Advance Publication

Journal of Atherosclerosis and Thrombosis

Journal of Atherosclerosis and Thrombosis  Vol.18, No. ● 1
Accepted for publication: June 23, 2011
Original Article Published online: September 15, 2011

Effects of Lipid-Lowering Therapy with Rosuvastatin on Kidney

Function and Oxidative Stress in Patients with Diabetic Nephropathy

Masanori Abe 1, Noriaki Maruyama 1, Kazuyoshi Okada 1, Shiro Matsumoto 1, Koichi Matsumoto 1,
and Masayoshi Soma 1, 2

1
Division of Nephrology, Hypertension and Endocrinology, Department of Internal Medicine, Nihon University School of
Medicine, Tokyo, Japan
2
Division of General Medicine, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan

Aim: We aimed to assess the effects of rosuvastatin treatment on lipid levels, a biomarker of oxidative
stress, albuminuria, and kidney function in patients with diabetic nephropathy.
Methods: We conducted a prospective, open-label, parallel group, controlled study of 104 patients
with diabetic nephropathy, low-density lipoprotein cholesterol (LDL-C) levels of ＞ 120 mg/dL, and
well-controlled blood pressure who were undergoing treatment with renin angiotensin system inhibi-
tors. Patients were randomly assigned to two groups: the rosuvastatin group (n = 52; 2.5 mg/day rosu-
vastatin, increased to 10 mg/day) and the control group (n = 52; no rosuvastatin administered). We
determined the efficacy of rosuvastatin by monitoring serum lipid profiles, high sensitivity C-reactive
protein (hs-CRP), malondialdehyde-modified LDL (MDA-LDL), and cystatin C levels. In addition,
urinary albumin, 8-hydroxydeoxyguanosine (8-OHdG) and liver-type fatty acid-binding protein
(L-FABP) levels were measured before and 6 months after rosuvastatin was added to the treatment.
Results: Rosuvastatin effectively reduced total cholesterol, LDL-C, triglycerides, non-high-density
lipoprotein cholesterol (non-HDL-C) levels, and the LDL-C/ HDL-C ratio in the rosuvastatin group.
These parameters remained unchanged in patients who were not treated with rosuvastatin. Although
there was no significant change in the estimated glomerular filtration rate level, serum cystatin C lev-
els and urinary albumin excretion rates were significantly decreased in the rosuvastatin group. In
addition, rosuvastatin significantly reduced hs-CRP and MDA-LDL levels. Moreover, urinary
8-OHdG and L-FABP levels at baseline (13.5±5.1 and 41.7±26.1 ng/mgCr, respectively) decreased
significantly at 6 months (11.5±4.0 and 26.9±13.4 ng/mgCr, respectively), and there was a signifi-
cant correlation (r = 0.48, p ＜ 0.01). Multivariate analysis revealed that albuminuria was significantly
correlated with only rosuvastatin use (p = 0.0006, R2 = 0.53).
Conclusion: Rosuvastatin administration reduced albuminuria, oxidative stress, and serum cystatin C
levels, independent of blood pressure and lipid levels.

J Atheroscler Thromb, 2011; 18:000-000.

Key words; Cystatin C, 8-OHdG, Diabetic nephropathy, L-FABP, MDA-LDL, Rosuvastatin

end-stage renal disease (ESRD). Interventions known

Introduction
Diabetic nephropathy is the leading cause of
Address for correspondence: Masanori Abe, Division of
Nephrology, Hypertension and Endocrinology, Department of
Internal Medicine, Nihon University School of Medicine, 30-1,
Oyaguchi Kami-chou, Itabashi-ku, Tokyo 173-8610, Japan
E-mail: abe.masanori@nihon-u.ac.jp
Received: February 19, 2011
Accepted for publication: June 23, 2011
to delay or prevent the progression of diabetic
nephropathy include tight control of blood pressure
(BP) and blood glucose and the use of renin angioten-
sin system (RAS) inhibitors, such as angiotensin con-
verting enzyme inhibitors (ACEIs) and angiotensin Ⅱ
receptor blockers (ARBs) 1-4). However, even with opti-
mal medical management in the context of clinical tri-
als, patients with diabetic nephropathy are at risk for
not only progressive loss of kidney function, but also

2 Abe et al .
cardiovascular disease (CVD) 5, 6). Hyperlipidemia may
play an important role in the progression of chronic
kidney disease (CKD) including diabetic nephropathy
through either the toxic effects of lipids on mesangial
cells or by promoting intrarenal atherosclerosis 7-9).
Although the pathogenesis of diabetic nephropathy is
multifactorial and the precise mechanisms of its action
are unclear, the rate of functional deterioration corre-
lates with the degree of renal tubulointerstitial fibro-
sis 10). Diabetic hyperglycemia is associated with
increased production of reactive oxygen species (ROS).
ROS damage to DNA necessitates the induction of
various DNA repair processes, which can result in the
urinary excretion of products such as 8-hydroxydeoxy-
guanosine (8-OHdG). Urinary 8-OHdG is therefore
a sensitive biomarker of oxidative DNA damage, and
also correlates significantly with the severity of tubu-
lointerstitial lesions 11). Furthermore, the liver-type
fatty acid-binding protein (L-FABP) is expressed in
proximal tubules. L-FABP plays a key role in fatty acid
metabolism in proximal tubules, and its expression is
induced by fatty acids 12). Tubulointerstitial inflamma-
tion induced by lipid toxicity might be provoked by
not only proteinuria but also other stressors. Various
stressors to proximal tubules overload fatty acids in
the cytoplasm and thereby damage the tubules by
releasing inflammatory factors, and such tubulointer-
stitial inflammation deteriorates renal function over
time; therefore, oxidative stress may contribute to the
progression of tubulointerstitial injury in patients with
diabetic nephropathy 11, 12).
In addition to lipid-lowering effects, statins, a
type of HMG-CoA reductase inhibitor, exert numer-
ous cardioprotective effects by increasing the bioavail-
ability of vascular nitric oxide (NO) and reducing oxi-
dative stress and inflammatory cytokines 13-15). Among
the statins available as medication, rosuvastatin is con-
sidered to have robust effects, including highly effec-
tive lowering of low-density lipoprotein cholesterol
(LDL-C), significant raising of high-density lipopro-
tein cholesterol (HDL-C), lowering of high-sensitivity
C-reactive protein (hs-CRP), and stabilizing of risk
factors and biomarkers of atherosclerosis both clini-
cally and in experimental animal models 16, 17); how-
ever, little is known about the renal protective effects
of rosuvastatin for regulation of urinary oxidative
stress markers and albuminuria in patients with dia-
betic nephropathy. Furthermore, no studies have
reported additional therapy for further reduction of
albuminuria if blood pressure has been well controlled
by RAS inhibitors. It remains unknown, therefore,
whether a ceiling of renoprotection exists, provided by
RAS inhibitors. Thus, we investigated whether the
Advance Publication
Journal of Atherosclerosis and Thrombosis
Accepted for publication: June 23, 2011
Published online: September 15, 2011
add-on effect of rosuvastatin was effective for reducing
albuminuria when given to diabetic patients with well-
controlled hypertension who were already undergoing
treatment with RAS inhibitors, and whether renopro-
tection is mediated by inhibiting oxidative stress in the
kidney.
Methods
Patients and Study Design
This study was conducted as a prospective, ran-
domized, and open-labeled clinical trial over 6
months. Enrollment criteria for the patients entailed:
1) type 2 diabetes mellitus in those who were not
treated with statins within 6 months of the start of the
trial 2) LDL-C ≥ 120 mg/dL; 3) stage 1-2 CKD, as
indicated by an estimated glomerular filtration rate
(eGFR) of ≥ 60 mL/min/1.73 m2; 4) albuminuria, i.e.,
urinary albumin/creatinine (Cr) ratio of ≥ 30 mg/g
(average of 2 consecutive measurements taken during a
4-week period before the study); and 5) BP ＜ 140/90
mmHg treated with RAS inhibitors including ACE
inhibitors and/or ARBs for at least 8 weeks before the
study.
Exclusion criteria were as follows: 1) age ＜ 20
years or ＞ 80 years; 2) eGFR ＜ 60 mL/min/1.73 m2;
3) BP ≥ 140/90 mmHg; 4) history of heart failure,
angina, myocardial infarction, or stroke within 6
months before the start of the trial; 5) previous treat-
ment with steroids or immunosuppressants; or 6) dia-
betes mellitus that led to hospitalization because of
diabetic ketoacidosis.
We designed this study to assess the effect of
rosuvastatin in patients with diabetic nephropathy.
After initial evaluation, we randomly assigned 52
patients to add-on therapy with rosuvastatin (rosuvas-
tatin group), while 52 patients continued with con-
ventional therapy as controls (control group) consecu-
tively. A computer-generated list was used for ran-
domization. Patients in the rosuvastatin group started
with 2.5 mg rosuvastatin once daily. This dose was
increased to 10 mg daily if target LDL-C levels ( ＜100
mg/dL) were not reached after 4 weeks. These subjects
were already being administered RAS inhibitors and
were controlled to ensure BP ＜ 140/90 mmHg. The
investigators subjectively adjusted the dose of antidia-
betic agents such that the level of glycated hemoglobin
(HbA1c), a glycemic target, achieved ＜ 7.0% in both
groups. We obtained written informed consent for
participation in the trial from all patients, and the
protocol of the trial was approved by the ethics com-
mittee of our institution. In addition, the study was
conducted in accordance with the Declaration of Hel-

Effect of Rosuvastatin on Diabetes
sinki. This prospective study was conducted between
December 2009 and December 2010, and the subjects
were followed for 6 months. Doses of ARBs and
ACEIs were not altered during the study period. All
patients were instructed on how to maintain their diet
and exercise therapy. Furthermore, all patients received
nutrition education from a dietitian according to the
Impact of the Kidney Disease Outcomes Quality Ini-
tiative guideline 18).
Laboratory Analysis
The glomerular filtration rate (GFR) was esti-
mated using the final recommended modified equa-
tion for Japanese patients of the Japanese Society of
Nephrology-Chronic Kidney Disease Initiatives
because the eGFR obtained by this method is more
accurate for application in Japanese patients with
CKD than values obtained using other equations 19).
The eGFR was calculated according to the following
formula: eGFR (mL/min/1.73 m2) = 194×sCr−1.094×
Age−0.287 (0.739×in the case of women).
Fasting blood samples were obtained from all
subjects, and HbA1c and plasma glucose were mea-
sured as criteria for glycemic control. Hemoglobin,
total bilirubin, aspartate aminotransferase, alanine
aminotransferase, lactate dehydrogenase, alkaline
phosphatase, γ-glutamyl transpeptidase, creatine
phosphokinase (CK), total cholesterol (TC), HDL-C,
and triglycerides (TG) were routinely measured fol-
lowing clinical chemistry procedures using commer-
cial kits. The serum concentration of LDL-C was esti-
mated using the Friedewald formula (LDL-C = TC−
HDL-C−TG×0.2) in patients with serum TG con-
centrations of ＜ 400 mg/dL. The percent changes of
serum TC, LDL-C, TG, HDL-C, non-HDL-C, and
LDL-C/HDL-C were calculated in all patients. Serum
malondialdehyde-modified LDL (MDA-LDL) was
assayed by enzyme-linked immunosorbent assay
(ELISA) as described previously 20). Serum cystatin C
was measured by the fully automated sol particle
immunoassay method described previously (Alfresa
Pharma Co., Osaka, Japan) 21), and hs-CRP was mea-
sured by latex agglutination. Urinary 8-OHdG levels
were measured with an ELISA kit that employs a
highly sensitive monoclonal antibody in the first
morning urine sample, as previously described
(8-OHdG Check; Japan Institute for the Control of
Aging, Shizuoka, Japan) 22). Similarly, urinary L-FABP
was measured with an ELISA kit that uses human
monoclonal antibodies, as described previously (CMIC
Co. Ltd., Tokyo, Japan) 12). These results were adjusted
for Cr (ng/mgCr) measured using the same urine sam-
ple. Urinary albumin excretion was assessed by mea-
Advance Publication
Journal of Atherosclerosis and Thrombosis
3
Accepted for publication: June 23, 2011
Published online: September 15, 2011
suring urinary concentrations of albumin and creati-
nine (albumin/Cr ratio) in the first morning urine
sample. Urinary albumin was measured using the
immunoturbidimetry method.
Safety Variables
At each visit, patients were questioned about
compliance (diet and medication), concomitant medi-
cation, and adverse events. Safety assessments were
performed repeatedly throughout the study. Adverse
events were graded on the basis of intensity (mild,
moderate, or severe). Serious adverse events were
defined as significant and untoward medical events
that resulted in death, hospitalization, or significant
disability or incapacity. Patient withdrawal from the
study was considered if allergy or intolerance to rosuv-
astatin appeared during the study, a hypertensive
emergency developed, or if either serum CK or trans-
aminase concentration increased ＞ 2-fold the upper
limit of the normal range and the patient concomi-
tantly exhibited symptoms such as muscular pain, loss
of appetite, or general fatigue, or if the patient was
subjected to any other condition or therapy that, in
the opinion of the investigators, might have posed a
risk to the patient or confounded the results of the
study.
Statistical Analysis
Results are expressed as the mean±SD. Because
many variables did not show a normal distribution,
non-parametric statistical tests were used throughout.
The unpaired t -test or Mann-Whitney U -test was
used to compare the mean baseline data values
between the groups. Intra-group comparisons were
assessed by the Wilcoxon signed rank test or paired
t -test. Changes in parameters at baseline and at 24
weeks were compared using analysis of variance with
repeated measurements, followed by a subsequent
multiple comparison test. Relationships between the
changes were studied using Pearson’s correlation and
multiple linear regression analysis. Statistical signifi-
cance was established at p ＜ 0.05. The SAS 8.13 statis-
tical package (SAS Institute, Cary, NC, USA) was uti-
lized for all analyses.
Results
Baseline Characteristics
We enrolled 104 subjects for this study and ran-
domly allocated them to the rosuvastatin group
(n = 52) or control group (n = 52). The baseline charac-
teristics and medications administered to the subjects
in the 2 groups are shown in Table 1. No significant
 Advance Publication
4 Abe et al .
Journal of Atherosclerosis and Thrombosis
Accepted for publication: June 23, 2011
Published online: September 15, 2011

Table 1. Baseline characteristics and medications of patients

Rosuvastatin group Control group p value
Number of patients (n) 52 52 −
Male/Female (n) 30/22 29/23 0.84
Age (years) 64.5±9.6 64.9±9.2 0.57
Smoking (%) 13.5 12.0 0.83
Hemoglobin A1c (%) 6.8±0.7 6.8±0.7 0.71
Fasting plasma glucose (mg/dL) 129±21 126±26 0.73
Body mass index (kg/m2) 22.7±2.3 22.9±2.7 0.71
Systolic blood pressure (mmHg) 125±10 126±9.9 0.75
Diastolic blood pressure (mmHg) 71±9 72±9 0.97
Heart rate (bpm) 74±10 74±10 0.99
Serum creatinine (mg/dL) 0.78±0.16 0.80±0.11 0.77
eGFR (mL/min/1.73 m2) 70.4±11.9 69.3±9.5 0.94
Cystatin C (mg/L) 0.80±0.13 0.78±0.13 0.85
High sensitivity-C-reactive protein (mg/L) 1.38±0.80 1.31±0.82 0.82
Total cholesterol (mg/dL) 227±23 224±25 0.38
LDL-cholesterol (mg/dL) 137±19 136±18 0.57
HDL-cholesterol (mg/dL) 49±10 49±12 0.83
non-HDL-cholesterol (mg/dL) 177±25 172±27 0.84
Triglyceride (mg/dL) 162±81 158±87 0.22
MDA-LDL (U/L) 156±42 151±46 0.48
Urinary albumin/creatinine ratio (mg/gCr) 141±86 142±83 0.57
Medicaton (%)
Antihypertensive agents
Angiotensin receptor blockers 94 92 0.69
Angiotensin converting enzyme inhibitors 17 19 0.79
Calcium channel blockers 63 67 0.67
Diuretics 35 37 0.83
Anti-diabetic agents
Sulfonylures 19 22 0.83
Meglitinides 17 14 0.95
Thiazolidinediones 14 14 0.70
Alpha-glucosidase inhibitors 17 18 0.69
Biguanide 8 8 0.71
DPP-4 inhibitors 17 18 0.69
Insulin 44 42 0.88
Antiplatelet agents 56 58 0.72
eGFR, estimated glomerular filtration rate; HDL, high-density lipoprotein; LDL, low-density lipoprotein; MDA, malondi-
aldehyde-modified; DPP-4, dipeptidyl peptidase-4

differences were observed between the 2 groups with
regard to the baseline characteristics or medications.
The dosage of antidiabetic agents did not differ
between the two groups. Although the mean body
mass index of all patients was 22.8±2.6 kg/m2 and
baseline BP was well controlled, adequate LDL-C
control had not been achieved in any of the enrolled
patients. During treatment, one subject from the rosu-
vastatin group withdrew from the study due to an
adverse reaction, and 2 subjects from the control
group withdrew due to congestive heart failure and
alteration of antihypertensive agents due to an increase
in BP; therefore, 51 patients in the rosuvastatin group
and 50 patients in the control group completed the
trial and were analyzed.
Changes in BP and Glycemic Control
As shown in Table 2, there were no significant
changes in BP or heart rate between the groups at
baseline and throughout the study period. Further-
 Advance Publication
Journal of Atherosclerosis and Thrombosis
Effect of Rosuvastatin on Diabetes 5
Accepted for publication: June 23, 2011
Published online: September 15, 2011

Table 2. Changes in blood pressure and glycemic control in the two gourps
Rosuvastatin group Control group
Baseline End p value Baseline End p value
Hemoglobin A1c (%) 6.8±0.7 6.7±0.7 0.11 6.8±0.7 6.7±0.6 0.19
Fasting plasma glucose (mg/dL) 129±21 125±23 0.17 126±26 123±22 0.47
Body mass index (kg/m2) 22.7±2.3 22.6±2.3 0.36 22.9±2.7 22.8±2.8 0.34
Systolic blood pressure (mmHg) 125±10 124±9.6 0.30 126±9.9 124±10 0.12
Diastolic blood pressure (mmHg) 71±9 71±9 0.13 72±9 71±8 0.07
Heart rate (bpm) 74±10 74±9 0.83 74±10 75±9 0.24

Table 3. Lipid profiles in the two groups

Rosuvastatin group Control group
Baseline End p value Baseline End p value
TC (mg/dL) 227±23 172±28 ＜ 0.0001 224±25 218±27 0.17
LDL-C (mg/dL) 137±19 83±16 ＜ 0.0001 136±18 134±13 0.24
HDL-C (mg/dL) 49±10 53±15 0.0004 49±12 49±12 0.07
non-HDL-C (mg/dL) 177±25 118±26 ＜ 0.0001 172±27 168±28 0.33
TG (mg/dL) 162±81 130±66 ＜ 0.0001 158±87 160±86 0.71
LDL-C/HDL-C ratio 2.8±0.7 1.6±0.5 ＜ 0.0001 2.8±0.7 2.8±0.7 0.69
HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TC, total cholesterol; TG, triglyceride.

more, there was no significant change in HbA1c or Kidney Function

fasting plasma glucose levels between the two groups,
and therefore, no patients were subjected to additional
anti-diabetic agents.
Lipid Profiles
The mean dosage of rosuvastatin at the end of
the study was 3.1±1.0 mg daily (2.5 mg daily, n = 40;
5.0 mg daily, n = 9; 10 mg daily, n = 2). TC, LDL-C,
HDL-C, non-HDL-C, TG, and LDL-C/HDL-C
ratios at baseline and after 6 months are shown in
Table 3. There were no significant changes in TC
LDL-C, HDL-C, non-HDL-C, TG, and LDL-C/
HDL-C in the control group. On the other hand, TC
and LDL-C after administration of rosuvastatin fell
from 227±23 mg/dL to 172±28 mg/dL and from
137±19 mg/dL to 83±16 mg/dL, respectively (both
p ＜ 0.0001). HDL-C after administration of rosuvas-
tatin increased from 49±10 mg/dL to 53±15 mg/dL
(p ＜ 0.05), while non-HDL-C fell from 177 ±25
mg/dL to 118±26 mg/dL (p ＜ 0.0001). LDL-C/
HDL-C ratios and TG after administration of rosuv-
astatin decreased from 2.8±0.7 to 1.6±0.5 (p ＜
0.0001) and from 162±81 to 130 ± 66 mg/dL (p ＜
0.0001), respectively.
As shown in Fig. 1, there was a significant
increase in sCr levels in the control group (from 0.78
±0.12 to 0.79±0.13 mg/dL, p ＜ 0.05), whereas there
was no significant change in sCr levels in the rosuvas-
tatin group during the treatment period (from 0.78±
0.16 mg/dL to 0.78±0.15 mg/dL).
Similarly to sCr levels, there was a significant
decrease in eGFR in the control group from baseline
to the end of the study (from 69.3±9.5 to 68.4±10.0
mL/min/1.73 m2, p ＜ 0.05), whereas there was no sig-
nificant change in eGFR in the rosuvastatin group
from baseline to the end of the study (from 70.4±
11.9 to 70.0±11.8 mL/min/1.73 m2). On the other
hand, serum cystatin C in the rosuvastatin group sig-
nificantly decreased from 0.80±0.13 to 0.76±0.13
mg/L (p ＜ 0.0001), whereas a significant increase was
observed in the control group from 0.80±0.11 to 0.81
±0.12 (p ＜ 0.05).
As shown in Fig. 2, there was no significant
change in the urinary albumin/Cr ratio in the control
group (from 142±83 to 141±72 mg/gCr), whereas
the urinary albumin/Cr ratio significantly decreased in
the rosuvastatin group (from 141±86 mg/gCr to 82
±54 mg/gCr) (p ＜ 0.01). Percent changes from base-
line values significantly decreased in the rosuvastatin
 Advance Publication
6 Abe et al .
Journal of Atherosclerosis and Thrombosis
Accepted for publication: June 23, 2011
Published online: September 15, 2011

Control group
Rosuvastatin group

Serum creati nine Cystatin C

(mg/dL) eGFR
(mg/L)
(mL/min/1.73m2) *
1.2 1.0 **
90
* 0.9
* 80
1.0 0.8
70
0.7
0.8 60
0.6
50 0.5
0.6
40 0.4
0.4 30 0.3
20 0.2
0 .2
10 0.1
0 0 0
Baseline End Baseline End Baseline End Baseline End Baseline End Baseline End

Fig. 1. Changes in kidney function parameters.

eGFR, estimated glomerular filtration rate; ＊p ＜ 0.05, ＊＊p ＜ 0.0001 vs. baseline.
* p < 0. 05, * * p < 0.0001 vs . b aseline .

Control group
Rosuvastatin group
Percent changes
U r i n a ry a l b um i n / C r (%)
(mg/gCr)
30
300 20
10
250
0
200 -10
* -20
150 -30
-40
100
-50
50 -60
†
-70
0
Baseline End Baseline End

Fig. 2. Changes in urinary albumin/Cr ratio and respective percent changes from baseline.
Cr, creatinine; ＊p ＜ 0.01 vs. baseline; p ＜ 0.01 vs. control group
* p < 0.01 vs. baseline; † p < 0.0001 vs. control group
 Advance Publication
Journal of Atherosclerosis and Thrombosis
Effect of Rosuvastatin on Diabetes 7
Accepted for publication: June 23, 2011
Published online: September 15, 2011

Control group
Rosuv as tati n gr oup

hs-CRP MDA-LDL
(mg/L) ( U/L )
3.5 p < 0.0001
220
p < 0.001
3 .0 200
180
2 .5 160
140 *
2.0
120
1.5 * 100
80
1 .0
60
0.5 40
20
0 0
Ba seline End Baseline End

Fig. 3. Changes in high sensitivity C-reactive protein and MDA-LDL levels.

hs-CRP, high sensitivity-C-reactive protein; MDA-LDL, malondialdehyde-modified low-density lipopro-
tein; ＊p ＜ 0.0001 vs. baseline.
* P < 0 .0001 vs. basel ine.

group compared with the control group (−40.1±
24% vs. 5.8±21.8%, p ＜ 0.0001).
hs-CRP and MDA-LDL
As shown in Fig. 3, there was no significant
change in hs-CRP in the control group (from 1.31±
0.82 to 1.32±0.81), whereas hs-CRP in the rosuvas-
tatin group significantly decreased (from 1.38±0.80
to 0.71±0.70 mg/L) (p ＜ 0.0001). There was also no
significant change in MDA-LDL in the control group,
whereas there was a significant reduction in MDA-
LDL in the rosuvastatin group (from 156±42 to 94±
28 U/L; p ＜ 0.0001). MDA-LDL was decreased by
40% in the rosuvastatin group compared with baseline
values.
Urinary 8-OHdG and L-FABP
As shown in Fig. 4, urinary 8-OHdG levels were
significantly decreased in the rosuvastatin group (from
13.5±5.1 to 11.5±4.0 ng/mgCr, p ＜ 0.001), and
there was a significant difference compared with the
control group at the end of the study (11.5±4.0
ng/mgCr vs. 14.1±5.2 ng/mgCr, p ＜ 0.05). Urinary
L-FABP significantly decreased in the rosuvastatin
group (from 41.7±26.1 to 26.9±13.4 ng/mgCr, p ＜
0.0001), and similarly, there was a significant differ-
ence compared with the control group at the end of
the study (26.9 ±13.4 ng/mgCr vs. 43.0 ±21.2
ng/mgCr, p ＜ 0.05). The urinary albumin/Cr ratio did
not correlate with urinary 8-OHdG and L-FABP in
either group at baseline or at the end of the study.
Correlation
To identify the determinants of a decrease in uri-
nary albumin excretion, multivariate analysis was per-
formed (Table 4). Multivariate regression analysis
with percent reduction of albuminuria as the depen-
dent variable and age, sex, change in mean blood pres-
sure, lipid profiles, and the presence or absence of
rosuvastatin as independent variables was performed
to investigate the effect of rosuvastatin and other risk
factors on albuminuria. The results revealed that the
use of rosuvastatin was the only factor that was signifi-
cantly related to albuminuria regression (p = 0.0006,
R2 = 0.53).
Table 5 shows the correlations among the moni-
tored parameters in the rosuvastatin group. Although
there were significant correlations between the lipid
parameters, such as changes in TC, LDL-C, non-
HDL-C, LDL/HDL-C, and MDA-LDL, a weak cor-
relation was observed between the change in albumin-
uria and that of MDA-LDL following rosuvastatin
treatment (r = 0.277; p = 0.041). Although the percent
change in the albumin/Cr ratio from baseline to the
 Advance Publication
8 Abe et al .
Journal of Atherosclerosis and Thrombosis
Accepted for publication: June 23, 2011
Published online: September 15, 2011

Control group
Rosuvastatin group

Urinary L-FABP
Urinary 8-OHdG
p < 0.05 (ng/mgCr)
(ng/mgCr)
p < 0.05
80
20
70
*
15 60

50 **

10 40

30

5 20

10

0 0
B as e l i n e End Ba s e l i n e End
Fig. 4. Changes in urinary 8-OHdG and L-FABP levels.
8-OHdG, 8-hydroxydeoxyguanosine; L-FABP, liver-type fatty acid-binding protein; ＊p ＜ 0.001, ＊＊p ＜ 0.0001 vs. baseline.
* P < 0.001, ** P < 0.0001 vs. baseline.

Table 4. Multivariate analysis of independent factors for regression of albuminuria (model R2 = 0.53)
Factor Standardized β 95% CI p value
Treatment assignment (statin vs no) −0.507 −25.7-−7.34 0.0006
Gender, male vs female 0.077 −2.51-7.62 0.319
Age (per additional y) −0.105 −0.90-0.17 0.179
Mean blood pressure (per additional mmHg) −0.200 −1.86-0.19 0.112
Total cholestrol (per additional mg/dL) 0.109 −0.10-0.29 0.357
LDL-cholesterol (per additional mg/dL) −0.168 −0.52-0.17 0.321
HDL-cholesterol (per additional mg/dL) 0.088 −0.40-1.24 0.318
Triglycerides (per additional mg/dL) 0.023 −0.16-0.21 0.767
MDA-LDL (per additional U/L) −0.159 −0.34-0.07 0.196
High sensitivity-CRP (per additional mg/L) −0.075 −8.76-3.41 0.385
CI, confidence interval; CRP, C-reactive protein; HDL, high-density lipoprotein; LDL, low-density lipoprotein;
MDA, malondialdehyde-modified.

end of the study did not correlate with the percent
change in urinary 8-OHdG and L-FABP in the rosuv-
astatin group, the change in urinary 8-OHdG was sig-
nificantly correlated with the change in L-FABP
(r = 0.48, p = 0.0003). Furthermore, multivariate anal-
ysis was performed to identify the lipids or oxidative
stress factors that decrease albuminuria. Multivariate
regression analysis with percent change in albuminuria
as the dependent variable and change in lipid profiles,
MDA-LDL, and hs-CRP as independent variables was
performed to investigate the effect of rosuvastatin on
albuminuria. The results revealed that no factor was
significantly related to albuminuria regression after
rosuvastatin treatment. Additionally, no significant
correlation was observed between the change in albu-
minuria and hemodynamics (systolic and diastolic
blood pressure; data not shown).
Although the dose of rosuvastatin was signifi-
cantly correlated with the percent decrease of TC,
LDL, non-HDL, LDL-C/HDL-C, and MDA-LDL,
there was no significant relationship with the change
in albuminuria, urinary 8-OHdG, and L-FABP.
 Advance Publication
Journal of Atherosclerosis and Thrombosis
Effect of Rosuvastatin on Diabetes 9
Accepted for publication: June 23, 2011
Published online: September 15, 2011

Table 5. Correlation coefficient (r) between the change in levels of lipid parameters and urinary markers after rosuvastatin treatment
Urinary
non- LDL-C/ MDA- Cystatin Urinary Urinary
LDL-C HDL-C TG hs-CRP albumin
HDL-C HDL-C LDL C 8-OHdG L-FABP
excretion
TC 0.69＊＊ −0.06 0.92＊＊ 0.31 0.67＊＊ 0.37＊＊ 0.06 0.03 0.02 0.06 0.03
LDL-C −0.01 0.67＊＊ 0.14 0.78＊＊ 0.50＊＊ 0.05 0.15 0.10 −0.01 0.01
＊＊
HDL-C −0.24 0.24 −0.59 −0.08 −0.17 −0.18 0.09 −0.07 −0.11
non-HDL-C 0.04 0.69＊＊ 0.39＊＊ 0.01 0.23 0.02 0.01 −0.09
TG 0.09 0.05 0.02 0.03 0.01 0.13 0.02
LDL-C/HDL-C 0.46＊＊ 0.05 0.01 0.05 0.06 0.02
MDA-LDL 0.18 0.05 0.28＊ −0.18 0.05
hs-CRP 0.13 0.06 0.01 0.07
Cystatin C 0.15 0.01 0.01
Urianry albumin excretion 0.21 0.04
Urinary 8-OHdG 0.48＊＊
＊
p ＜ 0.05, ＊＊p ＜ 0.01
HDL-C, high-density lipoprotein cholesterol; hs-CRP, high sensitivity C-reactive protein; LDL-C, low-density lipoprotein cholesterol; L-FABP, liver-
type fatty acid-binding protein; MDA, malondialdehyde-modified; TC, total cholesterol; TG, triglyceride; 8-OHdG, 8-hydroxydeoxyguanosine.

Safety reduction of albuminuria in this analysis, although the

During treatment, adverse reactions were
observed in 1 subject from the rosuvastatin group, and
administration of rosuvastatin was discontinued in
this individual. This subject had muscular pain, which
was considered to be attributed to rosuvastatin, and
was relieved by discontinuation of rosuvastatin treat-
ment; however, no elevated CK was observed in this
subject. In 1 patient from each group, the dose of
antidiabetic agents was increased due to increasing
HbA1c during the study period. In the same 2
patients, the dose of dipeptidyl peptidase-4 inhibitor
was also increased. On the other hand, none of the
patients had a hypoglycemic episode or decreased the
dose of antidiabetic agents.
Discussion
In the present study, rosuvastatin significantly
improved LDL-C, non-HDL-C, and HDL-C, as well
as the LDL-C/HDL-C ratio in patients with diabetic
nephropathy when compared with the values at base-
line and in the control group. Rosuvastatin reduces
both albuminuria and the rate of progression of kid-
ney disease in patients with diabetic nephropathy, and
the benefits appear to supplement those derived from
treatment with RAS inhibitors. In the present study,
MDA-LDL was significantly decreased by rosuvastatin
treatment. Furthermore, despite the fact that there
were no significant correlations between the reduction
of albuminuria and other lipid parameters, the change
in MDA-LDL was significantly correlated with the
correlation coefficient was small; therefore, it is possi-
ble that the decrease in MDA-LDL can be attributed
to the reduction of albuminuria. A reduction in the
serum concentration of MDA-LDL, which is a major
component of oxidized LDLs, may reduce not only
the likelihood of future atherosclerotic disease and car-
diovascular events, but also the progression of kidney
disease.
The pathogenesis of diabetic nephropathy is
multifactorial and its precise mechanisms of action
remain unclear; however, it is now widely accepted
that the rate of functional deterioration correlates with
the degree of renal tubulointerstitial fibrosis 10). Epi-
thelial cells of the proximal tubules play a major role
in orchestrating events in the renal interstitium in dia-
betic nephropathy 23). In addition, oxidative stress may
contribute to the progression of tubulointerstitial
injury in patients with diabetic nephropathy 11). In the
present study, we showed that rosuvastatin reduced
not only hs-CRP levels and MDA-LDL, but also uri-
nary 8-OHdG and L-FABP levels; therefore, the ben-
eficial effect of rosuvastatin in diabetic nephropathy
might be mediated by the systemic oxidative stress-
ameliorating effect, which is pleiotropic and regulates
anti-inflammatory reduction. The antioxidant effects
of statins likely contribute to their clinical efficacy in
treating cardiovascular diseases as well as other chronic
conditions associated with increased oxidative stress in
humans. Rosuvastatin is effective in protecting against
tubulointerstitial injury and in reducing oxidative
stress in diabetic patients with CKD; however, further

10 Abe et al .
long-term studies are needed for more precise evalua-
tion of the effects of rosuvastatin on albuminuria and
kidney function.
In a sub-analysis of the Fenofibrate Intervention
and Event Lowering in Diabetes (FIELD) study, con-
comitant decreases in eGFR and creatinine clearance
were observed following fenofibrate administration,
but no beneficial effects on albuminuria were noted 24).
On the other hand, meta-regression analysis showed
that statins reduced cardiovascular events in patients
with CKD at a rate similar to that seen in the general
population, and treatment effects did not vary signifi-
cantly with various stages of CKD, namely, the pre-
dialysis, dialysis, and transplant populations 25). Statin
therapy resulted in a small reduction in the rate of
kidney function loss in subjects with CVD but was
not significant in subjects with diabetic or hyperten-
sive kidney disease or glomerulonephritis when com-
pared to a placebo 26). Furthermore, statins seemed to
reduce proteinuria and albuminuria when compared
to a placebo 27); however, the antiproteinuric effect of
rosuvastatin in patients with diabetic nephropathy has
not been clarified because the meta-analyses in the
above studies were based on investigations using simv-
astatin or pravastatin treatment for subjects with CVD
who were not limited to diabetics. In the present
study, rosuvastatin treatment reduced albuminuria sig-
nificantly in diabetic patients. On the other hand,
statins did not improve GFR, but significantly
reduced proteinuria and albuminuria 25). In a sub-anal-
ysis of the Treating to New Targets (TNT) study,
treatment with 10 mg and 80 mg atorvastatin was
found to increase eGFR by 3.5 mL/min/1.73 m2 and
5.2 mL/min/1.73 m2, respectively 28). In contrast, in
the Prevention of Renal and Vascular End-stage Dis-
ease Intervention trial (PREVEND-IT), treatment
with 40 mg pravastatin did not result in any changes
in eGFR 29). Thus, the beneficial effect of statins on
eGFR in diabetic nephropathy remains controversial.
On the other hand, comparing the serum Cr with
conventional estimates, based on serum cystatin C
measurements for detecting very early reduction of
kidney function, can be useful for measuring kidney
function and will optimize early detection, prevention,
and treatment strategies for diabetic nephropathy 30, 31).
Furthermore, cystatin C is a potent predictor of car-
diovascular mortality beyond classical factors in
patients with coronary artery disease and normal or
mildly reduced kidney function 32). In the present
study, although the degree was small, eGFR decreased
in the control group. On the other hand, there was no
significant difference in eGFR in the rosuvastatin
group; in other words, eGFR could be maintained in
Advance Publication
Journal of Atherosclerosis and Thrombosis
Accepted for publication: June 23, 2011
Published online: September 15, 2011
the rosuvastatin group without decreasing. This find-
ing was expected because the present study period was
relatively short; however, the results revealed that cys-
tatin C, which is a more sensitive marker of changes
in GFR, is significantly reduced by rosuvastatin treat-
ment.
In conclusion, the present study demonstrated
that rosuvastatin administration reduced urinary albu-
min excretion, urinary 8-OHdG, and L-FABP in
patients with diabetic nephropathy and well-con-
trolled hypertension, independent of blood pressure
and lipid changes. This was achieved in part due to
reducing oxidative stress; however, the precise mecha-
nisms remain unclear. Rosuvastatin may ameliorate
the progression of tubulointerstitial lesions in diabetic
nephropathy. Furthermore, rosuvastatin treatment
resulted in a significant decrease of cystatin C after 24
weeks, suggesting that rosuvastatin might maintain
the GFR as well as contribute to a reduction in the
risk of CVD in patients with diabetic nephropathy.
Further prospective long-term clinical trials are needed
for a more precise evaluation of the effects of rosuvas-
tatin on renal outcome.
Conflicts of Interest Statement
We have no conflicts of interest.
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