Effect of long-acting erythropoiesis-stimulating agents on hemoglobin levels at the initiation of dialysis

Assessment of the effects of long-acting ESA on Hb level

The ability to use a higher dosage of epoetin could explain the beneficial effect of long-acting ESA on Hb. Based on the instructions for the use of long-acting ESA in the drug package insert, and referring to the recommended dose conversion ratio from darbepoetin or CERA to epoetin [15, 16], we can theoretically prescribe an approximately 1.5 times higher monthly estimated dose of epoetin in the predialytic phase of CKD. In Japan, max monthly dosage of epoetin-? or -? is 24,000 IU in predialytic phase of CKD patients. For darbepoetin-? and CERA, max monthly dosages are 240 and 250 ?g, respectively. Based on the dose conversion ratio to epoetin 200:1 for darbepoetin and 270:1 for CERA, at least one-half dosage of estimated epoetin was applicable to CKD patients. Indeed, as shown in Table 1, an estimated dose of epoetin 1.5 times higher was administered to the patients after 2011 compared with before 2010. It is thought that the switch from a short-acting to a long-acting ESA increases the available estimated dose of epoetin, and consequently, the Hb level at the initiation of dialysis.

Iron status is one of the important parts for the optimal treatment of anemia in ESKD patients. The difference of iron utilization could play some role more increasing of Hb level in patients with long-acting ESA than those of short-acting ESA. Actually, it is reported that difference of type of ESA [18] or difference of administration interval of ESA [19] make a changing of iron status favorably for treatment of anemia in ESKD patients. However, any remarkable differences did not exist between two patients group with long-acting ESA and short-acting ESA in the marker of iron status such as iron, ferritin, TSAT, and usage of iron agents. Therefore, it is not likely that the status and utilization of iron play some role for increasing Hb level in long-acting ESA in this study.

Another possibility is that, independent of dose, the potential direct effect of a long-acting ESA could play a role in the elevation of Hb level at the initiation of dialysis. On multiple regression analysis, use of long-acting ESA was more closely associated with Hb level than its estimated dose from the conversion ratio in our study. Several studies have suggested that the conversion ratio from epoetin to darbepoetin-? of 1:350 in the clinical setting is higher than the fundamental conversion ratio from the molecular structure of 1:200 [15, 20]. This might mean that darbepoetin-? has a potentially more powerful effect on increasing the Hb than we expected. Further study is needed to prove this issue.

Many clinical factors are thought to affect the Hb level at the initiation of dialysis. Residual renal function is thought to be the biggest contributor to Hb levels in CKD patients. It is well known that a positive relationship exists between endogenous erythropoietin concentration and the serum eGFR [21] in CKD patients. The present study was conducted by using a combined database from nine hospitals. The question arises of whether the policy and indication for starting dialysis are not standardized, but rather, are at each physician’s discretion. This could make a difference in the timing for starting dialysis, and, consequently, influence the Hb concentration at the initiation of dialysis. Therefore, in order to minimize this bias, multivariate regression analysis was performed to adjust for confounding variables, including renal function. After adjusting by serum creatinine level or eGFR, the positive association of long-acting ESA with Hb level remained statistically significant. Also, after simultaneously adjusting for other factors, as seen in Tables 4 and 5, the use of long-acting ESA was well-associated with Hb concentration. These findings imply that long-acting ESA plays a beneficial role in maintaining a higher Hb concentration than short-acting ESA. The reason is probably the higher estimated epoetin dose or other potential effect. We would like to emphasize that excluding the patients with suspicion of low responsiveness to ESA could lead an anticipating results.