Water Metabolism and Diabetes Insipidus

Chapter 1 WATER METABOLISM AND DIABETES INSIPIDUS



Water consumption and urine production are controlled by complex interactions between plasma osmolality, fluid volume in the vascular compart-ment, the thirst center, the kidney, the pituitary gland, and the hypothalamus. Dysfunction in any of these areas results in the clinical signs of polyuria and polydipsia. Vasopressin (antidiuretic hormone [ADH]) plays a key role in the control of renal water resorption, urine production and concentration, and water balance. In the presence of vasopressin and dehydration, the average dog and cat can pro-duce urine concentrated to or above 2300 mOsm/kg. In the absence of vasopressin or vasopressin action on the kidneys, the urine may be as dilute as 20 mOsm/kg.


Diabetes insipidus results from deficiencies in secretion of vasopressin or in its ability to interact normally with receptors located in the distal and collecting tubular cells of the kidney. The result of either disorder is impaired ability to conserve water and concentrate urine, with production of dilute urine and compensatory polydipsia. Because of the dramatic polyuria and polydipsia associated with diabetes mellitus and diabetes insipidus, the term diabetes was historically used for both conditions. However, the urine is tasteless (insipid) with diabetes insipidus because, unlike in diabetes mellitus (in which the urine is sweet from sugar), polyuria in diabetes insipidus is not the result of a glucose-induced osmotic diuresis.




PHYSIOLOGY OF WATER METABOLISM





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.



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.




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.



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.


Cellular Actions.

AVP acts via tissue receptors classified as V1 receptors in smooth muscle and V2 receptors in renal epithelia (Reeves et al, 1998). Only the latter receptors activate adenylate cyclase. The antidiuretic action of AVP is mediated through V2 cyclic AMP-dependent receptors, whereas its vasoconstrictive action is mediated through V1 phosphatidylinositol dependent receptors. Vasopressin stimulates V1 and V2 receptors, whereas the vasopressin analogue, desmopressin (DDAVP), which is commonly used for the treatment of central diabetes insipidus, has a strong affinity for V2 receptors with minimal pressor (V1) activity.


The major antidiuretic contribution of AVP is to increase the water permeability of terminal nephron segments or collecting ducts. The effects of AVP are mediated primarily by the intracellular second messenger cAMP (Fig. 1-4). AVP binds to the V2 receptors of hormone-responsive epithelial cells and activates membrane-associated adenylate cyclase to catalyze cAMP generation from ATP. cAMP-dependent activation of the protein kinase system leads to an increase in the water permeability of the luminal membrane of the cell as a result of insertion of aquaporin-2 water channels into the apical membrane of the epithelial cell. Transmembrane water movement occurs through these water channels, rather than by diffusion across the lipid bilayer or through junctional complexes (Fig. 1-5; Kanno et al, 1995; Lee et al, 1997). In essence, AVP, working via cAMP and protein kinase, alters water transport in hormone-responsive epithelia by causing the microtubule-dependent insertion of specialized membrane units (aquaporin-2 water channels) into the apical plasma membranes of these cells. The increase in water permeability in these segments augments osmotic water flow from the tubular lumen into a hypertonic medullary interstitium, thus providing for maximal urine concentration during antidiuresis (Reeves et al, 1998).


The intracellular concentration of cAMP appears to be the primary factor regulating the cellular actions of AVP. Increased concentrations of cAMP result from either enhanced formation (i.e., stimulation of adenyl cyclase following the interaction of AVP with receptors) or decreased catabolism. cAMP phosphodiesterase catalyzes the breakdown of cAMP to 5’AMP. Several drugs, hormones, and disease conditions change the renal tubular response to AVP by altering the interaction of AVP with its receptor, the activation of adenyl cyclase, or the catabolism of cAMP.


The collecting ducts convey urine from the distal tubule and collecting tubule to the renal pelvis. As the collecting ducts traverse the renal medulla, the urine within the ducts passes through regions of ever-increasing osmolality, up to a maximum of 2000 to 2500 mOsm/kg of water at the tip of the canine renal papilla. In the presence of vasopressin, collecting duct fluid moves into and equilibrates with this hyperosmotic environment until urine osmolality approaches that of medullary interstitial fluid. Vasa recta distribute absorbed water into the systemic circulation, maintaining the hypertonicity of the medullary interstitium. Vasopressin also increases the permeability of the papillary collecting duct epithelium to urea. Thus urine production is low in the presence of vasopressin and high in its absence.



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















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).



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.




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).



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.



Blood Volume and Pressure.

Thirst and AVP secretion may be stimulated by contraction of the extracellular fluid volume without a change in plasma osmolality. Such an extracellular fluid loss may occur secondary to hemorrhage, for example, and results in both increased fluid consumption and vasopressin secretion. Small decreases in volume have little effect on AVP secretion, but any reduction exceeding 10% of the extracellular fluid causes marked stimulation that not only conserves water but may also be important in maintaining blood pressure (Aron et al, 2001).


Volume-mediated release of AVP may occur as a consequence of stimuli arising from “volume receptors,” or baroreceptors. Low pressure baroreceptors are located in the venous bed of the systemic circulation, the right side of the heart, and the left atrium, whereas high pressure baroreceptors are located within the systemic arterial system of the carotid sinus and aortic arch (Reeves et al, 1998). The electrical activity of the baroreceptor is related to the degree of stretch in the vessel wall. Increases in pressure and wall tension increase receptor firing rate, whereas decreases in blood pressure or blood volume decrease electrical activity. An inverse relationship exists between baroreceptor electrical activity and AVP secretion; that is, decreased electrical activity of the baroreceptor stimulates AVP secretion. The afferent pathways for the atrial and carotid bifurcation baroreceptors appear to be the vagus and glossopharyngeal nerves, respectively. Electrical activation of the thirst center and neurosecretory cells containing AVP is controlled by groups of neurons located in the anterior hypothalamus near, but distinct from, the supraoptic and paraventricular nuclei.


The renin angiotensin system also participates in the regulation of AVP release. In all animal species studied, angiotensin is an effective dipsogen (thirst stimulant). In addition, particularly in the presence of a raised plasma osmolality, angiotensin may stimulate AVP release by direct action on AVP producing neurons and by stimulating afferent pathways from other regions of the brain. Hypovolemia stimulates renin secretion, which promotes angiotensin formation. The relative roles of the direct baroreceptor input versus angiotensin mechanisms in the thirst response to extracellular dehydration have yet to be determined.



Interaction of Plasma Osmolality and Blood Volume.

Normal day-to-day regulation of water balance involves interaction between osmotic and volume stimuli. In the case of vasopressin secretion, decreases in extracellular fluid volume sensitize the release of vasopressin to a given osmotic stimulus. Thus for a given increase in plasma osmolality, the increase in plasma vasopressin concentration is greater in hypovolemic states than with normovolemia.


In dehydration, an increase in plasma osmolality results in withdrawal of fluid from cells. The reduction in total body water is shared equally between intracellular and extracellular fluid compartments. The increase in plasma osmolality and the reduction of extracellular fluid volume act synergistically to stimulate vasopressin release. In salt depletion, however, plasma vasopressin concentrations remain constant or are slightly increased despite a fall in plasma osmolality. Hypovolemia in this situation, as a result of osmotic movements of water from the extracellular into the intracellular fluid space, appears to provide the sensitizing influence.


Thirst mechanisms also involve interactions between extracellular fluid volume and osmolality. During periods of dehydration, increased plasma osmolality provides approximately 70% of the increased thirst drive, and the remaining 30% is due to hypovolemia. In salt depletion, the situation is less clear, but the normal drinking behavior or increased drinking observed in experimental animals has been attributed to the associated hypovolemia (Ramsay, 1983).



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




DIFFERENTIAL DIAGNOSES FOR POLYDIPSIA AND POLYURIA


Increased thirst (polydipsia) and urine production (polyuria) are common owner concerns in small animal veterinary practice. In dogs and cats, normal water intake varies from 20 to 70 ml/kg per day, and normal urine output varies between 20 and 45 ml/kg per day (Barsanti et al, 2000). Polydipsia and polyuria in the dog and cat have been defined as water consumption greater than 100 ml/kg/day and urine production greater than 50 ml/kg/day, respectively. It is possible, however, for individual dogs and cats to have abnormal thirst and urine production within the limits of these normal values. Polyuria and polydipsia usually exist concurrently, and determining the primary component of the syndrome is one of the initial diagnostic considerations when approaching the problem of polydipsia and polyuria (see page 13).


A variety of metabolic disturbances can cause polydipsia and polyuria (Table 1-3). These disorders can be classified, on the basis of underlying pathophysiology, into primary pituitary and nephrogenic diabetes insipidus; secondary nephrogenic diabetes insipidus resulting from interference with the normal interaction of AVP with renal tubular V2 receptors, generation of intracellular cAMP, or renal tubular cell function, or from loss of the renal medullary interstitial concentration gradient; osmotic diuresis-induced polyuria and polydipsia; or interference with hypothalamic/pituitary secretion of AVP.


TABLE 1-3 DIFFERENTIAL DIAGNOSIS FOR POLYDIPSIA AND POLYURIA AND USEFUL DIAGNOSTIC TESTS










































































Disorder Diagnostic Aids
Diabetes mellitus Fasting blood glucose, urinalysis
Renal glycosuria Fasting blood glucose, urinalysis
Chronic renal failure BUN, creatinine, Ca:P, urinalysis
Postobstructive diuresis History, monitoring urine output
Pyometra History, CBC, abdominal radiography, abdominal ultrasonography
Escherichia coli & septicemia Blood cultures
Hypercalcemia Serum calcium
Hepatic insufficiency Biochemistry panel, bile acids, ammonia tolerance test, abdominal radiography and ultrasonography
Hyperadrenocorticism ACTH stimulation test, dexamethasone screening test, urine cortisol/creatinine ratio
Primary hyperaldosteronism Serum sodium and potassium, blood pressure, abdominal ultrasonography, ACTH stimulation test (aldosterone)
Bacterial pyelonephritis Urine culture, abdominal ultrasonography, excretory urography
Hypokalemia Serum potassium
Hyponatremia Serum sodium
Hypoadrenocorticism Na:K, ACTH stimulation test
Hyperthyroidism Serum thyroxine
Diabetes insipidus Modified water deprivation test
Psychogenic polydipsia Modified water deprivation test
Polycythemia CBC
Acromegaly Serum GH and IGF-I, CT scan
Paraneoplastic disorders
Intestinal leiomyosarcoma Abdominal ultrasonography, biopsy
Iatrogenic disorders History
Very low protein diet History



Osmotic diuresis









Acquired (secondary) nephrogenic diabetes insipidus


Several disorders may interfere with the normal interaction between AVP and its renal tubular receptors, affect renal tubular cell function, or decrease the hypertonic renal medullary interstitium, resulting in a loss of the normal osmotic gradient. Polyuria with a compensatory polydipsia results and can be quite severe. These disorders resemble primary NDI but are referred to as acquired or secondary, because AVP, AVP receptor sites, and postreceptor mechanisms responsible for water absorption are present.






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).




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







































Modified from DiBartola SP and De Morais HA: Disorders of potassium: Hypokalemia and hyperkalemia. In, DiBartola SP, editor: Fluid Therapy in Small Animal Practice, ed 2, Philadelphia, 2000, WB Saunders, p. 93. (source)


* Common cause.





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).



Primary and psychogenic polydipsia


Primary polydipsia is defined as a marked increase in water intake that cannot be explained as a compensatory mechanism for excessive fluid loss. In humans, primary polydipsia results from a defect in the thirst center or may be associated with mental illness (Reeves et al, 1998). Primary dysfunction of the thirst center resulting in compulsive water consumption has not been reported in the dog or cat, although an abnormal vasopressin response to hypertonic saline infusion has been reported in dogs with suspected primary polydipsia (van Vonderen et al, 1999). A psychogenic or behavioral basis for compulsive water consumption does occur in the dog but has not been reported in the cat. Psychogenic polydipsia may be induced by concurrent disease (e.g., hepatic insufficiency, hyperthyroidism) or may represent a learned behavior following a change in the pet’s environment. Polyuria is compensatory to prevent overhydration. Psychogenic polydipsia is diagnosed by exclusion of other causes of polyuria and polydipsia and by demonstrating that the dog or cat can concentrate urine to a specific gravity in excess of 1.030 after water deprivation. This syndrome is discussed in more detail in subsequent sections (page 17).





DIAGNOSTIC APPROACH TO POLYURIA AND POLYDIPSIA


Depending on the cause, the cost and time expenditure for evaluating a dog or cat with polyuria and polydipsia may be brief and inexpensive (e.g., diabetes mellitus) or time-consuming and costly (e.g., partial CDI). Therefore, the clinician should be reasonably sure that polyuria and polydipsia exist, preferably based on a combination of history, multiple random urine specific gravity determinations, and if necessary, quantitation of water consumption over several days with the dog or cat in the home environment. The average daily volume of water consumed by a dog is usually less than 60 ml/kg of body weight, with an upper normal limit of 100 ml/kg of body weight. Similar values are used for cats, although most cats drink considerably less than these amounts. If an owner knows the volume of water the pet is consuming in an average 24-hour period and if that amount exceeds the upper limit of normal, a diagnostic evaluation to determine the cause is warranted. If 24-hour water intake is normal, pathologic polyuria and polydipsia are unlikely and another inciting factor (e.g., hot weather) should be sought, or misinterpretation of polyuria (e.g., dysuria instead of polyuria) should be considered. If the owner is certain that a change in the volume of water consumption or urination exists, even though water consumption is still in the normal range, a diagnostic evaluation may still be warranted.


Assessment of urine specific gravity may be helpful in identifying polyuria and polydipsia and may provide clues to the underlying diagnosis, especially if multiple urine specific gravities are evaluated (Table 1-6). Urine specific gravity varies widely among healthy dogs and, in some dogs, can range from 1.006 to greater than 1.040 within a 24 hour period (van Vonderen et al, 1997b). Wide fluctuations in urine specific gravity have not been reported in healthy cats.



We prefer to have the owner collect several urine samples at different times of the day for 2 to 3 days, storing the urine samples in the refrigerator until they can be brought to the veterinary hospital for determination of urine specific gravity. Urine specific gravities measured from multiple urine samples that are consistently less than 1.030 (especially less than 1.020) support the presence of polyuria and polydipsia and the need for a diagnostic evaluation to determine the cause. Identification of one or more urine specific gravities greater than 1.030 supports normal urine concentrating ability and an intact, functioning pituitary vasopressin-renal tubular cell axis. Dogs and cats may still have polyuria and polydipsia despite identification of concentrated urine; possible differentials include disorders causing an osmotic diuresis (e.g., diabetes mellitus), psychogenic polydipsia and disorders in the regulation of AVP secretion (van Vonderen et al, 1999).


Many potential causes exist for the development of polyuria and polydipsia in dogs and cats (see Table 1-3), one of the least common being diabetes insipidus. An animal with a history of severe polydipsia and polyuria should be thoroughly evaluated for other causes of polydipsia and polyuria prior to performing specific diagnostic procedures for diabetes insipidus (Fig. 1-7). The array of differential diagnoses precludes premature or unsubstantiated formation of a diagnosis and treatment plan. It is necessary to establish a firm data base. Initial information allows inclusion or exclusion of the many common medical disorders associated with polyuria and polydipsia that are contrasted with the less common CDI, NDI, or psychogenic polydipsia.



Our diagnostic approach (see Fig. 1-7) to the animal with polyuria and polydipsia is initially to rule out the more common causes. Recommended initial diagnostic studies include a CBC, urinalysis with bacterial culture of urine obtained by antepubic cystocentesis, and a serum biochemistry profile that includes liver enzymes, BUN, calcium, phosphorus, sodium, potassium, cholesterol, blood glucose, total plasma protein, and plasma albumin. A serum thyroxine (T4) concentration should be measured in older cats. Depending on the history and physical examination findings, abdominal ultrasonography may be warranted to evaluate liver, kidney, adrenal, or uterine size and to search for calcified adrenals in patients with suspected hyperadrenocorticism. Careful evaluation of the history, physical examination findings, and initial data base usually provides the diagnosis outright (e.g., diabetes mellitus, pyometra) or offers clues that allow the clinician to focus on the underlying cause (e.g., increased serum alkaline phosphatase and cholesterol in hyperadrenocorticism).


Occasionally, the physical examination and initial data base are normal in the dog or cat with polyuria and polydipsia. Viable possibilities in these dogs and cats include diabetes insipidus, psychogenic water consumption, unusual hyperadrenocorticism, renal insufficiency without azotemia, and possibly mild hepatic insufficiency. Hyperadrenocorticism, renal insufficiency, and hepatic insufficiency should be ruled out before performing tests to establish a diagnosis of diabetes insipidus or psychogenic polydipsia. Diagnostic tests to consider include tests of the pituitary adrenocortical axis, liver function tests (e.g., pre- and postprandial bile acids), urine protein: creatinine ratio, contrast imaging of the kidney. and if indicated, renal biopsy.


Careful evaluation of urine specific gravity and urine protein loss may provide clues to the underlying diagnosis (Table 1-6). For example, if the urine specific gravity measured on multiple urine samples is consistently in the isosthenuric range (1.008 to 1.015), renal insufficiency should be considered the primary differential diagnosis, especially if the BUN and serum creatinine concentration are high normal or increased (i.e., ≥25 mg/dl and ≥0.8 mg/dl, respectively) and proteinuria is present. Although isosthenuria is relatively common in dogs with hyperadrenocorticism, psychogenic water consumption, hepatic insufficiency, pyelonephritis, and partial central diabetes insipidus with concurrent water restriction, urine specific gravities tend to fluctuate above (hyperadrenocorticism, psychogenic water consumption, hepatic insufficiency, pyelonephritis) and below (hyperadrenocorticism, psychogenic water consumption, partial central diabetes insipidus) the isosthenuric range in these disorders. In contrast, if the urine specific gravity is consistently less than 1.006, renal insufficiency and pyelonephritis are ruled out and diabetes insipidus, psychogenic water consumption, and hyperadrenocorticism should be considered.


The diagnosis of diabetes insipidus and psychogenic water consumption should be based on results of the modified water deprivation test, measurement of plasma osmolality, and response to synthetic vasopressin therapy (see Confirming the Diagnosis of Diabetes Insipidus, page 21). Ideally, all realistic causes of secondary acquired NDI should be ruled out before performing tests (especially the modified water deprivation test) to diagnose diabetes insipidus and psychogenic polydipsia. The recommended initial laboratory studies not only ensure that the veterinarian is pursuing a correct diagnosis but also alert the clinician to any concomitant medical problems. A logical, systematic approach may appear cumbersome but avoids misdiagnosis. More important, problems may be avoided by not subjecting an animal to unnecessary, expensive, and potentially harmful procedures, should the presumptive diagnosis be incorrect.



ETIOLOGY OF DIABETES INSIPIDUS AND PRIMARY POLYDIPSIA




Vasopressin deficiency-central diabetes insipidus




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).



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.



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.


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Jul 10, 2016 | Posted by in INTERNAL MEDICINE | Comments Off on Water Metabolism and Diabetes Insipidus

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