A Controlled, Prospective Study of the Effects of Atorvastatin onProteinuria and Progression of Kidney Disease

Stefano Bianchi, MD, Roberto Bigazzi, MD, Alberto Caiazza, MD, and Vito M. Campese, MD

● Background: Chronic kidney diseases, particularly if presenting with significant proteinuria, are commonlyassociated with substantial alteration of serum lipid levels. Experimental evidence suggests that lipid abnormalitiesmay contribute to the progression of kidney disease. However, studies in humans on the subject are scarce.Methods: In a prospective, controlled open-label study, the authors have evaluated the effects of one-year treatmentwith atorvastatin, a 3-hydroxy-3-methyglutaryl coenzyme A (HMG-CoA) reductase inhibitor, versus no treatment onproteinuria and progression of kidney disease in 56 patients with chronic kidney disease. Before randomization, allpatients had already been treated for one year with angiotensin-converting enzyme (ACE) inhibitors or angiotensinAT1 receptor antagonists (ARBs) and other antihypertensive drugs. Results: By the end of one-year treatment, urineprotein excretion decreased from 2.2 � 0.1 to 1.2 � 1.0 g every 24 hours (P < 0.01) in patients treated withatorvastatin in addition to ACE inhibitor and ARBs. By contrast, urinary protein excretion decreased only from 2.0 �0.1 to 1.8 � 0.1 g every 24 hours (P value not significant) in patients who did not receive atorvastatin in addition toACE inhibitor or ARBs. During this time, creatinine clearance decreased only slightly and not significantly (from51 � 1.8 to 49.8 � 1.7) in patients treated with atorvastatin. By contrast, during the same period of observation,creatinine clearance decreased from 50 � 1.9 to 44.2 � 1.6 mL/min (P < 0.01) in patients who did not receiveatorvastatin. Conclusions: This study has shown that treatment with atorvastatin in addition to a regimen with ACEinhibitors or ARBs may reduce proteinuria and the rate of progression of kidney disease in patients with chronickidney disease, proteinuria, and hypercholesterolemia. The benefits appear to occur in addition to those oftreatment with ACE inhibitor and ARBs. Am J Kidney Dis 41:565-570.© 2003 by the National Kidney Foundation, Inc.

INDEX WORDS: Proteinuria; atorvastatin; progression of kidney disease.

CHRONIC KIDNEY diseases (CKD) are as-sociated commonly with substantial abnor-

malities of lipid metabolism. Those consist ofincreased low-density lipoproteins (LDL), triglyc-erides, very-low-density lipoprotein (VLDL), li-poprotein(a) (Lp[a]), and reduced levels of high-density (HDL) cholesterol.1-3 Other abnormalitiesconsist of increased apolipoprotein B (Apo B)reduced HDL2 cholesterol, and increased ApoC-to-Apo C-II ratio.4-6 Dyslipidemia is moresevere in patients with proteinuria, particularlythose with nephrotic syndrome.3,7

Lipid abnormalities are one of the factors thatcontribute to the greater rate of cardiovascularmorbidity and mortality among CKD patientsthan in the general population.8-10

Some evidence also suggests that dyslipide-mia may contribute to the progression of kidneydisease. Hypercholesterolemia is a predictor ofloss of kidney function in both type 1 and type 2diabetics.11,12 Elevated levels of Apo B stronglycorrelate with the rate of deterioration in kidneyfunction in both diabetics and nondiabetic pa-tients with CKD.13 In nondiabetic patients, kid-ney disease progressed more rapidly in patientswith hypercholesterolemia and hypertriglyceride-mia than in those with normal lipids, indepen-dent of blood pressure levels.14,15 Low serum

HDL also is an independent predictor of morerapid rates of decline in glomerular filtration rate(GFR) in patients with nondiabetic kidney dis-eases.16

Studies in experimental animals have sug-gested that treatment with statins may retard theprogression of kidney disease.17,18 However, onlya few studies have evaluated the effects of statinson the progression of renal disease in humansubjects, and those have been done in a smallnumber of patients.19,20

The purpose of this study was to determine theeffects of atorvastatin, a 3-hydroxy-3-methyglu-taryl coenzyme A (HMG-CoA) reductase inhibi-tor, on the progression of kidney disease in agroup of patients with CKD and proteinuriasecondary to idiopathic glomerulopathies.

From Unita Operativa Nefrologia, Spedali Riuniti diLivorno, Livorno, Italy and the Division of Nephrology,Keck School of Medicine, USC, Los Angeles, CA.

Received August 5, 2002; accepted in revised form Octo-ber 31, 2002.

Address reprint requests to Vito M. Campese, MD, Divi-sion of Nephrology, Keck School of Medicine, USC, 1200North State St, Room # 4250, Los Angeles, CA 90033.E-mail: campese@hsc.usc.edu

© 2003 by the National Kidney Foundation, Inc.0272-6386/03/4103-0027$30.00/0doi:10.1053/ajkd.2003.50140

American Journal of Kidney Diseases, Vol 41, No 3 (March), 2003: pp 565-570 565

METHODS

This is a controlled, prospective, open-label study. Fifty-six patients with mild to moderate chronic kidney disease,proteinuria, and hypercholesterolemia were enrolled in thisstudy. All the patients had a clinical diagnosis of idiopathicchronic glomerulonephritis. These diagnoses were based onthe presence of proteinuria greater than 1 g every 24 hours,and no evidence of systemic disease known to cause glomer-ulonephritis. Because none of these patients underwentbiopsy, we cannot exclude the possibility that some of thesepatients may have renal diseases other than glomerulonephri-tis. Twenty-seven of 56 patients were hypertensive (officesystolic blood pressure �140 mm Hg and diastolic BP � 90mm Hg). The remaining 29 patients were normotensive.None of the hypertensive patients had ever been on antihy-pertensive treatment. Patients with diabetes mellitus; reno-vascular or malignant hypertension; secondary glomerulardisease; malignancies; myocardial infarction or cerebrovas-cular accident in the 6 months preceding the study; conges-tive heart failure; hepatic dysfunction; neuromuscular disor-ders; and a history of allergy to angiotensin-convertingenzyme (ACE) inhibitors, angiotensin II antagonists (ARBs),and statins were excluded from the study. Also excludedwere patients treated recently with steroids, nonsteroidalantiinflammatory drugs, or immunosuppressive agents.

The Human Research Committee of the Spedali Riuniti diLivorno, Italy, approved the study, and all subjects gave theirinformed consent. Each patient underwent follow-up for 2years. During the first year, all subjects were treated with anACE inhibitor or an ARB or a combination of these 2 drugs.Other antihypertensive drugs were used as needed to achievea blood pressure of less than 140/90 mm Hg. Patients alsowere advised to ingest a diet low in sodium (approximately2 g sodium per day) and low in cholesterol and saturated fat,and the recommended protein intake was 0.8 g/kg/d.

During the first 2 months of the study, hypertensivepatients were seen on a weekly basis until control of hyper-tension was achieved. Thereafter, patients were seen in theoutpatient clinic monthly. Urine protein excretion, creatinineclearance, and the lipid profile were measured at baselineand every 6 months thereafter.

At the end of 12 months of antihypertensive therapy,patients were randomly selected blindly to receive eitheratorvastatin (group A) or no atorvastatin (group B) whilecontinuing their previous therapy with antihypertensive drugs.The dose of atorvastatin was titrated to a maximum of 40 mgdaily until LDL levels were reduced to less than 120 mg/dLor by 40% compared with baseline values.

Serum lipids, proteinuria, and creatinine clearance weremeasured after 3, 6, 9, and 12 months after the initiation ofthe therapy with atorvastatin. The primary end-points of thestudy were changes in proteinuria and in creatinine clear-ance.

Serum concentrations of total cholesterol, triglycerides,low-density lipoprotein (LDL), and high-density lipoprotein(HDL) cholesterol were measured in fresh blood samplesdrawn after fasting overnight for at least 12 hours. Theselipids were measured by standard enzymatic methods. Theconcentration of LDL was measured by an enzymatic color-imetric assay (LDL-C Plus, Roche Diagnostic Corporation,

Indianapolis, IN). Urinary protein and creatinine were mea-sured by standard methods.

Body mass index (BMI) was calculated as weight (kilo-grams) divided by height (meters) squared. For statisticalanalysis, values for proteinuria were transformed logarithmi-cally given that they do not follow a normal distribution. Weused the Kolmogorov-Smirnov test for comparison of non-parametric parameters. Differences between baseline valuesand values at the end of the run-in period and of one yearwere analyzed by paired Student’s t-test. Between-groupdifferences were analyzed by analysis of covariance (AN-COVA).

RESULTS

The baseline clinical characteristics of all pa-tients included in the study are outlined in Table1. After the first year of run-in study, bloodpressure in the entire group was 133 � 1/84 � 1mm Hg. The clinical characteristics of the pa-tients in group A and group B at the time ofrandomization and after treatment with or with-out atorvastatin are outlined in Table 2. The ageof patients included in group A was 56.5 � 1.5years and that of patients included in group Bwas 56.8 � 1.5. Each group included 19 men and9 women. Before randomization, blood pressure,body mass index, serum levels of lipids, and

Table 1. Baseline Clinical Characteristics of thePatients at the Beginning of the Run-In Phase and

Study Phase

Start ofRun-In Phase

Start ofStudy Phase

No. of patients (M/F) 56 (38/18) —Age 55.6 � 1 —BMI (w/h2) 27.6 � 0.26 —Hypertension (yes/no) 27/29 —Office systolic BP (mm Hg) 144.3 � 2.4 133.0 � 1.0Office diastolic BP (mm Hg) 93.3 � 1.8 84.8 � 0.8CrCl (mL/min) 55.5 � 1.4 50.4 � 1.3UPE (g/24 h) 2.7 � 0.1 2.2 � 0.1Total cholesterol (mg/dL) 320.4 � 4.7 310.6 � 3.3LDL cholesterol (mg/dL) 189 � 5 198 � 4.1HDL cholesterol (mg/dL) 36.2 � 0.7 36.1 � 0.6Serum albumin (g/dL) 3.35 � 0.06 3.30 � 0.06

NOTE. To convert serum cholesterol in milligrams perdeciliter to millimoles per liter multiply by 0.02586. Toconvert serum albumin in milligrams per deciliter to milli-moles per liter multiply by 10.0. To convert serum triglycer-ides in milligrams per deciliter to millimoles per liter multiplyby 0.01129. Data are expressed as mean � SEM.

Abbreviations: BMI, body mass index; BP, blood pres-sure; CrCl, creatinine clearance; UPE, urinary protein ex-cretion.

BIANCHI ET AL566

urinary protein excretion were not different be-tween patients included in group A and thoseincluded in group B.

Of the patients treated with atorvastatin, 18received 10 mg of atorvastatin per day, 8 re-ceived 20 mg, and 2 received 40 mg/d. Bloodpressure throughout follow-up was not differentbetween patients treated with atorvastatin andthose not treated with atorvastatin (Table 2 andFig 1).

Table 3 describes the type of antihypertensiveand other drugs patients of both groups receivedthroughout the study. There was no difference intype and number of drugs used in the 2 groups.

By the end of one year of treatment withatorvastatin, urine protein excretion decreasedfrom 2.2 � 0.1 to 1.2 � 1.0 g every 24 hours(�45.5%). By contrast, in patients who did notreceive atorvastatin, urinary protein excretiondecreased only from 2.1 � 0.1 to 1.86 � 0.1 g

every 24 hours (�10%; P � 0.01; Table 2 andFig 2). During this time, total cholesterol andLDL cholesterol decreased in patients treatedwith atorvastatin, but did not change in patientstreated with conventional therapy (Table 2). Bycontrast, levels of VLDL cholesterol decreasedequally in both groups of subjects.

Creatinine clearance decreased only slightlyand not significantly (from 51 � 1.8 to 49.8 �1.7 mL/min [�2.0%]) in patients treated withatorvastatin. By contrast, during the same time,creatinine clearance decreased significantly (from50 � 1.9 to 44.2 � 1.6 mL/min [�11.6%] [P �0.01]) in patients not treated with atorvastatin(Table 2; Figs 2 and 3).

DISCUSSION

Our results show that treatment with atorvasta-tin, an HMG-CoA reductase inhibitor, reducesproteinuria and the rate of progression of renal

Table 2. Clinical Characteristics During the Run-In and Study Phase

Run-In Phase Study Phase

Months

�12 �6 0 3 6 9 12

Creatinine cl.(mL/min)Group A 56.0 � 1.9 52.8 � 1.9 50.8 � 1.8 50.3 � 1.7 50.2 � 1.7 50.2 � 1.7 49.8 � 1.7*Group B 54.9 � 2.0 51.4 � 1.9 50.0 � 1.9 49.3 � 1.7 48.1 � 1.7 46.6 � 1.6 44.2 � 1.5

Urine protein 2.8 (1.3-4.1) 2.8 (1-3.8) 2.5 (0.9-3.4) 2.3 (1-3.3) 1.7 (0.9-2.6) 1.7 (0.6-2.3)* 1.5 (0.6-2.1)†(g/24 h) 2.6 (1.6-4.3) 2.2 (1.2-3.4) 1.9 (1.1-3) 2 (1.1-3.1) 2.5 (0.9-3.4) 2.4 (0.8-3.2) 2.2 (0.7-3)

Total cholesterol 327 � 8 318 � 6 315 � 6 258 � 8* 237 � 5† 221 � 5† 211 � 5†(mg/dL) 313 � 4 302 � 5 306 � 3 309 � 5 304 � 6 303 � 3 305 � 5

LDL cholesterol 191 � 8 202 � 7 203 � 7 158 � 7* 137 � 6† 132 � 5† 121 � 4†(mg/dL) 184 � 5 186 � 5 193 � 3 202 � 5 202 � 5 207 � 4 206 � 4

VLDL cholesterol 101 � 5 83 � 4 79 � 5 70.3 � 3 66 � 3 60 � 3 60 � 2(mg/dL) 93 � 3 83 � 2 75 � 2 70 � 2 68 � 1 64 � 2 63 � 1

HDL cholesterol 35.5 � 1.1 34.9 � 1.1 34.9 � 1.0 35.6 � 1.0 37.0 � 0.9 36.9 � 0.9 38 � 0.9(mg/dL) 36.9 � 0.7 37.3 � 0.8 37.2 � 0.7 37.4 � 0.7 37 � 1 36.8 � 1 37.7 � 1

Triglycerides 223 � 10 183 � 8 174 � 9 155 � 7 148 � 7 134 � 7 132 � 5(mg/dL) 204 � 7 171 � 5 166 � 4 155 � 4 150 � 3 142 � 4 139 � 3

Systolic BP 143 � 3 135 � 2 133 � 1 131 � 1 133 � 1 130 � 1 131 � 1(mm Hg) 146 � 4 135 � 2 133 � 1 132 � 1 132 � 1 129 � 1 130 � 1

Diastolic BP 93 � 2 86 � 1 85 � 1 84 � 1 84 � 0.9 84 � 1 83 � 1(mm Hg) 94 � 3 86 � 1 84 � 1 84 � 1 82 � 1 82 � 1 83 � 1

Serum albumin 3.2 � 0.1 3.32 � 0.1 3.50 � 0.5(g/dL) 3.4 � 0.6 3.38 � 0.7 3.38 � 0.5

NOTE. To convert serum cholesterol in milligrams per deciliter to millimoles per liter multiply by 0.02586. To convert serumalbumin in milligrams per deciliter to millimoles per liter multiply by 10.0. To convert triglycerides in milligrams per deciliter tomillimoles per liter multiply by 0.01129.

*P � 0.05 versus untreated group.†P � 0.01 versus untreated group.

ATORVASTATIN, PROTEINURIA, AND KIDNEY FUNCTION 567

disease in patients with chronic kidney disease,proteinuria, and hypercholesterolemia. The ben-efits appear to be additive to that deriving fromtreatment with ACE inhibitors or ARBs.

It is now well established that when CKDensues, a variety of mechanisms come into playthat perpetuate and contribute to the progressionof kidney disease. Among those, dyslipidemiahas lately received a great deal of attention.

The lipid abnormalities most commonly ob-served in patients with chronic kidney diseaseinclude increased LDL cholesterol; increasedVLDL, triglycerides, and Lp(a); and reduction ofHDL cholesterol.1-3 These lipid abnormalitiesmay contribute to the progression of kidneydisease.11-15

The mechanisms responsible for these lipidabnormalities are complex, but proteinuria may

play a role.4 Equally complex are the mecha-nisms through which lipids can accelerate theprogression of renal disease. It is now clear thatLDL cholesterol can bind to specific receptors inmesangial cells and stimulate cell hypertro-phy.21,22 LDL can undergo a process of oxidationboth in mesangial cells and macrophages23-25 andstimulate cytokine formation, which ultimatelymediates tissue injury.17,26 Oxidized LDL mayattract monocytes directly27 or indirectly, viaactivation of monocyte chemoattractant pro-tein-1 (MCP-1). In vitro studies have shown thatLDL can stimulate fibronectin28 and collagenformation.29 Finally, LDL may activate the forma-tion of vasoactive substances, such as endothe-lin, thromboxane, and angiotensin II.17,30 Oxi-dized LDL may reduce nitric oxide in theglomeruli contributing to vasoconstriction.

Experimental studies have indicated that HMG-CoA reductase inhibitors may reduce the progres-sion of renal disease. These drugs reduce theproliferation of mesangial and vascular smoothmuscle cells induced by PDGF and insulinlikegrowth factor.17,23,31,32 Moreover, HMG-CoA re-ductase inhibitors inhibit the production of cyto-kines such as MCP-1, and the macrophage-colony stimulating factor.33-35 Studies have shownthat these drugs may upregulate nitric oxide(NO) synthase in vitro36,37 and in vivo,38 and theymay stimulate apoptosis,17,39 an important mecha-nism in the modulation of inflammatory damage.40

Despite the enormous amount of experimental

Fig 1. The bars indicatethe percent decrease in urineprotein excretion (UPE) inpatients treated with atorva-statin (group A) and thosenot treated (group B). Thepercent decline in protein-uria was significantly greaterin patients treated with ator-vastatin than those nottreated (P < 0.01).

Table 3. Antihypertensive and Antiplatelet DrugsAdministered to Patients Treated With Atorvastatin

(Group A) and Those Not Treated (Group B)

Therapeutic Class Group A Group B

ACE inhibitors 27/28 27/28AII antagonists 21/28 22/28Calcium channel-blockers 12/28 13/28Diuretics 9/28 10/28Alpha-blockers 3/28 3/28Beta-blockers 7/28 6/28Centrally acting drugs 8/28 7/28Aspirin and other

antiplatelet agents 19/28 18/28

BIANCHI ET AL568

work, the clinical evidence supporting a benefitof HMG-CoA reductase inhibitors in the progres-sion of renal disease is limited.19,20 Lee et al41

randomly selected 63 patients with well-con-trolled hypertension and proteinuria to receiveeither placebo or pravastatin (10 mg/d). After 6months of therapy, pravastatin reduced protein-uria by 54%, whereas creatinine clearance re-mained stable in the 2 groups. The investigatorsfound no correlation between changes in serumlipids and reduction of proteinuria, suggestingthat the effects of statins on proteinuria may becaused by mechanisms other than lipid-loweringeffects. These data support our findings.

Our findings also are supported by a recentmeta-analysis regarding the use of lipid-lower-ing agents in progressive renal disease. Thisanalysis has shown a modest but favorable effectof lipid-lowering drugs on both proteinuria anddecrease in glomerular filtration rate.42 However,these results were statistically heterogeneous.

A larger number of studies have evaluated theeffects of treatment with statins on proteinuria.Simvastatin decreased proteinuria in 16 patientswith idiopathic membranous glomerulonephri-tis,43 and fluvastatin reduced proteinuria in pa-tients with IgA nephropathy.44 By contrast, prav-astatin failed to reduce proteinuria in 16 patientswith nephrotic syndrome and renal insuffi-ciency45 and in 12 children with steroid-resistantnephrotic syndrome.46 Treatment with simvasta-tin for 12 months reduced the permselectivity ofthe basement membranes in patients with hyper-cholesterolemia.47

Our study has shown that HMG-CoA reduc-tase inhibitors reduce proteinuria and the rate of

progression of chronic kidney disease in patientswith CKD and significant proteinuria. Largerrandomized, controlled studies are necessary toconfirm these preliminary findings.

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