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From the University of Texas Southwestern at Dallas (R.T., H.M.);
Veterans Affairs Medical Center, Minneapolis, Minn (P.S., L.R.); and Merck
Research Laboratories, West Point, Pa (W.S., D.R., J.T., S.S.).
Correspondence to Robert D. Toto, MD, Director, Clinical Nephrology, Vanderbilt University, School of Medicine, Nashville, TN 37232-2372.
The mechanisms of hypertension in such populations are complex;
however, the RAAS is thought to be an important contributor to the
pathogenesis of hypertension and renal disease in renal failure.
Several studies have shown that treatment with ACE
inhibitors lowers BP, reduces proteinuria, and slows the
rate of progression of renal disease.9 10 11 12
Recently, a new class of drugs that selectively inhibit the RAAS by
specifically targeting the angiotensin II
AT1 receptor have been developed for the
treatment of hypertension. Losartan, the first of this new
class of antihypertensive agents, is an orally active, highly specific
competitive antagonist that blocks the binding of
angiotensin II to the AT1 receptor
subtype.13 In patients with essential
hypertension, once-daily doses of 50 or 100 mg losartan have
been shown to effectively lower BP throughout the 24-hour dosing
interval and to be well tolerated.14 15 16
Losartan is rapidly absorbed after oral administration and
undergoes carboxylation, forming an active metabolite, E-3174, and
several inactive metabolites.17 Both
losartan and its active metabolite are highly protein bound and
neither are removed by hemodialysis.18
Losartan clearance is primarily nonrenal, whereas clearance of
E-3174 occurs through both renal and nonrenal routes. Plasma
concentrations of E-3174, however, are not significantly altered in
patients with renal impairment or in patients undergoing
hemodialysis.18
The present study was designed to evaluate the antihypertensive
effectiveness, safety, and tolerability of losartan,
administered alone in once-daily doses of 50 or 100 mg or in
combination with a non–ACE inhibitor antihypertensive
agent, in patients with varying degrees of chronic renal insufficiency,
including end-stage renal disease.
Patient Selection
Study Design
Efficacy Variables
Measurements of trough BP were made immediately before the morning dose
at each visit, and peak BP measurements were made 5 to 8 hours after
dose at baseline, on the first day of losartan treatment, and
at weeks 1, 4, 8, and 12 of active treatment. Twenty-four–hour urine
collections were obtained in nonhemodialysis patients during the
baseline and active treatment periods for determination of
creatinine clearance and protein excretion. Laboratory
evaluations, including hematology, chemistry, and urinalysis, were
performed during the baseline period and after 4, 8, and 12 weeks of
active treatment. Tolerability of study treatment was assessed by
monitoring of spontaneous reports of adverse experiences at each
visit.
Renal Clearance Studies
Statistical Analysis
The incidence of adverse experiences across the three renal impairment
groups was analyzed with Fisher's exact test. Within-group
changes from baseline for selected laboratory parameters of
clinical importance (ie, serum uric acid, serum potassium, 24-hour
urine protein excretion, and creatinine clearance) were
evaluated with the Wilcoxon signed rank test. Statistical
significance was defined as a value of P
Of the 112 patients who were enrolled, 93 completed the study. Only 6
patients were discontinued because of clinical or laboratory adverse
experiences, 2 patients were withdrawn for uncontrolled hypertension,
and the remainder of those who did not complete the study were
discontinued for administrative reasons or protocol violations.
Losartan Dosage and Concomitant Antihypertensive
Therapy
Blood Pressure Reductions
The mean (±SD) baseline SiSBP/SiDBP in groups 1, 2, and 3 were
159.0±20.6/98.2±7.0, 160.7±23.2/100.4±7.3, and
163.7±19.3/103.3±6.9 mm Hg, respectively. Significant
decreases from baseline in trough SiDBP and SiSBP were observed in all
groups beginning at week 1 and continuing throughout therapy
(P
To further evaluate the BP-lowering efficacy of losartan in
this study, a separate analysis was done to determine the
antihypertensive effect of losartan in patients with mild and
moderate hypertension. Losartan was effective, regardless of
renal impairment group, in both mild (90 to 104 mm Hg) and
moderate (105 to 115 mm Hg) hypertensive subjects.
There was no consistent effect of age, sex, or race on the mean
reductions from baseline at week 12 in trough SiDBP among the three
renal insufficiency groups. While reductions in peak sitting BP were
also apparent in this study, the decreases in peak SiSBP/SiDBP after
the first dose of losartan were mild, averaging only
-5.6/-4.4 mm Hg in all patients.
Safety and Tolerability
Effects on Renal Function and Proteinuria
Of the subset of 11 patients in whom clearance studies for GFR and ERPF
were performed, 5 were in the mild renal insufficiency group and 6 were
in the moderate to severe renal insufficiency group. The mean age was
65.3±4.0 years; 9 were males, 3 were black, and 2 were diabetic. Two
patients were on losartan 50 mg and 9 patients were on
losartan 100 mg at the time of the second set of clearance
studies. Mean GFR was 34.1±3.6 mL/min per 1.73
m2 (mean±SE) at baseline and 33.8±6.1 mL/min
per 1.73 m2 after 8 weeks of losartan
treatment (P=NS). ERPF (n=10) was also not significantly
changed from baseline to 8 weeks of losartan treatment, with
mean values of 128.4±23.6 and 136.7±26.5 mL/min per 1.73
m2, respectively (P=NS). As noted
previously, the ERPF determination was not performed on 1 patient at
week 8.
There was a statistically significant reduction of
Overall, there were no clinically meaningful changes in the mean values
of laboratory parameters indicative of renal function (ie,
creatinine, BUN) during the course of the study. There were
fluctuations of 0.03 to 0.22 mmol/L (0.3 to 2.5 mg/dL) in serum
creatinine throughout the study. Sustained increases in
serum creatinine ranging from 0.04 to 0.18 mmol/L (0.5
to 2.0 mg/dL) were apparent in 10 patients; however, no corresponding
changes in creatinine clearance were observed in these
patients. Furthermore, no patients were discontinued due to increases
in serum creatinine. One patient with type I diabetes
progressed to end-stage renal failure requiring dialysis and
experienced a gradual increase in serum creatinine of
0.38 mmol/L (4.3 mg/dL) by the end of the study. This patient
entered the study with a baseline creatinine clearance of
12 mL/min per 1.73 m2, a serum
creatinine of 0.68 mmol/L (7.7 mg/dL), and a urine
protein excretion rate of
Other Laboratory Measurements
Mean changes in serum uric acid concentrations of -0.068 to 0.013
mmol/L (-1.153 to 0.211 mg/dL) were observed after 12 weeks of
treatment. Less than 10% of patients in any of the three renal
insufficiency groups experienced an increase from baseline to the final
study visit in serum uric acid of >0.12 mmol/L (2.0 mg/dL); 32%
of patients in group 3 had a decrease in serum uric acid of >0.12
mmol/L (2.0 mg/dL) (P
Only minor decreases were seen in hemoglobin (mean changes in three
groups ranged from 0.012 to 0.065 mmol/L [0.077 to 0.419 g/dL])
and hematocrit (-0.0043 to -0.015 [-0.432 to -1.470%]) at the
final study visit in each group. There were no reports of anemia, and
no patients were discontinued due to decreased hematocrit.
The mechanism of hypertension in chronic renal disease is complex and
involves a number of factors, including volume expansion and
vasoconstriction. The present study shows that selective antagonism
of the angiotensin II (AT1) receptor
subtype with losartan lowers BP in patients with renal
insufficiency and provides support for the importance of
angiotensin II in regulating BP in chronic renal failure.
The precise mechanism by which BP is reduced in this patient population
is not elucidated by this study; however, it is possible that
inhibition of angiotensin II receptors on vascular tissue
and in the kidney, heart, and sympathetic nervous system contribute to
the antihypertensive effect. Further studies are necessary to establish
the primary site of action for losartan's BP-lowering activity
in chronic renal failure and to determine whether its effect is
achieved through a direct action on peripheral resistance
or by a reduction in the increased sympathetic nervous system activity
observed in end-stage renal disease.20
The primary goal of this study was to determine the ability of
losartan to lower BP in patients with chronic renal
insufficiency. Losartan's effect on renal function was also
studied by determination of the 24 hour creatinine
clearance in all 69 patients in groups 1 and 2. Overall, treatment with
losartan for 12 weeks did not produce any significant change in
mean creatinine clearance among these patients.
Furthermore, in a subset of patients in which GFR and ERPF were
measured, no significant differences in the mean values during the
placebo baseline period and after 8 weeks of losartan treatment
were found. This subset of patients was similar to the mild and
moderate-to-severe renal insufficiency groups as a whole, and thus it
can be inferred that no significant changes in GFR or ERPF were induced
by losartan in these hypertensive patients with renal
impairment. In individual patients, increases or decreases in
creatinine clearance, GFR, or ERPF during the treatment
period were observed. Whether these changes are clinically significant
and whether they result from alterations in BP, renal
hemodynamics, concomitant medications, or progression
of disease cannot be ascertained from this study.
Some patients experienced an acute, transient rise in serum
creatinine during the study; however, overall trends in
creatinine clearance in these patients were maintained for
the duration of the study. In the study, all samples for serum
creatinine were collected
The
Losartan was generally well tolerated in this study, with only
four patients withdrawing because of a clinical adverse experience.
Headache was the most common adverse experience in the overall study
population and was reported with a similar incidence in all three renal
groups. Despite effectively reducing BP by the end of the first week of
treatment, losartan did not induce first-dose hypotension, even
among hemodialysis patients. The decreases in SiSBP and SiDBP 5 to
8 hours after the initial dose were mild, averaging only -4 to
-5 mm Hg in the mild renal insufficiency group, -5 to
-7 mm Hg in the moderate renal insufficiency group, and
-4 mm Hg in the hemodialysis group. Although hypotension
prompted withdrawal of two patients who were receiving therapy with
losartan 50 mg, neither episode was considered severe and
neither required treatment. There were no reports of first-dose
hypotension or angioedema.
Only minor changes in serum potassium were apparent at weeks 4, 8, and
12 in hemodialysis and nonhemodialysis patients. Eighteen percent of
the total study population experienced an increase in serum potassium
levels of >0.5 mmol/L by the end of the study, and only one
patient had an elevation in serum potassium that resulted in premature
withdrawal. However, the majority of these patients experienced
fluctuations in serum potassium during the treatment period that were
well within the normal range. It is expected that compounds that block
the RAAS can potentially increase serum potassium. Additionally,
hyperkalemia is not uncommon among patients with
compromised renal function, and patients with severe renal dysfunction
have been reported to be more susceptible to potassium retention
brought on by changes in dietary potassium intake or
endogenous factors,26 as well as
blockade of the RAAS.
Minor decreases in serum uric acid were noted during the treatment
period, which is consistent with the modest hypouricemic effect
of losartan that has been previously observed in clinical
studies with hypertensive patients treated with
losartan.27
Anemia is a well recognized complication of advanced renal disease
because of a diminution of the production of
erythropoietin.28 It has been suggested that
angiotensin II plays an important role in erythropoietin
production and that RAAS blockade in patients with compromised
production of erythropoietin, such as those with renal
insufficiency, can result in further reductions in hemoglobin and
hematocrit. Only minor decreases were observed in hemoglobin and
hematocrit with losartan treatment in this study, and there
were no adverse experiences or premature withdrawals as a result of
anemia.
The purpose of the present study was to gain experience with the
new angiotensin II receptor antagonist
losartan in patients with different degrees of renal
impairment. A limitation of the this study is the absence of a
comparative placebo-treated group. This study was not designed with a
placebo control arm, in that withholding antihypertensive treatment
from hypertensive patients with moderate to severe renal impairment and
those patients on hemodialysis would not be considered ethical, since
adequate BP control is essential.
In summary, the results of this 12-week study suggest that
losartan, administered at an initial dose of 50 mg once daily
and subsequently titrated to 100 mg, is highly effective in lowering BP
and is generally well tolerated in a hypertensive population with mild
to severe chronic renal insufficiency. In some patients, its efficacy
is enhanced by addition of a diuretic and/or other
antihypertensive agents. In addition, the BP-lowering effect of
losartan is accompanied by a significant reduction in
proteinuria in patients with chronic renal insufficiency.
Losartan may play an important role in the management of
hypertension in patients with various degrees of renal impairment due
to its efficacy and favorable tolerability profile.
Received December 19, 1996;
first decision February 18, 1997;
accepted October 1, 1997.
© 1998 American Heart Association, Inc.
Scientific Contributions
Efficacy and Tolerability of Losartan in Hypertensive Patients With Renal Impairment
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
Abstract—We evaluated the blood
pressure–lowering activity, tolerability, and safety of
losartan in 112 hypertensive (sitting diastolic
blood pressure, 90 to 115 mm Hg) patients with chronic renal
insufficiency including mild renal insufficiency (30 to 60 mL/min per
1.73 m2; n=51), moderate to severe renal insufficiency (10
to 29 mL/min per 1.73 m2; n=33), or hemodialysis (n=28).
After a 3-week placebo period, once-daily losatan was administered for
12 weeks. The daily dose of 50 mg was increased to 100 mg after 4 weeks
in patients whose sitting diastolic blood pressure remained
90 mm Hg or was reduced by <5 mm Hg. A second,
non–angiotensin-converting enzyme inhibitor,
antihypertensive drug was added after 8 weeks as needed.
Twenty-four–hour creatinine clearance was determined and
renal clearance studies of inulin and para-aminohippurate were done in
a subset of 11 patients. Trough sitting blood pressures were reduced at
the end of the first week in all groups. At weeks 4, 8, and 12, the
reductions in systolic blood pressure/diastolic
blood pressure averaged -11.9/-8.7, -10.8/-9.4, and
-14.7/-12.1 mm Hg in patients with mild renal
insufficiency; -7.7/-6.3, -13.1/-11.8, and -14.1/-10.6
mm Hg, in moderate to severe renal insufficiency; -17.0/-12.7,
-19.1/-14.4, and -22.7/-18.0 mm Hg in hemodialysis.
Creatinine clearance, glomerular filtration
rate, and effective renal plasma flow were stable. Losartan was
withdrawn in only 6 patients because of a clinical or laboratory
adverse experience. Hyperkalemia (>6 mEq/L) requiring
discontinuation of losartan occurred in only one (group 2)
patient. We conclude that once-daily losartan, given as
monotherapy at doses of 50 or 100 mg or in combination with other
antihypertensive drugs, was effective in reducing blood pressure in
hypertensive patients with chronic renal disease and that
losartan regimens were well tolerated in all groups, including
those on hemodialysis.
Key Words: losartan • angiotensin II • renal insufficiency • hemodialysis • renin-angiotensin-aldosterone system
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
Hypertension is a
major contributor to the progression of chronic renal
diseases1 2 3 4 and is present in most patients
with progressive renal disease and in all individuals with hypertensive
nephrosclerosis. Together, diabetic
nephropathy and hypertensive
nephrosclerosis account for nearly two thirds of the
new cases of end-stage renal disease in the United
States.5 Moreover, hypertension is an important
contributing factor to morbidity and mortality among hemodialysis
patients.5 6 7 Clinical studies in these patient
populations indicate that BP control plays a critical role in slowing
the progression of disease and may even prevent progression in some
patients with hypertensive
nephrosclerosis.3 8 9 10
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
This multicenter, open-label study was conducted at 18 clinical
centers in the United States. Institutional Review Board approval was
obtained from each center and all patients gave their informed consent.
All procedures performed in this study were conducted in accordance
with institutional guidelines.
Adult (age >21 years) male and female outpatients with a
diagnosis of hypertension associated with impaired renal function were
screened for enrollment. Patients with known or suspected renal artery
stenosis were excluded from participation. If eligible, all
current antihypertensive medications were withdrawn and patients
underwent a complete physical examination including medical history,
chest radiograph, ECG, and laboratory safety testing. Patients were
given 3 weeks of placebo treatment. Those with a trough SiDBP between
90 and 115 mm Hg at the end of the placebo baseline period
and whose CLcr after 3 weeks of placebo therapy
was 
60 mL/min per 1.73 m2 were eligible to
receive treatment with losartan. Patients were classified into
three groups on the basis of their baseline CLcr:
group 1 (mild renal insufficiency: CLcr of 30 to
60 mL/min per 1.73 m2); group 2 (moderate to
severe renal insufficiency: CLcr of 10 to 29
mL/min per 1.732); and group 3
(hemodialysis).
The study consisted of a 3-week placebo baseline period followed
by a 12-week, open-label active treatment period in which patients
received losartan once daily in the morning administered at a
starting dose of 50 mg. Hemodialysis patients who underwent morning or
early afternoon dialysis received losartan after dialysis on
these days and at approximately that same time on all other days. After
4 weeks of losartan therapy, patients whose trough SiDBP
remained at 90 mm Hg or whose trough SiDBP was <90
mm Hg but did not experience 5 mm Hg reduction from
baseline had their daily dose titrated to losartan 100 mg.
After 4 weeks of therapy with losartan 100 mg, patients who
continued to show inadequate BP control (ie, SiDBP 90 mm Hg
or <5 mm Hg decrease from baseline) had an additional
antihypertensive agent added to their daily losartan regimen.
The choice of the second antihypertensive drug was left to the
investigator's discretion with the stipulation that ACE
inhibitors were not to be used; dosage adjustments of the
second drug were permitted to optimize BP control after 2 weeks.
BP measurements were obtained with the use of a mercury
sphygmomanometer. The protocol provided specific, standardized steps
for all centers to follow in performing all sitting and standing BP
measurements for both trough and peak throughout the study. Trough
measurements were taken 22 to 26 hours after the prior day's dose; and
peak measurements were taken 5 to 8 hours after the day's dose.
Analyses were not performed or predefined in the protocol to
assess precision, reproducibility, and variation of BP measurements
within a center and among centers.
A subset of 11 nondialysis patients, enrolled from 3 centers,
underwent renal clearance studies at the end of the placebo baseline
period and after 8 weeks of treatment with losartan alone.
Clearance of inulin and PAH were performed to measure GFR and ERPF,
respectively.19 (One patient did not undergo the
ERPF measurement at week 8.) Patients presented fasting on the
morning of the study, after having taken their placebo or
losartan dose. They were water-loaded orally and with D5W
intravenously to 20 mL/kg or until a urine specific gravity
of 1.010 was achieved. Priming doses of inulin and PAH were given in
an intravenous bolus, followed by continuous infusions. The
infusion rate was adjusted for the patient's estimated GFR as assessed
by creatinine clearance in order to maintain an approximate
plasma concentration of 40 µmol/L (20 mg/dL) inulin and
92.5 µmol/L (2 mg/dL) PAH. After a 60-minute equilibration
period, four 30-minute urine collections were obtained with plasma
samples taken at the midpoint of each collection. Urine losses were
replaced with water (mL/min) orally. Plasma and urine samples for PAH
were determined by AutoAnalyser (Technicon); inulin samples were
assayed according to the method of Walser et
al.19 The values obtained from each collection
period were averaged, and GFR and ERPF were calculated as [(urine
concentration of inulin or PAH/plasma concentration of inulin or
PAH)xurine flow rate (mL/min)]. Each were corrected for 1.73
m2 body surface area. Results during the baseline
period were compared with results after 8 weeks of losartan
therapy by paired t test.
Changes from baseline in trough and peak SiDBP and SiSBP
were evaluated. Mean changes from baseline within each renal impairment
group were analyzed with a paired t test. All
patients with at least one active treatment period BP measurement were
included in the efficacy analyses; the last measurement of
withdrawn patients was carried forward to subsequent time points.
Additionally, changes from baseline in trough SiDBP at week 12 were
analyzed in demographic subgroups stratified according to age
(65/<65 years), sex, race (black/nonblack), or baseline hypertensive
category (<105/105 mm Hg). .05
(two-sided).
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
Patient Characteristics
Of the 112 patients enrolled in this study, 51 had mild renal
insufficiency (CLcr: 30 to 60 mL/min per 1.73
m2), 33 had moderate renal insufficiency
(CLcr: 10 to 29 mL/min per 1.73
m2), and 28 had end-stage renal disease requiring
hemodialysis. Table 1
presents the
baseline and demographic characteristics of patients in each group as
well as for the entire patient population.
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Table 1. Baseline and Demographic Characteristics
Among the 93 patients who completed 12 weeks of active treatment,
BP was controlled in 47 (50%) patients while on losartan
monotherapy. Among these patients, 26 (28%) were maintained on
losartan 50 mg. BP was controlled in the remaining 46 (50%)
patients with losartan and another antihypertensive agent(s).
There were no significant differences among the three renal
insufficiency groups in the distribution of patients who were
maintained on losartan monotherapy or were given concomitant
therapy involving a second antihypertensive drug (Table 2). The most frequently used second
antihypertensive agents were diuretics (n=24, 52%), of which
furosemide was the most commonly prescribed, and calcium channel
blockers (n=12, 26%), of which nifedipine (regular or
sustained release formulations) was the most frequently given.
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Table 2. Distribution of Patients According to Study Therapy
Eight patients were not included in the analyses of trough
BP because of missing valid baseline or posttreatment values. Data from
the remaining 104 patients who received therapy, excluding 1 patient in
group 2 who initially received treatment with losartan 100 mg
rather than 50 mg, were included in the analyses of trough BP
changes. .05). Fig 1 and 2 illustrate mean trough SiDBP and SiSBP
measurements at baseline and weeks 1, 4, 8, and 12 of active treatment
for the three groups. Mean changes in standing BP were similar to
changes observed in sitting BP. Twenty-four–hour urine sodium
excretion rate in group 1 averaged 166 mEq at baseline and did not
change significantly during the study (4 weeks, 164 mEq; 8 weeks, 173
mEq; and 12 weeks, 160 mEq). Similarly, in group 2 patients, urine
sodium at baseline was 115 mEq and was not significantly different
during the study (4 weeks, 128 mEq; 8 weeks, 135 mEq; and 12 weeks, 126
mEq). Therefore, the hypotensive effect of losartan in this
study was not dependent on very low sodium intake rates.
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Figure 1. Mean reduction from baseline in trough sitting
diastolic blood pressure after 1, 4, 8, and 12 weeks of
losartan therapy. CrCl indicates creatinine
clearance. *P .05.
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Figure 2. Mean reduction from baseline in trough sitting
systolic blood pressure after 1, 4, 8, and 12 weeks of
losartan therapy. CrCl indicates creatinine
clearance. *P .05.
Twenty-seven percent (n=30) of the total population reported
clinical adverse experiences that were considered by the investigator
to be possibly or probably related to study treatment. Those clinical
adverse experiences that were reported by 4% of patients in any one
renal insufficiency group are presented in Table 3 (the number of clinical adverse
experiences reported under "All Patients" does not
represent the total of the three groups). The occurrence of
hypotension, nausea, and cough appeared to be associated with the
degree of renal impairment as significantly more hemodialysis patients
reported these adverse experiences compared to patients with mild renal
insufficiency (P.05). It is unlikely that the three
reports of cough among hemodialysis patients are treatment related
because there was a higher incidence of respiratory complaints (ie,
dyspnea, allergic rhinitis, chronic obstructive pulmonary
disease) at study entry among patients in this group. Two patients with
moderate renal impairment reported flank pain during the study; neither
of these episodes were considered related to study treatment and
neither was associated with hematuria or increases in uric acid
excretion, serum creatinine, or BUN. Hypotension prompted
the early withdrawal of one patient each in groups 2 and 3, and two
additional patients in group 3 were discontinued because of skin rash
and dizziness, respectively.
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Table 3. Clinical Adverse Experiences Reported by at Least
4% of Patients in Any One Group
Mean creatinine clearances in groups 1 and 2 were not
significantly changed from the respective baseline values of 45.3 and
20.5 mL/min per 1.73 m2 after 12 weeks of therapy
(Table 4). There was, however, large
variability in the individual responses during treatment, and two
patients in group 2 experienced reductions in creatinine
clearance that were reported as adverse experiences. In both of these
patients, creatinine clearances returned toward baseline
values during continued losartan treatment.
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Table 4. Mean Changes From Baseline to Week 12 in
Creatinine Clearance 
23% in 24-hour
urine protein excretion relative to baseline after 12 weeks of
treatment in both the mild (2991 to 2307 mg/24 hours; mean decrease of
-684 mg/24 hours) and moderate to severe (3692 to 2795 mg/24 hours;
mean decrease of -897 mg/24 hours) renal insufficiency groups
(P.05). The time course of changes in the urine protein
excretion rate are shown in Fig 3 for
both groups.
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Figure 3. Mean changes from baseline in 24-hour urine
protein excretion rate after 1, 4, 8, and 12 weeks of losartan
therapy. Clcr indicates creatinine clearance. 14 g/24 hours. This event was not
considered related to losartan treatment and was considered a
natural progression of the patient's underlying disease process.
In the total population, laboratory abnormalities that were
considered drug related by the investigator were reported in 18
patients (16.5%). However, only 2 patients were discontinued because
of laboratory adverse experiences; a patient in group 2 was
discontinued because of hyperkalemia and a patient in
group 3 because of increased liver enzymes. Laboratory
parameters of specific interest in this study were the
magnitude of changes in serum concentrations of potassium, uric acid,
hemoglobin, and hematocrit. In each renal insufficiency group, only
small changes in mean serum potassium (-0.024 to 0.113 mmol/L;
P=NS) were observed. The proportion of patients exhibiting a
decrease in serum potassium of >0.5 mmol/L from baseline to the
final study visit ranged from 8% to 18%; the proportion of patients
having >0.5 mmol/L increase in serum potassium likewise ranged
from 15% to 23%. As mentioned previously, one patient in group 2 was
discontinued because of hyperkalemia. .05).
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
The results of this study demonstrate that the
angiotensin II receptor antagonist
losartan, administered once daily at doses of 50 or 100 mg, is
effective in lowering BP in hypertensive patients with varying degrees
of chronic renal insufficiency. Significant reductions in trough SiDBP
and SiSBP were apparent as early as the first week of treatment with
losartan 50 mg in patients with mild to severe renal
insufficiency and in patients requiring hemodialysis. The significant
reductions in BP were achieved with one half of the study population
remaining on monotherapy with losartan 50 or 100 mg throughout
the 12-week treatment period. The remaining 50% of patients were
treated with losartan 100 mg and other antihypertensive agents
during the last 4 weeks of the study; in the majority of these patients
the second antihypertensive drug was a diuretic. Although the
present study was not designed to answer the question of whether
100 mg per day of losartan was more effective than 50 mg per
day, we found that 21 of 67 (31%) patients titrated to 100 mg per day
were "controlled" on monotherapy. This finding suggests that nearly
one-third patients with hypertension and chronic renal insufficiency
may respond to the higher dose level. 24 to 30 hours after the start
of the 24-hour urine collection. Therefore, it is possible that the
creatinine clearances differed from serum
creatinine because of discrepancies in timing of sample
collection, collection error, or other random variation. 23% reduction in 24-hour urine protein excretion that
accompanied losartan therapy in this study was statistically
significant and is consistent with observations that blockade
of the RAAS reduces protein excretion in patients with
proteinuria.21 22 23 The results are also in
agreement with previous reports that losartan significantly
decreased protein excretion among patients with nephrotic range
proteinuria, whereas the glomerular filtration rate was
maintained.24 25 The antiproteinuric effects of
losartan in this study population were not the result of a
reduction in renal function as creatinine clearance was
essentially maintained at the end of the 12-week treatment period. In
addition, the fact that losartan lowered BP in patients with
chronic renal insufficiency (groups 1 and 2) whose average sodium
intake was about 3.5 g per day indicates that its antiproteinuric
effect is not dependent on a low sodium intake.
Selected Abbreviations and Acronyms
ACE
=
angiotensin-converting enzyme
BP
=
blood pressure
Clcr
=
creatinine clearance
ECG
=
electrocardiogram
ERPF
=
effective renal plasma flow
GFR
=
glomerular filtration rate
PAH
=
para-aminohippurate
RAAS
=
renin-angiotensin-aldosterone system
SiDBP
=
sitting diastolic blood pressure
SiSBP
=
sitting systolic blood pressure
Acknowledgments
We would like to acknowledge the following clinical
investigators who constitute the Collaborative Study group: John Bauer,
University of Missouri Health Science Center, Columbia; Barry Brenner,
Brigham and Women's Hospital, Boston; Vito Campese, University of
Southern California Medical Center, Los Angeles; Robert Davidson,
University of Washington Medical Center, Seattle; Annette Fitz, VA
Medical Center, Iowa City; Martin Gregory, University of Utah Hospital,
Salt Lake City; William Keane, Hennepin Medical Center, Minneapolis;
Francisco Llach, VA–Wadsworth Medical Center, Los Angeles; Daniel
O'Connor, VA Medical Center, La Jolla; Ronald Smith, Dallas
Nephrology Clinical Research Institute; Laura Svetky, Duke
University Medical Center, Durham; Nosratola Vaziri, University of
California Irvine Medical Center, Orange; John Wallin, Louisiana State
University School of Medicine, New Orleans; Lawrence Weisberg, Cooper
Hospital University Medical Center, Camden; Thomas Wiegmann, VA
Medical Center, Kansas City; Mark Williams, Joslin Diabetes Center and
New England Deaconess Hospital, Boston.
Footnotes
1 Members of the Collaborative Study group are listed in "Acknowledgments." 
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
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