NDT Advance Access originally published online on October 25, 2005
Nephrology Dialysis Transplantation 2006 21(2):337-344; doi:10.1093/ndt/gfi224
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© The Author [2005]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Original Articles: Clinical Nephrology
In vivo and in vitro effects of simvastatin on inflammatory markers in pre-dialysis patients
1 Department of Internal Medicine, Postgraduate School of Nephrology, 3 Nephrology Division and 2 Pharmacology Section, Neuroscience Department, University of Pisa, Pisa, Italy
Correspondence and offprint requests to: Vincenzo Panichi, MD, Dipartimento di Medicina Interna, Via Roma 67, 56100 Pisa, Italy. Email: v.panichi{at}med.unipi.it
Background. The beneficial effects of statins in reducing cardiovascular events have been attributed predominantly to their lipid-lowering effects, recent studies suggest that these effects might be due to their anti-inflammatory properties. We here investigate the in vivo and in vitro effects of simvastatin on cytokine production in pre-dialysis chronic renal failure patients.
Methods. Our clinical study has been designed as a randomized double-blind placebo controlled study. A total of 55 chronic kidney disease (CKD) patients at stages 3 and 4 (mean creatinine clearance 45 ml/min, range 15–60) were randomly assigned to receive simvastatin 40 mg/day or placebo, added to their ongoing treatment, for 6 months. Blood samples were obtained at baseline, and after 3 and 6 months of observation for the determination of lipids, inflammatory markers and renal function. For the in vitro studies, the effect of increasing doses of simvastatin on cytokine production [namely interleukin (IL)-6 and IL-8] in human cultured monocytes from 10 healthy subjects (HS) and 15 CKD patients stimulated by lipopolysaccharide (LPS) was investigated.
Results. A significant reduction in total cholesterol from 221±44 mg/dl to 184±41 mg/dl (3 months) and to 186±39 mg/dl (6 months) (P<0.02) and low-density lipoprotein cholesterol from 139±40 mg/dl to 104±29 mg/dl (3 months) and to 100±31 mg/dl (6 months) (P<0.001) was observed in the 28 patients treated with simvastatin. In this group, C-reactive protein (CRP) levels significantly decreased from 2.6 mg/l [interquartile range (IQR 4.9)] to 2.0 mg/l (IQR 1.9) (P = 0.03) at 6 months (P<0.05). A parallel reduction of IL-6 levels from 5.1 pg/ml (IQR 3.8) to 3.5 pg/ml (IQR 3.1) (P = 0.001) at 6 months was also observed. No significant reduction in inflammatory markers [CRP from 5.1 mg/l (IQR 1.9) to 5.4 mg/l (IQR 1.3) (P = NS) at 6 months] or plasma lipids [LDL-cholesterol from 127±32 mg/dl to 131±21 mg/dl (6 months)] was observed in the 27 patients of the placebo group. In the in vitro studies, the average value for cell-associated IL-6 and IL-8 was higher in CKD (155±95 pg/ml monocytes for IL-6 and 722±921 pg/ml monocytes for IL-8) vs HS (137±87 pg/ml monocytes and 186±125 pg/ml monocytes) (P<0.01) and was not affected by simvastatin alone. LPS resulted in a significant increase in cytokine production (IL-6: 1954±321 pg/ml monocytes for CKD and 1451±237 pg/ml monocytes for HS; P<0.001); the simultaneous addition of increasing doses of simvastatin to these cultures induced a dose-dependent inhibition of IL-6 and IL-8 production in stimulated peripheral blood mononuclear cells in all groups.
Conclusions. These results indicate that simvastatin in commonly used doses has an in vitro and in vivo anti-inflammatory effect in CKD patients, and may play an important role in counteracting the mechanisms involved on the pathogenesis of cardiovascular disease.
Keywords: chronic kidney disease; C-reactive protein; cytokines; simvastatin
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