Atorvastatin Increases Erythropoietin-Stimulating ...

Original Report: Patient-Oriented, Translational Research American

Journal of

Nephrology

Am J Nephrol 2009;29:392–397 DOI: 10.1159/000169658

Received: May 24, 2008 Accepted: September 3, 2008 Published online: October 31, 2008

Atorvastatin Increases Erythropoietin-Stimulating Agent Hyporesponsiveness in Maintenance Hemodialysis Patients: Role of Anti-Inflammation Effects Chih-Kang Chiang a–c Shao-Yu Yang a, c Yu-Sen Peng c Shih-Ping Hsu c Mei-Fen Pai c Jen-Wen Huang a Kuan-Yu Hung a, c Kuan-Dun Wu a Departments of a Internal Medicine, b Integrated Diagnostics & Therapeutics, National Taiwan University Hospital, College of Medicine, National Taiwan University, and c Internal Medicine, Far-Eastern Memorial Hospital, Pan-Chiao, Taipei, Taiwan

Key Words Erythropoietin-stimulating agent ⴢ Statins ⴢ Dialysis ⴢ Inflammation

Abstract Erythropoietin-stimulating agent (ESA) hyporesponsiveness is aggravated by chronic inflammation in maintenance hemodialysis (MHD) patients. Dyslipidemia is prevalent in MHD patients. Statin therapy has been demonstrated to not only be effective in lowering lipid levels, but also numerous pleiotropic effects including anti-inflammatory, anti-fibrotic and endothelial function improvement. Recently, a retrospective study has shown that statin therapy decreases ESA requirements in MHD patients. We conducted a prospective study to analyze the effect of statin therapy on ESA hyporesponsiveness, and especially emphasized its anti-inflammatory benefits in MHD patients. This prospective study enrolled 30 patients with baseline cholesterol 1220 mg/dl. Low-dose atorvastatin (10 mg/day) was prescribed for 12 weeks. We prospectively recorded patients’ biochemistry and hematological profiles, ESA prescription and some inflammatory markers at baseline, 4 weeks and 12 weeks. Statistically significant changes were noted after 4 and 12 weeks of statin

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therapy for cholesterol (272.5 8 41.1 to 184.4 8 37.6 and 196.4 8 40.2 mg/dl, p ! 0.05) and ESA hyporesponsiveness, which demonstrated as erythropoietin to hematocrit ratio (EHR) (129.3 8 58.2 to 122.3 8 53.5 and 121.0 8 53.3 EPO U/Hct/week, p ! 0.05). Mean values for proinflammatory cytokines included interleukin-6 and tumor necrotic factor- ␣ levels decreased by 30.8 and 10.6%, respectively. Thus, these data suggest that statin therapy may improve ESA hyporesponsiveness in dialysis patients. This improvement in ESA hyporesponsiveness is associated with the effects of statins on inflammation. Copyright © 2008 S. Karger AG, Basel

Introduction

Anemia is an important manifestation of chronic renal failure. Factors such as iron deficiency, severe hyperparathyroidism, aluminum toxicity, vitamin deficiency, malnutrition, suboptimal dialysis, and drugs (including angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers) have been identified as contributory factors to erythropoietin resistance in maintenance hemodialysis (MHD) patients [1–4]. Improving Kuan-Yu Hung, MD, PhD Department of Internal Medicine National Taiwan University Hospital, Taipei (Taiwan) Tel. +886 2 2312 3456, Fax +886 2 2322 2955 E-Mail [email protected]

ESA hyporesponsiveness is one of the major issues in taking care of dialysis patients. Improving ESA hyporesponsiveness is not only improving patients’ quality of life, but also reducing the burden of care cost [5–7]. In previously published literature, we and others successfully demonstrated that proinflammatory cytokines, such as interleukin (IL)-6, tumor necrotic factor (TNF)␣, IL-18 and C-reactive protein (CRP), were elevated in MHD patients and they also predicted patients’ outcome [8–14]. Chronic inflammation has been reported as one of the most important factors impacting ESA hyporesponsiveness [15]. Sirken et al. [16] reported that statin treatment successfully reduced ESA requirements by 25% in MHD patients. They postulated its possible mechanisms through anti-inflammatory effects. However, they did not check any inflammatory markers in their retrospective study. Therefore, we conducted a prospective study to examine the impact of statin therapy in ESA hyporesponsiveness, and especially emphasized its antiinflammatory effects. We hypothesized that statin therapy may improve ESA hyporesponsiveness through its anti-inflammatory effects.

Patients and Methods This is an open-labeled, interventional trial to evaluate the efficacy of low-dose atorvastatin (10 mg/tablet; Pfizer, USA) on ESA hyporesponsiveness, and the lipid-lowering and anti-inflammatory effects in MHD patients. Between September 2004 and March 2005, 32 MHD patients (14 males and 18 females) with a total cholesterol level 1220 mg/dl during a monthly survey and without contraindications were included in the study after providing informed consent. The intervention is based on the guidelines of dyslipidemia treatment of Taiwan National Health Insurance. The patients’ baseline characteristics and their laboratory parameters are shown in table 1. Patients who were 175 years of age were not included; other exclusion criteria were the presence of any kind of hospitalization or operation within 3 months, malignant diseases, treatment with immunosuppressant agents, connective tissue disease, any cardiovascular event in the previous 6 months, any acute disease, and hypersensitivity to statins. A 12-week supply of the atorvastatin (10 mg) was dispensed to the study patients at each 4-week prescription cycle in the hemodialysis center; adherence to the therapy was assessed by counting the number of pills at the following visit. For all patients, midweek predialysis arteriovenous blood samples were taken after an 8-hour overnight fast, at baseline, after 4 and 12 weeks of treatment in the study. This clinical study followed the Declaration of Helsinki and was permitted by the Human Research Committee of the Far Eastern Memorial Hospital. All patients that participated signed informed consent forms. Regarding the demographics and etiologies of end-stage renal disease (ESRD), we obtained the data on enrollment and during the study period from the medical charts and a computerized database at our unit. The re-

Statin Improves ESA Hyporesponsiveness

Table 1. Demographic and clinical characteristics of study patients at baseline (n = 30)

Male/female Age, years Body mass index Duration of HD, months Systolic blood pressure, mm Hg Diastolic blood pressure, mm Hg Alanine aminotransferase, U/l Fasting blood glucose, mg/dl Albumin, g/dl BUN, mg/dl Cr, mg/dl Kt/Vurea nPCR, g/dl/day Fe, ␮g/dl TIBC, ␮g/dl Ferritin, ␮g/l i-PTH, pg/dl Primary renal diseases, % Diabetes mellitus Chronic glomerulonephritis Other

12/18 57.4812.3 24.485.6 36.489.6 141812 7886 12.8810.4 128.8865.0 4.180.4 81.2821.4 11.083.0 1.3180.19 1.1280.2 74.4821.0 243.8837.8 641.88223.0 140.3823.8 66.7 26.7 6.6

combinant human erythropoietin (rhEPO), Recormon (Roche Diagnostics GmbH, Mannheim, Germany), was prescribed in our dialysis unit. ESA responsiveness was defined as EPO dosage per week divided by Hct level (EPO/Hct/week) and presented as erythropoietin to hematocrit ratio (EHR). A lower level of EHR meant better responsiveness. Blood samples were drawn from the arterial end of the vascular access just before starting HD and collected in Vacutainer tubes containing ethylenediamine tetraacetic acid as described elsewhere [17–19]. Plasma samples were centrifuged at 2,000 g for 5 min, aliquoted and kept frozen at –80 ° C until assayed. Blood urea nitrogen, creatinine, albumin, total cholesterol (CHO), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C), and other biochemistry parameters were measured by standard laboratory techniques with an automatic analyzer (Hitachi 747 autoanalyzer). hsCRP was measured by a high-sensitivity modified laser nephelometry technique (Berhing Diagnostics). The hsCRP assay was standardized according to the WHO First International Reference Standard and had a sensitivity of 0.1 ␮g/ml, with a standard reference range of between 0.1 and 0.4 mg/l. Plasma IL-18 levels were assayed using a commercially available immunoenzymatic method (Colorimetric Sandwich ELISA, Quantikine Human IL-18; R&D Inc., Minneapolis, Minn., USA). Plasma IL-6 and TNF- ␣ levels were measured with a commercially available enzyme-linked immunosorbent assay (Chemiluminescent Sandwich ELISA, Quantikine Human IL-6 and TNF- ␣; R&D Inc.). The ELISA kits were handled according to the manufacturer’s instructions. The detection limits for IL-18, IL-6, and TNF- ␣ were 12.5, 0.3, and 0.7 pg/ml, respectively.

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Statistics Results are expressed as means 8 SD unless otherwise stated. Statistical significance of the baseline biochemical parameters between baseline and 4 and 12 weeks was determined by paired t test for comparison between two means. Differences between the two related groups were examined by nonparametric analysis with Wilcoxon test for cytokines data. Analyses were performed using the SPSS 13.0 for Microsoft Window XP (statistical significance was taken as a p value !0.05).

Results

Initially, 32 patients with baseline cholesterol levels 1220 mg/dl were included in this study. Two patients were excluded from the final analysis. One patient discontinued atorvastatin therapy because of severe acne during the first 4 weeks; the other patient was withdrawn from the study for inadequate drug compliance; as listed in table 1, 30 patients were included in the final analysis with 12 male and 18 female patients. Mean age was 57.4 8 12.3 years. Iron profiles were 74.4 8 21.0 ␮g/dl in iron, 243.8 8 37.8 ␮g/dl in total iron-binding capacity, and 641.8 8 223.0 ␮g/l in ferritin levels. The mean intact parathyroid hormone level was 140.3 8 23.8 pg/dl. The etiologies of ESRD were diabetes mellitus in 20 patients, chronic glomerulonephritis in 8 patients, and other etiologies in 2 patients. Mean systolic and diastolic blood pressure was 141 8 12 and 78 8 6 mm Hg, respectively. Effects of Atorvastatin on Lipid Profiles As shown in table 2, the baseline CHO, TG, HDL-C and LDL-C were 272.5, 304.1, 56.8 and 162.9 mg/dl, respectively. CHO, TG and LDL-C levels were significantly reduced to 184.4, 209.7 and 94.3 mg/dl after 4 weeks of atorvastatin (10 mg/day) therapy. The estimated lipidlowering effect of atorvastatin on CHO and LDL-C levels is 32.3 and 42.1%. Atorvastatin also reduced HDL-C by 5.8%, but this was statistically insignificant. Similar lipid-lowering effects for atorvastatin therapy were found to last to the end of the study at week 12. Effects of Atorvastatin on ESA Hyporesponsiveness Hct levels at baseline were 33.2%, at week 4 they were 33.9%, and at week 12 they were 34.0%, which was slightly increased, and EPO dosage at baseline was 4,191 units/ week, at week 4 it was 4,095 units/week, and at week 12 it was 4,050 units/week, which was slightly decreased during the study period, but statistically insignificant. Erythropoietin responsiveness (EHR), which is defined as EPO 394

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Table 2. Effectiveness of atorvastatin on HD patients: lipid profiles and erythropoietin responsiveness

Cholesterol, mg/dl Triglyceride, mg/dl HDL-C, mg/dl LDL-C, mg/dl Albumin, g/dl AST, U/l ALT, U/l Hct, % EPO, units/week EHR, EPO/Hct/week hsCRP, mg/dl IL-18, pg/ml IL-6, pg/ml TNF-␣, pg/ml

Baseline

4 weeks

12 weeks

272.5841.1 304.18192.4 56.8810.5 162.9847.1 3.9880.27 13.687.7 12.689.9 33.283.1 4,19181,672 129.3858.2 0.8680.41 492.2844.4 3.2580.54 5.4780.27

184.4837.6* 209.78159.2* 53.5810.0 94.3827.8* 4.0180.41 12.685.1 12.387.4 33.982.2 4,09581,674 122.3853.5* 0.5180.35 470.5840.9 2.3680.44* 5.0580.21*

196.4840.2* 194.68105.0* 51.6812.2 103.8829.2* 4.0580.37 14.9587.1 14.3088.2 34.082.7 4,05081,702 121.0853.3* 0.4980.34 486.2847.4 2.2580.52* 5.0880.25*

* p < 0.05 as compared with baseline.

Table 3. Correlation coefficient (␳) between changes of proin-

flammatory cytokines and changes of EHR in atorvastatin-treated HD patients ⌬EHR

⌬ IL-18, % ⌬ IL-6, % ⌬ TNF-␣, %

4 weeks

12 weeks

0.12 0.25* 0.18*

0.09 0.28* 0.19*

Data expressed as Spearman‘s ␳ value. ⌬ = Change; EHR = erythropoietin to hematocrit ratio; IL-6 = interleukin-6; TNF-␣ = tumor necrosis factor-␣. ⌬ defined as 100% ! (post-intervention data – baseline data)/baseline data. * p < 0.05, ⌬ cytokines (%) vs. ⌬EHR.

dosage per week divided by Hct level (EPO/Hct/week), significantly improved from 129.3 to 122.3 and 121.0, respectively (p ! 0.05). The percentages of ESA hyporesponsiveness improved with levels of 5.4 and 6.4% at weeks 4 and 12, respectively. Effects of Atorvastatin on Proinflammatory Cytokines Proinflammatory cytokines levels, including IL-6 and TNF- ␣, were suppressed significantly after 4 or 12 weeks of atorvastatin therapy (table 2). IL-6 levels were suppressed from 3.25 to 2.36 and 2.25 pg/ml after 4 and 12 weeks of statin treatment (p ! 0.05). The absolute Chiang /Yang /Peng /Hsu /Pai /Huang / Hung /Wu

Table 4. Changes of proinflammatory cytokines in atorvastatin-

The study design provided stronger evidence in this issue by giving direct evidence of correcting inflammation and improving ESA hyporesponsiveness. Our work 4 weeks 12 weeks had three important issues deserving further discussion. –4.4 (–6.2 to 2.1) –1.2 (–7.1 to 1.2) ⌬ IL-18, % First, several potential mechanisms linking cytokines –27.4 (–47.2 to –6.8) –30.8 (–50.1 to –8.2) ⌬ IL-6, % –7.7 (–13.1 to –1.6) –7.1 (–14.0 to –1.1) ⌬ TNF-␣, % with anemia have been proposed, and a complex picture of interactions between different cytokine effects has Data expressed as median (quartiles). emerged. These mechanisms include bone marrow sup⌬ = Change; IL-6 = interleukin-6; TNF-␣ = tumor necrosis pression of erythropoiesis, reduced erythropoietin secrefactor-␣. * ⌬ defined as 100% ! (post-intervention data – baseline data)/ tion, intestinal bleeding and disrupted iron metabolism baseline data. [16]. IL-1 and TNF-␣ have all demonstrated suppressive effects on erythropoiesis [21, 22]. Moreover, IL-1 and IL6 can antagonize erythropoietin’s ability to stimulate bone marrow proliferation in culture [23]. In vitro evisuppression level of IL-6 ranged from 27.4 to 30.8% dence also suggested that IL-1␣, IL-1␤ and TNF-␣ inwithin 12 weeks. TNF- ␣ levels were also suppressed hibit erythropoietin production in a culture of the hufrom 5.47 to 5.05 and 5.08 pg/ml after 4 and 12 weeks of man hepatoma line G2 [24]. In vivo studies also suggeststatin treatment (p ! 0.05). The absolute suppression ed that intraperitoneal IL-6 injections and intravascular level of TNF- ␣ ranged from 7.2 to 7.7% within 12 weeks. injections of rhTNF-␣ can lead to watery diarrhea, vasThere was also a trend of decreasing hsCRP levels, but cular leak syndrome and necrosis of the villi [25], as well it was statistically insignificant. However, no effect with as an acute inflammatory response with hemorrhage in regards to statin therapy in IL-18 level was observed (ta- the cecum [26]. In the present study, atorvastatin therapy ble 4). Furthermore, we evaluated the correlation be- introduced suppression of proinflammatory cytokines tween changes of EHR and proinflammatory cytokines. (tables 2, 4), which may at least partially explain the imAs shown in table 3, the changes of proinflammatory provement of ESA hyporesponsiveness in MHD pacytokines (IL-6 and TNF- ␣) are mild, but significantly tients. Second, in chronic kidney disease patients, it is still associated with the changes of EHR (p = 0.18–0.28). The results, at least partially, suggest that atorvastatin treat- debated whether treatment including predialysis, dialysis ment improved ESA hyporesponsiveness by reducing and transplant or, for patients with dyslipidemia, statin treatment, leads to actual survival benefits. In a multiinflammation. center, randomized, double-blind, prospective study with type 2 diabetes mellitus receiving MHD patients, atorDiscussion vastatin therapy did not gain survival benefits in diabetic patients with MHD, but did increase the risk of cereThe chief findings in the present study are that low- brovascular events [27]. Several observational studies dose atorvastatin treatment (10 mg/day) improves eryth- also demonstrated that hypocholesterolemia or low LDLropoietin responsiveness in MHD patients. Proinflam- C levels have a risk of increasing mortality and morbidity, matory cytokines, such as IL-6 and TNF- ␣, were sup- which is called the ‘reverse epidemiology’ phenomenon pressed during the study period. The lipid-lowering [28–30]. These findings retard primary care physicians to effects of atorvastatin in MHD patients are similar in prescribed statin in preventing hypercholesterolemia-rethe general population without significant adverse ef- lated cardiovascular events. However, recent meta-analyfects [20]. These observations imply that atorvastatin sis helps us to clarify statin therapy in transforming the improves ESA hyporesponsiveness through correcting benefits of cardiovascular surrogate markers to clinical chronic inflammation by series follow-up of proinflam- outcome [31]. Our findings extend the pleiotropic effects matory cytokines in MHD patients. As compared with and extra benefits of statin therapy in correcting ESA hya previous retrospective study reported by Sirken et al. poresponsiveness, which can prompt primary care physi[16], we conducted a prospective, open-labeled, and in- cians to prescribe statin in treating MHD patients with tent-to-treat study to address the issue of statin therapy hypercholesterolemia. improving ESA hyporesponsiveness in MHD patients. treated HD patients


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Third, only 2 patients were excluded in the final analysis. The lipid-lowering effects of atorvastatin were equivalent to those observed in the general population and previous works involving MHD patients [20]. No significant clinical adverse effects, such as hepatotoxicity and muscle toxicity, were observed in patients receiving statin therapy. These findings suggest good atorvastatin adherence and tolerance in MHD patients. Several limitations of our study deserve consideration. First, this is a small-scale, intervention trial, which only included 30 patients in the final analysis. A larger prospective study is mandatory. Second, the findings of improving ESA hyporesponsiveness and suppressing proinflammatory cytokines as a cause and consequence, or just as an association effect, cannot be answered in this study. Third, the benefit of reducing EPO dosage is minor; only 150 units/week were saved. Thus, there is no reason to prescribe statins in correcting ESA hyporesponsiveness under the viewpoint of cost-benefit effects. In the USA, the median prescription of ESA is 10,000–20,000 units/ week as compared with 4,000 units/week in Taiwan. The

statin prescription may get more benefits in the USA. Finally, the inherent limitation of the current study is that it has no control group and is not randomized. The study can only be considered as a prospective longitudinal study with no control. However, hypercholesterolemia in MHD patients requires aggressive treatment with statins under the recent meta-analysis reports [31], which may also have benefits in ESA hyporesponsiveness with the support of the present study. In conclusion, our findings suggest that statin therapy may decrease EPO requirements in dialysis patients. The improvement in ESA hyporesponsiveness may be caused by the pleiotropic effect of statins on diminishing chronic inflammation in MHD patients. Acknowledgements We thank the National Science Council (NSC-95-2314-B-002307-MY2 and NSC-97-2314-B-002-051-MY3), FEMH-93-D006, and the Mrs. Hsiu-Chin Lee Kidney Research Foundation for grant support.

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