Keywords

Introduction

Diabetes insipidus (DI) is a clinical disorder characterized by an excessive urine output (diabetes) in which, as opposed to what is observed in diabetes mellitus, urine is hypotonic (<250 mmol/kg), diluted, and insipid. There are several mechanisms involved in the pathogenesis of the different clinical forms of DI, all of which are related to an insufficient amount or action of the antidiuretic hormone or arginine-vasopressin (ADH or AVP).

Consideration of the basic physiopathologic mechanisms involved in AVP regulation enables subsequent understanding of the potential diagnostic and treatment alternative tools that may be considered in the approach of a patient with DI. In this chapter, we will thoroughly revise the different clinical settings of DI, and we will discuss the algorithms that need to be followed for a correct approach and management of patients with this syndrome.

Basics in Anatomy and Physiology of the Posterior Pituitary

Normal Anatomy

The posterior pituitary (neurohypophysis) comprises the distal axons from hypothalamic magnocellular neurons whose cellular bodies are located in the supraoptic and paraventricular nuclei (Fig. 1). Although the anterior pituitary receives the majority of its vascularization from the hypothalamic-pituitary portal system, the posterior pituitary is mainly irrigated directly from posterior pituitary arteries derived from the internal carotid artery and the posterior communicant artery. Venous drainage is mainly conducted through the cavernous sinus and the internal jugular vein.

Fig. 1
figure 1

Schematic representation of the hypothalamic-pituitary axis, and where AVP is secreted. The precursor of AVP is packaged into neurosecretory granules and transported axonally into the posterior pituitary, through the pituitary stalk, and transformed into the active hormone

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Cerebral magnetic resonance imaging (MRI) has enabled the identification of the posterior pituitary as hyperintense (bright) in T1-weighted images. Furthermore, it allowed the documentation of some patients who exhibited this bright spot in ectopic locations, mostly in cases with associated anterior pituitary deficiencies and growth retardation. Abnormalities in the location of the posterior pituitary are probably due to genetic alterations in its migration down the pituitary stalk (Bichet 2011).

Antidiuretic Hormone or Arginine-Vasopressin (ADH or AVP): A Complex Regulatory System

AVP is a nonapeptidic hormone that consists of a six-amino-acid ring with a cysteine-cysteine bonding and a three-amino-acid terminal region. It is synthesized as precursor forms by the magnocellular and parvocellular neurons in the supraoptic and paraventricular nuclei of the hypothalamus. These precursors of AVP are packaged into neurosecretory granules, follow an axonal transport into the posterior pituitary through the pituitary stalk, and are then transformed into the active hormone (Fig. 1). AVP will thereafter be stored in vesicles in the posterior pituitary and will be ready to be released in response to stimulus (Table 1).

Table 1 Stimulatory and inhibitory factors of arginine-vasopressin (AVP) secretion
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Specifically, AVP is mainly regulated, thanks to the osmotic and the pressure-volume systems, which function as two independent, but related, mechanisms (Fig. 2). In fact, the roles of these two systems are so distinct that the existence of two different hormones, an antidiuretic hormone and a vasopressin hormone, was historically believed. This is why we currently name this hormone with either of the two terms.

Fig. 2
figure 2

Stimulation of AVP release by osmotic and volume changes. Schematic representation of the normal physiological relationships between plasma AVP levels and percentage increase in plasma osmolality (red thick dotted line) and plasma AVP levels and blood volume percentage depletion (blue continuous line). Note that AVP release is more sensitive to changes (increase) in osmolality (mediated by osmoreceptors), in comparison to changes (depletion) in volume (mediated by baroreceptors). However, when the non-osmotic stimulation of AVP occurs, the resultant plasma AVP concentrations are much higher than when the main trigger is the osmotic stimulation. Moreover, the non-osmotic stimulation of AVP can override the effect of hypoosmolality to suppress AVP

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Concerning the osmotic regulation, AVP secretion is relatively simple and straightforward. In this regard, subtle increases in serum osmolality (hypernatremia) will precede evident increases in AVP synthesis and release. This response is mediated by specific neurons, termed osmoreceptors, which are capable of detecting subtle changes in extracellular fluid osmolality and are present in both the central nervous system and in the periphery. The specific osmotic threshold for osmoreceptor sensitivity and vasopressin release is considerably variable between individuals and is also probably genetically determined, but, in general, it lies around 280 mosm/kg (Fig. 2).

The regulatory influence of the pressure-volume system is a little more complicated. Firstly, more pronounced decreases in extracellular fluid (hypovolemia) are required to stimulate AVP synthesis and release, an action which is mediated by stretch receptors, termed baroreceptors, located in the left atrium, carotid sinus, and aortic arch (Fig. 2). In this case, stimulus arising from these receptors inhibits vasopressin secretion, while a reduced discharge rate enhances vasopressin release. However, other inhibitory phenomena and/or the role of other simultaneous sympathetic impulses have to be also considered. For instance, the renin-angiotensin-aldosterone system plays an important role, and angiotensin II increases vasopressin secretion; opioid peptides that act through k-receptors inhibit it; cholecystokinin increases AVP release; and nitric oxide acts as an inhibitory modulator. The dopaminergic transmission seems to potently stimulate AVP release, for example, in situations like nausea and emesis; this effect is generally less significant but may acquire a relevant role in pathologic situations. In addition, vasopressin secretion is under the influence of a glucocorticoid-negative feedback system, and the usual AVP responses to a variety of stimuli (including hemorrhage, hypoxia, and hypertonic saline) may be attenuated, or even suppressed, by previously administering glucocorticoids.

In the majority of normal physiologic circumstances, AVP stimulation results from a coincident and synergistic combination of an increased osmolality and a decreased effective volume, such as in the setting of dehydration. In addition, there is evidence enough to suggest that a reduction in effective volume moves the curve of vasopressin response to osmolality to the left, thus reducing the osmotic threshold and leading to a greater AVP stimulation. In other words, the osmotic stimulus is much more sensitive to trigger AVP release than the stimulus of a reduced effective volume. However, when a greater decrease in effective volume is capable of triggering AVP release, its effect is much more potent than the osmotic stimulus, and the increase in AVP is significantly higher (Fig. 2). In a similar way, an excess in body fluids will reduce the effective osmolality and increase the effective volume, thus reducing AVP secretion. Therefore, the sensibility of AVP synthesis and release to osmoregulation allows plasma osmolality to be kept within a small range, mediated through kidney adaptation for water excretion regulation in response to subtle osmotic changes. Thirst may behave as an essential and additional protective mechanism to maintain an adequate plasma osmolality and volume, but, in normal circumstances, it does not really play a relevant role, since liquid ingestion is usually above real needs and excess water is normally excreted by the kidney. However, if water intake is not sufficiently enough to replace water losses, like in the setting of maximal antidiuresis, serum osmolality increases and stimulates thirst to an extent which parallels the existing osmolality increase.

Cellular Actions of Vasopressin Are Mediated by Specific Receptors

Vasopressin receptors (AVPR or V) differ concerning the target organ. In this regard, V1 receptors are mainly expressed in the vasculature (vascular smooth muscle), platelets, brain, liver, and anterior pituitary, although they can also be found in other locations; and V2 receptors are heavily expressed in cells of the renal collecting ducts. The third type of vasopressin receptor (V3) mediates stimulation of the adrenocorticotropin hormone (ACTH) in the anterior pituitary, which is a particular nonclassical action of AVP, and a V2 subtype receptor may stimulate the production of clot factor VIII.

Vasopressin actions are mediated through these vasopressin receptors, and include inhibition of diuresis, mainly through the protein aquaporin 2 (AQP2), which rapidly turns renal cells in the collecting ducts permeable to water, allowing reabsorption of water from urine into the blood and concentrating urine (Fig. 3), contraction of smooth muscle, aggregation of platelets, stimulation of liver glycogenolysis, modulation of ACTH release, central regulation of somatic functions such as thermoregulation and blood pressure, and modulation of social and reproductive behavior (for instance, stimulation of the thirst center in the cerebral cortex) (Fig. 4).

Fig. 3
figure 3

Schematic representation of water transport in the renal cell. Binding of AVP to the vasopressin receptor 2 (V2) on the basolateral side of the renal principal cell stimulates the release of the G alpha (Gα) protein, which, in turn, activates the adenyl cyclase and increases cAMP production. As a result, several phosphoproteins are activated, enabling trafficking of the aquaporin 2 (AQP2) to the apical membrane and the formation of AQP2 water channels. AQP2 may be continuously regenerated in recycling vesicles. Therefore, ongoing water permeability depends on the availability of AQP2 on the apical membrane, either by new generation or by recycling vesicles. Water enters the renal cells through this AQP2 channel and diffuses across the concentration gradient, from the tubular lumen, into the principal cell, and exits into the interstitium through other aquaporin channels (AQP3 and AQP4)

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Fig. 4
figure 4

Simplified summary of the mechanisms involved in hydro-electrolytic regulation, mediated by AVP. “(+)”, stimulus; “(−)”, inhibition. Fluid restriction and increased plasma osmolality stimulate the release of AVP. AVP, on its side, acts at different target organs in the body: it stimulates the activity of AQP2 in renal cells, to reabsorb water and contribute to the antidiuretic effect; stimulates aggregation of platelets; stimulates the smooth muscle in blood vessels, leading to vasoconstriction and contributing to the increase on effective intracellular volume; stimulates liver glycogenolysis; and modulates ACTH release, thermoregulation, blood pressure, and thirst in the pituitary gland and cerebral cortex. All these actions subsequently lead to normalization of total body water and will eventually lead to a negative feedback regulation for AVP release

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It is important to note that several situations, like pregnancy or stress, may produce alterations in the usual AVP regulation. Also, age may modify the effective circulating volume and renal function, which explains why the elderly may be predisposed to hydro-electrolytic imbalances. For instance, although their AVP secretion may be preserved, the elderly usually exhibit a reduced thirst reflex and a reduced ability to obtain the maximal or minimum urine concentrations, in order to retain water or excrete it, respectively.

A good understanding of these actions helps anticipate the clinical alterations which can be identified in cases with altered AVP secretion or action.

Subtypes of Diabetes Insipidus: Different Etiologies to one Same Syndrome

There are four main mechanisms which can be distinguished in the pathophysiology of DI:

  • Central DI (CDI): when the main alteration is found in the hypothalamus or posterior pituitary and an insufficient amount of AVP is synthesized or released. This type has been termed as hypothalamic, neurogenic, or pituitary DI.

  • Nephrogenic DI (NDI): when the kidney does not respond correctly to AVP.

  • Transient DI of pregnancy: where an altered AVP metabolism occurs, presumably during a limited period of time.

  • Primary polydipsia: where the initial pathogenic mechanism is related to the intake of fluid, and not as much in its excretion.

Table 2 shows a list of the most relevant causes under these previous mechanisms.

Table 2 Etiology of diabetes insipidus
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Neurogenic (Central) Diabetes Insipidus (CDI)

There are several clinical entities in which we can observe an absent or deficient release of AVP due to a defective neurohypophyseal function.

Hypothalamic Hereditary Diabetes Insipidus

This clinical syndrome is characterized by the development of early diabetes insipidus in infants, with the classical symptoms of thirst and increased fluid intake and urine output. As opposed to familial NDI, in familial CDI, the age of onset of symptoms may differ depending on the mutation. In fact, it may be asymptomatic during the first years, and, therefore, the diagnosis may be frequently overlooked, an observation which lies in accordance with the finding of a progressive decrease, or even disappearance, of the bright spot in MRI over time.

In the majority of cases, familial CDI is an autosomal dominant disorder caused by mutations in arginine vasopressin-neurophysin II (AVP-NPII) gene, which lead to aberrant preprohormone processing and gradual destruction of AVP-secreting cells,

Wolfram’s syndrome , also known as DIDMOAD (diabetes insipidus + diabetes mellitus + optic atrophy + sensorineural deafness), is an autosomal recessive neurodegenerative disease in which patients may develop diabetes insipidus. In this case, AVP deficiency is usually partial and of gradual onset. It is important to be aware that polyuria may sometimes be wrongly attributed to poor glycemic control, and a severe hyperosmolar state can occur if an untreated diabetes mellitus is associated with an unrecognized posterior pituitary deficiency. The genetic defect in this syndrome is located in chromosome region 4p16.1, which encodes a putative 890-amino acid transmembrane protein termed wolframin (Miller et al. 1970; Turkkahraman et al. 2015).

Central Diabetes Insipidus in the Setting of Solid Tumors or Hematologic Diseases

Suprasellar tumors such as craniopharyngioma, pinealoma, and germinoma are characteristically found in the basal area of the hypothalamus and are frequently associated with the development of diabetes insipidus. In fact, polydipsia and polyuria may be one of the first symptoms appearing in a patient with these types of tumors and should alert clinicians for the suspicion of these entities, especially when concomitant hypopituitarism exists. MRI will characteristically evidence an enlargement of the pituitary stalk, together with the hypothalamic mass.

Pituitary metastases are not frequent, but, when they appear, locations in the posterior lobe are much more frequent than those in the anterior lobe, presumably as a result of the greater and direct vascularization that it receives.

There have also been cases of pituitary lymphomas with diabetes insipidus as one of its cardinal symptoms. In addition, there have been cases of diabetes insipidus in patients with hepatic C virus (HCV) or human immunodeficiency virus (HIV), who develop lymphoproliferative diseases, and in patients with leukemia. The underlying pathophysiology may involve infiltration of the hypothalamus, thrombosis, or infection.

Diabetes Insipidus in the Neurosurgical Patient

Disorders of water homeostasis are frequent in neurosurgical patients, especially after subarachnoid hemorrhage; after traumatic brain injury, with intracranial tumors; and after pituitary surgery. In fact, diabetes insipidus is quite common in the acute phase after a neurosurgical intervention, although it is usually transient. Serum sodium levels are rarely significantly altered if the thirst reflex is maintained, but many neurosurgical patients have a diminished consciousness level because of brain injury, postoperative cerebral irritation, cerebral edema, sedation for airway management, or a combination of all these previous factors. Therefore, awareness of thirst and the ability to respond to plasma osmolality increases should be taken into account, and sodium levels should be frequently monitored.

Diabetes insipidus in subarachnoid hemorrhage (SAH) . DI may occur acutely in around 15% of patients with SAH, and, although it is transient in the majority of patients, up to 8% may present persistent DI 3 months after discharge. Hemorrhage from anterior communicating artery aneurysms is associated with an increased risk of developing DI, presumably due to a higher risk of compromising the vascularization of the anterior hypothalamus. Fluid replacement will be especially important in these patients, since hypovolemia may predispose to cerebral vasospasm and worsen outcomes.

Diabetes insipidus in traumatic brain injury (TBI) (Scranton and Baskin 2015). Polyuria may be observed immediately after brain injury in around 20% of patients, nearly always within the first 2 or 3 days. However, as it occurred after SAH, the majority of cases will resolve spontaneously, although it is possible that some “subclinical” cases remain undiagnosed and maintain normal plasma osmolality through increased water intake. The severity of head trauma, assessed with the Glasgow Coma Scale, and the presence of cerebral edema on imaging studies are directly related to the risk of developing DI after TBI. MRI may be useful to complement the diagnosis of CDI in this clinical setting, where hypothalamic hemorrhage, neurohypophyseal hemorrhage or apoplexy, or pituitary stalk section may be the frequent findings.

Diabetes insipidus in the context of pituitary adenomas . As it was previously highlighted, pituitary adenomas themselves rarely produce DI, so if DI develops in a patient with a pituitary mass, it should prompt the suspicion of craniopharyngioma or other granulomatous diseases. However, DI is very frequent after surgical intervention of pituitary adenomas, especially after transsphenoidal surgery. In fact, up to 80% of cases have been reported to develop transient DI in the early phase after pituitary surgery, usually within 2 days, with an abrupt onset of hypotonic polyuria and accompanying thirst. But, once again, most cases are resolved by the third postoperative day, and rates of persistent DI are usually not above 15%. Transection of the pituitary stalk, on the contrary, will almost inevitably lead to permanent DI.

It is important to exclude confounding factors of polyuria, including steroid-induced hyperglycemia, mannitol, and diuretics. If there is evidence of a plasma sodium >145 mmol/l in the presence of hypotonic (urine osmolality <300 mOsm/kg, or urine density <1.005) polyuria (>300 ml/h for 2 consecutive hours or >3 l/day), then it is highly suggestive of acute DI and warrants prompt management.

Some factors may be associated with the development of DI after pituitary surgery: for instance, young age, male sex, large tumors, intraoperative cerebral-spinal fluid fistula, Rathke cysts, craniopharyngiomas, ACTH-producing tumors, and the experience of the neurosurgical team. Also, patients receiving prophylactic high doses of hydrocortisone may have a higher risk of postoperative DI. This is probably because free water excretion is dependent, to some extent, on adequate adrenal function, and may be impaired in the presence of cortisol deficiency, so patients on an insufficient dose of parenteral hydrocortisone postoperatively may have their DI “masked” by the presence of relative cortisol deficiency. Interestingly, although radiotherapy has been associated with the development of anterior pituitary insufficiency in the long-term follow-up, DI does not seem to occur, presumably because of a different radiosensitivity for the neurohypophysis in comparison to the adenohypophysis.

A small group of patients will develop what has been known as “a triphasic response.” In this case, after the initial occurrence of DI, there is a putative release of pre-stored AVP from damaged neurohypophyseal cells, leading to antidiuresis and hyponatremia (syndrome of inadequate secretion of antidiuretic hormone – SIADH), mostly around day 7 after surgery, and where exogenous AVP or excessive fluids may exacerbate the clinical picture. But then, these damaged neurons undergo gliosis and lose their functional capacity to synthesize or release AVP, and permanent DI establishes.

Diabetes insipidus in other less frequent neurosurgical settings. DI may also develop in the context of granulomatous diseases. In this case, clinical manifestations in other extrapituitary locations will guide clinicians to the diagnosis. In addition, DI may develop, although less commonly, after other neurosurgical conditions, such as intracerebral hemorrhage, subdural hematoma, and brain abscesses. Some cases, however, will still be considered “idiopathic,” and an underlying autoimmune mechanism should be borne in mind, such as what is known as lymphocytic hypophysitis (Hannon et al. 2012; Loh and Verbalis 2007).

Adipsic Diabetes Insipidus: Essential Hypernatremia

Adipsic DI or adipsic hypernatremia is an infrequent complicated clinical variant, in which there is an absent responsiveness to osmotic stimuli because of an altered osmostat, but a normal response of baroreceptors is preserved. The neurosurgical setting in which this rare disorder has been most frequently described is in patients who have had clipping of an anterior communicating artery aneurysm, presumably reflecting an underlying lesion of hypothalamic osmoreceptors.

These patients do not exhibit thirst nor secrete AVP in response to hyperosmolality, leading to hypotonic polyuria, although they retain the ability to synthesize and release AVP in response to other non-osmotic stimuli such as hypotension. As a result, limited fluid intake and increased water excretion lead to hypernatremic dehydration. When dehydration is sufficiently significant so as to stimulate baroreceptors, some AVP is released, urine concentrates, and patients may achieve a hypernatremic equilibrium state with mild dehydration, and hypernatremia itself may subsequently lead to sodium excretion, which maintains this new equilibrium state. Fluid supplementation with variable infusion of hypotonic fluids to slowly reduce sodium concentrations and maintain them in the normal range and prophylaxis against thromboembolic complications deem necessary in the approach of these patients, as well as providing a fixed dose of desmopressin to limit fluid loss. Body weight can serve as a surrogate of adequate water and sodium balance. Further explanations of this complicated variant are beyond the scope of this chapter (Crowley et al. 2007).

Nephrogenic Diabetes Insipidus

In nephrogenic diabetes insipidus (NDI), the kidney is unable to concentrate urine despite normal or elevated AVP concentrations (Bockenhauer and Bichet 2015).

Congenital Nephrogenic Diabetes Insipidus

In congenital NDI, the classic and unequivocal symptoms of DI, polyuria, and polydipsia are present early during the first week after birth and are frequently also associated with vomiting, constipation, development alterations, and fever. Therefore, prompt recognition is vital to avoid the severe consequences derived from dehydration.

Two clinical subtypes can be distinguished: a “pure” NDI phenotype, which is characterized by loss of water exclusively and is caused by mutations in the AVPR2 (which encodes the vasopressin V2 receptor) or AQP2 genes, and a more “complex” type, characterized by loss of water and ions, caused by inactivating mutations in genes (SLC12A1, KCNJ1, CLCNKB, CLCNKA, BSND) that encode the membrane proteins of the thick ascending limb of the loop of Henle. A summary of the mutations identified in congenital NDI is shown in Table 3.

Table 3 Genetic mutations causing nephrogenic diabetes insipidus
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Acquired Nephrogenic Diabetes Insipidus

The acquired form of NDI is much more common than congenital forms. The ability to elaborate a hypertonic urine is usually preserved, although the nephron is unable to maximally concentrate urine. Therefore, DI symptoms are generally more moderate, and polyuria-polydipsia is rarely greater than 3 to 4 l/day.

Drugs are the most frequent cause of acquired NDI, with lithium therapy being at the top of the list. In fact, rates have been described to be as high as 85%, so if we take into account the relatively large number of patients who take lithium, it is not surprising to encounter this entity in everyday clinical practice. The precise underlying pathophysiology remains to be elucidated. However, it seems that there is a cytotoxic accumulation of lithium, which enters renal cells via the highly lithium-permeable epithelial sodium channels (ENaC) on the apical membrane and leads to the inhibition of signaling pathways that involve glycogen synthase kinase type 3 beta. Consequently, the normal function of AQP2 is dysregulated, and renal tubular cells suffer a constitutive damage due to the electrolyte imbalance caused (Fig. 5).

Fig. 5
figure 5

Schematic representation of the effects of chronic lithium exposure in renal tubular cells. Lithium competes with sodium in its entry into the renal tubular cell through the epithelial sodium channel (ENaC) on the apical membrane. This leads to the inhibition of the normal signaling pathway of aquaporin 2 (AQP2) formation, so the normal function of AQP2 is dysregulated. In addition, lithium accumulation is responsible for the development of cytotoxicity due to the electrolyte imbalance caused, which constitutively damages the renal cells

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Lithium is frequently prescribed in psychiatric disorders, and normal therapeutic lithium levels are enough to produce this hypotonic polyuric effect. Although interruption of treatment will eventually restore normality, cessation of lithium therapy is rarely an option, because, in the majority of cases, the beneficial effects of the drug on the psychiatric disorder outweigh the negative impact of the polyuric complications on the quality of life (Behl et al. 2015).

If long-term treatment with lithium is required, administration of ENaC blockers such as amiloride may block the uptake of lithium in the collecting ducts, thus preventing the inhibitory effect of intracellular lithium on water transport, increase urine osmolality, and ameliorate polyuria.

Other acquired causes of typically transient NDI include hypercalcemia, hypercalciuria, and obstructive uropathy. In this latter clinical setting, NDI seems to occur because hydrostatic pressure directly suppresses AQP2 expression for up to 30 days, which explains why after obstruction release, an increased diuresis occurs. In addition, chronic renal diseases in which the kidney structure is significantly altered, such as renal poliquistosis, renal infarctions, or infiltrative diseases, may also present with a clinical picture of DI.

Diabetes Insipidus in Pregnancy

Pregnancy is usually accompanied by a physiologic redistribution of body fluids, decreasing plasma osmolality and increasing intravascular volume, leading to an osmotic threshold reset. This normal effect is probably mediated by the hormone known as relaxin and is usually unremarkable.

Diabetes insipidus may occur transiently during pregnancy as a result of an increased release and activity of the enzyme cysteine-aminopeptidase (oxytocinase), which is synthesized by the placenta from week 20 of pregnancy onward and breaks down AVP. An extreme and abnormal oxytocinase activity would lead to the typical “resistant DI of pregnancy” and has sometimes been associated with concomitant preeclampsia, acute hepatic steatosis, and coagulopathies. Normal delivery and subsequent recovery of normal body fluids will usually resolve this situation. On the other hand, in a pregnant woman with an already insufficient AVP activity due to a preexisting DI of any other cause, an abnormally increased metabolism will lead to an increased clearance, which cannot be overcome by a corresponding increase in AVP secretion and release, and will cause a clinically significant DI.

Primary Polydipsia

Primary polydipsia (PP) is a state of hypotonic polyuria, and, in general, mean plasma osmolality is lower due to excessive fluid intake. Its complete pathophysiology has not been fully understood yet.

It is possible that a selective defect in osmoregulation of thirst exists, with normal AVP secretion, but an abnormally low osmotic threshold for thirst, leading to a “dipsogenic DI.” In addition, PP may develop due to hypothalamic lesions (for instance, hypothalamic sarcoidosis), drugs which cause mucosal dryness, or any disease that causes an elevation of the renin-angiotensin-aldosterone axis. However, the majority of cases occur in patients with psychiatric disorders such as schizophrenia and mania. In these patients, osmolalities may be higher early in the morning because of a relative fluid restriction during the night sleep. AVP administration will be useless, since these patients have altered concentration renal mechanisms.

Differential Diagnosis: Investigating a Patient with Polyuria and Polydipsia, where Do we Start our Clinical Approach?

There are several variables that should be considered when approaching a patient with polyuria and polydipsia:

  • Urine volume in 24 h. Patients in whom DI is suspected should record their urine output by collecting urine or quantifying the time and amount of each urination.

  • Rule out the presence of any osmotic agents such as hyperglycemia.

  • Rule out the existence of previous nephropathy.

  • Serum sodium concentration, osmolality, and renal function.

  • Urine sodium concentration and osmolality.

  • Preserved thirst mechanism.

Certain clinical features should alert clinicians for the potential presence of DI. For instance, if a patient acknowledges an increased thirst, especially for cold fluids, and/or his urine output is excessive and hypotonic (“clear”), we should probably search for biochemical parameters to rule out potential causes of polyuria/polydipsia (Fenske and Allolio 2012).

Basal Measurements of Serum and Urine Sodium and Osmolality

A serum osmolality >295 mosm/kg, serum sodium >145 mEq/l, and urine osmolality inadequately diluted (<300 mosm/kg or urine density <1.005) in the setting of polyuria/polydipsia are highly suspicious of DI, and dynamic studies may not be necessary.

The Urinary Concentration Test as an Indirect Measure of AVP Activity

Diabetes insipidus is diagnosed if, after fluid restriction, AVP secretion is normal, but inadequately low or with insufficient action in relation to urine osmolality. As a result, the initial most frequent diagnostic approach to a patient with suspected DI consists of the evaluation of the capacity of urinary concentration in a supervised fluid privation test (dehydration test), followed by the evaluation of urinary response to the administration of a vasopressin analogue or vasopressin itself (Miller et al. 1970). Although the urinary concentration mechanism may be disturbed under certain circumstances, such as anterior pituitary insufficiency, overhydration, or reduced glomerular filtration rate, which could limit the test validity, in general, its evaluation after supervised dehydration and subsequent vasopressin administration is widely used, and results may provide sufficient information. If polyuria is mild, the test can begin late in the afternoon and continue the following morning, so that most of the dehydration occurs overnight. However, in more severe forms, it is safer to directly proceed to a supervised test starting early in the morning.

A possible way of carrying out the dehydration test in order to obtain a differential diagnosis in a patient whose clinical setting is highly suspicious, but biochemical parameters are equivocal, is as follows:

  • The patient should have fasted for 8 h if possible, including restriction of any sort of food or liquid. Special attention should be paid to restriction of alcohol, coffee, tea, and tobacco during the previous days.

  • The patient will empty his bladder and his weight will be recorded.

  • Basal levels of plasma and urine osmolality and sodium are collected.

  • The patient is asked to refrain from any fluid or food intake during the duration of the dynamic test, and supervision is mandatory to avoid deviations.

  • Urine volume and urine osmolality and weight are repeated hourly.

  • Serum osmolality and sodium levels are recorded every 2 h.

  • The test is ended if:

    • Weight decreases >5%.

    • Plasma osmolality is >295 mOsm/kg.

    • Plasma sodium is >145 mEq/L.

    • Urine osmolality plateaus (less than 30 mOsm/kg increase in three consecutive samples).

  • Urine osmolality >800 mOsm/kg is highly suggestive of mild primary polydipsia.

  • If urine osmolality is <800 mOsm/kg, we will reevaluate plasma osmolality and sodium; then, we will administer 1 mcg of desmopressin (DDAVP) subcutaneously, and repeat urine osmolality after 30 and 60 min.

Interpretation of this test’s results is usually relatively straightforward (Fig. 6, Table 4). A normal response is characterized by plasma sodium and osmolality within stable and normal reference values, with progressive urine volume decrease, an increase in urine osmolality >800 mOsm/kg, and an increase in urine osmolality of <9% after DDAVP administration. Central DI, however, will be mainly characterized by persistent hypotonic urine after fluid privation, but an evident increase of >50% after exogenous DDAVP. Nephrogenic DI, on its side, is characterized by an insufficient response to the administration of DDAVP.

Fig. 6
figure 6

Diagnostic approach to the patient with hypotonic polyuria. Differential diagnosis of diabetes insipidus

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Table 4 Simple summary of the differential diagnosis in a patient with polyuria and polydipsia according to test results (see also Fig. 6). ↑: increased; ↓: decreased; AVP: arginine-vasopressin; DDAVP: pharmacological AVP analogue
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Direct Measurement of Plasma AVP Activity

With the development of the first sensitive and specific AVP radioimmunoassay (RIA) during the 1970s, a new tool became available to help in the differential diagnosis of patients with suspected DI. In this regard, for instance, undetectable levels of AVP after a dehydration test would be highly suggestive of central DI. AVP results should be cautiously interpreted, however, and always in the setting of its corresponding serum and urine osmolality.

Comparison between the diagnostic efficacies and accuracies of AVP measurement and the classical urine osmolality evaluation described above for the assessment of DI is difficult, since there is no “gold standard” with which test results may be compared. In addition, the area of normality of AVP release in response to a specific serum osmolality is variable and has been a matter of debate in several studies. Furthermore, there are well-characterized technical difficulties of the AVP assay, which entail a high pre-analytical instability. Taken together, these limitations in AVP measurement jeopardize the possibility of it being considered as an essential tool in the differential diagnosis of DI, although they might be useful in specific ambiguous cases.

Direct Measurement of Plasma Copeptin (Pro-AVP)

Plasma concentrations of copeptin and AVP in relation to serum osmolality are highly correlated. In fact, they have an equimolar secretion and response to osmotic, hemodynamic, and stress-related stimuli. Copeptin corresponds to the C-terminal glycoprotein of the AVP prohormone and represents a stable surrogate for endogenous plasma AVP levels, as opposed to AVP, whose quantification may be difficult. Therefore, copeptin has been suggested as a promising diagnostic marker for the diagnosis of AVP-dependent fluid disorders and has been considered very useful for identification of patients with severe neurohypophyseal damage after transsphenoidal surgery.

The relevance of copeptin in the differential diagnosis of DI has been studied by using the urinary concentration tests, as a surrogate of AVP activity. In this regard, in the absence of prior fluid deprivation, baseline copeptin levels >20 pmol/l identify patients with NDI, while baseline copeptin levels with prior fluid deprivation <2.5 pmol/l are highly suggestive of complete CDI. Upon osmotic stimulation, copeptin levels are accurate for the challenging clinical setting of differentiating patients with partial CDI and primary polydipsia (Fig. 7); in this case, the ratio of copeptin increase during an 8-h dehydration period to the serum sodium concentration measured after 16 h of water deprivation has a high specificity and sensitivity (100 and 86%, respectively) and a diagnostic yield of 94% to distinguish between the two clinical entities.

Fig. 7
figure 7

Differential diagnosis of diabetes insipidus using copeptin levels. CDI, central diabetes insipidus; NDI, nephrogenic diabetes insipidus

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Evaluation of copeptin levels may also be useful in the approach to patients with hyponatremia; in this setting, low levels of copeptin, together with low urine osmolality, would be suggestive of primary polydipsia, while the ratio of copeptin to urinary sodium would be useful to distinguish the syndrome of inappropriate antidiuretic hormone secretion (SIADH) from other AVP-dependent forms of hyponatremia.

Again, the lack of a “gold standard” with which to compare the results obtained by the evaluation of copeptin levels, the absence of very large study populations, and the still pending validation studies for cutoff levels in post hoc analyses limit the diagnostic relevance of this parameter. In addition, the sandwich immunoluminometric copeptin assay (LUMItest CT-pro-AVP) is not yet commercially available for everyday clinical practice all over the world, so its clinical implementation is still limited (Christ-Crain 2016).

Therapeutic Trial of DDAVP

In selected patients in which the diagnosis is still uncertain despite the previous approaches, a closely monitored therapeutic trial of DDAVP may be attempted. In this case, we would administer 10 ug of DDAVP intranasally twice a day for 2–3 days. If this procedure causes a significant antidiuretic effect, nephrogenic DI is effectively excluded. If polydipsia and polyuria are abolished and plasma sodium does not decrease below the normal range, the most probable diagnosis will be central (neurohypophyseal) DI. If DDAVP administration causes a reduction of urine output, without reduction in water intake, and hyponatremia appears, the patient will probably have primary polydipsia. Water intoxication is not frequent, but monitoring of this trial is recommended to avoid it.

AQP2 Measurements

Urinary AQP2 excretion could be measured by radioimmunoassay or quantitative Western analysis and could serve as an additional indicator of the response to AVP of the renal collecting duct in cases were nephrogenic DI is suspected. However, this is still an infrequent approach used in everyday clinical practice, since it is not readily available in most centers.

Carrier Detection and Perinatal Testing

In families with known autosomal CDI, or X-linked or autosomal NDI, mutation analysis is recommended before the birth of an infant, in order to allow early diagnosis and establish prompt treatment, avoiding the physical and mental retardation associated with dehydration episodes. Gene analysis is also important for the identification of nonobligatory female carriers in families with X-linked NDI.

Imaging Techniques in Diabetes Insipidus: Magnetic Resonance Imaging

Magnetic resonance imaging (MRI) allows visualization of the anterior and posterior pituitary, as well as the pituitary stalk. Because of the direct vascularization of the neurohypophysis, this latter lobe can be more rapidly visualized in a dynamic mode after gadolinium administration during an MRI. In fact, it is easily identified, as it was briefly mentioned previously, as a “bright spot” in the posterior part of the sella turcica on T1-weighted images. This hyperintensity may be seen in 80% of normal individuals but is absent in the majority of patients with CDI. It represents the normal AVP storage in the posterior pituitary lobe and has been seen to be correlated with AVP levels (Fig. 8).

Fig. 8
figure 8

Magnetic resonance imaging (MRI) showing the bright spot in a normal patient (a, pointing arrow) and its absence in a patient with central diabetes insipidus (b, square)

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In a patient who is being evaluated for the suspicion of diabetes insipidus, if this pituitary hyperintense spot is not seen in a pituitary MRI, it will probably reflect the loss of functional integrity of the neurohypophysis, serving as a non-specific indicator in the diagnosis of CDI. On the contrary, in patients with primary polydipsia, the bright spot is usually seen, while findings in patients with NDI may be variable.

Pituitary MRI has been reported to be the best technique with which to evaluate the sella turcica area, not only for identification of this bright spot but also to rule out other pituitary, pituitary stalk, and infundibulum alterations. Given the fact that more than 90% of AVP-producing neurons have to be destroyed for the development of clinical diabetes insipidus, it is easy to understand how a pituitary lesion needs to be considerably big in order to destroy a significant amount of hypothalamic cells, or the lesion should be located specifically where hypothalamic axons come together in the pituitary stalk. Therefore, small pituitary lesions rarely produce neurogenic DI. Conversely, pituitary stalk enlargement, which, by the way, is frequently associated with the absence of the bright spot, could be suggestive of infiltrative lesions or systemic diseases, as previously explained.

Follow-up MRI may be useful to evaluate the outcome of reversible diseases, for example, in cases with enlargement of the pituitary stalk. However, if no other pituitary lesion is observed, and the only finding is the absence of the hyperintense spot reflecting the absence of AVP storage, serial MRI may not be necessary.

Practical Clues for the Differential Diagnosis of Diabetes Insipidus in Ambiguous Cases

In ambiguous cases, clinical clues can guide us through the diagnosis. In this regard, findings suggestive of primary polydipsia include history of psychiatric disease or neurotic personality, fluctuating symptoms, and gradual onset of polydipsia, posterior pituitary bright spot and normal thickness of the pituitary stalk, plasma sodium in the low range of normal, and persistent polydipsia, or even development of hyponatremia after a therapeutic trial with desmopressin. Findings suggestive for partial central DI include previous head trauma or pituitary surgery, family history of DI, recent and distinct onset of symptoms, and consistent need for fluid intake during the night, preference for cold fluids, missing pituitary bright spot and/or enlargement of the pituitary stalk beyond 2–3 mm, serum sodium in the upper range of normal, and abolishment of thirst, polydipsia, and polyuria without development of hyponatremia after a standard dose of desmopressin. Finally, findings suggestive for partial nephrogenic diabetes insipidus include history of lithium or other drug therapies (e.g., cisplatin) interfering with urine concentration and presence of electrolyte disorders (like hypercalcemia or hypokalemia), posterior pituitary bright spot and normal pituitary stalk, and no effect of desmopressin on polyuria or polydipsia.

In addition, although ureic nitrogen (BUN) may not be useful for a differential diagnosis, serum uric acid levels may, in fact, differ: in central DI, uric acid levels may be high because of a coexistent moderate volume contraction and because AVP acts on V1 kidney receptors and increase urate clearance. Therefore, in the absence of AVP, uric acid levels will rise.

Treatment of Diabetes Insipidus

Treatment goals for patients with diabetes insipidus should seek the maintenance of sodium serum levels within normality; a comfortable urine output, around 2–4 l/day; and an acceptable and optimal quality of life. Patients and caregivers’ education regarding this disease is especially important; they should be trained on how to monitor liquid intake and urine output and how to promptly identify treatment overdose or insufficiency.

Current alternatives to emulate AVP’s action include formulations of the native antidiuretic hormone, vasopressin (Pitressin), and its analogue, desmopressin (DDAVP). Both produce antidiuresis by stimulating renal V2 receptors. High concentrations of vasopressin also stimulate contraction of smooth muscle in the gastrointestinal tract and blood vessels via its action at V1 receptors. However, DDAVP does not have this effect because it is relatively inactive at V1 receptors, thus avoiding a vasopressor effect.

The mainstay of treatment for patients with CDI involves the direct administration of desmopressin. However, standard doses of this drug will rarely be useful for the management of patients with NDI, who are insensitive to AVP. Although supranormal doses may be effective in some cases, the only practical approach for NDI concerns symptomatic control, i.e., reducing polyuria, thirst, and polydipsia, by reducing sodium intake, and using thiazide diuretics or prostaglandin synthetase inhibitors, as it will be now explained (Lamas et al. 2014).

Central Diabetes Insipidus

The first option of treatment for patients with CDI (i.e., AVP deficiency) is the administration of desmopressin (DDAVP). The formulation suitable for intravenous or subcutaneous administration is supplied in single-dose 1 mL ampoules and multidose 10 mL vials containing 4 ug/mL of the compound. This formulation has been the most extensively used in multiple reports and clinical trials. Nowadays, oral and intranasal formulations are also available, so patients requiring long-term treatment with DDAVP may choose between oral, subcutaneous, or intranasal routes; the intravenous route, although less frequently required, may be useful in the acute and emergency clinical setting. Urine output is rapidly decreased 15 or 60 min after its subcutaneous or oral administration, respectively.

Doses required may be highly variable depending on the patient and the route of administration. For instance, there are interindividual variations in the volume of distribution; clearance of DDAVP; differences in V2 sensitivity, or in the kinetics of the biochemical mechanisms that mediate the antidiuretic effect; and even because of adsorption of DDAVP to the plastic syringes used for its administration. Furthermore, the oral formulation has a 10–20% of the potency of the nasal formulation, since only 5% is absorbed in the intestine; and oral absorption may be up to 40–50% less if taken with food, so, in general, a 2–3-h fasting interval is advised in cases of oral formulations.

Increasing doses do not seem to achieve higher urine concentration capacity; however, the magnitude and duration of the antidiuretic effect have a direct relationship with the dosage administered. The fact that the kidney’s concentrating capacity decreases in the absence of AVP, requiring more than 8 h of continued stimulation to fully recover, may explain this issue. Table 5 shows the usual formulations and equivalent doses of DDAVP in everyday clinical practice. It can be observed how a 0.1 mg tablet is equivalent to 2.5–5 ug in intranasal spray.

Table 5 Comparison between different formulations of desmopressin
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Hyponatremia is a logical adverse effect of DDAVP use, mainly because of high fluid retention in the presence of high doses of AVP, so minimal doses will be always recommended. To avoid overdosing, patients are recommended to monitor their urine output for a minimum of, for example, 2 l/day. If urine output is significantly decreased, the DDAVP dose may be withheld, and reevaluation for persistence of DI may be necessary in some cases in which DI remission may be evidenced.

As it was explained before, in the acute setting of patients who underwent neurosurgery, development of DI is mainly mild and transient, and a preserved thirst mechanism will compensate for temporally increased liquid intake requirements. If esteemed necessary because of excessive and uncomfortable hypotonic polyuria, especially at night, or development of hypernatremia, one single parenteral dose of desmopressin (1–2 ug subcutaneous or intramuscular), which is active for 6–12 h, is usually enough. Further injections are seldom needed, only in cases with persistent or recurrent polyuria for more than 48 h. Associated hypokalemia must be ruled out, and, if present, it should be treated, since this may be a cause of renal resistance to desmopressin therapy. It is typical to withdraw desmopressin treatment at least once before discharge of patients from the hospital, to help identify those who have or have not resumed endogenous AVP secretion. In any case, patients and caregivers should be advised to monitor their balance between liquid intake and urine output during the first days after hospital discharge, and explain the potential symptoms of hyponatremia, in an attempt to promptly identify disorders of water homeostasis in these patients. This is especially relevant in today’s everyday clinical practice, where there is a trend for rapid hospital discharge after pituitary surgery. If diabetes insipidus persists, the usual forms of administering desmopressin may be used, according to patients’ tolerability and preference and in a proportional dose to the degree of AVP deficiency. For instance, a single nocturnal dose may be sufficient for patients with only partial CDI. Regular monitoring of serum electrolytes is mandatory in patients using DDAVP.

If the thirst mechanism is compromised and/or the patient is unable to compensate his urinary losses with liquid intake, maintenance of hydro-electrolytic homeostasis is complicated but may be preserved with administration of intravenous fluids and strict monitoring of body weight, urine output, and general physical examination. Water deficiency may be calculated with the following formula, 0.6 × body weight (kg) × ([serum Na/140] – 1), and serum electrolytes should be monitored every 6–8 h.

Vasopressin (Pitressin), as an injectable aqueous solution (20 U/ml in a 1 mL vial), has been available for decades, and some authors have advocated its intravenous infusion to achieve short-term control of antidiuresis. In this regard, the rate of infusion usually starts at 0.25–1 uU/kg/h and is increased every 30 min thereafter until the urine specific gravity (density) reaches 1.010–1.020 or the rate of urine output falls to around 100 mL/h (approximate average infusion rate of 0–5-3 uU/kg/h). Accidental overdoses, usually due to inadequate dilution of the concentrated formulation, may result in severe abdominal cramping, diarrhea, vomiting, and pallor due to stimulation of V1 receptors. However, Pitressin is, in general, less frequently used in daily clinical practice.

There are other several drugs for whom an antidiuretic effect and subsequent utility in CDI have been described. For instance, carbamazepine, frequently used in neurological disorders, reduces urine output by 30–90%, with an accompanying proportional increase in urine osmolality, when used at conventional doses of 200–800 mg. It seems that this effect may be related to plasma AVP reduction, but the exact underlying mechanism is not yet fully understood. The sulfonylurea chlorpropamide has also a significant antidiuretic effect in CDI; in this case, at conventional doses of 250–500 mg/day, it reduces urine volume by 30–90%, reaching a maximum within 3–10 days of treatment, and with an associated proportionate rise in urine osmolality, but no change in solute excretion or glomerular filtration rate. Apparently, the antidiuretic effect is achieved by potentiating the very low levels of plasma AVP that persist even in patients with severe CDI or by a direct effect on V2 receptors. Combination with chlorothiazide may enhance chlorpropamide’s effects. Clofibrate, on its side, at doses of 2 g per day, demonstrated to decrease urine volume by 50%, with a proportional urine osmolality increase. However, the underlying pathophysiology was even more uncertain, and the increased mortality observed in patients with long-term treatment led to its discontinuation in 2002.

Thiazide diuretics are mainly useful for the management of NDI, as it will be further explained below, but they may also play a relevant role in patients with CDI, especially with an accompanying restriction of sodium intake. Moreover, they potentiate the antidiuretic effect of other agents, so they may be frequently used in combination regimes. However, as with all antidiuretic treatments, an accurate diagnosis of the specific type of DI is essential for a safe and effective management (Oiso et al. 2013).

Nephrogenic Diabetes Insipidus

The main objective in the treatment of congenital NDI is to ameliorate symptoms and avoid the consequences of dehydration. Conversely, for acquired NDI, treatment should target the underlying cause. If this is not possible, treatment approaches will be similar, targeting the control of symptoms.

For pediatric NDI, correct dietetic counseling is essential to enable patients’ normal growth and development. Specifically, the diet’s osmotic load, i.e., the osmotically active substances in diet (mainly proteins and salt), should be minimized to avoid an increased urine output.

In the setting of acute decompensations of patients with NDI, they may develop hypernatremic dehydration states, exhibiting ongoing losses of essentially pure water. In this context, infusion of 0.9% saline may be excessive and worsen hypernatremia, leaving isotonic fluids only for acute intravascular volume expansion in the rare cases of hypovolemic shock. Therefore, patients with NDI should be generally treated with hypotonic fluids. If possible, prompt oral administration is preferred, for example, with water or milk, to enable the thirst physiology to properly regulate fluid intake. If necessary, 5% dextrose in water for intravenous supplementation may be used, which will not provide an osmotic load, and may help urine output to decrease substantially. However, it is important to remember that hypotonic fluids must not be administered as intravenous bolus. Instead, they should be given at an infusion rate only slightly greater than the urine output, providing just enough water to safely normalize plasma sodium levels at a rate <0.5 mmol/l/h (<10–12 mmol/l/day), but avoiding the risk of developing cerebral edema. Careful and close management of fluid balance in specialized centers warrants a favorable outcome of these patients.

The use of diuretics in polyuric syndromes may seem rather paradoxical, but they are relatively effective for long-term management of patients with NDI. In fact, treatment with hydrochlorothiazide reduces sodium excretion, reduces urine volume, and increases urine osmolality, together with a concomitant reduction of plasma volume and body weight. This occurs due to a decreased salt reabsorption through the thiazide-sensitive co-transporter SLC12A3 in the distal tubule, which results in a decreased dilution of urine and a reduction in extracellular fluid volume, which stimulates a compensatory increase in proximal tubular reabsorption of sodium and water, and thereby diminishes delivery of filtrate to the distal nephron and collecting tubules, where the defect in urinary concentration exists. Another complementary mechanism by which thiazides are useful for the management of NDI is inhibition of carbonic anhydrase in the proximal tubule, resulting in a reduced proximal sodium uptake and subsequent decreased glomerular filtration. Furthermore, thiazides may increase the expression of AQP2 in the apical membrane, favoring water reabsorption, although this effect in vivo still needs to be demonstrated.

Another family of drugs that have become a key component in the management of NDI, especially during the first years, are inhibitors of prostaglandins synthesis. Specifically, indomethacin effectively reduces water diuresis by a synergistic and independent effect of AVP, presumably by enhancing the proximal reabsorption of salt and water, but without a significant change in urine osmolality.

Novel approaches to NDI focus on restoring AVP signaling upstream of AQP2, provided there are no AQP2 mutations. Because in the majority of congenital NDI cases there is a misfolding and mistransporting of AVPR2, pharmacological chaperones may be a possible therapeutic approach. These chaperones are cell-permeable AVPR2 antagonists that fit into the AVP binding pocket of AVPR2 and allow a correct escape from the endoplasmic reticulum, subsequent transport to the cell membrane, and, thus, normal AVP signaling. An important issue to consider with this strategy is the AVPR2 antagonist’s affinity. In this regard, chaperones with high affinities will fit better into the binding pocket and allow a more efficient surface expression; however, they will less likely diffuse off the receptor and jeopardize normal AVP signaling. On the other hand, compounds with low affinities will be less efficient for the promotion of surface expression, but more likely to diffuse off the receptors. Therefore, presumably, the most optimal chaperon will be one with an intermediate affinity. However, the only orally active non-peptide AVPR1A antagonist, known as SR49059, did not demonstrate enough effectiveness in reducing urine output and was even associated with idiosyncratic increases in liver enzymes, which led to discontinuation of its investigation and commercialization. Cell-permeable agonists that stimulate AVPR2 independent of AVP could be another alternative for NDI patients, but there is still much to investigate in this field.

Enhancing cAMP production independent of AVPR2 could also be an interesting target in patients with AVPR2 mutations, for example, by stimulating prostaglandin E2 receptors coupled to adenylyl cyclase. This strategy would not be effective in patients with autosomal AQP2 mutations, since these abnormalities result in a defect downstream of cAMP production. However, there are still no clinical data on the use of these prostaglandin-receptor agonists in patients with NDI, and, because prostaglandin synthesis inhibitors have proven efficient in the management of NDI, it is not likely that receptor agonists prosper as an alternative treatment option.

Other less common, and still preliminary, attempts for short-term therapy in NDI include a combination of secretin and fluvastatin for patients with X-linked forms; cGMP phosphodiesterase inhibitors, such as sildenafil, to increase cGMP levels, enhance trafficking of AQP2 to the liminal membrane, and increase urine osmolality; and statins, which may increase the expression levels of AQP2 channels, independent of cholesterol homeostasis. Genome editing of somatic tissue or embryos to correct mutant genes could be a future line of investigation, although with considerable ethics limitations, especially in patients who carry AQP2 mutations, in whom other target-directed approaches deem more difficult (Bonfrate et al. 2015).

Special Populations (Children, Pregnant Women, and the Elderly)

Given the fact that infants and children usually take diets with proportionally larger quantities of water, it may be necessary to allow a variable higher urine output to prevent hyponatremia, depending on age, diet, and if the child takes liquids ad libitum. Management may be easier if a steady amount of liquid intake is established, and treatment is tailored accordingly, with the complimentary help of monitoring plasma sodium; urine volume, which is virtually impossible to quantify in children, will rarely be useful.

DDAVP may be administered using different formulations, according to the child’s age and caregivers’ preference. For instance, in infants under 12 months, rhinyl preparation of nasal spray can be diluted 1:10 with physiological saline and administered orally one to two times per day (1–5 ug). Subcutaneous formulations (0.02 ug/day – 0.08 ug × 2 times a day) may also achieve stable urine volumes and sodium levels. In general, starting treatment at low doses is recommended, with subsequent upward titration according to the effect. Usual doses in children will range from 10 to 20 ug intranasally, 60–240 ug of melt, or 100–400 ug of the oral tablet. It is particularly important to educate children with DI and/or their caregivers about their disease and its complications, to avoid the dangers of excessive fluid intake during treatment, dehydration if doses are omitted, or signs and symptoms of water intoxication.

Women with preexisting CDI who become pregnant and women who develop temporary gestational DI can usually be treated successfully with oral DDAVP, which is resistant to degradation in the placenta by leucine aminopeptidase. Doses required may be similar or slightly greater than usual, and, in general, in cases of gestational DI, DDAVP may be withdrawn 4–6 weeks after delivery. Dose monitoring is normally based on plasma sodium levels, but it should be noted that it might be 5 mmol/l lower that in the non-gravid state. DDAVP can be safely given to nursing mothers, since very little appears in breast milk.

Management of DI in the elderly is similar to that in young adults, but careful monitoring should be performed, since there is a higher risk of developing hyponatremia, especially with intranasal formulations. Presumably, the underlying explanation involves increased renal sensitivity to AVP and abnormalities in the osmoregulation of thirst and fluid intake.

Summary and Conclusions

Recent investigation has provided a substantial increase in the knowledge of the molecular physiology involved in urine concentration. Diabetes insipidus is characterized by an excessive hypotonic and diluted urine output, due to an insufficient amount or action of AVP.

Several circumstances can cause CDI, being the neurosurgical setting the most frequently observed in everyday clinical practice. The treatment of choice for long-term management of CDI is desmopressin tablet or melt, which should be individually titrated to achieve an optimal control of polyuria, thirst, and polydipsia.

Inherited forms of NDI are mainly due to mutations in the processing of two key proteins in the regulation of water permeability in the collecting duct, AVPR2 and AQP2; but the majority of cases of NDI are acquired, especially due to chronic lithium treatment. Management of NDI includes dietary modifications, thiazides, and inhibitors of prostaglandin synthesis, leaving other novel therapies, such as molecular chaperones or gene therapy approaches, for future investigation.

Patient and caregivers’ education on the pathophysiology of the disease deems necessary for a safe and effective management.