Effects of Atorvastatin on Inflammatory and Fibrinolytic Parameters in Patients with Chronic Kidney Disease
Marian Goicoechea*,
Soledad García de Vinuesa*,
Vicente Lahera,
Victoria Cachofeiro,
Francisco Gómez-Campderá*,
Almudena Vega*,
Soraya Abad* and
José Luño*
* Department of Nephrology, Hospital General Universitario Gregorio Marañón, and Department of Physiology. Universidad Complutense de Madrid, Madrid, Spain
Address correspondence to: Dr. Marian Goicoechea, Department of Nephrology, Hospital General Universitario Gregorio Marañon, C/Dr. Esquerdo 47, 28007 Madrid, Spain. Phone: +34915868319; Fax: +34915868318; E-mail: albvia{at}terra.es
Although substantial evidence suggests that treatment of dyslipidemiawith statins reduces mortality and morbidity that are associatedwith cardiovascular disease, only a few studies have examinedthe efficacy of statins on inflammatory and fibrinolytic statusin patients with chronic kidney disease (CKD). A 6-mo, prospective,randomized study was designed to assess the efficacy of atorvastatinin reducing circulating inflammatory and fibrinolytic parametersin patients with CKD. Sixty-six patients with CKD (stages 2,3, and 4) and LDL cholesterol levels 100 mg/dl were randomlyassigned (2:1) to receive 20 mg/d atorvastatin (n = 44) or nonatorvastatintherapy (n = 22). Lipid profile, renal function, fibrinolyticbalance (tissue plasminogen activator [t-PA] and plasminogenactivator inhibitor-1), and inflammatory markers (C-reactiveprotein [CRP], IL-1, IL-6, and TNF-) were measured before and6 mo after atorvastatin was added to the treatment. Twenty-fiveage-matched individuals with normal renal function (estimatedGFR >90 ml/min) were used as healthy control subjects. Patientswith CKD had higher CRP, IL-1, TNF-, and IL-6 levels than age-matchedpopulation with normal renal function. t-PA concentration washigher in patients with CKD (P = 0.000). Plasminogen activatorinhibitor-1 values were comparable in all patients. Total cholesteroland LDL cholesterol were significantly reduced only in patientswho received atorvastatin. In addition to the hypolipidemiceffect, atorvastatin treatment significantly reduced inflammatoryparameters: CRP (median 4.1 to 2.9; P = 0.015), TNF- (6.0 ±2.7 to 4.7 ± 2.4; P = 0.046), and IL-1 levels (1.9 ±0.7 to 1.2 ± 0.7; P = 0.001). These parameters remainedunchanged in patients who were not treated with atorvastatin.Fibrinolytic parameters were not modified by atorvastatin treatment.Patients with CKD showed higher levels of inflammatory parametersand t-PA levels than age-matched healthy control subjects. Atorvastatintreatment, in addition to its beneficial effect on cholesterollevels, improved the inflammatory state of these patients withoutmodifying fibrinolytic balance.
Patients with chronic kidney disease (CKD) have a markedly higherprevalence of cardiovascular disease (CVD) than the generalpopulation (1,2). They have an altered plasma lipid profilethat is characterized by increased levels of triglycerides,decreased levels of HDL cholesterol, and no consistent changein LDL cholesterol (3). Furthermore, dyslipidemia is considereda major cause of CVD in patients with CKD, and management ofdyslipidemia plays an important role in the therapy of thesepatients (4,5).
It has been established that the benefits of hepatic hydroxymethylglutaryl–CoA reductase inhibitors, or statins, in cardiovasculardisease can be explained not only by their lipid-lowering potentialbut also by non–lipid-related mechanisms, the so-called"pleiotropic effects." Some of these beneficial effects arerelated to the anti-inflammatory and fibrinolytic propertiesof statins, which may contribute to this positive effect ofstatins on the incidence of cardiovascular events (6,7).
It was published recently (8,9) that reducing the inflammatorycomponent of cardiovascular disease through the use of statintherapy improves the clinical outcome independent of the reductionin serum cholesterol levels. Although substantial evidence suggeststhat treatment of dyslipidemia with a statin reduces morbidityand mortality that are associated with CVD (10,11), only a fewstudies have examined the efficacy of statins on dyslipidemiaand the inflammatory (12) and fibrinolytic system in patientswith CKD, and most of these studies were performed in patientswho had ESRD and were on dialysis but not in nondialyzed patients.The present prospective study was designed to evaluate the inflammatoryand fibrinolytic status in patients with CKD in comparison withan age-matched group with normal renal function and to assessthe effect of atorvastatin on dyslipidemia and inflammatoryand fibrinolytic parameters in this population of patients withCKD.
Sixty-six patients with CKD (stages 2 to 4) from the Renal Clinicwere enrolled. Inclusion criteria were CKD with an estimatedGFR <90 ml/min and 15 ml/min. Exclusion criteria were levelsof fasting serum LDL cholesterol of <100 mg/dl and >200mg/dl; the existence of liver, cardiovascular, infectious, orsystemic disease unrelated to ESRD; and the history of vascularintervention, congestive heart failure, or myocardial infarctionwithin the 3 mo preceding the period of enrollment. No patienttook lipid-lowering medication during the 4-wk period beforethe study.
All patients who met the eligibility criteria (n = 66) wererandomly (2:1) assigned to two groups. Group A included 44 patientswho tool atorvastatin (20 mg/d for 6 mo), and group B included22 patients who did not take lipid-lowering drugs. Patientswho were already taking other drugs kept their pharmacologicschedule constant during the study. Fifty-five (83%) of 66 patientswere receiving renin-angiotensin system blockers, and theirdosages were not changed during atorvastatin therapy.
In addition, to analyze baseline inflammatory and fibrinolyticsystem in patients with CKD, we compared the basal data of patientswho had CKD with an age-matched control subjects (n = 25) whohad no renal disease (no history of renal impairment and estimatedGFR 90 ml/min). Venous blood samples were obtained before andafter 6 mo of atorvastatin treatment and stored frozen at –80°C.
Serum creatinine, total cholesterol, HDL cholesterol, LDL cholesterol,and serum triglyceride levels were determined by means of standardenzymatic methods. Serum fibrinogen was determined by a standardmethod. GFR was estimated by the Cockroft-Gault formula. High-sensitivityC-reactive protein (CRP) plasma levels were measured with alatex-based turbidimetric immunoassay on a Hitachi analyzer(Sigma Chemical Co., St. Louis, Mo). IL-6, IL-1, and TNF- weremeasured using quantitative sandwich enzyme immunoassay. A humanspecific mAb for IL-1, IL-6, or TNF- was precoated into microplates(R&D Systems, Minneapolis, MN). Tissue plasminogen activator(t-PA) and plasminogen activator inhibitor-1 (PAI-1) activitieswere evaluated using an immunoactivity assay using commercialkits.
Statistical Analyses
Data are expressed as means ± SD or medians (interquartileranges). Kolmogorov-Smirnov test was used to analyze the normalityof the distribution of the parameters measured. We assesseddifferences between baseline and 6-mo values using the 2 testand t test for paired data, univariate analysis for normallydistributed variables and Mann-Whitney U test for skewed variables.Spearman correlation coefficients were used to evaluate therelationship between lipid parameters and inflammatory mediators.Statistical significance was assumed at P < 0.05.
All patients from group A and 19 from group B completed thestudy; three were excluded from the study because they werelost in the follow-up. Patients with CKD showed a higher serumCRP (P = 0.002), IL-1 (P = 0.004), TNF- (P = 0.000), and IL-6levels (P = 0.001) compared with the control group (Table 1).t-PA levels were significantly elevated in patients with CKD(P = 0.000), and no differences were observed in PAI-1 levels(Table 1).
Table 1. Inflammatory and fibrinolysis parameters in patients with CKD: Comparison with age-matched general populationa
Table 2 lists baseline characteristics of the patients withCKD. There were no statistically significant differences betweenthe two study groups at the baseline evaluation.
Table 2. Clinical characteristics of patients with CKD at baselinea
Comparison of average serum lipid levels at the baseline andat the 6-mo end point showed the expected variations duringatorvastatin therapy in group A patients (Table 3): A significantreduction in serum total cholesterol levels (P < 0.001) andserum LDL cholesterol levels (P < 0.001). Conversely, thesame procedures showed no significant variations in lipid levelsin group B patients (Table 3).
Table 3. Renal function and lipid parameters in both groups of CKDa
Serum CRP levels decreased significantly (P = 0.015) in groupA. However, they remained stable in group B (Table 4). In addition,changes in CRP and serum cholesterol during the study were notcorrelated, suggesting that the atorvastatin-induced cholesteroland CPR reduction are independent from one another. In additionIL-1 and TNF- showed significant reductions in group A (P =0.001 and P = 0.046, respectively) and remained unchanged ingroup B. Reduction of IL-6 was not statistically significantin group A. Serum fibrinogen, t-PA, and PAI-1 were not modifiedby atorvastatin therapy (Table 4). Renal function was not changedduring the 6-mo period, and no significant differences wereobserved in these parameters between group A and group B (Table 3).
Pleiotropic effects of statins have important clinical implications,independent of their lipid-lowering effects (8–13). Alterationsin inflammatory responses, plaque stabilization, and improvedendothelial function are thought to be partially responsiblefor the reduction in cardiovascular morbidity and mortality(14). Patients with CKD, even those in the early stages of thedisorder, are at increased risk for CVD, and recent reviewssuggested that oxidant stress and inflammation may be the primarymediators or the "missing link" that explains the burden ofCVD in patients with CKD (15). Although statins reduced theincidence of cardiovascular events in patients with type 2 diabetes(16), these findings were not confirmed in patients who wereon hemodialysis in a recently published large, prospective study(17).
A few recent studies described the impact of statins on serumCRP levels in patients who were on long-term HD therapy. Ichiharaet al. (18) showed that fluvastatin (20 mg/d orally for 24 wk)significantly reduced serum CRP levels in these patients. Similarresults were obtained by Chang et al. (19) by testing simvastatin(20 mg/d orally for 8 wk) and by Vernagione et al. (20) (atorvastatin10 mg/d orally for 6 mo).
Our study describes the impact of atorvastatin on inflammatoryparameters in nondialysis patients with CKD. Recently, Panichiet al. (17) described that simvastatin in commonly used dosageshas an in vitro and in vivo anti-inflammatory effect in patientswith CKD. Our study confirms the findings of other authors (21,22),showing that patients with CKD have higher levels of inflammatorymarkers, such as CRP, IL-1, IL-6, and TNF-, than general population.As described in patients who had ESRD and were on HD therapy,statin treatment in group A patients significantly reduced inflammatoryparameters (CRP, IL-1, and TNF-) levels. Moreover, the absenceof correlation between reduction in serum CRP and serum totalcholesterol and serum LDL cholesterol levels that were obtainedin patients in group A indicates that the anti-inflammatoryeffects of atorvastatin likely are independent of its lipid-loweringaction.
Our study shows that CRP and IL-6 are significantly associated(r2 = 0.519, P < 0001). However, there is no significantreduction in plasma IL-6 after statin treatment. IL-6 is animportant regulator of CRP expression in the liver but not theonly one (21). Therefore, it is probable that other cytokines(IL-1 and TNF-) may be involved in CRP regulation. An alternativeexplanation for the discordant findings in CRP and IL-6 concentrationsmay be that the later has a greater diurnal variability andshorter half-life (2 to 4 h) than CRP (24 h).
Impaired fibrinolysis has been acknowledged as a risk factorfor cardiovascular ischemic complications. It has been speculatedthat the development of atherothrombotic events in hemodialysispatients is due, at least in part, to an impaired fibrinolysis(23). Limited data have been published about the fibrinolyticsystem in patients who have CKD and do not require chronic HD.Lottermoser et al. (22) showed that patients who were on hemodialysistherapy had a fibrinolysis system disturbed, with t-PA concentrationsmarkedly decreased and PAI-1 antigen concentrations unmodifiedcompared with normal renal function group. However, no differenceswere observed in patients with impaired renal function (creatinine1.3 to 6.5 mg/dl) in this study. Unexpected, our results showedthat patients with moderate CKD have elevated t-PA concentrationscompared with normal renal function, whereas PAI-1 antigen remainedunchanged with respect to the normal renal function group. Althoughno direct evidence is offered in this work, it might be hypothesizedthat elevated t-PA levels could be a consequence of an enhancedprocoagulant state in patients with CKD, which has been reportedin patients with CKD, probably as a consequence of uremia.
Finally, several experimental and clinical studies have shownthat statins produced favorable effects on thrombotic parameters(24). Statins diminish procoagulant activity, which is observedat various stages of the coagulation cascade (25). In some studiesthat were performed in patients who were on peritoneal dialysis,statins reduced fibrinogen levels and altered the levels andactivities of t-PA and PAI-1 (26,27). To our knowledge, thereare no available data in azotemic patients before the developmentof ESRD about the effect of statins on fibrinolysis. In ourstudy, 6-mo atorvastatin treatment did not modify fibrinolysisparameters: Serum fibrinogen, t-PA, and PAI-1 levels.
Treatment with atorvastatin (20 mg/d) for 6 mo in nondialysispatients with CKD induced, in addition to its lipid-loweringeffect, a significant decrease in inflammatory parameters. Suchevidence, similar to that observed in hemodialysis patients,could suggest a new therapeutic use of statins in the preventionof cardiovascular damage in patients with CKD.
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Abstract
Introduction
100 mg/dl were randomly assigned (2:1) to receive 20 mg/d atorvastatin (n = 44) or nonatorvastatin therapy (n = 22). Lipid profile, renal function, fibrinolytic balance (tissue plasminogen activator [t-PA] and plasminogen activator inhibitor-1), and inflammatory markers (C-reactive protein [CRP], IL-1
, IL-6, and TNF-
) were measured before and 6 mo after atorvastatin was added to the treatment. Twenty-five age-matched individuals with normal renal function (estimated GFR >90 ml/min) were used as healthy control subjects. Patients with CKD had higher CRP, IL-1
2 test and t test for paired data, univariate analysis for normally distributed variables and Mann-Whitney U test for skewed variables. Spearman correlation coefficients were used to evaluate the relationship between lipid parameters and inflammatory mediators. Statistical significance was assumed at P < 0.05. 
