REVIEW
EFFECTS OF STATINS ON RENAL FUNCTION
Effects of Statins on Renal Function
RAJIV AGARWAL, MD
Patients with chronic kidney disease (CKD) are much more likely
to die of cardiovascular disease than end-stage renal disease.
Dyslipidemia is highly prevalent in patients with CKD and may
contribute to the elevated cardiovascular risk as well as CKD
progression. Statins are lipid-lowering drugs that appear to pro-
tect the kidneys via cholesterol reduction as well as noncholes-
terol-mediated mechanisms. Subgroup analyses of major clinical
studies and meta-analyses of smaller trials indicate that statin
therapy slows the decline of the glomerular filtration rate. Addi-
tionally, statins appear to reduce proteinuria in patients with CKD.
Statins are well recognized to reduce cardiovascular morbidity
and mortality in patients with and without documented cardiovas-
cular disease and in certain high-risk populations, such as per-
sons with diabetes mellitus. However, conclusive evidence for
improved cardiovascular outcomes with statin therapy for CKD
is not yet available. Several ongoing studies are evaluating the ef-
fect of statins on cardiovascular end points in patients with CKD
and may provide data needed to support adjunctive use of these
agents in this high-risk population.
Mayo Clin Proc. 2007;82(11):1381-1390
ALLIANCE = Aggressive Lipid-Lowering Initiation Abates New Cardiac
Events; CAD = coronary artery disease; CARE = Cholesterol and Recur-
rent Events; CI = confidence interval; CKD = chronic kidney disease;
ESRD = end-stage renal disease; GFR = glomerular filtration rate;
GREACE = GREek Atorvastatin and Coronary–heart-disease Evaluation;
HMG-CoA = 3-hydroxy-3-methylglutaryl coenzyme A; LDL = low-density
lipoprotein; L-FABP = liver-type fatty acid-binding protein; MI = myocar-
dial infarction
C hronic kidney disease (CKD) affects an estimated 19
million people in the United States, representing 11%
of the total adult population.1,2 Chronic kidney disease may
be divided into 5 stages on the basis of glomerular filtration
rate (GFR) and evidence of structural or functional renal
abnormalities, such as persistent albuminuria or pro-
teinuria.3 Stages 1 and 2 are characterized by evidence of
kidney damage with normal or mildly reduced GFR, re-
spectively, whereas stages 3 to 5 indicate progressively
greater reductions in GFR below 60 mL/min per 1.73 m2
with or without known etiology of kidney damage. When
both kidneys are involved, any GFR less than 60 mL/min
per 1.73 m2 should be considered to be due to renal injury
and therefore pathological.
Rates of progression of CKD may differ; rarely, patients
may even improve. In general, however, the condition of
persons with CKD will deteriorate. The progressive course
of CKD is a function of many factors, including the pres-
ence of concomitant disease, such as diabetes mellitus or
proteinuric glomerular disease. Most patients with CKD
have stage 1 to 3 disease; an estimated 7.6 million people
Mayo Clin Proc. • November 2007;82(11):1381-1390
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
have stage 3 disease.1 However, nearly 500,000 people in
the United States are in the most advanced stage of CKD,
also known as end-stage renal disease (ESRD), and require
regular dialysis treatment.4
Although the progressive course of CKD is well recog-
nized, patients with CKD are likely to die of cardiovascular
disease before they reach ESRD.5 In fact, CKD is an inde-
pendent risk factor for cardiovascular disease, particularly
in higher-risk populations.5 This point is illustrated in a
post hoc analysis of pooled data from 4 major longitudinal,
community-based studies: of 26,912 subjects, 4278 had
preexisting cardiovascular disease.6 After adjusting for po-
tential confounders, the risk for the composite outcome of
myocardial infarction (MI), fatal coronary artery disease
(CAD), stroke, and all-cause mortality was significantly
higher in persons with than without CKD (hazard ratio,
1.35; 95% confidence interval [CI], 1.21-1.52). Notably,
the increased risk associated with CKD was comparable to
the risk associated with diabetes mellitus, hypertension, or
left ventricular hypertrophy, each of which is well docu-
mented as a cardiovascular risk factor. Similar findings
were obtained in a post hoc analysis of the Heart Outcomes
Prevention Evaluation (HOPE) study, which enrolled 9297
patients with vascular disease or diabetes mellitus.7 The
subset of patients with mild renal dysfunction had nearly
twice the risk of cardiovascular mortality and all-cause
mortality (both P<.001) as those with normal renal func-
tion. On the basis of a large body of evidence from these
and other studies, the American Heart Association recom-
mends that patients with CKD be placed in the highest risk
group for subsequent cardiovascular events. Current treat-
ment recommendations should take into account the high-
risk status of this group of patients.5
ROLE OF DYSLIPIDEMIA IN CKD
Many traditional and nontraditional cardiovascular risk
factors are highly prevalent in CKD.8 In the Framingham
From the Division of Nephrology, Department of Medicine, Indiana Uni-
versity School of Medicine, Richard L. Roundebush VA Medical Center,
Indianapolis.
Dr Agarwal has received honoraria and served as a consultant and on the
speakers’ bureau of Merck and AstraZeneca.
Individual reprints of this article are not available. Address correspondence to
Rajiv Agarwal, MD, Indiana University School of Medicine, Richard L. Rounde-
bush VA Medical Center, 1481 W Tenth St (111N), Indianapolis, IN 46202.
© 2007 Mayo Foundation for Medical Education and Research
• www.mayoclinicproceedings.com 1381
EFFECTS OF STATINS ON RENAL FUNCTION
Offspring Cohort, patients with CKD were significantly
more likely to have low levels of high-density lipoprotein
cholesterol (45% vs 29%; P<.001) and elevated triglycer-
ides (40% vs 30%; P<.001) and tended to be more likely to
have elevated low-density lipoprotein (LDL) cholesterol
(61% vs 45%; P=.06) than those without CKD.8 In the
Third National Health and Nutrition Examination Survey
(NHANES III), participants with CKD (GFR <60 mL/min
per 1.73 m2) had higher levels of apolipoprotein B and
lower levels of apolipoprotein A than those with normal
renal function (P=.003 and P=.021, respectively).9
Dyslipidemia is not only highly prevalent in CKD, but
it also increases the risk of renal dysfunction in other-
wise healthy individuals. The Physicians’ Health Study fol-
lowed 4483 initially healthy men for a mean of 14.2 years.10
After adjustment for potential confounding factors (cardio-
vascular risk factors and development of hypertension and
cardiovascular disease), men in the highest quartile of total
cholesterol/high-density lipoprotein cholesterol ratio had a
92% higher risk (95% CI, 22%-204%) of developing CKD
than those in the lowest quartile.
The role of dyslipidemia in promoting kidney damage
has been shown in experimental models. Rats fed a diet rich
in cholesterol and fat exhibited increased numbers of glo-
meruli with sclerotic foci vs those on a low-fat, cholesterol-
free diet.11 When administered to rats with kidney disease
caused by unilateral nephrectomy, the cholesterol- and fat-
rich diet augmented the glomerular lesions in the remaining
kidney.11 In rats fed a high-cholesterol diet, the severity
of the hypercholesterolemia correlated with proteinuria
(r=0.672) and was accompanied by increased numbers of
glomeruli with lipid deposits.12
Lipid deposition can directly damage the glomerular
basement membrane. It can also stimulate mesangial cell
activation and proliferation, a process similar to smooth
muscle cell proliferation in the evolution of atherosclerotic
plaque13,14 (Figure 1). Mesangial cells then release che-
mokines that recruit monocytes to the mesangium, where
they are transformed into resident macrophages that secrete
proinflammatory and profibrotic mediators capable of aug-
menting the proliferative process.15-17 The macrophages also
ingest lipids to become foam cells, which are commonly
detected at early stages of glomerulonephritis.18 Each of
these cell types is capable of producing reactive oxygen
species that oxidize LDL. Oxidized LDL, in turn, can
cause further monocyte recruitment, endothelial dysfunc-
tion, and mesangial cell cytotoxicity.17,19,20
The endothelin system is also upregulated in hyper-
cholesterolemia. Therefore, endothelin-A receptor block-
ade might protect the kidney from injury to the renal
microvessels. In fact, in a porcine model, endothelin-A
receptor blockade improved microvascular endothelial
1382 Mayo Clin Proc. • November 2007;82(11):1381-1390
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
function in the hypercholesterolemic kidney as well as
microvascular remodeling and function.21
EFFECTS OF STATINS ON RENAL DAMAGE
If dyslipidemia promotes renal injury, then reducing
dyslipidemia should slow or prevent the progression of
CKD. Indeed, experimental models show that 3-hy-
droxy-3-methylglutaryl coenzyme A (HMG-CoA) reduc-
tase inhibitors, or statins, decrease the severity of glo-
merular damage and preserve renal function.22-24 For
example, New Zealand rabbits fed a diet rich in cholester-
ol became hypercholesterolemic, with evidence of endo-
thelial dysfunction in renal segmental arteries as well as
glomerular hypertrophy and diffuse glomerulosclerosis.24
In this model, atorvastatin attenuated the increase in plasma
cholesterol and prevented renal artery endothelial dysfunc-
tion, glomerular hypertrophy, and most of the glomerulo-
sclerosis.
Statins lower serum cholesterol levels and may there-
fore be expected to reduce lipid deposits in the kidney.
Nevertheless, the exact mechanism by which statins protect
against renal damage is unclear. Statins inhibit the rate-
limiting enzyme (HMG-CoA reductase) in cholesterol syn-
thesis, but inhibition of this enzyme also leads to down-
stream inhibition of the synthesis of the isoprenoids
farnesyl pyrophosphate and geranyl pyrophosphate.25,26
These isoprenoids normally attach to intracellular signaling
proteins to facilitate a variety of cellular responses, includ-
ing gene expression, membrane trafficking, cell prolifera-
tion and migration, and programmed cell death. By block-
ing isoprenoid synthesis, statins produce an array of anti-
inflammatory and vascular effects that are independent of
cholesterol reduction. For example, stem cells govern nu-
merous ischemic and degenerative disorders, and recent
investigations have shown that statins may play a role in
modulating stem cell functions.27 Similarly, impaired en-
dothelial progenitor cell function is characteristic of vascu-
lar injury, and statin therapy may improve the regenerative
capacity of progenitor cells.28
Levels of advanced glycation end products (the result of
increasing oxidative stress) appear to increase as GFR de-
creases. In addition, renal insufficiency is associated with
increased levels of inflammatory and procoagulant bio-
markers, even in patients without cardiovascular disease.29
Attenuation of the inflammatory response to renal injury
is considered another possible explanation for the re-
noprotective actions of statin therapy. In an open-label trial
in which 91 patients with CKD were randomly assigned to
treatment with 10 mg/d of rosuvastatin or no lipid-lowering
treatment for 20 weeks, a 47% reduction in median high-
sensitivity C-reactive protein in treated patients was ac-
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 EFFECTS OF STATINS ON RENAL FUNCTION

Lipid deposition in kidney Direct injury to GBM

Mesangial cell activation

MCP-1, GM-CSF

Recruitment of monocytes

Production of proinflammatory
↑ Mesangial macrophages/foam cells and profibrotic mediators

Oxidation of LDL
and generation of
reactive oxygen species

Endothelial Cytotoxic action Mesangial cell Increased matrix

dysfunction on mesangial cells proliferation production

Renal injury

FIGURE 1. Schematic showing how lipid deposition can produce renal damage. GBM = glomerular
basement membrane; LDL = low-density lipoprotein; MCP-1 = monocyte chemoattractant protein-
1; GM-CSF = granulocyte-macrophage colony–stimulating factor. Adapted from Lippincott Williams
& Wilkins,14 with permission.

companied by a statistically significant improvement in
GFR.30
CLINICAL EFFECTS OF STATINS ON
RENAL FUNCTION
The efficacy of statin therapy in reducing major cardiovascu-
lar events and mortality has been established in a series of
large long-term outcome studies that enrolled patients with
or without evidence of cardiovascular disease and a wide
range of baseline cholesterol levels.31-35 Patients with renal
dysfunction were excluded from early statin trials, limiting
the availability of data on the efficacy of statin therapy in
these patients. However, some secondary-prevention studies
have reported the impact of statin therapy on renal function
as part of a secondary or post hoc analysis (Table 1).36-44
The Heart Protection Study evaluated simvastatin vs
placebo in 20,536 patients with occlusive arterial disease or
diabetes mellitus.34,39 Plasma creatinine levels were mea-
sured at baseline and again after 4 to 6 years of therapy. As
expected, plasma creatinine levels increased as patients
aged, but the increase in creatinine was smaller in the
simvastatin vs the placebo group (7.1 vs 8.9 µmol/L [0.08
vs 0.1 mg/dL]; P<.0001).39 Using the plasma creatinine
levels, GFR was estimated retrospectively with the simpli-
fied Modification of Diet in Renal Disease formula. The
decline in GFR during follow-up was significantly smaller
in patients assigned to treatment with simvastatin than in
those receiving placebo (5.9 vs 6.7 mL/min; P=.0003),
suggesting that statin therapy may slow the decline in renal
function over time.39
Two trials—the GREek Atorvastatin and Coronary–
heart-disease Evaluation (GREACE) study and the Aggres-
sive Lipid-Lowering Initiation Abates New Cardiac Events
(ALLIANCE) study—compared structured dose titration
with atorvastatin to achieve specific LDL-cholesterol goals

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EFFECTS OF STATINS ON RENAL FUNCTION

TABLE 1. Overview of Renal Outcomes in Major Statin Trials*

No. of Primary
Trial Patient population patients Statin/dose outcome Results

Secondary and post hoc analyses of renal outcomes in major statin trials
CARE36 Patients with CAD
and moderate CKD (GFR
<60 mL/min/1.73 m2) to
severe CKD (GFR
<40 mL/min/1.73 m2)
(TC <240 mg/dL)
GREACE37 Previously untreated 1600
dyslipidemic patients with
CAD
ALLIANCE 38 Dyslipidemic patients with
CAD and CrCl of 88.6
mL/min and 87.2 mL/min
at baseline for participants
receiving atorvastatin
therapy and usual care,
respectively
Heart Protection Patients ≤80 y with
Study39 occlusive arterial disease
or DM
690 Pravastatin Rate of change in GFR Statin was significantly superior to
(40 mg/d) vs placebo in slowing rate of decline of
placebo for GFR (by 2.5 mL/min/1.73 m2 per
≥3 y year; P=.0001) in patients with
severe CKD, but was not superior in
patients with mild CKD
Dose-titrated All-cause and coronary CrCl increased by 12% in atorvastatin
atorvastatin mortality, coronary group (P<.0001) and by 4.9% in the
(10-80 mg/d) morbidity (nonfatal MI, usual care group that also took statins
vs usual care revascularization, UA, (P=.003), but declined by 5.3%
for 3 y (mean) and CHF), stroke (P=.0001) in usual care patients
who did not take statins
2442 Atorvastatin Deterioration in renal Mean decline of 4.4% in the usual care
(titrated to 80 function in CAD group (P=.0001 vs baseline). CrCl did
mg/d) vs usual patients not change in the atorvastatin group
care for 4 y vs baseline. Highly significant
difference between the statin and
usual care groups in mean change
from baseline (P=.0001)
5963 Simvastatin Major coronary event, Smaller increase in plasma creatinine
(40 mg/d) vs stroke, or and smaller reduction in estimated
placebo for revascularization GFR with statin therapy vs placebo
4-8 y (mean) (P<.0001 and P=.0003, respectively)

Pravastatin Patients with and without 4491† Pravastatin Time to MI, coronary Significant reduction in primary
Pooling Project CAD and with moderate death, or PCR outcome in statin-treated patients
(WOSCOPS, CKD (GFR, 30-60 with moderate CKD (hazard ratio,
CARE, LIPID)40 mL/min/1.73 m2) 0.77; 95% confidence interval,
0.68-0.86); reduction in total
mortality in treated patients. Benefit
seen in patients with and without CAD
Studies conducted in patients with kidney disease
UK-HARP-I 41 Predialysis (n=242), dialysis 448 Simvastatin Efficacy and safety Statin treatment lowered LDL-C by
(n=73), and renal (20 mg/d) vs approximately 24%; no evidence
transplant (n=133) placebo + aspirin of toxicity
patients vs placebo
(2 × 2 factorial
design) for 1 y
ALERT42 Renal transplant patients, 2102 Fluvastatin vs Cardiac death, nonfatal No significant risk reduction in
with and without CAD placebo for MI, or coronary statin-treated patients
(TC, 154-346 mg/dL) 5.1 y (mean) intervention
4D Study43 Hemodialysis patients with 1255 Atorvastatin Composite of cardiac No significant difference in primary
and without CAD, with (20 mg/d) vs death, nonfatal MI, end point with statin treatment, but
type 2 DM and an LDL-C placebo for 4 y and stroke increased risk for fatal stroke (P=.04)
of 80-190 mg/dL (TG (mean)
<1000 mg/dL)
PREVEND-IT44 Patients ≤75 y with and 864 Fosinopril or CV mortality or CV No significant reduction in primary
without CAD and with placebo + hospitalization end point with statin treatment
microalbuminuria and pravastatin (P=.649)
CrCL <60% of normal (40 mg/d) or
age-adjusted value placebo (2 × 2
factorial) for 4 y

*ALERT = Assessment of Lescol in Renal Transplantation; ALLIANCE = Aggressive Lipid-Lowering Initiation Abates New Cardiac Events; CAD =
coronary artery disease; CARE = Cholesterol and Recurrent Events; CHF = chronic heart failure; CKD = chronic kidney disease; CrCl = creatinine
clearance; CV = cardiovascular; DM = diabetes mellitus; GFR = glomerular filtration rate; GREACE = GREek Atorvastatin and Coronary–heart-disease
Evaluation; LDL-C = low-density lipoprotein cholesterol; LIPID = Long-term Intervention with Pravastatin in Ischaemic Disease; MI = myocardial
infarction; PCR = percutaneous coronary revascularization; PREVEND-IT = Prevention of Renal and Vascular Endstage Disease Intervention Trial;
TC = total cholesterol; TG = triglyceride; UA = unstable angina; UK-HARP-I = First United Kingdom Heart and Renal Protection study; WOSCOPS =
West of Scotland Coronary Prevention Study; 4D Study = Die Deutsche Diabetes Dialyse Studie.
†Of whom 3310 (74%) had CAD.

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For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

vs usual care in patients with CAD.35,45 GREACE enrolled
1600 consecutive patients with CAD seen at a hospital
atherosclerosis clinic, whereas ALLIANCE studied 2442
patients enrolled in health maintenance organizations or Vet-
erans Administration settings. In both studies, creatinine
clearance declined by an average of 4.4% during 4 years in
patients assigned to usual care.37,38 In contrast, patients as-
signed to atorvastatin therapy had an 11.6% increase in
creatinine clearance in the GREACE study. Although creati-
nine clearance did not improve in the atorvastatin group in
the ALLIANCE study, no decline was seen. The difference
between treatments was highly significant in both studies
(P<.0001).
In contrast to these studies, a post hoc analysis of the
Cholesterol and Recurrent Events (CARE) trial found no
difference in the rate of decline in renal function with statin
therapy vs placebo. CARE evaluated pravastatin therapy
for 5 years in patients with previous MI who had average
cholesterol levels.32 Pravastatin did not slow the rate of
GFR decline relative to placebo in patients with a baseline
GFR of 60 mL/min per 1.73 m2 or higher or in those with a
baseline GFR lower than 60 mL/min per 1.73 m2.36 How-
ever, in the small subset of patients with a GFR of less than
40 mL/min per 1.73 m2 at baseline, pravastatin signifi-
cantly reduced GFR decline by 2.5 mL/min per year (95%
CI, 1.4-3.6; P=.0001) relative to placebo.
The previously described studies reflect the effect of
long-term statin therapy on renal function and therefore
include any natural age-associated decreases in GFR. The
effect of short-term rosuvastatin therapy on renal function
was explored in a pooled analysis of 13 clinical studies
involving nearly 4000 subjects.46 Creatinine levels were
measured at baseline and then again after 6 to 8 weeks
of treatment, and GFR was estimated by the Modification
of Diet in Renal Disease formula. Overall, rosuvastatin at
dosages of 5 to 40 mg/d increased GFR by a mean of 1.8
mL/min per 1.73 m2 (P<.01), with statistically significant
increases seen at each of the tested doses. Notably, ro-
suvastatin increased GFR by a mean of 2.8 mL/min per 1.73
m2 (95% CI, 2.4-3.2) in the subgroup with a baseline GFR
of less than 60 mL/min per 1.73 m2. Thus, short-term
rosuvastatin therapy may modestly increase GFR, even
among patients with CKD. Regarding long-term therapy,
when more than 10,000 patients received 5 to 40 mg/d of
rosuvastatin for 96 or more weeks, GFR remained un-
changed or tended to increase when compared with
baseline, irrespective of the level of renal function or hy-
pertensive or diabetic status.47
The effect of statin therapy on CKD was evaluated
prospectively in a study of 56 patients with a clinical diag-
nosis of idiopathic chronic glomerulonephritis.48 All pa-
tients in the study had proteinuria but no evidence of sys-
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EFFECTS OF STATINS ON RENAL FUNCTION
temic disease known to cause glomerulonephritis. Patients
were randomly assigned to receive additional treatment
with atorvastatin or no additional treatment. After 1 addi-
tional year of treatment, urinary protein excretion declined
from 2.2 to 1.2 g/d in the group treated with atorvastatin
(P<.01), whereas it remained essentially unchanged in the
group that received no additional treatment. Moreover, the
atorvastatin group showed a significantly smaller decline in
creatinine clearance than the group that received no addi-
tional treatment (2.0% vs 11.6%; P<.05).48 Thus, this study
provides evidence that statin therapy may reduce proteinuria
and the rate of renal function decline in patients with CKD.
Liver-type fatty acid-binding protein (L-FABP) is ex-
pressed in proximal renal tubules and is considered a
marker of progression of glomerulonephritis. In a study of
58 persons with and 20 persons without diabetes mellitus,
increased L-FABP levels were associated with the pro-
gression of diabetic nephropathy, the leading cause of
ESRD.49 After 12 months, 1 mg/d of pitavastatin effec-
tively decreased urinary L-FABP levels in patients with
early diabetic nephropathy. The investigators speculated
that the antioxidant effects of statins likely play a role in
slowing the progression of tubulointerstitial lesions in
diabetic nephropathy.
Statin therapy has also been evaluated in other cohorts
with proteinuria secondary to hypertension or type 2 diabe-
tes mellitus. Pravastatin was compared with placebo in a
randomized study of 63 normolipidemic patients with
well-controlled hypertension and proteinuria.50 After 6
months, pravastatin at a dosage of 10 mg/d significantly
reduced urinary protein excretion from 1.23 to 0.56 g/d
(P<.0001), whereas the placebo group showed only a
slight decline (from 1.19 to 1.10 g/d). The reduction in
proteinuria with pravastatin was evident whether or not
patients were cotreated with an angiotensin receptor
blocker. However, despite the observed decrease in pro-
teinuria, serum creatinine levels and creatinine clearance
remained relatively stable in both groups during the 6-
month treatment period.
Simvastatin was compared with cholestyramine in a
cohort of 86 hypertensive type 2 diabetes patients with
microalbuminuria, who had shown a decline in GFR of
about 3 mL/min per 1.73 m2 each year during the previous
2 to 4 years.51 After 4 years of treatment, 40 mg/d of sim-
vastatin and 30 g/d of cholestyramine similarly reduced
lipid levels, but only simvastatin significantly reduced uri-
nary albumin excretion and slowed the rate of GFR decline.
The GFR declined by an average of 0.21 mL/min per 1.73
m2 during the 4 years of simvastatin therapy and by 2.75
mL/min per 1.73 m2 with cholestyramine (P<.01). Thus,
the renoprotective effect of simvastatin in these patients
appeared independent of the reduction in lipid levels. In the
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EFFECTS OF STATINS ON RENAL FUNCTION
study of 91 patients with CKD discussed earlier,30 treat-
ment with 10 mg/d of rosuvastatin for 20 weeks produced a
statistically significant improvement in GFR.
Sandhu et al52 performed a systematic review and meta-
analysis to better characterize the effect of statins on pro-
teinuria and the rate of GFR decline. They identified 22
randomized controlled trials involving 38,867 participants
in which the effect of statin therapy on estimated GFR was
evaluated. Statins exhibited favorable effects in 18 of the
22 studies. Overall, the rate of decline in estimated GFR
with statins was 1.22 mL/min per year (95% CI, 0.44-2.00
mL/min per year). This rate of decline in GFR was slower
than that observed with the controls and corresponded to a
76% reduction in the rate of GFR loss. Interestingly, in this
meta-analysis, statin therapy was found to positively affect
the GFR in populations with cardiovascular disease but, in
contrast to the results found by Nakamura et al,49 not in
populations with diabetic or hypertensive kidney disease or
glomerulonephritis.
Comparable results were reported in an earlier, smaller
meta-analysis that evaluated the impact of lipid-lowering
therapy on GFR and proteinuria in patients with renal
disease.53 The meta-analysis for GFR reviewed 12 studies
(362 participants), 5 of which contained individual patient
data. A total of 10 studies used statins and 2 used gem-
fibrozil and probucol. Lipid-lowering therapy was associ-
ated with a 1.9 mL/min per year (95% CI, 0.3-3.4 mL/min
per year) slower decline in GFR vs controls (P=.008).
Lipid-lowering therapy was also associated with a greater
reduction in urinary protein or albumin excretion (P<.001).
However, substantial heterogeneity among trials was seen
in the latter analysis, calling into question the validity of
combining the results for proteinuria and albuminuria.
Nevertheless, this meta-analysis suggests that statins, which
were used in most of the studies, may slow GFR decline in
patients with CKD.
Although statins usually appear to reduce proteinuria
and slow the rate of GFR decline, discrepant findings have
been reported in some studies. Short-term therapy with
statins, particularly at high doses, has been reported to
induce proteinuria. Of 120 hypercholesterolemic patients
who were taking 40 mg/d of simvastatin, 10 developed
proteinuria.54,55 After resolution, proteinuria recurred in 2
patients when 40 mg/d of simvastatin was resumed. During
the clinical development of rosuvastatin, the highest stud-
ied dose (80 mg) was associated with dipstick-positive
proteinuria. On urine dipstick analysis, proteinuria of 2+ or
higher occurred at rates of 2%, 2%, and 4% at the currently
approved dosages of 10, 20, and 40 mg/d, respectively, vs
a rate of 3% with placebo.56 In many cases, rosuvastatin-
treated patients had normal urine dipstick findings when
testing was repeated, even when rosuvastatin was contin-
1386 Mayo Clin Proc. • November 2007;82(11):1381-1390
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
ued at the same dosage.56 Urinary protein electrophoresis
indicated that most of the protein excreted had a lower
molecular weight than albumin.47 This finding suggests
that the proteinuria was caused by reduced reabsorption
of normally filtered protein in renal tubule cells rather
than by glomerular leakage of albumin and other larger
proteins.
Protein uptake by renal proximal tubule cells occurs at
megalin and cubulin receptors via receptor-mediated en-
docytosis.54 Many protein ligands bind to these receptors,
but because cubulin lacks an endocytosis signaling se-
quence and binds to megalin, the megalin receptor is
thought to be responsible for internalizing the ligands at-
tached to both receptors.57 This endocytic process requires
the presence of prenylated guanosine-5'-triphosphate–
binding proteins.54 However, by inhibiting HMG-CoA re-
ductase, statins reduce the amount of mevalonate, a key
intermediate in the synthesis of the isoprenoids. This
mechanism is supported by experimental studies conducted
in primary cultures of human renal proximal tubule cells.
When incubated with these cells, statins (simvastatin,
pravastatin, rosuvastatin) inhibited protein uptake in a con-
centration-dependent manner; however, at the highest con-
centrations tested (50-500 µM), protein uptake was re-
duced by only 40% to 50%.58 However, statins were unable
to inhibit protein uptake once mevalonate was added to the
cultures. These findings suggest that the increase in urinary
protein excretion associated with high statin doses in some
patients is caused by reduction of prenylation and the
consequent inhibition of protein reabsorption in proximal
tubules. This scenario may help explain why statins can
transiently increase protein excretion and simultaneously
protect against renal damage. The National Lipid Asso-
ciation Statin Safety Assessment Task Force recently re-
ported that “proteinuria is at least possible with all statins
at some concentration, but is more likely to be seen with
statins that are potent inhibitors of HMG-CoA reduc-
tase.”59 The report concludes that statin-induced protein-
uria is not associated with either renal impairment or renal
failure.
In the aforementioned meta-analysis by Sandhu et al,52
the effects of statins on proteinuria and albuminuria were
evaluated in 9 studies (350 participants) and 7 studies (904
participants), respectively. When proteinuria and albumin-
uria were considered separately, statin therapy did not sig-
nificantly influence the rate of change in urinary protein or
albumin excretion. However, when considered together,
statins significantly reduced urinary protein and albumin
excretion compared with controls (standardized mean dif-
ference between treatments, –0.58 units of SD; 95% CI,
–0.98 to –0.17 units). These findings suggest that statin
therapy modestly reduces proteinuria and slows the rate of
• www.mayoclinicproceedings.com
 EFFECTS OF STATINS ON RENAL FUNCTION

TABLE 2. Overview of Ongoing Statin Studies in Patients With CKD*

Trial Design No. of patients Treatment Duration Primary end point
Renal end points
PLANET60 R, DB, 345 (≥18 y) with Rosuvastatin (10 mg) 1y Change in urinary protein excretion
MC diabetes who had or rosuvastatin (40 mg) (urinary protein/creatinine ratio)
proteinuria and vs atorvastatin (80 mg)
hypercholesterolemia
PLANET II60 R, DB, 345 (≥18 y) without Rosuvastatin (10 mg) 1y Change in urinary protein excretion
MC diabetes who had or rosuvastatin (40 mg) (urinary protein/creatinine ratio)
proteinuria and vs atorvastatin (80 mg)
hypercholesterolemia
Cardiovascular end points
SHARP61 R, DB, 9000, including 3000 Simvastatin (20 mg) + ≥4 y Time to first major vascular event (cardiac
PC, receiving HD ezetimibe (10 mg) vs death or nonfatal MI, fatal or nonfatal
MC placebo stroke, or revascularization); progression
to ESRD in predialysis cohort (secondary
end point)
AURORA62 R, DB, >2750 (50-80 y) Rosuvastatin (10 mg) Until 620 Time to major cardiovascular event
PC, receiving long-term HD vs placebo primary (cardiovascular death, nonfatal MI, or
MC events nonfatal stroke)
have
occurred
*AURORA = A study to evaluate the Use of Rosuvastatin in subjects On Regular hemodialysis: an Assessment of survival and cardiovascular events;
CKD = chronic kidney disease; DB = double-blind; ESRD = end-stage renal disease; HD = hemodialysis; MC = multicenter; MI = myocardial infarction;
PC = placebo-controlled; PLANET = Prospective evaLuation of proteinuriA and reNal function in diabETic patients (with progressive renal disease); R =
randomized; SHARP = Study of Heart and Renal Protection.

GFR decline, particularly in patients with cardiovascular
disease.
EFFECTS OF STATINS IN PATIENTS WITH
RENAL ALLOGRAFTS
The effects of statin therapy on major adverse cardiac
events in patients with renal allografts were examined in
2102 renal allograft recipients in the Assessment of Lescol
in Renal Transplantation (ALERT)42 (Table 1). After a
mean of 5.1 years, LDL cholesterol was reduced by 32% in
patients who received 40 mg/d of fluvastatin. Risk reduc-
tion for the primary end point was not significant, possibly
because the study was small and the total event rate was
low; thus, the study was underpowered to detect signifi-
cance. However, fewer deaths and nonfatal MI were ob-
served in the fluvastatin group vs the placebo group (70 vs
104; P=.005). Coronary intervention procedures did not
differ significantly between groups.42
EFFECTS OF STATINS ON CARDIOVASCULAR
OUTCOME IN PATIENTS WITH CKD
To date, no single trial has provided definitive evidence
that statins reduce the risk of cardiovascular morbidity and
mortality in patients with CKD. Die Deutsche Diabetes
Dialyse Studie (4D Study) prospectively evaluated 20 mg/d
of atorvastatin vs placebo in a cohort of 1255 patients
with type 2 diabetes mellitus who were receiving mainte-
nance hemodialysis.43 After a mean follow-up of 4 years,
atorvastatin did not significantly reduce the risk of the
primary end point—a composite of death from cardiac
causes, nonfatal MI, and stroke—compared with placebo
(relative risk, 0.92; 95% CI, 0.77-1.10; P=.37). Atorvastatin
did not reduce the risk of the individual components of the
primary end point, but it did increase the relative risk of a
fatal stroke (2.03; 95% CI, 1.05-3.93; P=.04).
The negative findings in the 4D study raise the possibil-
ity that it may be too late to start statin therapy once
patients with CKD require hemodialysis. A number of
ongoing clinical trials, as summarized in Table 2,60-62 are
further evaluating statin therapy in patients with impaired
renal function. The Study of Heart and Renal Protection
(SHARP)61 is comparing treatment with 20 mg/d of
simvastatin plus 10 mg/d of ezetimibe vs placebo in ap-
proximately 9000 patients with CKD, 3000 of whom are
undergoing dialysis. The study is designed to evaluate the
effect of lowering LDL cholesterol on the time to a first
major vascular event, defined as nonfatal MI or cardiac
death, nonfatal or fatal stroke, or revascularization (pri-
mary end point). The study will also evaluate the impact of
treatment on progression to ESRD in the predialysis co-
hort. Patients will be treated for at least 4 years.61
A study to evaluate the Use of Rosuvastatin in subjects
On Regular hemodialysis: an Assessment of survival and
cardiovascular events (AURORA)62 is a large-scale inter-
national study that is also evaluating an ESRD cohort.
More than 2750 patients with ESRD who have been receiv-
ing chronic hemodialysis for at least 3 months, regardless
of baseline lipid levels, are randomly assigned to treatment

Mayo Clin Proc. • November 2007;82(11):1381-1390 • www.mayoclinicproceedings.com 1387

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
EFFECTS OF STATINS ON RENAL FUNCTION

TABLE 3. Statins for Kidney Disease: Available Dosages, LDL-C Reductions,

Metabolic Pathway, and Principal Drug Interactions*
Reduction
Dosage in LDL-C Metabolic Clinically important
Statin (mg/d) (%) pathway drug interactions
Atorvastatin 10 39 CYP450 3A4 Cyclosporine, digoxin,
20 43 fibric acid, niacin,
40 50 erythromycin,
80 60 azole antifungals
Fluvastatin 20 22 CYP450 2C9 Cimetidine, diclofenac,
40 25 glibenclamide, omeprazole,
40† 36 phenytoin, ranitidine,
80 35 rifampicin
Pravastatin 10 22 Minimally Gemfibrozil
20 32 metabolized
40 34
Rosuvastatin 5 45 CYP450 2C9 Cyclosporine, gemfibrozil
10 52 (not extensively
20 55 metabolized)
40 63
Simvastatin 5 26 CYP450 3A4 Amiodarone, cyclosporine,
10 30 gemfibrozil, itraconazole,
20 38 ketoconazole, erythromycin,
40 41 clarithromycin, telithromycin,
80 47 HIV protease inhibitors,
nefazodone, verapamil
*CYP450 = cytochrome P450; HIV = human immunodeficiency virus; LDL-C = low-density lipoprotein
cholesterol.
†Twice daily.
Data from references 64-68.

with 10 mg/d of rosuvastatin or placebo. The primary end
point is the time to a major cardiovascular event, defined as
cardiovascular death, nonfatal MI, or nonfatal stroke.
Treatment will be administered until 620 patients have a
major cardiovascular event.62
SAFETY OF STATINS IN PATIENTS WITH NORMAL
AND IMPAIRED RENAL FUNCTION
Statin therapy is safe and well tolerated in most patients.63
Although statins increase liver function enzymes in a dose-
dependent manner in 0.5% to 2.0% of patients, it remains
unclear whether this increase reflects true hepatotoxicity.
In rare cases, statins produce severe myopathy character-
ized by muscle aches or weakness in combination with
elevated creatine kinase levels more than 10 times the
upper limit of normal. Myopathy is more likely to occur
when statins are used at high doses or when those that
are metabolized predominantly by the cytochrome P450
3A4 isoenzyme (atorvastatin and simvastatin) are ad-
ministered in combination with other medications that use
the same metabolic pathway (eg, macrolide antibiotics,
azole antifungals). Table 3 summarizes the most common
drug interactions with the currently available statins.64-68
Patients with diabetes mellitus–associated CKD are at
increased risk of myopathy and should be monitored care-
fully.63 Other risk factors for myopathy include advanced
age, small body frame, frailty, and perioperative periods.
The rate of fatal rhabdomyolysis with marketed statins is
extremely low (<1 death per million prescriptions). To
minimize such risk, patients with risk factors for myopathy
should be monitored carefully during statin therapy. The
Food and Drug Administration–approved package inserts
for the available statins indicate the intervals at which liver
function tests should be performed (Table 4).64-68 Because
patients with kidney disease are at increased risk of toxic-
ity, these guidelines should be strictly followed. All statins
may be administered to patients with mild to moderate
renal insufficiency, but, with the exception of atorvastatin
and fluvastatin, all require modified dosing for patients
with substantial or severe renal disease. Atorvastatin re-
quires no dose adjustments for any degree of renal insuffi-
ciency; currently, fluvastatin has not been studied in severe
renal disease.69
CONCLUSION
Patients with CKD are at high risk of adverse cardiovascu-
lar outcomes. Dyslipidemia is highly prevalent in patients
with CKD and may mediate progression of this disease.
Lipids deposited in the kidney appear to cause renal dam-
age in a manner analogous to the deposition of lipids in the
vascular wall in the development of atherosclerosis. Statins
may protect the kidney by reducing lipid levels as well as

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For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

TABLE 4. Recommendations for Statin Administration and Monitoring
in Patients with Kidney Disease*
Statin Dosage adjustment
Atorvastatin No dosage adjustment necessary. No studies in ESRD,
but drug is extensively bound to plasma proteins, so
hemodialysis should not substantially enhance clearance
Fluvastatin Not >40 mg in patients with severe renal impairment.
Otherwise, no dosage adjustment necessary. No substantial
(<6%) renal excretion
Pravastatin At 20 mg, renal impairment had no effect on the
pharmacokinetics. Patients with renal impairment should
be closely monitored
Rosuvastatin At 20 mg, no effect on plasma concentrations in patients
with CrCl ≥30 mL/min per 1.73 m2, but concentrations
increased substantially in patients with severe renal
impairment (CrCl <30 mL/min/1.73 m2) vs healthy
participants. Plasma concentrations were approximately
50% greater in hemodialysis patients than in healthy
participants
Simvastatin Does not undergo renal excretion, so no dosage modification
is required in patients with mild to moderate renal
insufficiency. Patients with severe renal insufficiency
should be started at 5 mg/d and closely monitored
*ALT = alanine aminotransferase; AST = aspartate aminotransferase; CrCl = creatinine clearance; ESRD = end-stage renal disease.
Data from references 64-68.
through nonlipid–dependent anti-inflammatory and vascu-
lar effects. Meta-analyses show that statins slow the rate of
GFR decline and may also reduce proteinuria in patients
with CKD. However, despite the well-recognized benefits
of statins in primary and secondary prevention of cardio-
vascular disease, conclusive evidence that statins improve
cardiovascular outcomes in patients with CKD is not yet
available. Ongoing studies are addressing this issue and
may provide the data needed to support adjunctive use of
statins in the CKD population.
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