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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.

Introduction

Anemia in patients with chronic kidney disease (CKD) is associated with poor renal, cardiovascular, and overall outcomes [1,2,3,4,5]. Observational studies and small randomized controlled trials (RCTs) showed that correction of anemia with erythropoiesis-stimulating agents (ESAs) was associated with beneficial outcomes in morbidity, mortality, and kidney function as well as quality of life in this patient population [6,7,8,9,10,11]. Furthermore, the beneficial effect of ESAs was greater with high hemoglobin (Hb) levels; however, the optimal target Hb level in ESA treatment remains controversial. A series of large RCTs comparing the effect of normalizing Hb level (> 13 g/dL) with conservative Hb level (10–11 g/dL) on mortality and cardiovascular disease (CVD) events was conducted over the past two decades and showed a consistent result of harm with normalizing Hb level [12,13,14,15]. The Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) trial [14] and the Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) [15] conducted on pre-dialysis CKD patients showed that targeting higher Hb level compared with targeting lower Hb level increased the incidence of CVD events, especially stroke, and mortality. Furthermore, post hoc analyses of CHOIR and TREAT trials suggested that poor outcomes might not have resulted from achieving higher Hb level itself but resulted from toxicities associated with high-dose ESAs, patient-related factors promoting ESA hyporesponsiveness, or a combination of both [16, 17]. Thus, in the management of anemia for CKD patients, ESA hyporesponsiveness should be predicted and appropriate dose of ESA should be administered to patients with ESA hyporesponsiveness. However, clinically relevant definition of ESA hyporesponsiveness is not available at present because its definition should be based on the index associated with poor renal, cardiovascular, or overall outcome [18].

The “oBservational clinical Research In chronic kidney disease patients with renal anemia: renal proGnosis in patients with Hyporesponsive anemia To Erythropoiesis-stimulating agents, darbepoetiN alfa (BRIGHTEN)” is a multicenter prospective observational study conducted in a real-world clinical setting in Japan to explore the prevalence of hyporesponsiveness to darbepoetin alfa (DA) and to establish an appropriate index of hyporesponsiveness to DA associated with poor renal outcome and CVD events in non-dialysis CKD patients. Patient enrollment started in June 2014, and the observation period ended in September 2018. Therefore, this study aimed to investigate the initial responsiveness to DA and its contributing factors using the data from the BRIGHTEN.

Materials and methods

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.

Fig. 1
figure 1

Screening of patient. DA darbepoetin alfa

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.

Results

The mean patient age was 70 ± 12 years (male 58.8%). Diabetic nephropathy was the leading cause of CKD (27.6%) followed by nephrosclerosis (23.5%) and chronic glomerulonephritis (22.5%). The prevalence of coronary artery disease, heart failure, stroke, and peripheral artery disease was 15. 8%, 7.0%, 11.7%, and 11.0%, respectively. Creatinine and Hb levels at DA initiation were 2.62 (1.89, 3.61) mg/dL and 9.8 ± 0.9 g/dL, respectively (Table1). The prevalence of patients with serum ferritin level < 50 μg and TSAT < 20% was 27.2% and 22.4%, respectively (Supplementary Fig. 1).

Table 1 Baseline characteristics

The most frequent number of DA administration during 12 weeks was 3 times (n = 697, 41.1%), followed by 4 (n = 265, 15.6%) and 2 (n = 248, 14.6%) times with a wide distribution of the total DA dose ranging from 15 μg to 900 μg (Figs. 2, 3). The total DA dose and hemoglobin levels increased in relation to the number of DA administration for 12 weeks (Fig. 3).

Fig. 2
figure 2

Number of DA administration during 12 weeks after DA initiation. DA darbepoetin alfa

Fig. 3
figure 3

Total DA dose and hemoglobin change during 12 weeks after DA initiation stratified by the number of DA administration. DA darbepoetin alfa

iEResI increased with the number of DA administration, especially in the total DA dose between 90 μg and 180 μg; whereas, it was not associated with the total DA dose and even lower in the total DA dose of > 180 μg (Table 2 and Fig. 4).

Table 2 iEResI stratified by cumulative DA doses and number of DA administration
Fig. 4
figure 4

Association between iEResI and the number of DA administration stratified by the total DA dose until 12 weeks. iEResI increased with the number of DA administration, especially in the total DA dose between 90 μg and 180 μg; whereas, it was not associated with the total DA dose and even lower in the total DA dose of  > 180 μg. DA Darbepoetin alfa, iEResI initial response index to erythropoiesis-stimulating agents. Note: The scale of vertical axes in each graph is not unified.

Notably, 225 patients (13.3%) had no response or even had reduced Hb level at week 12 (DA hyporesponsiveness group). A similar pattern of histograms of total DA dose during 12 weeks in two groups with and without DA hyporesponsiveness was observed; however, there was a statistically significant difference in the median cumulative DA dose between two groups with [100 (60, 180) μg] and without DA hyporesponsiveness [140 (90, 180) μg] (P < 0.0001) (Supplementary Fig. 2).

Multivariate analysis showed that male gender, hypoglycemic agent use, iron supplementation, not serum ferritin or TSAT level, and high eGFR were independently and significantly associated with better initial response to DA (P =  < 0.0001, 0.0108, < 0.0001, and 0.0476, respectively); whereas, high Hb, high CRP, high NT-proBNP, and high urinary PCR levels were significantly associated with poor initial response to DA (P =  < 0.0001, 0.0004, 0.0435, and 0.0009, respectively) (Table 3).

Table 3 Predictors associated with iEResI

Discussion

ESA hyporesponsiveness is a strong predictor of mortality and CVD events as well as poor renal survival in patients with CKD [16, 17, 21,22,23,24,25]. Although the definition of ESA hyporesponsiveness has been suggested in previous clinical guidelines for the treatment of anemia in patients with CKD, they were defined arbitrarily and were not associated with any outcomes [26, 27]. Only the Kidney Disease: Improving Global Outcomes (KDIGO) anemia guideline published in 2012 defined ESA hyporesponsiveness as “patients who have no increased Hb concentration from baseline after the first month of ESA treatment on appropriate weight-based dose [28]. This definition was based on the secondary analysis of the TREAT study, which revealed that diabetic pre-dialysis CKD patients with initial hyporesponsiveness to DA had poor cardiovascular outcome [17]. However, in the TREAT study, nearly half of study subjects had CVD and the DA dose used was quite different from those used in our clinical practice setting in Japan [15, 25]. Therefore, extrapolating this definition into clinical practice in Japan seems difficult. In this context, an evidence-based index of ESA hyporesponsiveness and clinical guidelines for anemia management in CKD patients with ESA hyporesponsiveness should be established in Japan.

In the current analysis, 225 patients (13.3%) showed no increase or even had decreased Hb level at 12 weeks after DA administration. This prevalence was similar to those reported in previous studies regardless of different definitions of ESA hyporesponsiveness adopted [29, 30]. Furthermore, the new index of initial responsiveness to DA (iEResI) was defined. Male gender, hypoglycemic agent use, iron supplementation, and high eGFR were positively associated with iEResI; whereas, high Hb, high CRP, high NT-proBNP levels, and high urinary PCR were negatively associated with iEResI. Previous studies have already shown that iron deficiency, decreased renal function, and inflammation were strong predictors for ESA hyporesponsiveness; however, reports regarding the association between gender difference or hypoglycemic agent use (proxy for diabetes) and ESA hyporesponsiveness are conflicting [23, 24, 29, 31]. In our study, iron supplementation, not serum ferritin or TSAT level, was associated with iEResI on the univariate and multivariate analysis. As shown in Supplementary Fig. 1, the prevalence of study subjects with iron deficiency (e.g., serum ferritin < 50 μg and TSAT < 20%) seems to be lower than that previously reported in dialysis-dependent CKD patients [32], which might make difficult to show significant and apparent relationship between these parameters of iron status and iEResI. The association between male gender and better initial responsiveness to DA may be a mathematical artifact. Namely, DA is administered through prefilled syringe at a dose of 15, 30, 40, 60, 120, or 180 μg for pre-dialysis CKD patients in Japan, not according to the body weight-adjusted dose for each patient. As the iEResI adopted in this study had a figure of “body weight” in the numerator, the iEResI value may be relatively higher in men than in women. Some studies reported that diabetes or insulin resistance was associated with ESA hyporesponsiveness in pre-dialysis CKD patients [29, 33]; whereas, others did not show any association between diabetes and ESA hyporesponsiveness in dialysis patients [23, 31]. In this study, patients with hypoglycemic agents use had higher prevalence of dyslipidemia than those without hypoglycemic agent use (67.6% vs. 49.7%; P < 0.0001). Statin use has also been reported to improve ESA responsiveness in dialysis and pre-dialysis CKD patients due to its anti-inflammatory effect [34, 35]. Although the prevalence of statin use was not obtained in this study, such a confounding factor may affect this association. Our results also showed that high urinary PCR was associated with ESA hyporesponsiveness, which is consistent with a previous report [24]. Although the exact mechanism by which proteinuria could affect the ESA responsiveness has not been clarified, proteinuria is a proxy for inflammation or histological damage of the kidney and for progressive kidney function decline which could affect endogenous erythropoietin production or response to ESA. Of interest, history of CVD was not associated with the iEResI in our study; whereas, NT-proBNP was significantly associated with the iEResI. As the aforementioned study showed that patients with history of heart failure not of coronary artery disease showed ESA hyporesponsiveness [23], history of CVD which has been usually used for adjustment of confounders in previous studies has a crucial week point, which means that the history of CVD can not represent the severity of CVD. On the other hand, BNP or NT-proBNP can represent the severity of CVD. Patients with severe CVD usually have more serious inflammation, or take more medication, which could be associated with anemia or poor response to ESA, compared to those with less severe CVD. Thus, we think that it is quite reasonable that NT-proBNP, not the history of CVD, was associated with the responsiveness to DA. Low Hb level before ESA treatment was reported as a predictor of ESA hyporesponsiveness [23, 29] because it means the presence of comorbidity or inflammation that could be directly associated with ESA hyporesponsiveness. Our study result showing the opposite association may be interpreted as patients with higher Hb level before DA initiation may be less dependent on erythropoietin. Age, malnutrition, and RAS inhibitor were also reported as predictive factors of ESA hyporesponsiveness [29, 36]; however, this study did not show any association between these factors and iEResI, although precise nutritional assessment other than serum albumin level was not performed for the BRIGHTEN.

Although the BRIGHTEN is nationwide prospective study that can closely monitor patients, several limitations should be considered. This study aimed to examine the initial responsiveness to DA in principally ESA-naïve patients. As ESA responsiveness is likely to change over time, 12 weeks may be relatively short to evaluate ESA responsiveness. As it is an observational study conducted in a real-world clinical setting, the dose and frequency of DA administration were not unified because they were determined based on the physician’s discretion and patients’ preference, which may affect the iEResI. Furthermore, there were many missing data about iron supplementation (type of agents, dose, and route of administration), so we could not analyze the relationship between the dose of iron supplementation and responsiveness to DA. Factors associated with ESA hyporesponsiveness could highly depend on patient characteristics studied, comorbid disease, and treatment for anemia itself (e.g., ESA dose); thus, our results could not be extrapolated to CKD patients in Western countries and to those undergoing chronic dialysis treatment.

In conclusion, in the current analysis of the BRIGHTEN, 13.3% of patients showed no increase or even decreased Hb level at 12 weeks after DA administration. Furthermore, male gender, hypoglycemic agent use, iron supplementation, high eGFR, low Hb, low CRP, low NT-proBNP, and low proteinuria were independently and significantly associated with better initial response to DA. In future analyses, we are planning to investigate the association between the iEResI as well as other ERIs and patient outcomes.

References

  1. Keane WF, Brenner BM, de Zeeuw D, et al. The risk of developing end-stage renal disease in patients with type 2 diabetes and nephropathy: the RENAAL study. Kidney Int. 2003;63:1499–507.

    Article  Google Scholar 

  2. Kovesdy CP, Trivedi BK, Kalantar-Zadeh K, et al. Association of anemia with outcomes in men with moderate and severe chronic kidney disease. Kidney Int. 2006;69:560–4.

    CAS  Article  Google Scholar 

  3. Levin A, Thompson CR, Ethier J, et al. Left ventricular mass index increase in early renal disease: impact of decline in hemoglobin. Am J Kidney Dis. 1999;34:125–34.

    CAS  Article  Google Scholar 

  4. Walker AM, Schneider G, Yeaw J, et al. Anemia as a predictor of cardiovascular events in patients with elevated serum creatinine. J Am Soc Nephrol. 2006;17:2293–8.

    CAS  Article  Google Scholar 

  5. Pisoni RL, Bragg-Gresham JL, Young EW, et al. Anemia management and outcomes from 12 countries in the Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J Kidney Dis. 2004;44:94–111.

    Article  Google Scholar 

  6. Hayashi T, Suzuki A, Shoji T, et al. Cardiovascular effect of normalizing the hematocrit level during erythropoietin therapy in predialysis patients with chronic renal failure. Am J Kidney Dis. 2000;35:250–6.

    CAS  Article  Google Scholar 

  7. Ofsthun N, Labrecque J, Lacson E, et al. The effects of higher hemoglobin levels on mortality and hospitalization in hemodialysis patients. Kidney Int. 2003;63:1908–14.

    Article  Google Scholar 

  8. De Nicola L, Conte G, Chiodini P, et al. Stability of target hemoglobin levels during the first year of epoetin treatment in patients with chronic kidney disease. Clin J Am Soc Nephrol. 2007;2:938–46.

    Article  Google Scholar 

  9. Kuriyama S, Tomonari H, Yoshida H, et al. Reversal of anemia by erythropoietin therapy retards the progression of chronic renal failure, especially in nondiabetic patients. Nephron. 1997;77:176–85.

    CAS  Article  Google Scholar 

  10. Tsubakihara Y, Gejyo F, Nishi S, et al. High target hemoglobin with erythropoiesis-stimulating agents has advantages in the renal function of non-dialysis chronic kidney disease patients. Ther Apher Dial. 2012;16:529–40.

    CAS  Article  Google Scholar 

  11. Revicki DA, Brown RE, Feeny DH, et al. Health-related quality of life associated with recombinant human erythropoietin therapy for predialysis chronic renal disease patients. Am J Kidney Dis. 1995;25:548–54.

    CAS  Article  Google Scholar 

  12. Besarab A, Bolton WK, Browne JK, et al. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med. 1998;339:584–90.

    CAS  Article  Google Scholar 

  13. Drüeke TB, Locatelli F, Clyne N, et al. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med. 2006;355:2071–84.

    Article  Google Scholar 

  14. Singh AK, Szczech L, Tang KL, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 2006;355:2085–98.

    CAS  Article  Google Scholar 

  15. Pfeffer MA, Burdmann EA, Chen CY, et al. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med. 2009;361:2019–32.

    Article  Google Scholar 

  16. Szczech LA, Barnhart HX, Inrig JK, et al. Secondary analysis of the CHOIR trial epoetin-alpha dose and achieved hemoglobin outcomes. Kidney Int. 2008;74:791–8.

    CAS  Article  Google Scholar 

  17. Solomon SD, Uno H, Lewis EF, et al. Erythropoietic response and outcomes in kidney disease and type 2 diabetes. N Engl J Med. 2010;363:1146–55.

    CAS  Article  Google Scholar 

  18. Yamamoto H, Nishi S, Tomo T, et al. 2015 Japanese society for dialysis therapy: guideline for renal anemia in chronic kidney disease. Ren Replace Ther. 2017;3:36.

    Article  Google Scholar 

  19. Kato H, Nangaku M, Hirakata H, et al. Rationale and design of observational clinical research in chronic kidney disease patients with renal anemia: renal prognosis in patients with hyporesponsive anemia to erythropoiesis-stimulating agents, darbepoetin alfa (BRIGHTEN Trial). Clin Exp Nephrol. 2018;22:78–84.

    CAS  Article  Google Scholar 

  20. Matsuo S, Imai E, Horio M, et al. Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis. 2009;53:982–92.

    CAS  Article  Google Scholar 

  21. Kilpatrick RD, Critchlow CW, Fishbane S, et al. Greater epoetin alfa responsiveness is associated with improved survival in hemodialysis patients. Clin J Am Soc Nephrol. 2008;3:1077–83.

    CAS  Article  Google Scholar 

  22. Fukuma S, Yamaguchi T, Hashimoto S, et al. Erythropoiesis-stimulating agent responsiveness and mortality in hemodialysis patients: results from a cohort study from the dialysis registry in Japan. Am J Kidney Dis. 2012;59:108–16.

    CAS  Article  Google Scholar 

  23. López-Gómez JM, Portolés JM, Aljama P. Factors that conditon the responce to erythropoietin in patients on hemodialysis and their relation to mortality. Kidney Int. 2008;74(Suppl):S75–81.

    Article  Google Scholar 

  24. Minutolo R, Conte G, Cianciaruso B, et al. Hyporesponsiveness to erythropoiesis-stimulating agents and renal survival in non-dialysis CKD patients. Nephrol Dial Transplant. 2012;27:2880–6.

    CAS  Article  Google Scholar 

  25. Tanaka T, Nangaku M, Imai E, et al. Safety and effectiveness of long-term use of darbepoetin alfa in non-dialysis patients with chronic kidney disease: a post-marketing surveillance study in Japan. Clin Exp Nephrol. 2019;23:231–43.

    CAS  Article  Google Scholar 

  26. Locatelli F, Aljama P, Bárány P, et al. Revised European best practice guidelines for the management of anaemia in patients with chronic renal failure. Nephrol Dial Transplant. 2004;19(Suppl 2):ii1–47.

    PubMed  Google Scholar 

  27. KDOQI. KDOQI Clinical Practice Guideline and Clinical Practice Recommendations for anemia in chronic kidney disease: 2007 update of hemoglobin target. Am J Kidney Dis. 2007;50:471–530.

    Article  Google Scholar 

  28. Kidney disease: improving global outcomes (KDIGO) Anemia Work Group. KDIGO clinical practice guideline for anemia in chronic kidney disease. Kidney Int. 2012;2(Suppl):S279–335.

    Google Scholar 

  29. Rossert J, Gassmann-Mayer C, Frei D, et al. Prevalence and predictors of epoetin hyporesponsiveness in chronic kidney disease patients. Nephrol Dial Transplant. 2007;22:794–800.

    Article  Google Scholar 

  30. Besarab A, Yee J. Candidate biomarkers for erythropoietin response in end-stage renal disease. Kidney Int. 2011;79:488–90.

    CAS  Article  Google Scholar 

  31. Ifudu O, Uribarri J, Rajwani I, et al. Gender modulates responsiveness to recombinant erythropoietin. Am J Kidney Dis. 2001;38:518–22.

    CAS  Article  Google Scholar 

  32. Nakai S, Hanafusa N, Masakane I, et al. An overview of regular dialysis treatment in Japan (as of 31 December 2012). Ther Apher Dial. 2014;6:535–602.

    Article  Google Scholar 

  33. Abe M, Okada K, Soma M, et al. Relationship between insulin resistance and erythropoietin responsiveness in hemodialysis patients. Clin Nephrol. 2011;75:49–58.

    CAS  PubMed  Google Scholar 

  34. Sirken G, Kung SC, Raja R. Decreased erythropoietin requirements in maintenance hemodialysis patients with statin therapy. ASAIO J. 2003;49:422–5.

    CAS  PubMed  Google Scholar 

  35. Chiang CK, Yang SY, Peng YS, et al. Atorvastatin increases erythropoietin-stimulating agent hyporesponsiveness in maintenance hemodialysis patients: role of anti-inflammation effects. Am J Nephrol. 2009;29:392–7.

    CAS  Article  Google Scholar 

  36. Kanbay M, Perazella MA, Kasapoglu B, et al. Erythropoiesis stimulatory agent-resistant anemia in dialysis patients: review of causes and management. Blood Purif. 2010;29:1–12.

    Article  Google Scholar 

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Acknowledgements

We would like to express our deepest gratitude to the patients, as well as the investigators and staff at the study sites (presented in the appendix) for their contribution to the study.

Funding

The authors reported the following financial supports: Masaomi Nangaku received honoraria, manuscript fees, and subsidies or donations from Kyowa Kirin Co. Ltd. (KKC). Takashi Wada received honoraria and subsidies or donations from KKC. Terumasa Hayashi received honoraria from KKC. Takao Masaki received honoraria and subsidies or donations from KKC. Hiroyasu Yamamoto received honoraria and manuscript fees from KKC. Hiroki Hase received honoraria from KKC. Masahiro Kamouchi received travel fees, gifts, and others from KKC. Tadao Akizawa is in Employment/Leadership position/Advisory role in KKC and received honoraria and manuscript fees from KKC. Yoshiharu Tsubakihara received honoraria from KKC. Shoichi Maruyama received honoraria and subsidies or donations from KKC. Ichiei Narita received honoraria and subsidies or donations from KKC.

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Correspondence to Ichiei Narita.

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This trial is funded by KKC. The KKC proposed the concept of this trial and provided information, but do not take any part in collecting, analyzing, or interpreting the results. The Translational Research Center for Medical Innovation, a third-party organization that is independent of the primary investigator’s institution, was contracted to perform the trial and manage the data.

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Hayashi, T., Kato, H., Tanabe, K. et al. Initial responsiveness to darbepoetin alfa and its contributing factors in non-dialysis chronic kidney disease patients in Japan. Clin Exp Nephrol 25, 110–119 (2021). https://doi.org/10.1007/s10157-020-01969-7

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Keywords

  • Erythropoiesis-stimulating agents
  • Hyporesponsiveness
  • Darbepoetin alfa
  • Chronic kidney disease
  • Pre-dialysis