Effects of Statins on Renal Function

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Effects of Statins on Renal Function

Rajiv Agarwal, MD*

This report reviews data on the development of proteinuria in patients with chronickidney disease who are treated with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) for dyslipidemia. Although subgroup analyses ofstatin trials have shown cardiovascular benefits in subjects with chronic kidneydisease, concern about statin-induced proteinuria remains high. Experimental studieshave suggested that the proteinuria seen with statin treatment results from theinhibition of receptor-mediated endocytosis, the likely mechanism of protein uptakein proximal tubular cells. Transient proteinuria may signify little more than theeffective inhibition of cholesterol synthesis at this site. The blockade of proteintrafficking in tubular cells is thought to reduce inflammation, slow fibrosis, anddiminish proteinuria in the long term. Post hoc analyses of large clinical trials insubjects without overt renal disease have generally supported this notion, showingthat statins most benefit patients with the greatest baseline renal deficits. Statins havealso been shown to preserve glomerular filtration rate and reduce proteinuria insubjects with nondiabetic renal disease. In conclusion, in the absence of prospective,randomized trials in renally impaired patients, the collective evidence indicates thatstatin therapy may slow the decrease in renal function that generally attends athero-sclerotic disease. The incidence of proteinuria with potent statins is only 1% to 2%when these drugs are given in recommended doses. Several large trials are currentlyunder way to examine the safety and efficacy of statins in renally compromisedpatients at high risk for cardiovascular disease. © 2006 Elsevier Inc. All rights
reserved. (Am J Cardiol 2006;97:748–755)
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-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) re-uctase inhibitors (statins) have noticeably improved car-iovascular outcomes in patients lacking significant kidneyisease and show promise of doing as much in renallyompromised patients.1 Evidence indicates that dyslipide-ia plays a role in initiating and sustaining chronic kidney

isease.2 Even in its earliest stage, renal impairment isssociated with a significantly greater prevalence of cardio-ascular risk factors, among them lower levels of apoli-oprotein A1 and higher levels of serum C-reactive protein,erum homocysteine, plasma fibrinogen, and serum lipopro-ein(a).3 Patients with nephrotic syndrome typically exhibitlevated levels of total cholesterol, low-density lipoproteinholesterol, and triglycerides, as well as low levels of high-ensity lipoprotein cholesterol.4 Statins can significantlymprove the lipid profiles of patients with chronic kidneyisease, lowering levels of total cholesterol by 18%, low-ensity lipoprotein cholesterol by 24%, and triglycerides by3% in some studies.5 With their pleiotropic effects, statinsre also believed to reduce vascular inflammation and im-

Division of Nephrology, Department of Medicine, Indiana Universitychool of Medicine; and Richard L. Roudebush VA Medical Center,ndianapolis, Indiana. Manuscript received July 30, 2005; revised manu-cript received and accepted September 20, 2005.

This study was supported by AstraZeneca, Wilmington, Delaware.* Corresponding author: Tel: 317-554-0000 ext. 2241; fax: 317-554-

298.
bE-mail address: [email protected] (R. Agarwal).
002-9149/06/$ – see front matter © 2006 Elsevier Inc. All rights reserved.oi:10.1016/j.amjcard.2005.09.110

rove endothelial function, thus inhibiting the processes thatnderlie atherogenesis and drive interactions between theascular endothelium and the immune system.2 Complicat-ng this picture, however, is the association of statin therapyith renal tubular effects and proteinuria.6 The dissemina-

ion of results from preapproval clinical trials of rosuvasta-in, a highly potent statin that became available commer-ially in 2003, has heightened concerns over this issue. Inandomized, controlled trials, subjects taking an unapprovedose of rosuvastatin (80 mg/day) had a 12% incidence ofroteinuria, along with hematuria and isolated renal failure,ome cases of which also were associated with myopathy.7

erein, I discuss 3 lines of evidence that indicate that statinherapy is renoprotective and consequently may help pre-erve kidney function in patients who have, or are at riskor, coronary heart disease.

xperimental Evidence That Statin-Inducedroteinuria Is Transient and Ultimately Renoprotective

he normal reabsorption of proteins, including albumin,ccurs through receptor-mediated endocytosis, a processequiring the presence of 2 multiligand endocytic recep-ors.8 In experiments in cultures of proximal tubular cellsrom opossums, Sidaway et al9 made 3 observations sup-orting the hypothesis that statins impede albumin uptake
y receptor-mediated endocytosis. Specifically, the investi-
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ators found that reductions in albumin uptake were (1)ependent on the statin dose, (2) associated with the in vitronhibition of HMG-CoA reductase and cholesterol synthe-is, and (3) related to alterations in receptor-mediated en-ocytosis of albumin (and other proteins) rather than tohanges in receptor binding. They surmised that the impair-ent in receptor-mediated endocytosis was caused not by a

eduction in cholesterol synthesis, because adding choles-erol did not correct the problem, but by the reduced pre-ylation of proteins critical to endocytosis.9

These experimental findings have since been replicatedn proximal tubular cells from the human kidney.10 In thepossum9 and human10 cell cultures, reduction in the cellu-ar uptake of albumin correlated well with the degree ofMG-CoA reductase inhibition by statins (pravastatin, ro-

uvastatin, and simvastatin), without altering cell viability.he addition of mevalonate, the product of HMG-CoA

eductase, reversed the statin-induced inhibition of receptor-ediated endocytosis,10 showing that impaired prenylation

f the proteins critical to receptor-mediated endocytosisesults in proteinuria.

Protein reabsorption stimulates profibrinogenic and proin-ammatory genes in the kidney.11 Low-density lipoprotein

s among the proteins known to be toxic to kidney cells.idney damage may also be caused by other lipoproteins.or example, small lipoprotein fragments, such as apoli-oprotein A, may leak through the glomerulus and comento contact with the tubules, causing injury. Although thisechanism has not been studied, urinary analysis for such

ragments may be of value.Preclinical data indicate that increased protein trafficking

ay contribute to tubulointerstitial disease.12 Therefore, it iseasonable to assume that the blockade of protein traffickingn the proximal tubule exerts a renoprotective effect overime. Unlike angiotensin-converting enzyme inhibitors andngiotensin receptor blockers, statins boost protein excre-ion by reducing receptor-mediated endocytosis. Thus, al-hough statins increase proteinuria in the short term, theyay reduce inflammation, slow fibrosis, and result in less

roteinuria in the long term. A long-term reduction in pro-einuria is associated with improved renal13 and cardiovas-ular14 outcomes. Clinical trial data involving renally healthynd renally compromised subjects support the validity of aong-term renoprotective effect of statin therapy.

vidence from Post Hoc Analyses of Large Statinrials of Subjects With Relative Renal Health

he idea that high-potency statins improve renal outcomess supported by post hoc analyses of results from 3 largeandomized trials involving subjects at high risk for cardio-ascular events but with little or no renal disease at baseline.

In the Heart Protection Study,15 the effects of randomlyssigned simvastatin 40 mg/day or matching placebo were
ssessed in �20,000 adults with coronary heart disease, i
ther occlusive arterial disease, or diabetes mellitus. Serumreatinine was measured at screening and again after a meanollow-up of 4.6 years. Although creatinine concentrationsncreased with age, subjects taking simvastatin had signifi-antly smaller increases than those taking placebo (7.13 vs.94 �mol/L, p �0.0001). Decreases in the estimated glo-erular filtration rate (GFR) were also significantly smallerith simvastatin than with placebo (5.9 vs 6.7 ml/min, p �.0003).15

In a post hoc analysis of the Cholesterol and Recurrentvents trial, Tonelli et al16 examined the effects of prava-tatin 40 mg/day in a subgroup of 690 subjects with cardio-ascular disease and moderate chronic renal insufficiencyGFR �60 ml/min/1.73 m2) who were followed for a me-ian of 58.9 months. The analysis revealed a significanttepwise inverse relation between pretreatment GFR and theetardation of renal function loss with pravastatin, withreater benefits accruing to subjects having lower GFRs ataseline. The rate of change in GFR with pravastatin wasndistinguishable from that of placebo in all subjects withompromised renal function (0.1 ml/min/1.73 m2 slower,� 0.49), noticeably slower (0.6 ml/min/1.73 m2, p �

.07) in those with GFRs �50 ml/min, and significantlylower (2.5 ml/min/1.73 m2, p � 0.0001) in those withFRs �40 ml/min. Pravastatin treatment was associatedith similarly lower rates of renal loss in subjects who hadroteinuria at baseline than in those who did not.

A subgroup analysis was conducted in 1,600 subjectsith coronary heart disease and serum creatinine concen-

rations �115 �mol/L who participated in the Greek Ator-astatin and Coronary Heart Disease Evaluation study.17

ubjects had been randomized to atorvastatin 10 to 80g/day or usual care and followed for 3 years. Those given

ose-titrated atorvastatin had a 12% increase in creatininelearance from baseline (p �0.0001), whereas those as-igned to usual care had a 5.3% decrease from baselinep �0.0001). As in the Cholesterol and Recurrent Eventstudy,16 treatment was most beneficial in subjects with renalysfunction (i.e., mean creatinine clearance of 61 ml/min).

Last, a recent post hoc subgroup analysis of data from 3andomized, double-blind, controlled trials with pravastatin0 mg/day was performed by Tonelli et al18 to determinehether pravastatin reduced the rate of kidney function lossver a 5-year period in patients with or at high risk fororonary disease and with varying degrees of kidney func-ion. More than 18,500 subjects were included in the anal-sis; the primary outcome was the rate of change in thestimated GFR. Pravastatin modestly reduced the rate ofidney function loss (8%, 95% confidence interval 1% to5%) and the risk for acute renal failure (relative risk 0.60,5% confidence interval 0.41 to 0.86) in this high-risk group;owever, in subjects with moderate chronic kidney diseasend proteinuria, there was a significant reduction in the ratef acute renal failure with pravastatin use. Despite this, the
nvestigators concluded that the reduction in mortality re-

Table 1Prospective, randomized trials assessing statin effects on renal function and proteinuria

Study Design(Year)

No. and Type ofKidney Disease

Treatment (mo) Effect on Renal Function Effect on Proteinuria Conclusions

Statin Control Statin Control

Nondiabetic nephropathyDouble blind,

controlled(1993)21

30; nephrotic syndromeor proteinuria �1 g/day

Simvastatin 10–40mg/day orplacebo (6)

Inulin clearance 214.3 ml/min/1.73 m2 (p �NS vs control)

Inulin clearance 214.1 ml/min/1.73 m2

24-hr proteinuria 2by 0.2 g (p �NS vs control)

24-hr proteinuria 2by 0.5 g

Statin therapy had noapparent effect onproteinuria

Controlled, openlabel (1996)22

17; idiopathicmembranousnephropathy plusnephrotic syndrome

Simvastatin 10–40mg/day or dietarytherapy (24)

Decline in GFR �1.27 ml/min/1.73 m2 permonth (p � NSvs control)

Decline in GFR �1.28 ml/min/1.73 m2 permonth

Protein/creatinineratio 2 0.39g/mmol (p � NSvs baseline)

Protein/creatinineratio virtuallyunchanged

Statin therapy reducedproteinuria but did notaffect the rate of decreasein kidney function


57; mild renaldysfunction

Pravastatin 10 mg/day(n � 29) or 5 mg/day (n � 3), orplacebo (6)

No change in Scrand BUN

Scr 1 by 0.5 mg/dl (p � 0.05 vsstatin) and BUN1 by 6.2 mg

Not reported Not reported Statin therapy attenuateddeterioration of renalfunction


21; IgA nephropathywith non-nephroticproteinuria andwell-preserved GFR

Fluvastatin 40 mg/dayor placebo (6)

CrCl remainedstable in allpatients

CrCl remainedstable in allpatients

24-hr proteinuria 2123 mg (p �0.05vs baseline)

24-hr proteinuria 1by 92 mg(p �0.01 vsstatin)

Statin therapy had anantiproteinuric effect


43; idiopathic nephroticsyndrome with Scr�2 mg/dl

Fluvastatin 20 mg/dayfor 8 week, withresponse titrationthereafter, orconservativetreatment (12)

CrCl 2 4.8 ml/min (p � NS)

CrCl 2 35.4 ml/min (p �0.0001)

Median 24-hrproteinuria 26 g (p � 0.049vs control)

Median 24-hrproteinuria 2 2 g

Statin use was associatedwith better control ofproteinuria and CrCl, aswell as with regression ofrenal fat deposits but notinterstitial fibrosis


40; IgA nephropathy(n � 27) or non-IgAproliferativeglomerulonephritis(n � 13)

Cerivastatin 0.15 mg/day or placebo (6)

CrCl unchanged CrCl unchanged 24-hr proteinuria 2by 1.0 g andurinary podocyteexcretion 2 by0.7 cells/ml (bothp �0.01 vsbaseline and vscontrol)

Neither parameterchanged

Statins may help restoreinjured podocytes inpatients with chronicglomerulonephritis


56; mild to moderatechronic kidneydisease

Atorvastatin �40 mg/day � ACEinhibitors or ARBsor antihypertensivetreatment only (12)

CrCl 2 by 1.2ml/min (p �NS vs baseline)

CrCl 2 by 5.8ml/min(p �0.01 vsbaseline)

24-hr proteinuria 2by 1.0 g(p �0.01 vsbaseline)

24-hr proteinuria 2by 0.24 g (p �NS vs baseline)

Statin therapy reducedproteinuria and slowedrate of progression ofkidney disease

Parallel, doubleblind,controlled(2002)28

63; proteinuria(300–3,000 mg/day)in well-controlledhypertensive patients

Pravastatin 10 mg/dayor placebo (6)

CrCl unchanged CrCl unchanged 24-hr proteinuria 2by 674 mg (54%, p �0.0001)

24-hr proteinuriaunchanged

Statins plus antihypertensivesmay reduce proteinuria inan additive manner andindependently of theirhemodynamic and lipid-lowering effects

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Table 1(continued)


30; pediatric IgAnephropathy withmoderate proteinuria

Fluvastatin 20 mg/day �dipyridamole5 mg/kg/day ordipyridamoleonly (12)

Hematuria, BUN,and Scrsignificantly 2from baseline(p �0.05); CrClsignificantly 1compared withcontrol (p �0.0001)

— 24-hr proteinuria 2 by0.8 g (p � 0.001 vsbaseline)

24-hr proteinuria 2 by0.4 g (p �0.05 vsbaseline)

Statin therapy had anantiproteinuric effect andimproved renal function

Diabetic nephropathyControlled,

double blind(1992)30

26; type 1 diabeticnephropathy withpersistentalbuminuria �300mg/24 hr


GFR 2 by 1 ml/min/1.73 m2

(p � NS vsbaseline)

GFR 1 by 2 ml/min/1.73 m2 (p � NSvs statin)

24-hr albuminuria 2by 113 �g/min (p �NS vs baseline)

24-hr albuminuria 2by 65 �g/min (p �NS vs baseline andvs statin)

Statin therapy had no effecton albuminuria

Controlled,double blind(1993)31

18; type 2 diabeticmicroalbuminuria


GFR 2 by 1 ml/min/1.73 m2

(p � NS vsbaseline)

GFR 2 by 8 ml/min/1.73 m2 (p � NSvs baseline and vsstatin)

UAE 2 by 2 �g/min(p � NS)

UAE 1 by 10 �g/min(p � NS vs baselineand vs statin)

Statin therapy had no impacton kidney function orUAE rates

Controlled,single blind(1995)32

34; type 2 diabeticproteinuria �150mg/day with normalScr

Lovastatin 20 mg/day,with upwardtitration forcholesterol control,or placebo (24)

GFR unchanged;Scr 1(p �0.025 vsbaseline)

GFR 2; Scr 1(p �0.025 vsbaseline)

Proteinuria 1 in bothgroups (p �0.05 vsbaseline), with nosignificantdifferences betweenthe 2 groups

— GFR stabilized with statintherapy, suggestingretardation in theprogression of diabeticnephropathy

Double blind,crossover(1997)33

19; type 2 diabeticmicroalbuminuria

Simvastatin 20 mg/day or placebo for1 yr, withcrossover (24)

CrCl unchanged CrCl unchanged UAE 2 by 25% after12 months

UAE 1 Statins may help preserverenal function

ACE � angiotensin-converting enzyme; ARB � angiotensin receptor blocker; BUN � blood urea nitrogen; CrCl � creatinine clearance; IgA � immunoglobulin A; Scr � serum creatinine; UAE � urinaryalbumin excretion.

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ains the primary rationale for the use of statins in thisopulation.18

In summary, post hoc analyses of large statin trials dem-nstrate that treatment with high-potency agents confersong-term renal benefits to patients at high risk for cardio-ascular events who are relatively free of kidney disease ataseline. Notably, subjects starting with the greatest renal def-cits appear to derive the most benefit from statin therapy.

vidence From Randomized, Controlled Trials ofntilipidemic Agents in Subjects With Renal Disease

ried et al19 performed a meta-analysis of 13 prospective,ontrolled clinical trials evaluating the effects of 6 antilipi-emic agents (simvastatin, pravastatin, lovastatin, fluva-tatin, gemfibrozil, and probucol) on renal function, protein-ria, or albuminuria in patients with renal disease. Theyound that treatment slowed the rate of decrease in GFR bymean of 1.9 ml/min/year, a result that compared favorablyith the protective effect on GFR (1.6 ml/min/year) of

ngiotensin-converting enzyme inhibitors.20 The positiveffect on GFR was independent of factors such as percent-ge change in cholesterol level or type of antilipidemicgent but correlated with increased follow-up time (p �.007). In general, antilipidemic treatment tended to reduceroteinuria (p � 0.077), with the results for individualtudies being statistically heterogenous.

Following on the work of Fried et al,19 13 randomized,ontrolled studies were examined that measured the effectf statins on kidney function. Table 1 lists the studies, withhe findings grouped by the presence or absence of diabeticidney disease or status as a renal transplant recipient.nother study examining the renal effects of statins inatients who had undergone kidney transplantation was alsovaluated.

Statins in nondiabetic nephropathy: Of the 9 stud-es21–29 that assessed the effect of statins in proteinuricubjects with nondiabetic kidney disease, 4 studies23,25,27,29

ound that statins either stabilized or improved GFR to atatistically significant degree compared with placebo. Threetudies25,27,29 also reported statistically significant decreasesn proteinuria after 1 year of statin therapy; the fourthtudy23 did not assess this parameter. Although the remain-ng 5 studies21,22,24,26,28 showed no difference between stat-ns and placebo in effect on GFR, 3 studies24,26,28 found thatfter 6 months of therapy, there was a statistically signifi-ant decrease in proteinuria in the statin group comparedith the placebo group. The other 2 studies noted no change

rom baseline with either statins or placebo.Besides reporting improvements in GFR and proteinuria

ith fluvastatin, Gheith et al25 found that this statin therapyaused a significant (p � 0.003) reduction in renal fateposits over 1 year in subjects with persistent nephrotic
yndrome. Although at study end, glomerular sclerosis was i
imilar in the fluvastatin and control groups, scores fornterstitial fibrosis were better in subjects who had receivedtatin therapy.

Statins in diabetic nephropathy: Of the 4 studies30–33

n subjects with diabetic nephropathy, only 1 study32 notedhe stabilization of GFR with statin treatment (lovastatin,ean dose 30 mg/day). This 2-year trial also reported a

tatistically significant increase in proteinuria at study endith statins and placebo (p �0.05). In a 2-year crossover

tudy of diabetic patients with microalbuminuria, 52 weeksf simvastatin 20 mg/day significantly reduced the rate oflbumin excretion (mean reduction 25%), whereas pla-ebo treatment increased it.33 The 2 remaining studiesn subjects with diabetic nephropathy30,31 indicated nohange in proteinuria with either simvastatin (10 to 20g/day) or placebo.

Statins in renal transplant patients: Holdaas et al34

onducted a double-blind, randomized, placebo-controlledrial in 2,102 renal transplant recipients with total choles-erol of 4.0 to 9.0 mmol/L (155 to 348 mg/dl). Subjects wereandomized 1:1 to fluvastatin 40 mg/day or placebo andere followed for a mean of 5.1 years. At study end, thereere no significant differences in primary risk reductionutcomes or most secondary outcomes (including allograftoss or the doubling of serum creatinine) between the treat-ent groups.In summary, 6 of the 8 studies examined indicated that

tatins exert a renoprotective effect in patients with nondi-betic nephropathy who require lipid-lowering therapy,enerally preserving GFR and lowering proteinuria. Theenoprotective effects of statins in patients with diabeticephropathy or recipients of renal transplants were lesspparent.

ncidence and Significance of Transient Proteinuriaith High-Potency Statins

he issue of transient proteinuria was most recently raiseduring the rosuvastatin phase II/III development program,n which �10,000 dyslipidemic subjects received rosuva-tatin 5 to 80 mg/day for up to 3.8 years. Vidt et al35 did aooled analysis of the approved dosages (5 to 40 mg) in aiverse population to gauge the incidence of proteinuria�2� on urine dipstick) in recipients of rosuvastatin. Thencidence proved to be dose dependent: 0.2% with 5 mg,.6% with 10 mg, 0.7% with 20 mg, and 1.2% with 40 mgompared with 0.6% with placebo (Table 2).35,36 A 12% rateas noted with 80 mg (not an approved dose).7 Of note, theroteinuria was mostly tubular in origin. In comparativetudies, the incidence of proteinuria with rosuvastatin (n �,317) was generally similar to that in subjects taking ator-astatin 10 to 80 mg/day, simvastatin 10 to 80 mg/day, andravastatin 10 to 40 mg/day (n � 2,789). Similar decreases
n serum creatinine concentrations were observed with all

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he statins studied, with levels decreasing by a mean of 2ol/L from baseline with rosuvastatin but remaining un-

hanged with placebo.As the pooled data show, microhematuria occurred in

.2% to 1.9% of subjects in the rosuvastatin group com-ared with 0.9% in the placebo group.35 The incidence oficrohematuria with rosuvastatin was unrelated to dose andas similar to that seen with atorvastatin, simvastatin, andravastatin. In addition, the estimated GFR was either un-hanged or tended to increase in subjects given rosuvastatinong term (i.e., �96 weeks). This finding was true regard-ess of subjects’ age, gender, hypertensive or diabetic status,evel of renal function at entry (GFR �60 vs �60 ml/min/.73 m2), or urine dipstick protein status before or duringreatment. When given in doses of 10 to 40 mg for �96eeks, rosuvastatin was associated with a mean decrease of

pproximately 5% in serum creatinine. This finding is sim-lar to that in the Heart Protection Study, in which simva-tatin 40-mg treatment was associated with lower concen-rations of serum creatinine compared with placebo.15

Given these findings, Vidt et al35 concluded that at theenerally recommended 10-mg starting dose of rosuva-tatin, evidence exists for a potential renoprotective effect.ssentially the same conclusion was reached in the Choles-

erol and Recurrent Events subgroup analysis of pravastatinn subjects with moderate renal insufficiency,16 although theeneficial effects of pravastatin on renal function did notlso extend to subjects with baseline GFRs �50 ml/min/.73 m2.

In summary, it appears that proteinuria is associatedrimarily with the degree of cholesterol inhibition affordedy a statin.35,36 Thus, the incidence of proteinuria withosuvastatin was 12% when patients received the 80-mgunapproved) dose in clinical trials but only 1% to 2% whenhey received 10 to 40 mg (approved) doses. Of note, thisower rate is similar to that of comparator statins. In con-

able 2tatin-related proteinuria and/or hematuria in the rosuvastatin clinical tria

reatment Dose (mg) n % Subjects with�2� Proteinuria

lacebo — 330 0.6osuvastatin 5 587 0.2

10 1,008 0.6 120 872 0.740 1,850 1.2 1

torvastatin 10 628 0.520 438 0.540 63 080 342 0.3

imvastatin 20 452 1.140 314 0.380 325 0

ravastatin 20 162 0.640 64 0

Adapted from Davidson,36 with permission.

rast, pravastatin, although largely excreted by the kidneys c

hen dosed at �10 mg, inhibits cholesterol synthesis to aesser degree and therefore appears to have less effect on theubular resorption of proteins.36

linical End Point Studies of Statins in Renallyompromised Patients

recently reported study assessed the effects of the angio-ensin-converting enzyme inhibitor fosinopril, pravastatin,r placebo in 864 subjects with microalbuminuria on all-ause mortality or nonfatal myocardial infarction, myocar-ial ischemia, heart failure, peripheral vascular disease, ornd-stage renal disease. However, neither fosinopril norravastatin had a statistically significant effect on these endoints.37 Although a statistically significant difference com-ared with placebo occurred for stroke with fosinopril (p �.048) and myocardial ischemia with pravastatin (p �.03), this effect was limited to subjects whose baselineicroalbuminuria was �50 mg/24 hours.Larger scale studies are now under way to investigate

irectly whether statins reduce the progression of renalisease as well as cardiovascular morbidity and mortality inubjects with chronic kidney disease38 and specifically inhose who undergo hemodialysis.39 The Study of Heart andenal Protection will evaluate the effect of simvastatin 20g plus ezetimibe 10 mg on major cardiovascular events

nd on the rate of progression to end-stage renal disease in,000 subjects with chronic kidney disease.

The recently reported German Diabetes and Dialysistudy40 assessed the effect of atorvastatin 20 mg in 1,200atients with type 2 diabetes on hemodialysis. After up to 4ears of treatment, despite a reduction in low-density li-oprotein cholesterol of 42%, to 72 mg/dl, there was noignificant effect on the incidence of the primary end point,combined incidence of nonfatal myocardial infarction and

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lacebo. There was a reduction in the rate of all cardiacvents combined but not in total mortality or all cerebro-ascular events combined. Because these results did noteflect those achieved in a statin trial with diabetic subjectsith no marked renal insufficiency,41 the investigators con-

luded that the benefits of treatment may be limited whenntervention with statins is postponed until patients haverogressed to end-stage renal disease.

An ongoing study, A Study Evaluating the Use of Ro-uvastatin in Patients Requiring Ongoing Renal Dialysis:n Assessment of Survival and Cardiovascular Events, willeasure the effects of rosuvastatin in approximately 3,000

emodialysis patients.

1. Tonelli M, Moyé L, Sacks FM, Kiberd B, Curhan G, for the Choles-terol and Recurrent Events (CARE) Trial Investigators. Pravastatin forsecondary prevention of cardiovascular events in persons with mildchronic renal insufficiency. Ann Intern Med 2003;138:98–104.

2. Campese VM, Nadim MK, Epstein M. Are 3-hydroxy-3-methylglu-taryl-CoA reductase inhibitors renoprotective? J Am Soc Nephrol2005;16(suppl):S11–S17.

3. Muntner P, Hamm LL, Kusek JW, Chen J, Whelton PK, He J. Theprevalence of nontraditional risk factors for coronary heart disease inpatients with chronic kidney disease. Ann Intern Med 2004;140:9–17.

4. Wheeler DC. Lipid abnormalities in the nephrotic syndrome: thetherapeutic role of statins. J Nephrol 2001;14(suppl):S70–S75.

5. Baigent C, Landray M, Leaper C, Altmann P, Armitage J, Baxter A,Cairns HS, Collins R, Foley RN, Frighi V, et al. First United KingdomHeart and Renal Protection (UK-HARP-I) study: biochemical efficacyand safety of simvastatin and safety of low-dose aspirin in chronickidney disease. Am J Kidney Dis 2005;45:473–484.

6. Deslypere JP, Delanghe J, Vermeulen A. Proteinuria as complicationof simvastatin treatment. Lancet 1990;336:1453.

7. Department of Health and Human Services, Food and Drug Administra-tion, Center for Drug Evaluation and Research. Endocrinologic and Met-abolic Drugs Advisory Committee: Wednesday, July 9, 2003. Availableat: http://www.fda.gov/ohrms/dockets/ac/03/transcripts/3968T1.doc. Ac-cessed June 29, 2005.

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Effects of Statins on Renal Function