Study design
The study design and other details of the study protocol have been published elsewhere [19]. The protocol was approved by the main institutional review board (Nagoya University; No. 2014-0027) and then by each participating center. The research was conducted under the health insurance system of Japan and in accordance with the principles of the Declaration of Helsinki and Ethical Guidelines on Clinical Studies of the Ministry of Health, Labor, and Welfare of Japan. Written informed consent was provided by each participant. The research was designed, implemented, and overseen by the BRIGHTEN Executive Committee, together with representatives of Translational Research Center for Medical Innovation, Kobe, Japan, a third-party organization independent of the investigators’ institutions and responsible for data collection and analysis. The manuscript was prepared by one of the authors and subsequently revised and edited by all authors. The study was registered to ClinicalTrials.gov (NCT02136563) and UMIN-CTR (UMIN000013464).
Study population
Patients aged ≥ 20 years with estimated glomerular filtration rate (eGFR) of < 60 mL/min/1.73 m2 (calculated with the Japanese equation [20]) who presented renal anemia (Hb < 11 g/dL) were enrolled from June 2014 to September 2016. Patients scheduled to initiate maintenance dialysis or undergo kidney transplantation until 24 weeks after registration; those with history of ESA treatment (administered with ESA temporarily and > 12 weeks before registration were eligible); and those with malignant tumors under treatment, hematologic diseases, or hemorrhagic diseases were excluded. Of 1980 patients enrolled in 168 facilities, 285 patients were excluded mainly due to the lack of Hb values at 0 and 12 weeks (84 ± 14 days). Finally, 1695 patients were included in the data analysis (Fig. 1). Patients were observed for 96 weeks since DA administration.
DA administration
DA was administered within 8 weeks after the registration along its product information (30 μg every 2 weeks for the initial dose, subcutaneously or intravenously, and the dosage and duration should be adjusted thereafter to maintain Hb levels at ≥ 11 g/dL); however, the dose adjustment was actually entrusted to the physicians’ discretion in each facility as the BRIGHTEN was conducted in a real-world clinical setting.
Data collection
Patient baseline characteristics (age, sex, etiology of CKD, smoking status, medical history, comorbidities, hypoglycemic agent use, renin–angiotensin system inhibitor use, iron supplementation, body mass index, and blood pressure) were collected at the study registration. The clear definition of diabetes and dyslipidemia was not adopted for the BRIGHTEN, while the diagnosis was entrusted to investigators’ judgement.
Complete blood count including Hb, serum creatinine, albumin, iron, ferritin, total iron-binding capacity (TIBC), hemoglobin A1c and urinary protein–creatinine ratio (PCR) were measured at each facility laboratory at the beginning of the study and on week 12. In addition, high-sensitivity C-reactive protein (CRP), folic acid, vitamin B12, aminoterminal pro-brain natriuretic peptide (NT-pro BNP), iron, ferritin, and TIBC were measured at the clinical laboratory company (SRL, Tokyo, Japan).
Response index to DA
For the assessment of ESA hyporesponsiveness, the use of the following formulae (ESA resistance index; ERI [21]) were originally planned.
$$ {\text{ERI } - \text{ 1A}}\, = \,\frac{{{\text{Dose of DA at }}12{\text{ weeks }}\left( {{\mu g}} \right)}}{{{\text{Concentration of Hb }}\left( {{\text{g}}/{\text{dL}}} \right){\text{ at }}12{\text{ weeks }} \times {\text{ body weight }}\left( {{\text{kg}}} \right)}}, $$
$$ {\text{ERI } - \text{ 1B}}\, = \,\frac{{{\text{Dose of DA at }}12{\text{ weeks }}\left( {{\mu g}} \right)}}{{{\text{Concentration of Hb }}\left( {{\text{g}}/{\text{dL}}} \right){\text{ at }}12{\text{ weeks}}}}, $$
$$ {\text{ERI } - \text{ 2A}}\, = \,\frac{{{\text{Total dose of DA during }}12{\text{ weeks }}\left( {{\mu g}} \right)}}{{\Delta {\text{Hb }}_{0 - 12}\left( {{\text{g}}/{\text{dL}}} \right){ } \times {\text{ body weight }}\left( {{\text{kg}}} \right)}}, $$
$$ {\text{ERI } - \text{ 2B}}\, = \,\frac{{{\text{Total dose of DA during }}12{\text{ weeks }}\left( {{\mu g}} \right)}}{{\Delta {\text{Hb }}_{0 - 12}\left( {{\text{g}}/{\text{dL}}} \right)}}, $$
where ΔHb 0–12 (g/dL) = Hb (g/dL) at 12 weeks—Hb (g/dL) before DA administration.
However, some patients showed decreased or no changes in Hb level (ΔHb 0–12 < 0 or = 0) during 12 weeks after DA administration; thus, these aforementioned formulae were not used in the data analysis. Instead, initial ESA response index (iEResI) was defined as a reciprocal of the ERI-2A.
$$ {\text{iEResI}}\, = \,\frac{{\Delta {\text{Hb }}_{0 - 12}\left( {{\text{g}}/{\text{dL}}} \right) \times {\text{ body weight }}\left( {{\text{kg}}} \right)}}{{{\text{Total dose of DA during }}12{\text{ weeks }}\left( {{\mu g}} \right)}}. $$
Statistical analysis
Baseline characteristics are reported as means ± standard deviation (SD), median [interquartile range (IQR)], or number (percentage). The Wilcoxon rank sum test was used to compare two groups. As regards the predictors of initial response to DA, the association of iEResI with the number of DA administration and total doses of DA was firstly investigated. Furthermore, contributing factors to iEResI were analyzed using the general linear model adjusted by gender as a factor. We included all baseline demographic and clinical variables into univariate analysis; then variables significantly associated with iEResI (P < 0.05) were incorporated into multivariate analysis. All analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC, USA), and P values of < 0.05 were considered significant.