Hemoglobin Concentration and the Risk of Hemorrhagic and Ischemic Stroke in Patients Undergoing Hemodialysis

The Q-cohort Study

Ryusuke Yotsueda; Shigeru Tanaka; Masatomo Taniguchi; Kiichiro Fujisaki; Kumiko Torisu; Kosuke Masutani; Hideki Hirakata; Takanari Kitazono; Kazuhiko Tsuruya


Nephrol Dial Transplant. 2018;33(5):856-864. 

In This Article

Abstract and Introduction


Background The contribution of the hemoglobin concentration to the incidence of hemorrhagic or ischemic stroke in patients undergoing hemodialysis is unclear.

Methods In total, 3436 patients undergoing prevalent hemodialysis were followed up for 4 years. The primary outcome was the first development of hemorrhagic or ischemic stroke. The baseline hemoglobin concentration was divided into quartiles [hemoglobin (g/dL): Q1, ≤9.7; Q2, 9.8–10.5; Q3, 10.6–11.1; Q4, ≥11.2]. The association between the hemoglobin concentration and each type of stroke was examined using the Kaplan–Meier method and a Cox proportional hazards model.

Results During the follow-up period, 76 (2.2%) patients developed hemorrhagic stroke and 139 (4.0%) developed ischemic stroke. The 4-year incidence rate of hemorrhagic stroke was significantly higher in patients with lower hemoglobin concentrations. Compared with the quartile of patients with the highest hemoglobin concentrations (Q4), the multivariable-adjusted hazard ratios for hemorrhagic stroke were 1.18 (95% confidence interval, 0.56–2.51), 1.59 (0.82–3.21) and 2.31 (1.16–4.73) in patients in Q3, Q2 and Q1, respectively. No association was identified between the 4-year incidence rate of ischemic stroke and the hemoglobin concentration. Compared with the quartile of patients with the lowest hemoglobin concentrations (Q1), the multivariable-adjusted hazard ratios for ischemic stroke were 1.17 (95% confidence interval, 0.73–1.89), 0.88 (0.51–1.51) and 1.10 (0.66–1.83) in patients in Q2, Q3 and Q4, respectively.

Conclusions Our results suggest that low hemoglobin concentrations are associated with a high risk of hemorrhagic stroke, but not of ischemic stroke, in patients undergoing hemodialysis.


Stroke is a major cause of death and disability in patients undergoing maintenance hemodialysis (HD).[1–3] Approximately 7% of deaths in patients undergoing HD in Japan are still caused by stroke despite the fact that these patients have improved longevity and reduced rates of cardiovascular death.[3] Therefore, identifying the risk factors for stroke is urgently needed to facilitate improvements in the prognosis of patients undergoing HD.

A close relationship between high hemoglobin concentrations and the incidence of stroke has been highlighted in the field of chronic kidney disease (CKD), including HD therapy.[4] The Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) was a large-scale randomized controlled trial involving patients with CKD receiving an erythropoiesis-stimulating agent (ESA). The TREAT study showed that there was a double risk of stroke in the patient group with higher target hemoglobin concentrations.[4] High hemoglobin concentrations increase blood viscosity and promote thrombosis,[5] which may at least in part explain the association between high hemoglobin concentrations and ischemic stroke. However, the TREAT study did not address the risk of ischemic stroke separate from hemorrhagic stroke.

Low hemoglobin concentrations have also emerged as an established risk factor for the development of cardiovascular disease in the general population[6] and in patients with CKD.[7,8] The interactions among a poor cardiovascular prognosis, kidney function and anemia form a vicious circle termed cardiorenal anemia syndrome.[9] Observational studies of the general population have shown an association between low hemoglobin concentrations and a high incidence of composite stroke.[10,11] In this context, the Hisayama study, a prospective population-based cohort survey in Japan, recently showed that low hematocrit levels were associated with a high risk of hemorrhagic stroke in adults in the general population.[12] These findings suggest an association between anemia and hemorrhagic stroke in the real-world setting. However, the contribution of anemia to the incidence of hemorrhagic stroke remains unclear in patients with CKD, including those undergoing HD.

Therefore, the present study was performed to determine the association between the hemoglobin concentration and the risk of hemorrhagic or ischemic stroke separately in a large-scale, prospective cohort study of patients undergoing maintenance HD.