Chronic kidney disease (CKD) has emerged as a leading public health issue with a high prevalence, poor outcome, and a heavy economic burden to society. Anemia is a highly prevalent complication among patients with CKD and is associated with an increased risk for death. Previous epidemiologic studies have suggested that the prevalence of anemia is 12.3% in CKD stage 3, 22.7% in CKD stage 4, and more than 50% in CKD stage 5 patients. The deficiency of erythropoietin (EPO) secretion is regarded to be the primary mechanism of renal anemia. As a result, the use of synthetic erythropoiesis-stimulating agents (ESAs) has been a mainstay of CKD-related anemia management, with some patients experiencing improved patient quality of life and a reduced need for blood transfusion, although randomized trial data have not shown a systematic benefit of ESAs for prolonging life or preventing cardiovascular events. In addition, an estimated 5% to 10% of patients with renal anemia exhibit an insufficient response to ESAs, as manifested by the persistence of anemia despite adequate dosing, or the requirement of higher than normal doses to achieve currently recommended hemoglobin targets.[5,6] Identification of mechanisms that affect EPO responsiveness could assist with development to strategies to optimize the management of anemia and improve the safety of ESA therapy among patients with CKD.
Several studies have reported an inverse association between ESA resistance and statin treatment. Sirken et al reported that statin treatment successfully reduced ESA requirements by 25% in maintenance hemodialysis (MHD) patients. Chiang et al also concluded from an interventional study that low-dose atorvastatin could improve ESA hyporesponsiveness in patients with end-stage renal disease (ESRD) receiving chronic dialysis. They postulated that the possible mechanism could be through the effect of statins on inflammation that in turn leads to ESA hyporesponsiveness among dialysis-dependent patients. Most existing studies have been conducted among dialysis-dependent patients with ESRD, but ESA therapy is also recommended in nondialysis-treated patients with CKD with hemoglobin concentration <100 g/L after the correction of other deficiency states (e.g., iron). Moreover, poor ESA responders with CKD experience higher rates of cardiovascular events, death, and worse renal survival than patients with a better response.[6,10] Therefore, the reversal of ESA hyporesponsiveness among patients with CKD may be particularly important as it may provide an opportunity to alter the progression of renal failure and favorably impact mortality and cardiovascular outcomes. Despite the increasing use of statins in patients with CKD, the potential relation between statin treatment and ESA hyporesponsiveness is not well understood among these patients. The objective of this retrospective real world study was to examine the association of statin therapy with ESA hyporesponsiveness among Chinese patients with CKD. We hypothesized that long-term statin therapy may improve ESA hyporesponsiveness in these patients.
2.1 Source population and cohort assembly
The source population was derived from baseline and follow-up EMR data obtained between April 2010 and April 2015 from adult patients diagnosed with CKD managed in the nephrology department at Peking University People's Hospital, one of the largest tertiary healthcare facilities in Beijing. A retrospective cohort of prevalent adult patients with CKD who had newly initiated ESA therapy, continued ESA treatment for at least 6 months, and had hemoglobin levels monitored for at least 6 months and at intervals not >3 months were included in the study. The index date was the date of ESA initiation. We excluded patients who experienced any of the following conditions before the index date or during study period: diagnosis of malignant tumors or hematologic disorders (e.g., aplastic anemia and other chronic bleeding disorders), receipt of blood transfusion(s) during the study period, or missing information on statin use. Of note, all patients were receiving usual clinical care throughout the whole study period.
2.2 Data collection and definitions
The EMR data included key variables such as patient demographics, medical history, laboratory tests, and drug prescriptions. Information on age, gender, presumed cause of CKD, serum creatinine, albumin, high-sensitive CRP, hemoglobin level, serum iron, transferrin saturation and ferritin levels, total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglyceride levels, ESA dosing, statin use and doses, and other medication use were extracted from the EMR before and during the study period, with linking of data elements at the individual patient level.
Estimated glomerular filtration rate (eGFR) was based on the CKD-EPI equation using baseline outpatient serum creatinine concentration and classified as stage 1 (eGFR ≥ 90 mL/min), stage 2 (eGFR 60–89 mL/min), stage 3 (eGFR 30–59 mL/min), stage 4 (eGFR 15–29 mL/min), and stage 5 (eGFR < 15 mL/min and not receiving renal replacement therapy).
Patients were considered statin nonusers if they had not previously received statin treatment and did not receive it during the study period. Patients were considered statin users if they were receiving statin treatment for at least 3 months prior to the index date and remained on statin treatment during follow-up.
The ESA hyporesponsiveness was defined as a failure, in the presence of adequate iron stores, to achieve and maintain the target hemoglobin level (110 g/L) at an ESA dose of or >300 IU/kg/wk when administered subcutaneously.
2.3 Statistical analysis
Statistical analyses were performed using SAS, version 9.4 (SAS Institute Inc, Cary, NC). Continuous variables were reported as mean values with standard deviations unless otherwise specified. Comparisons of continuous variables between 2 groups were performed using the t test or Wilcoxon signed rank tests where appropriate. The Chi-squared test was used to compare the categorical variables. Multivariable logistic regression models were constructed to assess the independent association between statin use and ESA hyporesponsiveness using a nested modeling approach that adjusted for different sets of clinical parameters including demographic, laboratory, and diagnostic measures. Specifically, the models progressively included patient demographics, baseline hemoglobin level, eGFR, serum albumin, baseline lipid profile, iron storage status, and receipt of angiotensin-converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB) treatment (Table 1). Odds ratio (OR) estimates were reported with 95% confidence intervals (CIs). Results were regarded as significant at the P < .05 level.
3.1 Study subjects
Among 2923 nondialysis-dependent patients with CKD who were older than 18 years and were followed up regularly at nephrology clinics between April 2010 and April 2015, 232 anemic patients who started ESA treatment for the 1st time and had hemoglobin levels monitored for at least 6 months and at intervals not >3 months were identified. Among these patients, 18 were excluded due to history of malignancy or hematologic disorders, 11 were excluded for receipt of blood transfusions during the study period, and 3 patients were excluded due to missing information related to statin usage prior to the index date or during the follow-up. Overall, 200 patients were included in the final analysis (Fig. 1).
The mean age of patients with CKD included in this study was 64 (±16) years, ranging from 20 to 98, and 59% were women. Of these patients, 69 had diabetic nephropathy (34.5%), 66 had glomerulonephritis (33%), 41 had hypertensive kidney damage (21.5%), and 24 had other diseases (12%). At baseline, 16.0%, 23.0%, and 61.0% of subjects selected were in CKD stages 3, 4, and 5, respectively (Table 2). The mean follow-up duration was 23.6 (±13.4) months, ranging from 6 to 56 months. Median number of hemoglobin tests was 6 (interquartile range [IQR] = 3–10), and the median interval between 2 consecutive hemoglobin tests was 41 days (IQR = 28–88 days).
3.2 Statin treatment
A total of 123 (61.5%) patients with CKD were defined as statin nonusers and 77 (38.5%) were considered statin users. Among statin users, 55 (71.4%), 4 (5.2%), and 18 (23.4%) patients were treated for coronary heart disease, stroke, and dyslipidemia, respectively. The most common statin prescriptions were for atorvastatin 20 mg/d (45.5%), atorvastatin 10 mg/d (14.3%), rosuvastatin 10 mg/d (9.1%), simvastatin 20 mg/d (7.8%), and simvastatin 40 mg/d (14.3%). There were no significant differences across baseline clinical characteristics for statin users and nonusers, except for higher total cholesterol level among statin users at baseline (1.90 mmol/L vs 1.43 mmol/L, P = .003) (Table 2). Of note, highly sensitive C-reactive protein (hs-CRP) level did not differ by statin usage (P = .78).
3.3 ESA hyporesponsiveness
Among all studied subjects, 165 (82.5%) were on regular iron supplements before initiation of ESA therapy and during follow-up. Among patients receiving iron supplementation, 12 (7.3% of iron users) patients received intravenous iron and 153 (92.7% of iron users) were taking oral supplementation. At baseline, no patients had absolute iron deficiency, which was defined as ferritin level <200 ng/mL. Baseline hemoglobin level was 78 (±16) g/L. The median dose of ESA for all patients was 133 IU/kg/wk (IQR = 100–282 IU/kg/wk).
Overall, 26 (13.0%) patients failed to reach target hemoglobin levels at a mean ESA dose of 348 ± 41 IU/kg/wk and were therefore classified as hyporesponders to ESA therapy. The rest of the patients with CKD (n = 174, 87.0%) achieved hemoglobin target within 6 months after ESA initiation at a mean dose of 220 ± 79 IU/kg/wk.
3.4 Effect of statin on ESA hyporesponsiveness
Overall, 6.5% of the statin users (5/77) and 17.1% of nonusers (21/123) were considered to have hyporesponsiveness to ESA therapy. In the univariate analysis, statin therapy was the only statistically significant factor associated with ESA hyporesponsiveness (P = .03, Table 1), while other previously reported factors associated with ESA hyporesponsiveness (e.g., iron insufficiency, inflammation, male gender, and ACEIs and/or ARB therapy[13–15]) were not found to be significantly associated with ESA hyporesponsiveness in our sample.
In logistic regression modeling, long-term statin treatment showed a protective association with ESA hyporesponsiveness in the unadjusted model (model 1, OR = 0.34, 95% CI: 0.12–0.96), and the association persisted after fully adjusting for all measured potential confounders (model 6, OR = 0.15, 95% CI: 0.03–0.64) (Table 3).
Among a cohort of Chinese adults with nondialysis-dependent CKD and anemia initiating ESA therapy, we found lower adjusted odds of ESA hyporesponsiveness with concomitant statin treatment. This association persisted after adjustment for patient demographics, baseline hemoglobin level, renal function, serum albumin, iron storage, lipid profile, and ACEI/ARB treatment.
Our study supports and extends previous studies that have reported an association between statin treatment and a lower risk of ESA hyporesponsiveness among patients with ESRD receiving chronic dialysis.[7,8,16] Sirken et al reported that statin treatment could reduce ESA requirements by 25% in hemodialysis patients. Chiang et al also observed that low-dose statin therapy (atorvastatin 10 mg/d) improved ESA responsiveness in dialysis-treated patients with ESRD in a prospective study. Our study builds upon these findings by exploring the association in less severe, nondialysis-dependent patients with CKD. It has been reported that poor ESA responders among patients with CKD are at a higher risk of cardiovascular events, death, and renal disease progression compared with patients that have a better response profile.[6,10] Therefore, the enhancement of ESA responsiveness among patients with CKD could potentially have important implications for clinical practice.
Other studies have consistently demonstrated a mechanistic link between chronic inflammation and ESA hyporesponsiveness, highlighting the association between increased inflammatory markers and a reduced response to ESA therapy.[16–19] In contrast, we did not observe an association between increased hs-CRP levels and ESA hyporesponsiveness as reported in other studies.[18,19] Reasons for this are not clear but may be explained, in part, by the timing of these measures, as baseline hs-CRP levels for statin users were taken and recorded after initiating statin treatment. Moreover, interleukin 6 (IL-6) may predict ESA responsiveness better than other biomarkers in patients with CKD.[17,20] It is also hypothesized that chronic inflammation can induce an enhanced state of T-cell activation, and the overproduction of erythropoiesis-inhibiting cytokines, such as IL-6 and tumor necrosis factor alpha (TNF-α), which may account for hyporesponsiveness to ESA therapy in patients with CKD. Furthermore, proinflammatory cytokines, including IL-6 and TNF-α, have been noted to be significantly suppressed after 12 weeks of statin therapy, resulting in an improved ESA responsiveness. Unfortunately, information on these cytokines were unavailable in our study. Therefore, future studies should more thoroughly explore these and other potential contributing pathways that lead to ESA hyporesponsiveness in the setting of CKD.
One of the strengths of our study is inclusion of adults with CKD that were closely monitored after initiation of ESA therapy and who had complete clinical evaluations. We also adjusted for a wide range of possible confounders but still found a strong, favorable association between statin treatment and ESA hyporesponsiveness in Chinese patients with CKD.
Several limitations should also be considered. As an observational, retrospective study, we cannot prove a causal relation between statin treatment and improved ESA hyporesponsiveness. We classified patients’ potential responses to ESA as hyporesponsive vs nonhyporesponsive. However, given the complexity of longitudinal response possibilities to ESA, this simplification may have reduced the power to identify risk factors. In other studies, ESA-resistance index (ERI) was based on monthly average hemoglobin levels and in addition, ESA doses were frequently used to try to classify ESA responsiveness. This index was not employed in our study because patients had hemoglobin measurements taken at varying time intervals, and ERI is considered to be more strongly related to EPO dose instead of patient-specific conditions. Finally, our relatively small sample size restricted our ability to stratify patients further by statin type and dose. Therefore, we consider our study as a hypothesis-generating study that adds further support to the potential link between statin treatment and ESA responsiveness in patients with CKD.
Statin therapy reduces lipid concentrations and cardiovascular endpoints across the severity of CKD and also reduces all-cause mortality in nondialysis-dependent patients with CKD. We found that long-term statin treatment is independently and inversely associated with ESA hyporesponsiveness among Chinese adults with CKD, which suggests potential additional benefits of statin therapy in this population. Large-scale, prospective studies are warranted to directly address the effect of statin therapy on ESA hyporesponsiveness and to delineate modifiable mechanisms underlying ESA hyporesponsiveness in the setting of CKD.
The authors express their appreciation to the steering committee members of AstraZeneca, Jiemin Wang, MD, MPH, Claudia Cabrera, PhD, Jia Wei, PhD, and Alan S. Go. The authors are also grateful to the study nurses, physicians, and medical directors for the time and energy they have contributed to this study.
ZS and MW analyzed, interpreted the patient data and were major contributors in writing the manuscript. LZ reviewed all patients’ clinical information and verified diagnoses. All authors contributed to the design of the study, interpretation of results and writing of the manuscript. All authors read and approved the final manuscript.
Conceptualization: Zhun Sui, Mi Wang, Li Zuo.
Data curation: Mi Wang.
Formal analysis: Zhun Sui, Mi Wang.
Investigation: Zhun Sui, Mi Wang.
Methodology: Zhun Sui, Mi Wang.
Project administration: Zhun Sui, Mi Wang.
Resources: Zhun Sui, Mi Wang.
Software: Zhun Sui, Mi Wang.
Writing – original draft: Zhun Sui, Mi Wang.
Writing – review & editing: Li Zuo.
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