Pleiotropic effect of erythropoiesis-stimulating agents on circulating endothelial progenitor cells in dialysis patients

A Correction to this article was published on 05 July 2021

This article has been updated

Abstract

Background

Recent studies have suggested that erythropoiesis-stimulating agents (ESAs) may accelerate not only angiogenesis but also vasculogenesis, beyond erythropoiesis.

Methods

We conducted a 12-week prospective study in 51 dialysis patients; 13 were treated with recombinant human erythropoietin (EPO, 5290.4 ± 586.9 IU/week), 16 with darbepoetin (DA, 42.9 ± 4.3 µg/week), 12 with epoetin β pegol (CERA, 40.5 ± 4.1 µg/week) and 10 with no ESAs. Vascular mediators comprising endothelial progenitor cells (EPCs), vascular endothelial growth factor (VEGF), matrix metalloproteinase-2 (MMP-2), and high-sensitivity C-reactive protein (hs-CRP) were measured at 0 and 12 weeks. EPCs were measured by flow cytometry as CD45lowCD34+CD133+ cells.

Results

The EPC count increased significantly to a greater extent in the EPO group than in the other three group, and increased significantly from 0 to 12 weeks in a EPO dose-dependent manner. In both the DA and CERA groups, the EPC count did not change at 12 weeks. Serum levels of VEGF, MMP-2 and hs-CRP were not affected by ESA treatment in all groups. In the CERA group, serum ferritin decreased significantly compared to the no-ESA group and correlated with CERA dose, although use of iron was permitted if required during the prospective study period of 12 weeks.

Conclusions

When patients on dialysis were treated with clinical doses of various ESAs, only EPO induced a significant increase of circulating EPCs from bone marrow, whereas, DA and CERA had no effect.

This is a preview of subscription content, access via your institution.

Fig. 1

Change history

References

  1. 1.

    Eguchi M, Masuda H, Asahara T. Endothelial progenitor cells for postnatal vasculogenesis. Clin Exp Nephrol. 2007;11:18–25.

    PubMed  Google Scholar 

  2. 2.

    Chateauvieux S, Grigorakaki C, Morceau F, Dicato M, Diederich M. Erythropoietin, erythropoiesis and beyond. Biochem Pharmacol. 2011;82:1291–303.

    CAS  PubMed  Google Scholar 

  3. 3.

    Ribatti D, Vacca A, Roccaro AM, Crivellato E, Presta M. Erythropoietin as an angiogenetic factor. Eur J Clin Invest. 2003;33:891–6.

    CAS  PubMed  Google Scholar 

  4. 4.

    Jaquet K, Krause K, Tawakol-Khodai M, Geidel S, Kuck KH. Erythropoietin and VEGF exhibit equal angiogenetic potential. Microvasc Res. 2002;64:326–323.

    CAS  PubMed  Google Scholar 

  5. 5.

    Heeschen C, Aicher A, Lehmann R, et al. Erythropoietin is a potent physiologic stimulus for endothelial progenitor cell mobilization. Blood. 2003;102:1340–6.

    CAS  PubMed  Google Scholar 

  6. 6.

    Bahlmann FH, de Groot K, Spandau JM, et al. Erythropoietin regulates endothelial progenitor cells. Blood. 2004;103:921–6.

    CAS  PubMed  Google Scholar 

  7. 7.

    Naito T, Sanaka T, Mikami H, et al. Modulation of circulating endothelial progenitor cells by erythropoiesis-stimulating agents in patients with chronic kidney disease stage G5 and 5D. Clin Nephrol. 2016;86:242–52.

    CAS  PubMed  Google Scholar 

  8. 8.

    Leshem-Rubinow E, Steinvil A, Zeltser D, et al. Association of angiotensin-converting enzyme inhibitor therapy initiation with a reduction in hemoglobin levels in patients without renal failure. Mayo Clin Proc. 2012;87:1189–95.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Le Meur Y, Lorgeot V, Comte L, et al. Plasma levels and metabolism of AcSDKP in patients with chronic renal failure: relationship with erythropoietin requirements. Am J Kidney Dis. 2001;38:510–7.

    PubMed  Google Scholar 

  10. 10.

    Matsusaka S, Mishima Y, Suenaga M, et al. Circulating endothelial progenitors and CXCR4-positive circulating endothelial cells are predictive markers for bevacizumab. Cancer. 2011;117:4026–32.

    CAS  PubMed  Google Scholar 

  11. 11.

    Prater DN, Case J, Ingram DA, Yoder MC. Working hypothesis to redefine endothelial progenitor cells. Leukemia. 2007;21:1141–9.

    CAS  PubMed  Google Scholar 

  12. 12.

    Locatelli F, Andrulli S, Memoli B, et al. Nutritional-inflammation status and resistance to erythropoietin therapy in haemodialysis patients. Nephrol Dial Transplant. 2006;21:991–8.

    CAS  PubMed  Google Scholar 

  13. 13.

    Morikami Y, Fujimori A, Okada S, Kumei M, Mizobuchi N, Sakai M. Twice-monthly administration of a lower dose of epoetin beta pegol can maintain adequate hemoglobin levels in hemodialysis patients. Ther Apher Dial. 2015;19:138–43.

    CAS  PubMed  Google Scholar 

  14. 14.

    Solomon A, Blum A, Peleg A, Lev El, Leshem-Lev D, Hasin Y. Endothelial progenitor cells are suppressed in anemic patients with acute coronary syndrome. Am J Med 2012;125:604–611.

  15. 15.

    Sturiale A, Coppolino G, Loddo S, et al. Effects of haemodialysis on circulating endothelial progenitor cell count. Blood Purif. 2007;25:242–51.

    PubMed  Google Scholar 

  16. 16.

    Georgescu A, Alexandru N, Andrei E, et al. Circulating microparticles and endothelial progenitor cells in atherosclerosis: pharmacological effects of irbesartan. J Thromb Haemost. 2012;10:680–91.

    CAS  PubMed  Google Scholar 

  17. 17.

    Saito H, Yamamoto Y, Yamamoto H. Diabetes alters subsets of endothelial progenitor cells that reside in blood, bone marrow, and spleen. Am J Physiol Cell Physiol. 2012;302:C892-901.

    CAS  PubMed  Google Scholar 

  18. 18.

    Xia WH, Yang Z, Xu SY, et al. Age-related decline in reendothelialization capacity of human endothelial progenitor cells is restored by shear stress. Hypertension. 2012;59:1225–31.

    CAS  PubMed  Google Scholar 

  19. 19.

    Yang JX, Tang WL, Wang XX. Superparamagnetic iron oxide nanoparticles may affect endothelial progenitor cell migration ability and adhesion capacity. Cytotherapy. 2010;12:251–9.

    CAS  PubMed  Google Scholar 

  20. 20.

    Elliott S, Sinclair AM. The effect of erythropoietin on normal and neoplastic cells. Biologics. 2012;6:163–89.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Kawai T, Kusano Y, Yamada K, Ueda C, Kawai A, Takao M. Long-term maintenance of hemoglobin levels in hemodialysis patients treated with bi-weekly epoetin beta pegol switched from darbepoetin alfa: a single-center, 12-month observational study in Japan. J Artif Organs. 2019;22:146–53.

    CAS  PubMed  Google Scholar 

  22. 22.

    Brines M, Cerami A. Discovering erythropoietin’s extra-hematopoietic functions: biology and clinical promise. Kidney Int. 2006;70:246–50.

    CAS  PubMed  Google Scholar 

  23. 23.

    Sinclair AM, Coxon A, McCaffery I, et al. Functional erythropoietin receptor is undetectable in endothelial, cardiac, neuronal, and renal cells. Blood. 2010;115:4264–72.

    CAS  PubMed  Google Scholar 

  24. 24.

    Brines M, Grasso G, Fiordaliso F, et al. Erythropoietin mediates tissue protection through an erythropoietin and common beta-subunit heteroreceptor. Proc Natl Acad Sci USA. 2004;101:14907–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Zhang Z, Yao L, Yang J, Wang Z, Du G. PI3K/Akt and HIF-1 signaling pathway in hypoxia-ischemia. Mol Med Rep. 2018;18:3547–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Westenbrink BD, Lipsic E, van der Meer P, et al. Erythropoietin improves cardiac function through endothelial progenitor cell and vascular endothelial growth factor mediated neovascularization. Eur Heart J. 2007;28:2018–27.

    CAS  PubMed  Google Scholar 

  27. 27.

    Cheng Y, Hu R, Lv L, Ling L, Jiang S. Erythropoietin improves the efficiency of endothelial progenitor cell therapy after myocardial infarction in mice: effects on transplanted cell survival and autologous endothelial progenitor cell mobilization. J Surg Res. 2012;176:e47-55.

    CAS  PubMed  Google Scholar 

  28. 28.

    Hand CC, Brines M. Promises and pitfalls in erythropoietin-mediated tissue protection: are nonerythropoietic derivatives a way forward? J Investig Med. 2011;59:1073–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Povsic TJ, Najjar SS, Prather K, et al. EPC mobilization after erythropoietin treatment in acute ST-elevation myocardial infarction: the REVEAL EPC substudy. J Thromb Thrombolysis. 2013;36:375–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Bahlmann FH, DeGroot K, Duckert T, et al. Endothelial progenitor cell proliferation and differentiation is regulated by erythropoietin. Kidney Int. 2003;64:1648–52.

    CAS  PubMed  Google Scholar 

  31. 31.

    Shimoni S, Bar I, Meledin V, Derazne E, Gandelman G, George J. Circulating endothelial progenitor cells and clinical outcome in patients with aortic stenosis. PLoS ONE. 2016;11:e0148766. https://doi.org/10.1371/journal.pone.0148766.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Krenning G, Dankers PY, Drouven JW, et al. Endothelial progenitor cell dysfunction in patients with progressive chronic kidney disease. Am J Physiol Renal Physiol. 2009;296:F1314–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Kiss Z, Elliot S, Jedynasty K, Tesar V, Szegedi J. Discovery and basic pharmacology of erythropoiesis-stimulating agents (ESAs), including the hyperglycosylated ESA, darbepoetin alfa: an update of the rationale and clinical impact. Eur J Clin Pharmacol. 2010;66:331–40.

    CAS  PubMed  Google Scholar 

  34. 34.

    Jarsch M, Brandt M, Lanzendorfer M, Haselbeck A. Comparative erythropoietin receptor binding kinetics of CERA and epoetin-beta determined by surface plasmon resonance and competition binding assay. Pharmacology. 2008;81:63–9.

    CAS  PubMed  Google Scholar 

  35. 35.

    Ribatti D. The discovery of endothelial progenitor cells. An historical review. Leuk Res. 2007;31:439–44.

    CAS  PubMed  Google Scholar 

  36. 36.

    Basak GW, Yasukawa S, Alfaro A, et al. Human embryonic stem cells hemangioblast express HLA-antigens. J Transl Med. 2009;7:27. https://doi.org/10.1186/1479-5876-7-27.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Mohler ER 3rd, Zhang L, Medenilla E, et al. Effect of darbepoetin alfa on endothelial progenitor cells and vascular reactivity in chronic kidney disease. Vasc Med. 2011;16:183–9.

    PubMed  Google Scholar 

  38. 38.

    Sakaguchi Y, Hamano T, Wada A, Masakane I. Types of erythropoietin-stimulating agents and mortality among patients undergoing hemodialysis. J Am Soc Nephrol. 2019;30:1037–48.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Onuma S, Honda H, Kobayashi Y, et al. Effects of long-term erythropoiesis-stimulating agents on iron metabolism in patients on hemodialysis. Ther Apher Dial. 2015;19:582–9.

    CAS  PubMed  Google Scholar 

  40. 40.

    Takasawa K, Takaeda C, Maeda T, Ueda N. Hepcidin-25, mean corpuscular volume, and ferritin as predictors of response to oral iron supplementation in hemodialysis patients. Nutrients. 2014;7:103–18.

    PubMed  PubMed Central  Google Scholar 

  41. 41.

    Maruyama Y, Yokoyama K, Yokoo T, Shigematsu T, Iseki K, Tsubakihara Y. The different association between serum ferritin and mortality in hemodialysis and peritoneal dialysis patients using Japanese nationwide dialysis registry. PLoS ONE. 2015;10:e0143430. https://doi.org/10.1371/journal.pone.0143430.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Trincavelli ML, Da Pozzo E, Ciampi O, et al. Regulation of erythropoietin receptor activity in endothelial cells by different erythropoietin (EPO) derivatives: an in vitro study. Int J Mol Sci. 2013;14:2258–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Westenbrink BD, Ruifrok WP, Voors AA, et al. Vascular endothelial growth factor is crucial for erythropoietin-induced improvement of cardiac function in heart failure. Cardiovasc Res. 2010;87:30–9.

    CAS  PubMed  Google Scholar 

  44. 44.

    Li Y, Ogle ME, Wallace GC IV, Lu ZY, Yu SP, Wei L. Erythropoietin attenuates intracerebral hemorrhage by diminishing matrix metalloproteinases and maintaining blood-brain barrier integrity in mice. Acta Neurochir Suppl. 2008;105:105–12.

    CAS  PubMed  Google Scholar 

  45. 45.

    Yeh KH, Tsai TH, Chai HT, et al. Comparison of acute versus convalescent stage high-sensitivity C-reactive protein level in predicting clinical outcome after acute ischemic stroke and impact of erythropoietin. J Transl Med. 2012;10:6. https://doi.org/10.1186/1479-5876-10-6.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Vacek TP, Rehman S, Neamtu D, Yu S, Givimani S, Tyagi SC. Matrix metalloproteinases in atherosclerosis: role of nitric oxide, hydrogen sulfide, homocysteine, and polymorphisms. Vasc Health Risk Manag. 2015;11:173–83.

    PubMed  PubMed Central  Google Scholar 

  47. 47.

    Chan CY, Chen YS, Lee HH, et al. Erythropoietin protects post-ischemic hearts by preventing extracellular matrix degradation: role of Jak2-ERK pathway. Life Sci. 2007;81:717–23.

    CAS  PubMed  Google Scholar 

  48. 48.

    Pfeffer MA, Burdmann EA, Chen CY, et al. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med. 2009;361:2019–32.

    PubMed  Google Scholar 

Download references

Funding

This study was supported in part by grants from the Kidney Foundation of Japan (grant number JKFB 17-7 (2017–2019)), and also by research funds from the Japanese Ministry of Health, Labor and Welfare (2015–2017).

Author information

Affiliations

Authors

Corresponding author

Correspondence to Takashi Naito.

Ethics declarations

Conflict of interest

The authors have declared that no conflict of interest exists.

Ethical approval

The study was a conducted in accordance with the Declaration of Helsinki and was approved by the independent Ethics Committee of Tokyo Women’s Medical University (No. 1135) and Tokyo Rosai Hospital (No. 2414).

Informed consent

Informed consent was obtained from all individuals participants included in the study.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

About this article

Verify currency and authenticity via CrossMark

Cite this article

Naito, T., Shun, M., Nishimura, H. et al. Pleiotropic effect of erythropoiesis-stimulating agents on circulating endothelial progenitor cells in dialysis patients. Clin Exp Nephrol (2021). https://doi.org/10.1007/s10157-021-02071-2

Download citation

Keywords

  • Erythropoiesis-stimulating agents
  • Endothelial progenitor cells
  • Recombinant human erythropoietin
  • Darbepoetin
  • Epoetin β pegol