Are 3-Hydroxy-3-Methylglutaryl-CoA Reductase Inhibitors Renoprotective?
Vito M. Campese*,
Mitra K. Nadim* and
Murray Epstein
* Division of Nephrology, Keck School of Medicine, University of Southern California, Los Angeles, California; and Division of Nephrology & Hypertension, University of Miami, Miami, Florida
Address correspondence to: Dr. Vito M. Campese, Department of Medicine, Physiology and Biophysics, Division of Nephrology and Hypertension Center, Keck School of Medicine, University of Southern California, 1200 North State Street, Los Angeles, CA 90033. Phone: 323-226-7337; Fax: 323-226-5390; E-mail: campese{at}usc.edu
Statins reduce serum cholesterol and cardiovascular morbidityand mortality. The mechanisms for these beneficial effects arereviewed. Altered inflammatory responses and improved endothelialfunction mediated by statins are thought to be partly responsiblefor the reduction of morbidity and mortality as a result ofcardiovascular events. In analogy, whether statins confer similarbenefits on the kidney has not been established. This reviewcritically considers the available data whereby dyslipidemiamediates renal dysfunction by modulating the inflammatory responseto diverse cytokines. Also reviewed is the emerging databaseindicating that statins may modulate renal function by alteringthe response of the kidney to dyslipidemia.
It is well established that 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA)reductase inhibitors (statins) reduce serum levels of cholesteroland cardiovascular morbidity and mortality. Less establishedis the role of lipids in the progression of kidney disease andthe potential beneficial effects of statins in patients withkidney disease. It is also well known that people with chronickidney disease (CKD), even those in the early stages of thedisorder, are at increased risk for cardiovascular disease (CVD)(1). Several nontraditional factors, including oxidant stressand elevated inflammatory markers, are associated with bothatherosclerosis and CKD, and two recent reviews suggest thatoxidant stress and inflammation may be the primary mediatorsor the "missing link" that explains the tremendous burden ofCVD in CKD (2,3). In this article, we consider emerging evidencethat statins, in addition to their cardiovascular effects, maymodulate renal function.
CKD is a worldwide problem, and patients with CKD are more likelyto die of CVD than the general population. Indeed, the KidneyDisease Outcomes Quality Initiative (K/DOQI) and National CholesterolEducation Program (NCEP) guidelines recognize CKD as a CVD riskequivalent (1). CKD patients frequently have a number of additionalrisk factors, beyond the traditional risk factors associatedwith CVD, including proteinuria, electrolyte imbalances, inflammation,increased oxidative stress, and altered nitric oxide (NO) levels,among others (4).
Microalbuminuria or proteinuria is often found in associationwith hyperlipidemia, especially in patients with diabetes andhypertension, and this may contribute to CVD in these patients.Hemodialysis patients have a characteristic dyslipidemia thatfurther contributes to CVD risk, presenting with very high levelsof VLDL and triglycerides, low levels of HDL, and raised levelsof small-dense LDL particles (5). Urinary protein loss may increaseserum lipoprotein levels. Alternatively, hyperlipidemia maycontribute to the progression of CKD by a mechanism similarto atherogenesis (6). Immunostaining of renal biopsies frompatients with glomerular disease demonstrated the accumulationof lipoproteins in the glomerular and mesangial cells as wellas within the mesangial matrix (7,8). This suggests that thevasculature and the kidney share a number of pathologic features.Atherogenesis depends on interplay of cellular components ofthe immune system such as monocytes, cytokines, and cell adhesionmolecules with lipids, platelets, and endothelial cells. Thesame interplay of these factors may contribute to progressionof kidney disease. Because statins are very effective in retardingpathologic processes that are responsible for CVD, it is conceivablethat similar pleiotropic effects may forestall progression ofkidney disease.
Inflammation and Progressive Kidney Disease: Role of Statins
In the kidney, mesangial cell proliferation in response to variousgrowth factors such as platelet-derived growth factor (PDGF),insulin, and IGF is important in subsequent mesangial matrixexpansion after glomerular injury. Mesangial cells bind bothLDL and oxidized LDL cholesterol (ox-LDL). Hyperlipidemia andhyperglycemia increase the production of mesangial matrix anddrive recruitment of inflammatory cells into the matrix, thusleading to the progression of CKD. Both LDL and high levelsof glucose have been shown to increase the expression of fibronectinmRNA and protein, leading to an increase in the mesangial matrixand cell number in cultured mesangial cells (9,10). LDL stimulatesthe expression of monocyte chemoattractant protein-1 (MCP-1)mRNA, leading to increased amounts of secreted monocyte chemotacticactivity (9). When bound to the extracellular matrix, ox-LDLhas been shown to be cytotoxic (10,11). Both LDL and ox-LDLinduce the expression of IL-6 and NF-, two factors that areimportant in the inflammatory and proliferative response ofmesangial cells. The transcription factor NF- has been linkedto inflammatory events associated with glomerulonephritis (12).
Statins inhibit the inflammatory response of the kidney throughmechanisms similar to those observed in the vasculature. Statinsdecrease MCP-1, IL-6, PDGF, NF-, vascular cellular adhesionmolecule-1 (VCAM-1), intracellular adhesion molecule-1 (ICAM-1),and fibronectin mRNA and proteins in mesangial cells (9,13–16)and inhibit the proliferative effects of LDL and high levelsof glucose and the cytotoxic effects of ox-LDL on mesangialcells (14,15,17). Statins reduce renal tubular epithelial proliferationin vitro (18). In the kidney, statins induce NO synthetase (NOS)and increase NO bioavailability (19), where NO may serve a protectiverole against inflammation in renal transplant recipients, innephrotoxic serum-induced glomerulonephritis and autoimmunetubular interstitial nephritis (20,21).
Simvastatin suppressed mesangial cell proliferation, mesangialmatrix expansion, and macrophage infiltration into the glomeruliin a rat model of glomerulonephritis (22). Pravastatin decreasedthe amount of intrarenal C-reactive protein (CRP), macrophages,and tubulointerstitial fibrosis in a rat model of chronic cyclosporine-inducednephropathy (23). Cerivastatin reduced proteinuria and renalinjury in stroke-prone spontaneously hypertensive rats independentof BP and cholesterol (24). Lovastatin prevented glomerularmacrophage infiltration and attenuated albuminuria in rats withpuromycin aminonucleoside nephrosis (25). The combination ofatorvastatin and salt restriction normalized aortic endothelialNOS (eNOS) and superoxide, and reduced left ventricular hypertrophyand proteinuria in Dahl salt-sensitive rats, suggesting thatupregulation of vascular eNOS and inhibition of oxidative stressmay contribute to the pleiotropic protective effects of atorvastatinagainst end-organ injury (26). This provides a platform forfuture studies to delineate further the contribution of pleiotropiceffects conferred by statins in protection against end-organinjury.
Effects of Dyslipidemia and Statins on Renal Function
Evidence suggests that dyslipidemia plays an important rolein the initiation and progression of CKD and that lipid-loweringagents may retard the progression of renal disease in patientswith CKD. Several studies have found correlations between baselinelipid measures and rate of decline in kidney function (27–29)The Physician’s Health Study assessed the probabilityof development of renal dysfunction (elevated creatinine 1.5mg/dl and/or reduced estimated creatinine clearance [CrCl],defined as 55 ml/min) in 4483 healthy male physicians (plasmacreatinine levels of <1.5 mg/dl at baseline) who providedblood samples in 1982 and 1996 (29). After 14 years, 134 (30%)men had elevated creatinine and 244 (5.4%) men had reduced CrCl.The relative risk for elevated creatinine was 1.77 (95% confidenceinterval [CI], 1.10 to 2.86) for total cholesterol 240 mg/dl,2.16 (95% CI, 1.42 to 3.27) for HDL <40 mg/dl, 2.34 (95%CI, 1.34 to 4.07) for the highest quartile of total cholesterol:HDLratio (6.8), and 2.16 (95% CI, 1.22 to 3.80) for the highestquartile of non-HDL cholesterol (196.1 mg/dl). The study showedthat the odds of progression of renal disease were directlyrelated to blood lipid levels at baseline.
Several studies have suggested that lipid-lowering drugs maypreserve renal function in patients with CKD. Fried et al. (30)performed a meta-analysis of 13 small, prospective, controlledtrials that examined the effects of antilipidemic agents (primarilystatins) on renal function, albuminuria, or proteinuria. Lipid-loweringagents significantly slowed the rate of decline in GFR comparedwith control subjects (–0.16 ml/min per mo; 95% CI, 0.03to 0.29 ml/min per mo; P = 0.008). This analysis also showeda trend toward a reduction of proteinuria with lipid-loweringtherapy (P = 0.077) and a decreased progression toward end-stagerenal disease (ESRD) in treated individuals. Two additionalstudies showed a 54% reduction in proteinuria with pravastatin10 mg/d (31) and approximately 35% reduction with simvastatin20 mg/d (32). It is interesting that the effects of simvastatinon proteinuria seemed to be independent of LDL reductions asa similar benefit was not seen in patients who were treatedwith cholestyramine despite similar LDL levels (32).
Bianchi et al. (33) conducted what is currently the only studyof reasonable size and duration designed to show a statin-mediatedreduction in the progression of kidney disease. This prospective,controlled, open-label study demonstrated that treatment withatorvastatin 10 to 40 mg/d reduced proteinuria and the rateof progression of kidney disease in 56 patients with CKD, proteinuria,and hypercholesterolemia. Before randomization to atorvastatinor placebo, all patients had been treated for 1 yr with angiotensin-convertingenzyme inhibitors (ACEI), angiotensin AT1 receptor antagonists(ARB), or a combination of ACEI and ARB. Urine protein excretiondecreased from 2.2 ± 0.1 to 1.2 ± 1.0 g/24 h (P< 0.01) in the atorvastatin group versus a nonsignificantdecrease from 2.0 ± 0.1 to 1.8 ± 0.1 g/24 h inpatients who did not receive atorvastatin in addition to ACEIand/or ARB. CrCl decreased markedly in patients who did notreceive atorvastatin (from 50 ± 1.9 to 44.2 ±1.6 ml/min; P < 0.01) and only slightly (from 51 ±1.8 to 49.8 ± 1.7; NS) in patients who were treated withatorvastatin.
Secondary or post hoc analysis of kidney function in some landmarkstatin trials have also suggested potential beneficial effectson kidney function. For example, serum creatinine was assessedas a secondary efficacy measure in the Heart Protection Studyof 20,536 people who did and did not have CVD and received simvastatin40 mg/d or placebo. Serum creatinine levels increased less amongsimvastatin-treated patients (7.13 µmol/L) compared withthe placebo group (8.94 µmol/L; P < 0.0001) (34). Apost hoc analysis of nearly 700 participants in the Cholesteroland Recurrent Events study (a randomized, placebo-controlled,secondary prevention trial of pravastatin) with estimated GFRof <60 ml/min per 1.73 m2 showed that the rate of GFR declinedid not differ between pravastatin and placebo groups (35).However, pravastatin significantly reduced the rate of declinein GFR compared with placebo in individuals with more severechronic renal insufficiency at baseline: –0.6 ml/min per1.73 m2/yr slower in those with a GFR of <50 ml/min per 1.73m2 (P = 0.07) and –2.5 ml/min per 1.73 m2/yr slower inthose with a GFR of <40 ml/min per 1.73 m2 (P = 0.0001).
The Greek Atorvastatin and CHD Evaluation (GREACE) study ofdyslipidemic CHD patients recently evaluated the impact of untreateddyslipidemia versus two treatment regimens, usual care and dosetitration with atorvastatin (10 to 80 mg/d), on renal function(12). In patients with untreated dyslipidemia and normal renalfunction at baseline, CrCl declined 5.2% (P < 0.0001) overthe 3-yr study period. The usual care group had a 4.9% increasein CrCl (P = 0.003), whereas the atorvastatin group had a 12%increase (P < 0.0001). Thus, statin treatment prevented thedecline and significantly improved renal function.
Dyslipidemia and CVD are very prevalent among ESRD patients.However, to date, only a few small studies have evaluated theeffects of statins on markers of risk or cardiovascular outcomein this patient population. In the US Renal Data Systems DialysisMorbidity and Mortality Wave-2 study, a retrospective analysisof data from 3716 ESRD patients, statin use was associated witha one-third decrease in all-cause and cardiovascular mortalityin dialysis patients over a 2-yr period (36). Among statin users,the cardiovascular-specific mortality rate was 61/1000 person-years;the corresponding rate for nonusers was 88/1000 person-years.
In an 8-wk randomized study of 44 hypercholesterolemic patients,simvastatin decreased plasma CRP levels and increased serumalbumin levels compared with a no-treatment group (31). In an18-wk trial, 28 ESRD hemodialysis patients with normal LDL andtotal cholesterol levels and borderline low HDL cholesterollevels were randomized to receive either simvastatin or atorvastatin(37). Treatment with either statin did not affect CRP levelsbut decreased ox-LDL and remnant lipoprotein cholesterol levels.Treatment also shifted LDL subfractions from small, dense fractionsto large, buoyant fractions.
Dyslipidemia and atherosclerotic vascular diseases are commonamong renal transplant recipients. Lipid-lowering drugs areused extensively in these patients. However, there are no studiesavailable to demonstrate a beneficial impact of these drugson cardiovascular outcome. Several observational studies alsosuggest that hyperlipidemia may play a role in chronic allograftnephropathy (38).
In vitro studies suggest that HMG-CoA reductase inhibitors mayinhibit the growth and proliferation of lymphocytes (39,40).This has led to speculation that these agents might reduce rejectionof solid-organ transplants. Indeed, two prospective studieshave shown that HMG-CoA reductase inhibitors started immediatelyafter transplantation of orthotopic hearts reduce graft vasculardisease and improve patient survival (41,42). One study of 48renal transplant recipients who were randomized to receive eitherpravastatin or placebo showed lower rate of acute rejectionamong patients who were treated with statin (25 versus 58%;P < 0.01) (43). However, another study with simvastatin didnot confirm this finding (44). In summary, the available studiesare scant and conflicting. Additional studies encompassing determinationof the role of HMG-CoA reductase inhibitors in transplant recipientsis necessary.
The mechanisms for the beneficial effects of statins on CVDand kidney disease have been studied extensively (Table 1).The current view of atherogenesis is that of an inflammatoryprocess, irrespective of the initial insult to the vascularwall (45). This hypothesis is supported by the association ofinflammatory markers, in particular CRP, with increased riskfor coronary disease (46). Interactions between the vascularendothelium and the immune system drive the development of plaques(47,48).
ox-LDL stimulates chemotaxis of monocytes and their transformationinto macrophages that engulf the lipids (48,49). The lipid-engorgedmacrophages become foam cells that die and form the lipid-richcore of the plaque. A collagen cap, preventing contact betweenthe prothrombotic lipids and the blood, covers this core. However,inflammatory cells may also secrete metalloproteinases thatdigest the collagen cap, causing plaque rupture, acute thromboticcomplications, and clinical events (48).
Statins reduce cholesterol synthesis by inhibiting HMG-CoA reductase,the rate-limiting step in its synthesis. A significant consequenceof the HMG-CoA reductase inhibition by statins is interferencewith the synthesis of the isoprenoid compounds farnesylpyrophosphateand geranylpyrophosphate. It is through the inhibition of isoprenylationthat statins exert a considerable number of non–lipid-dependenteffects. Normally, the isoprenoid compounds become attachedposttranslationally to intracellular signaling proteins suchas the GTPases Ras, Rac, and Rho. These intracellular signalingmolecules facilitate communication between growth factor receptorsand the cellular cytoskeleton to influence cell motility, membranetransport, and transcription factor activation (50). Some ofthese transcription factors, such as NF-, induce cell proliferationand activation of a variety of cytokines and chemokines, suchas MCP-1, VCAM, and ICAM to mention a few. Statins interferewith the anchoring of growth factors to the cell membrane andcytoskeleton and with signal transduction to the nucleus, thuspreventing the activation of transcription factors and cellproliferation.
Via interference with isoprenylation, statins exert significantanti-inflammatory and immunomodulatory effects. Some of themore significant effects are a decrease in adhesion moleculeexpression on vascular endothelial cells; a decrease in circulatingCRP; reduced synthesis of inflammatory cytokines IL-1, TNF-,TGF-, and IL-6; reduced synthesis of inducible cyclo-oxygenase-2;and inhibition of NF-, a DNA-binding protein that controls theexpression of genes encoding other cytokines, chemokines, interferons,MHC proteins, growth factors, and cell adhesion molecules (46,49–57).Statins may also block the differentiation of monocytes intomacrophages and induce apoptosis of these cells (58).
Of importance, statins cause an upregulation and stabilizationof eNOS and an increase in NO production (49–52,54,59,60),and NO plays regulatory and modulatory roles in inflammatoryconditions, inhibiting platelet aggregation, neutrophil adhesion,and cell proliferation and slowing cellular proliferation aftercytokine exposure (61–66).
The multiple pleiotropic effects cited above have the potentialto have a significant impact on the atherogenic processes atseveral points, reducing vascular inflammation and improvingendothelial function. A number of in vitro and in vivo studieshave investigated the effects of statins on the cells of thegeneral vasculature. In cultured vascular smooth muscle cells(VSMC) or endothelial cells, statins downregulated the activationof the transcription factors NF-, activator protein-1, and hypoxia-induciblefactor-1a (20). Inhibition of the activation of NF- led to decreasedsecretion of MCP-1, a chemoattractant for monocyte inflammatorycell and a mitogen for VSMC (67). In turn, the decreased secretionof MCP-1 caused by administration of atorvastatin, lovastatin,simvastatin, and fluvastatin stimulated apoptosis of VSMC (25,68).Statins also inhibit monocyte adhesion to endothelial cellsvia downregulation of surface integrins through inactivationof Rho GTPase (69). Thus statins could reduce the progressionof arteriosclerosis via reducing the activation and infiltrationof immune cells into plaque lesions (70).
Antioxidant effects may improve vascular function. Statins preventRac GTPase activation of NAD(P)H oxidase, reducing O–2generation in VSMC (71). In endothelial cells, ox-LDL contributesto the progression of atherosclerosis by decreasing levels ofeNOS mRNA and protein. Statins affect this process first byprotecting against the oxidation of LDL (19,72,73) and secondby stabilizing eNOS mRNA through blocking geranylgeranylationof Rho GTPase (19). Blocking geranylgeranylation of Rho GTPaseby statins also decreases the levels of the surface proteinendothelin-1, a potent vasoconstrictor and mitogen (72,74).These changes help to normalize vascular reactivity.
In vivo studies in animal models of atherosclerosis provideadditional support that these mechanisms are important to reducingatherogenesis. Inflammatory markers such as intimal macrophages,metalloproteinase expression, and IL-6 expression were decreasedin plaques from statin-treated monkeys (75). Atheroscleroticplaques in these statin-treated monkeys had substantially moreVSMC and collagen within the plaques, suggesting that the plaqueswere more stable and less likely to rupture (75). Furthermore,less endothelial dysfunction was observed as demonstrated bya decreased vasodilatory response to acetylcholine and a lesspronounced expression of VCAM-1 (75).
Treatment with statins normalizes endothelium-dependent vasodilatoryresponses in patients with hypertension, hypertriglyceridemia,or atherosclerosis and decreases levels of CRP and other inflammatorymarkers in patients with hyperlipidemia, mixed dyslipidemia(similar to that characterizing patients with renal disease),acute coronary syndrome, or type 2 diabetes (45,76–81).The recently completed REVERSAL trial suggests that the differentialreduction of CRP achieved with atorvastatin versus pravastatin,at comparable levels of LDL reduction, contributes to improvedoutcomes as demonstrated by halting plaque progression (82).However, it is still unclear whether all statins are equallyeffective at reducing CRP and whether they have an impact onother markers of inflammation. In addition, available data areinsufficient to demonstrate a correlation between statins’effects on CRP levels and on lipids or cardiovascular outcomes(53).
In conclusion, available evidence supports a substantial roleof dyslipidemia in the progression of kidney disease. Statinsmay modulate renal function by altering the response of thekidney to dyslipidemia.
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Top
Abstract
Introduction
, two factors that are important in the inflammatory and proliferative response of mesangial cells. The transcription factor NF-
1.5 mg/dl and/or reduced estimated creatinine clearance [CrCl], defined as 
55 ml/min) in 4483 healthy male physicians (plasma creatinine levels of <1.5 mg/dl at baseline) who provided blood samples in 1982 and 1996 (29). After 14 years, 134 (30%) men had elevated creatinine and 244 (5.4%) men had reduced CrCl. The relative risk for elevated creatinine was 1.77 (95% confidence interval [CI], 1.10 to 2.86) for total cholesterol 
, TGF-
and NF
