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Diabetes Insipidus a I C E L E F Y B CE Article #3 s a r a P Diabetes Insipidus a i c e l e F y b n Tracey A. Rossi, DVM o i t a a r t Linda A. Ross, DVM, MS, DACVIM s u l l I Cummings School of Veterinary Medicine at Tufts University ABSTRACT: Diabetes insipidus is a metabolic disorder caused by a deficiency in the production of or response to arginine vasopressin (AVP). The lack of , or inability to appropriately respond to , AVP results in a lack of tubular reabsorption of water and in urine of low specific gravity. Two main categories of diabetes insipidus are recognized in veterinary medicine : central and nephrogenic. iabetes insipidus is a metabolic disorder compulsive consumption of more water than the caused by decreased production of or kidneys can normally excrete. Primary polydipsia inadequate response to arginine vaso - caused by a dysfunction of the thirst center has D 1 pressin (AVP). A deficiency of AVP, or an not been reported in dogs or cats . Psychogenic inability of the distal tubule or collecting ducts polydipsia has been reported in dogs, with no spe - to respond to AVP appropriately, results in a cific breed or gender predisposition; it has not lack of tubular reabsorption of water and urine been documented in cats .4 When considering dia - of low specific gravity .2 betes insipidus as a diagnostic differential in a The main categories of diabetes insipidus rec - patient that has PU/PD, it is important to first ognized in veterinary medicine are central dia - rule out the more common causes (see the box on betes insipidus (CDI) and nephrogenic diabetes page 44 ). insipidus (NDI) . CDI is defined as decreased secretion or production of AVP, whereas NDI is PHYSIOLOGY OF WATER BALANCE defined by an inability of the kidneys to respond To understand how diabetes insipidus causes appropriately to AVP. Dogs and cats with diabetes PU/PD, it is important to first understand the key insipidus usually present with polyuria and poly - components of normal water balance : water dipsia (PU/PD). However, these clinical signs are intake, sensation of thirst, and regulation of water also present in animals with several more common excretion by the kidneys . The normal water intake diseases. In dogs, the most common causes of in dogs and cats varies from 20 to 70 ml/kg/day, PU/PD include renal failure, hyperadrenocorti - and the normal urine output varies between 20 cism, diabetes mellitus, and pyometra; in cats, they and 45 ml/kg/day .2 Animals are considered poly - include renal failure, diabetes mellitus, and hyper - dipsic if water consumption is greater than 100 thyroidism .3 Primary or psychogenic polydipsia is ml/kg/day and polyuric if urine production is another diagnostic differential greater than 50 ml/kg/day. 4 Water intake and loss to consider in a patient with vary from day to day, leading to changes in plasma suspected diabetes insipidus . osmolality; however, they are normally balanced so •Take CE tests This disease is characterized as that this change is minimal. In a healthy animal, • See full-text articles aDr. Ross discloses that she has the secretion of AVP and the thirst response work received financial support from to normalize the plasma osmolality and restore CompendiumVet.com Biopal, Inc., Worcester, MA. the circulating volume to normal. January 2008 43 COMPENDIUM 44 CE Diabetes Insipidus Common Causes of Polyuria and Polydipsia Dogs • Renal failure • Hyperadrenocorticism • Diabetes mellitus • Glucocorticoid therapy • Pyometra • Hypercalcemia • Hypoadrenocorticism • Hepatic insufficiency Cats • Renal failure • Diabetes mellitus • Hyperthyroidism • Postobstructive diuresis The thirst mechanism of animals with diabetes s insipidus is typically intact. Osmoreceptors within the a r a hypothalamus sense minute changes in plasma osmolal - P a i c e ity and the effective circulating volume. An increase in l e F y osmolality of as little as 1% affects the intake of water by b n o i increasing the sensation of thirst, leading to ingestion of t a r t water; it also increases the secretion of AVP, leading to s u l l water conservation by the kidneys . The stimulus for the I Figure 1. Diagram of the pituitary illustrating AVP sensation of thirst is thought to be very similar or equiv - release from the supraoptic and paraventricular nuclei alent to that for AVP release. It is unclear whether this and storage in the posterior pituitary. stimulus is caused by the osmoreceptors that sense an increase in the plasma osmolality or those that sense volume depletion. 5 causes a cascade of events, including the G protein–cou - pled up-regulation of adenylyl cyclase, which leads to Role of Arginine Vasopressin further production of cyclic adenosine monophosphate AVP, also called antidiuretic hormone , is a key compo - (cAMP) and activation of cAMP -dependent kinases. nent in regulating water intake and excretion. AVP is a These in turn promote the shuttling and insertion of an polypeptide that is synthesized in the supraoptic and aquaporin (AQP) water channel within the apical mem - paraventricular nuclei within the hypothalamus and is brane of the collecting duct, resulting in increased water stored in the posterior lobe of the pituitary gland 5 (Fig - reabsorption from the tubular lumen .6–8 The binding of ure 1 ). When secreted in response to changes in fluid AVP to V 2 receptors also induces the release of factor homeostasis , AVP helps control renal water reabsorption, VIII and von Willebrand’s factor from endothelial 6,9 the amount of urine produced, urine concentration, and , cells. In contrast, the binding of AVP to renal V 1 therefore , water balance. The main stimulus for AVP receptors is responsible for vasoconstriction and secretion is an increase in serum osmolality or a decrease increased prostaglandin release 6 (Figure 2 ). in the effective circulating volume .6 The normal serum osmolality is 280 to 310 mOsm/kg , and increases of 1% Role of Aquaporins or more stimulate AVP secretion. 6 Aquaporins are a family of integral membrane pro - The two main receptors for AVP within the kidneys teins that function as water -discriminating channels .10 are V 1 and V 2. The V 2 receptor mediates the antidiuretic Twelve mammalian aquaporins have been identified, response to AVP. When AVP binds to V 2 receptors, it and seven different renal aquaporins have been corre - COMPENDIUM January 2008 Diabetes Insipidus CE 45 s a r a P a i c e l e F y b n o i t a r t s u l l I Figure 2. Depiction of the binding of AVP to theV 2 receptor , which initiates a cascade of events: activation of G protein, increased production of cAMP, activation of protein kinase A (PKA) , and insertion of AQP2 in the apical membrane surface of the collecting duct as well as reabsorption of water. AC = adenylate cyclase lated with segmental permeability of the nephron .8,10 Of cient secretion of AVP from the neurohypophysis. 1 The the seven identified renal aquaporins, AQP2 appears to deficiency of AVP can be absolute or partial. An be the most important with regard to water homeosta - absolute deficiency causes persistent hyposthenuria sis . AQP3 and AQP4 are located on the basolateral (urine specific gravity [USG] ≤1.006) with severe membrane of the kidney collecting ducts and act to diuresis. Partial CDI is defined as an incomplete defi - facilitate water transport from the cell to the intersti - ciency of AVP and may result in a slightly higher USG, tium. AQP2 is a vasopressin-regulated water channel ranging from 1.008 to 1.020. No age, breed , or sex located on the apical membrane and within intracellular predilection is associated with the development of vesicles of the collecting duct principal cells. 8,10 When CDI. CDI can result from any condition that damages AVP binds to V 2 receptors, it promotes the insertion of the neurohypophyseal system. Causes of CDI include AQP2 -containing vesicles into the normally watertight head trauma, which can lead to either transient or per - luminal membrane, thereby increasing the permeability manent CDI; neoplasia; and hypothalamic –pituitary of the membrane to water. 8,10,11 When there is no longer malformations (cysts). Primary intracranial tumors that a stimulus for AVP secretion, the AQP2 channel is can lead to CDI include craniopharyngioma and pitu - removed from the luminal membrane by endocytosis. 6,7 itary adenocarcinoma .2,12 Advanced imaging techniques AQP2 is found in the urine in both soluble and mem - such as magnetic resonance imaging (MRI) or com - brane -bound forms. 10 The urinary excretion of AQP2 puted tomography (CT) would be warranted in the reflects physiologic regulation of the AQP2 water chan - workup of CDI secondary to a suspected intracranial nels by vasopressin. 11 lesion. Metastatic neoplasms that have been implicated as underlying causes of CDI include mammary carci - PATHOPHYSIOLOGY noma, lymphoma, malignant melanoma, and pancreatic Central Diabetes Insipidus carcinoma .2 However, in most cases , the cause of CDI CDI is a polyuric syndrome created by the insuffi - cannot be identified (idiopathic CDI). January 2008 COMPENDIUM 46 CE Diabetes Insipidus Table 1. Causes of Acquired NDI 8 few reported cases of congenital NDI have involved either puppies or adult dogs younger than 2 years. Cause Proposed Effect on AQP2 Breitschwerdt and Hribernik 14 reported a case of congeni - Hypokalemia a Down-regulation tal NDI in an 18 -month -old intact female Boston terrier Lithium b Down -regulation that was known to have had PU/PD since 6 months of Hypercalcemia/ Down -regulation or age. Another case of congenital NDI was diagnosed in a hypercalciuria a interference with shuttling 2- year -old Shiba inu after successful treatment for mechanism demodicosis. 15 The dog was consuming between 6 ,500 Ureteral obstruction Down -regulation and 7,500 ml/day (approximately 800 to 950 ml/kg/day) of water.
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