Patients with sepsis have ongoing mortality beyond short-term end points, and survivors consistently demonstrate impaired quality of life. The use of 28-day mortality as an end point for clinical studies may lead to inaccurate inferences. Both observational and interventional future studies should include longer-term end points to better-understand the natural history of sepsis and the effect of interventions on patient morbidities.

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1 It was supposed that inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG CoA) reductase (statins) might inhibit the expression of the ®brosis-related factor CTGF (connective tissue growth factor) by interfering with the isoprenylation of Rho proteins. 2 The human renal ®broblast cell line TK173 was used as an in vitro model system to study the statin-mediated modulation of the structure of the actin cytoskeleton and of the expression of CTGF mRNA. 3 Incubation of the cells with simvastatin or lovastatin time-dependently and reversibly changed cell morphology and the actin cytoskeleton with maximal e ects observed after about 18 h. 4 Within the same time period, statins reduced the basal expression of CTGF and interfered with CTGF induction by lysophosphatidic acid (LPA) or transforming growth factor beta. Simvastatin and lovastatin proved to be much more potent than pravastatin (IC 50 1 ± 3 mM compared to 500 mM). 5 The inhibition of CTGF expression was prevented when the cells were incubated with mevalonate or geranylgeranylpyrophosphate (GGPP) but not by farnesylpyrophosphate (FPP). Speci®c inhibition of geranylgeranyltransferase-I by GTI-286 inhibited LPA-mediated CTGF expression whereas an inhibitor of farnesyltransferases FTI-276 was ine ective. 6 Simvastatin reduced the binding of the small GTPase RhoA to cellular membranes. The e ect was prevented by mevalonate and GGPP, but not FPP. 7 These data are in agreement with the hypothesis that interference of statins with the expression of CTGF mRNA is primarily due to interference with the isoprenylation of RhoA, in line with previous studies, which have shown that RhoA is an essential mediator of CTGF induction. 8 The direct interference of statins with the synthesis of CTGF, a protein functionally related to the development of ®brosis, may thus be a novel mechanism underlying the bene®cial e ects of statins observed in renal diseases.

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