Diabetes Insipidus

Symposium on Endocrinology

Diabetes Insipidus Kenneth C. Bovee, D.V.M., M. Med. Sc. *

An absolute or relative lack of circulating antidiuretic hormone (ADH, vasopressin) results in diabetes insipidus. Urine specific gravity varies from 1.001 to 1.005 and urine osmolarity from 50 to 200 mOsm per kg. Affected animals generally have an increase in urine volume and thirst, which starts suddenly and reaches a peak in one to two days. Urine volume may range from 3 to 10 times normal per day, depending upon the degree of ADH deficiency present. If water intake is insufficient, the total solute concentration of body fluids increases. The failure of the kidney to concentrate urine in the presence of an increased solute concentration in the serum, together with demonstration that the kidney can respond to exogenous vasopressin, constitutes the criterion for establishing the diagnosis.5

PHYSIOLOGY OF ANTIDIURETIC HORMONE Antidiuretic hormone plays a fundamental role in the regulation of osmotic homeostasis by its action to increase water permeability on the renal tubules. The combination of ADH release and the thirst mechanism ensures the maintenance of normal water and osmotic concentration of body fluids. Arginine vasopressin is the active ADH in most mammalian species. The hormone is formed in the supraoptic and paraventricular nuclei of the hypothalamus and stored in the posterior lobe of the pituitary. A mechanism for the formation and release of the hormone by nerve fibers has recently been reviewed by Kleeman.10 When a stimulus for the release of vasopressin occurs there is a rapid release into the circulation. It appears that 10 to 20 per cent of the total content of the hormone in the posterior pituitary is readily releasable. After the releasable pool of hormone is discharged the

*Associate Professor of Medicine, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania

Veterinary Clinics o{North America- Vol. 7, No.3, August 1977

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gland continues to release vasopressin in response to stimuli, but at a reduced rate. Secretion of ADH is known to be stimulated by many changes including plasma osmolarity, blood volume, pain, decreased cardiac output, and hemorrhage (Fig. 1). Under homeostatic conditions, plasma osmolarity and blood volume appear to be the two major physiologic controls of vasopressin release. The importance of these two variables has not been adequately clarified due to the lack of a suitable method for accurately measuring blood vasopressin at the low concentrations normally present. However, a sensitive radioimmunoassay has recently been developed. 7 It has been demonstrated that the plasma vasopressin concentration remains relatively constant until plasma osmolarity rises above 295 mOsm per kg in the rat. As osmolarity was increased to 315 mOsm per kg, there was a linear rise in vasopressin concentration. When the blood volume was decreased plasma concentration of vasopressin did not increase until the blood volume depletion exceeded 8 per cent. Dunn1 concludes that under normal day to day circumstances vasopressin secretion is regulated primarily by plasma osmolarity, but under circumstances characterized by large changes in blood volume the osmotic stimulus may be significantly altered. 7 Many other minor factors control the release of vasopressin. There are a group of baroreceptors located in the carotid sinus, left atrium,

Increased Plasma Osmolarity /

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ADH release and regulation of concentration of body fluids.

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aorta, and pulmonary veins which respond to tension developed in the wall of the receptor organ rather than to the volume of blood present. 18 These receptors act through a reflex arc via the glossopharyngeal and vagus nerve to control ADH release independent of plasma osmolarity or renal hemodynamics. Alcohol inhibits the release of ADH apparently by blocking stimuli which ordinarily encourage its release. 9 Cholinergic agents such as acetylcholine stimulate the release of ADH when they are injected into the carotid artery or applied locally to the supraoptic nuclei. Several studies have suggested that the absence of glucocorticoids result in an increase in ADH release.L 6 Release of ADH may also be influenced by concentration of angiotensin II in the plasma. 15 The importance of these minor or secondary factors which control the release of ADH are presently poorly understood in clinical veterinary medicine. In man and the dog the half-life of vasopressin in the circulation is from 4 to 20 minutes. 13 The exact form of circulating vasopressin is not definitely known, but most is probably in the free peptide form. Inactivation of the hormone in plasma is negligible except in pregnancy. An ADH inactivator, vasopressinase, appears in significant quantities in the blood toward the end of the second month of pregnancy in women. The probable source of the enzyme is the placenta.20 Removal of vasopressin from the plasma is accomplished almost completely by the liver and kidney with the kidneys accounting for approximately 70 per cent of the total removal. Renal removal of the hormone is a combination of urinary excretion and tissue inactivation; about 10 per cent of the hormone is excreted in the active form in the unne. It is generally agreed that vasopressin plays a pivotal role in the concentration mechanism of the kidneys. The major effect of ADH on renal tissue is to increase the permeability of water in the distal tubule. A change in the circulating level of ADH promotes a parallel change in the rate of water reabsorption by the distal tubule, thereby providing the feedback control required to maintain body water balance. Although ADH is the major regulatory factor determining the amount of water excreted by the kidney, several intrarenal factors are known to influence the rate of urine flow and influence the effectiveness of ADH. The ascending limb of Henle actively reabsorbs sodium and chloride to provide a hypertonic interstitium. This interstitial hypertonicity which is maintained in the renal medulla and papilla allows water to passively leave the collecting duct and enter the interstitium once ADH has altered the permeability of the collecting duct. Thus, the effectiveness of ADH depends on the active electrolyte pump, which maintains a hypertonic interstitium. Several factors other than ADH may influence the rate of tubular water reabsorption and urinary concentration. A reduction in filtration

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or enhanced proximal tubular reabsorption may reduce distal tubular flow rate, resulting in osmotic equilibration of filtrate even in the absence of ADH. 3 ADH should be thought of as the final regulator of urinary concentration, but its dependence on normal hemodynamics and tubular transport mechanisms should not be forgotten. There is evidence that ADH also directly influences sodium transport in the kidney. However, the importance and site of this reabsorption are controversial. Vasopressin has been shown not to affect sodium reabsorption in the proximal tubule. 2 Pharmacologic doses of ADH can produce a marked diuresis in dehydrated animals, characterized by an increased loss of sodium, potassium, chloride, and phosphate. 11 The mechanism by which pharmacologic doses of ADH exert a diuretic effect is not clear. It has been proposed that the intracellular mediator of the physiologic effect of ADH is cyclic 3-5-adenosine monophosphate (cyclic AMP). 16 It is now agreed that ADH affects responsive tissue by interacting with a specific receptor complex on the cell membrane at the blood surface. A membrane bound adenyl cyclase is activated; this enzyme catalyzes the conversion of adenosine triphosphate (A TP) to cyclic AMP. The increase in the concentration of cyclic AMP in the cell results in the change in permeability and transport attributable to ADH. 8

ETIOLOGY OF DIABETES INSIPIDUS A form of diabetes insipidus may result from any lesion that damages the neurohypophysis. The disorder may be complete or partial and have the anatomic site of damage localized either in the supraoptic nuclei or in the pituitary stalk. The causes may be secondary to brain tumors, head trauma, infectious disorders, or vascular disturbances of the central nervous system. Primary and metastatic intracranial neoplasms seem to be the most common cause of confirmed cases in the dog14 and other species. In these cases, other signs of neurologic dysfunction accompany or quickly follow signs of diabetes insipidus. Even with devastating lesions in the hypothalamus diabetes insipidus may not occur, presumably because persistence of only a small fraction of the neurohypophyseal system protects against overt dysfunction. In some instances the etiology of reduced vasopressin may remain unknown. Diabetes insipidus has been reported in most domestic species. Familial diabetes insipidus has not been reported in any domesticated animals. Nephrogenic diabetes insipidus is a lack of response to the hormone at the distal nephron despite normal plasma levels of the hor-

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mane. A dog has been reported with this condition, but plasma vasopressin was not measured. 12 Clinical Manifestations The manifestations of diabetes insipidus are dramatic. Pronounced polydipsia, polyuria, and nocturia are prominent complaints. Withdrawal of water from the animal will result in rapid dehydration, weight loss, profound thirst, and rapid development of extracellular hypertonicity. Free access to water may lead to gastric distention following the intake of water and result in occasional vomiting. Other than the annoyance of polydipsia and polyuria, there may be no evidence of illness or other physiologic disturbances associated with this condition unless the animal suffers from the underlying disease which destroys the neurohypophyseal system. The degree of clinical dehydration, as noted by skin turgor and packed cell volume, varies from mild to severe, depending on access to water. Diagnosis The specific gravity of urine in diabetes insipidus is usually 1.001 to 1.005, corresponding to a urine osmolarity of 50 to 200 mOsm per kg. With restriction of fluid intake, the specific gravity may occasionally reach 1.010 with severe dehydration. Ideally, the animal should be placed in a metabolism cage for the collection of 24-hour urine volume and the measurement of fluid intake. During the period of cage adjustment, unless the animal consistently produces urine of very low specific gravity, it can be assumed that the animal secretes adequate amounts of ADH. The diagnosis of diabetes insipidus should be made with great care, because it usually indicates a lifetime of treatment. The use of an osmometer is often helpful in the differential diagnosis of polyuric states. 4 This instrument is usually available in most human hospitals and clinical laboratories. However, classic diabetes insipidus can be diagnosed with simple laboratory procedures that do not require an osmometer. In some polyuric animals, results of water deprivation tests performed the day following free access to water may be misleading. In order to determine true concentrating capacity it is ·commonly necessary to gradually reduce fluid intake over a period of three to four days? This is done by reducing water intake by 50 per cent on two or three consecutive days. This allows- for the reestablishment of renal medullary hypertonicity, which may have been depleted following a long period of polyuria. The result is the finding of a much more concentrated urine and a more accurate estimation of concentrating capacity. This water grading procedure has been essential to determine con-

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centrating capacity in many polyuric states. Of course, an animal that responds to such water grading with increased urine concentration is unlikely to have diabetes insipidus. The simplest test is to restrict water intake and to observe changes in urine volume and concentration. This must be carried out under careful supervision with frequent weighing, measurement of packed cell volume, plasma osmolarity, or plasma sodium concentration to avoid severe dehydration. A loss of 5 per cent of body weight may lead to serious circulatory disturbances. First, the bladder should be emptied and the urine specific gravity recorded. All food and fluid should be withheld for 8 to 12 hours, followed by measurement of urine specific gravity. In true diabetes insipidus, urine volume remains high and specific gravity remains below 1.005 (200 mOsm per kg) until dehydration is apparent. If results are equivocal at this point, the test may be continued four to eight more hours. It is seldom safe to continue the tests beyond 24 hours if the animal remains polyuric. If urine specific gravity rises above 1.010 in the absence of marked dehydration, the possibility of complete diabetes insipidus is eliminated.· In relation to osmolarity measurements, urine osmolarity during water deprivation tests remains less than 200 mOsm and seldom exceeds plasma osmolarity. Plasma osmolarity may be slightly elevated (310 to 320 mOsm per kg) and serum sodium concentrations may be slightly elevated (150 to 155 mEq per liter). During periods of prolonged water restriction, of course, these plasma solute concentrations increase and have great diagnostic value. In some cases it may be necessary to withhold water to force serum sodium concentration to 165 mEq per liter before an adequate response to exogenous vasopressin is seen. If the animal fails to produce a concentrated urine (specific gravity greater than 1.01 0) in response to water deprivation, it remains to be shown that the kidneys will respond to exogenous ADH to establish a diagnosis of diabetes insipidus. Administration of vasopressin should immediately follow the water deprivation test. While waiting for a response to vasopressin, limited water should be given and plasma indicators of fluid depletion must be monitored. The bladder is emptied and specific gravity recorded. A single injection of vasopressin tannate (2 to 10 units) in oil may be given following bladder evacuation. Urine specimens should be collected at 8, 12, 16, and 20 hours postinjection and should exhibit maximal concentrations. Fluid should be limited during this period. If the diagnosis is confirmed, the animal will not seek excessive water for 12 to 36 hours. These simple measures readily distinguish diabetes insipidus from other more obscure polyuric states. A common error in the vasopressin test is to institute the test before taking appropriate control measurements of urine volume and concentration. It should be recalled that

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many polyuric states, with appropriate levels of ADH, respond to exogenous ADH. Therefore, a response to ADH alone does not allow one to make a diagnosis of diabetes insipidus. These tests must be performed under carefully controlled conditions. Another test that may be used rarely, involves the intravenous infusion of hypertonic saline. It is based on the same principle as the water deprivation test, that is, it increases plasma osmolarity and acts as a potent stimulus to ADH release. This test requires simultaneous measurements of plasma and urine osmolarity; therefore, it is not practical for use by the practitioner and will not be described in detail. The saline infusion test is best used to differentiate more obscure causes of polyuria, such as psychogenic polydipsia and nephrogenic diabetes insipidus. With the advent of a sensitive radioimmunoassay of plasma vasopressin, these tests will not be necessary.

Differential Diagnosis Any condition that disturbs the normal action of the renal concentrating mechanism so that it fails to respond to vasopressin may produce polyuria and a low urine specific gravity. This renal unresponsiveness may result from metabolic and structural changes in the kidney. Structural and functional alterations in the renal medulla interfere with concentrating capacity; consequently, many acute and chronic renal diseases are associated with failure to concentrate urine. In a few cases, the polyuria is sufficient to suggest the possibility of diabetes insipidus. Polyuria may follow the oliguric state in acute tubular necrosis, but this is usually transient and the clinical setting rarely leaves the cause of polyuria in doubt. Early cases of hyperadrenocorticism with marked polyuria may also be confusing. However, these animals produce relatively concentrated urine following 18 hours of water deprivation. The polyuria associated with diabetes mellitus, pyometra, and corticosteroid therapy is usually resolved by careful consideration of the history and by routine laboratory procedures. The polyuria of chronic renal failure is seldom confused with that of diabetes insipidus. Urine specific gravity is rarely less than 1.010 in chronic renal failure. Other manifestations of the uremic syndrome are usually evident in such cases. The most difficult condition to differentiate from diabetes insipidus is psychogenic polydipsia, in which polydipsia and polyuria are dramatic, and urine specific gravity may be less than 1.005. This is a psychic disorder associated with primary polydipsia and results in a water diuresis. The urine is concentrated following water deprivation, but this usually requires moderate water deprivation for several days. The diagnosis is made only after performing careful laboratory tests designed to exclude more likely causes of polyuria. Other obscure

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causes of polyuria include potassium depletion and hypercalcemia, both of which impair the renal concentrating capacity. Usually these conditions impair maximal concentrating ability but do not cause the urine to be persistently hypotonic. The critical point in the differential diagnosis of diabetes insipidus is careful application of the water deprivation test and administration of vasopressin. These two tests in combination usually clarify the diagnosis. However, results of these tests are not always clear-cut. Diabetes insipidus does not always present as a clearly identified phenomenon; it may be present as a partial defect in ADH availability. Treatment

The treatment of diabetes insipidus is relatively simple and usually requires intramuscular injections of vasopressin at 24 to 60 hour intervals. The establishment of the effective dosage levels usually requires hospitalization for several days. A dosage level should be attained that brings about complete remission of symptoms. If this is not the case or if results are variable from day to day, the diagnosis should be reevaluated. The owner should be instructed in the proper handling of the medication, in care of syringes and needles, and in giving intramuscular injections. The response to treatment and the animal's general health should be reevaluated at regular intervals. Vasopressin tannate injection is a purified preparation of ADH in repositol form and is the drug of choice. The slow absorption of this product following subcutaneous or intramuscular injection usually relieves symptoms for 24 to 60 hours. The dose should not be repeated until symptoms begin to recur. Although the dose must be adjusted to the treatment of each animal, an initial dose of 0.1 unit per lb of body weight is used. Aqueous vasopressin is used diagnostically but has no place in the therapy of diabetes insipidus. Diuretics, particularly chlorothiazide, paradoxically reduce urine volume in diabetes insipidus. Diuretics alone have not proved effective in the hands of the author. These measures are used only as supplements to replacement therapy in some cases.

REFERENCES l. Agus, Z. S., and

2. 3. 4. 5.

(~oldberg, M.: Role of antidiuretic hormone in the abnormal water diuresis of anterior hypopituitarism in man. J. Clin. Invest., 50:1478, 197 J. Antoniou, L..D., Burke, T. ].. Robinson, R. R., eta!.: Vasopressin-related alterations of sodium reabsorption in the loop of Henle. Kidney Int., 3:6, 1973. Berliner, R. W., and Davidson, D. G.: Production of hypotonic urine in the absence of pituitary antidiuretic hormone. Am. J. Med., 24:730, 1958. Bovee, K. C.: Urine osmolarity as a definitive indicator of renal concentrating capacity. J.A.V.M.A., 155:30, 1969. Coggins, C. H., and Leaf, A.: Diabetes insipidus. Am. J. Med., 42:807, 1967.

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6. Dingman,]. F., and Despointes, R.: Adrenal steroid inhibition of vasopressin release from the neurohypophysis of normal subjects and patients with Addison's disease. ]. Clin. Invest., 39:1851, 1960. 7. Dunn, F. L., Grennan, T. ]., Nelson, A. E., et al.: The role of blood osmolality and volume in regulating vasopressin secretion in the rat.]. Clin. Invest., 52:3213, 1973. 8. Handler,]. S., and Orloff, J.: The mechanism of action of antidiuretic hormone. In Orloff and Berliner (eds.): Handbook of Renal Physiology, Bethesda, American Society of Physiology, I 973. 9. Kleeman, C. R.: Water metabolism. In Maxwell, M. H., and Kleeman, C. R. (eds.): Clinical Disorders of Fluid and Electrolyte Metabolism. New York, McGraw-Hill, 1972. 10. Kleeman, C. R., and Cutler, R. E.: The neurohypophysis. Ann. Rev. Physiol., 25:385, 1963. II. Kurtzman, N. A., and Rogers, P. W.: The diuretic effect of antidiuretic hormone. Clin. Res., 20:600, 1972. 12. Lage, A. L.: Nephrogenic diabetes insipidus in a dog . .J.A.V.M.A., 163:251, 1973. 13. Lauson, H. D.: Metabolism of antidiuretic hormones. Am . .J. Med., 42:713, 1967. 14. Madewell, B. R., Osborne, C. A., Norrdin, R. A., et al.: Clinicopathologic aspects of diabetes insipidus in the dog. J .A.A.H.A., 11:497, 1975. 15. Malvin, R. L.: Possible role of the renin-angiotensin system in the regulation of antidiuretic hormone secretion. Red. Proc. Fed. Am. Soc. Exp. Bioi., 30:1383, 1971. 16. Orloff, J., and Handler,]. S.: The similarity of effects of vasopressin, adenosine 3' -5' phosphate (cyclic AMP) and theophylline on the toad bladder. J. Clin. Invest., 41:702, 1962. 17. Sawyer, W. H., and Mills, E.: Control of vasopressin secretion. In Martini, N., and Ganong, W. F. (eds.): Neuroendocrinology. New York, Academic Press, 1966, p. 187. 18. Share, L.: Role of peripheral receptors in the increased release of vasopressin in response to hemorrhage. Endocrinology, 81:1140, 1967. 19. Share, L.: Vasopressin, its bioassay and the physiological control of its release. Am . .J. Med., 42:701, 1967. 20. Tuppy, H. L.: Enzymatic inactivation and degradation of oxytoxin and vasopressin. In Schachter (ed.): Polypeptides Which Affect Smooth Muscles and Blood Vessels. New York, Pergamon Press, 1960. University of Pennsylvania School of Veterinary Medicine 3800 Spruce Street Philadelphia, Pennsylvania 19104