NDT Advance Access published online on October 25, 2005
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfi224
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1 Department of Internal Medicine, Postgraduate School of Nephrology, Pisa, Italy
* To whom correspondence should be addressed. 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.
Received May 13, 2005
Accepted September 23, 2005
Original Articles
In vivo and in vitro effects of simvastatin on inflammatory markers in pre-dialysis patients
2 Pharmacology Section, Neuroscience Department, University of Pisa, Pisa, Italy
3 Nephrology Division, University of Pisa, Pisa, Italy
Vincenzo Panichi, E-mail: v.panichi{at}med.unipi.it
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