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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 6 1823-1827
Copyright © 1997 by The Endocrine Society

Clinical Studies

Urinary Excretion of Aquaporin-2 in the Diagnosis of Central Diabetes Insipidus1

Takako Saito, San-e Ishikawa, Sei Sasaki, Tomoatsu Nakamura, Kumiko Rokkaku, Akio Kawakami, Kazufumi Honda, Fumiaki Marumo and Toshikazu Saito

Division of Endocrinology and Metabolism (Ta.S., S.I., T.N., K.R., A.K. K.H., To.S.), Department of Medicine, Jichi Medical School, Tochigi 329–04; and Second Department of Internal Medicine (S.S., F.M.), Tokyo Medical and Dental University, Tokyo 113, 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-machi, Tochigi, 329–04, Japan. E-mail: saneiskw{at}jichi.ac.jp


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
We determined whether alteration in urinary excretion of aquaporin-2 (UAQP-2) is of value to diagnose central diabetes insipidus (CDI). First, UAQP-2 was determined in 16 normal subjects under ad libitum water drinking (n = 6) and after an overnight dehydration (n = 10). UAQP-2 has a positive correlation with plasma arginine vasopressin (AVP) levels (r = 0.61, P < 0.05) but not with urinary osmolality (Uosm). Second, a hypertonic saline (5% NaCl)-infusion test was studied in 5 normal subjects (21 to 25 yr old) and 10 patients with CDI (22–68 yr). After drinking water ad libitum, they were given 20 mL/kg water orally and then given 5% NaCl (0.05 mL/kg·min) iv for 120 min. Finally, 0.1 U of AVP was administered iv. During the period, 30-min urine collections were made. In the normal subjects, after the infusion of 5% NaCl, plasma AVP levels and Uosm markedly increased in parallel with an increase in plasma osmolality (Posm, 294–320 mOsm/kg H2O; Uosm, 102–737 mOsm/kg H2O; AVP, 0.4–2.6 pg/mL, P < 0.001). In the CDI patients, plasma AVP and Uosm failed to increase, despite an increase in Posm (Posm, 306–332; Uosm, 102–164; AVP, 0.9–1.2). UAQP-2 was markedly greater in the normal subjects than the CDI patients (7.2 vs. 0.9 pmol/L/mg creatinine, P < 0.05) under water intake ad libitum. UAQP-2 was changeable in the wide range in physiological condition. After the 5%-NaCl infusion, UAQP-2 elevated to 12.5 from 0.9 pmol/L·mg creatinine in the normal subjects. In contrast, UAQP-2 remained low during the 5%-NaCl infusion in the CDI patients. Exogenous AVP promptly increased UAQP-2 to a similar extent in two groups of the normal subjects and the CDI patients. These results indicate that measurement of UAQP-2 is of value to diagnose CDI in the 5%-NaCl infusion test.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
IN RESPONSE to arginine vasopressin (AVP), concentrated urine is produced by water reabsorption across renal collecting duct (1, 2). We recently cloned a complementary DNA of apical collecting duct water channel, aquaporin-2 (AQP-2), of the rat and human kidney (3, 4). AQP-2 is translocated from cytoplasmic vesicles to the apical plasma membrane, by shuttle trafficking, in collecting duct cells when the cells are stimulated by AVP (5, 6, 7, 8, 9, 10) and is again redistributed into cytoplasmic vesicles after removal of AVP stimulation (11). Also, AQP-2 is, in part, excreted into the urine (12, 13). Our previous study showed that urinary excretion of AQP-2 is significantly increased by the single injection of AVP in patients with central diabetes insipidus (CDI) (12). AQP-3 also is present on basolateral membrane of collecting duct cells, which is not AVP-sensitive (14, 15).

Impaired secretion of AVP from posterior pituitary occurs in patients with CDI (16). The patients suffer from polyuria and polydipsia because of the disturbance of renal water reabsorption in collecting duct cells. The disease has been diagnosed by the diminished secretion of AVP in response to hypertonic saline infusion or water deprivation testing (17). However, we have sometimes experienced unreliable diagnosis of CDI, because current diagnostic approach is limited.

The present study therefore was undertaken to determine whether urinary excretion of AQP-2 is of value in diagnosing CDI. We measured urinary excretion of AQP-2 by RIA in the normal subjects and the patients with CDI.


   Subjects and Methods
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 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Urinary excretion of AQP-2 in normal subjects

Sixteen normal subjects, 21–28 yr old, were divided into two groups. They were 11 males and 5 females. A group of 6 normal subjects drank water ad libitum; 30-min urine samples were taken and blood drawn at 0900 h. The other group of 10 normal subjects was prohibited water drinking from 2100 h a day before, and blood and 30-min urine samples were taken at 0900 h. Urine samples were subjected to measurement of urinary osmolality (Uosm) and urinary excretion of creatinine and AQP-2. Blood samples were used to measure plasma osmolality (Posm) and plasma AVP levels.

Hypertonic saline test

Hypertonic saline testing was carried out in 2 groups of subjects. The present protocol was approved by the ethical committee of Jichi Medical School Hospital for human study. We obtained informed consent from all the subjects to join the present protocol. The 1st group had 5 normal volunteers, with ages ranging from 21–25 yr (22.5 ± 0.2, mean± SE). They were 4 males and 1 female. The 2nd group of 10 patients had been diagnosed as idiopathic CDI. They were 7 males and 3 females, whose ages ranged from 22–68 yr (44.8 ± 5.6, mean ± SE). They had taken 1-deamino-8-D-AVP intranasally twice a day and discontinued the 1-deamino-8-D-AVP therapy 24 h before the start of the study.

After an overnight fast, the study was started at 0900 h. The subjects were allowed to drink water freely before the start of the present protocol. After urination, water (20 mL/kg) was given orally for 60 min. Thirty minutes later, 5% NaCl was administered iv at a rate of 0.05 mL/kg·min for 120 min. Thirty-minute urine collections were made during the observation period. Blood samples were collected at 15, 120, and 240 min. Thereafter, exogenous AVP at a dose of 0.1U, dissolved in 1 mL distilled water, was given iv. Two 15-min urine collections were made, and a blood sample was collected at 245 min. Urine and blood samples were subjected to measurement of urine volume, Uosm, urinary excretion of creatinine and AQP-2, serum sodium, Posm, and plasma AVP levels.

Uosm and Posm were measured by freezing-point depression (Model 3W2, Advanced Instrument, Needham Height, MA). Urinary creatinine in each urine sample was measured with an automatic clinical analyzer (Model 736, Hitachi Co., Tokyo, Japan), and serum Na was measured by flame photometer (Model 736, Hitachi Co.). Plasma AVP levels were measured by RIA using AVP RIA kits (Mitsubishi Chemistry, Tokyo, Japan), as described previously (18, 19). Urinary AQP-2 was determined as described below.

RIA of urinary AQP-2

The RIA of urinary AQP-2 was performed by the modified method described in our previous report (12). Urinary AQP-2-like immunoreactivity was measured by a specific RIA that used the polyclonal antibody against a synthetic portion of the C-terminal of human AQP-2 raised in rabbits (4, 12). A synthetic peptide (Tyr0.aquaporin-2[V257-A27l]), corresponding to the 15-amino-acid sequence of the C-terminal of AQP-2, was radioiodinated with iodine-125 (New England Nuclear, Boston, MA) by the chloramin T method, as described elsewhere (20). For the assay, 0.1 mL of the urine sample (diluted 1x:8x) or of a standard, 0.1 mL of assay buffer \[0.05 mol/L sodium phosphate (pH 7.4), 0.08 mol/L sodium chloride, 0.0l mol/L ethylenediamine tetra-acetate, 0.5% BSA, 0.5% NP-40, and 0.01% sodium azide\], and 0.1 mL of the antibody (final dilution, 1:12,000) were incubated at 4°C for 48 h, followed by the addition of 0.1 mL of the radiolabeled synthetic peptide (approximately l0,000 cpm) and further incubation at 4°C for 48 h. Bound and free quantities of radiolabeled ligand were separated by the double-antibody method. The serial dilution curve of the urine samples was parallel to that of the standard (data not shown). Each sample was analyzed in duplicate, and 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 20.74 pmol/tube caused 50% inhibition of binding of the radiolabeled ligand. When the 8x diluted urine samples (0.1 mL) were used, the range of results were distributed between 0.9 and 24.2 pmol/tube on the standard curve. Most of urinary AQP-2 levels in the patients with CDI were present at and around the minimal detectable levels on the standard curves.

Statistical analysis

The values of urine volume, Uosm, Posm, serum Na, plasma AVP levels, and the excretion of urinary AQP-2 were expressed as means ± SE. All values were compared with two-way ANOVA and Fisher’s t test. A P-value less than 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Urinary excretion of AQP-2 was determined in the normal subjects under ad libitum water drinking (n = 6) and after an overnight dehydration (n = 10). Figure 1Go shows the relationship of urinary AQP-2 excretion with Uosm or plasma AVP levels. Urine collection was made for 30 min in the morning. Urinary excretion of AQP-2 ranged from 4.6–27.4 pmol/L·mg creatinine. There is no significant relationship between urinary excretion of AQP-2 and Uosm. However, there is a significant relationship between urinary excretion of AQP-2 and plasma AVP levels (r = 0.61, P < 0.05).



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  		Figure 1. The relationships of urinary excretion of AQP-2 (UAQP-2) with Uosm or plasma AVP levels in the normal subjects (n = 16). {circ}, a 30-min urine collection under ad libitum water drinking; •, a 30-min urine collection after an overnight dehydration.

 
Figure 2Go shows the urinary excretion of AQP-2 in the normal volunteer and the patients with CDI under ad libitum water intake. Urinary excretion of AQP-2 was 8-fold greater in the normal subjects than in the patients with CDI.



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  		Figure 2. The urinary excretion of AQP-2 (UAQP-2) level in the control subjects and the patients with central diabetes insipidus (CDI) under ad libitum water intake. Values are means ± SEM.

 
The results of 5%-NaCl infusion testing are shown in Figs. 3Go and 4Go and Table 1Go. After an acute water load (20 mL/kg), marked water diuresis occurred in both groups of subjects. Urine volume enormously increased and Uosm conversely decreased (Fig. 3Go). Such an alteration was much evident in the normal subjects, compared with the patients with CDI. In response to water intake, serum Na and Posm were significantly reduced, leading to a reduction in plasma AVP level (Table 1Go). Urinary excretion of AQP-2 reduced to 2.60 ± 0.14 pmol/L·mg creatinine in the control subjects, a value one third of that under ad libitum water drinking (Fig. 4Go). Urinary excretion of AQP-2 was as low as 0.72 ± 0.01 pmol/L·mg creatinine in the patients with CDI. The minimal levels of urinary AQP-2, after water load in the normal subjects, was similar to that in the patients with CDI. Thereafter, the iv administration of 5% NaCl increased serum Na levels and Posm in both groups, increases being greater in the patients with CDI than in the control subjects. The increase in Posm produced an osmotic release of AVP in the normal subjects but impaired it in the patients with CDI (Table 1Go). Such a disturbance in AVP release failed to produce urinary concentration in the patients with CDI (Fig. 3Go). In contrast, urine volume rapidly reduced and Uosm increased in the normal subjects (P < 0.0001, normal subjects vs. patients with CDI).



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  		Figure 3. The changes in urine volume and Uosm in the control subjects and the patients with central diabetes insipidus (CDI) in the hypertonic saline infusion test. •, control subjects (n = 5); ({blacksquare}), patients with CDI (n = 10). Values are means ± SEM.

 


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  		Figure 4. The urinary excretion of AQP-2 (UAQP-2) levels in the control subjects and the patients with central diabetes insipidus (CDI) in the hypertonic saline infusion test. •, control subjects (n = 5); {blacksquare}, patients with CDI (n = 10); *, P < 0.05, vs. patients with CDI. Values are means ± SEM.

 

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  		Table 1. Changes in serum Na (SNa), Posm and plasma AVP levels in response to 5%-saline infusion in the control subjects and patients with central diabetes insipidus (CDI)

 
An increase in plasma AVP levels reflected the exaggerated excretion of AQP-2 into urine in the normal subjects (Fig. 4Go). This elevation was approximately 12-fold. When compared with the changes in urine volume and Uosm, the increase in urinary excretion of AQP-2 occurred 60 min later. An exogenous AVP further produced a prompt elevation of urinary AQP-2 excretion. In contrast, urinary excretion of AQP-2 remained low and did not respond at all to an increase in Posm in the patients with CDI (P = 0.0081, normal subjects vs. patients with CDI). It promptly increased in response to exogenous AVP.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The present study demonstrated that urinary excretion of AQP-2 closely reflects the condition of water metabolism. Urinary excretion of AQP-2 markedly decreased after an acute water load in the normal subjects, which was a level comparable with that in the patients with CDI. In contrast, after an overnight dehydration, urinary excretion of AQP-2 elevated in the normal subjects. As shown in Fig. 1Go, urinary excretion of AQP-2 was changeable in the wide range in physiological condition, and its variation positively correlated with that of plasma AVP levels.

The response of urinary excretion of AQP-2 to endogenous and exogenous AVP seems to be different. An increase in urinary excretion of AQP-2 was slow and its magnitude was 12-fold during the 5%-NaCl infusion test in the normal subjects. The percent change in urinary AQP-2 was much greater than that in plasma AVP after the 5%-NaCl administration in the normal subjects. This finding may depend upon the widely changeable range in urinary excretion of AQP-2, as compared with plasma AVP. The administration of exogenous AVP further produced a prompt increase in urinary excretion of AQP-2. However, as shown in Fig. 3Go, urine volume did not further decrease and Uosm did not further increase after the exogenous AVP in the normal subjects. In the patients with CDI, urinary excretion of AQP-2 did not respond to the 5%-NaCl infusion and remained low. Urinary excretion of AQP-2 markedly exaggerated in response to the administration of exogenous AVP, a value similar to that in the normal subjects. There may be a marked difference in the peak levels of plasma AVP between the 5%-NaCl infusion and the exogenous administration of AVP. The maneuver of exogenous AVP administration may have to transiently elevate plasma AVP levels to a large extent, though we did not measure plasma AVP levels immediately after the iv administration of AVP. Such a change may be closely related to a prompt increase in urinary excretion of AQP-2. The present finding suggested that a shuttle trafficking of AQP-2 is considerably fast in renal collecting duct cells, and AQP-2 is simultaneously excreted into the urine.

We would evaluate the efficacy of urinary excretion of AQP-2 in diagnosis of CDI. The basal levels of urinary excretion of AQP-2 in the patients with CDI was one eighth of that in the normal subjects. Urinary excretion of AQP-2 was positively correlated with plasma AVP levels (Fig. 1Go). Five percent-NaCl infusion testing showed that urinary excretion of AQP-2 gradually increased in response to an increase in Posm, mediated via AVP secretion, in the normal subjects. However, no alteration in urinary excretion of AQP-2 was observed in the patients with CDI. We consider that the observation period should be prolonged after ceasing 5%-NaCl infusion; i.e., two more 30-min urine collections may have to be made before the administration of exogenous AVP. The present study strongly indicated that the measurement of urinary AQP-2 is a useful tool for diagnosing CDI, in addition to other parameters previously evaluated. We should modify the maneuver of 5%-NaCl testing to further clarify the changes in urinary excretion of AQP-2.


   Footnotes
 
1 This work was supported by grants from the Ministry of Education, Science and Culture of Japan. The study was presented at the 29th Annual Meeting of The American Society of Nephrology, November 3–6, 1996, at New Orleans. Back

Received December 24, 1996.

Revised February 19, 1997.

Accepted February 26, 1997.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Ishikawa S. 1993 Cellular action of arginine vasopressin in the kidney. Endocrine J. 40:373–386.
  2. Wade JB, Stetson DL, Lewis SA. 1981 ADH action: evidence for a membrane shuttle mechanism. Ann NY Acad Sci. 372:106–117.[Medline]
  3. Fushimi K, Uchida S, Hara Y, Hirata Y, Marumo F, Sasaki S. 1993 Cloning and expression of apical membrane water channel of rat kidney collecting tubule. Nature. 361:549–552.[CrossRef][Medline]
  4. Sasaki S, Fushimi K, Saito H, et al. 1994 Cloning, characterization and chromosomal mapping of human aquaporin of collecting duct. J Clin Invest. 93:1250–1256.
  5. Nielsen S, DiGiovanni SR, Christensen EI, Knepper MA, Harris HW. 1992 Cellular and subcellular immunolocalization of vasopressin-regulated water channel in rat kidney. Proc Natl Acad Sci USA. 90:11663–11667.[Abstract/Free Full Text]
  6. Fushimi K, Sasaki S, Yamamoto T, et al. 1994 Functional characterization and cell immunolocalization of AQP-CD water channel in the kidney collecting duct. Am J Physiol. 267:F573–F582.
  7. DiGiovanni SR, Nielsen S, Christensen EI, Knepper MA. 1994 Regulation of collecting duct water channel expression by vasopressin in Brattleboro rat. Proc Natl Acad Sci USA. 91:8984–8988.[Abstract/Free Full Text]
  8. Nielsen S, Chou CL, Marples D, Christensen EI, Kishore BK, Knepper MA. 1995 Vasopressin increases water permeability of kidney collecting duct by inducing translocation of aquaporin-CD water channels to plasma membrane. Proc Natl Acad Sci USA. 92:1013–1017.[Abstract/Free Full Text]
  9. Sabolic I, Katsura T, Verbavatz JM, Brown D. 1995 The AQP2 water channel: effect of vasopressin treatment, microtubule disruption, and distribution in neonatal rats. J Membr Biol. 143:165–175.[Medline]
  10. Yamamoto T, Sasaki S, Fushimi K, et al. 1995 Vasopressin increases AQP-CD water channel in apical membrane of collecting duct cells in Brattleboro rats. Am J Physiol. 268:C1546–C1551.
  11. Saito T, Ishikawa S, Sasaki S, et al. 1997 Alteration in water channel AQP-2 by removal of AVP stimulation in collecting duct cells of dehydrated rats. Am J Physiol. (in press).
  12. Kanno K, Sasaki S, Hirata Y, et al. 1995 Urinary excretion of aquaporin-2 in patients with diabetes insipidus. N Engl J Med. 332:1540–1545.[Abstract/Free Full Text]
  13. Elliot S, Goldsmith P, Knepper M, Haughey M, Olson B. 1996 Urinary excretion of aquaporin-2 in humans: a potential marker of collecting duct responsiveness to vasopressin. J Am Soc Nephrol. 7:403–409.[Abstract]
  14. Ishibashi K, Sasaki S, Fushimi K, et al. 1994 Molecular cloning and expression of a member of the aquaporin family with permeability to glycerol and urea in addition to water expressed at the basolateral membrane of kidney collecting duct cells. Proc Natl Acad Sci USA. 91:6269–6273.[Abstract/Free Full Text]
  15. Miriam E, Erich EW, Suresh ST, Gustavo F. 1994 Cloning and expression of AQP-3, a water channel from the medullary collecting duct of rat kidney. Proc Natl Acad Sci USA. 91:10997–11001.[Abstract/Free Full Text]
  16. Moses AM, Streeten DHP. 1967 Differentiation of polyuric states by measurement of responses to changes in plasma osmolality induced by hypertonic saline infusions. Am J Med. 42:368–377.[CrossRef][Medline]
  17. Carter AC, Robbins J. 1947 The use of hypertonic saline infusions in the differential diagnosis of diabetes insipidus and psychogenic polydipsia. J Clin Endocrinol Metab. 7:753–766.[Abstract/Free Full Text]
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