We found very similar associations between patient characteristics and three methods of characterizing EPO hyporesponsiveness (total EPO dose, EPO dose per kg of body weight, or EPO dose per hemoglobin level). Given this finding, using the simplest of the three methods we investigated, total EPO dose, to characterize hyporesponsiveness seems justifiable. Our findings relating hyporesponsiveness to patient characteristics are largely in agreement with other studies in other populations that used different methods to characterize hyporesponsiveness. With respect to the proportion of patients classified as hyporesponsive, our definitions produced approximately 20%, 4.5%, and 15% of patients with any, chronic, and non-chronic hyporesponsiveness, respectively. Other studies have not separated chronic from non-chronic hyporesponsiveness. Attalah et al [2
] found that 17.6% of patients were hyporesponsive, defined as requiring > 450 U/kg/week IV EPO, with average 3-month hemoglobin < 11 g/dL, ferritin ≥ 500 ng/mL, and TSAT ≤ 50%. Johnson et al [3
] describe approximately 5% to 10% of patients as hyporesponsive, defined as requiring > 450 U/kg/week IV EPO.
Potential causes of hyporesponsiveness have been previously investigated and described, with varying levels of supporting evidence [3
]. Causes include absolute or functional iron deficiency, inflammation, infection, lack of dialysis adequacy, hyperparathyroidism, hemolysis, nutritional factor deficiencies, aluminum overload, pure red cell aplasia, malignancy, bone marrow disorders, myelosuppressive agent use, and use of angiotensin converting enzyme inhibitors and angiotensin receptor blockers.
Using data from a large dialysis organization, Kalantar-Zadeh et al [10
] examined predictors of hyporesponsiveness. Although they used a measure of hyporesponsiveness different from ours (fitting hemoglobin trajectories to individuals with mixed models), and their primary focus was on iron markers and osteodystrophy, their findings were similar with respect to age, sex, race, and major comorbid conditions, including cancer, CHF, and diabetes. One notable difference was with respect to dialysis duration; we found increasing hyporesponsiveness with longer dialysis duration, compared with their findings of decreased hyporesponsiveness. This may be due to the particular categorization of dialysis duration analyzed. The first 6 months after dialysis initiation, and in particular, the first 3 months, is a period of high risk. The mortality hazard appears to be highest shortly after initiation, and decreases during the first 6 months. Correspondingly, dialysis duration beyond 5 years shows further increasing risk, as patients continue to accumulate comorbidity. Therefore, investigation of hyporesponsiveness associations within the first year, and beyond 5 years, may be important for further study.
In another study by Kalantar-Zadeh et al [11
], the authors found associations between inflammatory markers and hyporesponsiveness. We did not have access to data on inflammatory markers; however, our findings of higher comorbidity burden, higher number of vascular access complications, and IV antibiotic use are in general agreement with the earlier findings, since inflammatory burden generally increases with these factors.
Limitations of the current study include lack of laboratory data; somewhat arbitrary definitions of hyporesponsiveness based on the ninetieth percentile of total monthly EPO dose, dose/kg, or dose/hemoglobin level; possible misclassification of comorbid conditions due to use of claims to identify them; lack of data on catheter use, which is known to be associated with increased risk of infection and inflammation; and residual confounding, which may explain some of the adjusted logistic regression findings. With respect to laboratory data, some definitions of hyporesponsiveness in the literature have included information on ferritin and TSAT; these data were not available in our study. Despite these unavailable data, our findings are generally similar to findings of other studies. Another limitation is that knowledge of the distribution of hemoglobin levels in a similar, large population is needed to define a ninetieth percentile. Simply examining the distribution in a small population (for example, at a particular dialysis facility) to find the appropriate cut point, which may not include any hyporesponsive individuals, would not be appropriate.
A potential limitation involves the 2008 timeframe of the data. This period is after release of CHOIR [12
] and CREATE [13
] study results, which produced a change in ESA dosing and hemoglobin levels, and before implementation of the Medicare reimbursement bundle, which may cause further declines in ESA doses and hemoglobin levels. However, use of the ninetieth percentile cut would still identify patients receiving the highest 10% of doses, given the overall population dosing levels at a point in time.