Pleiotropic renal actions of erythropoietin

doi:10.1016/S0140-6736(05)66622-6

The Lancet

Volume 365, Issue 9474, 28 May–3 June 2005, Pages 1890-1892

https://doi.org/10.1016/S0140-6736(05)66622-6 Get rights and content

Summary

Context

Erythropoietin (EPO), which is used clinically as recombinant human EPO (rHuEPO) for anaemia associated with end-stage renal failure and cancer chemotherapy, also has pleiotropic properties. Although EPO and its receptor are primary mediators of the normal physiological response to hypoxia, rHuEPO can provide impressive protection against acute ischaemic injury in several organs and tissues. The longer-acting hyperglycosylated derivative of EPO, darbepoetin-α, is also used for anaemia and has pleiotropic properties. However, the ability of EPO or its analogues to act directly to reduce the severity of renal injury associated with chronic renal failure is not known.

Starting point

Ferdinand Bahlmann and colleagues (Circulation 2004; 110: 1006–12) investigated whether low-dose subcutaneous darbepoetin-α could protect against renal dysfunction and injury in rats with induced chronic renal failure. Given once weekly, the drug improved renal function and reduced histological evidence of renal injury. Treated rats also had greater weight gain than controls, with no change in systemic blood pressure. The drug did not increase packed-cell volume and it improved survival.

Where next?

Although the pleiotropic actions of rHuEPO can ameliorate ischaemic and nephrotoxic acute renal failure, Bahlmann's work is the first evidence that darbepoetin-α reduces the renal dysfunction and injury of chronic renal failure. Thus rHuEPO and its analogues might have a use in patients with different types of renal failure. These pleiotropic actions, seen at lower doses, must be separated from the haemopoietic properties that occur at clinical doses and which, at the highest doses, might lead to unwanted effects. Novel analogues of EPO are devoid of haemopoietic activity but still possess protective properties. Their ability to reduce renal injury and dysfunction awaits investigation.

Section snippets

Erythropoietin—old hormone, new tricks

Erythropoietin (EPO) and its receptor are primary mediators of the normal physiological response to hypoxia. Recombinant human EPO (rHuEPO) and its longer-acting hyperglycosylated analogue, darbepoetin-α, are used to treat anaemia associated with chronic renal failure and non-myeloid cancer, and in patients receiving zidovudine. However, EPO also ameliorates acute ischaemic injury in several organs and tissues (table 1).1, 2, 3, 4, 5, 6, 7

Several in-vivo investigations have also shown that EPO

EPO to treat renal failure

Current interventions for chronic renal failure involve treatment of underlying causes, such as hypertension and diabetes (eg, treatment with angiotensin-converting-enzyme inhibitors), modification of diet (eg, dietary protein restriction), and reduction of risk factors (eg, stopping smoking). rHuEPO or darbepoetin-α can be given to correct consequential anaemia by increasing red-blood-cell mass. However, whether alteration of packed-cell volume by rHuEPO is beneficial or detrimental in the

Other EPO analogues

Because increasing the plasma levels of rHuEPO and darbepoetin-α will facilitate their haemopoietic actions and, possibly, unwanted effects, novel analogues of EPO that are devoid of haemopoietic activity but are still renoprotective have been developed.²⁹ Asialoerythropoietin (asialoEPO) has impressive neuroprotective properties: it reduced tissue injury in models of cerebral ischaemia, spinal-cord compression, and sciatic nerve crush-injury.³⁰ AsialoEPO is as neuroprotective as an equivalent

References (31)

A Österborg
New erythropoietic proteins: rationale and clinical data
Semin Oncol
(2004)
ML Brines et al.
Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury
Proc Natl Acad Sci USA
(2000)
M Abdelrahman et al.
Erythropoietin attenuates the tissue injury associated with hemorrhagic shock and myocardial ischemia
Shock
(2004)
AK Junk et al.
Erythropoietin administration protects retinal neurons from acute ischemia-reperfusion injury
Proc Natl Acad Sci USA
(2002)
M Celik et al.
Erythropoietin prevents motor neuron apoptosis and neurologic disability in experimental spinal cord ischemic injury
Proc Natl Acad Sci USA
(2002)
F Squadrito et al.
Recombinant human erythropoietin inhibits iNOS activity and reverts vascular dysfunction in splanchnic artery occlusion shock
Br J Pharmacol
(1999)
C Heeschen et al.
Erythropoietin is a potent physiologic stimulus for endothelial progenitor cell mobilization
Blood
(2003)
M Buemi et al.
Recombinant human erythropoietin stimulates angiogenesis and healing of ischemic skin wounds
Shock
(2004)
FH Bahlmann et al.
Low-dose therapy with the long-acting erythropoietin analogue darbepoetin alpha persistently activates endothelial Akt and attenuates progressive organ failure
Circulation
(2004)
T Nemoto et al.
Recombinant erythropoietin rapidly treats anemia in ischemic acute renal failure
Kidney Int
(2001)

NSA Patel et al.

Pretreatment with EPO reduces the injury and dysfunction caused by ischemia/reperfusion in the mouse kidney in vivo

Kidney Int

(2004)

H Gong et al.

EPO and α-MSH prevent ischemia/reperfusion-induced down-regulation of AQPs and sodium transporters in rat kidney

Kidney Int

(2004)

DA Vesey et al.

Erythropoietin protects against ischaemic acute renal injury

Nephrol Dial Transplant

(2004)

EJ Sharples et al.

Erythropoietin protects the kidney against the injury and dysfunction caused by ischemia-reperfusion

J Am Soc Nephrol

(2004)

CW Yang et al.

Preconditioning with erythropoietin protects against subsequent ischemia-reperfusion injury in rat kidney

FASEB J

(2003)

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Acute kidney injury (AKI) remains a frequent and serious complication of surgical procedures and critical illness that is consistently associated with worse outcomes and increased long-term morbidity and mortality. Much work has gone into finding kidney protective measures with disappointingly few therapeutic options available to prevent or to treat AKI. Research has defined some effective kidney protective practices and the purpose of this chapter is to help the clinician to differentiate better clinical practices that are either ineffective, detrimental, or protective to the kidney. The chapter will first provide an introduction to kidney physiology with particular focus on areas that make it vulnerable to injury. The chapter will then shift focus to diagnosis of kidney injury including definitions and early biomarkers that can help risk stratify patients. Then, specific mechanisms of postoperative and critical illness-associated kidney injury will be outlined. The rest of the chapter will review evidence from renal-protective research studies pertinent to the preoperative, intraoperative, and postoperative periods. After reading this chapter, the clinician should have a more robust framework for adoption (mostly avoidance) of renal protective practices (stratified based on level of evidence available) to guide their clinical practice.
Effect of a Single Bolus of Erythropoietin on Renoprotection in Patients Undergoing Thoracic Aortic Surgery With Moderate Hypothermic Circulatory Arrest
2016, Annals of Thoracic Surgery
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.
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2015, Pharmacological Reports
Some data in literature indicate increased apoptosis of polymorphonuclear cells (PMNs) in chronic kidney disease (CKD), what seems to be connected with anemia. Erythropoiesis-stimulating agents, used in anemia treatment in CKD may affect cells apoptosis. Aim of this study was to investigate impact of anemia treatment with methoxy polyethylene glycol-epoetin beta (CERA) on PMNs apoptosis in predialysis patients with CKD.
Percentage of early and late apoptotic PMNs was measured by flow cytometry based on annexin V and propidium iodide binding. CD90 (Fas), CD95L (FasL), CD16 and CD11b expression on PMNs were evaluated by flow cytometry after incubation with respective monoclonal antibody.
Percentage of PMNs in early and late apoptosis in CKD patients before CERA treatment was significantly higher to control group, which was accompanied by significantly higher Fas and Fas-L expression and significantly lower expression of CD16. CERA treatment downregulated significantly percentage of early, apoptotic PMNs but percentage of late apoptotic cells did not change and was still significantly higher to control group. In all investigated groups we observed a significant negative correlation between hemoglobin concentration and percentage of apoptotic PMNs, as well as Fas and FasL expression and significant positive correlation between Hb and CD16 expression.
Our results indicate that PMNs apoptosis is increased in predialysis patients with CKD and anemia treatment with CERA may diminish readiness of PMNs to undergo apoptosis. This antiapoptotic impact of anemia treatment with CERA seems to concern early apoptotic PMNs before they undergo to late, irreversible stage of apoptosis.
Role of recombinant human erythropoietin in mitomycin C-induced genotoxicity: Analysis of DNA fragmentation, chromosome aberrations and micronuclei in rat bone-marrow cells
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Citation Excerpt :
EPO, which is used clinically in the form of recombinant human EPO (rhEPO), has been successfully used in treatment of human anaemia associated with end-stage renal failure and cancer chemotherapy [12–14]. More recently, it has been established that the biological effects of rhEPO are not only limited to the haematopoietic system; many studies have shown that rhEPO is a pleiotropic cytokine that exerts broad tissue-protective effects in diverse non-hematopoietic organs [15–17]. Several investigations have shown that rhEPO can reduce genotoxic damage in brain and kidney of rats [18,19].
Mitomycin C (MMC) is one of the most effective chemotherapeutic agents. However, during clinical use several side effects may occur. Recombinant human erythropoietin (rhEPO), a glycoprotein that regulates haematopoiesis, has been shown to exert an important cyto-protective effect in many tissues. The aim of this study was to explore whether rhEPO protects against MMC-induced genotoxicity in rat bone-marrow cells. Adult male Wistar rats were divided into six groups of 18 animals each: a control group, a ‘rhEPO alone’ group, an ‘MMC alone’ group and three ‘rhEPO + MMC’ groups (pre-, co- and post-treatment conditions). Our results show that MMC induced a noticeable genotoxic effect in rat bone-marrow cells. rhEPO reduced the effects of MMC significantly in every type of experiment conducted, such as the frequency of micronuclei, the percentage of chromosome aberrations and the level of DNA damage measured with the comet assay. The protective effect of rhEPO was more efficient when it was given 24 h prior to MMC treatment.
Expression and Variations in EPO Associated with Oxygen Metabolism in Tibetan Sheep
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Rapid ReviewPleiotropic renal actions of erythropoietin

Summary

Context

Starting point

Where next?

Section snippets

Erythropoietin—old hormone, new tricks

EPO to treat renal failure

Other EPO analogues

Semin Oncol

Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury

Proc Natl Acad Sci USA

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

Shock

Erythropoietin administration protects retinal neurons from acute ischemia-reperfusion injury

Proc Natl Acad Sci USA

Erythropoietin prevents motor neuron apoptosis and neurologic disability in experimental spinal cord ischemic injury

Proc Natl Acad Sci USA

Recombinant human erythropoietin inhibits iNOS activity and reverts vascular dysfunction in splanchnic artery occlusion shock

Br J Pharmacol

Erythropoietin is a potent physiologic stimulus for endothelial progenitor cell mobilization

Blood

Recombinant human erythropoietin stimulates angiogenesis and healing of ischemic skin wounds

Shock

Low-dose therapy with the long-acting erythropoietin analogue darbepoetin alpha persistently activates endothelial Akt and attenuates progressive organ failure

Circulation

Recombinant erythropoietin rapidly treats anemia in ischemic acute renal failure

Kidney Int

Pretreatment with EPO reduces the injury and dysfunction caused by ischemia/reperfusion in the mouse kidney in vivo

Kidney Int

EPO and α-MSH prevent ischemia/reperfusion-induced down-regulation of AQPs and sodium transporters in rat kidney

Kidney Int

Erythropoietin protects against ischaemic acute renal injury

Nephrol Dial Transplant

Erythropoietin protects the kidney against the injury and dysfunction caused by ischemia-reperfusion

J Am Soc Nephrol

Preconditioning with erythropoietin protects against subsequent ischemia-reperfusion injury in rat kidney

FASEB J

Rapid Review
Pleiotropic renal actions of erythropoietin