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Published ahead of print on February 1, 2006
Clin J Am Soc Nephrol 1: 281-287, 2006
© 2006 American Society of Nephrology
doi: 10.2215/CJN.01281005
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Dialysis

Statin Treatment and Diabetes Affect Myeloperoxidase Activity in Maintenance Hemodialysis Patients

Peter Stenvinkel*, Ernesto Rodríguez-Ayala{dagger},{ddagger}, Ziad A. Massy§, Abdul Rashid Qureshi{dagger}, Peter Barany*, Bengt Fellström||, Olof Heimburger*, Bengt Lindholm{dagger}, and Anders Alvestrand*

* Divisions of Renal Medicine and {dagger} Baxter Novum, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Karolinska University Hospital at Huddinge, Stockholm, Sweden; {ddagger} Unidad de Investigación Médica en Enfermedades Nefrológicas Centro Médico Nacional Siglo XXI Instituto Mexicano del Seguro Social México D.F., Mexico City, Mexico; § INSERM ERI-12, University of Picardie and Amiens University Hospital, Amiens, France; and || Department of Medical Sciences, Renal Unit, University Hospital, Uppsala, Sweden

Address correspondence to: Dr. Peter Stenvinkel, Division of Renal Medicine K56, Karolinska University Hospital at Huddinge, 14186 Stockholm, Sweden. Phone: +46-8-5858-2532; Fax: +46-8-7114-742; E-mail: peter.stenvinkel{at}ki.se


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Myeloperoxidase (MPO), which is secreted during activation of neutrophils, may serve as one mechanistic link among persistent inflammation, oxidative stress, and cardiovascular disease. This study related MPO activity to inflammatory and oxidative stress biomarkers, comorbidity, and ongoing medication in prevalent hemodialysis (HD) patients. In a cross-sectional evaluation of 115 prevalent (vintage 25 mo) HD patients (62 men; 63 ± 1 yr), data on comorbidity (Davies score), diabetes, medication (statins and antihypertensive drugs), nutritional status (subjective global assessment), blood lipids (cholesterol, HDL cholesterol, and triglycerides), inflammatory biomarkers (serum albumin, C-reactive protein, TNF-{alpha}, and IL-6), oxidative stress biomarkers (pentosidine, 8-hydroxydeoxyguanosine, and MPO activity) were recorded. Patients with MPO activity greater than the median had significantly (P < 0.05) lower serum albumin levels (33.2 ± 0.7 versus 35.0 ± 0.5 g/L), higher 8-hydroxydeoxyguanosine levels (1.26 ± 0.08 versus 1.05 ± 0.06 ng/ml), and a lower prevalence of statin treatment (18 versus 36%). Therefore, the median MPO activity was significantly (P < 0.05) lower (17.7 versus 26.6 {Delta}OD630/min per mg protein) in the subgroup of 31 HD patients with ongoing statin treatment. In a multiple regression model, correction for the impact of age, gender, vintage, serum cholesterol, serum albumin, comorbidity, diabetes, and statin use, only diabetes (P < 0.01) and statin use (P < 0.01) were significantly associated to MPO activity. Fourteen patients who had diabetes and were receiving statin treatment had markedly (P = 0.001) lower median (19.9 versus 41.2 {Delta}OD630/min per mg protein) MPO activity compared with 18 who had diabetes and were not taking statins. This cross-sectional study suggests that both diabetes and statin treatment affect MPO activity in prevalent HD patients.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Patients with ESRD have significant cardiovascular risk factors, and once on dialysis they die at a more rapid rate than would be predicted by their Framingham risk factors alone (1). Much interest therefore has focused on the role of nontraditional risk factors for atherosclerosis, such as inflammation and increased oxidative stress (2). The inflammatory burden is high in ESRD patients, and a wide array of inflammatory biomarkers, such as C-reactive protein (CRP), IL-6, and leukocytes, have been proved to be robust predictors of poor outcome in this patient group (2). It is known that macrophages and neutrophils may vary considerably in their level of activation, ranging from a resting to a fully activated state. A recent study by Sela et al. (3) demonstrated that primed peripheral polymorphonuclear leukocytes are key mediators of low-grade inflammation and oxidative stress in chronic kidney disease.

Myeloperoxidase (MPO) is an abundant hemoprotein that is released by activated neutrophils, monocytes, and tissue-associated macrophages after inflammatory stimuli. MPO catalyzes a reaction between chloride and hydrogen peroxide to produce hypochlorous acid, which reacts with tyrosine residues of proteins to form 3-chlorotyrosine. As Himmelfarb et al. (4) documented, elevated levels of 3-chlorotyrosine in hemodialysis (HD) patients, oxidants that are generated by MPO, may contribute to the increased oxidative stress observed in this patient group. Indeed, higher activity of MPO has been reported in primed macrophages under inflammatory conditions in both patients with chronic kidney disease (3) and an experimental mouse model (5). Although MPO-generated oxidants are potent antimicrobial agents, these can also cause damage at inflammatory sites. As MPO predicts endothelial function in humans (6), probably by regulating nitric oxide bioavailability (7), increased MPO activity could serve as one mechanistic link among inflammation (activated leukocytes), oxidative stress, and endothelial dysfunction in ESRD. Indeed, in nonrenal patient groups, higher MPO levels are associated with increased risk for coronary artery disease (8), and Baldus et al. (9) demonstrated that MPO serum levels predicted cardiovascular events in 1090 patients with acute coronary syndromes.

Although increased MPO activity may serve as one important cardiovascular risk factor in ESRD, little is known about which factors may modulate its activity. However, a recent study in mice demonstrated that hydroxymethylglutaryl CoA reductase inhibitors (statins) downregulate MPO gene expression in macrophages (10). Because no clinical data on MPO activity have yet been reported in ESRD, we evaluated MPO activity in relation to inflammation, two other surrogate markers of oxidative stress (pentosidine [11] and 8-hydroxydeoxyguanosine [12]), diabetes, and drug therapies (antihypertensives and statins) in a cohort of prevalent HD patients.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusion
 References
 
Patients
We studied 115 (62 men) prevalent ESRD patients who were receiving regular HD at the Karolinska University Hospital at Huddinge. Median dialysis vintage was 25 mo (range 1 to 214 mo). Data on subjective global assessment (SGA), body mass index (kg/m2), diabetes, comorbidity score according to Davies (13), and smoking habits (current/former smokers versus nonsmokers) were recorded. The patients were divided according the use of statins (simvastatin, n = 15; atorvastatin, n = 10, fluvastatin, n = 4; and pravastatin, n = 2) or nonuse (n = 84) at the time of examination. Most patients were on antihypertensive medications (angiotensin-converting enzyme inhibitors and/or angiotensin II receptor blocker, n = 40; ß blockers, n = 49; and calcium channel blockers, n = 30) as well as other drugs that commonly are used in ESRD, such as phosphate and potassium binders; diuretics; and vitamins B, C, and D supplementation. Twenty-five patients (five statin users and 20 nonstatin users) received antibiotic treatment for various infectious complications. HD was performed three times a week (4 to 5 h per session) using bicarbonate dialysate and standard cellulose acetate (n = 13) or polysulphone (n = 102) dialysis membranes. Arteriovenous fistula was present in 67 patients, whereas 24 patients each used central dialysis catheters or grafts for dialysis access. The Ethics Committee of the Karolinska Institutet approved the study protocol at Karolinska University Hospital at Huddinge, Stockholm, and informed consent was obtained from the patients.

Study Design
Samples of venous blood were collected in the morning and before that day’s dialysis session. The plasma was separated, and samples were kept frozen at –70°C if not analyzed immediately. Plasma IL-6 was analyzed on an Immulite Automatic Immunoassay Analyzer (DPC, Los Angeles, CA) with an assay manufactured for this analyzer. TNF-{alpha} was analyzed in serum by an immunometric assay on an Immulite Analyzer (DPC) according to the instructions of the manufacturer. High-sensitivity CRP (hs-CRP) concentration (measured by nephelometry), leukocytes, neutrophils, and serum albumin concentration (bromcresol purple) were analyzed using routine methods at the Department of Laboratory Medicine, Karolinska University Hospital, Huddinge. Reversed-phase HPLC using fluorescence detection was used to determine plasma pentosidine (11) and homocysteine (14). Serum 8-hydroxydeoxyguanosine (8-OHdG) was determined by a competitive ELISA kit (Japanese Institute for the Control of Aging, Fukuroi, Shizuoka, Japan). SGA was used to evaluate the overall protein-energy nutritional status (15). SGA included six subjective assessments, three that were based on the patients’ weight loss, incidence of anorexia, and incidence of vomiting and three that were based on the subjective grading of muscle wasting, the presence of edema, and the loss of subcutaneous fat. On the basis of three consecutive assessments, each patient was given a score that reflects nutritional status as follows: 1 = normal nutrition, 2 = mild malnutrition, 3 = moderate malnutrition, and 4 = severe malnutrition. Malnutrition for the purpose of this study was defined as an SGA >1.

MPO activity was measured in fresh blood using the tetramethylbenzidine (Sigma, St. Louis, MO) reaction in neutrophils that were isolated with polymorphonuclear separation medium (Axis-Shield PoC AS, Oslo, Norway) (16). Protein content was measured using the Protein Assay from Bio-Rad Laboratories (Hercules, CA). Mixtures of a 100-µl aliquot of the samples and 100 µl of a stock solution (15 mM tetramethylbenzidine and 60 mM H2O2 in 300 mM sodium acetate buffer [pH 5.4]) were added to wells of a 96-well plate, and the MPO activity was measured in an ELISA reader at 630 nm over 2 min with readings taken every 15 s. The results were expressed as {Delta}OD630/min per mg protein. The coefficient of variation was 13.5%.

Statistical Analyses
Data are presented as mean ± SEM or median and range as appropriate. P < 0.05 was considered to be statistically significant. The distribution of MPO activity was not normal (Figure 1). The Wilcoxon rank sum test was used for comparisons between two groups for nonnormally distributed variables, whereas t test was used for normally distributed variables. We used Fisher exact test for nominal variables. Correlations were performed by the Spearman rank test. Differences among four groups were analyzed by ANOVA using Kruskal-Wallis test followed by Dunn’s procedure. We used stepwise (forward followed by backward) multiple regression analysis. The statistical analysis was performed using statistical software SAS version 9.1.3 (SAS Institute, Cary, NC).


Figure 1
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  		Figure 1. Distribution of myeloperoxidase (MPO) activity in 84 nonstatin and 31 statin users.

 

   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusion
 References
 
Patients were divided into two groups according to median MPO activity (22.8 {Delta}OD630/min per mg protein). Whereas HD patients with MPO activity greater than median had significantly (P < 0.05) lower serum albumin levels (33.2 ± 0.7 versus 35.0 ± 0.5 g/L), higher 8-OHdG levels (1.26 ± 0.8 versus 1.05 ± 0.06 ng/ml), and a lower prevalence of statin treatment (18 versus 36%), the difference in other clinical and laboratory parameters did not attain statistical significance (Table 1). No significant differences in MPO activity were observed between male and female HD patients (26.4 ± 2.6 versus 29.2 ± 3.2 {Delta}OD630/min per mg protein); malnourished and well-nourished patients (32.5 ± 3.3 versus 24.7 ± 3.2 {Delta}OD630/min per mg protein; P = 0.09); and patients with or without angiotensin-converting enzyme inhibitors/angiotensin II receptor blocker, ß blockers, or calcium-channel blockers (data not shown), respectively. Median MPO activity did not differ in patients who were using arteriovenous fistulas (22.8 {Delta}OD630/min per mg protein), central dialysis catheters (28.9 {Delta}OD630/min per mg protein), or grafts (20.5 {Delta}OD630/min per mg protein) for dialysis access. Median MPO activity tended (P = 0.06) to be higher in 25 patients who were receiving antibiotics (35.3 {Delta}OD630/min per mg protein) compared with 90 patients who were not receiving antibiotics (21.3 {Delta}OD630/min per mg protein). Whereas MPO activity correlated significantly with dialysis vintage ({rho} = –0.20; P < 0.05), serum albumin ({rho} = –0.19; P < 0.05), 8-OHdG ({rho} = 0.20; P < 0.05), and leukocyte count ({rho} = 0.19; P < 0.05), the correlations between MPO activity and age ({rho} = 0.01), pentosidine ({rho} = 0.06), homocysteine ({rho} = –0.15), neutrophils ({rho} = 0.16), hs-CRP ({rho} = 0.17), and IL-6 ({rho} = 0.10) levels did not attain statistical significance. In a multivariate model (backward followed by forward), including adjustment for the impact of dialysis vintage, serum albumin, 8-OHdG, and leukocytes (all correlated to MPO in univariate analysis), only serum albumin (estimate –0.03) was significantly (P < 0.05) associated with log MPO activity.


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  		Table 1. Clinical characteristics, blood lipids, inflammation, and oxidative stress biomarkers in HD patients divided according to median MPO activity (22.8 {Delta}OD630/min per mg protein)a

 
As the prevalence of statin users was lower in HD patients with MPO activity greater than median, we divided the patients into two groups: Nonstatin (n = 84) and statin (n = 31) users (Table 2). Whereas, age, gender, comorbidity, prevalence of malnutrition, and current/former smokers did not differ between the two groups, the prevalence of diabetes (55 versus 21%; P < 0.001) was markedly higher in the statin user group. As expected, significantly lower serum cholesterol levels (4.0 ± 0.3 versus 4.4 ± 0.1 mmol/L; P < 0.05) were observed in statin users. Whereas levels of leukocytes, neutrophils, hs-CRP, IL-6, TNF-{alpha}, pentosidine, homocysteine, and serum albumin did not differ between the two groups, the median MPO activity was significantly lower in statin users (17.7 versus 26.6 {Delta}OD630/min per mg protein; P < 0.05). In the whole patient group, the IL-6/hs-CRP ratio was significantly lower (1.8 versus 3.3 ± 0.8; P < 0.05) in nonusers of statins compared with statin users. No significant difference in median MPO activity (17.4 versus 19.2 {Delta}OD630/min per mg protein) was observed between 25 patients who were on lipophilic statins (simvastatin and atorvastatin) and six patients who were on nonlipophilic statins (pravastatin and fluvastatin). A stepwise multiple regression model analysis (Table 3) of log MPO activity, correcting for the impact of age, gender, dialysis vintage, Davies comorbidity score, diabetes, serum cholesterol, serum albumin, and CRP showed that only the use of statins (P = 0.01) and the presence of diabetes (P = 0.01) were independently associated with MPO activity. No interaction was demonstrated between diabetes x statin use.


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  		Table 2. Clinical characteristics, blood lipids, inflammation, and oxidative stress biomarkers in HD patients with or without statin treatment

 

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  		Table 3. A stepwise, forward, multivariate regression analysis of predictors of log MPO activity ({Delta}OD630/min per mg protein) in prevalent HD patientsa

 
To examine the influence of diabetes on MPO activity, we performed a subgroup analysis to compare 83 patients without diabetes and 32 patients with diabetes separately. Eighteen patients with diabetes and no statin treatment had significantly (P < 0.05) higher median MPO activity (41.2 versus 26.2 {Delta}OD630/min per mg protein) than 66 patients without diabetes or statin therapy (Figure 2). Moreover, whereas median MPO activity did not differ significantly in HD patients without diabetes and with and without ongoing statin therapy (15.9 versus 26.2 {Delta}OD630/min per mg protein), the difference in median MPO activity between HD patients with diabetes and with and without ongoing statin treatment (19.9 versus 41.2 {Delta}OD630/min per mg protein) was significant (P < 0.05).


Figure 2
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  		Figure 2. Box plots showing distribution of MPO activity in HD patients without and with diabetes and with and without ongoing statin treatment, respectively.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusion
 References
 
The chief finding of our study is that ongoing treatment with statins is associated with significantly lower MPO activity in prevalent HD patients. Of note, the observed difference persists even after correction for putative confounders, such as diabetes, comorbidity, vintage, age, and inflammation. Thus, our results are in accordance with recent in vitro data presented by Kumar et al. (10), who demonstrated that natural and synthetic statins strongly suppress MPO gene expression in both human and murine monocyte-macrophages and bone marrow precursors. Notably, repression of MPO gene expression was also observed in vivo in mice that were administered simvastatin. Moreover, the reduction in MPO mRNA levels correlated with reductions in MPO enzyme activity and protein levels (10). Our results are also compatible with results presented by Shishehbor et al. (17), which showed that statins promote systemic antioxidant effects through suppression of distinct oxidation pathways, including both MPO-derived and nitric oxide–derived oxidants. Recent data presented by Ivanovski et al. (18; Z.M., personal communication, December 2005) in apolipoprotein E–deficient mice showed that simvastatin treatment decreases nitrotyrosine levels. Indirect support for our finding is also provided by a study that demonstrated that statins decrease respiratory burst activity of human polymorphonuclear neutrophils in response to antineutrophilic cytoplasmic antibodies (19).

After dividing our cohort into HD patients with and without diabetes, we observed a significantly elevated MPO activity in statin-untreated patients with diabetes compared with statin-untreated patients without diabetes (Figure 2). Moreover, whereas the difference in MPO activity in patients without diabetes and with or without statins did not reach statistical significance, the difference in MPO activity in the subgroup of patients with diabetes and with and without statin treatment was significant (Figure 2). Thus, our data suggest that diabetes per se is associated with increased MPO activity and that statins may be particularly effective in decreasing MPO activity in this patient group. Indeed, reactive oxygen species have emerged as important molecules in the pathogenesis of diabetic vascular complications (20). Because Okouchi et al. (21) demonstrated that adhered neutrophils that are evaluated by MPO activity in vitro are enhanced by insulin treatment, it could be speculated that high MPO activity in diabetes is related to hyperinsulinemia. Although a recent study showed that vascular-bound MPO could use high glucose–stimulated hydrogen peroxide to amplify high glucose–induced injury to the vascular wall (22), data in the literature regarding MPO activity in diabetes are scarce and conflicting. Whereas MPO activity was significantly elevated in the vitreous of patients who had proliferative diabetic retinopathy (23), another study showed lower MPO activity in patients with diabetes (24). The observed discrepancies may be explained, at least partly, by differences in populations, methods, and examined tissues, and further studies are needed to evaluate MPO activity in patients who have diabetes and are well defined with respect to vascular and renal complications as well as to ongoing statin treatment.

Accumulating evidence in the literature suggests that the beneficial effects of statins are not limited to effects on serum cholesterol. Indeed, besides cholesterol lowering, statins may decrease oxidative stress and inflammation, enhance endothelial function, and mediate greater stability of atherosclerotic plaques (25). As statins suppress activities of transcription factors, such as NF-{kappa}B, while increasing the activity of peroxisome proliferator–activated receptor-{gamma} (26), modulation of these transcription factors could account for part of the documented anti-inflammatory effects. Because MPO has been implicated as a risk factor in chronic inflammatory conditions, such as atherosclerosis and neurodegenerative diseases, one could speculate that the protective effects of statins in these conditions (27,28) may be mediated, at least in part, via downregulation of MPO activity. Although statins effectively reduce vascular events in the nonrenal population (29), the beneficial effects of statin treatment on outcome in renal patients are less certain. The ALERT study showed that fluvastatin reduced cardiac deaths and nonfatal myocardial infarction in renal transplant patients (30). Further support for a protective effect of statins comes from registry data suggesting that statin prescription is associated with reduced mortality in HD patients (31). In contrast, the randomized 4D study demonstrated that atorvastatin had no effect on the composite primary end point of cardiovascular death, nonfatal myocardial infarction, and stroke in HD patients with type 2 diabetes (32). Thus, the results of two ongoing prospective statin studies in renal patients (SHARP and AURORA) are awaited with suspense.

As statins consistently decrease CRP concentrations in nonrenal patients (33), it can be postulated that this group of drugs may modulate inflammatory processes in the vessel wall. In accordance, most but not all studies have demonstrated that statins decrease CRP levels also in dialysis patients (34). In this cross-sectional study, CRP levels tended (although not statistically significantly) to be lower in statin users. As no difference was observed in median IL-6 levels between the two groups, the IL-6/hs-CRP ratio was significantly higher in statin users. Thus, in accordance with März et al. (35), our results suggest that statins may interfere with the generation and/or release of CRP from the liver rather than modulate local vascular inflammatory processes. Clearly, in future studies that evaluate the anti-inflammatory effects of statins in ESRD patients, both CRP and IL-6 should be evaluated.

The results of our study must be considered with the following caveats. First, the number of patients was limited, and no control group was evaluated for MPO activity. Thus, our clinical observation needs to be confirmed in larger patient cohorts. However, as evaluation of MPO activity is a time-consuming and laborious method performed in fresh blood samples, this method does not allow evaluation of large patient cohorts. Second, the cross-sectional nature of the study design does not allow us to draw any mechanistic conclusions. Third, we did not take into consideration the duration of statin treatment before investigation. Although unlikely, we cannot exclude the possibility that different durations of statin treatment in patients with and without diabetes may have affected the results. Fourth, as MPO activity tended to be higher in patients who were receiving antibiotic treatment, we cannot exclude that our results were affected by ongoing infectious complication. However, the prevalence of ongoing antibiotic treatment did not differ between statin (16%) and nonstatin (24%) users. Fifth, it could be argued that MPO activity is just a complicated and expensive way to analyze the neutrophil count. However, in a multiple regression model that included vintage, 8-OHdG, leukocytes, and serum albumin, no association was found between leukocytes and MPO activity. In accordance, a previous study demonstrated that MPO activity is independent of the amount of neutrophils (36). Finally, as the observed difference in total serum cholesterol levels was small between the nonstatin and statin users (Table 2), noncompliance in the statin users cannot be excluded.


   Conclusion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
References
 
The results of this cross-sectional evaluation of prevalent HD patients suggest that both the presence of diabetes and ongoing statin treatment affect MPO activity. As MPO-mediated endothelial dysfunction may serve as one important link among persistent inflammation, oxidative stress, and cardiovascular disease in ESRD, further prospective studies to evaluate MPO activity after the initiation of statin treatment are warranted, especially in patients with diabetes.


   Acknowledgments
 
This study was supported by an unconditional grant from Amgen Inc.


   Footnotes
 
Published online ahead of print. Publication date available at www.cjasn.org.

Received October 12, 2005. Accepted January 1, 2006.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 

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