OVERVIEW.

Plasma osmolality and its principal determinant, the plasma sodium concentration, are normally maintained within remarkably narrow ranges. This stability is achieved largely by adjusting total body water to keep it in balance with the serum sodium concentration. Water balance is controlled by an integrated system that involves precise regulation of water intake via thirst mechanisms and control of water output via stimulation of vasopressin secretion (Fig. 1-1). The major sources of fluid loss from the dog and cat include urine, the respiratory tract, and feces. As long as free access to water is allowed, total body water in hu-mans rarely varies by more than 1% to 2% (Aron et al, 2001). Some of the water necessary to maintain homeostasis is taken in with food; the majority is ingested as water.

FIGURE 1-1 Schematic illustration of the primary mechanisms involved in maintenance of water balance. Solid lines indicate osmotically stimulated pathways, and dashed lines indicate volume stimulated pathways. The dotted lines indicate negative feedback pathways. ANP, atrial natriuretic peptide; ADH, antidiuretic hormone; CNS, central nervous system; ECF, extracellular fluid; OPR, oropharyngeal reflex.

(From Reeves WB, Andreoli TE: The posterior pituitary and water metabolism. In Wilson JD, Foster DW (eds): Williams Textbook of Endocrinology, 8th ed. Philadelphia, WB Saunders, 1992, p 311.)

The capacity of the kidney to produce concentrated urine plays an important part in maintenance of water balance. Animals eat a diet that produces osmotically active material ultimately excreted in urine, thus requiring water in which to be excreted. The more concentrated urine the kidney can produce, the less water is required to excrete those solutes.

Urine-concentrating mechanisms can reduce but not completely prevent loss of water into the urine. Even if an animal is maximally concentrating urine, obligatory fluid loss is still considerable. This situation is exacerbated in a warm environment, in which significant quantities of fluid may be lost via dissipation of heat through panting. Body fluid can be brought back to normal only through increasing water intake. Not surprisingly, the mechanisms involved in the control of thirst and of vasopressin secretion have many similarities.

THE NEUROHYPOPHYSIS.

The neurohypophysis consists of a set of hypothalamic nuclei (supraoptic and paraventricular) responsible for the synthesis of oxytocin and vasopressin; the axonal processes of these neurons, which form the supraopticohypophysial tract; and the termini of these neurons within the posterior lobe of the pituitary (Fig. 1-2; Reeves et al, 1998). The neurosecretory cells in the paraventricular and supraoptic nuclei secrete vasopressin or oxytocin in response to appropriate stimuli. The neurosecretory cells receive neurogenic input from various sensor elements, including low-pressure baroreceptors located in the heart and arterial circulation and two circumventricular organs, the subfornical organ and the organum vasculosum of the lamina terminalis. These organs lie outside the blood brain barrier and may be important for osmoreception and interaction with blood-borne hormones, such as angiotensin II.

FIGURE 1-2 Schematic illustration of the relationship between the hormone synthesizing areas of the hypothalamus and the pituitary gland

VASOPRESSIN: BIOSYNTHESIS, TRANSPORT, AND METABOLISM.

Vasopressin and oxytocin are nonapeptides composed of a six-membered disulfide ring and a three-membered tail on which the terminal carboxyl group is amidated (Fig. 1-3). Arginine vasopressin (AVP) is the antidiuretic hormone in all mammals except swine and other members of the suborder Suina, in which lysine vasopressin is synthesized (Reeves et al, 1998). Vasopressin differs from oxytocin in most mammals only in the substitution of phenylalanine for isoleucine in the ring and arginine for leucine in the tail. The ratio of antidiuretic to pressor effects of vasopressin is increased markedly by substituting d-arginine for l-arginine at position 8. This modification, as well as removal of the terminal amino group from cysteine, yields 1 deamino (8 d-arginine) vasopressin (DDAVP), a synthetic commercially available product (see Fig. 1-3). DDAVP is a clinically useful analogue with prolonged and enhanced antidiuretic activity that does not require injection to be effective.

FIGURE 1-3 The chemical structures of oxytocin, vasopressin, and 1 deamino (8 D-arginine) vasopressin (DDAVP).

The production of vasopressin and oxytocin is associated with synthesis of specific binding proteins called neurophysins. One molecule of neurophysin I (estrogen-stimulated neurophysin) binds one molecule of oxytocin, and one molecule of neurophysin II (nicotine-stimulated neurophysin) binds one molecule of vasopressin (Reeves et al, 1998). The neurophysin peptide combination, often referred to as neurosecretory material, is transported along the axons of the hypothalamo-neurohypophyseal nerve tract and stored in granules in the nerve terminals located in the posterior pituitary gland (see Fig. 1-2). Release of vasopressin into the bloodstream occurs following electrical activation of the neurosecretory cells containing AVP. Secretion proceeds by a process of exocytosis, with release of vasopressin and neurophysin II into the bloodstream. In plasma, the neurophysin-vasopressin combination dissociates to release free vasopressin. Nearly all of the hormone in plasma exists in an unbound form, which because of its relatively low molecular weight, readily permeates peripheral and glomerular capillaries. Metabolic degradation of AVP appears to be mediated through binding of AVP to specific hormone receptors, with subsequent proteolytic cleavage of the peptide (Reeves et al, 1998). Renal excretion is the second method for elimination of circulating hormone and accounts for about one-fourth of total metabolic clearance.

ACTIONS OF VASOPRESSIN.

Clinical Effect.

The primary effect of AVP is to conserve body fluid by reducing the volume of urine production (Table 1-1). This antidiuretic action is achieved by promoting the reabsorption of solute free water in the distal and/or collecting tubules of the kidney. In the absence of AVP, the membranes lining this portion of the nephron are uniquely resistant to the diffusion of both water and solutes. Hence the hypotonic filtrate formed in the more proximal portion of the nephron passes unmodified through the distal tubule and collecting duct. In this condition, referred to as water diuresis, urine osmolality is low and urine volume is great (see Fig. 1-5).

TABLE 1-1 ACTIONS OF VASOPRESSIN

Target Organ	Action
Kidney Cortical and outer medullary collecting ducts Papillary collecting ducts Thick ascending limb of the loop of Henle Juxtaglomerular cells Heart Arterioles Brain Liver Adenohypophysis (anterior pituitary)	Enhances water permeability Enhances water and urea permeability Suppresses renin release Bradycardia Constriction Enhances passive avoidance behavior Enhances glycogenolysis and fatty acid synthesis Promotes ACTH secretion

In the presence of AVP and normal renal receptor activity, the hydro-osmotic permeability of the distal and collecting tubules increases, allowing water to back-diffuse down the osmotic gradient that normally exists between tubular fluid and the isotonic or hypertonic milieu of the renal cortex and medulla. Because water is reabsorbed without solute, the urine that remains within the lumen of the nephron has an increased osmotic concentration, as well as a decreased rate of flow through the tubules. The amount of water reabsorbed in the distal nephron depends on the plasma AVP concentration and the existence of a significant osmotic gradient in the renal interstitium. Vasopressin does not cause an active (i.e., energy-requiring) reabsorption of solute free water. It merely “opens the water channels” in the luminal membrane to allow water to flow in the direction of the higher osmolality (along the osmotic gradient). In the normal animal, the osmolality of the filtrate entering the distal tubule is low, whereas that of the renal interstitium is high, promoting reabsorption of water when the pores are open. Increasing the renal medullary interstitial osmolality increases the ability to reabsorb water and concentrate urine; thus desert rodents with extremely concentrated medullary interstitium can produce urine more concentrated than that of dogs and are remarkably capable of conserving fluid. Conversely, loss of the renal medullary hypertonicity may inhibit vasopressin’s antidiuretic activity (see Fig. 1-5). Decreased medullary hypertonicity (or lack thereof) can result from various causes, such as chronic water diuresis or reduced medullary blood flow. However, because a majority of fluid flowing from the loop of Henle can still be reabsorbed isotonically in the distal convoluted tubule and proximal collecting duct, loss of the hypertonic medullary concentration gradient alone rarely results in marked polyuria (Robertson, 1981).

FIGURE 1-5 Schematic representation of the effect of vasopressin on the formation of urine by the human nephron. The osmotic pressure of tissue and tubular fluid is indicated by the density of the shading. The numbers within the lumen of the nephron indicate typical rates of flow in milliliters per minute. Arrows indicate reabsorption of sodium (Na) or water (H₂O) by active (solid arrows) or passive (broken arrows) processes. Note that vasopressin acts only on the distal nephron, where it increases the hydro-osmotic permeability of tubular membranes. The fluid that reaches this part of the nephron normally amounts to between 10% and 15% of the total filtrate and is hypotonic owing to selective reabsorption of sodium in the ascending limb of the loop of Henle. In the absence of vasopressin, the membranes of the distal nephron remain relatively impermeable to water, as well as to solute, and the fluid issuing from Henle’s loop is excreted essentially unmodified as urine. With maximum vasopressin action, all but 5% to 10% of the water in this fluid is reabsorbed passively down the osmotic gradient that normally exists with the surrounding tissue. Remember that the concentration of the canine renal medullary interstitial fluid can be greater than 2500 mOsm/kg.

(Reprinted with permission from Frohman LA, Krieger DT: In Felig P, et al (eds): Endocrinology and Metabolism. New York, McGraw Hill Book Co, 1981, p 258.)

It should be noted that 85% to 90% of the fluid filtered by the glomerulus is reabsorbed isosmotically with sodium and glucose in the proximal portion of the nephron. Sodium is then selectively reabsorbed from the remaining fluid, making the fluid hypotonic as it reaches the distal nephron. An additional 90% of this remaining fluid can be reabsorbed under the influence of AVP (Robertson, 1981). However, if the oral intake of salt is high or if a poorly reabsorbed solute such as mannitol, urea, or glucose is present in the glomerular filtrate, fluid resorption from the proximal tubule is impaired. The resultant increase in fluid volume presented to the distal nephron may overwhelm its limited capacity to reabsorb water. As a consequence, urine osmolality decreases and volume increases, even in the presence of large amounts of vasopressin. This type of polyuria is referred to as solute diuresis to distinguish it from that due to a deficiency of vasopressin action (see Complications of the Modified Water Deprivation Test, page 29). Conversely, in clinical situations such as congestive heart failure, in which the proximal nephron reabsorbs increased amounts of filtrate, the capacity to excrete solute free water is greatly reduced, even in the absence of vasopressin.

The physiologic significance of other vasopressin actions, listed in Table 1-1, is less clear. It has been suggested that the pressor actions of vasopressin are somehow important in the maintenance of blood pressure during hypovolemia. Vasopressin also acts on the gastrointestinal tract and the central nervous system (CNS). The neurophysins have no recognized biologic action apart from complexing oxytocin and vasopressin in neurosecretory granules of the neurohypophysis.

THIRST CENTER.

Consumption of water to preserve body fluid tonicity is governed by the sense of thirst, which in turn is regulated by many of the same factors that determine AVP release. The sensation of thirst is controlled by osmoreceptors located close to the AVP synthesizing cells in the hypothalamus. The specificities of the osmoregulation of thirst and of AVP release are similar (e.g., hypertonic NaCl stimulates both thirst and AVP release), whereas hypertonic urea or glucose stimulates neither (Reeves et al, 1998). In spite of the functional similarities of the osmoregulation of thirst and AVP secretion, electrophysiologic studies indicate that they are mediated by two distinct but adjacent osmoreceptors.

REGULATION OF THIRST AND VASOPRESSIN SECRETION.

Changes in plasma osmolality and blood volume are the most important mechanisms controlling thirst and vasopressin secretion.

Plasma Osmolality.

The most important stimulus for thirst and vasopressin secretion under physiologic conditions is plasma osmolality. At plasma osmolalities below a certain minimum or threshold value (approximately 280 mOsm/kg), plasma vasopressin is uniformly suppressed to low or undetectable levels. Above this point, plasma vasopressin and the sensation of thirst increase in direct proportion to increases in plasma osmolality (Fig. 1-6). The relationship among thirst, plasma AVP concentration, and plasma osmolality is quite sophisticated. Increases of as little as 1% in plasma osmolality result in stimulation of water intake and vasopressin secretion (Hammer et al, 1980).

FIGURE 1-6 The relationship between plasma osmolality and plasma vasopressin level.

(Adapted from Robertson GL, Berl T: Water metabolism. In Brenner BM, Rector FC Jr (eds): The Kidney, 3rd ed. Philadelphia, WB Saunders, 1986, p 385.)

The osmoreceptor is not equally sensitive to all plasma solutes. Sodium and its anions, which normally contribute more than 95% of the total osmotic pressure of plasma, are the most potent solutes known to stimulate thirst and vasopressin secretion. Certain sugars, such as mannitol and sucrose, are also effective when administered intravenously. Conversely, an increase in plasma osmolality due to urea or glucose causes little or no direct stimulation of vasopressin secretion. Precisely how and why the osmoreceptor discriminates so effectively between different kinds of plasma solutes are still unsettled. One theory involves the osmotic decrease in cellular water content (i.e., cellular dehydration) created by a given solute, which would depend on the permeability characteristics unique to the osmoreceptor cell membrane. Cellular dehydration occurs when extracellular fluid osmolality is increased by a solute that cannot penetrate cell membranes. This causes water to be withdrawn from cells in an effort to equilibrate the osmotic gradient that is formed. Cellular dehydration, in turn, provides the signal for secretion of vasopressin and consumption of water.

Studies indicate that an important role is also played by the blood-brain barrier, again suggesting unique permeability characteristics. Osmoreceptors appear to be situated in an area of the brain where the blood-brain barrier is deficient and are thus influenced by the composition of plasma rather than cerebrospinal fluid (Aron et al, 2001). Two circumventricular organs, the subfornical organ and the organum vasculosum of the lamina terminalis, lie outside the blood-brain barrier and are believed to be important for osmoreception, interaction with blood-borne hormones (e.g., angiotensin II), and regulation of AVP secretion by neurosecretory cells.

Miscellaneous Factors.

A variety of nonosmotic and nonhemodynamic factors may also stimulate AVP secretion. With varying potency, these factors include nausea, hypoglycemia, the renin angiotensin system, and nonspecific stress caused by factors such as pain, emotion, and physical exercise. A large number of drugs and hormones have also been implicated in the alteration of vasopressin secretion. This list includes agents that either stimulate or inhibit AVP secretion, as well as substances that potentiate or inhibit the renal tubular response to AVP (Table 1-2; see Fig 1-4; Reeves et al, 1998).

TABLE 1-2 DRUGS AND HORMONES REPORTED TO AFFECT VASOPRESSIN SECRETION OR ACTION

SECRETION
Stimulate AVP release	Inhibit AVP release
Acetylcholine	α-Adrenergic drugs
Anesthetic agents	Atrial natriuretic peptide
Angiotensin II	Glucocorticoids
Apomorphine	Haloperidol
β-Adrenergic drugs	Oxilorphan
Barbiturates	Phenytoin
Carbamazepine	Promethazine
Clofibrate
Cyclophosphamide
Histamine
Insulin
Metoclopramide
Morphine and narcotic analogues
Prostaglandin E2
Vincristine

RENAL
Potentiate AVP action	Inhibit AVP action
Aspirin	α-Adrenergic drugs
Carbamazepine	Atrial natriuretic peptide
Chlorpropamide	Barbiturates
Nonsteroidal anti-inflammatory agents	Demeclocycline
	Glucocorticoids
Thiazides	Hypercalcemia
	Hypokalemia
	Methoxyflurane
	Prostaglandin E2
	Protein kinase C
	Tetracyclines
	Vinca alkaloids

FIGURE 1-4 Effects of selected drugs and electrolytes on vasopressin release and action. AA, arachidonic acid; AC, adenyl cyclase; PGE, prostaglandin E; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; PDE, phosphodiesterase;5’AMP, 5’-adenosine monophosphate.

(From DeBartola SP: Disorders of sodium and water: Hypernatremia and hyponatremia. In DiBartola SP (ed): Fluid Therapy in Small Animal Practice, 2nd ed. Philadelphia, WB Saunders, 2000, p 52.)

SATIATION OF THIRST.

Dehydrated animals have a remarkable capacity to consume the appropriate volume of water to repair a deficit. It has been demonstrated that dogs deprived of water for various periods of time drink just the volume of water needed to meet the deficit within 5 minutes. All animals have this capacity, although some species take longer to ingest the required amount of fluid. Satiation of thirst in dogs and cats requires restoration of normal plasma osmolality and blood volume, with correction of plasma osmolality playing the major role. In dogs with hypertonic volume depletion, restoration of osmolality in the carotid circulation without correcting osmolality outside the CNS caused a 70% decrease in drinking (Reeves et al, 1998). Restoration of blood volume in these dogs without ameliorating plasma hypertonicity reduced drinking by about 30%. Additional mechanisms may also play a minor role, including gastric distention and perhaps the participation of receptors in the liver. Similar inhibitory influences affect vasopressin secretion. Following voluntary rehydration in dehydrated animals, plasma vasopressin secretion returns to normal before redilution of the body fluids has been completed.

DIABETES MELLITUS.

Diabetes mellitus is one of the most common endocrinopathies in the dog and cat. As glucose utilization diminishes as a result of relative or absolute insulin deficiencies, glucose accumulates in the blood. When the rising blood glucose concentration exceeds the renal tubular capacity for glucose reabsorption, glucose appears in the urine and acts as an osmotic diuretic, causing increased water loss into the urine. The water loss results in hypovolemia, which in turn stimulates increased water intake. Urinalysis and fasting blood glucose measurement are usually sufficient screening tests for diagnosing diabetes mellitus.

PRIMARY RENAL GLYCOSURIA.

This uncommon disorder is seen primarily in the Basenji and Norwegian Elkhound. Primary renal glycosuria is a congenital renal tubular disorder resulting in an inability to reabsorb glucose from the ultrafiltrate in the nephron. In some dogs and cats, renal glycosuria may also be a component of a Fanconi-like syndrome, in which phosphate, potassium, uric acid, amino acids, sodium, and/or bicarbonate may also be inadequately reabsorbed from the ultrafiltrate. As in diabetes mellitus, glucose appears in the urine and acts as an osmotic diuretic, causing polyuria and, in turn, polydipsia. Urinalysis and fasting blood glucose measurement are sufficient initial screening tests for this disorder.

CHRONIC RENAL FAILURE.

Chronic renal failure is a syndrome in which the number of functioning nephrons progressively decreases as a result of structural damage to the kidney, as occurs with chronic interstitial nephritis, medullary interstitial amyloidosis, and chronic pyelonephritis. A compensatory increase is seen in glomerular filtration rate (GFR) per surviving nephron, but the amount of fluid presented to the distal renal tubules is increased. Increased tubular flow rate causes less urea, sodium, and other substances to be reabsorbed. The result is an osmotic diuresis that is further complicated by a reduced renal medullary concentration gradient. These factors contribute to polyuria. The water loss results in hypovolemia, which causes compensatory polydipsia. Such animals may have increased blood urea nitrogen (BUN), creatinine, and inorganic phosphorus concentrations, as well as nonregenerative anemia and isosthenuric urine (urine specific gravity of 1.008 to 1.015).

POSTOBSTRUCTIVE DIURESIS.

Postobstructive diuresis may occur in any animal but is most common after urethral obstruction is relieved in male cats with feline lower urinary tract disease (i.e., feline urologic syndrome). These animals often have dramatic elevations in BUN, which results from the obstruction and creates a marked osmotic diuresis once the obstruction is relieved. Postobstructive diuresis is self-limiting. The veterinarian, however, must be aware of this problem and maintain the animal’s hydration through aggressive fluid therapy, which can be slowly decreased over several days as the uremia clears and the osmotic diuresis declines.

PYOMETRA.

Bacterial endotoxins, especially those associated with Escherichia coli, can compete with AVP for its binding sites on the renal tubular membrane, causing a potentially reversible renal tubular insensitivity to AVP. The kidneys have an impaired ability to concentrate urine and conserve water, and polyuria with compensatory polydipsia develops. Pyometra is the most common infectious disorder associated with the development of polyuria and polydipsia, although it has also been reported with prostatic abscessation, pyelonephritis, and septicemia (Barsanti et al, 2000). Affected bitches and queens may produce extremely dilute urine, causing fluid depletion and compensatory polydipsia. Normal urine-concentrating ability usually returns within days of successfully eliminating pyometra. The diagnosis of secondary NDI is presumptive in any polyuric/polydipsic bitch or queen with pyometra.

HYPERCALCEMIA.

Increases in serum calcium concentration may inhibit binding of AVP to its receptor site, damage AVP receptors in the renal tubules, inactivate adenyl cyclase and interfere with the action of AVP at the renal tubular level (acquired NDI), or decrease transport of sodium and chloride into the renal medullary interstitium. Polydipsia and polyuria are common early signs of hypercalcemia, which is easily diagnosed with a serum biochemistry panel. Once hypercalcemia is identified, the clinician must undertake an often extensive diagnostic evaluation to determine its cause (see Chapter 16).

HEPATIC INSUFFICIENCY AND PORTOSYSTEMIC SHUNTS.

Liver insufficiency and portosystemic shunts are recognized causes of polyuria and polydipsia. Many of the metabolic causes of polyuria and polydipsia (e.g., diabetes mellitus, hyperadrenocorticism, hypercalcemia) secondarily affect the liver, making it difficult to determine the role of the liver in causing polyuria and polydipsia. The exact cause of the polyuria is not known but may involve loss of medullary hypertonicity secondary to impaired urea nitrogen production or altered renal blood flow, increased GFR and renal volume, hypokalemia, impaired metabolism of cortisol, and primary polydipsia (Deppe et al, 1999). Urea nitrogen is a major constituent in the establishment and maintenance of the renal medullary concentration gradient. Without urea nitrogen the kidney loses the ability to concentrate urine, causing polyuria and compensatory polydipsia. Hepatic insufficiency and portosystemic shunts are usually suspected after evaluation of a complete blood count (CBC), serum biochemistry panel, urinalysis, and abdominal ultrasonography; these causes are confirmed with a liver function test (e.g., pre- and postprandial bile acids, ammonia tolerance test), specialized diagnostic imaging (e.g., positive contrast portogram, technetium scan) and histologic evaluation of an hepatic biopsy.

HYPERADRENOCORTICISM (CUSHING’S SYNDROME).

Polyuria and polydipsia are common clinical signs of hyperadrenocorticism. Glucocorticoids inhibit AVP release by a direct effect within the hypothalamus and/or neurohypophysis (Papanek and Raff, 1994; Papanek et al, 1997). This inhibition of AVP release is characterized by both an increase in osmotic threshold and a decrease in the sensitivity of the AVP response to increasing osmolality (Biewenga et al, 1991). Hyperadrenocorticism also causes resistance to the effect of AVP in the kidney, possibly through interference with the action of AVP at the level of the renal collecting tubules or direct depression of renal tubular permeability to water. In a few patients, a deficiency in AVP may result from direct compression of neurosecretory cells by an enlarging pituitary tumor. Suspicion of hyperadrenocorticism is usually aroused after careful review of the history, physical examination, and results of CBC, serum biochemistry panel, and urinalysis. Confirmation requires appropriate pituitary adrenocortical function tests (see Chapter 6).

PRIMARY HYPERALDOSTERONISM.

Polyuria and polydipsia have been reported in cats and dogs with primary hyperaldosteronism. The mechanism for polyuria and polydipsia is not clear, although mineralocorticoid-induced renal resistance to the actions of AVP and disturbed osmoregulation of AVP release has been documented in a dog with primary hyperaldosteronism (Rijnberk et al, 2001). Similar abnormalities have been identified in dogs with glucocorticoid excess, suggesting similar mechanisms of action for the polyuria and polydipsia in hyperaldosteronism and hyperadrenocorticism. The typical findings with primary hyperaldosteronism include weakness, severe hypokalemia, hypernatremia, systemic hypertension and adrenomegaly on abdominal ultrasound. Plasma aldosterone concentrations before and after ACTH administration are increased, and plasma renin activity is suppressed (see Chapter 6).

PYELONEPHRITIS.

Infection and inflammation of the renal pelvis can destroy the countercurrent mechanism in the renal medulla, resulting in isosthenuria, polyuria, polydipsia, and eventually renal failure. Bacterial endotoxins, especially those associated with Escherichia coli, can also compete with AVP for its binding sites on the renal tubular membrane, causing a potentially reversible renal tubular insensitivity to AVP. A dog or cat with acute bacterial pyelonephritis may develop nonspecific systemic signs of lethargy, anorexia, and fever, and a neutrophilic leukocytosis may be identified on a CBC. Systemic signs are usually not present with chronic pyelonephritis. Pyelonephritis should also be suspected in a patient with recurring urinary tract infection. Urinalysis may reveal white blood cells and white blood cell casts, bacteria, and occasionally red blood cells. Culture of urine obtained by antepubic cystocentesis should be positive for bacterial growth. Abdominal ultrasonography and excretory urography may reveal abnormalities consistent with pyelonephritis (e.g., renal pelvis dilatation).

HYPOKALEMIA.

Hypokalemia is believed to render the terminal portion of the nephron less responsive to AVP, possibly by suppressing the generation of intracellular cAMP in renal tubular cells. Hypokalemia may also affect the hypertonic medullary interstitial gradient by interfering with solute accumulation and may interfere with release of AVP from the pituitary. Polyuria and polydipsia are not common clinical signs of hypokalemia. The most common clinical signs are related to neuromuscular dysfunction of skeletal, cardiac, and smooth muscle (e.g., weakness, cervical ventriflexion). Hypokalemia usually develops secondary to another disorder (Table 1-4), many of which also cause polyuria and polydipsia.

TABLE 1-4 CAUSES OF HYPOKALEMIA IN THE DOG AND CAT

* Common cause.

HYPOADRENOCORTICISM (ADDISON’S DISEASE).

Adrenocortical insufficiency results in impaired ability to concentrate urine (see Chapter 8). Despite normal kidney function and severe hypovolemia, most dogs with hypoadrenocorticism have a urine specific gravity of less than 1.030. Mineralocorticoid deficiency results in chronic sodium wasting, renal medullary solute washout, and loss of the medullary hypertonic gradient. Adrenalectomy in rats also decreases AVP-stimulated activation of renal medullary adenylate cyclase, primarily because of impairment in the coupling between the AVP receptor complex and adenylate cyclase. Treatment with dexamethasone corrects the defect. Hypercalcemia occurs in some patients with hypoadrenocorticism and may also play a role in the generation of polyuria and polydipsia.

Polyuria and polydipsia typically develop early in the course of the disease and are quickly overshadowed by the more worrisome and obvious vomiting, diarrhea, anorexia, weakness, and depression seen in these patients. The polyuria of hypoadrenocorticism can be difficult to differentiate from primary renal failure unless specific tests of the pituitary adrenocortical axis (e.g., ACTH stimulation test) are performed. Initial suspicion for hypoadrenocorticism usually follows evaluation of serum electrolytes, although hyperkalemia and hyponatremia can also occur with renal insufficiency.

HYPERTHYROIDISM.

Polyuria and polydipsia are common findings in cats and dogs with hyperthyroidism. The exact mechanism for the polyuria and polydipsia is not clear. Increased renal medullary blood flow may decrease medullary hypertonicity and impair water resorption from the distal portion of the nephron. Psychogenic polydipsia secondary to thyrotoxicosis and, in some patients, concurrent renal insufficiency may also contribute to the polyuria and polydipsia. The tentative diagnosis of hyperthyroidism is usually based on clinical signs, palpation of an enlarged thyroid lobe or lobes (i.e., goiter), and measurement of serum thyroxine (T₄) concentration.

ACROMEGALY.

Excessive secretion of growth hormone (GH) in the adult dog or cat results in acromegaly (see Chapter 2). Acromegaly causes carbohydrate intolerance and the eventual development of overt diabetes mellitus. In most cats and dogs with acromegaly, the polyuria is assumed to be caused by an osmotic diuresis induced by glycosuria. Renal insufficiency from a diabetic or GH-induced glomerulonephropathy may also play a role (Peterson et al, 1990).

POLYCYTHEMIA.

Polyuria and polydipsia may occur with polycythemia. Studies in 2 dogs with secondary polycythemia identified an increased osmotic threshold for AVP release, resulting in a delayed AVP response to increasing plasma osmolality (van Vonderen et al, 1997a). The authors attributed the abnormal AVP response to increased blood volume and hyperviscosity, which stimulate atrial natriuretic peptide (ANP) secretion and atrial and carotid bifurcation baroreceptors. ANP inhibits AVP release from the pituitary gland and the renal collecting duct’s responsiveness to AVP (Dillingham and Anderson, 1986; Lee et al, 1987).

DEFINITION.

CDI is a polyuric syndrome that results from a lack of sufficient AVP to concentrate the urine for water conservation. This deficiency may be absolute or partial. An absolute deficiency of AVP causes persistent hyposthenuria and severe diuresis. Urine specific gravity in dogs and cats with complete lack of AVP usually remains hyposthenuric (≤1.006), even with severe dehydration. A partial deficiency of AVP, referred to as a partial CDI, also causes persistent hyposthenuria and a marked diuresis as long as the dog or cat has unlimited access to water. During periods of water restriction, however, dogs and cats with partial CDI can increase their urine specific gravity into the isosthenuric range (1.008 to 1.015) but cannot typically concentrate their urine above 1.015 to 1.020, even with severe dehydration. For any dog or cat with partial CDI, maximum urine-concentrating ability during dehydration is inversely related to the severity of the deficiency in AVP secretion; that is, the more severe the AVP deficiency, the less concentrated the urine specific gravity during dehydration.

PATHOPHYSIOLOGY.

Destruction of the production sites for vasopressin–the supraoptic and paraventricular nuclei of the hypothalamus–and/or loss of the major ducts (axons) that carry AVP to the storage and release depots in the posterior pituitary (see Fig. 1-2) result in CDI. Permanent CDI requires an injury that is sufficiently high in the neurohypophyseal tract to cause bilateral neuronal degeneration in the supraoptic and paraventricular nuclei. Transection of the hypothalamic hypophyseal tract below the median eminence or removal of the posterior lobe of the pituitary usually causes transient (albeit severe) CDI and polyuria because sufficient hormone can be released from fibers ending in the median eminence and pituitary stalk to prevent occurrence of permanent diabetes insipidus (Fig. 1-8; Ramsay, 1983).

FIGURE 1-8 Mean urine specific gravity obtained before and for 3 months after hypophysectomy in four dogs treated with intraoperative polyionic fluids (solid line) and four dogs treated with intraoperative polyionic fluids and dexamethasone (dashed line).

(From Lantz GC, et al: Am J Vet Res 49: 1134, 1988.)

A triphasic response sufficient to cause diabetes insipidus has been reported following surgical damage to the hypothalamus of cats. Immediately following creation of the lesion, polydipsia and polyuria began and usually lasted 4 to 5 days. This was followed by a 6-day period of intense antidiuresis and then recurrence of permanent CDI. The first phase is believed to result from the acute damage that causes disruption in the ability to release stored AVP. The antidiuretic stage results from degeneration of hormone-laden tissue with release of excessive amounts of AVP into the circulation. This is supported by a lack of the usual diuretic response following administration of a water load during the second stage. If the posterior pituitary is also removed at the time of hypothalamic damage, the antidiuretic phase is not observed. With only minor damage to the hypothalamus, permanent CDI may not follow the second phase.

ETIOLOGY.

CDI may result from any condition that damages the neurohypophyseal system. Recognized causes for CDI in the dog and cat are listed in Table 1-7. Idiopathic cases of CDI are the most common, appearing at any age in any breed in either gender. Necropsies performed in dogs and cats with idiopathic CDI fail to identify an underlying reason for the AVP deficiency.

TABLE 1-7 RECOGNIZED CAUSES OF CENTRAL DIABETES INSIPIDUS IN HUMANS, DOGS, AND CATS

Autoimmune hypothalamitis has been suggested as a possible cause of idiopathic CDI in humans (Salvi et al, 1988). Circulating AVP cell antibodies, which bind to cell membranes of hypothalamic preparations, have been identified in some humans with CDI (Scherbaum, 1987). AVP cell antibodies have been identified prior to the development of CDI, and titers of AVP cell antibodies decline eventually to negative values with increasing duration of the disease (Bhan and O’Brien, 1982; Scherbaum et al, 1986). These patients also show a significant association with other endocrine disorders (e.g., immune thyroiditis, Addison’s disease), suggesting that, at least in some cases, polyendocrine autoimmunity may also involve the hypothalamus (see Chapter 3, page 91). A similar association between CDI and other endocrinopathies has not been identified in dogs and cats, nor have studies examining a possible immune basis for CDI been reported.

The most common identifiable causes for CDI in dogs and cats are head trauma (accidental or neurosurgical), neoplasia, and hypothalamic/pituitary malformations (e.g., cystic structures). Head trauma may cause transient or permanent CDI, depending on the viability of the cells in the supraoptic and paraventricular nuclei. Trauma-induced transection of the pituitary stalk often results in transient CDI, usually lasting 1 to 3 weeks (see Fig. 1-8; Lantz et al, 1988; Authement et al, 1989). The duration of diabetes insipidus depends on the location of the transection of the hypophyseal stalk relative to the hypothalamus. Transection at more proximal levels, close to the median eminence, is associated with a longer time for hypothalamic axons to undergo regeneration and secretion of ADH. Trauma-induced CDI should be suspected when severe polydipsia and polyuria develop within 48 hours of head trauma or when hypernatremia, hyposthenuria and hypertonic dehydration develop in a traumatized dog or cat that is being treated with intravenous fluids rather than water ad libitum (see page 29).

Primary intracranial tumors associated with diabetes insipidus in dogs and cats include craniopharyngioma, pituitary chromophobe adenoma, and pituitary chromophobe adenocarcinoma (Fig. 1-9; Neer and Reavis, 1983; Goossens et al, 1995; Harb et al, 1996). Tumor metastases to the hypothalamus and pituitary can also cause CDI. In humans, metastatic tumors most often spread from the lung or breast (Reeves et al, 1998). Metastatic mammary carcinoma, lymphoma, malignant melanoma, and pancreatic carcinoma have been reported to cause CDI by their presence in the pituitary gland or hypothalamus in dogs (Capen and Martin, 1983; Davenport et al, 1986). Metastatic neoplasia as a cause for CDI has not yet been reported in the cat.

FIGURE 1-9 Transverse (A) and sagittal (B) magnetic resonance images of the pituitary region in a 12-year-old male Boxer with central diabetes insipidus, hypothyroidism, and neurologic signs. A mass is evident in the region of the pituitary gland, hypothalamus, and rostral floor of the calvarium (arrows).