Diabetes Insipidus: A Pragmatic Approach to Management

Diabetes insipidus (DI) is a disorder of water balance characterized by polyuria and polydipsia. It can occur due to genetic and acquired causes that affect the secretion or action of arginine vasopressin (AVP) or antidiuretic hormone (ADH).Markedly increased thirst and urination are not only quite distressing but also increases the risk of volume depletion and hypernatremia in severe situations. A careful diagnosis of the type of DI and its etiology is based on careful clinical evaluation, measurement of urine and serum osmolality, and water deprivation test. Management includes the correction of any water deficit and the use of specific pharmacological agents, including desmopressin, thiazides, and amiloride.

cells in the thick ascending limb of the loop of Henle and collecting ducts of nephrons. Resultant action through Gs-adenylyl cyclase and increased cyclic adenosine monophosphate (cAMP) levels leads to activation of protein kinase A and subsequent translocation of AQP-2 water channels on the luminal surface. Therefore, more water diffuses into the principal cells and then into interstitial tissue via the AQP-3 and 4 channels that are constitutively expressed on the basolateral membrane of these cells [4]. This results in increased water reabsorption across the renal medullary concentration gradient. As a result, kidneys can concentrate urine [3].

Diabetes insipidus
Diabetes insipidus derives its name from the defining feature of hypotonic, dilute, and insipid (tasteless) urine. The hallmarks of DI include polyuria (urine output of >40-50 ml/kg/day in adults and >100 ml/kg/day in children) with the passage of dilute urine (urine osmolality <300 mOsm/L) and polydipsia. DI occurs due to inadequate secretion of AVP or impaired response of the kidneys to AVP. Therefore, the urinary concentrating ability of the kidneys is impaired, and the nephrons pass large quantities of dilute urine, irrespective of hydration status. The clinic spectrum varies from partial to complete DI [5].
Various types of DI include central, nephrogenic, and gestational DI and the related condition of primary polydipsia (PP).

Central Diabetes Insipidus
Central DI (CDI) results from defects in synthesis, transport and/or secretion of AVP due to a wide range of causes, including both acquired and congenital, as enlisted in Table 1. Congenital CDI (10%) occurs due to mutations in the AVP-NPII gene1 [4], or wolframin (WFS1) gene (Wolfram syndrome) [3]. Wolfram or DIDMOAD syndrome is characterized by central diabetes Insipidus, diabetes mellitus, optic atrophy and sensorineural deafness.

Congenital
Autosomal dominant -mutations in AVP-NPII gene. Autosomal recessive -Wolfram syndrome, mutations in WFS1 gene,   [6]. Another important cause of acquired CDI is intracranial tumors, infections, and infiltrative disorders. Langerhans cell histiocytosis (LCH) is a rare disorder that should be suspected in cases of CDI with multisystem (skeletal, pulmonary, dermatological, anterior pituitary dysfunction) involvement, but many patients may present with DI as the initial manifestation. Idiopathic central DI comprises almost one-fourth of cases [7]. AVP cell antibodies have been demonstrated in one-third of patients with idiopathic CDI [8].

Nephrogenic Diabetes Insipidus
Nephrogenic DI (NDI) occurs from an inability to concentrate urine in response to AVP due to congenital or acquired causes, enlisted in table 2. Complete NDI is typically associated with very high urine output of as much as 12 L daily. The commonest cause of NDI in children is inherited -90% of cases are due to X-linked mutations in the vasopressin receptor 2 (V2R) gene; 10% cases are autosomal dominant due to mutations in the AQP-2 gene [4]. These children usually present in the first year of life with frequent wet diapers, irritability, vomiting, dehydration, and failure to thrive [9].
Infiltrating disorders -sarcoidosis, amyloidosis, Sjogren's syndrome. Metabolic disorders -hypercalcemia, hypokalemia. Hematological -multiple myeloma, sickle cell anemia. Renal disorders -acute or chronic kidney disease, obstructive uropathy, polycystic kidney disease, renal infarction. In adults, acquired causes of nephrogenic DI are more common and include electrolyte abnormalities (hypokalemia and hypercalcemia), renal, hematological and infiltrative diseases and medications. Lithium can enter the principal cells of the collecting duct via epithelial sodium channels (EnaC) and inhibits the translocation of AQP-2 channels to the cell surface. Further long-term exposure may lead to downregulation of AQP-2 gene expression. In acquired nephrogenic DI, polyuria is of moderate severity (3-4 L/day).

Gestational Diabetes Insipidus
Gestational DI is rare (2-4 per 100,000 pregnancies), occurs in the third trimester, and spontaneously resolves 4-6 weeks after delivery [10]. The cause is increased degradation of AVP by vasopressinase, expressed by the placental trophoblasts [11]. There may be a mild underlying deficiency of AVP in these women that is unmasked during pregnancy. In addition, increased prostaglandin production may also blunt the action of AVP [10]. The risk of gestational DI is higher in women with liver disease, possibly because vasopressinase is metabolized by the liver. However, gestational DI may remain undiagnosed as polyuria is considered normal in pregnancy.

Primary Polydipsia
Excessive water intake over a prolonged period of time can also result in symptoms similar to DI and is classified as primary polydipsia (PP). This may occur as a result of an abnormal thirst mechanism or increased thirst (dipsogenic DI). Dipsogenic DI may occur due to chronic meningitis, chronic granulomatous diseases such as sarcoidosis, multiple sclerosis, tubercular meningitis, hypothalamic tumors, or injury.
Some patients may have underlying psychiatric illnesses such as compulsive disorders or schizophrenia and are classified as psychogenic polydipsia. Dry mouth may also result from certain drugs such as phenothiazines or anticholinergic agents. Due to excess fluid intake, serum osmolality is reduced and AVP secretion is suppressed in PP.

Clinical Presentation
The most common presenting symptom of DI is significant polyuria, defined as urine output of >40-50 ml/kg/day (at least 2.5-3 L/day, but may exceed 8-16 L) and polydipsia, defined as water intake of > 100 ml/kg/day [5,12]. Polyuria, however, should be differentiated from frequent micturition, urgency or dysuria, and other causes of polyuria as enlisted in Table 3.  Onset may be gradual or abrupt depending on the cause. Polyuria and polydipsia can result in significant distress. Individuals may complain of nocturia, disturbed sleep, fatigue, postural dizziness, and weight loss. Dehydration occurs only in severe cases, especially if there is a lack of access to water (as in infants or an unconscious patient) or thirst mechanism is impaired. In children, symptoms range from frequent urination, nocturia, enuresis, constant thirst, and irritability. Severe cases are at risk of dehydration, growth retardation, and even failure to thrive. On examination, there may be signs of dehydration such as dry mucosa, loss of skin turgor, hypotension, or tachycardia. Severe dehydration along with electrolyte disturbances, may rarely result in altered sensorium.
History and physical examination should also focus on features that may suggest intracranial disease, head trauma or surgery, anterior pituitary hormone deficits, medications, kidney disease, or systemic illness. Psychogenic polydipsia should be suspected in individuals with gradual onset of symptoms, fluctuating symptoms, and a history of psychiatric illness.

Adipsic Diabetes
Adipsic diabetes is characterized by impaired thirst despite a rise in serum osmolality and may result from a variety of intracranial causes that result in damage to the anterior hypothalamus, such as brain injury, ACA aneurysm, surgery for craniopharyngioma, or neurosarcoidosis [7]. These individuals are at high risk of dehydration and life-threatening hypernatremia, which can cause altered sensorium, seizures, and intracranial bleed [1].

Evaluation and diagnosis
The evaluation of suspected DI includes the following steps: The first step is the confirmation of actual polyuria, defined as urine output of ≥40-50 ml/kg/day or 3 L/day. In case of doubt, an estimation of 24-hour urine volume is useful. If polyuria is confirmed, urine specific gravity and urine osmolality is measured to determine if the person has hypotonic polyuria. In DI, urine osmolality is <300 mOsm/kg. Urine specific gravity <1.010 can be used for rapid screening since the results of urine osmolality may not be immediately available. Urine osmolality >800 mOsm/kg indicates solute diuresis and requires evaluation for other causes such as diabetes mellitus, kidney disease, medications (diuretics, mannitol). If hypotonic polyuria is documented, a careful evaluation of the type and cause of DI is needed. The presence of urine hypoosmolality (<300 mOsm/kg) and plasma hyperosmolality (>300 mOsm/kg) with polyuria clinches the diagnosis of DI. Hypernatremia (Na >145 mEq/L) and high serum osmolality (>300 mOsm/kg) suggest DI, while both remain normal or low in PP [2]. However, many individuals have indeterminate urine osmolality (300-800 mOsm/kg) and normal serum osmolality and electrolytes, requiring further confirmatory tests. This would require dynamic tests of the AVP-kidney axis (water deprivation test or infusion of hypertonic saline) and the estimation of plasma ADH concentration [7]. Misdiagnosis and inappropriate treatment carry significant risks, e.g., if desmopressin is used for primary polydipsia, it can cause hyponatremia.

Water deprivation test
Water deprivation test is an important test in the evaluation of suspected DI [13]. In response to water deprivation, AVP secretion is increased in normal individuals and those with PP, leading to a rise in urine osmolality >800 mOsm/kg. On the other hand, in CDI or NDI, there is an inability to concentrate urine in response to water deprivation and urine remains dilute (urine osmolality <300 mOsm/kg). After the administration of desmopressin, urine osmolality rises (>800 mOsm/kg) in CDI but not in NDI. The test protocol is described in Figure 1 and interpreted in Table 4. However, a significant proportion of patients may demonstrate urine osmolality of 300-800 mOsm/kg following water deprivation and do not exhibit a robust response to AVP. These include patients with partial DI (central or nephrogenic) and long-standing PP (in which renal medullary concentration gradient is reduced, mimicking nephrogenic DI) [14].

Measurement of AVP and copeptin
AVP levels are measured at the end of the water deprivation test (before administering AVP). AVP levels are low in CDI, elevated NDI, and may be normal or low in long-standing PP and partial CDI. However, since AVP is a small peptide that is rapidly cleared, its estimation is difficult and seldom done. Moreover, it is bound to platelets through vasopressin 1 (V1) receptors and levels may vary widely if the sample is not processed immediately and stored at -70°C.
Copeptin (C-terminal peptide of pro-vasopressin) is co-secreted with AVP and can be a surrogate of AVP secretion as it is more stable [15]. Baseline copeptin <2.6 pmol/L is diagnostic of CDI, while levels >21.4 pmol/L are diagnostic of NDI. If baseline levels are indeterminate, it could be either CDI or PP and copeptin is estimated after hypertonic saline infusion. A level of >4.9 pmol/L suggests PP [7].

Hypertonic saline infusion test
Hypertonic saline infusion along with measurement of copeptin can be considered if results of water deprivation are inconclusive. Figure 2 provides an algorithm for performing the hypertonic saline infusion test. Baseline plasma copeptin is >21.4 pmol/l in NDI while levels <2.6 pmol/L indicate CDI. Following hypertonic saline infusion, plasma copeptin levels <4.9 pmol/L suggest CDI, while levels of >4.9 pmol/L indicate PP [15].

Other evaluation
In doubtful cases, a careful therapeutic trial of desmopressin can be considered. Desmopressin 100 mcg is given orally every 12 hours for 48 hours; if symptoms resolve, it suggests CDI or PP; while there is no response in NDI. However, care must be taken as hyponatremia can occur in individuals with PP [16].
Further testing should be guided by clinical suspicion to determine the cause of DI [1]. On magnetic resonance imaging (MRI) of the sella and hypothalamus, the absence of posterior pituitary bright spot (on T1 weighted images) or thickened stalk (>3 mm) suggests CDI [1,17]. On the other hand, PP is characterized by normal posterior pituitary bright spot and pituitary stalk. MRI may also be useful in the detection of other causes of CDI as enlisted in Table 1.
In cases of CDI, evaluation of anterior pituitary functions is warranted as many individuals may have anterior pituitary hormone deficits, including growth hormone deficiency, partial or complete hypopituitarism [17]. Adrenal insufficiency may mask central DI that becomes apparent only after glucocorticoid replacement. Figure 3 provides an algorithm for the approach to polyuria evaluation.

Management of diabetes insipidus
The first concern is adequate hydration and replacement of water deficit, which is calculated as [6]: Water deficit (liters) = 0.6 x body weight (kg) x [(serum Na/140) -1] In most individuals who have normal thirst mechanism, it can guide the intake of oral fluids. However, in individuals with adipsic DI who have impaired thirst, a daily fluid intake should be fixed at which euvolemia and eunatremia are maintained [1]. They will also require more frequent monitoring of weight, intake/output records, and electrolytes.
In unconscious patients, water deficit can be corrected with plain water administered through Ryle's tube and with intravenous hypotonic fluids (5% dextrose or 0.45 saline) [3]. Isotonic fluid (0.9 saline) should be avoided as it can worsen hypernatremia. In NDI due to kidney disease, reduction of osmotic load by restricting the intake of sodium and proteins is important since increased solute excretion contributes to further increased urine output [9]. Causative agents, such as lithium should be discontinued.
In mild DI, fluid replacement is adequate, but more severe cases require pharmacological treatment [3]. Pharmacological management depends on the underlying cause. Most cases of CDI can be effectively managed with vasopressin or its analogue, desmopressin. Treatment of the underlying cause of CDI and NDI is also important. As follows, we describe medications used in the management of DI.

Desmopressin
Posterior pituitary extracts that contained vasopressin and oxytocin were used for the management of DI in the early 1900s. Pitressin (vasopressin tannate in oil) later became widely available but had significant vasopressor effects. Desmopressin or 1-deamino-8-D-AVP (DDAVP), a synthetic analogue of vasopressin, became available in the 1970s [12]. Desmopressin is resistant to degradation by vasopressinase and has a greater anti-diuretic effect with 2000-fold lower vasopressor activity [1]. So, it is associated with less risk of side effects such as vasoconstriction or hyponatremia.
Several formulations of desmopressin are available as enlisted in Table 5. With oral or nasal formulations, the maximum drug concentration is achieved within one hour; a decrease in urine output occurs in 1-2 hours and the effect lasts 6-18 hours [12]. Individual variations in clinical response exist. Therefore, the dose has to be adjusted at a weekly interval till a stable dose is attained over one month.

Formulation Dose Advantages Disadvantages
Intranasal spray 10-40 mcg (1 puff is 10 mcg) More rapid onset and longer duration of action. Used in the water deprivation test and if nasal or oral administration is not possible.
Robust effect -more risk of water intoxication or hyponatremia.

TABLE 5: Various formulations of desmopressin
Safety concerns: The most common adverse effects are hyponatremia and water intoxication, though the risk remains low [3]. No effect on blood pressure, heart rate, or body weight has been demonstrated and desmopressin appears to have no major safety concerns. Desmopressin also appears safe during pregnancy for gestational DI.

Other Drugs
Several other medications, including thiazide diuretics, carbamazepine, indomethacin, amiloride, etc., are available for the management of DI, especially NDI. The mechanism of benefit and the potential role of these agents is discussed in Table 6.

Mechanism of benefit Potential role in diabetes insipidus
Thiazide diuretics Inhibit sodium-chloride co-transport in distal tubule to increased urine sodium and osmolality. This results in reduced intravascular volume, increased renin-angiotensin-aldosterone activity and reduction in glomerular filtration. As a result, sodium and water reabsorption in the proximal tubule increases, reducing urine output.
Used in NDI -can reduce the urine output by almost 70% when used with a low-solute diet.

Carbamazepine
Increases endogenous secretion of AVP. Direct action on the renal collecting ducts -increases expression of AQP-2 channels.
Can be used doses of 200-800 mg/day for both CDI and NDI.

Indapamide
Mechanism is similar to thiazides.  Treatment of nephrogenic DI is usually with fluid replacement, reduced solute load, thiazides and indomethacin. The addition of amiloride further reduces urine volume and the risk of hypokalemia with thiazides. Patients with partial nephrogenic DI may be responsive to desmopressin [4]. Adrenal insufficiency may mark features of partial DI that becomes apparent only after glucocorticoid replacement. Therefore, vigilance is required in patients with hypopituitarism if DI is not apparent initially.

Management of postoperative diabetes insipidus
In the postoperative period, DI should be suspected if there is polyuria (urine output >40-50 ml/kg/day or >250 ml/hour for two consecutive hours) with or without hypovolemia. On laboratory evaluation, urine specific gravity <1.010 is helpful for prompt action since the reports of electrolytes and osmolality may be delayed. Urine osmolality is usually <100 mOsm/kg; additionally, the patient may have increased serum sodium and plasma osmolality. Other causes of postoperative polyuria need to be excluded: excessive perioperative fluids, uncontrolled diabetes mellitus or stress hyperglycemia, and diuretics. Water deprivation test is not feasible in this setting. Daily monitoring of fluid intake and output and body weight and twicedaily monitoring of serum electrolytes and urine osmolality is warranted [6].
In most individuals, postoperative DI is mild and transient. Some patients may have transient CDI over 1-4 days, followed by a phase of oliguria (4-7 days) due to the release of stored AVP from degenerating neurons and then permanent DI with the destruction of the AVP-secreting neurons [6]. This calls for close monitoring of water balance and electrolytes in the immediate postoperative period.
A single dose of subcutaneous or intravenous desmopressin can be administered. The next dose is administered only if urine output begins to increase again (>250 ml/hour for two hours with low urine specific gravity and/or osmolality) to avoid water intoxication and hyponatremia [6].

Conclusions
Diabetes insipidus is a relatively rare endocrine disorder that presents with hypotonic polyuria and polydipsia. It can result from either inadequate secretion of AVP (CDI), lack of renal response to AVP (NDI), or excessive fluid intake (PP). A careful diagnosis of the type of DI and its etiology is based on careful clinical evaluation, measurement of urine and serum osmolality, and water deprivation test. Management includes the correction of any water deficit and the use of specific pharmacological agents including desmopressin, thiazides and amiloride.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.