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      Anti-Inflammatory Effect of Simvastatin in Hemodialysis Patients

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          Abstract

          Background

          Patients in the final stages of renal failure have accelerated inflammation conditions. Inflammation causes progressive kidney damage, faster progression of atherogenesis, chronic malnutrition and increased anemia, resulting in lower life expectancy of patients under dialysis. Statins have pleiotropic effects, because the drug has effects more than just decreasing lipids such as antioxidant effects, changes in endothelial dysfunction, stabilizing the plaque and immune system regulator.

          Objectives

          The aim of the study was to evaluate anti-inflammatory effect of simvastatin (one of the statins) in patients under hemodialysis.

          Patients and Methods

          In this clinical trial study, 40 patients under hemodialysis were studied for 12 weeks. Patients were divided into treatment (25 cases) and control groups (15 cases). The treatment group received a daily dosage of 20 mg of simvastatin, while the control group received no medication. The serum amounts of hs-CRP, IL6, Hb and WBC count were measured and compared at baseline and after 12 weeks. In addition, probable hepatic and muscular complications were studied in patients.

          Results

          At baseline, each of treatment and control groups had similar characteristics. During the study, the average level of CRP decreased in the treatment group (P = 0.04), while it was increased in the control group. The amount of serum IL-6 dropped in the treatment group (P = 0.01); however, it was increased in the control group. In both groups, the level of Hb increased significantly at the end of study in the treatment group (P = 0.007) and the control group (P = 0.016). The average WBC count decreased significantly in the treatment group and the control group (P = 0.003). There was no significant change in hepatic and muscular enzymes in the two groups.

          Conclusions

          End stage renal disease (ESRD) have accelerated inflammatory conditions. Simvastatin clearly lowers the serum levels of CRP and IL-6, and the white blood cell count in dialysis patients. Administering Simvastatin to dialysis patients is safe.

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          Most cited references12

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          Biomarkers of inflammation and progression of chronic kidney disease.

          Marcello Tonelli, Frank Sacks, Marc Pfeffer … (2005)
          Chronic kidney disease is associated with higher levels of inflammatory biomarkers. Statins have anti-inflammatory properties and may attenuate loss of kidney function. Although inflammation may mediate progressive renal injury, the relation between statin use, markers of inflammation, and the rate of kidney function loss has not been elucidated. We examined the association between pravastatin use, levels of C-reactive protein (CRP), soluble tumor necrosis factor receptor II (sTNFrii), and the rate of kidney function loss. We performed a post hoc analysis of data from a randomized placebo controlled trial of pravastatin 40 mg daily in people with previous myocardial infarction. Glomerular filtration rate (GFR) was estimated using the Modification of Diet in Renal Disease Study (MDRD) GFR equation. We studied 687 subjects with chronic kidney disease (GFR < 60 mL/min/1.73 m(2)) who did not experience a cardiovascular event during follow-up. Multivariate linear regression was used to study the relation between baseline CRP and sTNFrii and the rate of kidney function loss in mL/min/1.73 m(2)/year. Cross-product interaction terms were used to determine if these relations varied with pravastatin use. Median baseline GFR was 54.5 mL/min/1.73 m(2) (interquartile range 49.7, 57.8) and median duration of follow-up was 58 months. Higher baseline CRP level was independently associated with more rapid kidney function loss (highest tertile 0.6 mL/min/1.73 m(2) per year faster than lowest tertile) (P= 0.001). A similar independent relation was observed between tertile of sTNFrii and rate of kidney function loss (highest tertile 0.5 mL/min/1.73 m(2) per year faster than lowest tertile) (P= 0.006). Subjects with both CRP and sTNFrii in the highest tertile ("inflamed" status) appeared to derive more renal benefit from pravastatin than those without (P for interaction 0.047). In these 108 subjects, renal function loss in pravastatin recipients was 0.8 mL/min/1.73 m(2)/year slower than placebo (95% CI 0 to 1.5 mL/min/1.73 m(2)/year slower) (P= 0.039). Higher CRP and sTNFrii are independently associated with faster rates of kidney function loss in chronic kidney disease. Pravastatin appears to prevent loss of kidney function to a greater extent in individuals with greater evidence of inflammation, although this was of borderline significance. These data suggest that inflammation may mediate the loss of kidney function among subjects with chronic kidney disease and concomitant coronary disease.
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            Statins: potential new indications in inflammatory conditions.

            Matthias Endres (2006)
            Hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are potent cholesterol-lowering drugs. In addition to their cholesterol-lowering properties, statins exert a number of so-called 'pleiotropic', vasculoprotective actions that include improvement of endothelial function, increased nitric oxide (NO) bioavailability, antioxidant properties, stabilisation of atherosclerotic plaques, regulation of progenitor cells, inhibition of inflammatory responses and immunomodulatory actions. Pleiotropic actions of statins may have potential clinical impact in vascular disease beyond cholesterol lowering. The ongoing Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), for example, tests the effects of statins in the primary prevention of cardiovascular disease among patients with low levels of low-density lipoprotein cholesterol (LDL-C) and elevated high-sensitivity C-reactive protein (hs-CRP). Additionally, previous studies have shown that although cholesterol is not an established stroke risk factor, statin therapy is associated with a reduction in the incidence of strokes. It is known that sudden withdrawal of statin treatment may acutely impair vascular function and increase morbidity and mortality in patients with vascular disease. Furthermore, the anti-inflammatory effects of statins may have clinical impact in a number of non-vascular conditions including multiple sclerosis and rheumatoid arthritis.
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              Effects of simvastatin on high-sensitivity C-reactive protein and serum albumin in hemodialysis patients.

              Won Min, Sang Lee, Jung Sik Park … (2002)
              A 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor is recommended in hemodialysis (HD) patients with hypercholesterolemia to improve their lipid profiles. We evaluated effects of simvastatin on markers for inflammation, oxidative stress, and coagulation in HD patients. Sixty-two maintenance HD patients with serum cholesterol levels of 200 mg/dL or greater were randomly assigned to the treatment group (n = 31; 8 men, 23 women; age, 63 +/- 11 years) and administered simvastatin, 20 mg/d, for 8 weeks or to the control group (n = 31; 10 men, 21 women; age, 60 +/- 12 years). We measured cholesterol, albumin, high-sensitivity C-reactive protein (hs-CRP), malondialdehyde (MDA; an index of lipid peroxidation), and D-dimer (a marker of intravascular coagulation) in blood at baseline and again at 8 weeks. Fifty-eight of 62 patients completed the study. In the control group, total cholesterol, serum albumin, hs-CRP, MDA, and D-dimer levels did not change. In the treatment group, simvastatin administration for 8 weeks significantly reduced total cholesterol levels from 232 +/- 25 to 165 +/- 39 mg/dL (P < 0.001) and hs-CRP levels from a median of 0.23 mg/dL (range, 0.05 to 1.63 mg/dL) to 0.12 mg/dL (range, <0.006 to 1.45 mg/dL; P < 0.01), whereas it increased serum albumin levels from 3.4 +/- 0.3 to 3.6 +/- 0.4 g/dL (P < 0.001). Administration of simvastatin did not affect MDA and D-dimer levels. These results suggest that in addition to the lipid-lowering effect, simvastatin had an antiinflammatory effect in HD patients. Considering that atherosclerosis is inflammation of the vascular wall, simvastatin may have a beneficial effect on cardiovascular disease, in part because it alleviates inflammation.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Jundishapur J Nat Pharm Prod
                Journal ID (iso-abbrev): Jundishapur J Nat Pharm Prod
                Journal ID (publisher-id): DOCS
                Title: Jundishapur Journal of Natural Pharmaceutical Products
                Publisher: DOCS
                ISSN (Print): 1735-7780
                ISSN (Electronic): 2228-7876
                Publication date (Electronic): 01 February 2015
                Publication date Collection: February 2015
                Volume: 10
                Issue: 1
                Electronic Location Identifier: e17962
                Affiliations
                [1 ]Diabetes Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, IR Iran
                Author notes
                [* ]Corresponding author: Leila Yazdanpanah, Diabetes Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Postal Code: 61357-15794, Ahvaz, IR Iran. Tel/Fax: +98-6113369539, E-mail: leila.yazdanpanah@ 123456gmail.com
                Article
                PMC ID: 4386319
                SO-VID: 8d79820d-8abf-4cec-b96f-aebeea19b0bd
                Copyright © Copyright © 2015, School of Pharmacy, Ahvaz Jundishapur University of Medical Sciences.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License ( http://creativecommons.org/licenses/by-nc/4.0/) which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly cited.

                History
                Date received : 01 February 2014
                Date revision received : 25 May 2014
                Date accepted : 06 September 2014
                Categories
                Subject: Research Article

                Keywords: anti-inflammatory agents,simvastatin,renal dialysis
                Data availability:
                Keywords: anti-inflammatory agents, simvastatin, renal dialysis

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