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June 2016
Einat Hertzberg-Bigelman MsC, Rami Barashi MD, Ran Levy PhD, Lena Cohen MSc, Jeremy Ben-Shoshan MD PhD, Gad Keren MD and Michal Entin-Meer PhD

Background: Chronic kidney disease (CKD) is often accompanied by impairment of cardiac function that may lead to major cardiac events. Erythropoietin (EPO), a kidney-produced protein, was shown to be beneficial to heart function. It was suggested that reduced EPO secretion in CKD may play a role in the initiation of heart damage. 

Objectives: To investigate molecular changes in the EPO/erythropoietin receptor (EPO-R) axis in rat cardiomyocytes using a rat model for CKD.

Methods: We established a rat model for CKD by kidney resection. Cardiac tissue sections were stained with Masson’s trichrome to assess interstitial fibrosis indicating cardiac damage. To evaluate changes in the EPO/EPO-R signaling cascade in the myocardium we measured cardiac EPO and EPO-R as well as the phosphorylation levels of STAT-5, a downstream element in this cascade.

Results: At 11 weeks after resection, animals presented severe renal failure reflected by reduced creatinine clearance, elevated blood urea nitrogen and presence of anemia. Histological analysis revealed enhanced fibrosis in cardiac sections of CKD animals compared to the sham controls. Parallel to these changes, we found that although cardiac EPO levels were similar in both groups, the expression of EPO-R and the activated form of its downstream protein STAT-5 were significantly lower in CKD animals.

Conclusions: CKD results in molecular changes in the EPO/EPO-R axis. These changes may play a role in early cardiac damage observed in the cardiorenal syndrome.

 

April 2008
B. Kristal, R. Shurtz-Swirski, O. Tanhilevski, G. Shapiro, G. Shkolnik, J. Chezar, T. Snitkovsky, M. Cohen-Mazor and S. Sela

Background: Polymorphonuclear leukocyte priming and low grade inflammation are related to severity of kidney disease. Erythropoietin-receptor is present on PMNLs[1].

Objectives: To evaluate the effect of 20 weeks of EPO[2]-alpha treatment on PMNL characteristics in relation to the rate of kidney function deterioration in patients with chronic kidney disease.

Methods: Forty anemic chronic kidney disease patients, stage 4-5, were assigned to EPO and non-EPO treatment for 20 weeks. A group of 20 healthy controls was also studied. PMNL priming and PMNL-derived low grade inflammation were estimated, in vivo and ex vivo, before and after EPO treatment: The rate of superoxide release, white blood cells and PMNL counts, serum alkaline phosphatase and PMNL viability were measured. EPO-receptor on PMNLs was assayed by flow cytometry. The effect of 20 weeks of EPO treatment on kidney function was related to the estimated glomerular filtration rate.

Results: EPO treatment attenuated superoxide release ex vivo and in vivo and promoted PMNL survival ex vivo. Decreased low grade inflammation was reflected by reduced WBC[3] and PMNL counts and ALP[4] activity following treatment. EPO retarded the deterioration in GFR[5]. The percent of PMNLs expressing EPO-R[6] was higher before EPO treatment and correlated positively with the rate of superoxide release. After 20 weeks of EPO treatment the percent of PMNLs expressing EPO-R was down-regulated.

Conclusions: These non-erythropoietic properties of EPO are mediated by EPO-R on PMNLs, not related to the anemia correction. A new renal protection effect of EPO via attenuation of PMNL priming that decreases systemic low grade inflammation and oxidative stress is suggested.






[1] PMNL = polymorphonuclear leukocytes

[2] EPO = erythropoietin

[3] WBC = white blood cells

[4] ALP = alkaline phosphatase

[5] GFR = glomerular filtration rate

[6] EPO = EPO-receptor


October 2006
H.S. Oster, M. Hoffman, S. Prutchi-Sagiv, O. Katz, D. Neumann and M. Mittelman
 Recombinant human erythropoietin has become an essential part of the management of anemic patients with end-stage renal disease. It is also used to treat the anemia associated with cancer and other diseases, and it improves quality of life. In recent years, studies in animals and humans have focused on the use of rHuEPO[1] for other indications. It has been found to play a role in both cardioprotection and neuroprotection. It has effects on the immune system, and can cause regression in hematologic diseases such as multiple myeloma. It may also improve the response of solid tumors to chemotherapy and radiation therapy. On the other hand, concerns have been raised following two studies of patients with solid tumors in whom those treated with rHuEPO had diminished survival. Criticism of the design of these studies makes it clear that large, well-designed, randomized trials must be performed to determine the role of rHuEPO in the treatment of cancer, and more generally to clarify the full clinical benefits of the drug, while minimizing the harm.







[1] rHuEPO = recombinant human erythropoietin


May 2003
D.S Silverberg, D. Wexler, M. Blum, D.Schwartz, G. Keren, D. Sheps, and A. Iaina

Background: Congestive heart failure is extremely common in octogenarians and is associated with severe fatigue, shortness of breath, recurrent hospitalizations, and death. These patients, many of whom are anemic, are often resistant to standard CHF[1] therapy including angiotensin-converting enzyme inhibitors, beta-blockers and diuretics.

Objectives: To examine whether correction of the anemia (hemoglobin <12 g/dl) in CHF patients lowers their resistance to therapy.

Methods: Forty octogenarians with anemia and severe resistant CHF were administered a combination of subcutaneous erythropoietin and intravenous iron sucrose.

Results: This combination therapy led to a marked improvement in cardiac function, shortness of breath and fatigue, a marked reduction in the rate of hospitalization and a stabilizing of renal function.

Conclusion: Anemia appears to be an important but ignored contributor to the progression of CHF, and its correction may improve cardiac and renal status as well as the quality of life in elderly patients.






[1] CHF = congestive heart failure


November 2002
Jacob Cohen, MSc, Lia Supino-Rosin, MSc, Eran Barzilay, BSc, Ronit Eisen-Lev, DMD, Moshe Mittelman, MD and Drorit Neumann, PhD
October 1999
Shaul Dollberg MD and Francis B. Mimouni MD
 Background and Objective: Very low birthweight infants (<1,500 g birthweight) often develop significant anemia that requires multiple blood transfusions, which carry a significant risk. Erythropoietin therapy is known to reduce the need for blood transfusions in preterm VLBW(1) infants. Analysis of cost had been reported in prospective studies with conflicting results. No studies comparing the cost-effectiveness of EPO(2) have been reported during routine use in preterm VLBW infants.

Methods: We compared the cost of treating anemia of prematurity in two consecutive 12-month periods: before and after the introduction of EPO therapy in our unit. The cost of blood bank charges as well as disposable items and the cost of EPO were compared.

Results: A significantly smaller number of infants required blood transfusions in the EPO group (2 of 25 vs. 9/21 before EPO was introduced). The cost of therapy for anemia of prematurity was significantly smaller in the EPO group (128±168 US$ per infant vs. 151±189 US$ per infant before the introduction of EPO).

Conclusion: We conclude that EPO is an efficient and cost-effective alternative to blood transfusions in VLBW infants.

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(1) VLBW = very low birthweight

(2) EPO = erythropoietin

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