriate vehicle by intraperitoneal injection. Renal function, structure, and immunohistochemistry for Bcl-2, Bcl-XL, and Bax were analyzed. DPO or EPO at T0 significantly abrogated renal dysfunction in IRI animals (serum creatinine for IRI 0.17 +/- 0.05 mmol/l vs DPO-IRI 0.08 +/- 0.03 mmol/l vs EPO-IRI 0.04 +/- 0.01 mmol/l, P = 0.01). Delayed administration of DPO or EPO (T6) also significantly abrogated subsequent renal dysfunction (serum creatinine for IRI 0.17 +/- 0.05 mmol/l vs DPO-IRI 0.06 +/- 0.01 mmol/l vs EPO-IRI 0.03 +/- 0.03 mmol/l, P = 0.01). There was also significantly decreased tissue injury (apoptosis, P < 0.05), decreased proapoptotic Bax, and increased regenerative capacity, especially in the outer stripe of the outer medulla, with DPO or EPO at T0 or T6. These results reaffirm the potential clinical application of DPO and EPO as novel renoprotective agents for patients at risk of ischemic acute renal failure or after having sustained an ischemic renal insult.

Topics: Acute Kidney Injury; Animals; Apoptosis; bcl-2-Associated X Protein; bcl-X Protein; Cell Division; Creatinine; Darbepoetin alfa; Disease Models, Animal; Erythropoietin; Immunohistochemistry; Injections, Intraperitoneal; Kidney Tubular Necrosis, Acute; Kidney Tubules, Proximal; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Regeneration; Reperfusion Injury; Time Factors

Radiocontrast-induced nephropathy (CIN) remains an important iatrogenic cause of acute renal failure in high-risk patients, despite the development of safer contrast media, the improvement of hydration protocols, and the introduction of additional preventive strategies. Erythropoietin (EPO) pretreatment may confer protection against acute renal failure through the induction of stress response genes.. The effect of EPO has been evaluated in a rat model of CIN, induced by iothalamate, following the inhibition of nitric oxide- and prostaglandin-synthesis with indomethacin and N(omega) nitro-L-arginine methyl ester (L-NAME). Twenty-two male Sprague-Dawley rats were subjected to saline (CTR) or EPO injections (3000 U/kg and 600 U/kg, 24 and 2 h before the induction of CIN, respectively).. The decline in creatinine clearance in CTR animals from 0.38 +/- 0.03 to 0.28 +/- 0.03 mL/min/100 g (p < 0.005), was prevented by EPO pretreatment (from 0.34 +/- 0.02 to 0.32 +/- 0.03 mL/min/100 g, NS). The extent of medullary thick ascending limb- and S3-tubular damage in the outer medulla, however, was comparable in the two experimental groups.. EPO pretreatment prevents renal dysfunction in a rat model of CIN. Further experimental and clinical studies are required to confirm these preliminary conclusions regarding a potential protective potency of EPO against CIN.

Topics: Acute Kidney Injury; Animals; Contrast Media; Creatinine; Disease Models, Animal; Erythropoietin; Kidney Medulla; Kidney Tubules; Male; Potassium; Random Allocation; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Sodium; Stress, Physiological; Urea

Topics: Acute Kidney Injury; Adult; Chlorates; Darbepoetin alfa; Erythropoietin; Fluid Therapy; Herbicides; Humans; Male; Renal Dialysis; Suicide, Attempted; Treatment Outcome

Complex cardiac surgery often requires blood transfusion. Some patients refuse transfusion, even when it is potentially life-threatening to do so. Although recombinant human erythropoietin (rhEPO) has been used to reduce the need for blood transfusion, it has been considered ineffective in critically ill patients. The time course of hematological responses in a Jehovah's Witness patient with acute renal failure and severe cardiac disease suggests that a trial of rhEPO should be considered for salvage therapy in critically ill patients.. The authors describe successful treatment of life-threatening anemia using recombinant human erythropoietin in a critically ill Jehovah's Witness patient after cardiac surgery.

Topics: Acute Kidney Injury; Blood Cell Count; Cardiac Surgical Procedures; Critical Care; Critical Illness; Erythropoietin; Female; Heart Diseases; Heart Valve Prosthesis Implantation; Humans; Jehovah's Witnesses; Middle Aged; Recombinant Proteins

To recognize the characteristics of anemia in patients with drug-associated renal parenchymal ARF and to investigate the possible relations among Hb, serum level of EPO and the renal tubulointerstitial injury.. Sixteen in-patients with drug-associated renal parenchymal ARF (including ATN and ATIN groups) for the last five years and 8 healthy volunteers (control group) were assessed in this study. The general information of these patients was analyzed retrospectively. Anemia related laboratory parameters, serum EPO, serum creatinine (Scr) and the renal tubular function from the samples on the time of renal biopsy in each group were compared. For pathological comparison of renal tubulointerstitial pathological changes, renal biopsy specimens from 5 patients with mild non-IgA mesangial proliferative glomerulonephritis were used as negative controls. The pathological changes in renal tubules and interstitial area were semi-quantitive scored by a computer imaging system. The correlations between Hb and EPO levels, as well as EPO level and renal function or pathological injury index were analyzed, respectively.. There was no significant difference among the ages, genders and the time intervals both from the administration to the onset of the disease and from the onset to the kidney biopsy among ATN and ATIN groups. Scr level was all higher than that in the control group (P<0.05). The renal tubular function injury index and the tubular interstitial pathologic injury index in the two groups were relatively elevated, in which the ATIN group had the highest indexes compared to the others (P<0.01). There were more anemia patients in ATIN group. It showed much lower levels of Hb, Hct and RBC than those in the control group (P<0.01). ATN group possessed fewer anemia patients and the levels of Hb, Hct and RBC remained in the normal range. The remarkable decline of EPO levels was found as 84.8% and 70.7% in the ATN and ATIN groups, respectively (P<0.01). In all patients with renal parenchyma ARF, the levels of Hb and EPO showed an obvious positive correlation (r=0.589, P<0.01), but the negative correlations existed between EPO and Scr, the renal tubular function injury index and renal tubular interstitial pathological injury index, respectively (P<0.05).. The mechanism of the anemia in the drug-associated parenchymal ARF patients may be due to the lack of intrinsic EPO secretion, mainly induced by acute renal tubular interstitial injury, which contributes to the decreased genesis of red blood cells.

Topics: Acute Kidney Injury; Adult; Anemia; Creatinine; Erythropoietin; Female; Humans; Male; Nephritis, Interstitial; Retrospective Studies

Recombinant human erythropoietin (EPO) is used widely to treat anemia in patients with chronic kidney disease, but the benefits of EPO use in patients with acute renal failure (ARF) are unclear. In vitro and animal studies suggest that EPO may promote renal recovery and decrease mortality in ARF.. We conducted a retrospective cohort study at a tertiary-care center to evaluate the use of EPO in 187 critically ill patients with ARF requiring renal replacement therapy.. Compared with patients not administered EPO (n = 116), patients administered EPO (n = 71) were significantly more likely to have baseline chronic kidney disease, have undergone vascular surgery, and have received intermittent hemodialysis, rather than continuous renal replacement therapy. In a propensity-adjusted analysis that controlled for differences between the 2 cohorts and baseline hemoglobin level, EPO use did not decrease the transfusion of packed red blood cells. Renal recovery was not more common in patients administered EPO: the odds ratio for renal recovery in the propensity-adjusted analysis was 0.63 (95% confidence interval, 0.30 to 1.3) with EPO use. In-hospital survival was more common in the EPO-treated group, but this potential benefit was not significant in propensity-adjusted analyses.. Although EPO use was not associated with a decrease in transfusion requirements or with renal recovery in our retrospective study, 37% of critically ill patients with ARF were treated with EPO at varying doses. A randomized controlled trial is needed to evaluate the potential benefits of EPO use in patients with ARF.

Topics: Acute Kidney Injury; Adult; Aged; Anemia; APACHE; Cohort Studies; Comorbidity; Critical Care; Critical Illness; Drug Evaluation; Erythrocyte Transfusion; Erythropoietin; Female; Hospital Mortality; Humans; Male; Middle Aged; Missouri; Postoperative Complications; Recombinant Proteins; Renal Dialysis; Renal Replacement Therapy; Retrospective Studies; Risk Factors; Treatment Outcome; Vascular Surgical Procedures

Topics: Acute Kidney Injury; Anemia; Cohort Studies; Drug Administration Schedule; Erythropoietin; Humans; Recombinant Proteins; Research Design; Retrospective Studies; Sample Size; Treatment Outcome

Ischemia-induced acute renal failure (ARF) is known to be associated with significant impairment of urinary concentrating ability and down-regulation of renal aquaporins (AQPs) and sodium transporters in rats. We tested whether treatment with erythropoietin (EPO) or alpha-melanocyte-stimulating hormone (alpha-MSH) in combination with EPO reduces the renal ischemia/reperfusion (I/R) injury and prevents the down-regulation of renal AQPs and major sodium transporters.. I/R-induced ARF was established in rats by 40-minute temporary bilateral obstruction of renal arteries, and rats were kept in metabolic cages for urine measurements. After 2 or 4 days following EPO and/or alpha-MSH treatment, kidneys were removed to determine the expression levels of AQPs and sodium transporters by semiquantitative immunoblotting.. Rats with ARF showed significant renal insufficiency, increased urine output, and high fractional excretion of urinary sodium. Consistent with this, immunoblotting and immunocytochemistry revealed that the kidney expression of AQPs (AQP-1, -2 and -3) and sodium transporters [Na,K-ATPase, rat type 1 bumetanide-sensitive Na-K-2Cl cotransporter (BSC-1), Na/H exchanger type 3 (NHE3), and thiazide-sensitive sodium chloride cotransporter (TSC)] in ARF rats was significantly decreased compared to sham-operated control rats. In contrast, EPO treatment at the time of ischemia of rats with ARF significantly prevented the ischemia-induced down-regulation of renal AQPs and sodium transporters and in parallel improved the urinary concentrating capability and renal sodium reabsorption. Importantly, similar effects were observed following the initiation of EPO or alpha-MSH treatment 4 hours after the onset of ischemia injury. Moreover, the combination of EPO with alpha-MSH potentiated the beneficial effects of single compound treatment.. EPO and/or alpha-MSH treatment significantly prevent I/R-induced injuries such as urinary-concentrating defects and down-regulation of renal AQPs and sodium transporters.

Topics: Acute Kidney Injury; alpha-MSH; Animals; Antibody Specificity; Aquaporin 1; Aquaporin 2; Aquaporin 3; Aquaporins; Down-Regulation; Erythropoietin; Immunoblotting; Kidney; Male; Rats; Rats, Wistar; Reperfusion Injury; Sodium; Sodium-Hydrogen Exchanger 3; Sodium-Hydrogen Exchangers; Sodium-Potassium-Exchanging ATPase; Water

Prior studies of dialysis practices and outcomes have included children with varied duration of end-stage renal disease (ESRD). This study evaluated dialysis characteristics, complications, practices, and outcomes in an incident pediatric cohort.. The cohort was limited to 1992 subjects enrolled in the North American Pediatric Renal Transplant Cooperative Study registry, starting hemodialysis (HD) or peritoneal dialysis (PD) between 1992 and 1998, without prior dialysis or transplantation.. At dialysis initiation, the median glomerular filtration rate (GFR; Schwartz formula) was 6 to 11 mL/min/1.73 m2, and 90th percentile was 14 to 25 mL/min/1.73 m2. GFR was not associated with age or race. PD was used in 97% of infants, 70 to 80% of children and 59% of adolescents. Blacks were significantly less likely to be started on PD than whites. Twenty percent of patients switched dialysis modality, largely due to infection, inadequate access or family choice. Younger children received HD almost exclusively through percutaneous catheters, while 57% of children more than six years old were dialyzed with fistula or graft after six months on HD. The prevalence of anemia (Hct <33%) still exceeded 40% after six months of dialysis. The median interval to transplantation was 1.4 years, and was significantly greater in non-white, young, and female patients. Mortality rates (deaths/1000 patient-years) varied with age, from 13.6 in infants to 2.2 in adolescents.. These data demonstrate considerable variability in patient management across pediatric centers. Prospective studies are needed to determine the optimum adequacy of care among children on dialysis and to identify populations at risk.

Topics: Acute Kidney Injury; Adolescent; Child; Child, Preschool; Cohort Studies; Erythropoietin; Female; Humans; Infant; Iron; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Male; Peritoneal Dialysis; Prospective Studies; Registries; Renal Dialysis; Retreatment

The anemia associated with acute renal failure (ARF) is currently treated with blood transfusions, while the anemia of chronic renal failure is treated with recombinant erythropoietin (EPO). We hypothesized that EPO treatment during ARF could rapidly improve hemoglobin levels and be a useful therapeutic approach. In addition, as tubular epithelial cells have EPO receptors that can mediate proliferation, enhanced recovery of renal function may occur with EPO use.. An established rat model of ischemic ARF was studied, using either moderate or severe ischemia. EPO was administered in a dose of 500 or 3000 U/kg starting at time of ischemia. Hematocrit (Hct), serum creatinine, reticulocyte count, and mortality rate were measured.. EPO treatment led to a rapid and significant increase in Hct at 48 and 72 hours after moderate ischemic renal reperfusion injury (IRI) in EPO (500 U/kg)-treated rats compared with control (saline treated) rats (mean +/- SE; 45.6 +/- 0.3% vs. 42.0 +/- 1.0%, P < 0.01) and (46.6 +/- 0.3 vs. 41.0 +/- 1.0, P < 0.01, N = 3 per group). In severe renal IRI, EPO treatment also led to significantly increased Hct at 48 (40.0 +/- 4.4% vs. 36.8 +/- 0.3%, P < 0.01, N = 3 per group) and 72 hours (43.5 +/- 1.5% vs. 34.7 +/- 2.3%, P < 0.01, N = 3 per group). Higher dose (3000 U/kg) EPO led to a more pronounced Hct increase after severe IRI at 48 hours compared with the 500 U/kg dose (43.5 +/- 0.3 vs. 40.3 +/- 0.3, P < 0.01, N = 3 per group). EPO treatment during moderate or severe renal IRI did not change the course of the renal dysfunction. EPO treatment (N = 19) had a significant protective effect on mortality during severe IRI. In addition, loss of body weight during ARF was not affected by EPO therapy.. Recombinant EPO can rapidly increase Hct and improve mortality during ARF. Human studies are warranted to evaluate the clinical applicability of this important finding.

Topics: Acute Kidney Injury; Anemia; Animals; Body Weight; Creatinine; Erythropoietin; Ischemia; Male; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Renal Circulation; Reperfusion Injury; Reticulocyte Count; Severity of Illness Index

Erythropoietin (Epo) is a growth factor whose synthesis mainly takes place in the kidney. Epo has been shown to support the growth not only of erythroid progenitor cells but also of certain other cell types. We attempted to establish whether Epo enhances the recovery from acute renal failure induced by cisplatin.. Sprague-Dawley rats were randomized into three groups. In the cisplatin group, animals received one intraperitoneal injection of cisplatin (6 mg/kg) and a daily injection of placebo for 9 days. In the cisplatin+Epo group, animals received intrapertoneal cisplatin and a daily injection of Epo (100 IU/kg) for 9 days. In the control group, animals received both placebo preparations alone. Para-aminohippuric acid and inulin clearances were determined after 4 and 9 days to evaluate renal blood flow and glomerular filtration rate. In addition, light microscopy and immunohistochemistry examinations were performed, and in situ proliferating cell nuclear antigen (PCNA) staining was done to estimate the degree of renal tubular cell regenerative activity. The potential role of epithelial growth factor (EGF) was evaluated by semi-quantitative assessment of EGF immunostaining.. Renal blood flow and glomerular filtration rate decreased significantly in cisplatin and cisplatin+Epo groups versus control group at day 4. However, at day 9, they both were significantly greater in cisplatin+Epo-treated animals than in rats that had received cisplatin alone. Tubular cell regeneration was significantly enhanced at day 4 in cisplatin+Epo group, compared with cisplatin and control groups respectively. EGF immunostaining was not significantly different between the three groups.. Epo significantly enhanced the rate of recovery from acute renal failure induced by cisplatin. PCNA staining indicated that Epo might act directly via stimulation of tubular cell regeneration.

Topics: Acute Kidney Injury; Animals; Antineoplastic Agents; Cisplatin; Diuresis; Erythropoietin; Glomerular Filtration Rate; Kidney; Male; Rats; Rats, Sprague-Dawley; Urine

Topics: Acute Kidney Injury; Adult; Anti-Inflammatory Agents; Erythropoietin; Female; Glomerulonephritis, Membranoproliferative; Humans; Kidney; Lipodystrophy; Pregnancy; Pregnancy Complications; Renal Dialysis; Steroids

Critically ill patients often develop anaemia which can be related to a number of factors. However, the exact causes of anaemia in many patients remain unexplained. We hypothesized that the relationship between erythropoietin (EPO) and haematocrit may be altered in critically ill patients.. Serum concentrations of EPO were serially determined by the ELISA method in 36 critically ill, non-hypoxaemic patients who stayed more than 7 days in the Intensive Care Unit, including 22 patients with sepsis and 14 without. Eighteen ambulatory patients with iron-deficiency anaemia served as a control group.. Two University Hospital Intensive Care Departments.. A significant inverse correlation between serum EPO and haematocrit levels was found in the control patients (r = -0.81, p < 0.001), but not in the critically ill patients (r = -0.09, NS), except in a subgroup of non-septic patients without renal failure (r = -0.61, p < 0.01).. EPO levels can be inappropriately low in critically ill patients, so that EPO deficiency may contribute to the development of anaemia in these patients. This phenomenon is observed not only in the presence of acute renal failure, but also in the presence of sepsis.

Topics: Acute Kidney Injury; Aged; Anemia, Hemolytic; Anemia, Iron-Deficiency; Case-Control Studies; Critical Illness; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Female; Hematocrit; Humans; Intensive Care Units; Male; Middle Aged; Regression Analysis; Respiratory Distress Syndrome; Sepsis

Erythropoietin (Epo) is a glycoprotein hormone produced in the kidney in response to hypoxia or anaemia. In acute renal failure (ARF) anaemia also occurs and current opinion is that Epo production is depressed with inappropriately low plasma levels throughout the uraemic phase. Our study was designed to determine the excretion of Epo in patients with ARF. Fifty-nine ventilated patients were studied, 39 with ARF and continuous veno-venous haemofiltration therapy (group 1) and 13 patients with normal renal function who served as a control group (group 2). All patients with ARF were anaemic and needed a mean transfusion of 0.6 units/day. Values for vitamin B12, folic acid, serum iron and ferritin were normal. While patients with normal renal function had Epo values within the normal range, patients with ARF had significantly higher values at the onset of haemofiltration therapy. Mean Epo (mean +/- SEM) values on days 0-2 were 92.6 +/- 11.7 mU/ml in group 1 and 16.5 +/- 6.4 mU/ml in group 2 (p < 0.0002). Epo levels declined in group 1 to 49 +/- 10.5 mU/ml on days 9 and 10 compared to 23 +/- 9.1 mU/ml in group 2 (ns). These values were maintained until the end of the observation period. No differences were seen between oliguric and non-oliguric patients. Our data show that patients with ARF have increased Epo levels at the beginning of the disease with a strong tendency to decrease, suggesting that there might be inadequate Epo levels during the course of acute renal failure.

Topics: Acute Kidney Injury; Erythropoietin; Female; Hemofiltration; Humans; Immunoenzyme Techniques; Male; Middle Aged; Prospective Studies

To study the role of erythropoietin (Epo) in the pathogenesis of anemia in acute renal failure (ARF), organ Epo mRNA was measured by RNase protection assay in rats with ARF induced by a one hour-occlusion of the left renal artery. Hematocrit was significantly decreased two hours, 24 hours and one week after renal artery occlusion. A significant reduction in serum haptoglobin at two hours and an increase in serum LDH at 24 hours indicated that hemolysis was the likely cause of the initial fall in hematocrit. However, despite the reduced hematocrit, serum Epo concentrations were not significantly different from controls, suggesting that the anemia is maintained because of lack of an appropriate Epo response. Right renal Epo mRNA levels were not significantly different in all groups, but Epo mRNA levels in post-ischemic kidneys were 50 to 67% lower than in contralateral kidneys. However, Epo mRNA in the post-ischemic kidney was increased sixfold by acute hemorrhage, a rise comparable to the ninefold increase observed in contralateral kidneys. In ARF rats exposed to 7.5% O2 for four hours, right kidney Epo mRNA increased 200-fold over normoxic levels, to a value similar to sham-operated hypoxic controls. Epo mRNA in the post-ischemic kidney also increased 200-fold, to 50% of the level in the contralateral kidney. Hepatic Epo mRNA levels were elevated to comparable levels in both groups. In this ARF model, mild anemia is associated with relative Epo deficiency. In the post-ischemic kidney, a substantial capacity for Epo production is retained but the sensitivity of the Epo response to blood oxygen availability is significantly reduced.

Topics: Acute Kidney Injury; Anemia; Animals; Erythropoietin; Hematocrit; Male; Rats; Rats, Wistar; Renal Artery Obstruction; RNA, Messenger

Twelve patients presenting postoperative acute renal failure (ARF), developing after peritonitis, are subjected to follow-up study. A comparative assessment of the renal function and anemic syndrome is done during three different periods: immediately after the operative intervention, after renal failure development, and at treatment completed. For the purpose a number of indicators are monitored, namely: hemoglobin, hematocrit, erythrocytes, blood platelets, urea, creatinine, serum calcium and iron levels, diuresis and creatinine clearance (Ccr). Two patients are given human recombinant erythropoietin (rHuEpo). As demonstrated by the results, erythropoietin (Epo) deficiency is the underlying cause of concurrent anemia occurring in postoperative ARF; the anemia syndrome develops parallel to renal failure development. In patients given rHuEpo the anemia lends itself readily to control, renal failure subsides completely within shorter periods of time, and the incidence of hemorrhagic accidents is reduced.

Topics: Acute Kidney Injury; Aged; Anemia; Combined Modality Therapy; Erythropoietin; Female; Humans; Kidney; Male; Middle Aged; Peritonitis; Postoperative Complications; Recombinant Proteins

Topics: Acute Kidney Injury; Adult; Anemia; Erythropoietin; Female; Humans; Pregnancy; Pregnancy Complications, Hematologic

Acute renal failure (ARF) is associated with erythropoietin (EPO) deficiency anemia. The present study was designed to determine whether the course of ARF can be altered by preventing EPO deficiency and the associated anemia. Sprague-Dawley rats were injected with a single dose of cisplatin (CP), 7 mg/kg intraperitoneally, and randomized into recombinant EPO-treated (EPO), placebo-treated (control), recombinant EPO-treated pair-fed (EPO-PF), and EPO-treated anemic (EPO-anemic) groups. They were then treated with daily injections of recombinant EPO, 100 U/kg, or placebo for 9 days. Animals in the EPO-anemic group received daily phlebotomies gauged to maintain hematocrits equal to those in the control group. Rats in the EPO-PF group were pair fed with the controls. The control and EPO-anemic groups showed a fall, whereas the EPO and EPO-PF groups showed a rise in hematocrit on day 9. Although blood volume on day 9 was significantly greater in the EPO group than in either the EPO-anemic group or the control group, it was comparable in the latter groups. An equally severe reduction in creatinine clearance (CCr) was found in all groups on day 4. However, measurements of CCr and inulin clearance on day 9 revealed a significantly greater functional recovery in the EPO, EPO-PF, and EPO-anemic groups than in the controls. The enhanced functional recovery with EPO administration was accompanied by an increased tubular regeneration and [3H]thymidine incorporation in the cortical tissue. No significant difference was found in either cortical tissue iron content or arterial blood pressure in the study groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acute Kidney Injury; Anemia; Animals; Blood Volume; Cisplatin; Erythropoietin; Glomerular Filtration Rate; Hematocrit; Iron; Kidney; Male; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Thymidine

PTH is incriminated as an uraemic toxin involved in the pathogenesis of anaemia in chronic renal failure. This fact was the background of our present studies performed in 14 patients with noninflammatory acute renal failure (NARF). Plasma levels of erythropoietin (EPO) and parathyroid hormone (PTH) were estimated in the anuric/oliguric (a/o) and polyuric (p) phase of NARF. In the a/o phase plasma EPO levels were predominantly normal, although inappropriately low to the degree of anaemia. In 50% of patients with NARF episodic short-term increases of plasma EPO levels were noticed which were not caused by worsening of anaemia. In the p phase plasma EPO concentrations were in the normal range (17.9 +/- 3.3 mU/ml) in spite of the same degree of anaemia as in the a/o phase. Plasma PTH levels were significantly elevated during the a/o phase (1.14 +/- 0.1 ng/ml), with a tendency to decline in the p phase (0.87 +/- 0.2 ng/ml). No correlation was found between plasma EPO and PTH concentrations. Results presented in this study suggest presence of relative EPO deficiency both during the a/o and p phases of NARF. As plasma PTH levels were not significantly correlated with serum EPO concentrations, its role in the pathogenesis of suppressed EPO levels seems unproven. Results presented in this study suggest deterioration of the physiological feedback between EPO secretion and the magnitude of erythropoiesis in NARF.

Topics: Acute Kidney Injury; Adult; Anemia; Erythropoietin; Female; Humans; Male; Parathyroid Hormone

Topics: Acute Kidney Injury; Adult; Anemia; Erythropoietin; Female; Hemolysis; Humans; Postoperative Complications; Transfusion Reaction

In this study, erythropoietin serum levels were serially determined in eight patients with acute renal failure to get a lead on the etiology of anemia in acute renal failure and to address the relationship between erythropoietin synthesis and renal excretory performance. Erythropoietin serum levels rapidly decreased after onset of acute renal failure to values of 12.8 +/- 10.3 mU/ml compared to 16.8 +/- 9.4 mU/ml in healthy controls. After restoration of renal function, erythropoietin levels climbed slowly in six patients (15.2 +/- 5.3 mU/ml), and in relation to prolonged anemia in these patients, a relative deficiency of erythropoietin could be observed. In one patient with thrombotic thrombocytopenic purpura causing acute renal failure, the decline of erythropoietin secretion was not observed, and in a phase of the disease when plasma exchange therapy was interrupted, markedly increased erythropoietin levels, up to 182 mU/ml, were detected despite the renal failure. Focusing on erythropoietin secretion in thrombotic thrombocytopenic purpura, we followed hormone synthesis in two other patients with the same disease, one of whom had mild renal insufficiency and one had normal renal function. High erythropoietin levels of up to 205 mU/ml were found in these patients, similar to the peak levels found in the patient with complete renal failure. Plasmapheresis treatment reduced erythropoietin production in all three patients with thrombotic thrombocytopenic purpura. In summary, our study indicates that in most cases of acute renal failure, erythropoietin synthesis is compromised and may contribute to the development of anemia in renal failure and aggravate the persistence of anemia after restoration of renal function.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acute Kidney Injury; Adult; Creatinine; Erythropoietin; Female; Hematocrit; Humans; Kidney Function Tests; Male; Purpura, Thrombotic Thrombocytopenic

Plasma erythropoietin (EPO) levels were assessed in 51 uraemic patients immediately after kidney transplantations and in 16 healthy subjects. Before transplantation EPO levels were significantly higher than in normals. In patients with acute renal failure of the transplanted kidney, a significant increase of plasma EPO level was noticed. Such an increase of plasma EPO was absent in patients with a normally functioning kidney transplant. In these last patients normalization of plasma EPO was found during the first month after transplantation. No significant correlation was found between plasma EPO level and the haematocrit value in kidney transplant patients. From results obtained in this study it seems, that factors other than EPO are also involved in the pathogenesis of anaemia in patients at the early phase after kidney transplantation.

Topics: Acute Kidney Injury; Adult; Erythropoietin; Female; Humans; Kidney Transplantation; Male

Plasma levels of erythropoietin (EPO) were estimated in 14 patients with noninflammatory acute renal failure during the oliguric anuric and polyuric phase respectively. During the anuric oliguric phase plasma EPO levels were 4 times higher than in healthy subjects, while during the polyuric phase normal plasma levels were found in spite of the presence of anaemia. Results presented in this paper suggest presence of an abnormal feedback between EPO secretion and degree of anaemia in patients with acute noninflammatory renal failure both during the anuric/oliguric and polyuric phase respectively. Abnormal EPO secretion does not seem to be the only or even dominant factor involved in the pathogenesis of anaemia in patients with noninflammatory acute renal failure.

Topics: Acute Kidney Injury; Adult; Aged; Anemia; Erythropoietin; Female; Humans; Male; Middle Aged

In 81 patients with failing kidney transplant, plasma levels of erythropoietin, iron, ferritin and TIBC were assessed. Progression of failure of the excretory function of the kidney transplant was accompanied by decreasing Hb and Ht values but increasing plasma levels of erythropoietin. In all examined patients presence of iron deficiency could be excluded. Results obtained in this study suggest that relative erythropoietin deficiency is the major cause of anaemia in patient with a failing kidney transplant.

Topics: Acute Kidney Injury; Adult; Anemia; Erythropoietin; Female; Humans; Kidney Transplantation; Male

Topics: Acute Kidney Injury; Anemia; Erythrocyte Aging; Erythropoiesis; Erythropoietin; Humans; Kidney Failure, Chronic; Recombinant Proteins

Adult female Wistar rats were injected with 125 mg/kg b.w. of human methemoglobin (M-Hb) in order to induce a first episode of hemodynamically-mediated acute renal failure (HMARF). Eleven days after the injection of M-Hb, other groups of rats received another equal dose of the drug in order to induce a second episode of HMARF. Evaluation of renal function, histopathology studies, and determinations of plasma and kidney erythropoietin (Epo) titers by radioimmunoassay in normoxic and hypoxic conditions were performed 1, 2, 3, 5 and 10 days after M-Hb administration. Treatment induced transient increases in plasma urea concentration, fractional sodium excretion, and urine volume, and significant depression in urine osmolality. In every case, the maximal effect of the first injection of M-Hb on the individual parameters was always greater than that of the second injection, and observed on the 5th post-injection day. Histologic sections showed interstitial cellular infiltration, desquamation of the proximal tubular epithelium and collapse or dilation of the tubular lumen. Treatment with M-Hb depressed Epo titers in both kidney homogenates and plasma in normoxic as well as hypoxic rats. Here again, the effect of the first injection of the drug was higher than that of the second one. These observations indicate that there is a negative correlation between kidney tubule injury and Epo production in normoxic and hypoxic conditions. The findings give support to the concept that Epo production is related to proximal tubular function.

Topics: Acute Kidney Injury; Analysis of Variance; Animals; Body Weight; Erythropoietin; Female; Kidney Tubules; Methemoglobin; Organ Size; Oxygen; Rats; Rats, Inbred Strains

Erythropoietin (Epo) was sequentially measured by radioimmunoassay in 11 patients with acute renal failure (ARF) of varied aetiology. Epo rapidly decreased to a level inappropriately low for the haemoglobin, the reduced Epo value persisting throughout the oliguric phase and for up to 2 weeks after the restoration of apparently normal renal function. Epo values found in ARF were: at referral 18.2 +/- 9.5, mid-oliguria 14.4 +/- 6.8, diuresis 15.6 +/- 5.8, and recovery 25.1 +/- 15.8 mU/ml. Results are compared with 34 patients with end-stage chronic renal failure, 42 with non-renal anaemia, and 96 normal subjects. Epo deficiency alone is an inadequate explanation of the rapid reduction in haemoglobin at the onset of ARF, but would appear to be an important factor in the maintenance of anaemia in prolonged ARF and accounts for the slow increase in haemoglobin following recovery.

Topics: Acute Kidney Injury; Erythropoietin; Female; Hemoglobins; Humans; Male

Serum erythropoietin (EPO) concentrations were markedly depressed relative to the degree of anaemia in 10 patients with acute tubular necrosis, and remained low long after restoration of excretory renal function as estimated by glomerular filtration rate. Evidence is presented that the low serum EPO level is due to defective synthesis and not to increased catabolism. It is suggested that the predominantly are generatory anaemia found in prolonged cases of acute tubular necrosis, and the slow restoration of red cell mass during recovery, are due to the deficient synthesis of EPO. A positive erythropoietic response in a therapeutic trial with recombinant human erythropoietin (rhEPO) appears to support this hypothesis.

Topics: Acute Kidney Injury; Adult; Aged; Anemia; Creatinine; Erythropoietin; Female; Half-Life; Hemoglobins; Humans; Kidney Tubular Necrosis, Acute; Male; Middle Aged; Recombinant Proteins

Topics: Acute Kidney Injury; Aged; Erythropoietin; Hemoglobins; Humans; Postoperative Complications

Topics: Acute Kidney Injury; Adult; Aged; Erythropoietin; Female; Humans; Male

The treatment of renal failure includes dietary modification, drug treatment and hormonal supplements as well as renal transplantation. The rationale for these therapies and the associated problems likely to present to the GP are given practical consideration.

Topics: Acute Kidney Injury; Erythropoietin; Humans; Immunosuppressive Agents; Kidney Transplantation; Polycystic Kidney Diseases

Topics: Acute Kidney Injury; Anemia; Animals; Erythropoietin; Humans; Male; Rats; Rats, Inbred Strains; Uremia

In a survey the correlations between hypoxia, acidosis and nephrology are presented. In chronic oxygen deficiency the individual aspects concern the uncertainties of erythropoietin and the carotid-sinusoidal natriuresis stimulated by chemoreceptors. The effects of acute ischaemic hypoxic reactions are described with regard to the acute renal failure. The regulatory renal function of acidification and its disturbance in chronic renal insufficiency as well as the renotubular acidosis are discussed. Finally the authors enter the influence on the renal function during positive pressure respiration (e.g. for the purpose of the normalisation of the pulmonary gas exchange in acute respiratory insufficiency) as well as on reactions of the haemodialysis (bicarbonate and acetate dialysis) to the blood gas and acid-base metabolism, taking into consideration the pulmonary function.

Topics: Acid-Base Equilibrium; Acidosis, Renal Tubular; Acidosis, Respiratory; Acute Kidney Injury; Erythropoietin; Glomerular Filtration Rate; Humans; Hypercapnia; Hypoxia; Kidney; Kidney Tubules; Natriuresis; Positive-Pressure Respiration; Renal Dialysis

Adult female Wistar rats were injected with 1 mg/kg body weight of uranyl nitrate (UN). Evaluation of renal function, histopathology studies, and determination of plasma erythropoietin (Ep) titers after exposure to 456 mb for 16 h were performed at 1, 2, 7, 10, 15, and 21 days after drug injection. Plasma urea and creatinine concentrations markedly increased during the first seven days after injection, reaching maximal values on day 7 and decreasing thereafter. Significant increases in urine volume and significant depressions in urine osmolality also were observed; both alterations were most marked on day 7 after injection. A coagulative necrosis of the epithelium of proximal convoluted tubules, desquamation of the necrotic cells, and dilation or collapse of the tubular lumen were observed; the lesions were more marked on day 7. Plasma Ep levels in UN-treated rats exposed to hypobaria were markedly lower than in noninjected controls similarly exposed. Measurements were performed one, two, and seven days after UN injection, with maximal depression observed on day 7. These observations indicate that there is a correlation between the extent of both tubule damage and degree of renal dysfunction and plasma Ep production during exposure to hypoxia in UN-treated rats. This suggests that the renal Ep component is derived primarily from tubular cells.

Topics: Acute Kidney Injury; Animals; Blood Urea Nitrogen; Body Weight; Calcinosis; Erythropoietin; Feeding Behavior; Female; Organ Size; Oxygen; Rats; Time Factors; Uranyl Nitrate; Water-Electrolyte Balance

The relative roles of erythropoietin and potential inhibitors of erythropoiesis in the development of anemia in children with renal disease have been studied. Thirty-five children with renal disease of varied origins and severity were compared with 30 children with anemia of similar severity and with normal renal function. Serum erythropoietin was measured by radioimmunoassay; erythroid (CFU-E) and granulocytic (CFU-GM) progenitor cell growth were assessed in fetal mouse liver cell and normal human bone marrow cell cultures, respectively. The degree of serum inhibition of in vitro CFU-E growth in children with renal disease correlated with both creatinine clearance (r = 0.59, P less than 0.001) and hematocrit level (r = 0.55, P less than 0.005). Serum from children with renal disease inhibited in vitro CFU-E growth in a dose-related manner. Normal serum did not inhibit CFU-E growth in culture. The mean serum erythropoietin concentration was significantly (P less than 0.025) higher in children with anemia of renal disease (32.4 +/- 2.4 mU/ml) in comparison with serum values in normal children (19.6 +/- 1.5 mU/ml), but serum erythropoietin levels did not correlate with hematocrit level, creatinine clearance, or serum inhibition of in vitro erythropoiesis. In contrast, children with anemia and normal renal function showed a significant (P less than 0.001) linear increase in serum erythropoietin concentration (range 28.7 to 327 mU/ml), increased reticulocyte count, and stimulation of CFU-E formation with decreasing hematocrit levels. Coincubation of human urinary erythropoietin in the presence of serum from patients with uremia revealed markedly less immunoreactivity in the radioimmunoassay and less biologic activity in the fetal mouse liver CFU-E assay for erythropoietin than when erythropoietin was incubated with normal human serum, suggesting some alteration of erythropoietin in the presence of uremic serum, which reduced both the immunologic and biologic activity of erythropoietin. Normal and uremic sera inhibited CFU-GM growth to the same degree in comparison with controls. In conclusion, relative erythropoietin deficiency, direct alteration in the biologic activity of erythropoietin by uremic toxins, and serum inhibition of erythroid progenitor cells in the bone marrow are probably important factors in the pathogenesis of anemia in children with renal disease.

Topics: Acute Kidney Injury; Adolescent; Anemia; Animals; Bone Marrow; Child; Child, Preschool; Colony-Forming Units Assay; Creatinine; Erythropoiesis; Erythropoietin; Female; Hematocrit; Humans; Male; Mice; Radioimmunoassay; Renal Dialysis; Stem Cells; Uremia

Topics: Acute Kidney Injury; Adolescent; Adult; Animals; Blood Proteins; Erythropoiesis; Erythropoietin; Female; Humans; Hypoxia; Male; Mice; Middle Aged; Polycythemia; Transfusion Reaction

Topics: Acute Disease; Acute Kidney Injury; Animals; Erythropoiesis; Erythropoietin; Male; Rats; Uremia

Topics: Acute Kidney Injury; Erythropoietin; Gastrins; Glucose; Humans; Hypertension, Renal; Insulin; Kidney; Parathyroid Hormone; Renin; Vitamin D

Topics: Acute Kidney Injury; Adult; Anemia; Animals; Blood Platelets; Disseminated Intravascular Coagulation; Erythropoietin; Female; Folic Acid; Hemolysis; Humans; Kidney Diseases; Kidney Failure, Chronic; Kidney Transplantation; Polycythemia; Pre-Eclampsia; Pregnancy; Rabbits; Renal Dialysis; Transplantation, Homologous

Topics: Acute Kidney Injury; Adult; Animals; Dogs; Erythropoietin; Female; Haplorhini; Humans; Kidney; Kidney Diseases; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Renal Dialysis; Transplantation, Homologous

Topics: Acute Kidney Injury; Aged; Anemia; Animals; Erythropoietin; Female; Haplorhini; Humans; Kidney Failure, Chronic; Kidney Neoplasms; Macaca; Male; Mice; Mice, Inbred Strains; Middle Aged; Uremia

Topics: Acute Kidney Injury; Anemia; Animals; Blood Urea Nitrogen; Dogs; Erythropoiesis; Erythropoietin; Female; Humans; Hydronephrosis; Hypoxia; Iron Isotopes; Kidney Diseases; Kidney Failure, Chronic; Kidney Neoplasms; Kidney Transplantation; Mice; Nephrectomy; Peritoneal Dialysis; Polycythemia; Rabbits; Testosterone; Transplantation, Homologous; Uremia

Topics: Acute Kidney Injury; Adult; Blood Group Incompatibility; Ceruloplasmin; Erythropoietin; Humans; Middle Aged

Topics: Acute Kidney Injury; Adolescent; Adult; Erythrocyte Count; Erythropoietin; Female; Hemoglobins; Humans; Male; Middle Aged; Transfusion Reaction; Urea

Topics: Acute Kidney Injury; Anemia; Epoetin Alfa; Erythropoietin; Humans; Renal Insufficiency