The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 6 2235-2237
Copyright © 1999 by The Endocrine Society
Urinary Excretion of Aquaporin-2 Water Channel Differentiates Psychogenic Polydipsia from Central Diabetes Insipidus1
Takako Saito,
San-e Ishikawa,
Takashi Ito,
Hideo Oda,
Fumiko Ando,
Minori Higashiyama,
Shoichiro Nagasaka,
Masashi Hieda and
Toshikazu Saito
Division of Endocrinology and Metabolism (Ta.S., S.I., F.A., Mi.H.,
S.N., To.S.), Department of Medicine, Jichi Medical School, Tochigi
329-0498; and Departments of Medicine and Psychiatry (T.I., H.O.,
Ma.H.), Tokyo Metropolitan Matsuzawa Hospital, Tokyo 156,
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) water channel under ad
libitum water intake is of value to differentiate polyuria
caused by psychogenic polydipsia from central diabetes insipidus. A
30-min urine collection was made at 0900 h in 3 groups of: 11
patients with central diabetes insipidus (22–68 yr old), 10 patients
with psychogenic polydipsia (28–60 yr old), and 15 normal subjects
(21–38 yr old). In the patients with central diabetes insipidus, the
plasma arginine vasopressin level was low despite
hyperosmolality, resulting in hypotonic urine. Urinary excretion of
AQP-2 was 37 ± 15 fmol/mg creatinine, a value one-fifth less than
that in the normal subjects. In the patients with psychogenic
polydipsia, plasma arginine vasopressin and urinary osmolality were as
low as those in the patients with central diabetes insipidus. However,
urinary excretion of AQP-2 of 187 ± 45 fmol/mg creatinine was not
decreased, and its excretion was equal to that in the normal subjects.
These results indicate that urinary excretion of AQP-2, under ad
libitum water drinking, participates in the differentiation of
psychogenic polydipsia from central diabetes insipidus.
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Introduction
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PSYCHOGENIC polydipsia causes a marked
polyuria with hypotonic urine (1, 2). Arginine vasopressin (AVP)
secretion is suppressed by hypoosmolality caused by excess intake of
water. Suppression of AVP release obliges us to differentiate
psychogenic polydipsia from central diabetes insipidus. Osmotic
stimulation tests have been carried out to determine the reserve
function of the posterior pituitary gland. Plasma AVP levels increase
in response to an increase in plasma osmolality (Posm) in patients with
psychogenic polydipsia but not in those with central diabetes
insipidus.
In response to AVP, concentrated urine is produced by water
reabsorption across the renal collecting duct (3, 4). Aquaporin-2
(AQP-2) is an AVP-regulated water channel of the collecting duct; it is
translocated from the cytoplasmic vesicles to the apical plasma
membranes by shuttle trafficking when the cells are stimulated by AVP
(5, 6, 7), and it is again redistributed into the cytoplasmic vesicles
after removal of AVP stimulation (8). Also, AQP-2 is, in part, excreted
into the urine (9, 10). We demonstrated that urinary excretion of AQP-2
is of great value in diagnosing central diabetes insipidus in the
hypertonic saline infusion test and impaired water excretion in the
acute oral water load test (11, 12).
The present study was undertaken to determine whether urinary excretion
of AQP-2, under ad libitum water intake, is a useful tool
for diagnosing psychogenic polydipsia.
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Subjects and Methods
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Subjects
Three groups of subjects were examined in the present study. The
first group had 11 patients who had been diagnosed as having idiopathic
central diabetes insipidus. They were 7 males and 4 females, whose ages
ranged from 22–68 yr. They had taken 1-deamino-8-D-AVP
(DDAVP) intranasally, twice a day, and discontinued
the DDAVP therapy 24 h before the study. The second
group of 10 patients were diagnosed as having psychogenic polydipsia.
They were 7 males and 3 females, with ages ranging from 28–60 yr.
Basically, they had been treated for psychiatric disorders, including
schizophrenia, atypical psychiatric disorder, and chronic alcoholism.
They were hospitalized in Tokyo Metropolitan Matsuzawa Hospital. Urine
volume for the 24-h period before the urine collection for AQP-2
analysis ranged from 2640–8490 mL (4670 ± 980 mL, mean ±
SEM). The third group had 15 normal volunteers, with ages
ranging from 21–38 yr. They were 10 males and 5 females. The present
study was approved by the ethical committees of Jichi Medical School
Hospital and Tokyo Metropolitan Matsuzawa Hospital for human study. We
obtained informed consent from all the subjects to join the study.
All the subjects drank water ad libitum, and 30-min urine
collection was made and blood drawn at 0900 h. Urine samples were
subjected to measurements of urinary osmolality (Uosm) and urinary
excretion of creatinine and AQP-2. Blood samples were used to measure
Posm and plasma AVP levels. Uosm and Posm were measured by
freezing-point depression (Model 3W2, Advanced Instruments, Needham
Height, MA). Urinary creatinine was measured with an automatic clinical
analyzer (Model 736, Hitachi Co., Tokyo, Japan). Plasma AVP
levels were determined by RIA using AVP RIA kits (Mitsubishi Chemistry,
Tokyo, Japan) (13). Urinary excretion of AQP-2 was measured as
described below.
RIA of AQP-2
The RIA of urinary AQP-2 was performed by the method described
in our previous reports (11, 12). Urinary AQP-2-like immunoreactivity
was measured by a specific RIA that used the polyclonal antibody
against a synthetic portion (Tyr0-AQP-2
[V257-A271]) of the C-terminal of human AQP-2 raised in rabbits. A
synthetic peptide [Tyr0-AQP-2 (V257-A271)] was
radioiodinated with iodine-125 (New England Nuclear, Boston, MA) by the
chloramine-T method. For the assay, 0.1 mL of the urine samples
(diluted 1–8 times) or a standard, 0.1 mL assay buffer [ 0.05 mol/L
sodium phosphate (pH 7.4), 0.08 mol/L sodium chloride, 0.01 mol/L EDTA,
0.5% BSA, 0.5% Noridet P-40, and 0.01% sodium azide], and 0.1 mL of
the antibody (final dilution, 1:12,000) was incubated at 4 C for
48 h, followed by the addition of 0.1 mL of the radiolabeled
synthetic peptide (
10,000 cpm) and further incubation at 4 C for
48 h. Bound and free quantities of radiolabeled ligand were
separated by the double-antibody method. All samples were analyzed in
duplicate. The intra- and interassay coefficients of variation were
less than 10%. The minimal detectable quantity of AQP-2 was 0.86
pmol/tube, and an amount equivalent to 6.9 pmol/tube caused 50%
inhibition of binding of the radiolabeled ligand.
Statistical analysis
Uosm, Posm, plasma AVP, and urinary excretion of AQP-2 were
expressed as the mean ± SEM. All values were compared
with Fisher’s t test. A P value less than 0.05
was considered significant.
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Results
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In the patients with central diabetes insipidus, the plasma AVP
level was low despite hyperosmolality of 297.8 ± 3.4
mosmol/kg H2O, resulting in hypotonic urine (Fig. 1
). Urinary excretion of AQP-2 was
one-fifth less in the patients with central diabetes insipidus than in
the normal subjects. AQP-2 is the AVP-dependent water channel of
collecting duct cells and is recycling between the cytoplasmic vesicles
and the apical plasma membranes in the cells (5, 6, 7, 8). AQP-2 is partly
excreted into the urine, which is approximately 3% of AQP-2 in the
collecting duct cells (14). In normal subjects, urinary excretion of
AQP-2 is changeable in a wide range in physiological conditions (11).
Because urinary excretion of AQP-2 has a positive correlation with
plasma AVP levels in normal subjects (11), the reduced urinary
excretion of AQP-2 was in concert with the impaired secretion of AVP in
central diabetes insipidus.
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Figure 1. Posm, plasma AVP (PAVP),
Uosm, and urinary excretion of AQP-2 (UAQP-2), under ad
libitum water drinking, in 15 normal subjects (NL, •), 11
patients with central diabetes insipidus (CDI,  ) and 10 patients
with psychogenic polydipsia (PP,  ). *, P <
0.01; **, P < 0.05 vs. the normal
subjects. Value are means ± SEM.
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In the patients with psychogenic polydipsia, Uosm was as low as that in
the patients with central diabetes insipidus (Fig. 1
). The plasma AVP
level was low because of the reduced Posm, which was derived from an
exaggerated intake of water. Urinary excretion of AQP-2, however, was
not decreased; and rather, its excretion kept the normal range. The
relationship between plasma AVP levels and urinary excretion of AQP-2
is shown in Fig. 2. The urinary excretion
of AQP-2 in the patients with psychogenic polydipsia was dissociated
from the positive correlation between plasma AVP and urinary excretion
of AQP-2 in the normal subjects.
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Discussion
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The present study demonstrated the clinical tool, of urinary
excretion of AQP-2, in differentiating psychogenic polydipsia from
central diabetes insipidus. What is involved in the marked difference
in urinary excretion of AQP-2 in these two disorders? There is a
possibility that, as patients with psychogenic polydipsia reduce water
intake during sleep, antidiuresis may occur periodically at night and
the production of AQP-2 be somewhat restored. Because approximately 3%
of AQP-2 in collecting duct cells is excreted into the urine, urinary
excretion of AQP-2 may keep relatively high, despite hypotonic urine.
It seemed that the present results are distinct from down-regulation of
kidney AQP-2 content in rats under chronic water load (15). The
difference may come from the periodicity of water intake in a day, in
the patients with psychogenic polydipsia. Collecting-duct flow rate is
increased and renal medullary tissue tonicity may be reduced in
patients with psychogenic polydipsia. These environmental alterations,
according to a peculiar drinking behavior, could cause accompanying
changes in the action of AVP or AQP-2 in collecting duct cells and the
pattern of AQP-2 excretion from them. As a whole, these changes may
disrupt the positive relationship between urinary excretion of AQP-2
and plasma AVP levels. At the present time, however, other factors
involved in urinary excretion of AQP-2 remain undetermined. Further
study will be necessary to elucidate the exact mechanism.
In conclusion, urinary excretion of AQP-2, under ad libitum
water drinking, participates in the differentiation of polyuria caused
by psychogenic polydipsia from central diabetes insipidus.
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Footnotes
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1 This work was supported by grants from the Ministry of Welfare of
Japan. 
Received November 10, 1998.
Revised February 8, 1999.
Accepted February 22, 1999.
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Abstract
Introduction
