Diabetes Insipidus

Physiology of Water Balance

The control of extracellular tonicity (osmolality) and volume within a narrow range is critical for normal cellular structure and function (Chapter 52). Extracellular fluid tonicity is regulated almost exclusively by water intake and excretion, whereas extracellular volume is regulated by sodium intake and excretion. The control of plasma tonicity and intravascular volume involves a complex integration of endocrine, neural, behavioral, and paracrine systems (Fig. 552-1). Vasopressin, secreted from the posterior pituitary, is the principal regulator of tonicity, with its release largely stimulated by increases in plasma tonicity. Volume homeostasis is largely regulated by the renin-angiotensin-aldosterone system, with contributions from both vasopressin and the natriuretic peptide family.

Figure 552-1 Regulation of vasopressin (VP) secretion and serum osmolality. Hyperosmolality, hypovolemia, and hypotension are sensed by osmosensors, volume sensors, and barosensors, respectively. These stimulate both VP secretion and thirst. VP, acting on the kidney, causes increased reabsorption of water (antidiuresis). Thirst causes increased water ingestion. The results of these dual negative feedback loops cause a reduction in hyperosmolality or in hypotension or hypovolemia. Additional stimuli for VP secretion include nausea, hypoglycemia, and pain.

(From Muglia LJ, Majzoub JA: Disorders of the posterior pituitary. In Sperling MA, editor: Pediatric endocrinology, ed 2, Philadelphia, 2002, WB Saunders.)

Vasopressin, a 9-amino-acid peptide, has both antidiuretic and vascular pressor activity and is synthesized in the paraventricular and supraoptic nuclei of the hypothalamus. It is transported to the posterior pituitary via axonal projections, where it is stored awaiting release into the systemic circulation. The half-life of vasopressin in the circulation is 5 min. In addition to responding to osmotic stimuli, vasopressin is secreted in response to significant decreases in intravascular volume and pressure (minimum of 8% decrement) via afferent baroreceptor pathways arising from the aortic arch (carotid sinus) and volume receptor pathways in the cardiac atria and pulmonary veins. Osmotic and hemodynamic stimuli interact synergistically.

The sensation of thirst is regulated by cortical as well as hypothalamic neurons. The thirst threshold is approximately 10 mOsm/kg higher (i.e., 293 mOsm/kg) than the osmotic threshold for vasopressin release. Therefore, under conditions of hyperosmolality, vasopressin is released before thirst is initiated, allowing ingested water to be retained. Chemoreceptors present in the oropharynx rapidly down-regulate vasopressin release following water ingestion.

Vasopressin exerts its principal effect on the kidney via V₂ receptors located primarily in the collecting tubule, the thick ascending limb of the loop of Henle, and the periglomerular tubules. The human V₂ receptor gene is located on the long arm of the X chromosome (Xq28) at the locus associated with congenital, X-linked, vasopressin-resistant diabetes insipidus. Activation of the V₂ receptor results in increases in intracellular cyclic adenosine monophosphate (cAMP), which leads to the insertion of the aquaporin-2 water channel into the apical (luminal) membrane. This allows water movement along its osmotic gradient into the hypertonic inner medullary interstitium from the tubule lumen and excretion of concentrated urine. In contrast to aquaporin-2, aquaporins-3 and -4 are expressed on the basolateral membrane of the collecting duct cells, and aquaporin-1 is expressed in the proximal tubule. These channels may also contribute to urinary concentrating ability.

Atrial natriuretic peptide (ANP), initially isolated from cardiac atrial muscle, has a number of important effects on salt and water balance, including stimulation of natriuresis, inhibition of sodium resorption, and inhibition of vasopressin secretion. ANP is expressed in endothelial cells and vascular smooth muscle, where it appears to regulate relaxation of arterial smooth muscle. ANP is also expressed in the brain, along with other natriuretic family members; the physiologic role of these factors has yet to be defined.

Approach to the Patient with Polyuria, Polydipsia, and Hypernatremia

The cause of pathologic polyuria or polydipsia (exceeding 2 L/m²/24 hr) may be difficult to establish in children. Infants can present with irritability, failure to thrive, and intermittent fever. Patients with suspected DI should have a careful history taken, which should quantify the child’s daily fluid intake and output and establish the voiding pattern, nocturia, and primary or secondary enuresis. A complete physical examination should establish the patient’s hydration status, and the physician should search for evidence of visual and central nervous system dysfunction as well as other pituitary hormone deficiencies.

If pathologic polyuria or polydipsia is present, the following should be obtained: serum for osmolality, sodium, potassium, blood urea nitrogen, creatinine, glucose, and calcium; urine for osmolality, specific gravity, and glucose determination. The diagnosis of DI is established if the serum osmolality is >300 mOsm/kg and the urine osmolality is <300 mOsm/kg. DI is unlikely if the serum osmolality is <270 mOsm/kg or the urine osmolality is >600 mOsm/kg. If the patient’s serum osmolality is <300 mOsm/kg (but >270 mOsm/kg) and pathologic polyuria and polydipsia are present, a water deprivation test is indicated to establish the diagnosis of DI and to differentiate central from nephrogenic causes.

In the inpatient postneurosurgical setting, central DI is likely if hyperosmolality (serum osmolality >300 mOsm/kg) is associated with urine osmolality less than serum osmolality. It is important to distinguish between polyuria resulting from postsurgical central DI and polyuria resulting from the normal diuresis of fluids received intraoperatively. Both cases may be associated with a large volume (>200 mL/m²/hr) of dilute urine, although in patients with DI, the serum osmolality is high in comparison with patients undergoing postoperative diuresis.

Causes of Hypernatremia

Hypernatremia is discussed in Chapter 52.3.

Treatment of Central Diabetes Insipidus

Treatment of Nephrogenic Diabetes Insipidus

The treatment of acquired NDI focuses on eliminating, if possible, the underlying disorder, such as offending drugs, hypercalcemia, hypokalemia, or ureteral obstruction. Congenital nephrogenic diabetes insipidus is often difficult to treat. The main goals are to ensure the intake of adequate calories for growth and to avoid severe dehydration. Foods with the highest ratio of caloric content to osmotic load (Na <1 mmol/kg/24 hr) should be ingested to maximize growth and to minimize the urine volume required to excrete the solute load. Even with the early institution of therapy, however, growth failure and mental retardation are common.

Pharmacologic approaches to the treatment of NDI include the use of thiazide diuretics and are intended to decrease the overall urine output. Thiazides appear to induce a state of mild volume depletion by enhancing sodium excretion at the expense of water and by causing a decrease in the glomerular filtration rate, which results in proximal tubular sodium and water reabsorption. Indomethacin and amiloride may be used in combination with thiazides to further reduce polyuria. High-dose DDAVP therapy, in combination with indomethacin, has been used in some subjects with NDI. This treatment could prove useful in patients with genetic defects in the V₂ receptor associated with a reduced binding affinity for vasopressin.