REF: Manual of Endocrinology and Metabolism - Norman Lavin, M.D. 1994

A. Definition
Diabetes insipidus (DI) is the excretion of a large amount of dilute urine (hypotonic polyuria). To qualify for this diagnosis the urinary volume should be more than 30 ml/kg/day, the urine osmolality less than 300 mOsm/kg, and the specific gravity less than 1.010.

B. Etiology
Hypotonic polyuria could result from any of three different defects:

1. Inadequate secretion of AVP, which is known as central, or neurogenic, DI.
2. Impaired renal responsiveness to AVP, which is known as nephrogenic DI.
3. Increased water intake or primary polydipsia, also known as dipsogenic DI.

C. Central diabetes insipidus
Definition:
Central DI is a polyuric syndrome that results from a lack of sufficient AVP to concentrate the urine. It is characterized by the following symptoms:

1. Inappropriately dilute urine in the presence of strong osmotic or nonosmotic stimuli for AVP secretion
2. The absence of intrinsic renal disease
3. A rise in urine osmolality following the administration of AVP

Etiology:
The main causes of central DI are summarized in Table 7-1 Table 7-1. Central DI is either familial or acquired.

1. The familial disease is inherited as an autosomal dominant trait; it shows variable expression among affected individuals, and all patients respond to exogenous AVP administration.
2. The acquired form of central DI may result from any disease affecting the hypothalamus-posterior pituitary region such as trauma, neoplastic disease, ischemia, granulomatous or infiltrative disease, infections, and autoimmune disease. Some of the cases are idiopathic. Anterior pituitary diseases or tumors rarely cause DI.

Pathophysiology:
Polyuria does not occur until AVP secretion becomes insufficient to maintain urinary concentration, which occurs when AVP secretory capacity is reduced by more than 75%. The intact thirst mechanism is essential to offset the hyperosmolality that results from the polyuria. The thirst mechanism stabilizes plasma osmolality at a level only slightly above normal no matter how severe the polyuria is. If DI is accompanied by hyperosmolarity and hypernatremia, an associated defect in thirst mechanism or some other impediment to water intake is responsible.

The development of DI following surgical or traumatic injury to the hypothalamus-posterior pituitary region follows a transient, permanent, or triphasic pattern. Transient DI usually has an abrupt onset within 24 hours of the injury and resolves within a few days. Permanent DI also has an abrupt onset, but it persists. The triphasic pattern is characterized by an immediate postinjury hypoosmolar polyuria, which lasts 4-5 days. The urine flow falls and the osmolality rises for 5-7 days; then the final phase consists of permanent polyuria.

Clinical manifestations:
The cardinal symptoms of DI are polyuria, thirst, and polydipsia. Urine volume varies between a few liters per day in partial DI to 20 liters per day in complete DI, and the onset is usually abrupt. Patients usually show a particular predilection for cold or iced drinks. If access to water is interrupted, hyperosmolality develops rapidly, and CNS symptoms such as irritability, mental dullness, ataxia, hyperthermia, and coma are seen.

Laboratory findings:

1. A large urinary volume generally greater than 3 liters per day
2. Urine osmolality less than 200 mOsm/kg
3. Slightly elevated plasma osmolality (depending on thirst and water intake)
4. Inappropriately low serum AVP levels despite slightly elevated plasma osmolality

Diagnosis:
Central DI must be separated from nephrogenic DI and primary polydipsia (see Chap. 7, sec. II.D. below and sec. II.H.3.). It can be differentiated from osmotic diuresis by measurements of serum and urine solute concentrations, which disclose osmotic diuretics such as glucose, mannitol, and urea. Serum electrolytes and creatinine help identify renal failure, hypercalcemia, and hypokalemia. A history of recent head trauma or surgery points to central DI as a cause of the polyuric state.

D. Nephrogenic diabetes insipidus

Nephrogenic DI is a polyuric disorder that results from renal insensitivity to the antidiuretic effect of AVP. This disorder is characterized by

• · Presence of normal rates of renal filtration and solute excretion
• · Persistently hypotonic urine
• · Normal or high levels of AVP
• · Failure of exogenous AVP to raise urine osmolality or to reduce urine volume

For the polyuria to occur, the renal insensitivity needs to be great enough to prevent urine concentration at a plasma AVP level achievable under ordinary conditions.

1. Etiology.

The major causes of nephrogenic DI are given in Table 7-2 Table 7-2. Similar to the etiology of central DI, nephrogenic DI is either familial or acquired. Familial nephrogenic DI has X-linked inheritance; transmission is from mother to male newborn. Female carriers might have unusual thirst, nocturnal water consumption, and impaired urine concentrating ability after water deprivation. Polyuria in the familial form usually begins in infancy. Conditions that cause nephrogenic DI include hypokalemia, hypercalcemia, sickle cell disease, urinary outflow obstruction, and a variety of agents, including lithium, demeclocycline, and methoxyflurane (see Table 7-2 Table 7-2).

2. Pathophysiology.

The cardinal feature of nephrogenic DI is the failure of collecting tubules to increase water permeability in response to AVP, resulting in the excretion of hypotonic urine. The basic defect in familial nephrogenic DI resides in the AVP receptor V2 type--both renal and extrarenal. This defect diminishes cAMP formation in renal tubules in response to AVP.

Both hypercalcemia and hypokalemia cause a concentrating defect. Hypokalemia can lead to a prostaglandin E2-mediated inhibition of adenyl cyclase activation by AVP. Hypercalcemia reduces the medullary solute content and inhibits adenyl cyclase activation by AVP. Demeclocyclin and lithium inhibit AVP-stimulated cAMP formation in the collecting tubules.

3. Diagnosis.

Familial nephrogenic DI becomes apparent in infancy. There is usually a positive family history, and the polyuria does not respond to AVP administration. Similarly, acquired nephrogenic DI is also resistant to AVP administration.

E. Diabetes insipidus of pregnancy

DI of pregnancy has features of both central and nephrogenic DI. It is caused by the degradation of circulating AVP by the enzyme vasopressinase. The polyuria usually begins in the third trimester and resolves spontaneously after delivery. AVP levels are low. The polyuria does not respond to exogenous AVP but does respond to desmopressin.

F. Primary polydipsia

1. Compulsive water drinkers.

Excessive intake of water causes expansion and dilution of body fluids, which results in a fall in plasma osmolality that suppresses AVP secretion, thereby inducing dilution of the urine. Plasma osmolality stabilizes at a lower level, approximating the osmotic threshold for AVP secretion. This form is seen in compulsive water drinkers.

2. Dipsogenic DI.

Dipsogenic DI is seen when the osmotic threshold for thirst is paradoxically lower than that for AVP secretion. This reversal of the normal relationship between thirst and AVP secretion results in chronic thirst, polydipsia, and polyuria. The hallmark of primary polydipsia is diluted plasma, diluted urine, and suppressed AVP secretion.

G. Diagnostic studies of polyuric states

It is sometimes difficult to determine the etiology of a polyuric state without performing specific tests, but certain factors suggest the most likely diagnosis. A large urinary volume and a low plasma osmolality (less than 285 mOsm/kg), with a history of psychiatric disorder or episodic polyuria, suggest primary polydipsia. A history of recent head trauma or surgery on the hypothalamic-pituitary region, coupled with the sudden onset of polyuria, suggests central DI.

The most commonly used method of distinguishing among polyuric states involves fluid restriction combined with AVP administration. The basis of the test is that under normal conditions the dehydration that results from fluid restriction causes maximum AVP release, which in turn produces maximum urinary concentration. Therefore administration of exogenous AVP has no further effect on urine osmolality.

1. Water deprivation test

a. Method.

In the water deprivation test patients are denied all fluids until they are sufficiently dehydrated to provide a potent stimulus for AVP secretion (plasma osmolality more than 295 mOsm/kg). The deprivation lasts for 4-18 hours, with hourly measurements of urine osmolality, and continues until urine osmolality of three consecutive hourly samples varies by less than 30 mOsm/kg or until the patient loses 5% of body weight. In patients with urine output exceeding 10 liters a day, the test should be started at 6 A.M. to allow careful supervision during the period of water deprivation (the urine osmolality usually plateaus within 4-8 hours). In patients with lower degrees of polyuria, 12-18 hours of fluid deprivation may be required. In such cases fluid deprivation is usually started the night before (10 P.M. or midnight).

Patients with primary polydipsia can be severely volume overloaded, so fluid deprivation for more than 16 hours might be needed before endogenous AVP is released and the urine is concentrated. If the urine osmolality does not increase above that of plasma (300 mOsm/kg), despite evident dehydration, dipsogenic DI can be excluded. In such patients 5 units of AVP or 1 micro-g of desmopressin should be injected subcutaneously and urine osmolality measured 30, 60, and 120 minutes later. Plasma osmolality is measured before starting the fluid deprivation, at the end of fluid deprivation, and after AVP administration.

b. Interpretation of results

(1) If dehydration does not increase urine osmolality above that of plasma despite evident dehydration, dipsogenic DI can be excluded. If neither urine nor plasma osmolality increases during dehydration and body weight does not decrease according to the urinary volume, surreptitious drinking should be suspected.

(2) Normal individuals and patients with dipsogenic DI display urine osmolality greater than plasma osmolality following fluid restriction and demonstrate a minimum (less than 10%) increase in urine osmolality after vasopressin injection.

(3) In patients with central or nephrogenic DI the urine osmolality remains below serum osmolality following dehydration. However, in patients with partial DI (central or nephrogenic) urine osmolality rises above serum osmolality following dehydration. After AVP administration, urine osmolality increases by less than 10% in normal subjects, more than 50% in patients with central DI, and less than 50% in patients with nephrogenic DI. The water deprivation test has a sensitivity and specificity of about 95% when performed properly.

(4) Despite the high sensitivity and specificity of the water deprivation test, it may fail to differentiate between partial central DI and partial nephrogenic DI, where urine osmolality may increase above plasma osmolality following water deprivation. In these circumstances, one of three approaches could help reach an accurate diagnosis.

(a) Concurrent measurements of plasma AVP levels, plasma osmolality, and urine osmolality. In patients with partial central DI, plasma AVP levels are low for the concurrent level of plasma osmolality, whereas in partial nephrogenic DI, plasma AVP levels are elevated.

(b) Patients are given a therapeutic trial of desmopressin (10-25 micro-g intranasally or 1-2 micro-g subcutaneously) for 2-3 days. In patients with central DI this treatment promptly reduces polydipsia and polyuria and does not produce water intoxication; however, this therapy has no effect on patients with nephrogenic DI.

(c) Hypertonic saline infusion. A solution of 3% saline is infused to raise serum sodium to 145-150 mmol/liter; blood samples are obtained for measurements of serum osmolality and plasma AVP levels. Patients with primary polydipsia and nephrogenic DI exhibit normal stimulation of AVP release in response to the hypertonicity, whereas patients with central DI exhibit little or no rise in plasma AVP levels.

(5) When a diagnosis of central DI is made, a careful evaluation of the hypothalamus-posterior pituitary region is mandatory to determine if neoplasms are present; computed tomography (CT) or magnetic resonance imaging (MRI) of the head should be obtained. Breast examination, mammography, and chest radiographic examination should be done to look for breast and lung tumors.

H. Therapy of DI

1. Central DI

a. The specific therapy for central DI is AVP replacement. The most widely used preparation, desmopressin, provides antidiuretic activity for 8-20 hours with negligible pressor effect. It can be taken as a nasal spray by both adults and children. The drug is best started at night to find the lowest effective dosage that prevents nocturia, usually 5-10 micro-g given once or twice a day. A nasal catheter is calibrated for a 5-20 micro-g dose range for convenience. Headache can be a side effect, but it usually subsides on reduction of the dosage. A parenteral form is available for patients who cannot take the drug intranasally. An oral form is unavailable in the United States.

b. Chlorpropamide can be used in patients with partial central DI, because it enhances AVP action on the renal tubules as well as stimulates AVP secretion. Chlorpropamide is given in a dosage of 250-500 mg a day. About 50-80% of patients with partial central DI respond to this dosage. Hypoglycemia is a common and sometimes serious side effect of chlorpropamide therapy.

c. Clofibrate and carbamazepine stimulate AVP release and can be used in partial central DI. Carbamazepine appears to increase sensitivity to AVP.

2. Nephrogenic DI.

Neither AVP and its analogue, desmopressin, nor drugs that stimulate endogenous AVP or augment its effect on the kidneys are effective in treating nephrogenic DI. The most effective therapy is the combination of thiazide diuretics and mild salt depletion. Thiazide diuretics can be used in all forms of DI. These agents induce a mild salt depletion that results in a secondary increase in isotonic proximal fluid absorption and a decrease in the volume of fluids delivered to the collecting duct. Salt restriction augments this effect.

Prostaglandin synthesis inhibitors such as ibuprofen, indomethacin, and aspirin reduce the delivery of solutes to the distal tubules, thereby reducing urine volume and increasing urine osmolality. They may be used adjunctively to treat nephrogenic DI.

3. Primary polydipsia.

AVP and thiazide diuretics should not be used in patients with dipsogenic DI because these agents diminish water excretion without reducing water intake, and therefore can induce serious water intoxication. Treatment should focus on behavior modification to reduce water intake.

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