Erythropoietin Resistance Increases Risk of Mortality in Patients with Anemia, CKD

Erythropoietin resistance may be associated with a greater risk of all-cause mortality in patients receiving maintenance hemodialysis, according to findings from a recent study.

An indicator of hematopoietic response to erythropoiesis-stimulating agents used to treat anemia in chronic kidney disease (CKD), erythropoietin resistance index was significantly influenced by patients’ dialysis vintage, white blood cell count, flux dialyzer use, body mass index, sex, and albumin levels.¹

“Some patients with erythropoiesis-stimulating agent hyporesponsiveness, which is called erythropoietin resistance, require the use of erythropoiesis-stimulating agents at doses higher than usual to maintain the recommended hemoglobin concentration,” wrote investigators.¹ “Evidence of increased cardiovascular risks, mortality and other adverse outcomes regarding erythropoiesis-stimulating agent hyporesponsiveness has been observed in hemodialysis patients.”

A condition in which blood does not produce enough hemoglobin, anemia is common in people with CKD and is especially prevalent among those with advanced disease. More than 37 million adults in the US are estimated to have CKD, and as many as 1 out of every 7 people with kidney disease also have anemia. Erythropoietin-stimulating agents are frequently used to activate red blood cell production, but patients with erythropoietin resistance may require larger treatment doses and experience adverse outcomes.^2,3

To identify factors influencing maintenance hemodialysis patients’ erythropoietin resistance index and its association with mortality, Li Zuo, MD, director of the nephrology department at Peking University People’s Hospital in China, and colleagues examined participants from the China Dialysis Outcomes and Practice Patterns Study (DOPPS) 5, an observational prospective cohort study of hemodialysis patients from hemodialysis facilities in China. For inclusion, patients were required to be ≥ 18 years of age and receive treatment with regular hemodialysis for > 3 months.¹

Erythropoietin resistance index was used to evaluate patients’ hematopoietic response to erythropoiesis-stimulating agents and was calculated using the average weekly dose over the most recent month of data collection and baseline variables. The study’s primary outcome was all-cause mortality and the secondary outcome was cardiac/vascular mortality during the follow-up period.¹

In total, 1270 participants from DOPPS5 were included in the study. Patients were predominantly male (54.1%) and had a mean age of 60 (Standard deviation [SD], 49.0-71.0) years.¹

Investigators divided participants into 2 groups, low erythropoietin resistance index (n = 635) and high erythropoietin resistance index (n = 635), based on the cohort’s median erythropoietin resistance index, 14.03. The median value in the low group was 9.2 (6.4–11.6) and 19.4 (16.4–25.7) in the high group.¹

Investigators pointed out participants in the low erythropoietin resistance index group tended to have a longer dialysis vintage and greater white blood cell, hemoglobin, and creatine levels than those with a high erythropoietin resistance index at baseline (all P <.05). Monthly erythropoiesis-stimulating agents and single dose erythropoiesis-stimulating agents were increased in the high ERI group (both P <.05).¹

Multivariate logistic regression showed longer dialysis vintage (Odds ratio [OR], 0.957; 95% Confidence interval [CI], 0.929–0.986; P = .004), increased white blood cell count (OR, 0.900; 95% CI, 0.844–0.960; P = .001), high flux dialyzer use (OR, 0.866; 95% CI, 0.755–0.993; P = .040), greater body mass index (OR, 0.860; 95% CI, 0.828–0.892; P < .001), male sex (OR, 0.708; 95% CI, 0.625–0.801; P < .001), and increased albumin (OR, 0.512; 95% CI, 0.389–0.673; P < .001) had a negative association with erythropoietin resistance.¹

After a median follow-up of 1.9 (Interquartile range [IQR], 1.2- 2.1) years, investigators observed 176 deaths, including 89 cardiac/vascular deaths. In the low erythropoietin resistance index group, all-cause mortality was 12.8% (n = 81) and cardiac/vascular mortality was 6.6% (n = 42). Of note, both all-cause (15%; n = 91) and cardiac/vascular (7.4%; n = 47) mortality were greater in the high erythropoietin resistance index group.¹

Cox regression analysis showed the erythropoietin resistance index as a continuous variable was positively associated with all-cause mortality (P <.05), but no correlation was found for cardiac/vascular mortality in the crude model. After adjusting for age, sex, body mass index, dialysis vintage, primary kidney diseases, modified Charlson Comorbidity Index, and fistula use, the relationship between erythropoietin resistance index and all-cause mortality remained positive (Hazard ratio [HR], 1.021; 95% CI, 1.003–1.040; P <.05).¹

Investigators noted a lack of routine testing for several laboratory values, inevitable bias due to missing data, and a short median follow-up were potential limitations to the study that should be considered.¹

“More attention should be given to detecting erythropoiesis-stimulating agent resistance and determining the appropriate dosage of erythropoiesis-stimulating agents to achieve the target hemoglobin level. The underlying influencing factors of high erythropoietin resistance index should be determined and controlled and thus to achieve a better management of anemia,” investigators concluded.¹

References:

1. Zhao X, Gan L, Hou FF, et al. The influencing factors of the erythropoietin resistance index and its association with all-cause mortality in maintenance hemodialysis patients. Renal Failure. doi:10.1080/0886022X.2023.2290922
2. National Institutes of Health. Anemia in Chronic Kidney Disease. Kidney Disease. September 2020. Accessed January 19, 2024. https://www.niddk.nih.gov/health-information/kidney-disease/anemia
3. Cleveland Clinic. Erythropoietin. Health Library. November 10, 2022. Accessed January 19, 2024. https://my.clevelandclinic.org/health/articles/14573-erythropoietin