Before AVP was biochemically characterized, early studies used the general term “antidiuretic hormone” (ADH) to describe this substance. Now that AVP is known to be the only naturally occurring antidiuretic substance, it is more appropriate to refer to it by its correct hormonal designation. AVP is a nine–amino acid peptide that is synthesized in the hypothalamus. It is composed of a six–amino acid, ringlike structure formed by a disulfide bridge, with a three–amino acid tail, at the end of which the terminal carboxyl group is amidated. Substitution of lysine for arginine in position 8 yields lysine vasopressin, the antidiuretic hormone found in pigs and other members of the suborder Suina. Substitution of isoleucine for phenylalanine at position 3 and of leucine for arginine at position 8 yields oxytocin, a hormone found in all mammals and in many submammalian species. Oxytocin has weak antidiuretic activity but is a potent constrictor of smooth muscle in mammary glands and uterus, especially in the gravid state. As implied by their names, arginine and lysine vasopressin also cause the constriction of blood vessels, which was the property that led to the original discovery of them in the late 19th century, but this pressor effect occurs only at concentrations many times higher than those required to produce antidiuresis. This is probably of little physiologic or pathologic importance in humans except under conditions of severe hypotension and hypovolemia, where it acts to supplement the vasoconstrictive actions of angiotensin II (Ang II) and the sympathetic nervous system. The multiple actions of AVP are mediated by different G protein–coupled receptors, designated V _1a , V _1b , and V ₂ .

AVP and oxytocin are produced by the neurohypophysis, often referred to as the “posterior pituitary gland,” because the neural lobe is located centrally and posterior to the adenohypophysis, or anterior pituitary gland, in the sella turcica. However, it is important to understand that the posterior pituitary gland consists only of the distal axons of the magnocellular neurons that comprise the neurohypophysis. The cell bodies of these axons are located in specialized (magnocellular) neural cells located in two discrete areas of the hypothalamus, the paired supraoptic nuclei (SON) and paraventricular nuclei (PVN; Fig. 14.2 ). In adults, the posterior pituitary is connected to the brain by a short stalk through the diaphragm sellae. The neurohypophysis is supplied with blood by branches of the superior and inferior hypophysial arteries, which arise from the posterior communicating and intracavernous portion of the internal carotid artery. In the posterior pituitary, the arterioles break up into localized capillary networks that drain directly into the jugular vein via the sellar, cavernous, and lateral venous sinuses. Many of the neurosecretory neurons that terminate higher in the infundibulum and median eminence originate in parvicellular neurons in the PVN; they are functionally distinct from the magnocellular neurons that terminate in the posterior pituitary because they primarily enhance secretion of adrenocorticotropic hormone (ACTH) from the anterior pituitary. AVP-containing neurons also project from parvicellular neurons of the PVN to other areas of the brain, including the limbic system, nucleus tractus solitarius, and lateral gray matter of the spinal cord. The full extent of the functions of these extrahypophysial projections are still under study.

Summary of the main anterior hypothalamic pathways that mediate secretion of arginine vasopressin (AVP) and oxytocin.

The vascular organ of the lamina terminalis (OVLT) is especially sensitive to hyperosmolality. Hyperosmolality also activates other neurons in the anterior hypothalamus, such as those in the subfornical organ (SFO) and median preoptic nucleus (MnPO), and magnocellular neurons, which are intrinsically osmosensitive. Circulating angiotensin II (Ang II) activates neurons of the SFO, an essential site of Ang II action, as well as cells throughout the lamina terminalis and MnPO. In response to hyperosmolality or Ang II, projections from the SFO and OVLT to the MnPO activate excitatory and inhibitory interneurons that project to the supraoptic nucleus (SON) and paraventricular nucleus (PVN) to modulate direct inputs to these areas from the circumventricular organs. Cholecystokinin (CCK) acts primarily on gastric vagal afferents that terminate in the nucleus of the solitary tract (NST) but, at higher doses, it can also act at the area postrema (AP). Although neurons are apparently activated in the ventrolateral medulla (VLM) and NST, most neurohypophyseal secretion appears to be stimulated by monosynaptic projections from A ₂ -C ₂ cells, and possibly also noncatecholaminergic somatostatin-inhibin B cells, of the NST. Baroreceptor-mediated stimuli, such as hypovolemia and hypotension, are more complex. The major projection to magnocellular AVP neurons appears to arise from A ₁ cells of the VLM that are activated by excitatory interneurons from the NST. Other areas, such as the parabrachial nucleus (PBN), may contribute multisynaptic projections. Cranial nerves IX and X, which terminate in the NST, also contribute input to magnocellular AVP neurons. AC, Anterior commissure; OC, optic chiasm; PIT, anterior pituitary.

From Stricker EM, Verbalis JG. Water intake and body fluids. In Squire LR, Bloom FE, McConnell SK, et al, eds. Fundamental Neuroscience. San Diego: Academic Press; 2003:1011−1029.

The genes encoding the AVP and oxytocin precursors are located in close proximity on chromosome 20 but are expressed in mutually exclusive populations of neurohypophyseal neurons. The AVP gene consists of approximately 2000 base pairs and contains three exons separated by two intervening sequences or introns ( Fig. 14.3 ). Each exon encodes one of the three functional domains of the preprohormone, although small parts of the nonconserved sequences of neurophysin are located in the first and third exons that code for AVP and the C-terminal glycoprotein, called copeptin, respectively. The nontranscribed 5′-flanking genomic region or promoter, which regulates expression of the mRNA for the AVP gene, shows extensive sequence homology across several species but is markedly different from the otherwise closely related gene for oxytocin. Regulatory regions of the AVP gene promoter of the rat contain several putative regulatory elements including a glucocorticoid response element, cyclic adenosine monophosphate (cAMP) response element, and four activating protein-2 (AP-2) binding sites. Experimental studies have suggested that the DNA sequences between the AVP and oxytocin genes, the intergenic region, may contain critical sites for cell-specific expression of these two hormones.

The arginine vasopressin (AVP) gene and its protein products.

The three exons encode a 145−amino acid prohormone with an NH ₂ -terminal signal peptide. The prohormone is packaged into neurosecretory granules of magnocellular neurons. During axonal transport of the granules from the hypothalamus to the posterior pituitary, enzymatic cleavage of the prohormone generates the final products—AVP, neurophysin, and a COOH-terminal glycoprotein called copeptin. When afferent stimulation depolarizes the AVP-containing neurons, the three products are released into capillaries of the posterior pituitary in equimolar amounts.

Adapted from Richter D, Schmale H. The structure of the precursor to arginine vasopressin, a model preprohormone. Prog Brain Res. 1983;60:227−233.

The AVP mRNA is also expressed in a number of other neurons including but not limited to the parvicellular neurons of the PVN and SON. AVP and oxytocin genes are also expressed in several peripheral tissues including the adrenal medulla, ovary, testis, thymus, and certain sensory ganglia. However, the AVP mRNA in these tissues appears to be shorter (620 bases) than its hypothalamic counterpart (720 bases), apparently because of tissue-specific differences in the length of the polyA tails. More importantly, the levels of AVP in peripheral tissues are generally two or three orders of magnitude lower than in the neurohypophysis, suggesting that AVP in these tissues likely has paracrine rather than endocrine functions. This is consistent with the observation that destruction of the neurohypophysis essentially eliminates AVP from the plasma, despite the presence of these multiple peripheral sites of AVP synthesis.

The secretion of AVP and its associated neurophysin and copeptin peptide fragments occurs by a calcium-dependent exocytotic process, similar to that described for other neurosecretory systems. Secretion is triggered by propagation of an electrical impulse along the axon that causes depolarization of the cell membrane, an influx of Ca ²⁺ , fusion of secretory granules with the cell membrane, and extrusion of their contents. This view is supported by the observation that AVP, neurophysin, and glycoprotein copeptin are released simultaneously by many stimuli. However, at the physiologic pH of plasma, there is no binding of AVP or oxytocin to their respective neurophysins, so after secretion, each peptide circulates independently in the bloodstream.

Stimuli for secretion of AVP or oxytocin also stimulate transcription and increase the mRNA content of both prohormones in the magnocellular neurons. This has been well documented in rats, in which dehydration, which stimulates secretion of AVP, accelerates transcription and increases the levels of AVP (and oxytocin) mRNA, ^, and hypoosmolality, which inhibits the secretion of AVP, produces a decrease in the content of AVP mRNA. These and other studies have indicated that the major control of AVP synthesis most likely resides at the level of transcription.

Antidiuresis occurs via interaction of the circulating hormone with AVP V ₂ receptors in the kidney, which results in increased water permeability of the collecting duct through the insertion of the aquaporin-2 (AQP2) water channel into the apical membranes of collecting tubule principal cells (see Chapter 10 ). The importance of AVP for maintaining water balance is underscored by the fact that the normal pituitary stores of this hormone are large, allowing more than 1 week’s supply of hormone for maximal antidiuresis under conditions of sustained dehydration. Knowledge of the different conditions that stimulate pituitary AVP release in humans is therefore essential for understanding water metabolism.

AVP secretion is influenced by many different stimuli, but since the pioneering studies of ADH secretion by Ernest Basil Verney, it has been clear that the most important stimulus under physiologic conditions is the osmotic pressure of plasma. With further refinement of radioimmunoassays for AVP, the unique sensitivity of this hormone to small changes in osmolality, as well as the corresponding sensitivity of the kidney to small changes in plasma AVP levels, have become apparent. Although the magnocellular neurons themselves have been found to have intrinsic osmoreceptive properties, research over the past several decades has clearly shown that the most sensitive osmoreceptive cells that can sense small changes in plasma osmolality and transduce these changes into AVP secretion are located in the anterior hypothalamus, likely in or near the circumventricular organ termed the “organum vasculosum of the lamina terminalis” (OVLT; see Fig. 14.2 ). Perhaps the strongest evidence for location of the primary osmoreceptors in this area of the brain are the multiple studies that have demonstrated that destruction of this area disrupts osmotically stimulated AVP secretion and thirst, without affecting the neurohypophysis or its response to nonosmotic stimuli. ^,

Although some debate still exists with regard to the exact pattern of osmotically stimulated AVP secretion, most studies to date have supported the concept of a discrete osmotic threshold for AVP secretion, above which there is a linear positive relationship between plasma osmolality and AVP levels ( Fig. 14.4 ). At plasma osmolalities below a threshold level, AVP secretion is suppressed to low or undetectable levels; above this point, AVP secretion increases linearly in direct proportion to plasma osmolality. The slope of the regression line relating AVP secretion to plasma osmolality can vary significantly across individual human subjects, in part because of genetic factors, but also in relation to other factors. In general, each 1-mOsm/kg H ₂ O increase in plasma osmolality causes an increase in the plasma AVP level, ranging from 0.4 to 1.0 pg/mL. The renal response to circulating AVP is similarly linear, with urinary concentration that is directly proportional to AVP levels from 0.5 to 4 to 5 pg/mL, after which urinary osmolality is maximal and cannot increase further, despite additional increases in AVP levels ( Fig. 14.5 ). Thus changes of as little as 1% in plasma osmolality are sufficient to cause significant increases in plasma AVP levels, with proportional increases in urine concentration, and maximal antidiuresis is achieved after increases in plasma osmolality of only 5 to 10 mOsm/kg H ₂ O (2%−4%) above the threshold for AVP secretion.

Comparative sensitivity of arginine vasopressin (AVP) secretion in response to increases in plasma osmolality versus decreases in blood volume or blood pressure in human subjects.

The arrow indicates the low plasma AVP concentrations found at basal plasma osmolality. Note that AVP secretion is much more sensitive to small changes in blood osmolality than to small changes in volume or pressure.

Adapted from Robertson GL. Posterior pituitary. In Felig P, Baxter J, Frohman LA, eds. Endocrinology and Metabolism. New York: McGraw-Hill; 1986:338−386.

Relationship of plasma osmolality, plasma arginine vasopressin (AVP) concentrations, urine osmolality, and urine volume in humans.

The osmotic threshold for AVP secretion defines the point at which urine concentration begins to increase, but the osmotic threshold for thirst is significantly higher and approximates the point at which maximal urine concentration has already been achieved. Note also that because of the inverse relation between urine osmolality and urine volume, changes in plasma AVP concentrations have much larger effects on urine volume at low plasma AVP concentrations than at high plasma AVP concentrations.

Adapted from Robinson AG. Disorders of antidiuretic hormone secretion. J Clin Endocrinol Metab. 1985;14:55−88.

However, even this analysis underestimates the sensitivity of this system to regulate free water excretion. Urinary osmolality is directly proportional to plasma AVP levels as a consequence of the fall in urine flow induced by AVP, but urine volume is inversely related to urine osmolality (see Fig. 14.5 ). An increase in plasma AVP concentration from 0.5 to 2 pg/mL has a much greater relative effect to decrease urine flow than a subsequent increase in AVP concentration from 2 to 5 pg/mL, thereby magnifying the physiologic effects of small changes in lower plasma AVP levels. Furthermore, the rapid response of AVP secretion to changes in plasma osmolality, coupled with the short half-life of AVP in human plasma (10−20 minutes), allows the kidneys to respond to changes in plasma osmolality on a minute-to-minute basis. The net result is a finely tuned osmoregulatory system that adjusts the rate of free water excretion accurately to the ambient plasma osmolality, primarily via changes in pituitary AVP secretion.

The set point of the osmoregulatory system also varies from person to person. In healthy adults, the osmotic threshold for AVP secretion ranges from 275 to 290 mOsm/kg H ₂ O (averaging ≈280−285 mOsm/kg H ₂ O). Similar to sensitivity, individual differences in the set point of the osmoregulatory system are relatively constant over time and appear to be genetically determined. However, multiple factors can alter the sensitivity and/or set point of the osmoregulatory system for AVP secretion, in addition to genetic influences. Foremost among these are acute changes in blood pressure, effective blood volume, or both (discussed in the following section). Aging has been found to increase the sensitivity of the osmoregulatory system in multiple studies. ^, Metabolic factors, such as serum Ca ²⁺ levels and various drugs, can alter the slope of the plasma AVP-osmolality relationship as well. Lesser degrees of shifting of the osmosensitivity and set point for AVP secretion have been noted with alterations in gonadal hormones. Some studies have found increased osmosensitivity in women, particularly during the luteal phase of the menstrual cycle, and in estrogen-treated men, but these effects were relatively minor, and others have found no significant gender differences. The set point of the osmoregulatory system is reduced more dramatically and reproducibly during pregnancy. Evidence has suggested the possible involvement of the placental hormone relaxin, rather than gonadal steroids or human chorionic gonadotropin hormone in pregnancy-associated resetting of the osmostat for AVP secretion. Both the changes in volume and osmolality have been reproduced by the infusion of relaxin into virgin female and normal rats and reversed in pregnant rats by immunoneutralization of relaxin. Increased nitric oxide (NO) production by relaxin has been reported to increase vasodilation, and estrogens also increase NO synthesis. That multiple factors can influence the set point and sensitivity of osmotically regulated AVP secretion is not surprising because AVP secretion reflects a balance of bimodal inhibitory and stimulatory inputs to the neurohypophysis from protean afferent inputs.

Understanding the osmoregulatory mechanism also requires addressing the observation that AVP secretion is not equally sensitive to all plasma solutes. Sodium and its anions, which normally contribute more than 95% of the osmotic pressure of plasma, are the most potent solutes in terms of their capacity to stimulate AVP secretion and thirst, although certain sugars such as mannitol and sucrose are also equally effective when infused intravenously. In contrast, increases in plasma osmolality caused by noneffective solutes such as urea or glucose result in little or no increase in plasma AVP levels in nondiabetic humans or animals. ^, These differences in response to various plasma solutes are independent of any recognized nonosmotic influence, indicating that they are a property of the osmoregulatory mechanism itself. According to current concepts, the osmoreceptor neuron is stimulated by osmotically induced changes in its water content. In this case, the stimulatory potency of any given solute would be an inverse function of the rate at which it moves from the plasma to the inside of the osmoreceptor neuron. Solutes that penetrate slowly, or not at all, create an osmotic gradient that causes an efflux of water from the osmoreceptor, and the resultant shrinkage of the osmoreceptor neuron activates a stretch-inactivated, noncationic channel that initiates depolarization and firing of the neuron. Conversely, solutes that penetrate the cell readily create no gradient and thus have no effect on the water content and cell volume of the osmoreceptors. This mechanism agrees well with the observed relationship between the effect of certain solutes on AVP secretion, such as Na ⁺ , mannitol, and glucose, and the rate at which they penetrate the blood-brain barrier.

Many neurotransmitters have been implicated in mediating the actions of the osmoreceptors on the neurohypophysis. The supraoptic nucleus is richly innervated by multiple pathways including acetylcholine, catecholamines, glutamate, gamma-aminobutyric acid (GABA), histamine, opioids, Ang II, and dopamine. Studies have supported a potential role for all of these and others in the regulation of AVP secretion, as has local secretion of AVP into the hypothalamus from dendrites of the AVP-secreting neurons. Although it remains unclear which of these are involved in the normal physiologic control of AVP secretion, in view of the likelihood that the osmoregulatory system is bimodal and integrated with multiple different afferent pathways, it seems clear that magnocellular AVP neurons are influenced by a complex mixture of neurotransmitter systems, rather than only a few.

Exactly how cells sense volume changes is a critical step for all the mechanisms activated to achieve osmoregulation. Some of the most exciting data have come from studies of brain osmoreceptors. The cellular osmosensing mechanism used by the OVLT cells is an intrinsic depolarizing receptor potential. This potential is generated in these cells via a molecular transduction complex. Studies have suggested that this likely includes members of the transient receptor potential vanilloid (TRPV) family of cation channel proteins. These channels are generally activated by cell membrane stretch to cause a nonselective conductance of cations, with a preference for Ca ²⁺ . Multiple studies have characterized various members of the TRPV family as cellular mechanoreceptors in different tissues. Both in vitro and in vivo studies of the TRPV family of cation channel proteins have provided evidence supporting the roles of TRPV1, TRPV2, and TRPV4 proteins in the transduction of osmotic stimuli in mammals. Consistent with these studies, it is of great interest that interindividual genetic variation in the TRPV4 gene affects TRPV4 function and may influence water balance on a population-wide basis. The details of exactly how and where various members of the TRPV family of cation channel proteins participate in osmoregulation in different species remain to be ascertained by future studies. However, a strong case can already be made for their involvement in the transduction of osmotic stimuli in the neural cells in the OVLT and surrounding hypothalamus that regulate osmotic homeostasis, which appears to have been highly conserved throughout evolution.

In healthy adults, an increase in effective plasma osmolality of only 2% to 3% above basal levels produces a strong desire to drink. This response is not dependent on changes in ECF or plasma volume because it occurs similarly whether plasma osmolality is raised by the infusion of hypertonic solutions or water deprivation. The absolute level of plasma osmolality at which a person develops a conscious urge to seek and drink water is termed the “osmotic thirst threshold.” It varies appreciably among individuals, likely as a result of genetic factors, but in healthy adults, it averages approximately 295 mOsm/kg H ₂ O. Of physiologic significance is the fact that this level is above the osmotic threshold for AVP release and approximates the plasma osmolality at which maximal concentration of the urine is normally achieved (see Fig. 14.5 ).

The brain pathways that mediate osmotic thirst have not been well defined, but evidence suggests that the initiation of drinking requires osmoreceptors located in the anteroventral hypothalamus and OVLT in the same area as the osmoreceptors that control osmotic AVP secretion. ^, Whether the osmoreceptors for AVP and thirst are the same cells or are simply located in the same general area remains unknown. However, the properties of the osmoreceptors are similar. Ineffective plasma solutes such as urea and glucose, which have little or no effect on AVP secretion, are equally ineffective at stimulating thirst, whereas effective solutes such as NaCl and mannitol can stimulate thirst. ^, The sensitivities of the thirst and AVP osmoreceptors cannot be compared precisely, but they are also probably similar. Thus in healthy adults, the intensity of thirst increases rapidly in direct proportion to serum [Na ⁺ ] or plasma osmolality and generally becomes intolerable at levels only 3% to 5% above the threshold level. Water consumption also appears to be proportional to the intensity of thirst in humans and animals and, under conditions of maximal osmotic stimulation, can reach rates as high as 20 to 25 L/day. The dilution of body fluids by ingested water complements the retention of water that occurs during AVP-induced antidiuresis, and both responses occur concurrently when drinking water is available.

As with AVP secretion, the osmoregulation of thirst appears to be bimodal because a modest decline in plasma osmolality induces a sense of satiation and reduces the basal rate of spontaneous fluid intake. ^, This effect is sufficient to prevent hypotonic overhydration, even when antidiuresis is fixed at maximal levels for prolonged periods, suggesting that osmotically inappropriate secretion of AVP (syndrome of inappropriate antidiuresis [SIAD]) should not result in the development of hyponatremia unless the satiety mechanism is impaired or fluid intake is inappropriately high for some other reason, such as the unregulated components of fluid intake discussed earlier. Also similar to AVP secretion, thirst can be influenced by oropharyngeal or upper gastrointestinal receptors that respond to the act of drinking itself. In humans, however, the rapid relief of thirst provided by this mechanism lasts only a matter of minutes, and thirst quickly recurs until enough water is absorbed to lower plasma osmolality to normal. Therefore although local oropharyngeal sensations may have a significant short-term influence on thirst, it is the hypothalamic osmoreceptors that ultimately determine the volume of water intake in response to dehydration.

In contrast, the threshold for producing hypovolemic or extracellular thirst is significantly higher in animals and humans. Studies in several species have shown that sustained decreases in plasma volume or blood pressure of at least 4% to 8%, and in some species 10% to 15%, are necessary to stimulate drinking consistently. ^, In humans, the degree of hypovolemia or hypotension required to produce thirst has not been precisely defined, but it has been difficult to demonstrate any effects of mild to moderate hypovolemia to stimulate thirst independently of osmotic changes occurring with dehydration. This blunted sensitivity to changes in ECF volume or blood pressure in humans probably represents an adaptation that occurred as a result of the erect posture of primates, which predisposes them to wider fluctuations in atrial filling pressures as a result of the orthostatic pooling of blood in the lower body. Stimulation of thirst (and AVP secretion) by such transient postural changes in blood pressure might lead to overdrinking and inappropriate antidiuresis in situations in which the ECF volume was actually normal but transiently maldistributed. Consistent with a blunted response to baroreceptor activation, studies have also shown that the systemic infusion of Ang II to pharmacologic levels is a much less potent stimulus to thirst in humans than in animals, in whom it is one of the most potent dipsogens known. Nonetheless, this response is not completely absent in humans, as demonstrated by rare cases of polydipsia in patients with pathologic causes of hyperreninemia. The pathways whereby hypovolemia or hypotension produces thirst have not been well defined but probably involve the same brainstem baroreceptive pathways that mediate hemodynamic effects on AVP secretion, as well as a likely contribution from circulating levels of Ang II in some species.

Studies of the neural circuitry underlying drinking behavior have identified a new type of thirst that precedes physiologic challenges to osmotic and volume homeostasis, which has been termed “anticipatory thirst.” The best studied example of this is the increase in drinking that occurs in animals in the final hours of their awake period, perhaps serving to maintain hydration during the sleep period when there is no fluid intake. This drinking behavior appears to be mediated by vasopressin-containing neurons in the suprachiasmatic nucleus (SCN), which is the brain nucleus that controls diurnal rhythms. SCN vasopressin neurons project to the OVLT, where they excite thirst-activating neurons, thereby enabling maintenance of osmotic homeostasis during sleep.

A synthesis of what is presently known about the regulation of AVP secretion and thirst in humans leads to a relatively simple but elegant system to maintain water balance. Under normal physiologic conditions, the sensitivity of the osmoregulatory system for AVP secretion accounts for the maintenance of plasma osmolality within narrow limits by adjusting renal water excretion to small changes in osmolality. Stimulated thirst does not represent a major regulatory mechanism under these conditions, and unregulated fluid ingestion supplies adequate water in excess of true “need,” which is then excreted in relation to osmoregulated pituitary AVP secretion. However, when unregulated water intake cannot adequately supply body needs in the presence of plasma AVP levels sufficient to produce maximal antidiuresis, plasma osmolality rises to levels that stimulate thirst (see Fig. 14.5 ), and water intake increases proportionally to the elevation of osmolality above this thirst threshold.

In such a system, thirst essentially represents a backup mechanism that becomes active when pituitary and renal mechanisms prove insufficient to maintain plasma osmolality within a few percentage points of basal levels. This arrangement has the advantage of freeing humans from frequent episodes of thirst. These would require a diversion of activities toward behavior oriented to seeking water when water deficiency is sufficiently mild to be compensated for by renal water conservation but would stimulate water ingestion once water deficiency reaches potentially harmful levels. Stimulation of AVP secretion at plasma osmolalities below the threshold for subjective thirst acts to maintain an excess of body water sufficient to eliminate the need to drink whenever slight elevations in plasma osmolality occur. This system of differential effective thresholds for thirst and AVP secretion nicely complements many studies that have demonstrated excess unregulated (or need-free) drinking in humans and animals. Only when this mechanism becomes inadequate to maintain body fluid homeostasis does thirst-induced regulated fluid intake become the predominant defense mechanism for the prevention of severe dehydration.

AVP-D is caused by inadequate blood levels of AVP in response to osmotic stimulation. In most cases, this is due to destruction of the neurohypophysis by a variety of acquired or congenital anatomic lesions that destroy or damage the neurohypophysis by pressure or infiltration (see Box 14.1 ). The severity of the resulting hypotonic diuresis depends on the degree of destruction of the neurohypophysis, leading to complete or partial deficiency of AVP secretion. However, it can also be due to decreased secretion of AVP as a result of abnormal osmoreceptor input to the neurohypophysis or increased metabolism of AVP secreted by the posterior pituitary.

Despite the wide variety of lesions that can potentially cause AVP-D, it is much more common not to have AVP-D in the presence of such lesions. This apparent inconsistency can be understood by considering several common principles of neurohypophyseal physiology and pathophysiology that are relevant to all these etiologies.

First, the synthesis of AVP occurs in the hypothalamus (see Fig. 14.2 ); the posterior pituitary simply represents the site of storage and secretion of the neurosecretory granules that contain AVP. Consequently, lesions contained within the sella turcica that destroy only the posterior pituitary generally do not cause AVP-D because the cell bodies of the magnocellular neurons that synthesize AVP remain intact, and the site of release of AVP shifts more superiorly, typically into the blood vessels of the median eminence at the base of the brain. Perhaps the best examples of this phenomenon are large pituitary macroadenomas that completely destroy the anterior and posterior pituitary. AVP-D is a distinctly unusual presentation for such pituitary adenomas because destruction of the posterior pituitary by such slowly enlarging intrasellar lesions merely destroys the nerve terminals, but not the cell bodies, of the AVP neurons. As this occurs, the site of release of AVP shifts more superiorly to the pituitary stalk and median eminence. Sometimes this can be detected on noncontrast magnetic resonance imaging (MRI) scans as a shift of the pituitary bright spot more superiorly to the level of the infundibulum or median eminence, but this process is often too diffuse to be detected in this manner. The development of AVP-D from a pituitary adenoma is so uncommon, even with macroadenomas that completely obliterate sellar contents sufficiently to cause panhypopituitarism, that its presence should lead to consideration of alternative diagnoses, such as craniopharyngioma. This often causes damage to the median eminence because of adherence of the capsule to the base of the hypothalamus, more rapidly enlarging sellar or suprasellar masses that do not allow sufficient time for shifting the site of AVP release more superiorly (e.g., metastatic lesions and acute hemorrhage), or granulomatous disease, with more diffuse hypothalamic involvement (e.g., sarcoidosis and histiocytosis). With large pituitary adenomas that produce ACTH deficiency, it is actually more likely that patients will present with hypoosmolality from a SIAD-like picture as a result of the impaired free water excretion that accompanies hypocortisolism.

A second general principle is that the capacity of the neurohypophysis to synthesize AVP is greatly in excess of the body’s daily needs for maintenance of water homeostasis. Carefully controlled studies of surgical section of the pituitary stalk in dogs have clearly demonstrated that destruction of 80% to 90% of the magnocellular neurons in the hypothalamus is required to produce polyuria and polydipsia in this species. Thus even lesions that cause destruction of the AVP magnocellular neuron cell bodies must result in a large degree of destruction to produce AVP-D. The most illustrative example of this is surgical section of the pituitary stalk in humans. Necropsy studies of these patients have revealed atrophy of the posterior pituitary and loss of the magnocellular neurons in the hypothalamus. This loss of magnocellular cells presumably results from the retrograde degeneration of neurons whose axons were cut during surgery. As is generally true for all neurons, the likelihood of retrograde neuronal degeneration depends on the proximity of the axotomy, in this case, section of the pituitary stalk, to the cell body of the neuron. This was shown clearly in studies of human subjects in whom section of the pituitary stalk at the level of the diaphragm sellae (a low stalk section) produced transient but not permanent DI, whereas section at the level of the infundibulum (a high stalk section) was required to cause permanent DI in most cases.

Several genetic causes of AVP deficiency have also been characterized. Before the application of techniques for the amplification of genomic DNA, the only experimental model to study the mechanism of hereditary hypothalamic DI was the Brattleboro rat, a strain that was found serendipitously to have AVP-D. In this animal, the disease demonstrates a classic pattern of autosomal recessive inheritance in which AVP-D is expressed only in the homozygotes. The hereditary basis of the disease has been found to be a single base deletion producing a translational frameshift beginning in the third portion of the neurophysin coding sequence. Because the gene lacks a stop codon, there is a modified neurophysin, no glycopeptide, and a long polylysine tail. Although the mutant prohormone accumulates in the endoplasmic reticulum, sufficient AVP is produced by the normal allele that the heterozygotes are asymptomatic. In contrast, almost all families with genetic AVP-D in humans that have been described to date demonstrate an autosomal dominant mode of inheritance. In these cases, AVP-D is expressed, despite the expression of one normal allele, which is sufficient to prevent the disease in the heterozygous Brattleboro rats. Numerous studies have been directed at understanding this apparent anomaly. Two important clues about the cause of the AVP-D in familial genetic AVP-D are the following:

• 1.

  Severe to partial deficiencies of AVP and overt signs of AVP-D do not develop in these patients until several months to several years after birth and then gradually progress over the ensuing decades, ^, suggesting adequate initial function of the normal allele, with later decompensation.

• 2.

  A limited number of autopsy studies have suggested that some of these cases are associated with gliosis and a marked loss of magnocellular AVP neurons in the hypothalamus, although other studies have shown normal neurons, with decreased expression of AVP or no hypothalamic abnormality. In most of these cases, the hyperintense signal normally emitted by the neurohypophysis in T1-weighted MRI scans is also absent, although some exceptions have been reported.

Another interesting, but as yet unexplained, observation is that some adults in these families have been described in whom AVP-D was clinically apparent during childhood but who went into remission as adults, without evidence that their remissions could be attributed to renal or adrenal insufficiency or to increased AVP synthesis.

The autosomal dominant form of familial AVP-D is caused by diverse mutations in the gene that codes for the AVP-neurophysin precursor. All the mutations identified to date have been in the coding region of the gene and affect only one allele. Allelic variants associated with familial AVP are located in any of the three exons, with each predicted to alter or delete amino acid residues in the signal peptide, AVP, and neurophysin moieties of the precursor. Only the C-terminus glycopeptide, or copeptin moiety, has not been found to be affected. Most are missense mutations, but nonsense mutations (premature stop codons) and deletions also occur. One feature shared by all the mutations is that they are predicted to alter or delete one or more amino acids known, or reasonably presumed, to be crucial for processing, folding, and oligomerization of the precursor protein in the endoplasmic reticulum. ^, Because of the related functional effects of the mutations, the common clinical characteristics of the disease, the dominant-negative mode of transmission, and the autopsy and hormonal evidence of postnatal neurohypophyseal degeneration, it has been postulated that all the mutations act by causing the production of an abnormal precursor protein that accumulates and eventually damages the neurons because it cannot be correctly processed, folded, and transported out of the endoplasmic reticulum. Expression studies of mutant DNA from several human mutations in cultured neuroblastoma cells have supported this misfolding-neurotoxicity hypothesis by demonstrating abnormal trafficking and accumulation of mutant prohormone in the endoplasmic reticulum with low or absent expression in the Golgi apparatus, suggesting defects in packaging into neurosecretory granules. However, cell death may not be necessary to decrease available AVP. Normally, proteins retained in the endoplasmic reticulum are selectively degraded but, if excess mutant is produced and the selective normal degradative process is overwhelmed, an alternate, nonselective, degradative system (autophagy) is activated. As more and more mutant precursor builds up in the endoplasmic reticulum, the normal wild-type protein becomes trapped with the mutant protein and degraded by the activated nonspecific degradative system. In this case, the amount of AVP that matures and is packaged would be markedly reduced. ^, This explanation is consistent with cases in which little pathology is found in the magnocellular neurons and also with AVP-D in which a small amount of circulating AVP can still be detected.

Wolfram syndrome is a rare autosomal recessive neurodegenerative disease with AVP-D, diabetes mellitus, optic atrophy, and deafness (DIDMOAD). The genetic defect is the protein wolframin, which is found in the endoplasmic reticulum and is important for folding proteins. Wolframin is involved in beta cell proliferation, intracellular protein processing, and calcium homeostasis, producing a wide spectrum of endocrine and central nervous system (CNS) disorders. AVP-D is usually a late manifestation associated with decreased magnocellular neurons in the paraventricular and supraoptic nuclei.

Idiopathic forms of AVP deficiency represent a large pathogenic category in adults and children. A study in children has revealed that more than half (54%) of all cases of AVP-D were classified as idiopathic. These patients do not have historic or clinical evidence of any injury or disease that can be linked to their AVP-D, and MRI of the pituitary-hypothalamic area generally reveals no abnormality other than the absence of the posterior pituitary bright spot and sometimes varying degrees of thickening of the pituitary stalk. Several lines of evidence have suggested that many of these patients may have had an autoimmune destruction of the neurohypophysis to account for their AVP-D. First, the entity of lymphocytic infundibuloneurohypophysitis has been documented to be present in a subset of patients with idiopathic AVP-D. Lymphocytic infiltration of the anterior pituitary, lymphocytic hypophysitis, has been recognized as a cause of anterior pituitary deficiency for many years, but it was not until an autopsy called attention to a similar finding in the posterior pituitary of a patient with idiopathic AVP-D that this pathology was recognized to occur in the neurohypophysis as well. Since that initial report, a number of similar cases have been described, including cases in the postpartum period, which is characteristic of lymphocytic hypophysitis. With the advent of MRI, lymphocytic infundibuloneurohypophysitis has been diagnosed based on the appearance of a thickened stalk and/or enlargement of the posterior pituitary, mimicking a pituitary tumor. In these cases, the characteristic bright spot on MRI T1-weighted images is lost. The enlargement of the stalk can mimic a neoplastic process, resulting in some of these patients undergoing surgery based on the suspicion of a pituitary tumor.

Since then, a number of patients with a suspicion of infundibuloneurohypophysitis and no other obvious cause of AVP-D have been followed and have shown regression of the thickened pituitary stalk over time. ^{, ,} Several cases have been reported with the coexistence of AVP-D and adenohypophysitis; these presumably represent cases of combined lymphocytic infundibuloneurohypophysitis and hypophysitis. ^{, , ,} A second line of evidence supporting an autoimmune cause in many cases of idiopathic AVP-D is based on the finding of AVP antibodies in the serum of as many as one-third of patients with idiopathic AVP-D and two-thirds of those with Langerhans cell histiocytosis X, but not in patients with AVP-D caused by tumors. One form of infundibuloneurohypophysitis occurs in middle-aged to older men and is associated with immunoglobulin G4 (IgG4)-related systemic disease. ^, Various organs, especially the pancreas, are infiltrated with IgG4 plasma cells, and neurohypophysitis is only one manifestation of a multiorgan disease that may include other endocrine glands. This cause should be considered as a cause of AVP-D based on age and gender at presentation and evidence of other systemic diseases. The diagnosis can be established by elevated serum IgG4 levels and characteristic histology of biopsies. Response to steroids or other immunosuppressive drugs is characteristic.

There is extensive literature in animals indicating that the primary osmoreceptors controlling AVP secretion and thirst are located in the anterior hypothalamus; lesions of this region in animals, called the “AV3V area,” cause hyperosmolality through a combination of impaired thirst and impaired osmotically stimulated AVP secretion. ^, Initial reports in humans described this syndrome as essential hypernatremia, and subsequent studies used the term “adipsic hypernatremia” in recognition of the profound thirst deficits found in most of the patients. On the basis of the known pathophysiology, all these syndromes can be grouped together, termed “disorders of osmoreceptor dysfunction.” Although the pathologies responsible for this condition can be quite varied, all the cases reported to date have been due to various degrees of osmoreceptor destruction associated with a variety of different brain lesions, as summarized in Box 14.1 . Many of these are the same types of lesions that can cause AVP-D, but in contrast to AVP-D, these lesions usually occur more rostrally in the hypothalamus, consistent with the anterior hypothalamic location of the primary osmoreceptor cells (see Fig. 14.2 ). One lesion that is unique to this disorder is an anterior communicating cerebral artery aneurysm. Because the small arterioles that feed the anterior wall of the third ventricle originate from the anterior communicating cerebral artery, an aneurysm in this region —but more often following surgical repair of such an aneurysm that sometimes involves ligation of the anterior communicating artery —produces infarction of the part of the hypothalamus containing the osmoreceptor cells.

The cardinal defect of patients with this disorder is lack of the osmoreceptors that regulate thirst. With rare exceptions, osmoregulation of AVP is also impaired, although the hormonal response to nonosmotic stimuli remains intact ( Fig. 14.9 ). ^, Four major patterns of osmoreceptor dysfunction have been described, and each is characterized by defects in thirst and/or AVP secretory responses, as follows: 1. upward resetting of the osmostat for both thirst and AVP secretion (normal AVP and thirst responses but at an abnormally high plasma osmolality); 2. partial osmoreceptor destruction (blunted AVP and thirst responses at all plasma osmolalities); 3. total osmoreceptor destruction (absent AVP secretion and thirst, regardless of plasma osmolality); and 4. selective dysfunction of thirst osmoregulation with intact AVP secretion. Regardless of the actual pattern, the hallmark of this disorder is an abnormal thirst response in addition to variable defects in AVP secretion. Thus such patients fail to drink sufficiently as their plasma osmolality rises and, as a result, the new set point for plasma osmolality rises far above the normal thirst threshold. Unlike patients with typical AVP-D, whose polydipsia maintains their plasma osmolality within a normal range, patients with osmoreceptor dysfunction often have a plasma osmolality in the range of 300 to 340 mOsm/kg H ₂ O. This underscores the critical role played by thirst mechanisms in maintaining body fluid homeostasis; intact renal function is insufficient to maintain plasma osmolality within normal ranges in such cases.

Plasma arginine vasopressin (AVP) responses to arterial hypotension produced by the infusion of trimethaphan in patients with AVP-D (central diabetes insipidus) and osmoreceptor dysfunction (adipsic AVP-D).

Normal responses in healthy volunteers are shown by the shaded area. Note that despite absent or markedly blunted AVP responses to hyperosmolality, patients with osmoreceptor dysfunction respond normally to baroreceptor stimulation induced by hypotension.

From Baylis PH, Thompson CJ. Diabetes insipidus and hyperosmolar syndromes. In Becker KL, ed. Principles and Practice of Endocrinology and Metabolism. Philadelphia: JB Lippincott; 1995:257.

The rate of the development and severity of hyperosmolality and hypertonic dehydration in patients with osmoreceptor dysfunction are influenced by a number of factors. First is the ability to maintain some degree of osmotically stimulated thirst and AVP secretion, which will determine the new set point for plasma osmolality. Second are environmental influences that affect the rate of water output. When physical activity is minimal and the ambient temperature is not elevated, the overall rates of renal and insensible water loss are low and the patient’s diet may be sufficient to maintain a relatively normal balance for long periods of time. Anything that increases perspiration, respiration, or urine output greatly accelerates the rate of water loss and thereby uncovers the patient’s inability to mount an appropriate compensatory increase in water intake. Under these conditions, severe and potentially fatal hypernatremia can develop relatively quickly. When the dehydration is only moderate (plasma osmolality = 300 to 330 mOsm/kg H ₂ O), the patient is usually asymptomatic and signs of volume depletion are minimal; but if the dehydration becomes severe, the patient can exhibit symptoms and signs of hypovolemia, including weakness, postural dizziness, paralysis, confusion, coma, azotemia, hypokalemia, hyperglycemia, and secondary hyperaldosteronism (see “Clinical Manifestations of AVP-D and AVP-R” later). In severe cases, there may also be rhabdomyolysis, with marked serum elevations in muscle enzyme levels and occasionally acute renal failure.

However, a third factor also influences the degree of hyperosmolality and dehydration present in these patients. For all cases of osmoreceptor dysfunction, it is important to remember that afferent pathways from the brainstem to the hypothalamus remain intact; therefore these patients will usually have normal AVP and renal concentrating responses to baroreceptor-mediated stimuli, such as hypovolemia and hypotension (see Fig. 14.9 ), or to other nonosmotic stimuli, such as nausea. ^, This has the effect of preventing severe dehydration because, as hypovolemia develops, this will stimulate AVP secretion via baroreceptive pathways through the brainstem (see Fig. 14.2 ). Although protective, this effect often causes diagnostic confusion because sometimes these patients appear to have AVP-D yet at other times they can concentrate their urine quite normally. Nonetheless, the presence of refractory hyperosmolality with absent or inappropriate thirst should alert clinicians to the presence of osmoreceptor dysfunction, regardless of occasional apparent normal urine concentration.

In a few patients with osmoreceptor dysfunction, forced hydration has been found to lead to hyponatremia in association with inappropriate urine concentration. ^, This paradoxic defect resembles that seen in SIAD and has been postulated to be caused by two different pathogenic mechanisms. One is continuous or fixed secretion of AVP because of loss of the capacity for osmotic inhibition and stimulation of hormone secretion. These observations, as well as electrophysiologic data, have strongly suggested that the osmoregulatory system is bimodal (i.e., it is composed of inhibitory and stimulatory input to the neurohypophysis). The other cause of the diluting defect appears to be hypersensitivity to the antidiuretic effects of AVP because, in some patients, urine osmolality may remain elevated, even when the hormone is undetectable.

Hypodipsia is also a common occurrence in older adults in the absence of any overt hypothalamic lesion. In such cases, it is not clear whether the defect is in the hypothalamic osmoreceptors, in their projections to the cortex, or in some other regulatory mechanism. However, in most cases, the osmoreceptor is likely not involved because basal and stimulated plasma AVP levels have been found to be normal, or even hyperresponsive, in relation to plasma osmolality in older adults, with the exception of only a few studies that showed decreased plasma levels of AVP relative to plasma osmolality.

A relative deficiency of plasma AVP can also result from an increase in the rate of AVP metabolism. ^, This condition has been observed only in pregnancy and therefore has been generally termed “gestational diabetes insipidus.” ^, It is due to the action of a circulating enzyme called cysteine aminopeptidase (oxytocinase or vasopressinase) that is normally produced by the placenta to degrade circulating oxytocin and prevent premature uterine contractions. Because of the close structural similarity between AVP and oxytocin, this enzyme degrades both peptides. Although there is no deficiency of AVP secretion or resistance to AVP action in the kidney, it is classified as AVP-D because plasma AVP levels are low relative to plasma osmolality. There are two types of gestational AVP-D. In the first type, the activity of cysteine aminopeptidase is extremely elevated. This syndrome has been referred to as vasopressin-resistant AVP-D of pregnancy. It can occur in association with preeclampsia, acute fatty liver, and coagulopathies (e.g., HELLP syndrome [ h emolysis, e levated l iver enzymes, and l ow p latelet count]). These patients have decreased metabolism of vasopressinase by the liver. Usually, in subsequent pregnancies, these women have neither AVP-D nor acute fatty liver. In the second type, the accelerated metabolic clearance of vasopressin produces AVP-D in a patient with borderline AVP from an unrelated disease process (e.g., partial AVP-D or mild AVP-R). AVP is rapidly destroyed, and the neurohypophysis is unable to keep up with the increased demand. Labor and parturition usually proceed normally, and patients have no trouble with lactation. Severe dehydration can occur if AVP-D is unrecognized, which may pose a threat to a pregnant woman and her fetus. The relationship of this disorder to the transient AVP-R of pregnancy is not clear.

The pathophysiology of gestational AVP-D is similar to that of AVP-D. The only exception is that the polyuria is usually not corrected by the administration of AVP because this is rapidly degraded, just as is endogenous AVP, but it can be controlled by treatment with desmopressin, the AVP V ₂ receptor agonist that is more resistant to degradation by oxytocinase or vasopressinase. It should be remembered that patients with partial AVP-D in whom only low levels of AVP can be maintained, or patients with compensated AVP-R in whom the lack of response of the kidney to AVP may not be absolute, can be relatively asymptomatic with regard to polyuria. However, with accelerated destruction of AVP during pregnancy, the underlying AVP-D or AVP-R may become clinically manifest. Consequently, patients presenting with gestational AVP-D should not be assumed simply to have excess oxytocinase or vasopressinase; rather, these patients should be evaluated for other possible underlying pathologic diagnoses (see Box 14.1 ).

Resistance to the antidiuretic action of AVP is usually due to some defect within the kidney and is referred to as AVP-R, previously called nephrogenic diabetes insipidus (NDI). Clinical studies of AVP-R have indicated that symptomatic polyuria is present from birth, plasma AVP levels are normal or elevated, resistance to the antidiuretic effect of AVP can be partial or almost complete, and the disease affects mostly males and is usually, although not always, mild or absent in carrier females. More than 90% of cases of congenital AVP-R are caused by mutations of the AVP V ₂ receptor. ^, Most mutations occur in the part of the receptor that is highly conserved among species and/or is conserved among similar receptors, such as homologies with AVP V _1A or oxytocin receptors. The effect of a number of these mutations on receptor synthesis, processing, trafficking, and function has been studied by in vitro expression. ^,

Approximately 10% of the V ₂ receptor mutations causing congenital AVP-R are thought to occur de novo. This high incidence of de novo cases, coupled with the large number of mutations that have been identified, hinders the clinical use of genetic identification because it is necessary to sequence the entire open reading frame of the receptor gene rather than short sequences of DNA. Nonetheless, because the gene is relatively small, the use of automated gene sequencing techniques in selected families can be used to define mutations in patients with clinical disease and asymptomatic carriers. Although most female carriers of the X-linked V ₂ receptors defect have no clinical disease, some have been reported with symptomatic AVP-R. Carriers can have a decreased maximum urine osmolality in response to plasma AVP levels but are generally asymptomatic because of the absence of overt polyuria.

Congenital AVP-R can also result from mutations of the autosomal gene that codes for AQP2, the protein that forms the water channels in the apical membrane of renal medullary collecting duct tubules. When the proband is a girl, it is likely the defect is a mutation of the AQP2 gene on chromosome 12, region q12-q13. More than 25 different mutations of the AQP2 gene have been described. The patients may be heterozygous for two different recessive mutations or homozygous for the same abnormality from each parent. Because most of these mutations are recessive, the patients usually do not present with a family history of AVP-R unless they share a recent common ancestor (i.e., consanguinity is present). Functional expression studies of these mutations have shown that all of them result in varying degrees of reduced water transport because the mutant aquaporins are not expressed in normal amounts, are retained in various cellular organelles, or simply do not function as effective water channels. Regardless of the type of mutation, the phenotype of AVP-R from AQP2 mutations is identical to that produced by V ₂ receptor mutations. Of interest, and sometimes helpful clinically, an AVP V ₂ receptor agonist still stimulates the release of von Willebrand factor (vWF) from the Weibel-Palade bodies of endothelial cells in patients with AQP2 mutations. Some of the defects in cellular routing and water transport can be reversed by treatment with chemicals that act like chaperones, suggesting that misfolding of the mutant AQP2 may be responsible for misrouting.

AVP-R can also be caused by a variety of drugs, diseases, and metabolic disturbances including lithium, hypokalemia, and hypercalcemia (see Box 14.1 ). Some of these disorders (e.g., polycystic kidney disease) act to distort the normal architecture of the kidney and interfere with the normal urine concentration process. However, experimental studies in animal models have suggested that many of these disorders evidence downregulation of AQP2 expression in the renal collecting tubules ( Fig. 14.10 ). ^, Bioinformatic integration of transcriptomic and proteomic data from prior studies has revealed that acquired AVP-R models map to three core processes: oxidative stress, apoptosis/autophagy, and inflammatory signaling. These processes cause loss of AQP2 function through translational repression, accelerated degradation of proteins, and/or transcriptional repression. The polyuria associated with potassium deficiency develops in parallel with decreased expression of kidney AQP2, and repletion of potassium reestablishes the normal urinary concentrating mechanism and normalizes the renal expression of AQP2. Similarly, hypercalcemia has also been found to be associated with downregulation of AQP2. A low-protein diet diminishes urinary concentrating ability, primarily by a decreased delivery of urea to the inner medulla, thus decreasing the medullary concentration gradient. In addition, rats fed a low-protein diet also appear to downregulate AQP2, which could be an additional component of the decreased ability to concentrate the urine. Bilateral urinary tract obstruction causes an inability to maximumly concentrate the urine, and rat models have demonstrated a downregulation of AQP2, which persists for several days after release of the obstruction. However, it is not yet clear which of these effects on AQP2 expression are primary or secondary and which cellular mechanism(s) are responsible for the downregulation of AQP2 expression.

Kidney expression of the water channel aquaporin-2 in various animal models of polyuria and water retention.

Note that kidney aquaporin-2 expression is uniformly downregulated relative to levels in controls in all animal models of polyuria but upregulated in animal models of inappropriate antidiuresis. DI ^+/+ , Genetic diabetes insipidus; Hyper-Ca, hypercalcemia; Hypo-K, hypokalemia; Urinary obstr, ureteral obstruction.

From Nielsen S, Kwon TH, Christensen BM, et al. Physiology and pathophysiology of renal aquaporins. J Am Soc Nephrol. 1999;10:647−663.

The administration of lithium to treat psychiatric disorders is the most common cause of medication-induced AVP-R. Up to 10% to 20% of patients on chronic lithium therapy develop some degree of AVP-R. These adverse effects are mediated by lithium entry into the principal cells in the collecting tubule via the epithelial sodium channel (ENaC). Here, lithium inhibits signaling pathways that involve glycogen synthase kinase type 3 beta (GSK3beta), resulting in dysfunction of the aquaporin AQP2 water channel. Lithium is also known to interfere with the production of cAMP. As a result of both of these effects, lithium produces a dramatic (up to 95%) reduction in kidney AQP2 levels in animals. The defect of aquaporins is slow to correct in experimental animals and humans. In some cases, it can be permanent and is associated with glomerular disease or tubulointerstitial nephropathy. Several other medications that are known to induce renal concentrating defects have also been associated with abnormalities of AQP2 synthesis.

Similar to AVP-D, renal insensitivity to the antidiuretic effect of AVP also results in the excretion of an increased volume of dilute urine, decrease in body water, and rise in plasma osmolality, which by stimulating thirst induces a compensatory increase in water intake. As a consequence, the osmolality of body fluid stabilizes at a slightly higher level, which approximates the osmotic threshold for thirst. As in patients with AVP-D, the magnitude of polyuria and polydipsia varies greatly depending on a number of factors including the degree of renal insensitivity to AVP, individual differences in the set points and sensitivity of thirst and AVP secretion, and total solute load. It is important to note that the renal insensitivity to AVP need not be complete for polyuria to occur; it is only necessary that the defect is great enough to prevent the concentration of the urine at plasma AVP levels achievable under ordinary conditions of ad libitum water intake (i.e., at plasma osmolalities near the osmotic threshold for thirst). Calculations similar to those used for states of AVP-D indicate that this requirement is not met until the renal sensitivity to AVP is reduced by more than 10-fold. Because renal insensitivity to the hormone is often incomplete, especially in cases of acquired rather than congenital AVP-R, many patients with AVP-R are able to concentrate their urine to varying degrees when they are deprived of water or given large doses of the AVP V2R agonist desmopressin.

Information about the renal concentration mechanism from studies of AQP2 expression in experimental animals has suggested that a form of AVP-R is likely associated with all types of AVP-D, as well as with primary polydipsia. Brattleboro rats have been found to have low levels of kidney AQP2 expression compared with Long-Evans control rats; AQP2 levels are corrected by treatment with AVP or desmopressin, but this process takes 3 to 5 days, during which time urine concentration remains subnormal, despite pharmacologic concentrations of AVP. Similarly, physiologic suppression of AVP by chronic overadministration of water produces a downregulation of AQP2 in the renal collecting duct. Clinically, it is well known that patients with both AVP-D and primary polydipsia often fail to achieve maximally concentrated urine when they are given desmopressin during a water deprivation test to differentiate among the various causes of hypotonic polyuria. This effect has long been attributed to a washout of the medullary concentration gradient as a result of the high urine flow rates in polyuric patients; however, based on the results of animal studies, it seems certain that at least part of the decreased response to AVP is due to a downregulation of kidney AQP2 expression. This also explains why it takes time, often several days, to restore normal urinary concentration after patients with AVP-D and primary polydipsia are treated with water restriction and/or antidiuretic therapy.

Excessive fluid intake also causes hypotonic polyuria and, by definition, polydipsia. Consequently, this disorder must be differentiated from the various causes of AVP-D and AVP-R. Furthermore, it is apparent that despite normal pituitary and kidney function, patients with this disorder share many characteristics of both AVP-D (AVP secretion is suppressed as a result of the decreased plasma osmolality) and AVP-R (kidney AQP2 expression is decreased as a result of the suppressed plasma AVP levels). Many different names have been used to describe patients with excessive fluid intake, but the term “primary polydipsia” remains the best descriptor because it does not presume any particular cause for the increased fluid intake. Primary polydipsia is often due to a severe mental illness, such as schizophrenia, mania, or an obsessive-compulsive disorder, in which case it is termed “psychogenic polydipsia.” These patients usually deny true thirst and attribute their polydipsia to bizarre motives, such as a need to cleanse their body of poisons. Studies of a series of patients with polydipsia in psychiatric hospitals have shown an incidence as high as 42% of patients with some form of polydipsia and, in most reported cases, there was no obvious explanation for the polydipsia.

However, primary polydipsia can also be caused by an abnormality in the osmoregulatory control of thirst, in which case it has been termed “dipsogenic diabetes insipidus.” These patients have no overt psychiatric illness and invariably attribute their polydipsia to a nearly constant thirst. Dipsogenic polydipsia is usually idiopathic but can also be secondary to organic structural lesions in the hypothalamus identical to any of the disorders described as causes of AVP-D, such as neurosarcoidosis of the hypothalamus, tuberculous meningitis, multiple sclerosis, or trauma. Consequently, all polydipsic patients should be evaluated with an MRI scan of the brain before concluding that excessive water intake has an idiopathic or psychiatric cause. Primary polydipsia can also be produced by medications that cause a dry mouth or by any peripheral disorder causing pathologic elevations of renin and/or angiotensin levels.

Finally, primary polydipsia is sometimes caused by physicians, nurses, or the lay press who advise a high fluid intake for valid (e.g., recurrent nephrolithiasis) or unsubstantiated reasons of health. These patients lack overt signs of mental illness but also deny thirst and usually attribute their polydipsia to habits acquired from years of adherence to their drinking regimen.

The pathophysiology of primary polydipsia is essentially the reverse of that in AVP-D—the excessive intake of water expands and slightly dilutes body fluids, suppresses AVP secretion, and dilutes the urine. The resultant increase in the rate of water excretion balances the increase in intake, and the osmolality of body water stabilizes at a new, slightly lower level that approximates the osmotic threshold for AVP secretion. The magnitude of the polyuria and polydipsia vary considerably, depending on the nature or intensity of the stimulus to drink. In patients with abnormal thirst, the polydipsia and polyuria are relatively constant from day to day. However, in patients with psychogenic polydipsia, water intake and urine output tend to fluctuate widely and, at times, can be quite large.

Occasionally, fluid intake rises to such extraordinary levels that the excretory capacity of the kidneys is exceeded and dilutional hyponatremia develops. There is little question that excessive water intake alone can sometimes be sufficient to override renal excretory capacity and produce severe hyponatremia. Although the water excretion rate of normal adult kidneys can generally exceed 20 L/day, maximum hourly rates rarely exceed 1000 mL/h. Because many psychiatric patients drink predominantly during the day or during intense drinking binges, they can transiently achieve symptomatic levels of hyponatremia, with the total daily volume of water intake <20 L if ingested rapidly enough. This likely accounts for many of the patients who present with maximally dilute urine, accounting for up to 50% of patients in some studies, and are corrected quickly via free water diuresis. The prevalence of this disorder, based on hospital admissions for acute symptomatic hyponatremia, may have been underestimated because studies of polydipsic psychiatric patients have shown a marked diurnal variation in serum [Na ⁺ ], from 141 mEq/L at 7 am to 130 mEq/L at 4 pm , suggesting that many such patients drink excessively during the daytime but then correct themselves via water diuresis at night. This and other considerations have led to defining this disorder as the “psychosis, intermittent hyponatremia, and polydipsia” (PIP) syndrome.

However, many other cases of hyponatremia with psychogenic polydipsia have been found to meet the criteria for a diagnosis of SIAD, suggesting the presence of nonosmotically stimulated AVP secretion. As might be expected, in the presence of much higher than normal water intake, almost any impairment of urinary dilution and water excretion can exacerbate the development of a positive water balance and thereby produce hypoosmolality. Acute psychosis itself can also cause AVP secretion, which often appears to take the form of a reset osmostat. It is therefore apparent that no single mechanism can completely explain the occurrence of hyponatremia in polydipsic psychiatric patients, but the combination of higher than normal water intake plus modest elevations of plasma AVP levels from a variety of potential sources appears to account for a significant portion of these cases.

The therapeutic agents available for the treatment of AVP-R and AVP-D are shown in Box 14.2 . Water should be considered a therapeutic agent because, when ingested or infused in sufficient quantity, there is no abnormality of body fluid volume or composition.

As noted previously, in most patients with AVP-D and AVP-R, thirst remains intact and the patient will drink sufficient fluid to maintain a relatively normal fluid balance. A patient with known AVP-D should therefore be treated to decrease the polyuria and polydipsia to acceptable levels that allow them to maintain a normal lifestyle. Because the major goal of therapy is improvement in symptomatology, the therapeutic regimen prescribed should be individually tailored to each patient to accommodate his or her needs. The safety of the prescribed agent and use of a regimen that avoids potential detrimental effects of overtreatment are primary considerations because of the relatively benign course of AVP-D and AVP-R in most cases and the potential adverse consequences of medication-induced hyponatremia. Available treatments are summarized for different types of hypotonic polyuria.

In considering clinical disorders that result from excessive or inappropriate secretion of AVP, it is important to remember the many other variables that also influence renal water excretion. These factors fall into four broad categories.

SIAD, previously called the Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH), is the most common cause of hyponatremia in hospitalized patients. As first described by Schwartz and associates in two patients with bronchogenic carcinoma, and later characterized further by Bartter and Schwartz, patients with this syndrome have serum hypoosmolality when excreting urine that is less than maximally dilute (>100 mOsm/kg H ₂ O). Thus a diagnostic criterion for this syndrome is the presence of inappropriate urine concentration. The development of hyponatremia with very dilute urine (<100 mOsm/kg H ₂ O) should raise suspicion of a primary polydipsic disorder. Although large volumes of fluid need to be ingested to overwhelm the normal water excretory ability, this volume need not be excessively high if there are concomitant decreases in solute intake. In SIAD, the urinary Na ⁺ concentration is dependent on intake because Na ⁺ balance is well maintained. As such, urinary Na ⁺ concentration is usually high, but it may be low in patients with the syndrome who are receiving a low-sodium diet. The presence of Na ⁺ in the urine is helpful in excluding extrarenal causes of hypovolemic hyponatremia, but a low urinary Na ⁺ concentration does not exclude SIAD. Before the diagnosis of SIAD is made, other causes for a decreased diluting capacity, such as renal, pituitary, adrenal, thyroid, cardiac, or hepatic disease, must be excluded. In addition, nonosmotic stimuli for AVP release, particularly hemodynamic derangements (e.g., caused by hypotension, nausea, or drugs), should be ruled out.

Another clue to the presence of SIAD is the finding of hypouricemia. In one study, 16 of 17 patients with a diagnosis of SIAD had levels below 4 mg/dL, whereas in 13 patients with hyponatremia of other causes, the level was higher than 5 mg/dL. Hypouricemia appears to occur as a consequence of increased urate clearance. Measurement of an elevated level of AVP can confirm the clinical diagnosis but is not necessary. It should be noted that most patients with SIAD have AVP levels in the normal range (2−10 pg/mL); the presence of any measurable AVP is, however, abnormal in the hypoosmolar state. Plasma AVP levels have never been a requirement for the diagnosis of SIAD, in part because they are elevated in states of hypovolemic hyponatremia and SIAD, and therefore have little differential diagnostic value. For similar reasons, the measurement of copeptin levels has been found to be of little diagnostic value in the differential diagnosis of hyponatremia. Because the presence of hyponatremia is itself evidence for abnormal dilution, a formal urine-diluting test need not be performed in most cases. The water loading test is helpful in determining whether an abnormality remains in a patient whose serum [Na ⁺ ] has been corrected by water restriction. Because Brattleboro rats receiving AVP have displayed upregulation of AQP2 expression, the excretion of AQP2 has been investigated as a marker for the persistent secretion of AVP. The excretion of the water channel remains elevated in patients with SIAD, but this is not specific to this entity because a similar pattern was observed in patients with hyponatremia due to hypopituitarism.

Pathophysiology

In 1953, Leaf and associates described the effects of chronic AVP administration on Na ⁺ and water balance. They noted that high-volume water intake was required for the development of hyponatremia. Concomitant with the water retention, an increment in urinary Na ⁺ excretion was observed. The relative contributions of the water retention and Na ⁺ loss to the development of hyponatremia were subsequently investigated. Acute water loading causes transient natriuresis but, when water intake is increased more slowly, no significant negative Na ⁺ loss can be documented. These studies have clearly demonstrated that hyponatremia is mainly a consequence of water retention; however, it must be noted that the net increase in water balance fails to account entirely for the decrement in serum [Na ⁺ ].

In a carefully studied model of SIAD in rats, the retained water was found to be distributed in the intracellular space and in equilibrium with the tonicity of the ECF. The natriuresis and kaliuresis that occur early in the development of this model contribute to a decrement of body solutes and, in part, account for the observed hyponatremia. Studies involving analysis of whole-body water and electrolyte content have demonstrated that the relative contributions of water retention and solute losses vary with the duration of induced hyponatremia; the former is central to the process but, with more prolonged hyponatremia, Na ⁺ depletion becomes predominant. In this regard, it has even been suggested that the natriuresis and volume contraction are important components of the syndrome that maintains the secretion of AVP, with atrial natriuretic peptide as a potential mediator of the Na ⁺ loss. Therefore although natriuresis frequently accompanies the syndrome, nonosmotically stimulated AVP secretion is essential. Finally, patients with the syndrome must also have abnormal thirst regulation, whereby the osmotic inhibition of water intake is not operant. The mechanism of this failure to suppress thirst is not fully understood but may simply reflect the continued ingestion of beverages for reasons other than true thirst.

After the initial retention of water, loss of Na ⁺ , and development of hyponatremia, continued administration of AVP is accompanied by reestablishment of Na ⁺ balance and a decline in the hydroosmotic effect of the hormone. The integrity of renal regulation of Na ⁺ balance is manifested by the ability to conserve Na ⁺ during Na ⁺ restriction and by the normal excretion of a Na ⁺ load. Thus the mechanisms that regulate Na ⁺ excretion are intact. Loss of the hydroosmotic effect of AVP, albeit to varying degrees, has been evident in many studies ^, because urine flow increases and urine osmolality decreases, despite continued administration of the hormone. This effect has been termed “vasopressin escape.” Several studies have demonstrated that hypotonic ECF volume expansion, rather than chronic administration of AVP per se, is needed for escape to occur because the escape phenomenon is seen only when a positive water balance is achieved.

The cellular mechanisms responsible for vasopressin escape have been the subject of some investigation. Studies of broken epithelial cell preparations of the toad urinary bladder have revealed downregulation of AVP receptors, as well as vasopressin binding in the inner medulla. Post-cAMP mechanisms are probably also operant. In this regard, a decrease in the expression of AQP2 has been reported in the process of escape from desmopressin-induced antidiuresis, without a concomitant change in basolateral AQP3 and AQP4. ^, The decrement in AQP2 was associated with decreased V ₂ R responsiveness. The distal tubule also has an increase in the expression of sodium transporters, including both the alpha and gamma subunits of the epithelial sodium channel (ENaC) and the thiazide-sensitive Na ⁺ -Cl ⁻ cotransporter. In addition to a renal mechanism, it appears that chronic hyponatremia causes a decrement in hypothalamic AVP mRNA production, a process that could ameliorate the syndrome in the clinical setting.

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