Diabetes insipidus (DI) is a disease process that results in either decreased release of or response to antidiuretic hormone (ADH, also known as vasopressin or AVP), which can cause electrolyte imbalances. There are two types of diabetes insipidus, central and nephrogenic, and each has congenital and acquired causes.
Idiopathic central diabetes insipidus is the most common cause, in which no identifiable cause was determined. The congenital form of central diabetes insipidus is rare and is associated with hypothalamus malformations, defects in ADH precursor synthesis, or deficiency in ADH.
Acquired forms of central diabetes insipidus include autoimmune and vascular diseases, sarcoidosis, craniopharyngioma, Langerhans Cell Histiocytosis, surgery, trauma, structural malformations, metastasis, hypoxic brain injury, or ischemia.
The congenital form of nephrogenic diabetes insipidus is associated with mutations in either the AVPR2 or AQP2 gene. AVPR2 receptor defects are the source of 90% of congenital nephrogenic diabetes insipidus forms of nephrogenic diabetes insipidus are more common and can stem from multiple drug treatments including lithium, antibiotics, antifungals, and antineoplastic agents. Other acquired causes include renal disease, sickle cell disease, obstructive uropathy, pregnancy, craniopharyngioma surgery, and electrolyte disturbances such as hypokalemia and hypercalcemia.
Diabetes insipidus is an uncommon disease process with a low prevalence of 1:25,0000. In clinical practice, congenital forms of diabetes insipidus constitute less than 10% of patient cases.
Water balance is regulated by ADH, thirst, and kidney function. ADH is produced by the posterior pituitary and released into the blood supply via the inferior hypophyseal arteries. Subsequently, ADH targets the kidney and binds to V2-receptors on the renal collecting tubule. This leads to a signaling cascade of Gs-adenyl cyclase system activation which increases cyclic 3',5'-adenosine monophosphate (cAMP), leading to the phosphorylation of preformed AQP2 water channels. The AQP2 channels translocate to the cell membrane and promote water flow by an osmotic gradient from the lumen into the cells of the collecting duct.
In central diabetes insipidus, there is a deficiency of ADH. In nephrogenic diabetes insipidus, ADH is available, but there is a lack of response by the kidneys.
Apelin is a diuretic neuropeptide that has shown to counteract ADH and may play a role in regulating fluid balance. In lactating mice, water deprivation demonstrated an increase in ADH release and depletion of hypothalamic stores, in conjunction with decreased apelin concentrations and increased hypothalamic stores.
The most common findings in patients with diabetes insipidus are polydipsia, polyuria, and nocturia.
Polyuria is defined as urine output more than 3 L/day in adults or 2 L/m2 in children. In children, symptoms can be nonspecific, and they may present with severe dehydration, constipation, vomiting, fevers, irritability, failure to thrive, and growth retardation. In patients with central nervous system (CNS) tumors, headaches, and visual defects may present in addition to the classic symptoms.
Additional symptoms in patients with diabetes insipidus may include weakness, lethargy, fatigue, and myalgias.
The differentials for polyuria should include primary polydipsia and uncontrolled diabetes mellitus.
Calculate the plasma osmolality: 2[Na+] + [Glucose]/18 + [BUN]/2.8
To differentiate central and nephrogenic diabetes insipidus, perform a water deprivation test and desmopressin (DDAVP) trial. Typically a 7-hour deprivation test is adequate to diagnose diabetes insipidus. Primary polydipsia may require longer dehydration periods.
In adults, the water restriction test should be discontinued when one of the following is reached:
In newborns and young infants, if nephrogenic diabetes insipidus is suspected the diagnostic test of choice is DDAVP (1 mcg subcutaneously or intravenously over 20 minutes, maximum dose 0.4 mcg/kg).
In children, water deprivation test should be closely monitored. If one of the following endpoints are reached discontinue the trial:
The water deprivation trial is most accurate when DDAVP is not given. After water deprivation, studies have demonstrated DDAVP can increase urine osmolality greater than 100% incomplete central diabetes insipidus and up to 50% in partial central diabetes insipidus.
In cases of nephrogenic diabetes insipidus, water deprivation suboptimally increases urine osmolality. DDAVP minimally increases urine osmolality in partial nephrogenic diabetes insipidus, with no increase urine osmolality in complete nephrogenic diabetes insipidus.
Central diabetes insipidus is diagnosed when there is evidence of plasma hyperosmolality (greater than 300 mosm/l), urine hyperosmolality (less than 300 mosm/l or urine/plasma osmolality less than 1), with polyuria (urinary volume greater than 4 mL/kg/hr to 5 mL/kg/hr for two consecutive hours after surgery).
Copeptin and AQP2 have also been utilized to differentiate nephrogenic and central diabetes insipidus. In central diabetes insipidus, AQP2 increases with DDAVP administration. On the contrary, in patients with nephrogenic diabetes insipidus, the AQP2 excretion does not increase after DDAVP administration.
When suspecting a structural cause of diabetes insipidus, MRI imaging can identify malformations of the posterior pituitary.
DDAVP, an ADH analog, can be administered orally, intranasally, subcutaneously, or intravenously. In adults, the dose is ten mcg by nasal insufflation or 4 mcg subcutaneously or intravenously. In newborns or very young infants, the dose is one mcg subcutaneously or intravenously over 20 minutes with a maximum dose of 0.4 mcg/kg.
Central Diabetes Insipidus
The preferred therapy is DDAVP. Typically, therapy is maintained for the duration of central diabetes insipidus, which varies depending on the cause. The minimum dose should be administered to control polyuria adequately.
It is important to monitor for hyponatremia, as water retention can lead to sodium concentration changes that may cause brain injury. The patients and families should be educated to observe for symptoms of nausea, vomiting, lethargy, headaches, confusion, seizures, and coma.
Other treatment options for central diabetes insipidus include low-solute diet (low salt, low protein), thiazide diuretics, chlorpropamide, carbamazepine, and non-steroidal anti-inflammatory drugs (NSAID).
DDAVP is considered safe the pregnancy.
Nephrogenic Diabetes Insipidus
The first step is correct the underlying cause. If possible, discontinue the offending agent such as lithium.
Low-solute diet may decrease the urine output. The lower amount of total solutes ingested, the lower the urine volume that will be excreted.
Thiazide diuretics may be used in conjunction with dietary changes. The mechanism of administering a diuretic in the setting of polyuria is to promote the reduction of urine volume, which triggers the endogenous release of aldosterone. By having less water delivered distally, there would be less water loss in the collecting tubule, where ADH targets its effects.
Other treatment options include DDAVP and NSAIDs. NSAIDs inhibit prostaglandin synthesis, which has antagonistic the effects of ADH.
Patients with significant electrolyte abnormalities should be closely monitored and admitted to the hospital.
There are many causes of DI and it is best managed by an interprofessional team that includes the primary care provider, nurse practitioner, internist, and a pharmacist. The key is to hydrate and replace the electrolytes and then manage the primary condition causing DI. The pharmacist should keep track of all medications that can cause DI and make the appropriate recommendations to the physician.
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