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Relationship between anti-erythropoietin receptor autoantibodies and responsiveness to erythropoiesis-stimulating agents in patients on hemodialysis: a multi-center cross-sectional study

  • Akinori HaraEmail author
  • Yoshitaka Koshino
  • Yukie Kurokawa
  • Yasuyuki Shinozaki
  • Taito Miyake
  • Shinji Kitajima
  • Tadashi Toyama
  • Yasunori Iwata
  • Norihiko Sakai
  • Miho Shimizu
  • Kengo Furuichi
  • Hiroyuki Nakamura
  • Takashi Wada
Original article
  • 57 Downloads

Abstract

Background

A decreased response to erythropoiesis-stimulating agents (ESAs) leads to refractory anemia and worse prognosis in patients with chronic kidney disease. We examined the association between autoantibodies to the erythropoietin receptor (EPOR) and responsiveness to ESAs in patients on maintenance hemodialysis.

Methods

A total of 108 Japanese patients on maintenance hemodialysis at three institutions were enrolled. Sera from these patients were screened for anti-EPOR antibodies using an enzyme-linked immunosorbent assay. An ESA resistance index (ERI) was calculated, and patients in the highest ERI quartile were defined as ESA hyporesponsive.

Results

Anti-EPOR antibodies were detected in 11 patients (10%). Body mass index and hemoglobin, platelet, magnesium, and ferritin levels decreased with higher ERI levels. On the other hand, C-reactive protein (CRP) levels and the prevalence of anti-EPOR antibodies increased with higher ERI levels. In multivariate analysis, the presence of anti-EPOR antibodies together with CRP was a significant risk factor for ESA hyporesponsiveness.

Conclusions

Anti-EPOR antibodies were detected in patients on maintenance hemodialysis, and these autoantibodies were independent factors for hyporesponsiveness to ESAs in these patients.

Keywords

Erythropoiesis-stimulating agents Erythropoietin receptor Autoantibodies Anemia Hemodialysis 

Notes

Acknowledgements

We thank Hiroka Yamazaki, Yoshiko Isaki, and Mayumi Fukuta for their assistance with data collection.

Funding

This work was supported by a grant from The Kidney Foundation, Japan (number JKFB17-3) and the Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research (JSPS KAKENHI) Grant number JP16K09608.

Compliance with ethical standards

Conflict of interest

All the authors have declared no competing interest.

Ethical approval

All the procedures performed in studies involving human participants were in accordance with the ethical standards of the medical ethics committee of Kanazawa University at which the studies were conducted (approval number 1590) and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

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

References

  1. 1.
    Macdougall IC, Cooper AC. Erythropoietin resistance: the role of inflammation and pro-inflammatory cytokines. Nephrol Dial Transplant. 2002;17:39–433.CrossRefGoogle Scholar
  2. 2.
    Luo J, Jensen DE, Maroni BJ, Brunelli SM. Spectrum and burden of erythropoiesis-stimulating agent hyporesponsiveness among contemporary hemodialysis patients. Am J Kidney Dis. 2016;68:763–71.CrossRefGoogle Scholar
  3. 3.
    Yamamoto H, Nishi S, Tomo T, Masakane I, Saito K, Nangaku M, et al. 2015 Japanese Society for dialysis therapy: guidelines for renal anemia in chronic kidney disease. Renal Replace Ther. 2017;3:36.CrossRefGoogle Scholar
  4. 4.
    KDIGO. Chapter 3: use of ESAs and other agents to treat anemia in CKD. Kidney Int Suppl. 2012;2:299–310.CrossRefGoogle Scholar
  5. 5.
    Hara A, Furuichi K, Higuchi M, Iwata Y, Sakai N, Kaneko S, et al. Autoantibodies to erythropoietin receptor in patients with immune-mediated diseases: relationship to anaemia with erythroid hypoplasia. Br J Haematol. 2013;160:244–50.CrossRefGoogle Scholar
  6. 6.
    Koibuchi K, Miyagi M, Arai T, Aoki T, Aikawa A, Sakai K. Comparing the efficacy of continuous erythropoietin receptor activator and darbepoetin Alfa treatments in Japanese patients with chronic kidney disease during the predialysis period: a propensity-matched analysis. Nephrology. 2015;20:22–8.CrossRefGoogle Scholar
  7. 7.
    Daugirdas JT. The post: pre-dialysis plasma urea nitrogen ratio to estimate K.t/V and NPCR: mathematical modeling. Int J Artif Organs. 1989;12:411–9.Google Scholar
  8. 8.
    Okamoto T, Hatakeyama S, Tanaka Y, Imanishi K, Takashima T, Saitoh F, et al. Butyrylcholinesterase level as an independent factor of erythropoiesis-stimulating agent resistance in patients on maintenance hemodialysis: a single-center cross-sectional study. Clin Exp Nephrol. 2018;22:1174–81.CrossRefGoogle Scholar
  9. 9.
    Schwarzbeck A, Wittenmeier KW, Hällfritzsch U. Anaemia in dialysis patients as a side-effect of sartanes. Lancet. 1998;352:286.CrossRefGoogle Scholar
  10. 10.
    Hara A, Furuichi K, Yamahana J, Yasuda H, Iwata Y, Sakai N, et al. Effect of autoantibodies to erythropoietin receptor in systemic lupus erythematosus with biopsy-proven lupus nephritis. J Rheumatol. 2016;43:1328–34.CrossRefGoogle Scholar
  11. 11.
    Hara A, Furuichi K, Koshino A, Yasuda H, Tran T, Iwata Y, et al. Clinical and pathological significance of autoantibodies to erythropoietin receptor in type 2 diabetic patients with CKD. Kidney Int Rep. 2017;3:133–41.CrossRefGoogle Scholar
  12. 12.
    Bradbury BD, Critchlow CW, Weir MR, Stewart R, Krishnan M, Hakim RH. Impact of elevated C-reactive protein levels on erythropoiesis- stimulating agent (ESA) dose and responsiveness in hemodialysis patients. Nephrol Dial Transplant. 2009;24:919–25.CrossRefGoogle Scholar
  13. 13.
    Rattanasompattikul M, Molnar MZ, Zaritsky JJ, Hatamizadeh P, Jing J, Norris KC, et al. Association of malnutrition-inflammation complex and responsiveness to erythropoiesis-stimulating agents in long-term hemodialysis patients. Nephrol Dial Transplant. 2013;28:1936–45.CrossRefGoogle Scholar
  14. 14.
    Chen Y, Abbate M, Tang L, Cai G, Gong Z, Wei R, et al. L-Carnitine supplementation for adults with end-stage kidney disease requiring maintenance hemodialysis: a systematic review and meta-analysis. Am J Clin Nutr. 2014;99:408–22.CrossRefGoogle Scholar
  15. 15.
    Biesalski HK. Parenteral ascorbic acid in haemodialysis patients. Curr Opin Clin Nutr Metab Care. 2008;11:741–6.CrossRefGoogle Scholar
  16. 16.
    Rusu A, Rusu F, Zalutchi D, Muresan A, Gherman Caprioara M, Kacso I. The influence of vitamin E supplementation on erythropoietin responsiveness in chronic hemodialysis patients with low levels of erythrocyte superoxide dismutase. Int Urol Nephrol. 2013;45:495–501.CrossRefGoogle Scholar
  17. 17.
    Kobayashi H, Abe M, Okada K, Tei R, Maruyama N, Kikuchi F, et al. Oral zinc supplementation reduces the erythropoietin responsiveness index in patients on hemodialysis. Nutrients. 2015;7:3783–95.CrossRefGoogle Scholar
  18. 18.
    Higuchi T, Matsukawa Y, Okada K, Oikawa O, Yamazaki T, Ohnishi Y, et al. Correction of copper deficiency improves erythropoietin unresponsiveness in hemodialysis patients with anemia. Intern Med. 2006;45:271–3.CrossRefGoogle Scholar
  19. 19.
    Altura BM, Altura BT. Role of magnesium in patho-physiological processes and the clinical utility of magnesium ion selective electrodes. Scand J Clin Lab Investig Suppl. 1996;224:211–34.CrossRefGoogle Scholar
  20. 20.
    Sakaguchi Y, Fujii N, Shoji T, Hayashi T, Rakugi H, Isaka Y. Hypomagnesemia is a significant predictor of cardiovascular and non-cardiovascular mortality in patients undergoing hemodialysis. Kidney Int. 2014;85:174–81.CrossRefGoogle Scholar
  21. 21.
    Allegra A, Corica F, Ientile R, Naso A, Corsonello A, Montalto G, et al. Effect of intravenous recombinant erythropoietin administration on plasma and erythrocyte magnesium concentrations in patients on hemodialysis. Nephron. 1996;74:499–500.CrossRefGoogle Scholar
  22. 22.
    Drüeke TB, Parfrey PS. Summary of the KDIGO guideline on anemia and comment: reading between the (guide)line(s). Kidney Int. 2012;82:952–60.CrossRefGoogle Scholar

Copyright information

© Japanese Society of Nephrology 2019

Authors and Affiliations

  • Akinori Hara
    • 1
    • 2
    Email author
  • Yoshitaka Koshino
    • 3
  • Yukie Kurokawa
    • 3
  • Yasuyuki Shinozaki
    • 4
    • 5
  • Taito Miyake
    • 1
    • 4
  • Shinji Kitajima
    • 1
    • 4
  • Tadashi Toyama
    • 1
    • 4
  • Yasunori Iwata
    • 1
    • 4
  • Norihiko Sakai
    • 1
    • 4
  • Miho Shimizu
    • 1
    • 4
  • Kengo Furuichi
    • 1
  • Hiroyuki Nakamura
    • 2
  • Takashi Wada
    • 1
    • 4
  1. 1.Division of NephrologyKanazawa University HospitalKanazawaJapan
  2. 2.Department of Environmental and Preventive Medicine, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health SciencesKanazawa UniversityKanazawaJapan
  3. 3.Department of Internal MedicineMizuho HospitalKahokuJapan
  4. 4.Department of Nephrology and Laboratory Medicine, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health SciencesKanazawa UniversityKanazawaJapan
  5. 5.Department of NephrologyKanazawa Medical CenterKanazawaJapan

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