Nephrol Dial Transplant (2003) 18: 1806–1813

DOI: 10.1093/ndt/gfg284

Original Article

Antiproteinuric efficacy of losartan in comparison with amlodipine in

non-diabetic proteinuric renal diseases: a double-blind, randomized
clinical trial

Manuel Praga1, Carlos Fernández Andrade2, José Luño3, Manuel Arias4, Rafael Poveda5,

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Jose Mora6, Marti Valles Prat7, Francisco Rivera8, Jose Marı́a Galceran9, Jorge Martı́nez Ara10,
Román Aguirre11, Carmen Bernis12, Rafael Marı́n13 and Jose Marı́a Campistoll4

1
Hospital 12 de Octubre, Madrid, 2Hospital Virgen del Rocio, Sevilla, 3Hospital Gregorio Marañón, Madrid, 4Hospital
Marques de Valdecilla Santander, 5Hospital de Bellvitge, Barcelona, 6Fundación Puigvert, Barcelona, 7Hospital Josep
Trueta, Gerona, 8Hospital General de Alicante, 9Hospital de Palamos (Gerona), 10Hospital La Paz, Madrid, 11Hospital de
Galdakano, Vizcaya, 12Hospital de la Princesa, Madrid, 13Hospital Central de Asturias and 14Hospital Clı́nico y Provincial,
Barcelona, Spain

Abstract proteinuria decrease induced by losartan. Both losartan

Background. Proteinuria is a significant independent and amlodipine induced a similar and significant blood
determinant of the progression of chronic renal dis- pressure reduction. Target blood pressure was achieved
eases. It induces an increased synthesis of angiotensin with the initial dose of study medication (50 mg daily)
II, endothelin and profibrogenic growth factors, such in 76% of losartan group patients and in 68% of the
as transforming growth factor- (TGF-), by mesan- amlodipine group patients (5 mg daily). Urinary TGF-
gial and tubular cells. The antiproteinuric effect of  significantly decreased with losartan ( 22.4% of the
angiotensin-converting enzyme inhibitors (ACEIs) in baseline values after 20 weeks of treatment), whereas
diabetic and non-diabetic nephropathies predicts it tended to increase with amlodipine (between-group
long-term renoprotection afforded by these drugs. difference P < 0.05). A significant correlation between
Angiotensin II receptor antagonists are renoprotective
in patients with type 2 diabetes, but studies about their
effect in non-diabetic proteinuric nephropathies are
very scarce.
Methods. We randomly assigned 97 patients with non-
diabetic nephropathies and proteinuria >1.5 g/24 h to
proteinuria decrease and urinary TGF- reduction
was found in the losartan group (r = 0.41, P < 0.005).
Serum creatinine and serum potassium remained stable
during the study in both groups.
Conclusions. Losartan induced a drastic decrease in
proteinuria accompanied by a reduction in urinary
treatment with losartan (50 mg daily) or amlodipine
(5 mg daily) for 20 weeks. Doses of the study medi-
cations were titrated to achieve a target blood pressure
<140/90 mmHg in both groups. Primary outcome was
the decrease in the level of 24 h proteinuria. Secondary
excretion of TGF- in patients with non-diabetic
proteinuric renal diseases.
Keywords: angiotensin II blockade; losartan; progres-
sion of renal disease; proteinuria; transforming-
outcomes were changes in the plasma and urinary levels growth factor- (TGF-)
of TGF-.
Results. The baseline characteristics in both groups
were similar. Proteinuria decreased by 32.4% (95%
confidence interval 38.4 to 21.8%) after 4 weeks of Introduction
treatment and by 50.4% ( 58.9 to 40.2%) after 20
weeks in the losartan group, whereas no significant
The level of proteinuria has long been recognized as a
proteinuria changes were observed in the amlodipine
prognostic marker of paramount importance in any
group (P < 0.001). There was no significant correlation
chronic renal disease. Prospective studies have shown
between the level of baseline proteinuria and the
that proteinuria is a significant independent determi-
Correspondence and offprint requests to: Dr Manuel Praga, Servicio
nant of the progression of chronic renal diseases,
de Nefrologı́a, Hospital 12 de Octubre, Carretera de Andalucı́a, demonstrating a strong association of greater protein-
Km 5,400, 28041 Madrid, Spain. Email: mpragat@senefro.org uria with more rapid decline in renal function [1–3].

ß 2003 European Renal Association–European Dialysis and Transplant Association

Antiproteinuric efficacy of losartan in comparison with amlodipine
In the last few years, a large number of experimental
studies have provided compelling evidence of the
harmful effects that proteins abnormally filtered by a
diseased glomerulus induce on glomerular and tubu-
lointerstitial structures [4–6]. Increased synthesis of
angiotensin II and endothelin-1 by the kidney has been
demonstrated in proteinuric renal diseases [4–6].
Angiotensin II stimulates the synthesis of transforming
1807
Patients
The criteria for eligibility included age older than 18 years,
a chronic proteinuric nephropathy (defined by a proteinuria
>1.5 g/24 h) of non-diabetic cause, and hypertension (a
systolic blood pressure of >140 mmHg while sitting and/or a
diastolic blood pressure of >90 mmHg while sitting). Serum
creatinine was required to be 2.5 mg/dl. Patients were
excluded if they had severe hypertension (systolic blood
growth factor- (TGF-), and angiotensin II blockade pressure >170 mmHg and/or diastolic blood pressure
by angiotensin-converting enzyme inhibitors (ACEIs) >105 mmHg despite treatment with antihypertensive agents,
or angiotensin II receptor blockers (ARBs) results in a or patients requiring more than one antihypertensive drug),
decrease in TGF- expression and matrix accumulation secondary types of hypertension (renal artery stenosis,
[7]. Overproduction of TGF-, the most important
fibrogenic cytokine identified so far, plays a key role in
renal fibrosis, through an increased synthesis of matrix
proteins such as collagen, fibronectin and proteogly-
cans, and increased production of protease inhibitors
such as PAI-1 and TIMP [4,5,7].
In this scenario, any therapeutic intervention that
reduces the level of proteinuria should have an
important beneficial influence on the progression of
proteinuric nephropathies. This assessment has been
validated by the results of several therapeutic trials
performed in the last decade. ACEIs, drugs whose
antiproteinuric and renoprotective properties had been
demonstrated repeatedly in experimental models of
renal disease progression, showed a significant bene-
ficial influence on the progression of both diabetic
and non-diabetic nephropathies in prospective and
multicentre studies [8,9]. The slowing in the progres-
sion of renal insufficiency was always strongly related
to proteinuria decrease induced by ACEIs, whereas
it appears to be largely independent of the blood
pressure-lowering effects induced by these agents [8,9].
ARBs have reproduced the beneficial effects of
ACEIs in experimental models of renal disease. Recent
prospective, multicentre studies have shown that ARBs
delay the progression of nephropathy in patients with
type 2 diabetes [10,11]. As in the trials using ACEIs,
the beneficial influence of ARBs was associated with a
significant proteinuria decrease. In contrast, informa-
tion about the renoprotective effects of ARBs in non-
diabetic proteinuric nephropathies is scarce.
We undertook a prospective and multicentre study in
patients with non-diabetic proteinuric renal diseases in
order to compare the effect of an ARB (losartan) and a
calcium channel blocker (amlodipine) on the levels of
24 h proteinuria. Secondary objectives of the study were
to assess the effect of both treatments on the plasma
primary aldosteronism, pheochromocytoma or other revers-
ible forms of hypertension), rapidly deteriorating renal
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function (defined by an increase of >50% in the level of
serum creatinine during the last 6 months) or severe obesity
(body mass index >35 kg/m2). We also excluded patients who
required diuretics because of oedema, who had received a
diagnosis of type 1 or type 2 diabetes, who had had a myo-
cardial infarction within the previous 6 months or who had
any history of heart failure.
Sample size calculation
Assuming a standard deviation on proteinuria reduction of
1.50 g/24 h, in order to detect a difference of 1.00 g/24 h in
mean reduction in proteinuria between both treatment arms
with a power equal to 90% and a type I error of 0.05 (two-
tailed), it was calculated that a sample size of 49 patients per
group would be necessary.
Study design
All the patients that met the eligibility criteria followed a wash-
out/placebo period during which all the antihypertensive
drugs, including diuretics, were withdrawn and a placebo was
administered. The duration of this wash-out/placebo period
was 8 weeks for patients taking ACEIs or ARAs, 4 weeks for
those receiving other classes of antihypertensive agents and
2 weeks for patients without antihypertensive treatment.
During this wash-out/placebo period, an -blocker (doxazosin)
could be prescribed to patients with a systolic blood pressure
>170 mmHg and/or diastolic blood pressure >105 mmHg.
After completing the wash-out/placebo period, patients
who fulfilled the enrolment criteria were assigned randomly to
receive either losartan 50 mg or amlodipine 5 mg once daily, in
a double-blind design. After 4 weeks (week 4), hydrochloro-
thiazide (12.5 mg once daily) was added if the blood pressure
was above the target level of a systolic blood pressure of
<140 mmHg and a diastolic blood pressure of <90 mmHg.
and urinary levels of TGF-, as well as to evaluate the
safety and tolerability of both treatments.
Subjects and methods
We conducted an investigator-initiated, prospective, double-
blind, randomized study of 20 weeks duration in 14 centres in
Spain. The study protocol was reviewed and approved by
each centre’s institutional review board, and signed consent
was obtained from all patients prior to study entry.
After an additional 4 weeks (week 8), the dose of losartan or
amlodipine was increased to 100 mg and 10 mg once daily,
respectively, if blood pressure was still above the target level.
If after another 4 weeks (week 12) systolic blood pressure
was still >140 mmHg or diastolic blood pressure was
>90 mmHg, the dose of hydrochlorothiazide was increased
to 25 mg once daily (see Figure 1, study design).
Clinical and laboratory procedures
At study entry and completion, a complete physical
examination and electrocardiogram (ECG) were obtained.
1808 M. Praga et al.

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Fig. 1. Study design.

After randomization (week 0 or baseline), included patients Outcome measures

undertook visits after 2, 4, 8, 12, 16 and 20 weeks. Blood
pressure was measured at every visit, using a standard The primary efficacy measure was the decrease in the level
mercury sphygmomanometer. It was measured in the sitting of 24 h proteinuria. The secondary end points were changes
position after at least 5 min of rest. The proper cuff size was in the plasma and urinary levels of TGF-.
used on the same arm throughout the study. Korotkoff
phase V was used as the criterion for diastolic blood pressure.
Three consecutive measurements, at 1 min intervals, were
Statistical analysis
performed, and the average of the three readings was In order to normalize the data, right asymmetrical continuous
calculated. Heart rate was also recorded at every visit.
Patients were questioned at each visit about the occurrence of
adverse symptoms.
All analyses were performed after an overnight fast. Blood
was drawn for routine haematology and blood chemistry
[including standard blood count, serum creatinine, urea,
sodium, potassium, bilirubin, alkaline phosphatase, aspartate
aminotransferase, alanine aminotransferase, glucose, uric
acid, total and high-density lipoprotein (HDL) serum
cholesterol and triglycerides] at baseline and at weeks 4 and
20. Serum creatinine and serum potassium were also mea-
sured at week 2. Twenty-four hour proteinuria was measured
at baseline and at weeks 4, 8 and 20. In addition, urinary
creatinine and sodium were measured in the urine collections
variables (proteinuria and TGF-) were log-transformed,
and therefore geometric means were calculated. For other
continuous variables (BP and laboratory parameters),
arithmetic means were calculated.
Baseline measurements were assessed with arithmetic and
geometric means, and post-baseline measurements were
assessed with LS-arithmetic means and LS-geometric means
adjusted for baseline measurement.
For arithmetic means, the SD and 95% confidence interval
(CI) are presented. For geometric means and LS-means, only
the 95% CI is presented.
For continuous variables, between-group comparisons
were performed with analysis of co-variance, with baseline
measurement as a co-variate; least squared means were
at baseline, week 4 and week 20. Plasma levels of TGF- were presented. For discrete variables, e.g. adverse events,
determined at baseline and at weeks 4 and 20. The 24 h urine differences between groups were assessed with the relative
collections for measurement of urinary TGF- were obtained risk and 2 test P-value, or Fisher’s exact test when the 2
at baseline, week 4 and week 20. criteria were not met.
Measurements of 24 h proteinuria and urinary creatinine,
as well as the measurement of TGF-, were performed by a
central laboratory. The remaining measurements were
determined by local laboratories. Standard blood count, Results
proteinuria and blood chemistry were measured by routine
techniques. Plasma and urinary concentration of TGF-1 A total of 112 eligible patients entered the wash-out/
were measured by enzyme-linked immunosorbent assay placebo period. Fifteen patients were excluded because
(ELISA; Quantikine, R&D Systems Inc., Minneapolis, MN, of severe hypertension (eight patients), proteinuria
USA) as described previously [12]. <1.5 g/24 h (three patients), refusal to sign informed
Antiproteinuric efficacy of losartan in comparison with amlodipine
consent (three patients) and severe oedema (one
patient). The remaining 97 patients were randomly
assigned to receive losartan (50 patients) or amlodipine
(47 patients). For the 97 included patients, there were
no significant changes in serum creatinine during the
wash-out/placebo period. Creatinine clearance showed
a mild, non-significant decrease from 78 ± 40 (69–86)
ml/min at the onset of the wash-out/placebo period
to 77 ± 37 (70–85) ml/min at baseline. The baseline
demographic, clinical and laboratory characteristics of
the two groups were similar (Tables 1 and 2). Adverse
clinical events resulted in discontinuation in three
patients (6%) in the losartan group and in six patients
(12%) in the amlodipine group. These patients were
1809
149 (146–151)/93 (91–94) mmHg at baseline to 131
(128–135)/83 (81–85) mmHg at week 20 in the losar-
tan group (P < 0.00001) and to 136 (133–141)/85
(84–88) mmHg at week 20 in the amlodipine group
(P < 0.00001). There were no significant differences in
the reduction of blood pressure between both groups
(Figure 2). The proportion of patients in whom the
target blood pressure was achieved was similar in both
groups (62% in the losartan group and 53% in the
amlodipine group, NS). Almost half of the patients in
the losartan group (23 patients) achieved the target
blood pressure (<140 mmHg for systolic and <90
mmHg for diastolic blood pressure) with the initial dose
of 50 mg daily without diuretics, whereas other 15

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included in the intention-to-treat analyses.
Clinical management
The blood pressure measurements for the two groups
are shown in Figure 2. Both treatments provided a
significant reduction of both systolic and diastolic
blood pressures. Blood pressure decreased from
patients needed the addition of diuretics. Only 12
(24%) patients in this group needed to increase losartan
doses to 100 mg daily. In the amlodipine group, 32
patients (68%) maintained the initial dose of 5 mg daily
throughout the study, with or without diuretics,
because of the achievement of target blood pressure.
Primary outcome

Table 1. Baseline characteristics

Levels of 24 h proteinuria in both groups are shown
in Figure 3. There were no significant changes in the
Losartan Amlodipine
amlodipine group throughout the study: 2.8 (2.4–3.3)
(n = 50) (n = 47) g/24 h at baseline, 3.1 (2.5–3.6) g/24 h after 4 weeks,
2.7 (2.3–3.1) g/24 h at week 8 and 2.5 (2.1–3.1) g/24 h at
Gender (M/F; %) 74/26 73/27 week 20. In contrast, proteinuria showed a drastic
Age (years) 48 ± 13 47 ± 14 decrease in the losartan group: it decreased from
(44–52) (43–52) 2.8 (2.4–3.3) g/24 h at baseline to 1.9 (1.7–2.2) g/24 h
Systolic blood pressure 149 ± 14 149 ± 11 (P < 0.0001) after 4 weeks [ 32.4% ( 38.4 to
(mmHg) (144–153) (146–152)
Diastolic blood pressure 93 ± 7 92 ± 7 21.8%)], 1.6 (1.4–1.9) g/24 h (P < 0.0001) at week 8
(mmHg) (91–95) (90–94) [ 41.3% ( 48.16 to 29.9%)] and 1.4 (1.1–1.7) g/24 h
Weight (kg)/height (cm) 78 ± 13/169 ± 9 77 ± 14/166 ± 8 at week 20 (P < 0.0001) [ 50.4% ( 58.9 to 40.2%)]
(74–82)/(166–171) (73–81)/(164–169) (P < 0.0001 with respect to the amlodipine group at
Body mass index (kg/m2) 27.2 ± 4.1 27.8 ± 4.4 every measurement).
(26–28.4) (26.5–29.1)
Serum creatinine (mg/dl) 1.4 ± 0.5 1.3 ± 0.5 No correlation was found between the level of
(1.3–1.6) (1.1–1.4) proteinuria at baseline and the percentage proteinuria
Proteinuria (g/24 h)a 3.1 2.5 reduction at week 20 considering the whole group of 97
(2.5–3.8) (2–3.2) randomized patients and patients of the losartan and
Arithmetic means ± SD are presented. Numbers in parentheses
amlodipine groups separately.
represent the 95% CIs. There were no significant further reductions in the
a
The geometric mean is presented. level of proteinuria in those patients (n = 11) in whom

Table 2. Renal disease diagnosis

Losartan (n = 50) Amlodipine (n = 47) Total (n = 97)

Glomerulonephritis 34 28 62
IgA nephropathy 17 11 28
Membranous nephropathy 6 8 14
Focal glomerulosclerosis 6 4 10
Membranoproliferative glomerulonephritis 2 2 4
Other glomerulonephritis 3 3 6
Hyperfiltration diseases 5 3 8
Hypertensive nephrosclerosis 3 3 6
Hereditary nephropathies 2 3 5
Systemic diseases 2 3 5
Chronic tubulointerstitial nephropathies 1 2 3
Unknown cause 3 5 8
1810 M. Praga et al.

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Fig. 2. Evolution of systolic (SBP), diastolic (DBP) and mean (MBP) blood pressure during the study.

the dose of losartan was increased to 100 mg after

week 8 because of blood pressure >140/90 mmHg:
4.3 (2.9–6.3) g/24 h at baseline, 2.1 (1.3–3.3) g/24 h at
week 8 [ 50.3% ( 30 to 64.6%)] and 1.8 (1.1–3.1)
g/24 h at week 20 [ 12.4% (24.2 to 38.3%) with
respect to values at week 8].

Secondary outcomes
In the losartan group, daily urinary excretion of TGF-
decreased from 16.2 (14.0–19.0) ng/24 h at baseline to
13.5 (9–14.2) ng/24 h at week 4 [ 16.3% ( 33.2 to Fig. 3. Changes in proteinuria during the study (*P < 0.0001,
5.0%)] and to 12.5 (10.1–15.6) ng/24 h at week 20 reduction between groups).
Antiproteinuric efficacy of losartan in comparison with amlodipine 1811
the study (NS). Adverse clinical events resulted in
discontinuation of three patients (6%) in the losartan
group (anxiety, dizziness and serum creatinine increase)
and of six patients (12%) in the amlodipine group
(anaemia, angina pectoris, diarrhoea and oedema in
three patients). There were three serious adverse events,
not related to study treatments: two in two patients of
the losartan group (fever and dysuria) and one in the
amlodipine group (angina pectoris).

Discussion

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In our study, losartan induced a drastic decrease in
Fig. 4. Changes in urinary TGF- at weeks 4 and 20. proteinuria in patients with non-diabetic proteinuric
renal disease, moderate hypertension and a serum
creatinine <2.5 mg/dl. In contrast, patients treated
[ 22.2% ( 37.6 to 3.6%)] (P < 0.05 with respect to with amlodipine did not show significant variations
baseline values). In the amlodipine group, TGF- in the level of proteinuria throughout the study.
increased from the baseline levels to 17.1 (13.7–21.3) Proteinuria decrease was also evident among our
ng/24 h at week 4 and to 17.6 (14.1–22.2) ng/24 h at losartan group patients with lower levels of baseline
week 20. These differences between the losartan and proteinuria, and no correlation between baseline
amlodipine groups were significant (P < 0.05) (Figure proteinuria and the degree of proteinuria reduction
4). A significant correlation between the percentage was observed.
proteinuria decrease and urinary TGF- changes was
found in the losartan group (r = 0.41, P < 0.0034),
whereas no correlation was found in the amlodipine
group.
There were no significant changes in plasma levels of
Only a few studies, including a small number of
patients, had previously investigated the effects of
ARBs on the proteinuria levels of chronic non-diabetic
renal diseases [13–18]. Our study confirms and extends
these preliminary data, demonstrating for the first time
TGF- either in the losartan group [6.9 (5.7–8) ng/ml at
baseline, 8.1 (6.5–10.1) ng/ml at week 4 and 7 (5.6–8.7)
ng/ml at week 20] or in the amlodipine group [6.9
(5.7–8) ng/ml, 8.2 ng/ml and 8 (6.4–10) ng/ml, respec-
tively].
Effects on other laboratory parameters
As shown in Table 3, there were no significant changes
in haematocrit, haemoglobin, leukocyte count or
platelet count either in the losartan group or in the
amlodipine group. Serum creatinine showed a non-
significant increase from 1.4 ± 0.5 to 1.6 ± 0.7 mg/dl
in the losartan group and from 1.3 ± 0.5 to 1.4 ± 0.6
mg/dl in the amlodipine group, whereas creatinine
clearance decreased from 74 ± 37 to 70 ± 37 ml/min in
the losartan group and from 82 ± 38 to 81 ± 43 ml/min
in the amlodipine group. There were also no significant
changes in the levels of serum glucose, uric acid, total
and HDL cholesterol and triglycerides (Table 3). Serum
potassium showed a mild, non-significant, increase
(from 4.3 ± 0.3 to 4.5 ± 0.5 mEq/l) in the losartan
group. There were no significant changes in the levels of
24 h urinary sodium excretion.
Adverse experiences
Seven patients (14%) in the losartan group and 12
(25%) in the amlodipine group had minor adverse
experiences related to study medications throughout
in a multicentre, randomized design including a large
number of patients a significant reduction in pro-
teinuria by losartan in patients with non-diabetic
nephropathies.
In the last few years, several prospective clinical
studies have shown that proteinuria is a significant
independent determinant of the progression of chronic
renal diseases, reporting a strong association of greater
proteinuria with a more rapid decline in renal function
[1–3,8–11]. Conversely, those therapeutic measures that
decrease proteinuria are accompanied by a significant
slowing in the rate of renal failure progression. Most of
these data come from the prospective studies performed
with ACEIs, that have demonstrated a beneficial
influence of these drugs on the long-term evolution of
both diabetic and non-diabetic proteinuric renal
diseases [8,9]. Recent studies have demonstrated that
ARBs are effective in delaying the progression of
nephropathy in type 2 diabetes [10,11]. Our study,
showing a drastic antiproteinuric effect of losartan in
non-diabetic renal diseases, might predict a long-term
renoprotection by ARBs in these diseases. However,
the short duration of our study should be emphasized;
further studies with longer follow-up are required in
order to confirm these aspects.
Both losartan and amlodipine induced a significant
and sustained blood pressure reduction (Figure 2).
Lower values of both systolic and diastolic blood
pressure in the losartan group were observed; however,
analysis of co-variance did not find significant
differences in blood pressure values between both
1812 M. Praga et al.
Table 3. Evolution of laboratory parameters during the study

Losartan Amlodipine

Baseline Week 20 Baseline Week 20

Haemoglobin (g/dl) 14.2 ± 1.7 14.1 ± 1.5 14.4 ± 1.8 14.4 ± 2

(13.7–14.7) (13.7–14.6) (13.8–15) (13.8–15)
[9.4–17.7] [10.3–17.2] [10.6–18.5] [8.8–18.8]
Creatinine (mg/dl) 1.4 ± 0.5 1.6 ± 0.7 1.3 ± 0.5 1.4 ± 0.6
(1.3–1.6) (1.4–1.8) (1.1–1.5) (1.2–1.6)
[0.6–2.7] [0.4–3.4] [0.6–2.5] [0.6–3.3]
Creatinine clearance (ml/min) 74 ± 37 70 ± 37 82 ± 38 81 ± 43
(64–85) (59–81) (70–93) (68–94)
[17–188] [13–204] [28–180] [22–197]
Glucose (mg/dl) 100 ± 30 100 ± 24 100 ± 20 101 ± 25

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(91–109) (92–107) (94–106) (94–109)
[73–284] [74–213] [77–191] [73–196]
Uric acid (mg/dl) 6.8 ± 1.6 7.3 ± 1.7 6.4 ± 1.6 6.8 ± 1.5
(6.3–7.2) (6.8–7.8) (5.9–7) (6.3–7.2)
[3.2–11] [4.2–12.5] [2.9–10] [4.2–11.2]
Total cholesterol (mg/dl) 218 ± 36 209 ± 39 230 ± 53 238 ± 46
(208–229) (197–221) (213–247) (224–251)
[119–305] [96–272] [156–382] [152–373]
HDL-cholesterol (mg/dl) 51 ± 16 48 ± 15 52 ± 17 52 ± 13
(46–56) (43–53) (46–59) (47–57)
[23–86] [25–83] [29–108] [29–88]
Triglycerides (mg/dl) 131 ± 76 167 ± 103 149 ± 89 149 ± 77
(109–153) (136–199) (119–179) (125–173)
[23–392] [42–476] [44–459] [40–341]
Sodium (mEq/l) 140 ± 1 140 ± 2 140 ± 2 140 ± 2
(140–141) (140–141) (139–141) (140–141)
[136–144] [136–146] [136–146] [135–146]
Potassium (mEq/l) 4.3 ± 0.3 4.5 ± 0.5 4.3 ± 0.5 4.1 ± 0.4
(4.2–4.4) (4.4–4.6) (4.2–4.5) (4–4.3)
[3.2–5.4] [3.8–6.1] [3–6.2] [3.5–5.2]

Arithmetic means ± SD are presented. Numbers in parentheses represent 95% CIs, and numbers in square brackets represent ranges.

groups throughout the study. As in previous studies
with ACEIs, the reduction in proteinuria by losartan
was already significant after 4 weeks of treatment. In
spite of a similar reduction of blood pressure, patients
treated with amlodipine did not show significant
changes in the level of proteinuria. Dihydropyridine
calcium channel blockers, including amlodipine, lack
the antiproteinuric effect that non-dihydropiridine
calcium channel blockers such as diltiazem and
verapamil have shown in some studies. Sixty-two
percent of patients in the losartan group and 53% in the
amlodipine group reached the target blood pressure
(<140/90 mmHg) during the study. Interestingly,
almost half of the patients in both groups reached the
target blood pressure with the initial dose of both
losartan (50 mg daily) and amlodipine (5 mg daily),
without the addition of diuretics or titration of doses.
It should be considered, however, that patients with
severe hypertension or those receiving more than one
antihypertensive drug were excluded from the study, as
titrated to 100 mg daily because of blood pressure
>140/90 mmHg at week 8 did not show a greater
decrease in proteinuria after losartan increase; all of
them had shown a clear decrease in proteinuria with
the initial dose of 50 mg daily. A recent study [18] has
reported a greater antiproteinuric effect of 100 mg of
losartan daily in comparison with 50 mg daily in 10
patients with proteinuric non-diabetic nephropathies.
Although our study includes a larger number of
patients, it should be emphasized that it was not
designed specifically to analyse the optimal antipro-
teinuric dose of losartan.
In the last few years, pathogenic mechanisms
through which proteinuria induces the appearance of
interstitial infiltrates and progressive tubulointerstitial
fibrosis have been partially clarified. Increased synthe-
sis of angiotensin II by the kidney plays a central role
in these events, activating the transcription factor NF-
B and increasing the expression of several cytokines,
chemoattractants, cell adhesion molecules and growth
stated in Methods. In addition, blood pressure was
targeted to <140/90 mmHg, whereas, according to
current guidelines, values <130/80 mmHg should be
recommended for the long-term control of patients
with proteinuria and renal insufficiency. Most patients
in the losartan group showed a drastic decrease in
factors [4–7]. Among them, TGF- has a pivotal role
in renal scarring, stimulating the synthesis of matrix
proteins and decreasing matrix degradation by in-
creasing the activity of protease inhibitors [7]. In our
study, we assessed the influence of losartan and
amlodipine treatments on urinary and plasma levels
proteinuria with the initial dose of 50 mg daily. In fact, of TGF-. We found a significant between-group
those patients (n = 11) in whom losartan dose was difference, with a significant decrease of urinary
Antiproteinuric efficacy of losartan in comparison with amlodipine 1813
TGF- after 20 weeks of losartan treatment, whereas it 2. Locatelli F, Marcelli D, Comelli M et al. Proteinuria and blood
tended to increase with amlodipine. The reduction of pressure as causal components of progression to end-stage renal
failure: Northern Italian Cooperative Study Group. Nephrol
urinary TGF- showed a significant correlation with
the proteinuria decrease in the losartan group. These
findings are relevant, because several experimental
studies have provided compelling evidence of the
Dial Transplant 1996; 11: 461–467
3. Ruggenenti P, Perna A, Mosconi L et al. Urinary protein
excretion rate is the best independent predictor of ESRF in
non-diabetic proteinuric chronic nephropathies. Kidney Int
important role of TGF- in the progression of both 1998; 53: 1209–1216
diabetic and non-diabetic chronic nephropathies, 4. Egido J. Vasoactive hormones and renal sclerosis. Kidney Int
suggesting that TGF- should be a therapeutic target 1996; 49: 578–597
5. Remuzzi G, Ruggenenti P, Benigni A. Understanding the
in these diseases [7]. In addition, several experimental nature of renal disease progression. Kidney Int 1997; 51: 2–15
and clinical studies strongly suggest that urinary TGF- 6. Eddy AA. Molecular insights into renal interstitial fibrosis.
 represents a very sensitive marker of the activity of J Am Soc Nephrol 1996; 7: 2495–2508
TGF- in the renal system [19,20]. In contrast to the 7. Border WA, Noble NA. Transforming growth factor- in
significant decrease of urinary TGF-, we did not kidney fibrosis: a target for gene therapy. Kidney Int 1997; 51:

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observe significant changes in the plasma levels of 1388–1396
8. Maschio G, Alberti D, Janin G et al. Effect of the angiotensin-
TGF-. It is possible that longer periods of observa-
tion (the duration of our study was 20 weeks) are
needed in order to assess the real influences of ARBs
or other treatments on the plasma levels of these
factors.
Both losartan and amlodipine treatments were well
tolerated throughout the study. Seven patients (14%)
in the losartan group and 12 patients (25%) in the
amlodipine group showed minor adverse events related
to the study medications. Only one patient in the
losartan group showed a significant increase in serum
creatinine levels leading to study discontinuation, and
hyperkalaemia was not recorded among losartan
converting-enzyme inhibitor benazepril on the progression of
chronic renal insufficiency. N Engl J Med 1996; 334: 939–945
9. The GISEN Group. Randomised placebo-controlled trial of
effect of ramipril on declining in glomerular filtration rate and
risk of terminal renal failure in proteinuric, non-diabetic
nephropathy. Lancet 1997; 349: 1857–1863
10. Lewis EJ, Hunsicker LG, Clarke WR et al. Renoprotective
effect of the angiotensin-receptor antagonist irbersartan in
patients with nephropathy due to type 2 diabetes. N Engl J
Med 2001; 345: 851–860
11. Brenner BM, Cooper ME, De Zeeuw D et al. Effects of
losartan on renal and cardiovascular outcomes in patients with
type 2 diabetes and nephropathy. N Engl J Med 2001; 345:
861–869
12. Campistol JM, Iñigo P, Jiménez W et al. Losartan decreases
patients. No significant changes in laboratory param- plasma levels of TGF-1 in transplant patients with chronic
eters were observed (Table 2), including serum creati- allograft nephropathy. Kidney Int 1999; 56: 714–719
nine, creatinine clearance and serum potassium. 13. Nielsen S, Dollerup J, Nielsen B et al. Losartan reduces
In summary, losartan induced a drastic proteinuria albuminuria in patients with essential hypertension. An enalapril
decrease and a significant decrease of urinary TGF- in
patients with non-diabetic proteinuric nephropathies.
Studies with a longer follow-up are required in order to
evaluate whether or not these effects are accompanied
by a long-term renoprotection of ARBs in non-diabetic
renal diseases.
Acknowledgements. The authors acknowledge the participation
of the following: Clinical Investigators at the Hospital Virgen del
Rocio, Sevilla, Coral Navarro and Rodrigo Zamora; Hospital 12 de
Octubre, Madrid, Enrique Morales and Mari Cruz Casal; Hospital
Marques de Valdecilla, Santander, Gema Fernandez Fresnedosos;
Hospital de Bellvitge, Barcelona, Rosa Ramos; Hospital Dr Josep
Trueta, Gerona, Josep Bronsoms; Hospital General de Alicante,
Jesús Olivares; Hospital Gregorio Marañon, Madrid; Ma Angeles
Goicoechea, Ma Soledad Garcı́a de Vinuesa and Francisco Gómez;
Hospital Clı́nico y Provincial, Barcelona, Aleix Cases. Central
Laboratory: Wladimiro Jiménez and Pablo Iñigo, Hospital Clinico
y Provincial, Barcelona. Statistician: Eduardo Sobreviela, Logitest,
Madrid. Study Coordinator: Lourdes Lopez-Bravo, Merck Sharp &
Dohme, Spain. This work was supported by a grant from Merck
Sharp & Dohme, Spain.
controlled 3 month study. Nephrol Dial Transplant 1997; 12
[Suppl 2]: 19–23
14. Chan JCN, Critchley JA, Tomlinson B et al. Antihypertensive
and anti-albuminuric effects of losartan potassium and felodipine
in Chinese elderly hypertensive patients with or without
non-insulin dependent diabetes mellitus. Am J Nephrol 1997;
17: 72–80
15. Fernández Andrade C, Russo D, Iversen B et al. Comparison
of losartan and amlodipine in renally impaired hypertensive
patients. Kidney Int 1998; 54 [Suppl 68]: S120–S124
16. Holdaas H, Hartmann A, Berg KJ et al. Renal effects of
losartan and amlodipine in hypertensive patients with non-
diabetic nephropathy. Nephrol Dial Transplant 1998; 13:
3096–3102
17. Plum J, Bünten B, Németh R, Grabensee B. Effects of the
angiotensin II antagonist valsartan on blood pressure,
proteinuria, and renal hemodynamics in patients with chronic
renal failure and hypertension. J Am Soc Nephrol 1998; 9:
2223–2234
18. Laverman G, Henning RH, de Jong PE et al. Optimal
antiproteinuric dose of losartan in nondiabetic patients with
nephrotic range proteinuria. Am J Kidney Dis 2001; 38:
1381–1384
19. Honkanen E, Teppo AM, Tornroth T et al. Urinary
Conflict of interest statement. None declared.
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Received for publication: 29.11.02
Accepted in revised form: 3.4.03