Proceedings of the Fourth Genoa Meeting on Hypertension, Diabetes, and Renal Diseases
Statins and Renal Diseases: From Primary Prevention to Renal Replacement Therapy
Giuseppe D’Amico
Department of Nephrology and Immunology, San Carlo Hospital, and Fondazione "D’Amico" per la Ricerca sulle Malattie Renali, Milan, Italy
Address correspondence to: Dr. Giuseppe D’Amico, Fondazione "D’Amico," per la Ricerca sulle Malattie Renali, c/o Ospedale San Carlo Borromeo, Via Pio II 3, 20153 Milan, Italy. Phone: +39-02-48705804; Fax: +39-02-40222222; E-mail: giuseppe.damico{at}scb.sined.net
In glomerular diseases with nephrotic syndrome or protractedsevere proteinuria, alterations of the lipid metabolism occurand are characterized mainly by increase of LDL cholesteroland frequently also of triglycerides and by qualitative abnormalitiesof HDL cholesterol and LDL cholesterol. In all renal diseases,when renal insufficiency develops, hyperlipidemia also occurs,with a near-elective increase in VLDL and intermediate-densitylipoprotein cholesterol and a decrease of mature HDL cholesterol.There is clear evidence that these abnormalities may inducecardiovascular complications and, probably, also an acceleratedprogression of the renal damage. The inhibitors of 3-hydroxy-3-methylglutarylCoA reductase, the so-called statins, are effective in controllinghypercholesterolemia, even in the more advanced stages of renalfailure and in patients who are on maintenance dialysis. Thisantilipidemic effect of statins combines with other effects—antioxidant,anti-inflammatory, immunomodulatory, and antithrombotic (called"pleiotropic" effects)—as a result of the inhibition ofthe mevalonate pathway induced by these agents. Also becauseof these non–lipid-dependent effects, statins could havean antiatherosclerotic and renoprotective effect, which hasbeen demonstrated clearly in vivo on renal cells and in experimentalmodels of nephropathy but is still less evident in human renaldiseases. Ongoing large trials will establish more clearly whethersuch effects are present in renal patients.
Meta-analysis of the data of the literature reviewed all ofthe controlled trials on the effect of the various statins inhyperlipidemic patients and confirmed that all of these drugsare able to reduce dyslipidemia, although at different dosages(1). Moreover, it showed that statins can protect against theoccurrence of cardiovascular events and stroke. The reductionof risk of ischemic heart disease events for a 1.0-mm/L decreaseof LDL cholesterol concentration was 11% (4 to 18%) after 1yr, 24% (17 to 30%) after 2 yr, 33% (28 to 37%) between thethird and fifth years, and 36% (26 to 45%) after 6 yr or more(1). It now is universally accepted that the protective effectof this class of drugs is that it blocks the 3-hydroxy-3-methylglutarylCoA reductase, so inhibiting not only the synthesis of cholesterolbut also the mevalonate pathway and the synthesis of the so-calledisoprenoids (farnesyl pyrophosphate and geranylgeranyl pyrophosphate)is not the simple consequence of the antilipidemic effect ofthe drugs (2–5). Isoprenoids are essential for the posttranslationalmodification of several proteins that are involved in importantsignaling pathways, such as the small GTP-binding proteins Rasand Rho, and their inhibition interferes with numerous importantcellular functions, leading to many additional effects of thestatins, called "pleiotropic." Because of this inhibition, statinsprotect the endothelial function (increased endothelial nitricoxide synthase expression and reduced endothelin-1 expression),act as antioxidants (inhibition of NAD[P]H oxidase, reducedsuperoxide formation, reduced LDL oxidation, and increased oxygenfree radical scavenging), as anti-inflammatory agents (inhibitionof proinflammatory cytokines, NF-B activation, leukocyte–endothelialcell adhesion, and reduction of C-reactive protein), as immunomodulatoryagents (reduced monocyte and T cell activation, inhibition ofIFN-, and shift from TH1 to TH2), and as antithrombotic agents(reduced tissue factor expression and increased fibrinolyticactivity), as reviewed recently by Mason (6,7).
It is highly probable that some of these effects of statins,together with their antilipidemic action, can be helpful inthe treatment of proteinuric glomerular diseases as well asall renal diseases that induce chronic renal failure, includingthe terminal stage of maintenance dialysis. There is the rationalefor a potential protective effect of these drugs on the rateof the progression of renal damage. However, the evidence stillis insufficient, at least in humans. We briefly review the accumulatedevidence, starting with the in vitro studies on cultured cellsand the in vivo experimental models of renal diseases.
Many studies have demonstrated the existence of non–LDL-dependenteffects of statins on mesangial cells (8–17), on tubularcells (18–20), and, as already stressed, on endothelialvascular cells. These effects are potentially advantageous,especially in inflammatory glomerular diseases, because theycould inhibit the cytokine activation network, proliferation,production of extracellular matrix, glomerular sclerosis, andtubulointerstitial inflammatory processes.
Another inhibitory effect of statins was demonstrated recentlyon the proximal tubular cells of opossum (21) and of human (22):Inhibition of the receptor-mediated mechanisms of reabsorptionof the proteins that reached the tubular lumen in physiologicand pathologic conditions. This inhibition, which can be reversedby mevalonate, may increase the urinary excretion of proteins,especially after administration of the more potent statins thatusually are metabolized also at the renal level. As correctlystressed by Agarwal (23), we cannot say at the moment whethersuch effect is renoprotective (the reabsorptive load of proximaltubular cells, especially when abnormal amounts of high molecularweight proteins transit in the tubular lumen, may have an injuringeffect on these cells) or toxic.
In 1990, the group of Klahr (24) demonstrated that the administrationof 4 mg/kg per d lovastatin in rats with puromycin aminonucleoside–inducednephrosis reduced not only hypercholesterolemia but also histologiclesions (global sclerosis) while increasing inulin clearance;proteinuria was not modified. In a model of mesangial proliferativeglomerulonephritis induced by anti–Thy-1 in rats, simvastatin(4 mg/kg per d), while reducing hypercholesterolemia, decreasedproteinuria and serum creatinine, induced a 70% suppressionof mesangial cell proliferation and of mesangial matrix expansionand type IV collagen synthesis, inhibited monocyte-macrophagerecruitment in glomeruli, and reduced the PDGF- chain proteinand mRNA expression in glomeruli (25). In diabetic nephropathythat was induced by streptozotocin in rat, lovastatin (4 mg/kgper d) administration, started at day 1, reduced proteinuriaat 3, 6, and 12 mo and suppressed the increase of TGF-1 RNAin isolated glomeruli between 2 wk and 12 mo; all these effectswere reversed by mevalonate (26). In the same experimental model,cerivastatin (0.5 mg/kg per d) reduced proteinuria and BP, decreasedmacrophage infiltration and intercellular adhesion molecule-1expression in glomeruli, and partially suppressed renal NF-Bactivity (27). Finally, in the same model of diabetic nephropathy,Qin et al. (28) demonstrated the protective effect of simvastatin(2 mg/kg per d) on proteinuria, histologic lesions (both glomerularand tubulointerstitial), and overexpression of TGF-1 and vascularendothelial growth factor; all these effects were potentiatedby the combination of the statin and losartan. In a model ofunilateral ureteral obstruction in mouse, fluvastatin (10 or40 mg/kg per d) but not pravastatin (10 mg/kg per d) reducedinterstitial fibrosis, appearance of -smooth muscle actin–positivemyofibroblasts in the interstitium, and induction of heme oxygenase-1mRNA 12 h after ligation of the ureter (29). In a rat modelof chronic cyclosporine-induced nephropathy, pravastatin attwo dosages (5 and 20 mg/kg per d) suppressed afferent arteriolopathy,striped interstitial fibrosis, and tubular atrophy; reducedthe number of recruited macrophages, TGF-1, and osteopontinmRNA; and increased endothelial nitric oxide synthase protein(30). Finally, in the rat transgenic for human renin and angiotensinogen(dTGR), cerivastatin (0.5 mg/kg per d), given from weeks 4 to7, induced reduction (60%) of proteinuria, serum creatinine,and arterial hypertension and attenuated leukocyte infiltrationand intercellular adhesion molecule-1 expression in the kidney(31).
It is worth stressing that the beneficial effects in these variousanimal models have been obtained with dosages that exceededthose of therapeutic use in human and with all of the availablestatins, independent of their prevalent hydro- or lipophilicity.Many of these effects seem to be independent of the cholesterol-loweringaction of the drugs, related to an antioxidant, anti-inflammatory,immunomodulatory pleiotropic action.
Effects on Lipid Abnormalities and Cardiovascular Complications
Lipid abnormalities are present not only in patients with glomerulardiseases and massive proteinuria (increase in LDL cholesterol,with a high proportion of dense LDL, and frequently also hypertriglyceridemia,but also in all chronic renal diseases with impaired renal function(discrete lipoprotein qualitative abnormalities in the earlierstages of renal insufficiency; a more evident near-electiveincrease in VLDL and intermediate-density lipoprotein cholesterol,with slightly increased LDL cholesterol characterized by a smalldense LDL phenotype; and often a reduced HDL cholesterol, inpatients with more severe functional impairment or on maintenancedialysis). These abnormalities increase the cardiovascular riskin patients with nephrotic syndrome (32). In chronic renal failure,the risk for cardiovascular complications also is very high,but it is more difficult to distinguish the role of dyslipidemiafrom that of the many other coexisting risk factors (e.g., cardiomyopathy,high BP, fluid overload, anemia, vascular calcifications, hyperhomocysteinemia).This relative risk was 1.8 greater in the >6000 participantswho participated in the Second National Health and NutritionExamination Survey and had mild to moderate renal insufficiency(33). In another study in >1000 adults, adjusted risk was3.4 greater in patients with GFR <15 ml/min than in patientswith normal renal function (34). All statins induce a markedreduction of LDL cholesterol, and the most powerful statinseven induce a marked reduction of triglycerides in patientswith nephrotic syndrome (35). Clinical and pharmacokinetic studieshave demonstrated that, even in patients who have chronic renalfailure and are on maintenance dialysis, statins are well toleratedand effective, providing equivalent control of lipid levelsto that seen in matched control subjects (36–40). In particular,pravastatin was able to reduce intermediate-density lipoproteinin patients who were on hemo- and peritoneal dialysis (41).
As for the protection that statins might provide from the cardiovascularcomplications as a result of these antilipidemic effects andeventually from their pleiotropic effects, the available datastill are insufficient and controversial. Pravastatin significantlyreduced the incidence of cardiovascular events, especially majorcoronary events, in the subgroup of 1711 patients who had chronicrenal insufficiency (creatinine clearance 75 ml/min) and participatedin the large Cholesterol and Recurrent Events (CARE) study (42).
A noncontrolled study of 3716 patients who were on dialysisin the United States demonstrated that the subgroup of patientswho were using statins at baseline had a 36% reduced risk forcardiovascular-specific mortality (43). A more recent retrospectiveanalysis of data from the Dialysis Outcomes and Practice Pattern(DOPPS) study on 17,221 patients who were randomly selectedfrom representative dialysis facilities in France, Germany,Italy, Spain, the United Kingdom, Japan, and the United Statesdemonstrated that patients who had been prescribed statins forany reason (11.8% of the total population) had a 23% lower relativerisk for cardiac mortality and 31% lower risk for death (44).Three ongoing controlled clinical trials among patients withchronic renal disease, mainly dialyzed patients, presumablywill give a more clear answer about the effect of statins oncardiovascular risk.
Effects on Renal Disease Progression
There now is much evidence that dyslipidemia can favor progressionof renal damage both in diabetic and in nondiabetic diseases(45–52). A secondary analysis of the Modification of Dietin Renal Disease (MDRD) Study demonstrated that HDL cholesteroland triglyceride-rich lipoproteins were correlated with an unfavorableeffect on the progression of renal disease (53). Also in theAtherosclerosis Risk in Communities (ARIC) study of 12,728 individualswho had baseline serum creatinine <2 mg/dl and were followedfor 2.9 yr, high triglycerides and low HDL cholesterol predictedan increased risk for renal functional impairment (54).
In correcting dyslipidemia, statins, even independent of theiradditional pleiotropic protective effects on the renal and vascularsystem, should have a protective effect on the progression ofrenal damage. However, the evidence still is scanty. In patientswith nephrotic syndrome, a mild protective effect is suggestedby the meta-analysis of Fried et al. (55), who reported on 13randomized trials of a small number of patients who were treatedfor short periods of time. More recently, Bianchi et al. (56),who reported on 56 patients who had chronic renal disease andwere randomly assigned to atorvastatin or placebo for 12 mo,found that in treated patients, proteinuria was significantlyreduced starting from the sixth month, and the rate of declineof renal function was lower at the end of the study. In a posthoc subgroup analysis of the large CARE randomized trial ofpravastatin versus placebo, patients who had a calculated creatinineclearance <40 ml/min and were treated with the statin hada reduced rate of renal loss in comparison with nontreated patients,especially when their baseline proteinuria was elevated (57).Finally, in the controlled, randomized Greek Atorvastatin andCoronary Heart Disease (GREACE) study of dyslipidemic patientswith coronary heart disease, a subgroup analysis reported that,whereas untreated patients showed a 5.2% decrease in creatinineclearance, treated patients had a 4.9% increase of clearance,and the difference was statistically very significant (58).
The statins, because of their antilipidemic effect and otherpleiotropic lipid-independent effects, are potentially usefulnot only in controlling dyslipidemia in patients with renaldisease but also in protecting them from the cardiovascularcomplications that are particularly frequent in these patients.Recent evidence does suggest that statin therapy also may havea renoprotective effect. However, large studies are needed and,in part, are already ongoing, to confirm these additional beneficialeffects.
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Abstract
Introduction
B activation, leukocyte–endothelial cell adhesion, and reduction of C-reactive protein), as immunomodulatory agents (reduced monocyte and T cell activation, inhibition of IFN-
, and shift from TH1 to TH2), and as antithrombotic agents (reduced tissue factor expression and increased fibrinolytic activity), as reviewed recently by Mason (6,7). 
chain protein and mRNA expression in glomeruli (25). In diabetic nephropathy that was induced by streptozotocin in rat, lovastatin (4 mg/kg per d) administration, started at day 1, reduced proteinuria at 3, 6, and 12 mo and suppressed the increase of TGF-
-smooth muscle actin–positive myofibroblasts in the interstitium, and induction of heme oxygenase-1 mRNA 12 h after ligation of the ureter (29). In a rat model of chronic cyclosporine-induced nephropathy, pravastatin at two dosages (5 and 20 mg/kg per d) suppressed afferent arteriolopathy, striped interstitial fibrosis, and tubular atrophy; reduced the number of recruited macrophages, TGF-
75 ml/min) and participated in the large Cholesterol and Recurrent Events (CARE) study (42). 
