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The Journal of International Medical Research

2009; 37: 892 898

Antiproteinuric Effect of Angiotensinconverting Enzyme Inhibitors and an


Angiotensin II Receptor Blocker in
Patients with Lupus Nephritis
N KITAMURA, Y MATSUKAWA, M TAKEI

AND

S SAWADA

Division of Haematology and Rheumatology, Department of Medicine, School of Medicine,


Nihon University, Tokyo, Japan
Although the effects of angiotensin II
receptor blockers (ARBs) on non-diabetic
glomerulonephritis have been reported,
studies of their effects on collagenvascular diseases, particularly lupus
nephritis, are limited. In this retrospective,
observational study, systemic lupus
erythematosus (SLE) patients (n = 7) with
lupus
nephritis
and
uncontrolled
proteinuria were treated with an
angiotensin-converting enzyme inhibitor
followed by the ARB losartan (25 50
mg/day). Urinary protein excretion and
renal function were evaluated. After 12
months of losartan, mean urinary protein

excretion decreased significantly by


84.8%. Mean systolic and diastolic blood
pressures also decreased significantly
during the 12 months of losartan
treatment, although not in normotensive
patients.
Complement
4,
total
complement activity and anti-dsDNA
antibody levels, which are indices of SLE
activity, and serum creatinine levels,
which is an index of renal function,
showed no change in response to losartan
treatment. A more extensive evaluation of
the effects of ARBs in patients with lupus
nephritis
and
poorly
controlled
proteinuria is required.

KEY WORDS: SYSTEMIC LUPUS ERYTHEMATOSUS; LUPUS NEPHRITIS; PROTEINURIA; RENAL FUNCTION;
ANGIOTENSIN-CONVERTING ENZYME INHIBITOR (ACEI); ANGIOTENSIN II RECEPTOR BLOCKER (ARB);
LOSARTAN

Introduction
The reninangiotensin system is thought to
be involved in the progression of chronic
renal disease of both diabetic and nondiabetic origin.1 It has been shown that
angiotensin-converting
enzyme
(ACE)
inhibitors reduce urinary protein excretion
and attenuate the development of renal
injury.2 The angiotensin II receptor blockers

(ARBs) are an alternative class of drugs that


also inhibit the activity of the renin
angiotensin system.3 It has been shown that
ARBs not only effectively reduce urinary
protein excretion, but also prevent the
progression of renal failure in diabetic
nephropathy.4 It is not known, however,
whether ARBs reduce urinary protein
excretion or prevent the progression of renal

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N Kitamura, Y Matsukawa, M Takei et al.


Antiproteinuric effects in lupus nephritis
dysfunction in non-diabetic nephropathy,
particularly lupus nephritis. This study was
designed to investigate the efficacy of the
ARB,
losartan,
in
systemic
lupus
erythematosus (SLE) patients with lupus
nephritis who were resistant to steroid and
immunosuppressive treatment.

Patients and methods


PATIENTS
This retrospective, observational study
analysed data collected during daily
examinations of SLE patients at Itabashi
Hospital, Nihon University (Tokyo, Japan)
between 2002 and 2005. All patients had a
diagnosis of SLE and clinical and
pathological evidence of lupus nephritis
according to the World Health Organization
(WHO) classification system.5 Although
serological activity and other complications
of SLE had been improved in response to
treatment with corticosteroids and/or
immunosuppressive
drugs
prior
to
enrolment, proteinuria (mean SD of 6.8
5.7 g/day for the study population) remained
evident at the start of the study. Prior to
treatment, all patients gave their informed
consent to the Ethical Committee of Nihon
University
School
of
Medicine
for
participation in this study.

STUDY TREATMENT AND


EVALUATIONS
After administration of an ACE inhibitor (5
mg/day enalapril) for the treatment of
proteinuria for 6 months, 50 mg/day
losartan was then added to the dosing
regimen. Treatment did not change for at
least 3 months before the start of the study
and throughout the study, except for the
tapering of corticosteroids which were only
increased or decreased if required by changes
in the patients condition. All evaluations
were made before and during the 12 months

of treatment with losartan and included


blood pressure, serum creatinine levels (to
evaluate any adverse effects of losartan
treatment on renal function) and urinary
protein excretion. At the same time,
erythrocyte
sedimentation
rate,
complements 3 and 4 (C3 and C4), total
complement activity (CH50) and antidsDNA antibody levels were measured to
evaluate SLE status. The primary end-point
was a measured improvement in the level of
proteinuria. The secondary end-point was
any renal adverse effect that might be
associated with losartan.

STATISTICAL ANALYSIS
Statistical analyses were performed using the
StatView statistical program (SAS Institute
Inc., Cary, NC, USA). Laboratory data before
and after treatment were compared using
Wilcoxons signed rank test. A P-value < 0.05
was considered to be statistically significant.

Results
Seven patients were enrolled in the study and
their baseline clinical characteristics are
shown in Table 1. All the patients were
females of mean SD age 41.1 17.4 years.
The patients were diagnosed with SLE and
had clinical and pathological evidence of
lupus nephritis according to WHO criteria:5
two patients were classified as having WHO
type III SLE, three had WHO type IV SLE, and
two had WHO type V SLE. Prior to treatment,
patients mean SD systolic and diastolic
blood pressures were 147 14 and 93 7
mmHg, respectively. Two patients (numbers
3 and 6 in Table 1) had normal blood
pressure at baseline (defined as systolic blood
pressure < 140 mmHg and/or diastolic blood
pressure < 90 mmHg based on WHO
hypertension criteria.6
The decrease in proteinuria observed after
losartan treatment, expressed as a

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894

61
27
51
63
18
36
32

F
F
F
F
F
F
F

Sex

40
80
80
80
160
80
160

Anti-nuclear
antibody
titre
2.4
16.5
58.0
40.1
16.2
22.5
14.6

99
69
112
97
131
88
72

Anti-dsDNA
antibody
C3
(IU/ml) (mg/dl)
34
13
22
27
29
21
19

C4
(mg/dl)
43.8
25.4
43.4
43.8
63.3
48.2
46.1

IVb
Vb
III
IVa
Va
IVa
III

16.5
7.5
1.3
1.9
10.1
8.5
1.8

166/96
148/96
128/84
156/100
140/98
134/82
162/96

Total
Urinary
CH50
protein SBP/DBP
(U/ml) WHO type (g/day) (mmHg)

F, female; SBP/DBP, systolic/diastolic blood pressure; WHO, World Health Organization; PSL, prednisolone.

1
2
3
4
5
6
7

Patient

Age
(years)

Complement

PSL
PSL
PSL
PSL
PSL
PSL
PSL

15 mg
18 mg
7.5 mg
15 mg
13 mg
12 mg
20 mg

Therapy
(mg/day)

TABLE 1:
Baseline demographic and clinical characteristics of the patients with systemic lupus erythematosus and evidence of lupus
nephritis who were enrolled in the study

N Kitamura, Y Matsukawa, M Takei et al.


Antiproteinuric effects in lupus nephritis

N Kitamura, Y Matsukawa, M Takei et al.


Antiproteinuric effects in lupus nephritis
percentage of the baseline value (100%), is
shown in Fig. 1. Proteinuria decreased in all
seven patients, the mean SD being
decreased significantly by 53.2 8.3% after 3
months, 62.7 5.6% after 6 months and 84.8
9.6% after 12 months (P < 0.01 compared
with baseline).
Changes in systolic and diastolic blood
pressures before and after treatment with
losartan for 12 months are shown in Fig. 2:

mean SD values were significantly reduced


to 122.6 12 and 75.1 6 mmHg,
respectively (P < 0.01 compared with
baseline). The two patients who had normal
blood pressure at baseline showed no
significant decline in blood pressure after 12
months treatment with losartan.
Changes in C4, CH50 and anti-dsDNA
antibody levels, analysed to evaluate the
effect of losartan treatment on changes in

Protein excretion (%)

100
80
**

60

**

40

**

**

12

20
0
Baseline

6
Time (months)

FIGURE 1: Urinary protein excretion in patients with systemic lupus erythematosus


and lupus nephritis shown as a percentage of the baseline prior to losartan treatment
(**P < 0.01 compared with baseline; mean SD of seven patients)

Systolic

Diastolic

180

180

160

160

Blood pressure (mmHg)

Blood pressure (mmHg)

140
120
100
80
60

140

120
100
80
60

Baseline

Baseline

12 months

12 months

FIGURE 2: Blood pressure at baseline and after 12 months of treatment with losartan
in patients with systemic lupus erythematosus and lupus nephritis (*P < 0.05
compared with baseline; seven patients)

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N Kitamura, Y Matsukawa, M Takei et al.


Antiproteinuric effects in lupus nephritis
or immunosuppressive drugs such as
cyclosporine
A,
intravenous
cyclophosphamide, azathioprine and mizoribine,
which reduce the transition rate to renal
failure and the mortality rate due to renal
failure.8 10 Proteinuria is, however, reported
to be uncontrolled in about 10% of patients
with lupus nephritis and the condition
progresses to renal failure even with
aggressive treatment using corticosteroids and
immunosuppressive drugs.11 Conditions
including azotaemia, anaemia, hypertension,
hyperlipidaemia and nephritic syndrome
have been suggested as prognostic factors for
lupus nephritis,12 but the degree of leakage of
urinary protein from the glomeruli, in
particular,
is
a
major
factor
in
tubulointerstitial damage. Indeed, glomerular
function has been reported to be maintained
by reducing urinary protein in various renal
disorders.13,14 Decreasing urinary protein is,
therefore, expected to lead to an improvement
in the renal outcome of SLE in patients with
lupus nephritis who show uncontrolled
proteinuria despite aggressive treatment.
In the present study, the ARB losartan was

serum activity of SLE, are shown in Fig. 3.


Before treatment, the mean SD C4 level was
23.2 7.1 mg/dl, CH50 was 44.2 11.3 U/ml
and anti-dsDNA antibody was 13.7 8.8
IU/ml. After treatment with losartan for 12
months, the mean SD C4 level was 25.1
8.7 mg/dl, CH50 was 41.1 9.4 U/ml and
anti-dsDNA antibody was 14.1 10.2 IU/ml.
None of these was significantly different from
baseline, so there was no significant difference
between the serum activity of SLE at baseline
and after 12 months treatment with losartan.
Changes in serum creatinine levels before
and after 12 months treatment with losartan
showed no significant difference in the mean
SD levels (0.93 0.49 mg/dl versus 0.96
0.60 mg/dl, respectively) (Fig. 4).

Discussion
Lupus nephritis is one of the most frequent
organ complications of SLE and it is
considered to occur as the result of the
development of deposits of an immune
complex, consisting primarily of dsDNA and
its antibody, in the glomeruli.7 Currently,
lupus nephritis is treated with corticosteroids

NS

80

Serum CH50 (U/ml)

Serum C4 (mg/dl)

CH50

NS

60

40

20

60

40

20

0
Baseline

12 months

Baseline

Anti-dsDNA antibody
Serum anti-dsDNA antibody (IU/ml)

C4
80

NS

40

30

20

10

12 months

Baseline

12 months

FIGURE 3: Serum complement 4 (C4), total complement activity (CH50) and antidsDNA antibody levels at baseline and after 12 months of treatment with losartan in
patients with systemic lupus erythematosus and lupus nephritis (NS, not statistically
significant compared with baseline; seven patients)

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N Kitamura, Y Matsukawa, M Takei et al.


Antiproteinuric effects in lupus nephritis

Serum Cr (mg/dl)

NS

0
Baseline

12 months

FIGURE 4: Serum creatinine (Cr)


levels at baseline and after 12
months of treatment with losartan
in patients with systemic lupus
erythematosus and lupus nephritis
(NS, not statistically significant
compared with baseline; seven
patients)
administered to SLE patients with
serologically low SLE disease activity and no
organ complications except for the kidney,
but in whom proteinuria was poorly
controlled. A mean improvement of 84.8%
in the rate of proteinuria was observed after
12 months of losartan. Reports have
suggested that ARBs have a protective effect
in kidney and that they reduce proteinuria
in glomerulonephritis associated with
conditions other than lupus nephritis, such
as
IgA
nephropathy
and
diabetic
nephropathy.15 17 No reduction in
proteinuria has previously been reported in
SLE patients with lupus nephritis, with the
exception of one report by Kanda et al.18
The mechanism by which proteinuria is
reduced in chronic glomerulonephritis by the
administration of an ARB appears to be a
decrease in the intraglomerular pressure due
to dilation of the glomerular efferent

arterioles.19 Kanno et al.20 reported, however,


that glomerulosclerosis and interstitial fibrosis
of the kidney could be markedly prevented by
long-term administration of an ARB in a rat
partial nephrectomy model. De Albuquerque
et al.21 found that an ACE inhibitor inhibited
the production of T-helper 2 cytokines and
transforming growth factor-1 in murine
lupus nephritis. Moreover, Esteban et al.22
demonstrated that blocking angiotensin II
receptor types 1 and 2 can suppress the
nuclear factor (NF) B pathway in renal tissue
and control inflammatory cell infiltration
into renal tissue. In the present study, no
change was noted in the activity of SLE itself
or in renal function after the administration
of the ARB losartan. The above reports
suggest, however, that blocking of the renin
angiotensin system with an ARB reduces
proteinuria in lupus nephritis not simply by
reducing the intraglomerular pressure but
also by mitigating local glomerular
inflammation.20 22 Furthermore, Iino et al.23
showed that losartan reduced proteinuria in
patients with chronic kidney disease and
hypertension compared with amlidipine. This
effect may contribute to the renal protective
effects of losartan and is beyond just the
extent of blood pressure control.
In conclusion, losartan was administered
to SLE patients with proteinuria that had not
been controlled by previous treatment with
conventional therapy, and a significant
decrease in the mean urinary protein
excretion rate of 84.8% was observed after 12
months of treatment with losartan. Further
evaluation of the administration of ARBs is
needed in larger numbers of patients with
lupus nephritis showing uncontrolled
proteinuria.

Conflicts of interest
The authors had no conflicts of interest to
declare in relation to this article.

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N Kitamura, Y Matsukawa, M Takei et al.


Antiproteinuric effects in lupus nephritis
Received for publication 28 January 2009 Accepted subject to revision 5 February 2009
Revised accepted 3 June 2009
Copyright 2009 Field House Publishing LLP
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Authors address for correspondence


Dr Noboru Kitamura
Division of Haematology and Rheumatology, Department of Medicine, School of Medicine,
Nihon University, 30-1 Oyaguchi Kamimachi Itabashi-ku, Tokyo 173-8610, Japan.
E-mail: noboruk@med.nihon-u.ac.jp

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