Dialysate related cytokine induction and response to recombinant human erythropoietin in haemodialysis patients

Sitter, Thomas; Bergner, Albrecht; Schiffl, Helmut

doi:10.1093/ndt/15.8.1207

Cited by 181 publications

(142 citation statements)

References 9 publications

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“…The proinflammatory cytokine IL-6 is also enhanced in patients who need higher doses of Epo to achieve target hematocrit (62), and CRP is a good predictor for Epo resistance in hemodialysis patients with low hemoglobin levels (12,75). Finally, an improved Epo response coincided with reversal of enhanced IL-6 and CRP levels in ESRD by treatment with an ultrapure dialysate (156). As regulation of inflammatory pathways involves upregulation of SOCS, this potentially could interfere with intracellular signaling of Epo, thereby possibly explaining Epo resistance and hampered erythropoiesis.…”

Section: How Does Epo Influence the Cardiorenal Connectors?mentioning

confidence: 96%

Erythropoietin and the cardiorenal syndrome: cellular mechanisms on the cardiorenal connectors

Jie

Verhaar²,

Cramer³

et al. 2006

American Journal of Physiology-Renal Physiology

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We have recently proposed severe cardiorenal syndrome (SCRS), in which cardiac and renal failure mutually amplify progressive failure of both organs. This frequent pathophysiological condition has an extremely poor prognosis. Interactions between inflammation, the renin-angiotensin system, the balance between the nitric oxide and reactive oxygen species and the sympathetic nervous system form the cardiorenal connectors and are cornerstones in the pathophysiology of SCRS. An absolute deficit of erythropoietin (Epo) and decreased sensitivity to Epo in this syndrome both contribute to the development of anemia, which is more pronounced than renal anemia in the absence of heart failure. Besides expression on erythroid progenitor cells, Epo receptors are present in the heart, kidney, and vascular system, in which activation results in antiapoptosis, proliferation, and possibly antioxidation and anti-inflammation. Interestingly, Epo can improve cardiac and renal function. We have therefore reviewed the literature with respect to Epo and the cardiorenal connectors. Indeed, there are indications that Epo can diminish inflammation, reduce renin-angiotensin system activity, and shift the nitric oxide and reactive oxygen species balance toward nitric oxide. Information about Epo and the sympathetic nervous system is scarce. This analysis underscores the relevance of a further understanding of clinical and cellular mechanisms underlying protective effects of Epo, because this will support better treatment of SCRS. heart failure; renal failure; anemia; nitric oxide; reactive oxygen species COEXISTENCE OF RENAL AND cardiac disease is associated with high morbidity and mortality. This pathophysiological condition, in which combined cardiac and renal dysfunction amplifies a progression in the failure of the individual organ, has recently been denoted as severe cardiorenal syndrome (SCRS) (19,20).In patients with declined renal function measured by glomerular filtration rate (GFR), an independent increased risk for cardiovascular events has been found. The hazard ratio for cardiovascular events was 1.4 with a GFR Ͻ60 ml/min and increased with diminished renal function to 2.8 in patients with a GFR Ͻ30 ml/min (99). A 40% higher adjusted risk for adverse cardiovascular outcomes or death was observed in those with relatively minor degrees of renal dysfunction (120). The prevalence of chronic renal failure (CRF) is reportedly high in patients with congestive heart failure (CHF). Furthermore, the prevalence and severity of CRF correlate with the severity of CHF (44, 72). These data support that combined cardiac and renal failure is a profound problem, and a further understanding of the underlying pathophysiological and molecular mechanisms is needed to improve therapy.Our group proposed an interactive network of cardiorenal connectors, i.e., the renin-angiotensin system (RAS), nitric oxide and reactive oxygen species (NO-ROS) balance, the sympathetic nervous system (SNS), and inflammation, as the cornerstones of the pathophysiology o...

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Section: How Does Epo Influence the Cardiorenal Connectors?mentioning

confidence: 96%

Erythropoietin and the cardiorenal syndrome: cellular mechanisms on the cardiorenal connectors

Jie

Verhaar²,

Cramer³

et al. 2006

American Journal of Physiology-Renal Physiology

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“…9,[16][17][18] Inflammatory hepcidin induction is accompanied by impaired dietary iron uptake, iron sequestration, and anemia, 18 implicating hepcidin as a controlling factor in AI. AI (also sometimes referred to as the anemia of chronic disease) has been reported in numerous patient populations [19][20][21][22][23][24] and is characterized by a relative resistance to erythropoiesis-stimulating agent (ESA; epoetin alfa or darbepoetin alfa) therapy. [25][26][27][28][29][30] In the current work, neutralization of hepcidin in vitro and in vivo illustrated that an antihepcidin therapy substantially modulated iron transport and effectively treated anemia in a mouse model of AI.…”

Section: Introductionmentioning

confidence: 99%

Antihepcidin antibody treatment modulates iron metabolism and is effective in a mouse model of inflammation-induced anemia

Sasu¹,

Cooke²,

Arvedson³

et al. 2010

Blood

217

203

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Iron maldistribution has been implicated in multiple diseases, including the anemia of inflammation (AI), atherosclerosis, diabetes, and neurodegenerative disorders. Iron metabolism is controlled by hepcidin, a 25-amino acid peptide. Hepcidin is induced by inflammation, causes iron to be sequestered, and thus, potentially contributes to AI. Human hepcidin (hHepc) overexpression in mice caused an iron-deficient phenotype, including stunted growth, hair loss, and iron-deficient erythropoiesis. It also caused resistance to supraphysiologic levels of erythropoiesis-stimulating agent, supporting the hypothesis that hepcidin may influence response to treatment in AI. To explore the role of hepcidin in inflammatory anemia, a mouse AI model was developed with heat-killed Brucella abortus treatment. Suppression of hepcidin mRNA was a successful anemia treatment in this model. High-affinity antibodies specific for hHepc were generated, and hHepc knock-in mice were produced to enable antibody testing. Antibody treatment neutralized hHepc in vitro and in vivo and facilitated anemia treatment in hHepc knock-in mice with AI. These data indicate that antihepcidin antibodies may be an effective treatment for patients with inflammatory anemia. The ability to manipulate iron metabolism in vivo may also allow investigation of the role of iron in a number of other pathologic conditions. (Blood. 2010;115(17):3616-3624)

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“…The presence of an inflammatory disorder increases the resistance to treatment with erythropoietic agents, including the production of inflammatory cytokines that interfere with iron metabolism, reducing their availability in the bone marrow and causing functional iron deficiency. The process of dialysis may be associated with an increase in the induction of cytokines and the appearance of an inflammatory response syndrome [180] .…”

Section: Resistancementioning

confidence: 99%

Use of agents stimulating erythropoiesis in digestive diseases

López¹,

Sicilia²,

García³

2009

WJG

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Anemia is the most common complication of inflammatory bowel disease (IBD). Control and inadequate treatment leads to a worse quality of life and increased morbidity and hospitalization. Blood loss, and to a lesser extent, malabsorption of iron are the main causes of iron deficiency in IBD. There is also a variable component of anemia related to chronic inflammation. The anemia of chronic renal failure has been treated for many years with recombinant human erythropoietin (rHuEPO), which significantly improves quality of life and survival. Subsequently, rHuEPO has been used progressively in other conditions that occur with anemia of chronic processes such as cancer, rheumatoid arthritis or IBD, and anemia associated with the treatment of hepatitis C virus. Erythropoietic agents complete the range of available therapeutic options for treatment of anemia associated with IBD, which begins by treating the basis of the inflammatory disease, along with intravenous iron therapy as first choice. In cases of resistance to treatment with iron, combined therapy with erythropoietic agents aims to achieve near-normal levels of hemoglobin/hematocrit (11-12 g/dL). New formulations of intravenous iron (iron carboxymaltose) and the new generation of erythropoietic agents (darbepoetin and continuous erythropoietin receptor activator) will allow better dosing with the same efficacy and safety.

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Dialysate related cytokine induction and response to recombinant human erythropoietin in haemodialysis patients

Cited by 181 publications

References 9 publications

Erythropoietin and the cardiorenal syndrome: cellular mechanisms on the cardiorenal connectors

Erythropoietin and the cardiorenal syndrome: cellular mechanisms on the cardiorenal connectors

Antihepcidin antibody treatment modulates iron metabolism and is effective in a mouse model of inflammation-induced anemia

Use of agents stimulating erythropoiesis in digestive diseases

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