Nephrogenic Diabetes Insipidus
|Title:||Nephrogenic Diabetes Insipidus|
|Publisher:||Pediatrics in Review|
|Date Published:||April 01, 1996|
Nephrogenic diabetes insipidus (NDI) is a disorder, either congenital or acquired, in which antidiuretic hormone (ADH) secretion is normal, but the ability to concentrate urine is reduced because of insensitivity of the collecting tubule to ADH. The antidiuretic action of arginine vasopressin requires binding of the hormone to the renal type V2 receptor on the basolateral membrane of the collecting duct principal cell. Binding results in activation of adenylate cyclase, generation of cAMP, and increased reabsorption of water across the apical membrane of the renal collecting duct cell. The defect in NDI may be located at any of the steps from binding of vasopressin to the final effect of the hormone on the luminal membrane.
Congenital NDI is a rare heritable disorder, inherited in a sex-linked dominant pattern with complete expression only in the afflicted male and variable penetrance in the female. To date, at least 2 dozen different mutations of the vasopressin V2 receptor gene have been identified in patients who have congenital NDI. Acquired NDI is much more common, but rarely as severe as the congenital disorder. The most common causes of acquired NDI are listed in the Table.
The primary symptoms of diabetes insipidus are polyuria and polydypsia. With the hereditary disorder, manifestations appear within the first weeks of life. Irritability, constipation, poor feeding, and poor weight gain often are noted. Infants are eager to suck, but may vomit during or shortly after feeding. They cry excessively; if not satisfied with additional milk, they may quiet with water.
Unless the condition is recognized early, children experience frequent bouts of hypertonic dehydration. Hypernatremia and hypertonic volume contraction are associated with potentially severe central nervous system complications related to cerebral cell dehydration. Particularly because dehydration may lead to fever, children who have NDI are often suspected of having an infection. In fact, body temperature can be normalized with rehydration.
Beyond infancy, nocturia and enuresis are frequent complaints. Children may get up five or six times during the night because of intense thirst, and nocturia may be so troublesome as to make sleep almost impossible. Untreated, most patients fail to grow normally. Failure to thrive is assumed to be related to polydypsia, with children taking water in preference to food, resulting in caloric deprivation. In addition, excessive fluid intake induces anorexia and vomiting, which contribute to malnutrition. Recurrent episodes of hypernatremic dehydration may affect cognitive development. Psychological development may be affected by a permanent demand for drinking and the urge for frequent voiding, which compete with playing and learning.
Children who have NDI frequently develop hydronephrosis and dilation of the urinary collecting system, probably from large urine flow and stretched bladders. Because hydronephrosis itself may be a cause rather than a consequence of NDI, obstructive uropathy must be ruled out. The daily volume of urine may be 4 to 10 L. The urine is pale or colorless; the specific gravity varies from 1.001 to 1.005, with a corresponding osmolality of 50 to 200 mOsm/kg water. Plasma vasopressin levels are normal or only slightly increased. Other abnormal laboratory findings are primarily the result of chronic dehydration. Serum sodium concentration usually is above normal, sometimes reaching a value of 170 mmol/L. Serum chloride concentration also is increased.
Because there is no curative treatment for patients who have inherited NDI, it is important to exclude acquired forms of NDI for which specific forms of therapy are available. Polyuria in a dehydrated infant who has a high serum sodium concentration constitutes presumptive evidence of a renal concentrating defect. To confirm the assumption and to distinguish the renal forms of diabetes insipidus from the central form, a short water deprivation test followed by ADH administration should be performed. The purpose of water deprivation is to increase plasma osmolality to a point that usually is associated with sufficient release of ADH from the neurohypophysis to induce a concentrated urine. If after an increase in plasma osmolality of >10 mOsm/L the urine is still dilute, the patient has either central or nephrogenic diabetes insipidus. DDAVP (1-desamino-8-D-arginine vasopressin) then is administered intranasally (10 µg for infants, 20 µg for children). Patients who have NDI do not increase their urine osmolality, which remains below 200 mOsm/kg water, and cannot reduce their urine volume.
Adequate replacement of urinary fluid losses is the most important component of therapy. Infants who have NDI are at increased risk because they do not have free access to fluids. If polyuria is only mild or moderate, oral hydration may be sufficient to maintain adequate water balance.
Thiazide diuretics, such as hydrochlorothiazide (HCTZ), were the first drugs shown to be safe and clinically useful in the management of NDI. HCTZ inhibits sodium-dependent chloride transport in the early distal tubule, leading to slight volume contraction that, in turn, results in increased proximal iso-osmotic fluid absorption and decreased urine volume. Chronic administration of HCTZ may lead to potassium excretion, hypokalemia, and alkalosis. These abnormalities can be corrected by administration of potassium salts.
Prostaglandin-synthetase inhibitors, such as indomethacin, have been used with encouraging results. They reduce urine volume by decreasing glomerular filtration or by increasing medullary solute concentration. Prolonged use of prostaglandin-synthetase inhibitors frequently is complicated by severe side effects related to the gastrointestinal tract (nausea, vomiting, abdominal pain, ulceration), hematopoietic system (neutropenia, thrombocytopenia), and kidneys (acute interstitial nephritis). Thus, although the combination of a prostaglandin-synthetase inhibitor with HCTZ often is effective, long-term treatment requires careful clinical and laboratory monitoring. The combination of the potassium-sparing diuretic amiloride with HCTZ seems to be as effective as the indomethacin-HCTZ regimen in decreasing urine volume and increasing urine osmolality. Combined administration of amiloride and HCTZ results in a more marked sodium excretion than that obtained with either diuretic given as a single agent. Amiloride blunts the potassium loss secondary to prolonged use of thiazides and, thus, prevents hypokalemia. The amiloride-HCTZ regimen appears to have only minor long-term side effects.
Albert Einstein College of Medicine, Yeshiva University, Montefiore Medical Center, Bronx, NY (Corrine Benchimol, MD)
Address correspondence and reprint requests to Pediatrics in Review, American Academy of Pediatrics, 141 Northwest Point Blvd, P.O. Box 927, Elk Grove Village, IL 60009-0927
This translation by the NDI Foundation is to assist the lay reader. To provide a clear, accessible interpretation of the original article, we eliminated or simplified some technical detail and complicated scientific language. We concentrated our translation on those aspects of the article dealing directly with NDI. The NDI Foundation thanks the researchers for their work toward understanding and more effectively treating this disorder.
© Copyright NDI Foundation 2007 (JC)
Congenital NDI is inherited and expresses itself primarily in males. Its symptoms may appear in the first weeks of life and, in addition to excessive thirst and frequent urination, often include constipation, irritability, poor feeding and poor weight gain. Afflicted infants may be eager to suck, only to vomit shortly after or during feeding.
Early recognition of congenital NDI is important, for this disorder could lead to dehydration and excessive amounts of sodium in the blood. These conditions are associated with potentially severe central nervous system complications. If NDI goes untreated, most patients fail to grow normally. This failure is assumed to result from the patient's preference for water over food. This excessive fluid intake induces vomiting and anorexia, which contributes to malnutrition. Children with NDI suffer from excessive thirst, often experience involuntary discharge of urine and excessive need to urinate during the night. Excessive sodium in the blood due to NDI may affect cognitive development. The NDI child's frequent need to urinate and his constant need for fluid intake could interfere with playing and learning and thus impair normal psychological development.
X-linked congenital NDI occurs when something in the kidney called the V2 receptor fails to respond to the antidiuretic hormone (ADH). It is ADH which tells the body to concentrate urine. The V2 receptor fails to respond to ADH because of a mutation in its genetic structure. As a result, the kidneys do not respond to ADH's request to process some water for the body's needs and, instead constantly routes most water out of the body as urine. To date, at least 24 different types of mutation of the V2 receptor gene have been identified in patients with congenital NDI.