High Erythropoiesis Resistance Index Is a Significant Predictor of Cardiovascular and All-Cause Mortality in Chinese Maintenance Hemodialysis Patients

Xiangxue Lu, Jialing Zhang, Shixiang Wang, Qian Yu, Han Li, Xiangxue Lu, Jialing Zhang, Shixiang Wang, Qian Yu, Han Li

Abstract

Background: Renal anemia is a common complication of hemodialysis patients. Erythropoietin (EPO) hyporesponsiveness has been recognized as an important factor to poor efficacy of recombinant human erythropoietin in the treatment of renal anemia. More importantly, increased erythropoiesis resistance index (ERI) may be associated with inflammation and increased mortality.

Objective: The objective of this research was to investigate correlated factors of EPO responsiveness and to clarify the relationships between EPO hyporesponsiveness and cardiovascular mortality and all-cause mortality among maintenance hemodialysis patients.

Methods: This prospective cohort study enrolled 276 maintenance hemodialysis patients for a 55-month follow-up to investigate the factors related to ERI and its relationship to all-cause mortality and cardiovascular mortality.

Results: ERI was positively correlated with predialysis serum high-sensitivity C-reactive protein (r = 0.234, p < 0.001), alkaline phosphatase (r = 0.134, p = 0.028), and ferritin (r = 0.155, p = 0.010) and negatively correlated with albumin (r = -0.206, p < 0.001) and creatinine (r = -0.232, p < 0.001). As multiple linear regression showed, predialysis serum albumin, high-sensitivity C-reactive protein, ferritin, and creatinine were independent correlated factors of ERI (p < 0.05). Kaplan-Meier curves showed that the cumulative incidences of both cardiovascular mortality and all-cause mortality were significantly higher in patients with ERI > 11.04 IU/kg/w/g/dL (both p < 0.01). The high ERI group was significantly associated with higher risk for all-cause mortality (OR 1.781, 95% CI 1.091 to 2.910, p = 0.021) and cardiovascular mortality (OR 1.972, 95% CI 1.139 to 3.417, p = 0.015) after adjusting for confounders.

Conclusions: Predialysis serum albumin, high-sensitivity C-reactive protein, ferritin, and creatinine were independent correlated factors of EPO responsiveness among maintenance hemodialysis patients. Patients with higher ERI values had a higher all-cause mortality rate and cardiovascular mortality rate.

Conflict of interest statement

The authors declare that there is no conflict of interest regarding the publication of this article.

Copyright © 2020 Xiangxue Lu et al.

Figures

Figure 1
Figure 1
Kaplan–Meier plots for all-cause mortality and cardiovascular mortality in MHD patients. (a) Patients with ERI > 11.04 had significantly higher all-cause mortality (log rank = 6.719; p < 0.01). (b) Patients with ERI > 11.04 had significantly higher cardiovascular mortality (log rank = 7.800; p < 0.01).

References

    1. Li Y., Shi H., Wang W.-M., et al. Prevalence, awareness, and treatment of anemia in Chinese patients with nondialysis chronic kidney disease: first multicenter, cross-sectional study. Medicine (Baltimore) 2016;95(24, article e3872) doi: 10.1097/MD.0000000000003872.
    1. Suzuki M., Hada Y., Akaishi M., et al. Effects of anemia correction by erythropoiesis-stimulating agents on cardiovascular function in non-dialysis patients with chronic kidney disease. International Heart Journal. 2012;53(4):238–243. doi: 10.1536/ihj.53.238.
    1. Hauber B., Caloyeras J., Posner J., Brommage D., Tzivelekis S., Pollock A. Hemodialysis patients’ preferences for the management of anemia. BMC Nephrology. 2017;18(1):p. 253. doi: 10.1186/s12882-017-0664-9.
    1. Mikhail A., Brown C., Williams J. A., et al. Renal association clinical practice guideline on anaemia of chronic kidney disease. BMC Nephrology. 2017;18(1):p. 345. doi: 10.1186/s12882-017-0688-1.
    1. Kim I. Y., Kim J. H., Kim M. J., et al. Low 1,25-dihydroxyvitamin D level is associated with erythropoietin deficiency and endogenous erythropoietin resistance in patients with chronic kidney disease. International Urology and Nephrology. 2018;50(12):2255–2260. doi: 10.1007/s11255-018-1967-x.
    1. Marcelli D., Bayh I., Merello J. I., et al. Dynamics of the erythropoiesis stimulating agent resistance index in incident hemodiafiltration and high-flux hemodialysis patients. Kidney International. 2016;90(1):192–202. doi: 10.1016/j.kint.2016.03.009.
    1. OGAWA T., NITTA K. Erythropoiesis-stimulating agent hyporesponsiveness in end-stage renal disease patients. Contributions to Nephrology. 2015;185:76–86. doi: 10.1159/000380972.
    1. Koulouridis I., Alfayez M., Trikalinos T. A., Balk E. M., Jaber B. L. Dose of erythropoiesis-stimulating agents and adverse outcomes in CKD: a metaregression analysis. American Journal of Kidney Diseases. 2013;61(1):44–56. doi: 10.1053/j.ajkd.2012.07.014.
    1. Chung S., Song H. C., Shin S. J., et al. Relationship between erythropoietin resistance index and left ventricular mass and function and cardiovascular events in patients on chronic hemodialysis. Hemodialysis International. 2012;16(2):181–187. doi: 10.1111/j.1542-4758.2011.00644.x.
    1. Okazaki M., Komatsu M., Kawaguchi H., Tsuchiya K., Nitta K. Erythropoietin resistance index and the all-cause mortality of chronic hemodialysis patients. Blood Purification. 2014;37(2):106–112. doi: 10.1159/000358215.
    1. Iio K., Kabata D., Iio R., et al. Parathyroid hormone and premature thymus ageing in patients with chronic kidney disease. Scientific Reports. 2019;9(1):p. 813. doi: 10.1038/s41598-018-37511-9.
    1. FISHBANE S., BERNS J. S. Hemoglobin cycling in hemodialysis patients treated with recombinant human erythropoietin. Kidney International. 2005;68(3):1337–1343. doi: 10.1111/j.1523-1755.2005.00532.x.
    1. Nangaku M. Pathogenesis and treatment of anemia in chronic kidney disease. Rinshō Ketsueki. 2017;58(10):1860–1863. doi: 10.11406/rinketsu.58.1860.
    1. FISHBANE S., SPINOWITZ B. Update on anemia in ESRD and earlier stages of CKD: core curriculum 2018. American Journal of Kidney Diseases. 2018;71(3):423–435. doi: 10.1053/j.ajkd.2017.09.026.
    1. Bamgbola O. Resistance to erythropoietin-stimulating agents: etiology, evaluation, and therapeutic considerations. Pediatric Nephrology. 2012;27(2):195–205. doi: 10.1007/s00467-011-1839-4.
    1. Coyne D. It’s time to compare anemia management strategies in hemodialysis. Clinical Journal of the American Society of Nephrology. 2010;5(4):740–742. doi: 10.2215/CJN.02490409.
    1. Kharagjitsingh A. V., Korevaar J. C., Vandenbroucke J. A. N. P., et al. Incidence of recombinant erythropoietin (EPO) hyporesponse, EPO-associated antibodies, and pure red cell aplasia in dialysis patients. Kidney International. 2005;68(3):1215–1222. doi: 10.1111/j.1523-1755.2005.00514.x.
    1. Kim J. K., Park B. S., Park M. J., et al. The predictive parameters of erythropoietin hyporesponsiveness in patients on continuous ambulatory peritoneal dialysis. The Korean Journal of Internal Medicine. 2001;16(2):110–117. doi: 10.3904/kjim.2001.16.2.110.
    1. Cozzolino M., Mangano M., Stucchi A., Ciceri P., Conte F., Galassi A. Cardiovascular disease in dialysis patients. Nephrol Dial Transplant. 2018;33(supplement_3):iii28–iii34.
    1. Locatelli F., Andrulli S., Memoli B., et al. Nutritional-inflammation status and resistance to erythropoietin therapy in haemodialysis patients. Nephrology, Dialysis, Transplantation. 2006;21(4):991–998. doi: 10.1093/ndt/gfk011.
    1. Kalantar-Zadeh K., Lee G. H., Miller J. E., et al. Predictors of hyporesponsiveness to erythropoiesis-stimulating agents in hemodialysis patients. American Journal of Kidney Diseases. 2009;53(5):823–834. doi: 10.1053/j.ajkd.2008.12.040.
    1. Karaboyas A., Morgenstern H., Pisoni R. L., et al. Association between serum ferritin and mortality: findings from the USA, Japan and European Dialysis Outcomes and Practice Patterns Study. Nephrology, Dialysis, Transplantation. 2018;33(12):2234–2244. doi: 10.1093/ndt/gfy190.
    1. Simmen S., Cosin-Roger J., Melhem H., et al. Iron prevents hypoxia-associated inflammation through the regulation of nuclear factor-κB in the intestinal epithelium. Cellular and Molecular Gastroenterology and Hepatology. 2019;7(2):339–355. doi: 10.1016/j.jcmgh.2018.10.006.
    1. Zarjou A., Black L. M., McCullough K. R., et al. Ferritin light chain confers protection against sepsis-induced inflammation and organ injury. Frontiers in Immunology. 2019;10:p. 131. doi: 10.3389/fimmu.2019.00131.
    1. Gotsman I., Shauer A., Zwas D. R., Tahiroglu I., Lotan C., Keren A. Low serum albumin: a significant predictor of reduced survival in patients with chronic heart failure. Caspian Journal of Internal Medicine. 2019;42(3):365–372. doi: 10.1002/clc.23153.
    1. Antunes S. Hypoalbuminemia seems to be associated with a higher rate of hospitalization in hemodialysis patients. Jornal Brasileiro de Nefrologia. 2016;38(1):70–75. doi: 10.5935/0101-2800.20160011.
    1. Katalinic L., Premuzic V., Basic-Jukic N., Barisic I., Jelakovic B. Hypoproteinemia as a factor in assessing malnutrition and predicting survival on hemodialysis. Journal of Artificial Organs. 2019;22(3):230–236. doi: 10.1007/s10047-019-01098-3.
    1. Walther C. Interdialytic creatinine change versus predialysis creatinine as indicators of nutritional status in maintenance hemodialysis. Nephrology, Dialysis, Transplantation. 2012;27(2):771–776. doi: 10.1093/ndt/gfr389.
    1. Park J., Mehrotra R., Rhee C. M., et al. Serum creatinine level, a surrogate of muscle mass, predicts mortality in peritoneal dialysis patients. Nephrology, Dialysis, Transplantation. 2013;28(8):2146–2155. doi: 10.1093/ndt/gft213.
    1. Roetker N. S., Peng Y., Ashfaq A., Gilbertson D. T., Wetmore J. B. Adherence to kidney disease: improving global outcomes mineral and bone guidelines for monitoring biochemical parameters. American Journal of Nephrology. 2019;49(3):225–232. doi: 10.1159/000497477.
    1. BRANCACCIO D., COZZOLINO M., GALLIENI M. Hyperparathyroidism and anemia in uremic subjects: a combined therapeutic approach. J Am Soc Nephrol. 2004;15(90010):21S–224. doi: 10.1097/01.ASN.0000093369.09194.12.
    1. KIDNEY DISEASE: IMPROVING GLOBAL OUTCOMES C K D M B D U W G. KDIGO 2017 Clinical practice guideline update for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD) Kidney International Supplements. 2017;7(1):1–59.
    1. Fukuma S., Yamaguchi T., Hashimoto S., et al. Erythropoiesis-stimulating agent responsiveness and mortality in hemodialysis patients: results from a cohort study from the dialysis registry in Japan. American Journal of Kidney Diseases. 2012;59(1):108–116. doi: 10.1053/j.ajkd.2011.07.014.
    1. Schneider A., Gutjahr-Lengsfeld L., Ritz E., et al. Longitudinal assessments of erythropoietin-stimulating agent responsiveness and the association with specific clinical outcomes in dialysis patients. Nephron. Clinical Practice. 2014;128(1-2):147–152. doi: 10.1159/000367975.
    1. Ogawa T., Shimizu H., Kyono A., et al. Relationship between responsiveness to erythropoiesis-stimulating agent and long-term outcomes in chronic hemodialysis patients: a single-center cohort study. International Urology and Nephrology. 2014;46(1):151–159. doi: 10.1007/s11255-013-0494-z.

Source: PubMed

3
Abonneren