Skip to main content

Advertisement

SpringerLink
Log in

Association between hyporesponsiveness to erythropoiesis-stimulating agents and risk of brain hemorrhage in patients undergoing hemodialysis: the Q-Cohort Study

  • Original article
  • Published:
Clinical and Experimental Nephrology Aims and scope Submit manuscript

Abstract

Background

Hyporesponsiveness to erythropoiesis-stimulating agents (ESAs) is associated with increased risks of all cause and cardiovascular mortality in patients undergoing hemodialysis (HD). However, the impact of the hematopoietic response to ESAs on the development of stroke, including brain hemorrhage and infarction, remains unclear.

Methods

In total, 2886 patients undergoing maintenance HD registered in the Q-Cohort Study who were treated with ESAs were prospectively followed up for 4 years. The hematopoietic response to ESAs was evaluated by the erythropoietin resistance index (ERI), calculated by dividing the weekly dose of ESA by post-HD weight and hemoglobin (U/kg/week/g/dL). The primary outcomes were the incidences of brain hemorrhage and infarction. Patients were divided into quartiles based on their ERI at baseline (Q1, ≤ 4.1; Q2, 4.2–7.0; Q3, 7.1–11.2; and Q4, ≥ 11.3). The risks of brain hemorrhage and infarction were estimated using Cox proportional hazards models, adjusting for potential confounders.

Results

During the 4 year follow-up period, 71 patients developed brain hemorrhage and 116 developed brain infarction. In the multivariable analysis, the incidence of brain hemorrhage in the highest quartile (Q4) was significantly higher than that in the lowest quartile (Q1) (hazard ratio [95% confidence interval], 2.18 [1.08–4.42]). However, the association between the ERI and the incidence of brain infarction was not significant.

Conclusions

A higher ERI was associated with an increased risk of brain hemorrhage, but not brain infarction, in patients undergoing maintenance HD. A high ERI is thus an important risk factor for brain hemorrhage in these patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Seliger SL, Gillen DL, Longstreth WT, Kestenbaum B, Stehman-Breen CO. Elevated risk of stroke among patients with end-stage renal disease. Kidney Int. 2003;64:603–9.

    Article  Google Scholar 

  2. Yahalom G, Schwartz R, Schwammenthal Y, Merzeliak O, Toashi M, Orion D, et al. Chronic kidney disease and clinical outcome in patients with acute stroke. Stroke. 2009;40:1296–303.

    Article  Google Scholar 

  3. Babitt JL, Lin HY. Mechanisms of anemia in CKD. J Am Soc Nephrol. 2012;23:1631–4.

    Article  CAS  Google Scholar 

  4. Eschbach JW, Abdulhadi MH, Browne JK, Delano BG, Downing MR, Egrie JC, et al. Recombinant human erythropoietin in anemic patients with end-stage renal disease. Results of a phase III multicenter clinical trial. Ann Intern Med. 1989;111:992–1000.

    Article  CAS  Google Scholar 

  5. Kalantar-Zadeh K, Lee GH, Miller JE, Streja E, Jing J, Robertson JA, et al. Predictors of hyporesponsiveness to erythropoiesis-stimulating agents in hemodialysis patients. Am J Kidney Dis. 2009;53:823–34.

    Article  CAS  Google Scholar 

  6. Eriguchi R, Taniguchi M, Ninomiya T, Hirakata H, Fujimi S, Tsuruya K, et al. Hyporesponsiveness to erythropoiesis-stimulating agent as a prognostic factor in Japanese hemodialysis patients: the Q-Cohort study. J Nephrol. 2015;28:217–25.

    Article  CAS  Google Scholar 

  7. López-Gómez JM, Portolés JM, Aljama P. Factors that condition the response to erythropoietin in patients on hemodialysis and their relation to mortality. Kidney Int. 2008;74:75–81.

    Article  Google Scholar 

  8. Pfeffer MA, Burdmann EA, Chen C-Y, Cooper ME, de Zeeuw D, Eckardt K, et al. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med. 2009;361:2019–32.

    Article  Google Scholar 

  9. Solomon SD, Uno H, Lewis EF, Eckardt K-U, Lin J, Burdmann EA, et al. Erythropoietic response and outcomes in kidney disease and type 2 diabetes. N Engl J Med. 2010;363:1146–55.

    Article  CAS  Google Scholar 

  10. Yamada S, Tsuruya K, Taniguchi M, Tokumoto M, Fujisaki K, Hirakata H, et al. Association between serum phosphate levels and stroke risk in patients undergoing hemodialysis: the Q-Cohort Study. Stroke. 2016;47:2189–96.

    Article  CAS  Google Scholar 

  11. Tanaka S, Ninomiya T, Taniguchi M, Fujisaki K, Tokumoto M, Hirakata H, et al. Comparison of oral versus intravenous vitamin D receptor activator in reducing infection-related mortality in hemodialysis patients: the Q-Cohort Study. Nephrol Dial Transplant. 2016;31:1152–60.

    Article  CAS  Google Scholar 

  12. Yotsueda R, Taniguchi M, Tanaka S, Eriguchi M, Fujisaki K, Torisu K, et al. Cardiothoracic ratio and all-cause mortality and cardiovascular disease events in hemodialysis patients: the Q-Cohort Study. Am J Kidney Dis. 2017;70:84–92.

    Article  Google Scholar 

  13. Payne RB, Little AJ, Williams RB, Milner JR. Interpretation of serum calcium in patients with abnormal serum proteins. Br Med J. 1973;4:643–6.

    Article  CAS  Google Scholar 

  14. Singh AK, Szczech L, Tang KL, Barnhart H, Sapp S, Wolfson M, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 2006;355:2085–98.

    Article  CAS  Google Scholar 

  15. Drüeke TB, Locatelli F, Clyne N, Eckardt K-U, Macdougall IC, Tsakiris D, et al. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med. 2006;355:2071–84.

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  17. 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.

    Article  CAS  Google Scholar 

  18. Cranenburg ECM, Schurgers LJ, Uiterwijk HH, Beulens JWJ, Dalmeijer GW, Westerhuis R, et al. Vitamin K intake and status are low in hemodialysis patients. Kidney Int. 2012;82:605–10.

    Article  CAS  Google Scholar 

  19. Shearer MJ, Fu X, Booth SL. Vitamin K nutrition, metabolism, and requirements: current concepts and future research. Adv Nutr. 2012;3:182–95.

    Article  CAS  Google Scholar 

  20. Sturgeon JD, Folsom AR, Longstreth WT, Shahar E, Rosamond WD, Cushman M. Hemostatic and inflammatory risk factors for intracerebral hemorrhage in a pooled cohort. Stroke. 2008;39:2268–73.

    Article  Google Scholar 

  21. Pavese I, Satta F, Todi F, Di Palma M, Piergrossi P, Migliore A, et al. High serum levels of TNF-α and IL-6 predict the clinical outcome of treatment with human recombinant erythropoietin in anaemic cancer patients. Ann Oncol. 2010;21:1523–8.

    Article  CAS  Google Scholar 

  22. Roche M, Rondeau P, Singh NR, Tarnus E, Bourdon E. The antioxidant properties of serum albumin. FEBS Lett. 2008;582:1783–7.

    Article  CAS  Google Scholar 

  23. Li B, Wang Z, Hong J, Che Y, Chen R, Hu Z, et al. Iron deficiency promotes aortic medial degeneration via destructing cytoskeleton of vascular smooth muscle cells. Clin Transl Med. 2021;11: e276.

    CAS  Google Scholar 

  24. Stenvinkel P, Heimbürger O, Paultre F, Diczfalusy U, Wang T, Berglund L, et al. Strong association between malnutrition, inflammation, and atherosclerosis in chronic renal failure. Kidney Int. 1999;55:1899–911.

    Article  CAS  Google Scholar 

  25. Iseki K, Fukiyama K. Predictors of stroke in patients receiving chronic hemodialysis. Kidney Int. 1996;50:1672–5.

    Article  CAS  Google Scholar 

  26. Seliger SL, Gillen DL, Tirschwell D, Wasse H, Kestenbaum BR, Stehman-Breen CO. Risk factors for incident stroke among patients with end-stage renal disease. J Am Soc Nephrol. 2003;14:2623–31.

    Article  Google Scholar 

Download references

Acknowledgements

We appreciate the contribution of the participants in the Q-Cohort Study, members of the Society for the Study of Kidney Disease. The following personnel (institutions) participated in the study: Takashi Ando (Hakozaki Park Internal Medicine Clinic), Takashi Ariyoshi (Ariyoshi Clinic), Koichiro Goto (Goto Clinic), Fumitada Hattori (Nagao Hospital), Harumichi Higashi (St Mary’s Hospital), Tadashi Hirano (Hakujyuji Hospital), Kei Hori (Munakata Medical Association Hospital), Takashi Inenaga (Ekisaikai Moji Hospital), Hidetoshi Kanai (Kokura Memorial Hospital), Shigemi Kiyama (Kiyama Naika), Tetsuo Komota (Komota Clinic), Hiromasa Kuma (Kuma Clinic), Toshiro Maeda (Kozenkai-Maeda Hospital), Junichi Makino (Makino Clinic), Dai Matsuo (Hirao Clinic), Chiaki Miishima (Miishima Clinic), Koji Mitsuiki (Japanese Red Cross Fukuoka Hospital), Kenichi Motomura (Motomura Naika Clinic), Sadatoshi Nakamura, Hidetoshi Nakamura (Kokura Daiichi Hospital), Koichi Nakashima (Ohashi Internal Circulatory Clinic), Nobumitsu Okita (Shiroishi Kyoritsu Hospital), Shinichiro Osato (Osato Jin Clinic), Sakura Sakamoto (Fujiyamato Spa Hospital), Keiko Shigematsu (Shigematsu Clinic), Kazumasa Shimamatsu (Shimamatsu Naika Iin), Yoshito Shogakiuchi (Shin-Ai Clinic), Hiroaki Takamura (Hara Hospital), Kazuhito Takeda (Iizuka Hospital), Asuka Terai (Chidoribashi Hospital), Hideyoshi Tanaka (Mojiko-Jin Clinic), Suguru Tomooka (Hakozaki Park Internal Medicine Clinic), Jiro Toyonaga (Fukuoka Renal Clinic), Hiroshi Tsuruta (Steel Memorial Yawata Hospital), Ryutaro Yamaguchi (Shiseikai Hospital), Taihei Yanagida (Saiseikai Yahata General Hospital), Tetsuro Yanase (Yanase Internal Medicine Clinic), Tetsuhiko Yoshida (Hamanomachi Hospital), Takahiro Yoshimitsu (Gofukumachi Kidney Clinic, Harasanshin Hospital) and Koji Yoshitomi (Yoshitomi Medical Clinic). We also thank Angela Morben, DVM, ELS, from Edanz (https://jp.edanz.com/ac), for editing a draft of this manuscript.

Funding

This study was supported by the Kidney Foundation (H19 JKFB 07-13, H20 JKFB 08-8, H23 JKFB 11-11) and the Japan Dialysis Outcome Research Foundation (H19-076-02, H20-003).

Author information

Authors and Affiliations

  1. Division of Internal Medicine, Fukuoka Dental College, Fukuoka, Japan

    Yushi Uchida

  2. Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan

    Yushi Uchida, Toshiaki Nakano, Hiromasa Kitamura & Takanari Kitazono

  3. Fukuoka Renal Clinic, Fukuoka, Japan

    Masatomo Taniguchi

  4. Department of Nephrology, Nara Medical University, Nara, Japan

    Kazuhiko Tsuruya

Authors
  1. Yushi Uchida
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Toshiaki Nakano
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hiromasa Kitamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Masatomo Taniguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kazuhiko Tsuruya
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Takanari Kitazono
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

YU: contributed to the study design, statistical analysis, data interpretation and drafting of the article. TN: contributed to the statistical analysis, data interpretation and drafting of the article. HK: contributed to the statistical analysis and data interpretation. MT: contributed to the data acquisition and critical revision of the article. KT: contributed to the funding, data acquisition and critical revision of the article. TK: contributed to critical revision of the article and supervision of the study. All authors provided critical reviews of the draft and approved the final version.

Corresponding author

Correspondence to Toshiaki Nakano.

Additional information

Publisher's Note

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

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 222 KB)

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Uchida, Y., Nakano, T., Kitamura, H. et al. Association between hyporesponsiveness to erythropoiesis-stimulating agents and risk of brain hemorrhage in patients undergoing hemodialysis: the Q-Cohort Study. Clin Exp Nephrol 27, 79–88 (2023). https://doi.org/10.1007/s10157-022-02278-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10157-022-02278-x

Keywords

Search

Navigation