The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 4 1665-1671
Copyright © 2001 by The Endocrine Society
Close Association of Urinary Excretion of Aquaporin-2 with Appropriate and Inappropriate Arginine Vasopressin-Dependent Antidiuresis in Hyponatremia in Elderly Subjects1
San-e Ishikawa,
Takako Saito,
Akinori Fukagawa,
Minori Higashiyama,
Tomoatsu Nakamura,
Ikuyo Kusaka,
Shoichiro Nagasaka,
Kazufumi Honda and
Toshikazu Saito
Division of Endocrinology and Metabolism, Department of Medicine,
Jichi Medical School, Tochigi 329-0498 Japan
Address all correspondence and requests for reprints to: San-e Ishikawa, M.D., Division of Endocrinology and Metabolism, Department of Medicine, Jichi Medical School, 3311-1 Yakushiji Minamikawachi Tochigi 329-0498 Japan. E-mail: saneiskw{at}jichi.ac.jp
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Abstract
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The present study was undertaken to determine whether urinary excretion
of aquaporin-2 (AQP-2) participates in the involvement of arginine
vasopressin (AVP) in hyponatremia less than 130 mmol/L in 33 elderly
subjects (
65 yr old) during the last 5-yr period. Subjects
were separated into euvolemic hyponatremia groups: 13 with
hypopituitarism, 8 with syndrome of inappropriate secretion of
antidiuretic hormone (SIADH), 8 with mineralocorticoid-responsive
hyponatremia of the elderly, and 4 with miscellaneous diseases.
Approximately 40% of those with hyponatremia was derived from
hypopituitarism, but severe hyponatremia was found in the patients
with SIADH and mineralocorticoid-responsive hyponatremia of the
elderly. Plasma AVP levels remained relatively high despite
hypoosmolality and were tightly linked with exaggerated urinary
excretion of AQP-2 and antidiuresis in the 3 groups of patients, except
for one miscellaneous one. An acute water load test verified the
impairment in water excretion, because the percent excretion of the
water load was less than 42% and the minimal urinary osmolality was
not sufficiently diluted. Also, plasma AVP and urinary excretion of
AQP-2 were not reduced after the water load. The inappropriate
secretion of AVP was evident in the patients with SIADH and
hypopituitarism, and hydrocortisone replacement normalized urinary
excretion of AQP-2 and renal water excretion in those with
hypopituitarism. In contrast, the appropriate antidiuresis seemed to
compensate loss of body fluid in the patients with
mineralocorticoid-responsive hyponatremia of the elderly, who lost
circulatory blood volume by 7.3% (mean). Fludrocortisone acetate
increased renal sodium handling and body fluid, resulting in the
reduction in AVP release and urinary excretion of AQP-2 in
mineralocorticoid-responsive hyponatremia of the elderly. These
findings indicate that urinary excretion of AQP-2 may be a more
sensitive measure of AVP effect on renal collecting duct cells than are
plasma AVP levels, and that increased urinary excretion of AQP-2 shows
exaggerated AVP-induced antidiuresis in hyponatremic subjects in the
elderly. In addition, mineralocorticoid-responsive hyponatremia of the
elderly has to be carefully differentiated from SIADH in elderly
subjects.
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Introduction
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HYPONATREMIA MAY NOT infrequently occur in
elderly subjects who are usually asymptomatic. In most clinical
settings, there seems neither dehydration nor edema in the hyponatremic
subjects in the elderly; and so, hyponatremia is classified into a
category of euvolemic hyponatremia (1). Because it is not
always easy to evaluate dehydration in elderly subjects by physical
examination, syndrome of inappropriate secretion of antidiuretic
hormone (SIADH) seems to be overdiagnosed in the elderly, hyponatremic
subjects. Nonsuppressible release of arginine vasopressin (AVP),
despite hypoosmolality, produces an increase in antidiuresis in kidney
in the pathological states of impaired water excretion
(2, 3, 4, 5, 6, 7, 8, 9, 10). We have to differentiate an inappropriate
antidiuresis from an appropriate one. In other words, the impairment in
water excretion linked with the inappropriate secretion of AVP results
in dilutional hyponatremia and associated alteration in renal sodium
(Na) handling in SIADH (2, 3, 11). In salt-wasting
syndrome, water retention, dependent on nonosmotic secretion of AVP,
seems likely to compensate loss of body fluid toward the steady-state
(12, 13, 14, 15). We have suggested a group of hyponatremia with
mild depletion of total body fluid in the elderly, and hyponatremia is
well responsive to fludrocortisone acetate, resulting in the
normalization of serum Na levels and total body fluid
(13). There is no activation of renin-aldosterone system,
despite the depletion of body fluid being less than 10%. The disorder
is not similar to classical salt-wasting syndrome and is designated as
mineralocorticoid-responsive hyponatremia of the elderly in the present
study. It is important to differentiate this disorder from SIADH,
because the diagnostic criteria is almost overlapped with that of
SIADH, except for the presence of mild dehydration
(13). This is extremely important because the expected
therapy biflucates. Recently, Ayus and Arieff (16)
reported that water restriction therapy does not always improve the
physical condition in elderly, hyponatremic patients, but instead,
accelerates their mortality.
In the present study, we examined hyponatremia of less than 130 mmol/L
in the elderly subjects during the last 5-yr period. We demonstrated
that hyponatremia in the elderly was classified into euvolemic
hyponatremia to a great extent, and the therapeutic approach verifies
the pathological role of AVP by measuring urinary excretion of
aquaporin-2 (AQP-2).
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Subjects and Methods
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Subjects
Thirty-three elderly subjects having hyponatremia less than 130
mmol/L of serum Na levels were examined between August 1994 and July
1999. We had collected hyponatremic subjects whose ages were 65 yr or
older. They were admitted to the Endocrine and Metabolic Ward of Jichi
Medical School Hospital because of various symptoms closely associated
with hyponatremia. Some patients complained of the disturbance of
consciousness, generalized malaise, nausea or vomiting. The others were
to have further hyponatremia evaluation.
The hyponatremic patients were divided into 4 subgroups, including
SIADH, mineralocorticoid-responsive hyponatremia of the elderly,
hypopituitarism, and miscellaneous diseases. Thirteen patients with
hypopituitarism included 9 with hypopituitarism and 4 with isolated
ACTH deficiency. Their plasma ACTH levels and serum cortisol in the
early morning were as low as 3.1 ± 0.5 pmol/L and 88.3 ±
22.1 nmol/L, respectively. Eight patients with SIADH were diagnosed by
Schwartz and Bartter’s criteria (2). Physical examination
showed neither dehydration nor edema. SIADH occurred in 2 patients with
ectopic production of AVP in lung cancer, 2 patients after cerebral
infarction, 1 patient after head trauma, 1 patient after carbamazepin
abuse, and 2 patients in whom the cause was considered idiopathic. In 8
patients with mineralocorticoid-responsive hyponatremia of the elderly,
there was neither renal nor adrenal dysfunction. ACTH and cortisol were
all within the normal ranges. Physical findings showed mild dry skin
and/or dry tongue in 5 of 8 patients, suggesting the presence of
dehydration. Mineralocorticoid-responsive hyponatremia of the elderly
occurred in 3 patients after head injury, one with collagen disease,
one with primary amyloidosis, and 3 in whom the cause was considered
idiopathic. Three of the 8 patients with mineralocorticoid-responsive
hyponatremia of the elderly could not be differentiated from SIADH
patients, and they were initially diagnosed as having SIADH. They had
restricted water intake (15–20 mL/kg·day) and had taken a high-salt
diet for a couple of weeks, but they had no response to such
treatments. Thereafter, fludrocortisone acetate (0.1–0.2 mg per day)
improved hyponatremia, indicating their diagnosis was changed to
mineralocorticoid-responsive hyponatremia of the elderly
(13). The miscellaneous group included 1 hypothyroidism, 2
furosemide-induced hyponatremia, and 1 Addison’s disease patient. As
mentioned above, the elderly, hyponatremic subjects had been picked in
the Endocrine and Metabolic Ward, and we excluded hyponatremic patients
with edematous diseases, including congestive heart failure, liver
cirrhosis with ascites, and nephrotic syndrome. The reasons were
that there is, in general, hypervolemic hyponatremia more than 130
mmol/L in most of patients with these edematous diseases (17, 18). Also, the diagnosis of the above-mentioned primary
edematous diseases is easy, in which hyponatremia is not critical for
their diagnosis. Also, 16 age-matched normal subjects served as
control. Blood and 1-h urine collections were made at 0900 h to
measure hematocrit, plasma osmolality (Posm), plasma AVP levels, and
urinary excretions of AQP-2 and creatinine. The present study was
approved by the ethical committee of Jichi Medical School Hospital for
human study. We obtained informed consent from all the subjects who
joined in the present protocol.
An acute water loading test was carried out. The patients and seven
control subjects had free access to drinking water until the study.
Water (20 mL/kg) was drunk for 30 min; and thereafter, urine
collections were made at 30-min intervals for 4 h to measure urine
volume, urinary osmolality (Uosm), and urinary excretions of AQP-2 and
creatinine. Also, blood collections were made at 1-h intervals for
4 h to measure Posm and plasma AVP levels.
After the completion of diagnosis, the patients started the specific
treatments. Treatment for the patients with hypopituitarism had been
replaced by hydrocortisone (20–30 mg per day) and those with
mineralocorticoid-responsive hyponatremia of the elderly had been
treated with high-salt diet and fludrocortisone acetate (0.1–0.3 mg
per day) (13). In the patients with
mineralocorticoid-responsive hyponatremia of the elderly and
hypopituitarism serum Na levels, hematocrit, plasma AVP, and urinary
excretion of AQP-2 were determined again at steady-state after the
treatment. We also analyzed hematocrit on admission and at steady-state
after the treatment, and the percent change in circulating blood volume
was calculated by taking data at the steady-state as zero, determined
by the percent changes in hematocrit (Ht): (Ht2
- Ht1)/Ht2 x 100
(13).
Measurements
Blood was collected in chilled tubes containing
EDTA-Na2 (1 mg per mL blood) and centrifuged at
3000 rpm at 4 C for 15 min. The supernatants were decanted and frozen
at -20 C until the time of assay for plasma AVP, aldosterone,
ACTH, and plasma renin activity (PRA). Plasma AVP was measured by RIA
using AVP RIA kits (Mitsubishi Chemistry, Tokyo, Japan)
(6). PRA and plasma aldosterone concentrations were
determined by RIA using PRA RIA kits (Yoshitomi Pharmaceutical Co.,
Osaka) and Aldosterone RIA kits (Dainabott Lab., Tokyo, Japan)
(19, 20), respectively. Plasma ACTH and serum cortisol
were measured by RIA using ACTH RIA kits (Yoshitomi Pharmaceutical Co.)
and Cortisol RIA kits (Dainabott Lab.), respectively. Urinary excretion
of AQP-2 was determined by RIA as described previously in our reports
(21, 22). Posm and Uosm were measured by freezing-point
depression (Model 3W2, Advanced Instruments, Needham Height, MA). The
normal value of plasma AVP is 0.2–2.2 pmol/L; that of PRA, 0.08–0.81
ng/L at supine position; that of plasma aldosterone, 30.5–174.8
pmol/L; that of ACTH, 2.0–11.5 pmol/L; and that of serum cortisol,
110.4–504.9 nmol/L. The normal value of urinary excretion of AQP-2 is
153.8 ± 28.1 fmol/mg creatinine under ad libitum water
drinking conditions (22).
Statistical analysis
All values were expressed as means ± SEM. The
data were analyzed by Student’s t test. A P
value less than 0.05 was considered significant.
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Results
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Table 1
shows the clinical and
laboratory findings in the four groups of patients. According to the
our definition, all the hyponatremic patients were 65 yr or older, and
there was no difference in the ages among the four groups of patients.
Systolic blood pressure was significantly lower in the patients with
mineralocorticoid-responsive hyponatremia of the elderly than those
with SIADH or hypopituitarism. Serum Na levels on admission were as low
as 116.0 ± 2.6 and 114.9 ± 2.3 mmol/L in the patients with
SIADH and mineralocorticoid-responsive hyponatremia of the elderly,
respectively. The severity of hyponatremia was significantly different
among the groups; hyponatremia was more manifest in the groups of SIADH
and mineralocorticoid-responsive hyponatremia of the elderly than those
of hypopituitarism and miscellaneous diseases. On the contrary, serum K
levels elevated to the upper normal range in both groups of
mineralocorticoid-responsive hyponatremia of the elderly and
hypopituitarism, values significantly greater than that of the SIADH
patients. Renal function was normal in all the patients. Serum levels
of uric acid were 154.4 ± 17.8 and 101.0 ± 17.8 µmol/L in
the patients with SIADH and mineralocorticoid-responsive hyponatremia
of the elderly, respectively. They were significantly less than those
in the patients with hypopituitarism and in the miscellaneous group.
Although Posm was extremely low, Uosm remained high (more than 500
mmol/kg in all the four groups of patients) and urinary excretion of Na
was also increased in the four groups. Physical findings revealed mild
dehydration in five out of eight patients with
mineralocorticoid-responsive hyponatremia of the elderly and two
patients with Addison’s disease and furosemide-induced hyponatremia.
No patient had edema.
Figure 1 shows the relationship between
Posm and plasma AVP levels. Closed triangles show their
relationship in the normal subjects (n = 22). The distribution in
the four groups of the hyponatremic patients was totally distinct from
that of the normal subjects. Plasma AVP levels were not suppressed,
despite hypoosmolality, which should be completely suppressed to
undetectable levels in the normal subjects (23). The
exaggerated releases of AVP were plotted in a wide range of the low
Posm, and they were not distinct from one another among the four groups
of patients. However, plasma AVP levels seemed extremely high in two
patients with SIADH dependent on ectopic production of AVP in lung
cancer.
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Figure 1. Relationship between Posm and plasma AVP
levels in five groups of elderly subjects. Closed
circles, SIADH; open circles,
mineralocorticoid-responsive hyponatremia of the elderly; closed
squares, hypopituitarism; open squares,
miscellaneous group; closed triangles, control subjects.
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Figure 2 shows plasma AVP levels and
urinary excretion of AQP-2 in the hyponatremic patients and the control
subjects. Plasma AVP levels seemed to be elevated in the four groups of
patients; but statistically, they were not significantly different from
the control subjects. In contrast, urinary excretion of AQP-2 was
significantly higher in the three groups of patients than that in the
control subjects (n = 16). Urinary excretion levels of AQP-2 were
569.9 ± 162.7, 623.4 ± 127.8, and 352.8 ± 53.6
fmol/mg creatinine in the patients with SIADH,
mineralocorticoid-responsive hyponatremia of the elderly, and
hypopituitarism, respectively.
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Figure 2. Plasma AVP levels and urinary excretion of
AQP-2 (UAQP-2) in four groups of elderly subjects. Open
circles, means ± SEM.
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PRA and aldosterone concentration are shown in Table 2. PRA was low-normal in the patients
with mineralocorticoid-responsive hyponatremia of the elderly and
hypopituitarism, and mid-normal in the SIADH patients. Also, plasma
aldosterone concentrations were normal in these three groups of
patients. In the patients with hypopituitarism, plasma ACTH and serum
cortisol were low. These reduced levels of plasma ACTH seemed to affect
the low concentration of plasma aldosterone.
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Table 2. Plasma renin activity, plasma aldosterone, plasma
ACTH, and serum cortisol in four groups of elderly subjects (values are
means ± SEM)
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The results of an acute oral water load test are shown in Table 3. An acute oral water load (20 mL/kg)
produced water diuresis in the control subjects, as the percent
excretion of the water load was 79.0 ± 4.4% during the 4 h
observation period. The minimal Uosm was as low as 90.6 ± 6.2
mmol/kg, which was responsible for the decrease in plasma AVP levels
after the reduction in Posm (data not shown). In contrast, the percent
excretions of water load were less than 42% in the three groups of
patients, and they were significantly less than that in the control
subjects. The basal levels of Uosm were rather lower in the patient
groups than in the control subjects (P < 0.001), but
the minimal Uosm remained as high as 350 mmol/kg or more in the three
groups of patients, values significantly greater than that in the
control subjects. The impaired water excretion was in concert with the
nonsuppressible levels of plasma AVP, despite hypoosmolality in the
three groups of patients. Basal levels of urinary excretion of AQP-2
were 2- to 4-fold greater in the three groups of patients than in the
control subjects. The maneuver of an acute oral water load gradually
decreased urinary excretion of AQP-2, and its nadir was obtained at
60–90 min (22). The minimal urinary excretion of AQP-2
remained high in the patient groups, and differences were evident
between either of the three groups of patients and the control
subjects.
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Table 3. An acute oral water load test (20 ml/kg BW) in three
groups of elderly subjects with hyponatremia and control subjects
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Changes in serum Na levels and hematocrit and percent changes in
circulatory blood volume before and after the specific treatments are
shown in Table 4. After the treatment
with fludrocortisone acetate, serum Na levels were gradually elevated,
and they normalized in approximately a month in the patients with
mineralocorticoid-responsive hyponatremia of the elderly. Also, the
decrease in circulatory blood volume was 7.3 ± 0.8% below the
normal value on the admission, by calculating the changes in hematocrit
between the time of admission and the time of recovery. In the patients
with hypopituitarism, hydrocortisone therapy normalized serum Na
levels. The circulatory blood volume was reduced by 5.1 ± 1.1%
after the hydrocortisone treatment. In addition, the increase in
circulatory blood volume was 8.2 ± 2.4% over the normal value,
on admission, in the patients with SIADH (n = 6), except for those
with lung cancer.
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Table 4. Changes in serum Na levels and hematocrit and
percent changes in circulatory blood volume (CBV) before and after the
treatments
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Figure 3 shows that the specific
treatments altered plasma AVP levels and urinary excretion of AQP-2 in
the patients with mineralocorticoid-responsive hyponatremia of the
elderly and hypopituitarism. In the patients with
mineralocorticoid-responsive hyponatremia of the elderly, urinary
excretion of AQP-2 was remarkably reduced to below 250 fmol/mg
creatinine at steady-state, in accordance with the decrease in plasma
AVP levels. Hydrocortisone therapy normalized urinary excretion of
AQP-2 in the patients with hypopituitarism, though plasma AVP levels
remained unchanged. Also, the impairment in water excretion totally
disappeared, because the acute water load test verified that the
percent excretion of water load was 105.1 ± 11.9%.
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Figure 3. The reduction in plasma AVP and UAQP-2 in
response to hydrocortisone and fludrocortisone acetate therapy in the
patients with hypopituitarism and mineralocorticoid-responsive
hyponatremia of the elderly, respectively. Open circles,
Patients with hypopituitarism (n = 8); closed
circles, those with mineralocorticoid-responsive hyponatremia
of the elderly [plasma AVP (n = 8), UAQP-2 (n = 4)]. *,
P < 0.01 vs. that before the
treatment. Values are means ± SEM.
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Discussion
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The present study demonstrated moderate and severe hyponatremia
less than 130 mmol/L in the elderly patients whose ages were 65
yr or older. The causes of hyponatremia were divided into the four
groups of SIADH, mineralocorticoid-responsive hyponatremia of the
elderly, hypopituitarism, and miscellaneous diseases. The former three
diseases exert euvolemic hyponatremia, which should have less than
±10% alteration in circulating blood volume (1, 13).
In the present study, plasma AVP levels remained relatively high
despite hypoosmolality, which should suppress plasma AVP to
undetectable levels in normal subjects (23). This
alteration in AVP release played a crucial role in the impaired water
excretion in the present hyponatremic subjects. Also, the exaggerated
antidiuresis was evident because of the disturbance of urinary dilution
in an acute oral water load and the increased urinary excretion of
AQP-2. AQP-2 is an AVP-regulated water channel of renal collecting duct
cells (24). Approximately 3% of the AQP-2 present in
collecting duct cells is excreted into urine (21, 22, 25).
Urinary excretion of AQP-2 has a positive correlation with plasma AVP
levels, and it results from the sum of the AVP release from posterior
pituitary and the hydroosmotic action of AVP in renal collecting duct
cells (26). However, in the hyponatremic subjects with
impaired water excretion, urinary excretion of AQP-2 was much more
manifest than that expected from the plasma AVP levels, compared with
that in the normal subjects (in preparation). In other words, we
recognized that plasma AVP levels were relatively high, compared with
hypoosmolality in the elderly, hyponatremic patients, though the levels
of plasma AVP were almost equivalent to those in the control subjects.
This was much clearly demonstrated by the urinary excretion of AQP-2,
because urinary excretion of AQP-2 accounts for the antidiuretic action
of AVP as an absolute value. The increased urinary excretion of AQP-2
revealed the augmentation of AVP-induced antidiuresis in the three
groups of subjects, but urinary excretion of AQP-2 could not
differentiate the pathological state of appropriate secretion of AVP
from that of inappropriate one. The urinary excretion of AQP-2 in the
patients with SIADH had a response to an acute water load different
from from that of patients with hypopituitarism and
mineralocorticoid-responsive hyponatremia of the elderly. This may be
attributable to the enormous increase in plasma AVP in the SIADH
patients, which was derived from the ectopic production of AVP in lung
cancer.
The key was to evaluate its pathological role in the impaired water
excretion in the hyponatremic patients. They were classified into two
pathological states by determining the appropriate or inappropriate
secretion of AVP. The inappropriate secretion of AVP should be the
major determinant for promoting hyponatremia in the patients with
SIADH and hypopituitarism, because the nonsuppressible release of
AVP causes volume expansion along with renal loss of Na. Several
studies in animal models have suggested that SIADH with prolonged
natriuresis can result in a negative Na balance (27, 28).
An increase in circulatory blood volume was gradually reduced in their
steady-states, and the volume expansion could result in being less than
10% over the normal value. Hyponatremia associated with SIADH and
hypopituitarism was termed as euvolemic hyponatremia (1).
In fact, there was neither edema nor dehydration. As calculated by the
changes in hematocrit, there were 8.2 ± 2.4% and 5.1 ±
1.1% increases in circulatory blood volume over the normal value on
admission in the patients with SIADH and hypopituitarism, respectively.
There is evidence for the involvement of nonsuppressible release of AVP
in water retention in hypopituitarism, particularly in
pituitary-adrenocortical dysfunction (29, 30, 31, 32, 33). The
impaired water excretion is closely linked to the nonsuppressible
levels of plasma AVP (31, 32) and the up-regulation of
AQP-2 messenger RNA expression in glucocorticoid-deficient rats
(34). An AVP V2 receptor antagonist
blocks its up-regulation of AQP-2 gene and normalizes renal water
excretion (34). Also, similar results were obtained with
hydrocortisone replacement in glucocorticoid-deficient rats and
patients with hypopituitarism, i.e. hydrocortisone
replacement normalizes AVP secretion, urinary excretion of AQP-2, and
water diuresis (22, 34, 35).
The appropriate secretion of AVP is implicated in the impaired water
excretion in mineralocorticoid-responsive hyponatremia of the elderly
and furosemide-induced hyponatremia patients. There was a decrease in
circulatory blood volume, which was 7.3 ± 0.8% below the normal
value in the patients with mineralocorticoid-responsive hyponatremia of
the elderly. Physical findings revealed mild dehydration in five out of
eight patients with mineralocorticoid-responsive hyponatremia of the
elderly. The elevation of plasma AVP is therefore suggested to be an
accessory event to maintain circulating blood volume. However, this
change could deteriorate hyponatremia in these pathological states. The
possible mechanisms whereby hyponatremia is worsening in
mineralocorticoid-responsive hyponatremia of the elderly should be
discussed. The renal involvement in Na wasting would have to be the
primary factor for the pathogenesis. There were the findings of low
renin and low aldosterone and reduced renal response to aldosterone in
the elderly patients (12, 13). These alterations could
exert a latent subclinical impairment in renal Na handling. The
findings seem to resemble those in renal tubular acidosis type IV.
However, there is a remarkable difference in clinical manifestation
between mineralocorticoid-responsive hyponatremia of the elderly and
renal tubular acidosis type IV. Namely, hyperkalemia is frequently
found without a decrease in serum Na and an increase in urinary Na
excretion in renal tubular acidosis type IV (36), whereas
hyponatremia should be the major derangement in
mineralocorticoid-responsive hyponatremia of the elderly. As mentioned
earlier, the impaired water excretion takes place relative
increase in circulatory volume, and exaggerates hyponatremia in such a
Nadepleted hyponatremic state. The elevation of urinary excretion
of AQP-2 clearly verified the AVP-dependent antidiuresis, and it was
normalized after the therapy with fludrocortisone acetate in the
patients with mineralocorticoid-responsive hyponatremia of the elderly.
We did not find statistically significant elevation of serum atrial and
brain natriuretic peptides, but they seemed high (n = 4, data not
shown). Natriuretic peptides might be associated with renal Na loss in
mineralocorticoid-responsive hyponatremia of the elderly.
We have experienced difficulty in diagnosis for hyponatremia in the
elderly subjects. SIADH could be easily overdiagnosed based on the
criteria of Schwartz and Bartter (2), and it seems
unlikely to be differentiated clearly from mineralocorticoid-responsive
hyponatremia of the elderly (37, 38). The reasons may be
as follows: Physical finding of dehydration less than 10% below the
normal value of circulatory blood volume is not always easy to explain
in the elderly subjects. We don’t have a good marker for dehydration,
and thus the criteria of SIADH by Schwartz and Bartter may include
hyponatremia associated with mineralocorticoidresponsive
hyponatremia of the elderly as SIADH, even if measuring plasma AVP and
renin-aldosterone system. In the present study, the three out of eight
patients with mineralocorticoid-responsive hyponatremia of the elderly
were initially diagnosed as having SIADH. Because circulating blood
volume should be increased to a certain extent in patients with SIADH,
water restriction is an essential therapy for SIADH. However, this
maneuver deteriorated clinical and laboratory findings, and the
administration of fludrocortisone acetate ameliorated hyponatremia,
along with the increase in circulatory blood volume in the patients
with mineralocorticoid-responsive hyponatremia of the elderly. The
possibility that mineralocorticoid treatment might be expected to
improve water homeostasis simply as a result of reduced natriuresis
associated with SIADH is poor, because the changes in circulatory blood
volume during each therapy were totally different between the patients
with SIADH and mineralocorticoid-responsive hyponatremia of the
elderly. Recently, Ayus and Arieff (16) reported that
water restriction therapy does not always improve the physical
condition of elderly patients suffering from hyponatremia; and instead,
it accelerates their mortality. This cautious report implicates that
salt-wasting-related hyponatremia could have occupied to a
considerable extent in a group of hyponatremic patients in the
elderly.
In conclusion, we demonstrated the characteristics of hyponatremia in
the elderly subjects. The hyponatremia belonged to a group of euvolemic
hyponatremia. Nonsuppressible release of AVP, despite hypoosmolality,
was linked with the impairment in water excretion and involved in the
mechanism for hyponatremia in the elderly. The inappropriate
antidiuresis was evident in the patients with SIADH and
hypopituitarism, whereas the appropriate antidiuresis was indicated by
the findings of normalization of plasma AVP and urinary excretion of
AQP-2 after the fludrocortisone acetate therapy. The present study
indicates that urinary excretion of AQP-2 may be a more sensitive
measure of AVP effect on renal collecting duct cells than are plasma
AVP levels, and that increased urinary excretion of AQP-2 shows
exaggerated AVP-induced antidiuresis in hyponatremic subjects in the
elderly. In addition, mineralocorticoid-responsive hyponatremia of the
elderly has to be carefully differentiated from SIADH in elderly
subjects.
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Footnotes
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1 The present study was supported by grants from the Ministry of
Welfare and the Ministry of Education, Science and Culture of
Japan. 
Received June 13, 2000.
Revised September 18, 2000.
Revised December 15, 2000.
Accepted December 22, 2000.
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Abstract
Introduction
