Association of Erythropoietin Resistance with Sleep Apnea Syndrome and Prognosis in Patients on Maintenance Hemodialysis

Background: Nocturnal intermitted hypoxia with sleep apnea syndrome (SAS) is known to stimulate erythropoietin (EPO) production and is associated with prognosis in populations without kidney dysfunction. However, it remains unresolved whether SAS severity is related to EPO production, EPO resistance, and cardiovascular events in patients with end stage kidney disease. In this study, we investigated the association between SAS severity and EPO resistance in hemodialysis patients. Methods: We investigated the association between the nocturnal 3% oxygen desaturation index (3%ODI) and the EPO resistance index (ERI) in 134 hemodialysis patients who underwent overnight pulse oximetry at Shonan Kamakura General Hospital from December 2012 to April 2013. After evaluating overnight pulse oximetry, these patients were divided into 4 groups (low or high 3% ODI and ERI levels) and followed up to investigate major adverse cardiovascular events (MACEs) for about 8 years until April 2021. MACEs included cardiac events, cerebrovascular events, peripheral artery disease events, and cardiovascular death. The association between 3% ODI and ERI was investigated by multiple linear regression analysis with covariants: age, sex, duration of hemodialysis, history of diabetes mellitus, systolic blood pressure, and serum of albumin, c-reactive protein, beta-2 microglobulin, phosphate, and parathyroid hormone. The cumulative incidence of MACEs across the groups was assessed using the log-rank test for trend with Kaplan-Meier curve. Results: The baseline characteristics of 134 patients were as follows: the median age was 67 years, 37.3% were diabetic, and the median duration of HD was 69 months, median 3% ODI was 11.3 %, median ERI was 8.94. 3% ODI was independently associated with ERI (beta co-efficient = -1.2%, p=0.002) by multiple linear regression analysis. The Highest incidence of MACE was shown in the group with high 3% ODI and high ERI compared with low 3% ODI and low ERI (p for trend=0.01, hazard ratio=2.43). Conclusion: Hemodialysis patients with hypoxemia were associated with lower ERI than patients without hypoxemia. However, it should be noted that patients with nocturnal hypoxemia had a higher likelihood of developing cardiovascular disorders, especially in those with high EPO resistance.