Diseases Affecting The Vasopressin System

DIABETES INSIPIDUS (DI) DI is a disease of impaired renal conservation of water owing either to an inadequate secretion of vasopressin from the neurohypophysis (central DI) or to an insufficient renal response to vasopressin (nephrogenic DI). Very rarely, DI can be caused by an abnormally high rate of degradation of vasopressin by circulating vasopressinases. Pregnancy may accentuate or reveal central and/or nephrogenic DI by increasing plasma levels of vasopressinase and by reducing the renal sensitivity to vasopressin. Patients with DI excrete large volumes (>30 mL/kg/day) of dilute (<200 mOsm/kg) urine and, if their thirst mechanism is functioning normally, are polydipsic. The diagnosis of DI rests on demonstrating that the patient is unable to reduce urine volume and increase urine osmolality during a period of carefully observed fluid deprivation. Central DI can be distinguished from nephrogenic DI by administration of desmopressin, which will increase urine osmolality in patients with central DI but have little or no effect in patients with nephrogenic DI. DI can be differentiated from primary polydipsia by measuring plasma osmolality, which will be low to low-normal in patients with primary polydipsia and high to high-normal in patients with DI.

Central DI Head injury, either surgical or traumatic, in the region of the pituitary and/or hypothalamus may cause central DI. Postoperative central DI may be transient, permanent, or triphasic (recovery followed by permanent relapse). Other causes include hypothalamic or pituitary tumors, cerebral aneurysms, CNS ischemia, and brain infiltrations and infections. Finally, central DI may be idiopathic or familial. Familial central DI usually is autosomal dominant (chromosome 20); vaso-pressin deficiency occurs several months or years after birth and worsens gradually. Autosomal dominant central DI results from mutations in the vasopressin gene that cause the prohormone to misfold and oligomerize improperly, resulting in accumulation of the mutant vasopressin precursor in the affected neuron and neuronal death. Rarely, familial central DI is autosomal recessive owing to a mutation in the vasopressin peptide itself that gives rise to an inactive vasopressin peptide.

Antidiuretic peptides are the primary treatment for central DI, with desmopressin being the preferred peptide. For patients with central DI who cannot tolerate antidiuretic peptides because of side effects or allergic reactions, other treatment options are available. Chlorpropamide, an oral sul-fonylurea, potentiates the action of small or residual amounts of circulating vasopressin and will reduce urine volume in more than half of all patients with central DI. A dose of 125-500 mg daily is particularly effective in patients with partial central DI. If polyuria is not controlled satisfactorily with chlorpropamide alone, addition of a thiazide diuretic (see Chapter 28) to the regimen usually results in an adequate reduction in the volume of urine. Carbamazepine (800-1000 mg daily in divided doses) and clofibrate (1-2 g daily in divided doses) also reduce urine volume in patients with central DI. Long-term use of these agents may induce serious adverse effects; therefore, car-bamazepine and clofibrate are used rarely to treat central DI. The antidiuretic mechanisms of chlor-propamide, carbamazepine, and clofibrate are not clear. These agents are not effective in nephrogenic DI, which indicates that functional V2 receptors are required for the antidiuretic effect. Since carbamazepine inhibits and chlorpropamide has little effect on vasopressin secretion, it is likely that carbamazepine and chlorpropamide act directly on the kidney to enhance V2 receptor-mediated antidiuresis.

Nephrogenic DI Nephrogenic DI may be congenital or acquired. Hypercalcemia, hypokalemia, postobstructive renal failure, lithium, foscarnet, clozapine, demeclocycline, and other drugs can induce nephrogenic DI. As many as 1 in 3 patients treated with lithium may develop nephrogenic DI. X-linked nephrogenic DI is caused by mutations in the gene encoding the V2 receptor, which maps to Xq28. A number of missense, nonsense, and frame-shift mutations in this gene have been identified in patients with this disorder, causing impaired routing of the V2 receptor to the cell surface, defective coupling to G proteins, or decreased affinity of the receptor for vasopressin. Autosomal recessive and dominant nephrogenic DI result from inactivating mutations in aquaporin 2. These findings establish that aquaporin 2 is essential for the antidiuretic effect of vasopressin.

Although the mainstay of treatment of nephrogenic DI is assurance of an adequate intake of water, drugs also can be used to reduce polyuria. Amiloride blocks the uptake of lithium by the Na+ channel in the collecting-duct system and is used off-label for lithium-induced nephrogenic DI. Paradoxically, thiazide diuretics reduce the polyuria of patients with DI and often are used to treat non-lithium-induced nephrogenic DI. In infants with nephrogenic DI, thiazides may be crucially important because uncontrolled polyuria may exceed the child's capacity to imbibe and absorb fluids. The natriuretic action of thiazides and resulting depletion of extracellular fluid volume may play an important role in the thiazide-induced antidiuresis since these effects appear to parallel the ability of thiazides to cause natriuresis, and the drugs are given in doses similar to those used to mobilize edema fluid. In patients with DI, a 50% reduction of urine volume is a good response to thiazides. Moderate restriction of sodium intake can enhance the antidiuretic effectiveness of thiazides.

While case reports describe the effectiveness of indomethacin in the treatment of nephrogenic DI, other cyclooxygenase inhibitors (e.g., ibuprofen) appear to be less effective. The mechanism of the effect may involve a decrease in glomerular filtration rate, an increase in medullary solute concentration, and/or enhanced proximal reabsorption of fluid. Also, since prostaglandins attenuate vasopressin-induced antidiuresis in patients with at least a partially intact V2-receptor system, some of the antidiuretic response to indomethacin may be due to diminution of the prostaglandin effect and enhancement of the effects of vasopressin on principal cells of the collecting duct.

SYNDROME OF INAPPROPRIATE SECRETION OF ANTIDIURETIC HORMONE (SIADH) SIADH is a disease of impaired water excretion with accompanying hyponatremia and hypo-osmolality caused by the inappropriate secretion of vasopressin. The clinical manifestations of plasma hypotonicity resulting from SIADH may include lethargy, anorexia, nausea and vomiting, muscle cramps, coma, convulsions, and death. A multitude of disorders can induce SIADH, including malignancies, pulmonary diseases, CNS injuries/diseases (e.g., head trauma, infections, and tumors), and general surgery. The three drug classes most commonly implicated in drug-induced SIADH include psychotropic medications (e.g., fluoxetine, haloperidol, and tricyclic antidepressants), sulfonylureas (e.g., chloropropamide), and vinca alkaloids (e.g., vincristine and vinblastine). Other drugs strongly associated with SIADH include thiazide diuretics, clonidine, enalapril, ifosphamide, and methyldopa. In a normal individual, an elevation in plasma vasopressin per se does not induce plasma hypotonicity because the person simply stops drinking owing to an osmotically induced aversion to fluids. Therefore, plasma hypotonicity only occurs when excessive fluid intake (oral or intravenous) accompanies inappropriate secretion of vasopressin. Treatment of hypotonicity in the setting of SIADH includes water restriction, intravenous administration of hypertonic saline, loop diuretics (which interfere with the concentrating ability of the kidneys), and drugs that inhibit the effect of vasopressin to increase water permeability in the collecting ducts. To inhibit vasopressin's action in the collecting ducts, demeclocycline, a tetracycline, is the preferred drug.

Although lithium can inhibit the renal actions of vasopressin, it is effective in only a minority of patients, may induce irreversible renal damage when used chronically, and has a low therapeutic index. Therefore, lithium should be considered for use only in patients with symptomatic SIADH who cannot be controlled by other means or in whom tetracyclines are contraindicated, e.g., patients with liver disease. It is important to stress that the majority of patients with SIADH do not require therapy because plasma Na+ stabilizes in the range of 125-132 mM; such patients usually are asymptomatic. Only when symptomatic hypotonicity ensues, generally when plasma Na+ levels drop below 120 mM, should therapy with demeclocycline be initiated. Since hypotonicity, which causes an influx of water into cells with resulting cerebral swelling, is the cause of symptoms, the goal of therapy is simply to increase plasma osmolality toward normal.

OTHER WATER-RETAINING STATES In patients with congestive heart failure, cirrhosis, or nephrotic syndrome, effective blood volume often is reduced, and hypovolemia frequently is exacerbated by the liberal use of diuretics. Since hypovolemia stimulates vasopressin release, patients may become hyponatremic owing to vasopressin-mediated retention of water. The development of potent orally active V2 receptor antagonists and specific inhibitors of water channels in the collecting duct would provide an effective therapeutic strategy not only in patients with SIADH but also in the much more common setting of hyponatremia in patients with heart failure, cirrhosis, or nephrotic syndrome.

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