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(Hypertension. 1997;30:168-176.)
© 1997 American Heart Association, Inc.
Articles |
Intrarenal Determinants of Sodium Retention in Mild Heart Failure
Effects of Angiotensin-Converting Enzyme Inhibition
From 1a Clinica Medica (M.V., M.A.E.R., S.C., I.E., B.G., B.T., M.C.) and Cattedra di Nefrologia (P.M., L.D., B.M.), Università Federico II, Naples, Italy; Istituto Neurologico Mediterraneo NeuroMed (M.V., A.F.M., S.R.), Pozzilli, Italy; Nephrology Section (M.E.), Department of Veterans Affairs Medical Center, Miami, Fla; and Dipartimento di Medicina Sperimentale e Patologia (M.V.), Università La Sapienza, Rome, Italy.
Correspondence to Prof Massimo Volpe, MD, 1a Clinica Medica, Federico II University, via Pansini, 5, 80131 Napoli, Italy. E-mail volpema{at}cds.unina.it
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Abstract The onset and the mechanisms leading to Na+ retention in incipient congestive heart failure (CHF) have not been systematically investigated. To investigate renal Na+ handling in the early or mild stages of CHF, Na+ balance and renal clearances were assessed in 10 asymptomatic patients with idiopathic or ischemic dilated cardiomyopathy and mild heart failure (HF) off treatment (left ventricular ejection fraction, 29.7±2%) and in 10 matched normal subjects during a diet containing 100 mmol/d of NaCl and after 8 days of high salt intake (250 mmol/d). Six patients were studied again after 6 weeks of treatment with enalapril (5 mg/d PO). At the end of the high salt diet, in patients with mild HF the cumulative Na+ balance exceeded by 110 mmol that of normal subjects (F=3.86, P<.001). During high salt intake, renal plasma flow and glomerular filtration rate were similarly increased in both normal subjects and mild HF patients. In spite of comparable increases of filtered Na+ in the two groups, fractional excretion of Na+, fractional clearance of free water, and fractional excretion of K+ (indexes of distal delivery of Na+) increased in normal subjects and were reduced in patients with mild HF. During enalapril treatment, in the mild HF patients the cumulative Na+ balance was restored to normal; furthermore, enalapril significantly attenuated the abnormalities in the distal delivery of Na+. Our results indicate that a defective adaptation of Na+ reabsorption in the proximal nephron is associated with Na+ retention in response to increased salt intake in the early or mild stages of HF. These abnormalities of renal Na+ handling are largely reversed by enalapril.
Key Words: cardiomyopathy • kidney • natriuretic peptides • catecholamines • renin-angiotensin system
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Introduction |
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The impaired ability to excrete ingested Na+ is an essential feature of patients with CHF.1 2 3 4 The initial mechanisms responsible for the abnormal renal Na+ retention observed in CHF have not been fully defined. A fundamental problem in the attempts to identify the cause of this abnormality is the lack of studies that adequately characterize the effects of varying dietary Na+ intake on the hemodynamic, hormonal, and metabolic profiles of patients with CHF. Furthermore, most of the studies have been performed in patients with severe CHF, some of whom were receiving concomitant diuretic therapy.1 2 3 In spite of the need for controlled studies, which has been reiterated over the last 4 decades in a number of editorials and studies,1 4 5 6 7 only fragmentary information concerning the mechanisms and the onset of renal Na+ retention in patients with mild or incipient CHF is available.
Milder stages or forms of CHF may provide more suitable models for the investigation of this issue in humans. Barger et al6 in 1959 stated that "the preoccupation with the late stages of the disease, and with the role of the kidney in the production of edema in patients with CHF, has tended to obscure the evidence that changes in Na+ and water metabolism are present in heart disease at a time when the cardiovascular system is only slightly impaired." This statement was substantiated by the same authors in an experimental dog model8 and more recently by our group in patients with DCM who exhibited asymptomatic to mildly symptomatic HF in the absence of signs or symptoms of congestion.9 10 We were able to detect in patients with mild HF a reduced ability to excrete a moderate Na+ load, which is associated with early impairment of cardiac hemodynamic and endocrine adaptations.9 The renal mechanisms underlying these responses, however, were not explored.
The present study was designed to extend our earlier observations and to investigate the effects of a moderate increase in dietary salt intake on both renal handling of Na+ and concomitant changes in salt-regulating hormones in patients with DCM and mild HF. The study was repeated after a 6-week treatment with the ACE inhibitor enalapril.
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Methods |
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Study Subjects and Patients
The study population included 10 patients with chronic, stable, mild HF and no signs or symptoms of congestion. The patients were recruited in the outpatient clinic of our institution for treatment of cardiovascular diseases. Ten normal volunteers were also studied. All subjects gave written informed consent before participation in the study, which was approved by the ethical committee of our institution. Normal status was established by history, physical examination, and laboratory analyses, which included a complete blood count, serum glucose and cholesterol concentrations, plasma protein electrophoresis, indexes of liver and renal function (blood urea nitrogen, serum creatinine and electrolytes, creatinine clearance, and complete urinalysis), a chest radiograph, M- and B-mode echocardiograms, and ultrasonography of the kidneys and bladder. The normal group comprised 7 male and 3 female subjects aged 45±4 years (range, 23 to 58 years). The patients with HF were those fulfilling the inclusion criteria enrolled consecutively from the outpatient clinic during 1994. They included 8 male and 2 female subjects aged 51±2 years (range, 38 to 61 years). The cause of HF was idiopathic DCM in 4 patients and coronary artery disease in 6 patients. Patients were considered to have idiopathic DCM when no obvious underlying cause of HF could be discovered during the clinical evaluation, which also included coronary angiography. The diagnosis of coronary artery disease was based on the documentation of at least one myocardial infarction and/or on the result of coronary angiography.
Exclusion criteria included angina pectoris, myocardial infarction
within the previous 3 months, systemic arterial
hypertension, atrial fibrillation or severe ventricular
arrhythmias, renal failure or serum creatinine
levels 
1.2 mg/dL, alteration of urinalysis, diabetes, recent
acute cardiac decompensation as defined by the sudden onset of
pulmonary congestion or peripheral edema,
valvular disease or significant mitral
regurgitation, cardiothoracic anatomy not
allowing satisfactory and reproducible recording of the
echocardiogram, diseases of kidneys or prostate or bladder, and
previous treatment with diuretics.
The definition of mild HF was based on the criteria outlined below.
Patients showed no reduction in their functional capacity (class I
according to the New York Heart Association
classification11 ), and there was mild-to-moderate
limitation of exercise capacity, as determined by
cardiopulmonary exercise testing using a standard protocol
(upright bicycling with a stepwise increase of 10 W/min). Mean exercise
duration was 8.9±0.8 minutes. Peak oxygen consumption averaged
16.2±1.9 mL · kg-1 ·
min-1. In all patients,
echocardiographic end-diastolic left
ventricular diameter exceeded 55 mm (mean,
64.6±1.6 mm), and left ventricular ejection fraction,
as determined by radionuclide technique, was <50% (mean, 29.7±2.2%)
on at least one measurement within 3 months before the study. The
individual demographic and clinical characteristics of the patients who
completed the study are presented in Table 1
. Previous treatment included nitrates
in 7 patients, and ACE inhibitors in 9 patients; 2 patients
had never been treated before.
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Experimental Protocol
All drug therapy was discontinued, and patients were kept off
treatment for at least 3 weeks before the beginning of the study.
Alcohol, caffeine, cigarettes, and physical exercise were all
prohibited within 48 hours from the beginning and throughout the study.
Patients were admitted to the metabolic ward, where
accurate assessment of daily weights (in the morning before breakfast),
total fluid intake and output, and the timing and completion of all
24-hour urine collections were controlled by research personnel. An
accurate daily record was kept of fluid, Na+,
K+, protein, and caloric intake. All subjects received a
daily diet containing 100 mmol Na+, 50 mmol
K+, 65 g protein, 50 g fat, 270 g
carbohydrate, and 100 mg phosphorus in the form of pasta, meat, fish,
eggs, bread, vegetables, fruit, milk, and sugar. Personal food
preferences were allowed as much as possible, and all meals were
prepared by the institution kitchen. Water intake was kept between 1500
and 1800 mL/d.
Urinary volume and electrolyte excretion were measured daily on urine collections obtained beginning at 7 AM and ending at 7 AM on the next day. To ensure that Na+ balance was being achieved, urine collections were promptly analyzed for urinary volume and electrolyte excretion, and creatinine and urea clearances were calculated. The achievement of Na+ balance was demonstrated by the lack of differences in Na+ excretion over the last 3 days of the 100 mmol Na+ diet. For the purpose of data analysis, the 24-hour urine collection that ended on the morning of the study of renal function (the last day of the 100 mmol Na+ diet) was used as a baseline. After 6 days on this diet, blood samples were taken for the baseline biochemical and hormonal measurements, and radionuclide assessment of cardiac function was performed. Subsequently, renal clearances were performed. All these measurements were obtained with the patient sitting in a comfortable chair. A daily Na+ supplement of 150 mmol (three doses of 50 mmol crystalline Na+ chloride, each wrapped in wafers administered during the meals) was then added to the diet for 8 days. Consumption of NaCl tablets was checked daily by the research personnel. Urinary volume and electrolyte excretion were measured daily, and hormonal measurements and renal clearances were performed again on day 8 of the high salt regimen.
To evaluate the effects of ACE inhibition, in 6 of the patients with mild HF the same experimental protocol was repeated after 6 weeks of effective treatment with enalapril (Merck & Co, Inc) (5 mg/24 h). This dosage of enalapril, in fact, caused inhibition of ACE, as shown by significant increases of PRA (from 2.2±0.2 to 4.9±0.7 ng · mL-1 · h-1, P<.05). The efficacy of this dosage of enalapril is also supported by previous data12 showing that 2.5 mg of the drug is sufficient to cause >80% inhibition of ACE activity in plasma and to effectively inhibit angiotensin I pressor response. The drug was administered every night at 8 PM.
M- and B-mode echocardiograms were recorded for measurements of ventricular dimensions at baseline. Body weight and peripheral hematocrit were measured daily. Biochemical parameters including serum electrolytes, total proteins, albumin, blood urea nitrogen, and creatinine clearances were measured at the end of the low salt diet period and on days 4 and 8 of the high salt diet. Plasma levels of ANP and BNP (not measured in the ACE-inhibited group), PRA and PA concentrations, and PNE levels were measured at the end of each dietary period.
Renal Clearances
Studies of renal function were started at 8:30 AM
after an overnight fast for all patients. The temperature (22°C) and
the lights of the study room were maintained at constant levels. Renal
clearances were performed at baseline (ie, when equilibrium was
achieved on the 100 mmol Na+ diet) and after 8 days of
250 mmol/d of Na+ intake. Renal function
studies were performed during a state of water diuresis in
order to assess the tubular function of the proximal
nephron.13 14 In fact, the subjects received a water
loading of 10 mL/kg body wt of drinking water over a 60-minute period.
At 9:30 AM, blood was taken via a cannula previously
introduced into an antecubital vein for measurement of hematocrit,
proteins, osmolality, basal PAH, and inulin. Subsequently, a priming
bolus of PAH (0.05 mL/kg of 20% PAH diluted in 50 mL of 5% glucose
solution) and inulin (0.5 mL/kg of a 10% solution) was given,
immediately followed by a constant infusion of a solution containing
1.25 mL of 10% inulinx(creatinine clearance) and 0.0625
mL of 20% PAHx(creatinine clearancex5) diluted in 500 mL
of 5% glucose. This infusion yields plasma concentrations of 20 and 4
mg/dL, respectively. A 45-minute equilibration was allowed
before starting the measurements; at the end of this period, subjects
were asked to void their bladders. Three 30-minute renal clearance
periods were observed with subjects voiding their bladders at 30-minute
intervals. Urine and blood samples were collected at each interval for
determination of PAH, inulin, electrolytes, and osmolality. Urine and
blood losses were replaced throughout the study via a cannula placed in
the contralateral antecubital vein. BP, measured by the
sphygmomanometric technique, following the recommendations of the
American Heart Association,15 and HR were measured at
30-minute intervals.
Calculations
GFR (mL/min) and RPF (mL/min) were estimated from clearances of
inulin and PAH, respectively, and were corrected by body surface area.
Clearance is defined as U · V/P, where U is urinary
concentration, V is urinary volume, and P is the mean plasma
concentration between the start point and the end point of that period.
The renal parameters were calculated as previously
reported16 : RPF was calculated as PAH clearance/ PAH
extraction ratio, where the PAH extraction ratio was assumed to be
0.8517 ; RBF (mL/min), RPF/(1-Hct); RVR (mm Hg ·
mL-1 · min-1),
mean arterial pressure/RBF; FENa (%),
Na+ clearance/GFR; CH2O (mL/min), total urine
volume-osmolar clearance (mL/min); FCH2O (%),
CH2O/GFR; FLNa (mmol/min), GFRxplasma
Na+ (mmol/L); and FEK (%),
K+ clearance/GFR.
Laboratory Methods
Blood samples for plasma ANP and BNP and for PNE measurements
were collected in prechilled tubes containing EDTA and spun immediately
(within 10 minutes); blood samples for measurements of PRA and PA
concentrations were collected at room temperature. The plasma was then
separated and frozen until the time of the assay, which did not exceed
4 weeks. PRA was measured by enzymatic assay, as previously
described.18 The sensitivity of the assay is 50 pg per
tube angiotensin I; intra-assay and interassay variability
coefficients were 6% and 10%, respectively. PNE assay was performed
with reverse-phase high-performance liquid
chromatography as previously described by our
laboratory.19 ANP and BNP were extracted from plasma with
Sep-Pak C18 cartridges (Amersham International Ltd). Plasma
immunoreactive ANP levels were determined by RIA as previously
described by our laboratory.20 Intra-assay and interassay
variation coefficients were 6.8% and 10.1%, respectively. The RIA
sensitivity was 1 fmol per tube. The anti–hBNP-32 antibody used was
generated against synthetic hBNP-32 (Peninsula Laboratories). A portion
(100 µL) of reconstituted BNP extract was incubated in duplicate with
100 µL of anti–hBNP-32 antibody at 4°C for 24 hours. Then
125I-hBNP-32 (
8000 cpm) was added, mixed, and incubated
at 4°C for 20 hours. The minimal detectable quantity in the RIA was
0.5 fmol per tube. Intra-assay and interassay coefficients of variation
were 5.8% and 14.8%, respectively. The range of percent recoveries
for radiolabeled 125I-hBNP-32 with this assay was >70%.
PA concentrations were measured by a RIA technique using a commercial
kit (Diagnostic Product Corp). K+ and
Na+ levels in urine were measured by ion-selective
electrodes (Beckman E2A Na/K system). Osmolarity was determined by
using a standard micro-osmometer.
Statistical Analysis
Data are presented as mean±SEM. Analysis of
data was performed with a commercial statistical package (Systat for
Windows rel.5, SYSTAT Inc). Distribution of data was assessed by the
Bartlett test. 
2 Analysis was used for
comparison of descriptive parameters. Comparisons of the
basal data of the different groups were performed by unpaired
t test or Wilcoxon signed-rank test, as appropriate.
One-way ANOVA for repeated measures followed by post hoc
analysis based on linear contrasts was performed to detect
changes over time within the same group. Between-group comparisons of
the responses were tested by two-way ANOVA (factoring by group and
time).
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Results |
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Characteristics of the Study Groups
The two study groups (normal subjects and patients with mild HF) were comparable with regard to demographic and clinical characteristics and renal function. In contrast, basal left ventricular ejection fraction and peak filling rate were significantly depressed in patients with mild HF (Table 2
).
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As shown in Fig 1, basal PRA and PA
concentrations were not different in the two study groups, whereas
plasma ANP and BNP levels were significantly elevated in patients with
mild HF. Venous PNE was not significantly different in the two groups
at baseline (normal subjects, 218±93 pg/mL; mild HF patients,
345±118 pg/mL).
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P<.05 vs the
corresponding value for normal subjects.
Hemodynamic and Hormonal Responses to High
Salt Diet
The increase of Na+ dietary intake from 100 to
250 mmol/d was not accompanied by significant changes in HR
in either group (normal subjects, from 66.8±4.1 to 67.5±3.9 bpm on
day 8; patients with mild HF, from 70.4±3.4 to 70.8±2.3 bpm; one-way
ANOVA: P=NS in both groups) and
systolic/diastolic BP (normal subjects, from
115.6±5.4/75.8±2.1 to 115.6±4.9/78.8±3.3 mm Hg, both
P=NS; mild HF, from 113.5±5.8/76.5±3.1 to
114.5±3.0/79.0±2.3 mm Hg, both P=NS).
As shown in Fig 1
, PRA and PA concentrations significantly fell to a
similar extent in both groups in response to increased salt intake. In
contrast, significant increases of plasma ANP and BNP levels were
observed only in normal subjects, whereas these hormones remained
unchanged in patients with HF during high Na+ intake.
Venous PNE did not change significantly in either group during high
salt diet (normal subjects, 241±81 pg/mL on day 8; mild HF,
281±109 pg/mL; P=NS).
Effects of High Salt Diet on Fluid and Na+
Balance
At the beginning of high salt diet, the two groups showed similar
values of peripheral hematocrit (0.408±0.015 in normal
subjects and 0.416±0.008 in patients with HF), total serum proteins
(67.3±0.8 and 69.4±1.7 g/L, respectively), and urinary volume.
These findings demonstrate that volume and hydration state as well as
nutritional status did not differ in the two groups at baseline.
Fig 2 shows the effects of high salt
intake on UNaV and cumulative Na+ balance in
the two groups. The 8-day high salt intake produced significant
increases of UNaV in both groups. However, the small and
systematic differences in UNaV observed along the study
resulted in a higher cumulative Na+ balance in patients
with mild HF (+338±39 mmol on day 8) than in normal subjects
(+228±28 mmol) (two-way ANOVA: F=3.86, P<.001). In
particular, although normal subjects achieved equilibrium around day 4,
patients with mild HF continued to retain Na+ throughout
the high salt diet. It can be estimated that equilibrium was achieved
in normal subjects at the expense of an extracellular volume expansion
of 1.6 L, whereas in patients with mild HF a larger volume expansion
(2.4 L) was not sufficient to restore Na+ balance within
the time frame of the study.
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Accordingly, in patients with mild HF, the larger Na+ retention was associated with a greater hemodilution, as demonstrated by the more marked decrements of peripheral hematocrit, which fell to 0.384±0.013 on day 4 and to 0.395±0.011 on day 8 in normal subjects (F=8.98, P<.05), and to 0.390±0.007 and 0.385±0.007, respectively, in patients with mild HF (F=22.7, P<.001; two-way ANOVA: F=30.1, P<.05).
Body weight did not change significantly in either group (from 69.3±2.4 to 69.1±2.3 kg in normal subjects; from 66.0±2.4 to 66.2±2.2 kg in patients with mild HF). The lack of changes in body weight, however, may reflect the influence of the dietary regimen maintained during the hospitalization.
Clearance Studies and Renal Na+ Handling
All renal dynamic studies were performed in a state of maximal
water diuresis as indicated by the low values of urinary
osmolality. Urinary osmolalities were not significantly different in
the two groups on either low and high salt intake (normal subjects,
75.3±13.3 and 71.3±5.4 mOsm/kg H2O, respectively;
patients with mild HF, 93.4±17.2 and 105.4±25.7 mOsm/kg
H2O). Consistently, there were no significant
differences between the two groups on both salt regimens in urinary
volume (normal subjects, from 11.4±1.0 to 12.0±1.3 mL/min; patients
with mild HF, from 9.6±0.7 to 9.8±0.7 mL/min), plasma osmolality
(normal subjects, from 290.8±4.1 to 284.8±4.1 mOsm/kg
H2O; patients with mild HF, from 285.5±2.2 to 288.0±2.7
mOsm/kg H2O), osmolar clearance (normal subjects, from
2.8±0.3 to 2.8±0.2 mL/min; patients with mild HF, from 2.8±0.5 to
3.0±0.3 mL/min), and CH2O (normal subjects, from 8.4±0.9
to 9.6±1.0 mL/min; patients with mild HF, from 7.6±0.7 to 7.7±0.6
mL/min).
As shown in Fig 3, during high
Na+ diet, GFR increased in patients with mild HF
(P<.01) and in normal subjects (P<.01).
Comparable significant increases in RPF were observed after high salt
intake in both groups. Because the increases in GFR and RPF were
comparable, the filtration fraction remained unchanged in both groups
(from 23.4±1.7% to 22.9±1.5% in patients with mild HF; from
20.2±0.9% to 20.8±0.9% in normal subjects).
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RBF rose in patients with mild HF (from 851.7±61.6 to 968.0±70.9
mL/min, P<.001) and normal subjects (from 877.4±57.0 to
930.7±65.8 mL/min, P<.05) during high salt intake (Fig 3).
Since mean arterial BP was unmodified in both groups during
clearance studies, RVR showed comparable decreases in the two groups
during high salt diet (Fig 3).
As shown in Fig 4, with the increased
supply of dietary Na+, FENa increased in normal
subjects and was reduced in patients with mild HF (two-way ANOVA:
F=4.70, P<.05). This finding was not dependent on
alterations of FLNa, since this parameter
increased by the same extent in both groups (Fig 4). As also shown in
Fig 4, during high salt diet, FCH2O and FEK
increased in normal subjects and decreased in patients with mild HF so
that, on the last day of high salt regimen, both these
parameters were lower in patients with mild HF than in
normal subjects (two-way ANOVA: F=10.03, P<.01 and F=38.34,
P<.001, respectively).
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The parallel changes in FCH2O and FEK, obtained in a state of maximal water diuresis, indicate that distal delivery of Na+ increased in normal subjects and decreased in patients with mild HF, thus suggesting that the reabsorption of Na+ at the proximal nephron level was decreased in normal subjects and increased in patients with HF.
Effects of ACE Inhibition
In 6 of the patients with mild HF, the effects of high salt intake
on renal Na+ handling were assessed again during chronic
treatment with enalapril. In these patients, systolic and
diastolic BP and HR (118.2±9.4/76.3±6.3 mm Hg and
70.1±3.2 bpm, respectively) were similar to those measured in the
untreated group at baseline and did not change significantly during the
high salt diet (116.3±6.4/77.2±4.0 mm Hg and 69.0±2.4 bpm,
respectively). In the patients treated with enalapril, left
ventricular ejection fraction was not significantly
different from the value measured before treatment (33.8±1.9% and
32.6±2.3%, P=NS). ANP plasma levels were not modified by
ACE-inhibition (31.3±8.4 pg/mL) but increased significantly
during high salt intake (44.8±8.0 pg/mL). PRA was increased
significantly by enalapril (4.9±0.7 ng ·
mL-1 · h-1)
and was suppressed by 41.5±21.2% during high salt diet. Finally, PNE
was 231±78 and 221±51 pg/mL in the group of patients treated
with enalapril before and after the high salt diet, respectively.
As shown in Fig 5, a significant
natriuretic response was also induced in these subjects by
salt loading (F=17.7, P<.001). However, analysis of
cumulative Na+ balance showed that equilibrium was achieved
in the group treated with enalapril (no further significant changes
occurred after day 4 on high salt diet), so that their response was
statistically comparable to that observed in the control subjects but
different from that recorded in the untreated group (F=2.074,
P<.05). In particular, the net cumulative Na+
balance was 240±43 mmol. From these data, it can be estimated
that extracellular volume expansion was 1.7 L in the ACE-inhibited
patients, a value that is quite similar to that detected in normal
subjects under the same dietary conditions.
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In the patients treated with enalapril, the renal
hemodynamic response to high salt diet was comparable
to those responses observed in the other two study groups. In fact, RPF
and RBF increased (from 439.3±7.7 to 472.7±11 mL/min,
P<.05, and from 757.8±13.8 to 791.2±15.6,
P<.05, respectively), and RVR decreased (from 0.124±0.005
to 0.120±0.005 mm Hg ·
mL-1 · min-1,
P<.05). GFR, shown in Fig 6, also increased in these patients after
high salt intake, whereas the filtration fraction remained unchanged
(from 21.9±1.7% to 24.8±1.1%). As also shown in Fig 6, enalapril
treatment was associated with increases of both FLNa and
FENa in response to high salt regimen. In particular,
FLNa showed an increase comparable to that observed in
normal subjects but different from that detected in the untreated group
(two-way ANOVA: F=4.98, P<.05). In the patients receiving
enalapril, FEK increased significantly (Fig 6) compared
with that in normal subjects, and FCH2O tended to increase
in response to high salt intake (from 0.128% to 0.130%), although
statistical significance was not achieved. However, two-way ANOVA
showed a significant difference also in the behavior of
FCH2O in enalapril-treated patients compared with the
untreated patients (F=8.62, P<.05 and F=24.13,
P<.001, respectively), whereas no difference was found in
enalapril-treated patients compared with the normal subjects. These
findings indicate that in the ACE-inhibited patients, after high salt
diet, distal delivery of Na+ increased as in the normal
subjects.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The present study demonstrates that deranged renal Na+ handling associated with Na+ retention is an early hallmark of HF. In particular, our studies, based on a controlled moderate increase of Na+ intake in untreated patients with DCM and mild HF with no signs or symptoms of congestion, reveal an enhancement of Na+ reabsorption in the proximal nephron in response to the volume expansion associated with high salt intake. This contrasts markedly with the expected reduction in proximal nephron reabsorption of Na+ that we observed in normal subjects. This defective renal adaptation to salt excess is associated with a greater Na+ retention (
100 mmol) and more
marked extracellular volume expansion (0.8 L) in the patients with
mild HF. Furthermore, the present study demonstrates that treatment
with enalapril restored the natriuretic response and
impeded the increase in proximal reabsorption of Na+ in the
patients with mild HF. In spite of the widespread recognition that an impairment in Na+ excretion complicates the clinical course of CHF, the initial mechanisms underlying abnormal renal Na+ retention remain incompletely defined. In advanced CHF, RBF and GFR decline as the kidneys participate in the vasoconstrictive response to diminished cardiac output.21 22 In contrast, normal values of GFR have been observed in patients with milder degrees of HF.23 Also, our patients with mild HF showed normal values of RPF and GFR on low Na+ intake and exhibited an augmentation of these parameters, as well as reductions of RVR, similar to those observed in normal subjects in response to high salt intake. These observations indicate that the adjustments of RPF and GFR secondary to expansion of blood volume are preserved in these patients and rule out the potential contribution of impaired adaptations of renal perfusion or function to increased Na+ dietary supply in the genesis of Na+ retention in the early stage of HF.
Since filtered Na+ was similar to that observed in normal subjects, a derangement of tubular Na+ handling is most likely involved in the pathogenesis of Na+ retention in the patients with mild HF. In accord with this formulation, an overriding importance of increased tubular reabsorption of Na+ in HF was postulated by Barger et al,8 who observed also that dogs with experimental CHF failed to excrete a salt load infused directly into the renal artery.5 Subsequent studies by Bennett et al24 performed in patients with severe CHF and marked extracellular fluid volume expansion before and after administration of diuretics demonstrated inappropriately enhanced proximal Na+ reabsorption for any given level of extracellular fluid volume.
The present results confirm and extend to mild HF those observations and demonstrate that whereas in normal subjects volume expansion due to increased Na+ intake was associated with a reduction in the tubular reabsorption of Na+, in patients with mild HF this mechanism was impaired.
Our present results show that in normal subjects, as expected, the
augmented Na+ intake promoted volume expansion and
increased UNaV through increases of RPF and GFR that led to
increased filtered Na+ without affecting systemic
hemodynamics. This adaptation permitted us to achieve a
new Na+ balance at the expense of an extracellular volume
expansion of 1.6 L.
In order to define more precisely the site of the abnormality in tubular Na+ reabsorption, our studies were performed in a state of maximal water diuresis. In this regard, our findings indicate that the conditions achieved were reasonably stable and that the two experimental groups displayed a comparable state of maximal diuresis during both clearance studies, as indicated by the lack of significant differences in urinary osmolality, plasma osmolality, osmolar clearance, urinary volume, and CH2O. The parallel increases of FCH2O and of FEK, which reflect an increment of distal Na+ delivery, indicate a reduction of Na+ reabsorption at the proximal nephron level.13 14 25 26 On the other hand, the suppression of PRA and PA and the increase of natriuretic peptides may suggest reduction of Na+ reabsorption at the distal level also. A contribution of this latter mechanism cannot be excluded by our present data.
In patients with mild HF, augmented Na+ intake produced a
greater volume expansion (of 2.4 L) related to a significantly
higher cumulative Na+ balance (+338 mmol on day 8).
This was not due to abnormalities in the response of either systemic
(BP and HR were unchanged as in normal subjects) or renal
hemodynamics (GFR, RPF, and, consequently,
FLNa, increased as in normal subjects). In contrast, it is
likely that the inability to adequately raise Na+ excretion
is dependent on a tubular defect. Indeed, a decrease rather than an
increment of FENa was observed despite the presence of a
progressive and even greater volume expansion, which was not sufficient
to restore external Na+ balance within the time frame of
the study.
Although the present study cannot elucidate completely the exact site and the intrinsic mechanisms mediating Na+ retention in these patients, our findings, obtained in a state of maximal water diuresis, strongly indicate that the defect is localized at the proximal nephron level. Indeed, we detected decreases of both FCH2O and FEK during increased salt intake in the patients with mild HF. This reflects a reduced distal Na+ delivery and, thus, an increment in the proximal nephron reabsorption of Na+. The postulated impaired adaptation at the proximal level is not dependent on variations of the Starling or physical forces, because the filtration fraction did not change, as also observed in normal subjects. Again, we cannot completely rule out concomitant alterations in the distal reabsorption of Na+ or a potential redistribution of intrarenal blood flow from superficial to juxtamedullary proximal tubules. In particular, the capacity of the diluting segment to transport Na+ could not be tested in the present study, since distal Na+ delivery was decreased and achieved very low levels in the patients with mild HF during the high salt diet.
The contrasting responses in the release of ANP and BNP in the two experimental groups may account in part for the differing adaptations of tubular reabsorption of Na+ to increased salt intake. Indeed, in concert with previous findings from studies in experimental animal models of severe CHF27 and in patients with mild HF,9 10 28 plasma ANP levels increased significantly in response to high salt diet in normal subjects only and not in the patients with mild HF. Because ANP has been reported to promote renal Na+ excretion through indirect and/or direct effects on tubular Na+ reabsorption, at both the proximal29 30 31 and the distal level,32 33 34 35 the lack of the physiological increase of ANP in the cardiopathic patients suggests that an impaired cardiac endocrine response may contribute to the abnormal renal handling of Na+. Indeed, increased plasma ANP levels induced by exogenous infusion in these patients can enhance Na+ excretion.10 Furthermore, the potential contribution of atrial hormones in maintaining the natriuretic response in the patients with mild HF is also supported by the observation that restoration of the cardiac endocrine response by ACE inhibition was accompanied by a normal natriuretic response.
Favorable effects of ACE inhibitors have been shown on hemodynamics, progression of disease, and survival36 37 in patients with mild HF. Therefore, we considered it relevant to determine whether and how ACE inhibitors may influence the renal adaptations to increased salt intake at this stage of the disease. Our results show that a short course of treatment with enalapril, at a dosage that did not significantly affect cardiac and systemic hemodynamics in our patients, was able to restore Na+ balance and prevent Na+ retention in these patients. Concomitantly, this treatment impeded the decrease of distal Na+ delivery, ie, the enhancement of Na+ reabsorption at the proximal nephron level, observed in the patients with mild HF during high salt intake.
The beneficial effects of ACE inhibition on renal Na+ handling suggest an involvement of the RAS in mediating the renal Na+ retention in these patients. A possible contribution of the circulating RAS in the retention of Na+ and water in the more advanced stages of patients with CHF is supported by a number of studies.2 3 However, in milder or earlier stages of the disease, previous investigators38 and our laboratory9 10 28 failed to observe activation or impaired regulation of the RAS. Our present data do not support an involvement of the circulating RAS in the pathogenesis of Na+ retention, since similar suppressions of PRA and PA concentrations were produced by high salt diet in normal subjects and in patients with HF. However, we cannot exclude the possibility that local changes of angiotensin II intrarenal concentrations may play a permissive role in causing increased proximal reabsorption of Na+.39 40 The lack of increases of ANP after a high salt diet might enhance the angiotensin II–induced proximal reabsorption of Na+ in the patients with mild HF.
The investigation of renal handling of Na+ in patients with mild or initial HF may have some important advantages. The long history of the disease, in fact, precludes repeated detailed studies from the onset of asymptomatic cardiac abnormalities to the time that overt failure appears. In addition, because of the multiple cardiovascular and neurohormonal defects, studies in patients with advanced CHF provide relatively little help in the understanding of the mechanisms by which alterations in cardiac function lead to abnormalities in Na+ excretion. The experimental approach used in our present study circumvents many of these confounding variables. In particular, the exposure to salt loading may unmask an early predisposition to retain Na+ in the milder stages of the disease.
Although the present results cannot define a potential role of the altered renal adjustments to high salt intake in the further development of the disease toward overt congestion, our findings highlight the need for an early identification and therapeutic management of salt retention in patients with left ventricular dysfunction.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was partially supported by Italian National Research Council grant 91.00128.PF41 (targeted project, "Prevention and Control of Disease Factors"; subproject, "Cardiomyopathies"). The authors wish to thank Prof Giuseppe Conte for the critical reading of the manuscript and Dr Biagio Ungaro for his technical collaboration.
Received August 7, 1996; first decision September 3, 1996; accepted January 6, 1997.
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Braunwald E, Plauth WH Jr, Morrow AJ. A method for detection and quantification of impaired sodium excretion: results of an oral sodium tolerance test in normals and in patients with heart disease. Circulation. 1965;32:223-231.
2. Ayers CR, Bowden RE, Schrank JP. Mechanisms of sodium retention in congestive heart failure. Adv Exp Med Biol. 1972;17:227-243.
3. Chonko AM, Bay WH, Stein JH, Ferris TF. The role of renin and aldosterone in salt retention of edema. Am J Med. 1977;63:881-889.[Medline] [Order article via Infotrieve]
4. Cody RJ, Covit AB, Schaer GL, Laragh JH, Sealey JE, Feldschuh J. Sodium and water balance in chronic congestive heart failure. J Clin Invest. 1986;77:1441-1452.
5. Barger AC. The pathogenesis of sodium retention in congestive heart failure. Metabolism. 1956;5:480-489.[Medline] [Order article via Infotrieve]
6.
Barger AC, Muldowney FP, Liebowitz MR.
Role of the kidney in the pathogenesis of congestive heart
failure. Circulation. 1959;20:273-285.
7. Hamilton RW, Buckalew VM Jr. Sodium, water, and congestive heart failure. Ann Intern Med. 1984;100:902-903.
8. Barger AC, Ross RS, Price HL, Roe BB. Reduced sodium excretion in dogs with mild valvular lesion of the heart, and in dogs with congestive failure. Am J Physiol. 1955;180:249-260.
9. Volpe M, Tritto C, DeLuca N, Rubattu S, Rao MAE, Lamenza F, Mirante A, Enea I, Rendina V, Mele AF, Trimarco B, Condorelli M. Abnormalities of sodium handling and of cardiovascular adaptations during high salt diet in patients with mild heart failure. Circulation. 1993;88(pt 1):1620-1627.
10. Volpe M, Tritto C, DeLuca N, Mele AF, Lembo G, Rubattu S, Romano M, deCampora P, Enea I, Ricciardelli B, Trimarco B, Condorelli M. Failure of atrial natriuretic factor to increase with saline load in patients with dilated cardiomyopathy and mild heart failure. J Clin Invest. 1991;88:1481-1489.
11. Criteria Committee of the New York Heart Association. Nomenclature and Criteria for Diagnosis of Disease of the Heart and Blood Vessels. Boston, Mass: Little Brown & Co; 1973:286.
12. Biollaz J, Burnier M, Turini GA, Brunner DB, Pochet M, Gomez HJ, Jones KH, Ferber F, Abrams WB, Gavras H, Brunner HR. Three new long acting converting enzyme inhibitors: relationship between plasma converting-enzyme activity and response to angiotensin I. Clin Pharmacol Ther. 1981;29:665-670.[Medline] [Order article via Infotrieve]
13. Conte G, DalCanton A, Sabbatini M, Napodano P, DeNicola L, Gigliotti G, Fuiano G, Testa A, Esposito C, Russo D, Andreucci VE. Acute cyclosporine renal dysfunction reversed by dopamine infusion in healthy subjects. Kidney Int. 1989;36:1086-1092.[Medline] [Order article via Infotrieve]
14. Cianciaruso B, Bellizzi V, Capuano A, Bovi G, Nastasi A, Conte G, DeNicola L. Short-term effects of low protein-normal sodium diet on renal function in chronic renal failure. Kidney Int. 1994;45:852-860.[Medline] [Order article via Infotrieve]
15.
Kirkendall MW, Burton MC, Epstein FM, Freis ED.
Recommendations for human blood pressure determination by
sphygmomanometers. Circulation. 1967;36:980-986.
16. Sturrock NDC, Lang CC, Baylis PH, Struthers AD. Sequential effects of cyclosporine therapy on blood pressure, renal function and neurohormones. Kidney Int. 1994;45:1203-1210.[Medline] [Order article via Infotrieve]
17. Chan AYM, Cheng MLL, Keil LC, Majers BD. Functional response of healthy and diseased glomeruli to a large, protein-rich meal. J Clin Invest. 1988;81:245-254.
18. Preibisz JJ, Sealey JE, Aceto RM, Laragh JH. Plasma renin activity measurements: an update. Cardiovasc Rev Rep. 1982;5:787-804.
19.
Trimarco B, Lembo G, Ricciardelli B, DeLuca N, Rendina
V, Condorelli GL, Volpe M. Salt-induced plasticity in
cardiopulmonary baroreceptor reflexes in salt-resistant
hypertensive patients. Hypertension. 1991;18:483-493.
20.
Volpe M, Lembo G, Condorelli GL, DeLuca N, Lamenza F,
Indolfi C, Trimarco B. Converting enzyme inhibition prevents the
effects of atrial natriuretic factor on
arterial baroreflexes. Circulation. 1990;82:1214-1221.
21. Merrill DJ. Edema and decreased renal blood flow in patients with chronic congestive heart failure: evidence of forward failure as the primary cause of edema. J Clin Invest. 1946;25:389-396.
22. Cody RJ, Ljungman S, Covit AB, Kubo SH, Sealey JE, Pondolfino K, Clark M, James G, Laragh JH. Regulation of glomerular filtration rate in chronic congestive heart failure patients. Kidney Int. 1988;34:361-367.[Medline] [Order article via Infotrieve]
23.
Kilcoyne MM, Schmidt DH, Cannon PJ. Intrarenal
blood flow in congestive heart failure. Circulation. 1973;47:786-797.
24. Bennett WM, Bagby GC, Antonovic JN, Porter JA. Influence of volume expansion on proximal tubular sodium reabsorption in congestive heart failure. Am Heart J. 1973;1:55-64.
25. Seldin DW, Eknoyan G, Suki WN, Rector FC. Localization of diuretic action from the pattern of water and electrolyte excretion. Ann N Y Acad Sci. 1966;139:328-342.[Medline] [Order article via Infotrieve]
26. Cianciaruso B, Bellizzi V, Minutolo R, Colucci G, Bisesti V, Russo D, Conte G, DeNicola L. Renal adaptation of dietary sodium restriction in moderate renal failure resulting from chronic glomerular disease. J Am Soc Nephrol. 1996;7:306-313.[Abstract]
27.
Redfield MM, Edwards BS, McGoon MD, Heublein DM, Aarhus
LL, Burnett JC. Failure of atrial natriuretic factor
to increase with volume expansion in acute and chronic congestive heart
failure in the dog. Circulation. 1989;80:651-657.
28.
Volpe M, Tritto C, DeLuca N, Rubattu S, Mele AF, Lembo
G, Enea I, deCampora P, Rendina V, Romano M, Trimarco B, Condorelli
M. Angiotensin converting enzyme inhibition restores
cardiac and hormonal responses to volume overload in patients with
dilated cardiomyopathy and mild heart
failure. Circulation. 1992;86:1800-1809.
29. Atlas SA, Cody RJ, Camargo MJF, Pecker MS, Volpe M, Laragh JH. Atrial natriuretic factor and its role in circulatory physiology. In: Edwards CRW, Lincoln DW, eds. Recent Advances in Endocrinology and Metabolism. London, UK: Churchill Livingstone; 1989:281-313.
30. Cody RJ, Atlas SA, Laragh JH, Kubo SH, Covit AB, Ryman KS, Shaknovich A, Pondolfino K, Clark M, Camargo MJF, Scarborough RM, Lewicki JA. Atrial natriuretic factor in normals and heart failure patients: plasma levels and renal, hormonal and hemodynamic responses to peptide infusion. J Clin Invest. 1986;78:1362-1374.
31. DeNicola L, Romano G, Memoli B, Cianciaruso B, Sabbatini M, Russo D, Caglioti A, Fuiano G, DalCanton A, Conte G. Extra-natriuretic effects of atrial peptide in humans. Kidney Int. 1993;43:307-313.[Medline] [Order article via Infotrieve]
32. Legault L, Cernacek P, Levy M, Maher E, Farber D. Renal tubular responsiveness to atrial natriuretic peptide in sodium-retaining chronic caval dogs: a possible role for kinins and luminal actions of the peptide. J Clin Invest. 1992;90:1425-1435.
33. Margulies KB, Cavero PG, Seymour AA, Delaney NG, Burnett JC Jr. Neutral endopeptidase inhibition potentiates the renal actions of atrial natriuretic factor. Kidney Int. 1990;38:67-72.[Medline] [Order article via Infotrieve]
34.
Cavero PG, Margulies KB, Winaver J, Seymour AA, Delaney
NG, Burnett JC Jr. Cardiorenal actions of neutral
endopeptidase inhibition in experimental congestive
heart failure. Circulation. 1990;82:196-201.
35. Schmitt F, Martinez F, Ikeni A, Savoiu C, Natov S, Laborde K, Lacour B, Grunfeld JP, Hannedouche T. Acute renal effects of neutral endopeptidase inhibition in humans. Am J Physiol. 1994;267(pt 2):F20-F27.
36. Konstam MA, Kronenberg MW, Udelson JE, Kinan D, Metherall J, Dolan N, Edens T, Hove D, Kilcoyne L, Benedict C, Youngblood M, Berrett J, Yusuf S for the SOLVD Investigators. Effectiveness of preload reserve as a determinant of clinical status in patients with left ventricular systolic dysfunction. Am J Cardiol. 1992;69:1591-1595.[Medline] [Order article via Infotrieve]
37.
Konstam MA, Kronenberg HW, Rousseau ME, Udelson JE,
Melin J, Stewart D, Dolan N, Edens TR, Ahn S, Kinan D, Howe DM,
Kilcoyne L, Metherall J, Benedict C, Yusuf F, Pouleur H for the SOLVD
Investigators. Effects of angiotensin converting enzyme
inhibitor enalapril on the long-term progression of left
ventricular dilatation in patients with
asymptomatic systolic dysfunction.
Circulation. 1993;88:2277-2283.
38. Kubo SH. Neurohormonal activation and the response to converting enzyme inhibitors in congestive heart failure. Circulation. 1990;2(suppl III):III-107-III-113.
39. Liu FY, Cogan MG. Angiotensin II stimulates early proximal bicarbonate absorption in the rat by decreasing cyclic adenosine monophosphate. J Clin Invest. 1989;84:83-91.
40. DeNicola L, Thomson SC, Wead LM, Brown MR, Gabbai FB. Arginine feeding modifies cyclosporine nephrotoxicity in rats. J Clin Invest. 1993;92:1859-1865.
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