Initial responsiveness to darbepoetin alfa and its contributing factors in non-dialysis chronic kidney disease patients in Japan

Abstract

Background Hyporesponsiveness to erythropoiesis-stimulating agents (ESAs) is associated with cardiovascular events and poor renal outcome in patients with chronic kidney disease (CKD). This study aimed to investigate the initial responsiveness to darbepoetin alfa (DA) and its contributing factors using the data from the BRIGHTEN. Methods Of 1980 patients enrolled at 168 facilities, 1695 were included in this analysis [285 patients were excluded mainly due to lack of hemoglobin (Hb) values]. The initial ESA response index (iEResI) was defined as a ratio of Hb changes over 12 weeks after DA administration per weight-adjusted total DA dose and contributing factors to iEResI were analyzed. Results The mean age was 70 ± 12 years (male 58.8%; diabetic nephropathy 27.6%). The median creatinine and mean Hb levels at DA initiation were 2.62 mg/dL and 9.8 g/dL, respectively. The most frequent number of DA administration during 12 weeks was 3 times (41.1%), followed by 4 (15.6%) times with a wide distribution of the total DA dose (15–900 μg). Remarkably, 225 patients (13.3%) did not respond to DA. Multivariate analysis showed that male gender, hypoglycemic agent use, iron supplementation, high eGFR, low Hb, low CRP, low NT-proBNP, and low urinary protein–creatinine ratio were independently associated with better initial response to DA (P = < 0.0001, 0.0108, < 0.0001, 0.0476, < 0.0001, 0.0004, 0.0435, and 0.0009, respectively). Conclusions Non-responder to DA accounted for 13.3% of patients with non-dialysis CKD. Iron supplementation, low CRP, low NT-proBNP, and less proteinuria were predictive and modifiable factors associated with better initial response to DA.

Factors Affecting Doses of Roxadustat Versus Darbepoetin Alfa for Anemia in Nondialysis Patients

“…This difference between DD and NDD CKD patients may suggest the finding in this study occurred by chance, could have been affected by medication use (e.g., statins), or could suggest that NDD CKD patients with DM are more responsive to DA, with this responsiveness abating as CKD progresses [25, 49]. Other potential factors in patients with DM that have previously been identified to affect ESA hyporesponsiveness that may have influenced this finding include gender, hypoglycemic agent use, eGFR, baseline hemoglobin, baseline N-terminal pro-B-natriuretic protein, and iron supplementation [50]. Because any potential difference in roxadustat and DA dosing is likely multifactorial in nature, the effect of DM on roxadustat and DA dosing, particularly in CKD patients beginning dialysis, must be studied to better inform ESA recommendations.…”

“…The development of anemia in patients with CKD does not solely originate from endogenous erythropoietin deficiency but may also result from multiple other factors, including elevated hepcidin concentrations and disease states that increase inflammation (e.g., diabetes and progressed CKD) [6-10]. Similarly, ESA dosing in patients with anemia of CKD may be affected by a variety of clinical and patient-specific factors such as gender, the estimated glomerular filtration rate (eGFR), hemoglobin concentration, and high-sensitivity C-reactive protein (hs-CRP) [10]. Patients who require excessively high or progressively increasing ESA doses to maintain hemoglobin concentrations within a target range or are unable to achieve that target range may have ESA hyporesponsiveness or resistance [11, 12].…”

“…ESA hyporesponsiveness has been associated with elevated risks of mortality and end-stage kidney disease development [9, 13]. In Japan, ESA hyporesponsiveness occurs in approximately 10% of patients and is associated with increased risk of cardiovascular events and death [10].…”

Clinical parameters among patients in Japan with anemia and non-dialysis-dependent chronic kidney disease with and without diabetes mellitus who received roxadustat

“…Reduced synthesis of erythropoietin, dysregulated oxygen sensing, functional iron deficiency, elevated hepcidin concentrations, and increased inflammation from disease states such as diabetes mellitus are characteristic of anemia of CKD pathogenesis [1,[6][7][8]. Anemia of CKD is associated with reduced health-related quality of life and elevated risk for hospitalization, mortality, and cardiovascular events as well as increased length of hospital stay [9,10].…”

Skeletal Muscle Mass Is Associated With Erythropoietin Response in Hemodialysis Patients

“…ESAs have enabled to archive recommended hemoglobin level and are the most established agents for renal anemia [5] [6]. On the other hand, approximately 15% of the patient are hyporesponsive to ESA [7] [8]. ESA hyporesponsiveness is associated with mortality and cardiovascular events in patients with CKD [9] [10].…”