Definition and Pathophysiology

If urine output is greater than 3 L/day and the urine is dilute (urine osmolality <250 mOsm/L), total solute excretion is relatively normal, and polyuria is due to excessive excretion of water. In general, diuresis is marked and urine osmolality (Uosm) is often less than 100 mOsm/L. Water diuresis is usually secondary to excess water intake (as in primary polydipsia) or inability of the renal tubules to reabsorb free water (as in central or nephrogenic diabetes insipidus). A good understanding of water homeostasis is critical for recognizing and managing water diuresis.

Normal plasma osmolality is 275 to 285 mOsm/L. To maintain this steady state, water intake must equal water excretion. The primary stimulus for water ingestion is thirst, mediated either by an increase in effective osmolality or a decrease in blood pressure (BP) or effective circulating volume. Under normal circumstances, water intake generally exceeds physiologic requirements.

Unlike water intake, water excretion is very tightly regulated by multiple factors. The most dominant regulating factor affecting water excretion is arginine vasopressin (AVP), a polypeptide synthesized in the hypothalamus and secreted by the posterior pituitary gland. Once released, AVP binds to vasopressin-2 (V2) receptors located on the basolateral membranes of renal epithelial cells lining the collecting ducts. Binding of AVP to V2 receptors initiates a sequence of cellular events, ultimately resulting in insertion of water channels into the luminal cell membrane. The presence of these water channels permits passive diffusion of water (hence its reabsorption) across the collecting duct. Any derangement in this process results in lack of or inadequate water reabsorption by the collecting duct, resulting in water diuresis. The major stimulus for AVP release is plasma hypertonicity. AVP release is also affected by other nonosmotic factors like effective circulating volume, hypoglycemia, and drugs. In summary, water diuresis occurs either because of excessive water intake sufficient enough to overwhelm the renal excretory capacity (primary polydipsia) or impairment of renal water reabsorption itself (central or nephrogenic diabetes insipidus). Impaired renal water reabsorptive capacity (leading to water diuresis) in turn can occur either as a result of failure of AVP release in response to normal physiologic stimuli (central or neurogenic diabetes insipidus) or failure of the kidney to respond to AVP (nephrogenic diabetes insipidus). In most patients, the degree of polyuria is primarily determined by the degree of AVP lack or resistance.

Primary Polydipsia

Primary polydipsia can be recognized clinically based on the history of the patient. Usually there is a history of psychiatric illness along with a history of excessive water intake. Many patients with chronic psychiatric illnesses have a moderate to marked increase in water intake (up to 40 L/day).^3,4 It is presumed that a central defect in thirst regulation plays an important role in the pathogenesis of primary polydipsia. In some cases, the osmotic threshold for thirst is reduced below the threshold for the release of AVP. The mechanism responsible for abnormal thirst regulation in this setting is unclear. There is evidence that these patients have other defects in central neurohumoral control as well.⁵ Hyponatremia, when present, also points to the diagnosis of primary polydipsia. The diagnosis of primary polydipsia is usually evident from low urine and plasma osmolalities in the face of polyuria. Hypothalamic diseases such as sarcoidosis, trauma, and certain drugs like phenothiazines can lead to primary polydipsia (Table 10-1). There is no proven specific therapy for psychogenic polydipsia. Free water restriction is the mainstay of therapy.

TABLE 10-1 Causes of Polyuria

ATN, acute tubular necrosis; AVP, arginine vasopressin.

Central Diabetes Insipidus

Inadequate secretion of AVP (central diabetes insipidus) can be caused by a large number of disorders that act at one or more of the sites involved in AVP secretion, interfering with the physiologic chain of events that lead to hormone release. However, the most common causes of central diabetes insipidus account for the vast majority of cases. These common causes include neurosurgery, head trauma, brain death, primary or secondary tumors of the hypothalamus, or infiltrative diseases such as Langerhans cell histiocytosis (see Table 10-1).

Nephrogenic Diabetes Insipidus

Nephrogenic diabetes insipidus refers to a decrease in urinary concentrating ability that results from renal resistance to the action of AVP. The collecting duct cells can fail to respond to the actions of AVP. Other factors that can cause renal resistance to AVP are problems that interfere with the renal countercurrent concentrating mechanism, such as medullary injury or decreased sodium chloride reabsorption in the medullary aspect of the thick ascending limb of the loop of Henle. In children, nephrogenic diabetes insipidus is usually hereditary. Congenital or hereditary nephrogenic diabetes insipidus is an X-linked recessive disorder resulting from mutations in the V2 AVP receptor gene.⁶ The X-linked inheritance pattern means that males tend to have marked polyuria. Female carriers are usually asymptomatic but occasionally have severe polyuria. In addition, different mutations are associated with different degrees of AVP resistance. Nephrogenic diabetes insipidus also can be inherited as an autosomal recessive disorder due to mutations in the aquaporin gene that result in absent or defective water channels, thereby causing resistance to the action of AVP.⁷

The most common cause of nephrogenic diabetes insipidus in adults is chronic lithium ingestion (see Table 10-1). Polyuria occurs in about 20% to 30% of patients on chronic lithium therapy. The impairment in the nephron’s concentrating ability is thought to be due to decreased density of V2 receptors or to decreased expression of aquaporin-2, a water channel protein. Other secondary causes of nephrogenic diabetes insipidus include hypercalcemia, hypokalemia, sickle cell disease, and other drugs (see Table 10-1). A water diuresis also can follow relief of obstructive nephropathy. Hypercalcemia-induced nephrogenic diabetes insipidus occurs when the plasma calcium concentration is persistently above 11 mg/dL (2.75 mmol/L). This defect is generally reversible with correction of hypercalcemia. The mechanism(s) responsible for hypercalcemia-induced nephrogenic diabetes insipidus remain incompletely understood. Compared to hypercalcemia-induced diabetes insipidus, hypokalemia-induced nephrogenic diabetes insipidus is less severe and often asymptomatic. A rare form of nephrogenic diabetes insipidus can occur during the second half of pregnancy (gestational diabetes insipidus). This condition is thought to be caused by release of a vasopressinase from the placenta, leading to rapid degradation of endogenous or exogenous AVP.⁸

Approach to Hypotonic Polyuria (Water Diuresis)

The correct diagnosis is often suggested by the plasma sodium concentration and the history. When the problem is primary polydipsia, the plasma sodium concentration is usually low (dilutional), whereas when the problem is central or nephrogenic diabetes insipidus, the plasma sodium concentration typically is normal or high (due to loss of solute free water in excess of solutes). The rate of onset of polyuria can sometimes provide a clue about the diagnosis; when central diabetes insipidus is the problem, the onset of polyuria is generally abrupt, whereas when nephrogenic diabetes insipidus or primary polydipsia is the problem, the onset of polyuria tends to be more gradual. When the diagnosis of central versus nephrogenic diabetes insipidus is unclear, the diagnosis can be confirmed by determining the urinary response to an acute increase in plasma osmolality induced either by water restriction or, less commonly, by administration of hypertonic saline (Figure 10-1).

Figure 10-1 Approach to polyuria.

*Response to AVP is defined as a greater than 9% increase in urine osmolality between 30 and 60 minutes after vasopressin administration (see text for details). AVP, arginine vasopressin; DI, diabetes insipidus; UTS, urine total solute concentration.

Comparing urinary osmolality after dehydration with that after vasopressin administration can help differentiate diabetes insipidus due to vasopressin deficiency from other causes of water diuresis (see Figure 10-1). In this test, fluids are withheld long enough to result in stable hourly urinary osmolalities (<30 mmol/kg rise in urine osmolality for 3 consecutive hours). Plasma osmolality and urine osmolality are measured at this time point, then the patient is given 5 units of aqueous vasopressin intravenously (IV). The clinician then measures the osmolality of a urine sample collected during the interval from 30 to 60 minutes after administration of vasopressin. In subjects with normal pituitary function, urinary osmolality does not rise by more than 9% after vasopressin injection. However, in central diabetes insipidus, the increase in urine osmolality after vasopressin administration exceeds 9%. To ensure adequacy of dehydration, plasma osmolality prior to vasopressin administration should be greater than 288 mmol/kg. There is little or no increase in urine osmolality with dehydration in patients with nephrogenic diabetes insipidus, and there is no further change after vasopressin injection. In the future, a novel method to confirm the results of the water restriction test will be to measure the urinary excretion of aquaporin-2, the collecting tubule water channel that normally fuses with the luminal membrane of the collecting tubule cells under the influence of AVP. In one study, urinary aquaporin-2 excretion increased substantially and to a similar extent after the administration of vasopressin in normal subjects and those with central diabetes insipidus.⁹ However, in patients with hereditary nephrogenic diabetes insipidus, urinary aquaporin-2 excretion was unchanged after vasopressin administration.

Treatment of Water Diuresis

Central diabetes insipidus can be treated by replacing AVP. The agent of choice is desmopressin, since it has prolonged antidiuretic activity and very minimal vasopressor effect. It is usually administered intranasally at doses of 10 to 20 µg once or twice a day. Patients with central diabetes insipidus with some residual releasable AVP can be treated with drugs such as carbamazepine (100-300 mg twice daily), clofibrate (500 mg every 6 hours), or chlorpropamide (125-250 mg once or twice a day) that stimulate AVP release.

Primary polydipsia can only be treated by eliminating the underlying problem. In patients with schizophrenia and polydipsia, clozapine has been shown to have a beneficial effect.

The mainstay of treatment of nephrogenic diabetes insipidus is solute restriction and diuretics. Thiazide diuretics in combination with a low-salt diet can diminish the degree of polyuria in patients with persistent and symptomatic nephrogenic diabetes insipidus. Thiazide diuretics (hydrochlorothiazide) act by inducing mild volume depletion. Hypovolemia induces an increase in proximal sodium and water reabsorption, thereby diminishing water delivery to the AVP-sensitive sites in the collecting tubules and reducing the urine output. The potassium-sparing diuretic, amiloride, also may be helpful.¹⁰