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Oski's Pediatrics: Principles and Practice, 3rd Edition (June 1999): By Julia A. McMillan (Editor), Catherine D.

Deangelis (Editor), Ralph D. Feigin (Editor), Joesph B. Warshaw (Editor), Frank A. Oski (Editor), Joseph B. Warshaw By Lippincott Williams & Wilkins Publishers CHAPTER 339: NEPHROGENIC DIABETES INSIPIDUS Oski’s Pediatrics: Principles and Practice CHAPTER 339 NEPHROGENIC DIABETES INSIPIDUS L. Leighton Hill and Arundhati S. Kale Nephrogenic diabetes insipidus (NDI) is a hereditary or acquired disorder characterized by renal tubular resistance to the antidiuretic hormone arginine vasopressin (AVP). The inability to concentrate the urine because of this tubular disease leads to marked polyuria with compensatory polydipsia. Two different hereditary forms of NDI exist: X-linked and autosomal recessive. A majority (more than 90%) of congenital NDI cases are caused by mutations of the AVP receptor 2 gene (AVPR2) and occur predominantly in males, consistent with an X-linked inheritance. A minority of cases are caused by mutations of the aquaporin 2 gene (AQP2) that show an autosomal recessive hereditary pattern. The AVPR2 gene is located in chromosome region Xq28 and the AQP2 gene in chromosome region 12q13. In the X-linked cases, females usually show a limited tubular response to vasopressin. Even in males, variations in the degree of severity of the defect occur; most males are diagnosed in early infancy because of a severe defect, but some have a mild enough disease to escape detection until the second or third decade of life. The defect in hereditary NDI, at least in males with the severe defect, usually is more severe than that seen in the acquired type, which have two general causes. The first is the loss of the concentration gradient in the medullary interstitial tissues as a result of the tissue destruction occurring with obstructive uropathy, vesicoureteral reflux, sickle cell nephropathy, cystic disease, pyelonephritis, interstitial nephritis, or nephrocalcinosis. The second cause is decreased responsiveness to AVP of the distal tubules and collecting ducts, although the concentration gradient in the medullary interstitial tissues remains intact. Conditions that cause this alteration include hypokalemic states, hypercalcemia, amyloidosis, sarcoidosis, and various drugs that interfere with the action of AVP, such as lithium, demeclocycline hydrochloride, cisplatin, vinblastine sulfate, methoxyflurane, amphotericin B, and colchicine. NDI associated with this second group of conditions more closely resembles hereditary NDI than does NDI associated with the first group. NDI also can be seen as part of Fanconi syndrome, most likely because of the chronic hypokalemia that often occurs. PATHOPHYSIOLOGY AVP is thought to act on at least two different types of receptors. The V1 (platelet/vascular/hepatic) receptor is cyclase independent and is linked to the hydrolysis of phosphatidylinositol. The V2 or renal receptor is linked to adenylate cyclase and is phosphatidylinositol independent. In normal individuals, the antidiuretic action of AVP is mediated by a sequence of steps that begins with AVP binding to its cell surface receptor AVP2; this leads to a cascade of events, including activation of adenylate cyclase and production of cyclic adenosine monophosphate (cAMP). The final step in the pathway is an increase in specific water channels (AQP2) on the luminal surface that facilitate water transport. Normal levels of AVP are found in patients with NDI as measured by radioimmunoassay. Extrarenal vasopressin V2-like receptors also exist that mediate vasodilation, increase plasma renin activity, and stimulate the release of factor VIIIc and von Willebrand factor. In NDI, V1 receptor responses appear to remain intact, but renal V2 receptor responses are abnormal, with no antidiuretic response to the administration of either AVP or the V2-specific agonist desmopressin acetate (DDAVP) and no increase in plasma cAMP concentration. In hereditary NDI, the V2 abnormality may be generalized (renal and extrarenal) or may be limited to the kidney. The two forms of hereditary NDI can be distinguished by clinical testing. DDAVP elicits extrarenal (coagulation and vasodilatory) responses in patients with autosomal recessive NDI, but not in patients with X-linked NDI.

BUN. and the vomiting. chloride. With rehydration. The most important test is a well-controlled water deprivation or concentration test performed in the hospital during the day under close medical supervision (Table 339-2). and although the urine remains dilute. the serum sodium level often is elevated early in the morning because of insufficient fluid intake during the night but may return to normal during the day with adequate fluid intake. If the polyuria continues and the urine is not concentrated despite a 4% to 5% body weight loss or the completion of the whole time course of the water deprivation test. DIAGNOSIS The diagnosis of NDI is suspected when polyuria.e. bouts of dehydration. Elevated body temperature. diabetes mellitus. hypernatremia. Marked dilatation of the urinary tract also may be seen in patients not identified as having NDI until later in childhood. When the patient is in water balance. When a child with NDI is well hydrated. Small amounts of protein and a few red blood cells may be found in the urine. A urine-to-plasma osmolality ratio of 2. a dramatic reversal in the condition is seen: the signs and symptoms of dehydration disappear. The differential diagnosis includes other causes of polyuria such as central (AVP-deficient) diabetes insipidus. specific gravity less than 1. Patients with chronic renal insufficiency have azotemia even when hydrated. The urinalysis usually is normal. The large fluid ingestion may interfere with attaining adequate caloric intake. The chief differential often is between central diabetes insipidus and NDI (vasopressin-resistant). but it may be found to be massive later if control of water balance is not good.CLINICAL FEATURES The most common clinical manifestations of NDI are shown in Table 339-1. and generally have a much milder degree of polyuria than do patients with diabetes insipidus. leads to failure to thrive. TABLE 339-2. The constant need for intake of liquids interferes with normal sleep patterns. and creatinine levels return to normal. Water deprivation test . In the infant with NDI.006 and urine osmolality less than 200 mOsm/kg) despite evidence of dehydration. often leads to multiple investigations that attempt to identify possible bacterial. viral. usually demonstrate isosthenuria rather than hyposthenuria. Chronic severe constipation is another result of the constant tendency toward negative water balance that characterizes NDI. the sodium. Clinical manifestations of nephrogenic diabetes insipidus LABORATORY FINDINGS Hypernatremia and hyperchloremia commonly are seen when the patient has been in negative water balance. or parasitic infections. and a positive family history are noted. irritability. Patients with primary polydipsia have normal to low-normal serum sodium concentrations.. and other manifestations disappear until dehydration recurs. along with the deleterious effects of the chronic hypernatremia. Assessment and documentation of the magnitude of the polyuria and polydipsia by measuring intakes and outputs are essential. polydipsia. a consequence of the dehydration. TABLE 339-1. except that the urine is inappropriately dilute (i. and the blood urea nitrogen (BUN) may be elevated during dehydration. the glomerular filtration rate and all other renal function tests are normal. The patient should not be allowed to lose more than 5% of body weight before the study is terminated. psychogenic water drinking. aside from the inability to conserve water. even during periods of dehydration. this inadequate caloric intake. Careful weighings are essential. Patients with diabetes mellitus have elevated blood and urine sugars and seldom have hypernatremia. This condition usually is minimal at the time of diagnosis in very young infants.0 or more is sufficient to rule out both NDI and central diabetes insipidus. the protein and red blood cells disappear. then these two diagnoses remain strong possibilities. Polyuria is constant. and chronic renal insufficiency. the fever abates. dilute urines. Ultrasound examination may reveal marked dilatation of the urinary tract in NDI because of extremely high water turnover. as are periodic observations of vital signs and urine and serum osmolalities and sodium levels.

If no response (decrease in volume of urine and increase in osmolality of the urine) occurs. a synthetic analogue of 8-arginine vasopressin. The intake of volumes of this magnitude may be very difficult to achieve purely from a mechanical point of view. The DDAVP should be given intranasally at a dosage of 10 µg in infants and 20 µg in older children. The obligatory urine volume is determined by dividing the total solute load for excretion by the maximum ability to concentrate.5 L. lowsodium diet. Early identification of newborns with the disease allows prevention of dehydration episodes.5 or greater would indicate an adequate tubular response to antidiuretic substances. the person with no disease would have an obligatory renal water requirement of 0. a diet yielding approximately 600 mOsm of solute for renal excretion per day). whether the defect is hereditary or acquired must be determined. If the patient fails to concentrate the urine with the water deprivation test and also after DDAVP or aqueous vasopressin stimulation. with an obligatory renal water excretion of 6 L/ 2-hour intervals after administration. An alternative test is to give aqueous vasopressin USP (Pitressin) at a dosage of 2 U/m2 body surface area intravenously over a 1-hour period in 20 mL of isotonic saline. The same diet is assumed for each of these three conditions (i.e. Urines should be measured for volume and for concentration (specific gravity and osmolality) at 1. This high free water intake should be spaced fairly evenly over the 24-hour period. and bouts of dehydration in infancy strongly suggest that the defect is hereditary. If the patient fails to concentrate with the water deprivation test but does respond to DDAVP or aqueous vasopressin stimulation by decreasing urine volume to less than 20 mL/m2/hour and by raising the urine-to-plasma osmolality ratio to at least 1. In older children. and the patient with NDI would have severe polyuria. the patient with chronic renal insufficiency would have a mild polyuria. Two disease states. and 1 hour and 2 hours after the infusion for measurement of volume. These studies should be sufficient to rule in or rule out the causes of secondary or acquired NDI mentioned above. and serum calcium levels. and possibly cystography.200 mOsm/L of urine water. Serum sodium level and osmolality should be tested before and 4 hours after the administration of the DDAVP. low-electrolyte commercial formula suffices. Onset at an early age.The next step in the diagnostic process is to test the renal tubular response to antidiuretic substances. In the infant. specific gravity. then a diagnosis of NDI is indicated. Fluid intake as high as 300 to 400 mL/kg/day may be required just to maintain water balance. then a second dose should be given and additional urine samples collected and tested for volume and concentration. As can be seen in this theoretic example. A diet that results in a low renal solute load is of major importance in reducing the obligatory renal water requirement.5. a family history of polyuria. With either of these stimulation tests (DDAVP or aqueous vasopressin). The importance of a low renal solute load in determining the volume of obligatory urine water is shown in Table 339-3. and hydrochlorothiazide therapy may ensure normal physical and mental development. with an obligatory water excretion of 2 L/day. the daily protein intake should be approximately 2 g/kg and the total daily sodium content should be in the range of 1 to 2 g. a low-protein. The infant is allowed to take in fluid during this test. BUN. a urine-to-plasma osmolality ratio of 1. Once a diagnosis of NDI is made. and early treatment with unrestricted water intake. at the conclusion of the infusion. ultrasound studies of the kidneys and urinary tract. then a diagnosis of central (AVP-deficient) diabetes insipidus is indicated. If the diet of the patient with NDI were reduced in protein and sodium chloride content so that the renal solute load was decreased to 300 . breast milk is preferable. but if it is unavailable. The workup also should include a thorough drug exposure history. creatinine. Gene analysis can be performed in newborns with a strong family history of NDI and also in all patients with a definitive diagnosis of NDI. water should be ingested even at night to prevent early-morning dehydration and hypernatremia. equaling one-half or more of the patient's total body water each day. chronic renal insufficiency and NDI. Urines should be obtained during the aqueous vasopressin infusion. The testing substance of choice is desmopressin acetate (DDAVP). and the daily sodium intake should not exceed 1 mEq/kg of body weight. Roughly 6% of the total calories should come from protein. The normal child should be able to concentrate up to 1. and the patient with NDI can concentrate in the vicinity of 100 mOsm/L. and osmolality.. are compared with the normal state. Such a diet is reasonably low in protein and sodium chloride. the patient with chronic renal failure can usually concentrate up to approximately 300 mOsm/L. TREATMENT The daily water turnover of infants and children with NDI can be enormous. measurement of serum electrolyte.

Therefore. Aochberg Z. Experimental transfer of adenovirusmediated genes either by direct perfusion into the renal artery or by retrograde infusion into the renal pelvis in rats resulted in expression of the gene in renal tissue. Williams RH. Bichet DG. N Engl J Med 1988. The thiazide diuretics increase sodium excretion. J Am Soc Nephrol 1997. Oksche A. .318:881. Kidney Int 1991. Brennan B. The thiazide diuretics can be used to further diminish the polyuria. Acta Pediatr Scand 1981. As a result. gene therapy is being investigated. Prostaglandin synthetase inhibitors in the treatment of nephrogenic diabetes insipidus.g. Lonergan M. The thiazide may decrease urine volume by as much as 20% to 40%. these patients benefit from the provision of extra free water and a diet that yields a low renal solute load.70:39. This result shows the promise of gene transfer therapy as a treatment modality in the future. these drugs are valuable in the very young infant who has a great physical problem in taking in the volume of free water required to stay in water balance. Platelet vasopressin receptors in patients with congenital nephrogenic diabetes insipidus. which is almost inevitable at the high water turnover rates these patients experience when untreated. The decrease in urine volume also prevents or lessens dilatation of the urinary tract. Congenital nephrogenic diabetes insipidus. Ann Intern Med 1947. increased proximal tubular reabsorption of salt and water occurs. a dramatic decrease. many of the principles outlined for the therapy of hereditary NDI also apply to treatment of patients with the acquired variety. The effects of prostaglandins on renal function are quite complex and appear to vary with the particular prostaglandin involved and the particular situation under which it is tested. In particular. Nephrogenic diabetes insipidus transmitted by females and appearing during infancy in males.12:1951. however. sodium restriction to the level previously recommended is vital. With a slower flow rate through the collecting ducts. However. et al. Arthus MF. prostaglandin synthetase inhibitors usually inhibit water excretion. Because the effect of the thiazide is almost completely nullified by a high sodium intake. Obviously. and delivery of water to the concentrating sites in the kidney is less.39:693. Lonergan M. some water diffuses from the collecting duct lumen to the medullary interstitial tissues despite the lack of effect of AVP. J Clin Endocrinol Metab 1988. TABLE 339-3. In general. Henry C. Rosenthal W. Water turnover related to inability to concentrate urine Selected Readings Bichet DG. Seligsohn U. With the identification of specific genes involved in hereditary NDI. Bichet DG. thereby producing a borderline low blood volume. The other agents that appear to be helpful in the management of NDI are prostaglandin synthetase inhibitors (e. Monn E. Hemodynamic and coagulation responses to 1-desamino-8-d-arginine vasopressin in a patient with congenital nephrogenic diabetes insipidus.27:84. Razi M. treatment of the acquired types of NDI varies depending on the therapy necessary to address the underlying disease causing the secondary tubular defect.mOsm/day. the obligatory renal water excretion would be only 3 L/day instead of 6 L/day. indomethacin). Normal response of factor VIII and von Willebrand factor to 1desamino-8-d-arginine vasopressin in nephrogenic diabetes insipidus.67:191..

potassium depletion. which. Urine osmolality will remain lower than 450 mOsm/kg. Serum sodium levels should be evaluated at intervals to avoid hyperosmolality from inadvertent water restriction. and failure to thrive. Pediatrics 1999. hypercalcemia. Cogdell DE: Clinical utility of direct mutation testing for congenital nephrogenic diabetes insipidus in families. the diagnosis can be made on the basis of a history of polydipsia and polyuria that are not sensitive to the administration of vasopressin. pyelonephritis. Carefully monitored water restriction does not increase the tubular reabsorption of water (TcH2 O) to above 3 mL/min/m2. it is usually best to allow water as demanded and to restrict salt. In some children. and many patients show improvement with administration of prostaglandin inhibitors such as indomethacin or tolmetin. vasopressin should be administered. aquaporin-2. Wilden RS.5 mEq/kg/24 h. sodium intake should continue to be restricted to 2–2. . adjustment to an elevated serum osmolality may develop. It is wise to confirm this diagnosis by performing a vasopressin test. the interstitial fluid of the papilla is hyperosmolar to the fluid in the collecting duct. Genetic counseling and mutation testing are available. et al By McGraw-Hill Education Europe 2002 Chapter 22 . cystinosis and other renal tubular disorders and obstructive uropathy—and as a result of nephrotoxic drugs. The congenital Xlinked recessive form of nephrogenic diabetes insipidus results from mutations in the vasopressin receptor. desmopressin acetate. and convulsions. Treatment with hydrochlorothiazide is helpful. Hay Jr. AVPR2. acting via cAMP. These children are particularly susceptible to episodes of dehydration. The symptoms are limited to polyuria. In later childhood. whereas serum osmolality rises and total body weight falls. permits water to move across the cell membrane in response to the osmotic gradient. Before weight reduction greater than 5% occurs or before serum osmolality exceeds 320 mOsm/kg. In infants. Clinically. The luminal cells have a specific receptor for antidiuretic hormone (ADH).Kidney & Urinary Tract NEPHROGENIC DIABETES INSIPIDUS In the normal kidney. Autosomal (recessive and dominant) forms of nephrogenic diabetes insipidus are caused by mutations of the AQP2 gene that codes for a water channel protein.103:632. vomiting. Urine concentrating ability is impaired in a number of conditions—sickle cell anemia.Current Pediatric Diagnosis & Treatment 16th Ed: William W. or lypressin. fever. particularly if the solute intake is unrestricted. polydipsia.

 Inability to concentrate urine after fluid restriction. In these conditions. which results if significant damage to the vasopressin neurons has occurred. children with unexplained diabetes insipidus should have regularly repeated MRI scans. . The affected child typically has nocturia or enuresis and cannot go through the night without drinking water.  Subnormal plasma AVP concentration.010. Familial diabetes insipidus may have a more insidious onset and a slowly progressive course. and the DIDMOAD syndrome (diabetes insipidus. packaging. and the infant may present with severe dehydration. in which transient diabetes insipidus occurs initially secondary to edema in the hypothalamic-pituitary area. In this situation. This is in contrast to germinomas in which diabetes insipidus is often the presenting symptom.  Hyperosmolality of plasma. constipation. Accidental or surgical trauma to the axons of the vasopressin-containing neurons can lead to transient or permanent diabetes insipidus. consequently. It is especially difficult to recognize polyuria and polydipsia in a young infant on an ordinary feeding regimen.  Urine specific gravity (< 1. Genetic causes of vasopressin deficiency are rare and include inherited mutations in the vasopressin structural gene. symptoms may also include failure to thrive. Midline brain abnormalities such as septo-optic dysplasia and holoprosencephaly may also be associated with central diabetes insipidus. circulatory collapse. Dehydration may occur if fluid intake is not sufficient to keep up with urine losses or if there is concomitant damage to the normal thirst mechanism. Treating these patients with glucocorticoids may unmask underlying polyuria and polydipsia. a result of vasopressin deficiency. and unexplained fevers. as well as germinomas. optic atrophy. Hypothalamic tumors and infiltrative diseases occur in a significant number of children who present with diabetes insipidus.Chapeter 30 – Endocrine Disorders CENTRAL DIABETES INSIPIDUS Essentials Of Diagnosis And Typical Features  Polydipsia and polyuria (> 2 L/m2/day). defects in the neurophysin protein. In infants. Clinical Findings The onset of diabetes insipidus is often abrupt with polyuria and intense thirst. is caused by defects in hypothalamic vasopressin synthesis. General Considerations Central diabetes insipidus. osmolality < 300 mOsm/kg). Germinomas may be undetectable by magnetic resonance imaging (MRI) for several years. which is due to unregulated release of vasopressin from the dying neurons.  Responsiveness to AVP administration. or transport along the neurohypophyseal tract to the posterior pituitary gland. MRI scans characteristically show thickening or a mass within the infundibular stalk. vomiting. The third phase is permanent diabetes insipidus. and convulsions. and deafness). Symptoms and signs of AVP deficiency may be absent in patients with panhypopituitarism due to the impaired excretion of free water that may accompany adrenal insufficiency. a triphasic pattern often results. Cold water is typically the preferred fluid. diabetes insipidus usually develops only after surgical intervention. Infiltrative diseases such as histiocytosis and lymphocytic hypophysitis are other causes of diabetes insipidus in children. diabetes mellitus. This is followed in 2–5 days by SIADH. In patients with craniopharyngiomas.

A blood sample should be obtained within a few minutes of the urine collection and analyzed for osmolality. After 7 hours of fluid deprivation. J Clin Endocrinol Metab 1999. a serum osmolality of greater than 290 mOsm/kg associated with excretion of dilute urine (osmolality < 300 mOsm/kg) is suggestive of diabetes insipidus. Leger J et al: Thickened pituitary stalk on magnetic resonance imaging in children with central diabetes insipidus. a first morning void is obtained to determine urine osmolality. An absent posterior bright spot on MRI also correlates with AVP deficiency. infants are often given extra free water. OTHER THERAPY Specific therapy is directed toward treatment of specific causative diseases when they are identified. When the diagnosis of central diabetes insipidus is made. After withholding fluids from midnight on. Chlorothiazides. the risk of water overload with DDAVP therapy is great. a formal water deprivation test performed in the hospital is indicated. sodium. Measurement of serum AVP concentration at the end of the test and the administration of parenteral AVP may help to distinguish between central neurogenic and nephrogenic forms of diabetes insipidus.Diagnosis The diagnosis of diabetes insipidus is confirmed when hypotonic urine accompanies hypertonic serum. Response to vasopressin or desmopressin indicates central rather than nephrogenic diabetes insipidus. consequently. histiocytosis. rather than DDAVP. Children with primary polydipsia will produce appropriately concentrated urine. as prescribed for nephrogenic diabetes insipidus. creatinine. If screening results are unclear or if symptoms preclude safely withholding fluids at home. with various forms of hypercalcemia (including hypervitaminosis D). may also be helpful in the infant with central diabetes insipidus. In children with symptoms of increased thirst and urination. Decreased ability to concentrate urine may also occur with hypokalemia (eg. Treatment A. primary polydipsia must be distinguished from true diabetes insipidus. potassium. and a standard urinalysis. 79:84. and calcium. Treatment of diabetes insipidus in infants is more difficult because formula and breast milk have a large amount of free water. Radiation therapy.84:1954. and with renal tubular abnormalities (eg. Cheetham T: Diabetes insipidus. an MRI scan with contrast should be obtained to evaluate for tumors or infiltrative processes. sodium. Arch Dis Child 1998. If the history reveals that the child can go through the night comfortably without drinking. B. The aim of therapy is to provide the child with antidiuresis and uninterrupted sleep during the night and allow for approximately one hour of diuresis before the next DDAVP dose. or surgery may be indicated for germinomas. to maintain normal hydration. hyperaldosteronism). and craniopharyngiomas. chemotherapy. Baylis PH. screening tests can be obtained as an outpatient. . MEDICAL TREATMENT The treatment of choice for partial and total diabetes insipidus is desmopressin acetate (DDAVP) administered orally or intranasally. Fanconi syndrome). For this reason.

The collecting duct concentrates urine by reabsorbing water. In contrast to diabetes mellitus (DM). Merrily P M Poth. or surgical ablation results in decreased vasopressin secretion and central diabetes insipidus (CDI). MD. locus Xq28) or defective or absent aquaporin. thirst. on a ship named Hopewell.emedicine. DI may be idiopathic or inherited either as an autosomal dominant or as an autosomal recessive trait (locus 20p13). Secretion of vasopressin occurs in the posterior pituitary gland and is regulated at the paraventricular and supraoptic nuclei. American Society of Pediatric Nephrology. MACE. American Association of University Professors. Department of Pediatrics. . Society for Experimental Biology and a function controlled by the posterior pituitary gland via secretion of vasopressin or antidiuretic hormone (ADH). Uniformed Services University of the Health Sciences. NDI arises from defective or absent receptor sites at the cortical collecting duct segment of the nephron (X-linked. Department of Pediatrics. Professor of Clinical Pediatrics. According to legend. The X-linked variety of NDI accounts for about 90% of all such cases. dehydration. increased urine output resulting in hypernatremia. Mary L Windle. pressure. Director of Pediatric Endocrinology. and George P Chrousos. 2006 Synonyms and related keywords: diabetes insipidus. The renal tubular collecting ducts are unable to concentrate urine secondary to vasopressin deficiency or resistance. amino acids. MD. Adjunct Assistant Professor. Consulting Staff. Creighton University School of Medicine James CM Chan. American Chemical Society. Department of Pediatrics and Neuroscience.htm Last Updated: July 26. The gypsy woman curses the housewife. Southern Society for Pediatric Research. MD. and virtually all electrolytes is completed by the time the urine has reached this segment of the nephron. Athens University Medical School INTRODUCTION Background: The word diabetes is derived from the Greek verb diabainein. Department of Pediatrics. Polydipsia follows as the thirst mechanism urges replenishment of body water. MD. University of Nebraska Medical Center College of Pharmacy. American Academy of Pediatrics. central diabetes insipidus. the inability to conserve water by reabsorption in the collecting duct depletes body water. Nephrogenic DI (NDI) reached North America in 1761. Scottish folklore reports the existence of the disease in Scotland before 1761. a gypsy woman traveling with her thirsty son is denied water by a housewife. American Society of Nephrology. the protein that transports water at the collecting duct (autosomal recessive. PhD. Department of Pediatrics. Pharmacy Editor. as in urination. or to go through. Department of Pediatrics. Pathophysiology: The basis of water loss in DI is distinct from water loss caused by DM. eMedicine. Inc. New York Academy of Sciences. nephrogenic diabetes insipidus. American Medical Association. Stephen Kemp. FAAP. DI. is a member of the following medical societies: Alpha Omega Alpha. causing the housewife's sons to crave water while condemning her daughters to pass the curse on to future generations. MD. University of Arkansas and Arkansas Children's Hospital. which describes the excretion of sweet urine. Canada. Insipidus comes from a Latin word meaning without taste. State University of New York at Stony Brook. MACP. American Heart Association. American Society for Bone and Mineral Research. Division of Pediatric Endocrinology. American Association for the Advancement of Science. and Western Society for Pediatric Research Editor(s): Thomas A Wilson. polydipsia. Professor. but leaves sodium unaffected. vasopressin V2 receptor deficiency. locus 12q13). Chair. Department of Pediatrics.Diabetes Insipidus http://www. PharmD. which means to stand with legs apart. MD. Professor. Consequently. Maine Medical Center Coauthor(s): Karl S Roth. Alternatively. Professor and Chair. International Society of Nephrology. diabetes insipidus (DI) describes the passing of tasteless urine because of its relatively low sodium content. The net result is an extremely diluted. carried by Ulster Scots who arrived in Nova Scotia. Section of Pediatric Endocrinology. which sense changes in osmolality. Professor. CDI. Destruction of the paraventricular or supraoptic nuclei or of the posterior pituitary by tumor. hypernatremia. Reabsorption of sugars. American Physiological Society. NDI Author: James CM Chan.

and neurosurgical procedures are the most common causes of CDI. vasopressin is transported in the blood to receptor sites on the basolateral surface of the collecting duct membrane. • . or luminal. Mortality/Morbidity: • Dehydration results from an inability to reabsorb free water at a site distal to electrolyte reabsorption. activation of the vasopressin receptor increases cyclic adenosine monophosphate (AMP) production and stimulates protein kinase A. Seizures are a consequence of the electrolyte abnormalities introduced in the central nervous system (CNS) by severe hypernatremia and hyperosmolar dehydration. In the presence of vasopressin stimulus.) The male-to-female ratio is 60:40. Absence of the vasopressin receptor does not allow this process to take place. which produces hyperosmolar dehydration. Children who present with autosomal dominant CDI are often older than 1 year. often in neonates younger than 1 week. malformations. and autosomal recessive forms) develop in early infancy. The mutation for males is 4 cases per million population. Mental retardation results from the damage to the CNS caused by severe hyperosmolarity. the ducts do not respond appropriately to vasopressin. defective or absent aquaporin impairs the process in the presence of normal V2 receptors. Children who present with autosomal recessive CDI are generally younger than 1 year. Of the genetic etiologies. be evenly distributed between the sexes.As a consequence of one of these defects. the overall incidence in the general population is estimated to be 3 cases per 100. Diminished blood volume increases blood viscosity and the risk of sludging and thrombosis. • • Age: • • DI occurs in people of a wide age range. Normally. Any patient unable to continuously replace water loss is vulnerable to dehydration. seizures.000 population (0. Frequency: • In the US: Tumors. autosomal dominant. surface of the tubule cell occurs. exocytic insertion of aquaporin into the apical. infiltrative lesions. although it exceeds the recessive variety by a ratio of 9:1. Autosomal dominant and autosomal recessive forms of NDI affect both sexes equally. Through a G protein–adenylate cyclase coupling. and potential hypoxia. leading to increased recycling of the protein aquaporin in the plasma membrane. leading to hypernatremia. Failure to thrive occurs because of the patient's constant thirst conferring a sense of fullness that offsets the sense of hunger. X-linked NDI is very rare.003%. Autosomal dominant and autosomal recessive CDI occur equally in both sexes. therefore. NDI forms (including X-linked. especially in warm weather when insensible water loss through perspiration and respiration substantially increases risk. Death can occur from a hypovolemic shock or a hypernatremic seizure. NDI caused by an X-linked mutation affects males only. The affected individual eats less than necessary for normal growth. all of which are thought to account for the frequent occurrence of mental retardation. • • • • Sex: • CDI secondary to hypothalamic-pituitary lesions occurs at random and should. causing inhibition of water uptake and polyuria. hyperchloremia. Alternatively. Electrolyte abnormalities are caused by the loss of urinary free water. Aquaporin enhances water entry into the cell from the lumen. and prerenal azotemia.

NDI with an autosomal dominant or recessive pattern is due to mutations in the gene designated AQP2. along with detectable signs of dehydration (eg. X-linked NDI occurs from mutations in the antidiuretic arginine vasopressin V2 receptor (AVPR2) gene. In severely dehydrated patients. skin turgor is not diminished in individuals with hypernatremic dehydration despite significant dehydration. Mobile fecaliths may be palpable in the abdomen. decreased tearing. constipation. The earliest signs of diabetes insipidus (DI) include a vigorous suck with vomiting. sometimes. poor feeding. optic atrophy. irritability). irritability is generally due to a borderline state of dehydration coupled with hypernatremia and. • • • • Physical: • The typical examination shows an irritable infant with a dripping wet diaper. Often. In older infants and young children. fever. failure to thrive. tachycardia).CLINICAL History: • Diagnosis may be difficult in infants and children because of nonspecific presenting features (eg. diminished skin turgor. and mental retardation (Wolfram syndrome) may be inherited in an autosomal recessive pattern (locus 4p16) or may be due to mitochondrial deletions. At all ages. dry mucous membranes. • • Causes: DI is due either to (1) deficiency of vasopressin secretion by the pituitary gland (CDI or neurogenic DI) or to (2) renal tubular unresponsiveness to vasopressin (NDI). mapped to locus 20p13. and excessively wet diapers from urination. • Genetic causes o CDI with an autosomal dominant pattern inheritance is due to a mutation in the prepro-arginine vasopressin (prepro-AVP2) gene. CDI tends to develop suddenly. Hypotension may be present because of hypovolemic shock. o o o . Nocturia is common and expected because of increased urine production. mapped to Xq28. Therefore. destructive lesions of the pituitary and/or hypothalamus are the most common cause of DI. and neurosurgical procedures. this gene directs water channel formation in the distal membrane and has not yet been mapped. fever without apparent cause. tumor. CDI with diabetes mellitus. a high index of suspicion is necessary. • Nongenetic causes o o Typical injuries include head trauma. the pulse may be thready and rapid.

terminate the test and obtain appropriate urine and blood specimens for osmolality. • • o o • An accurate 24-hour urine collection is important. and the number of osmoles excreted per day is small. Limit water deprivation to 4 hours for infants and 7 hours for children. Monitor urine specific gravity hourly. while the serum osmolarity is greater than 300 mOsm/kg. obtain urine and blood for osmolality. A normal response should be observed in CDI and psychogenic DI but not in NDI.014 or greater. The normal response to dehydration or desmopressin acetate (DDAVP) includes urine osmolality greater than 450 mOsm/kg. if the specific gravity is 1. The total urine output is high. Dilute urine with a relatively high serum sodium and osmolarity effectively establishes the diagnosis.DIFFERENTIALS Head_Trauma Medullary_Cystic_Disease Sickle Cell Anemia Other Problems to be Considered: Histiocytosis X Hypercalcemic nephropathy Hypokalemic nephropathy Interstitial nephritis Posterior fossa tumor Neurosurgical ablation of neurohypophysis Psychogenic polydipsia Water intoxication (excessive consumption) WORKUP Lab Studies: • The urine specific gravity of the first morning urine is helpful in assessing renal ability to concentrate urine. Deprive the patient of water after breakfast until significant dehydration occurs. finding a distinction between normal and pathological inability to concentrate the urine may be difficult because infants generally exhibit a constitutional hyposthenuria. and an increase in urine/serum osmolality from baseline of 1. Weigh the patient every 2 hours and limit dehydration to 2-5% loss of body weight.0 or more. The water deprivation test is performed as follows: o Collect baseline urine and blood for osmolality and electrolytes. administer intranasal desmopressin (see Medication) and replace urine output with fluids. The definitive diagnostic study is the water deprivation test.5. The serum sodium may be as high as 170 mEq/L. urine/serum osmolality greater than or equal to 1. . If polyuria persists. Patients with prerenal azotemia present with severe dehydration. In young infants. which can be used both to confirm the diagnosis and to distinguish between central diabetes insipidus (CDI) and NDI by response to a vasopressin analogue. After 4 hours (2 h in infants).

hypoplasia. TREATMENT Medical Care: • Treat patients in an inpatient setting because of the risk of severe dehydration. and destruction secondary to mass lesions. Heat exposure should be minimized. Imaging Studies: • Cranial MRI can be used to exclude pituitary cysts.• Serum potassium and calcium concentrations are important to exclude the possibility of polyuria secondary to hypokalemia or hypercalcemia. Protein should comprise 6% of caloric intake. Sodium intake must be maintained at 0. MEDICATION For central diabetes insipidus (CDI). Other useful medications include chlorpropamide and thiazide diuretics. Provide young children 8% of their caloric intake as protein to enable normal growth. and oral dosage forms. Consultations: • • Nephrologist Endocrinologist: The presence of central diabetes insipidus should prompt an evaluation of anterior pituitary function.7 mEq/kg/d. so take care to calculate the dose correctly. • Surgical Care: Demonstration of an intracranial mass necessitates surgical care.7 mEq/kg/d. Often. • Activity: • Activities resulting in increased insensible water loss should be moderated in the presence of massive urinary water loss to prevent dehydration. the treatment of choice is desmopressin (a synthetic vasopressin analogue). Distinguishing between central and nephrogenic etiology is essential to the treatment modality. It is available in parenteral. • . both of which interfere with renal concentrating mechanisms. Destructive or compressive intracranial lesions mandate inpatient stay. intranasal. Diagnostic radiologist • Diet: • Provide affected infants a breast milk diet to decrease solute load. The latter 2 can result in a 25-75% reduction in urine volume and can be used in combination with each other. The doses are quite different depending upon the preparation used. especially when participating in sports. and sodium should be reduced to 0. the bright spot that is thought to represent vasopressin-secreting neurons in the posterior pituitary is absent in CDI.

NDI cannot be treated effectively with desmopressin because the receptor sites are defective and the kidney is prevented from responding. Use only the aqueous preparation. ADH) may be used to diagnose NDI. demeclocycline. nasal (100 mcg/mL rhinal tube). dilute in 0. Dosage must be individualized. As an aqueous preparation. hyponatremia may occur from overdose.1-0.Usually safe but benefits must outweigh the risks. Thiazide diuretics. use of a synthetic vasopressin analogue (ie. which has a short half-life. and indomethacin or aspirin are useful when coupled with a low-solute diet. tricyclic antidepressants. every patient must be individually evaluated for optimal dose Vasopressin (Pitressin) -. increased biological activity reported with chlorpropamide.A synthetic analogue (1-[3mercaptopropionic acid]-8-D-arginine vasopressin monoacetate trihydrate) of pituitary ADH.and 0. heparin. chronic renal disease with nitrogen retention Decreased biological activity reported with lithium.2mg tab) preparations.3 mL/d (5-30 mcg/d) intranasally qd or divided bid/tid >4 years: 0. Vasopressin tannate in oil.5 mL/d (0. coronary. Consequently. amiloride. Use carefully and monitor serum sodium and body weight because of the danger of overdose and consequent water intoxication.5 mU (0. This permits its safe use in distinguishing CDI from NDI by obviating prolonged fluid accumulation in the former.1. not to exceed 60 U/d IV: Administer as in adults IM/SC: 2.2 mg/d PO divided bid/tid 0.2 mg/d PO divided bid/tid Documented hypersensitivity.5-10 U IM/SC bid/qid prn Documented hypersensitivity. cerebral. portal. Increases water resorption at distal renal tubular epithelium (ADH effect) and promotes smooth muscle contraction throughout vascular bed of renal tubular epithelium (vasopressor effects). Increases cellular permeability of collecting ducts. and PO (0.5-1 mL/d (2-4 mcg/d) IV/SC divided bid 0. not to exceed 10 mU/kg/h 5-10 U IM/SC bid/qid prn. should not be used. epinephrine. platelet-type von Willebrand disease. desmopressin) is required.1-1. or SC. dosage may be doubled q30min prn. which has a longer action.2-2 mcg/d) IV/SQ divided bid 0. It has a very short natural half-life.05-0. Drug is supplied as parenteral (4 mcg/mL).05-0.DI of central origin is due to absence of vasopressin secretion by the pituitary. However vasoconstriction also increased in splanchnic.Has vasopressor and antidiuretic hormone (ADH) activity.0005 unit)/kg/h IV continuous infusion initially. Desmopressin acetate (DDAVP) -. and alcohol. 0. and fludrocortisone Drug Name Adult Dose Pediatric Dose Contraindications Interactions Pregnancy Precautions Drug Name Adult Dose Pediatric Dose Contraindications Interactions . fludrocortisone and chlorpropamide increase effects of desmopressin B . IM. and intrahepatic vessels. carbamazepine. pulmonary.9% NaCl or 5% glucose to 0.05-0. it can be administered parenterally. Drug Category: Pituitary hormones -. clofibrate. 0.1-1 U/mL. resulting in reabsorption of water by kidneys. peripheral. The natural compound vasopressin (ie. water loss due to NDI Coadministration with demeclocycline and lithium decreases effects.4 mL/d (10-40 mcg) intranasally divided bid/tid 0.

the 2 agents are synergistic with respect to antidiuresis. goiter.Usually safe but benefits must outweigh the risks. potassium-sparing. caution in renal disease. cardiac disease.Pregnancy Precautions C . antineoplastics. HydroDIURIL. Hydrochlorothiazide (Esidrix. Microzide) -Thiazide diuretic. lithium. elevated serum potassium levels (>5. 5-10 mg/d PO. Drug Name Adult Dose Pediatric Dose Contraindications Interactions Pregnancy Precautions Drug Name Adult Dose Pediatric Dose Contraindications Interactions Pregnancy . so risk of hypokalemia is decreased in combination with hydrochlorothiazide. antigout agents.5 mg/d >2 years: 2-4 mg/kg/d PO bid/qd.Usually safe but benefits must outweigh the risks. asthma. and nondepolarizing muscle relaxants B . reducing the loss of free water to the collecting system and increasing urine concentration. thus drawing additional water along. lithium generally should not be administered with diuretics because they may reduce renal clearance and add a high risk of lithium toxicity. not to exceed 37. and antihypertensive effects of loop. administration of nonsteroidal antiinflammatory agents can reduce diuretic. Combination of decreased free water delivery to distal tubule and increased sodium chloride reabsorption in proximal tubule underlies the efficacy in DI therapy.Safety for use during pregnancy has not been established.Potassium-sparing diuretic. and sulfonylureas.Thiazide diuretics impair sodium chloride reabsorption in the distal tubule. may induce nausea in children <4 y Documented hypersensitivity. loop diuretics. diazoxide. amphotericin B. calcium salts. evidence of diabetic nephropathy Concomitant therapy with potassium supplementation may increase serum potassium levels so use caution and monitor serum potassium levels frequently if concomitant use of these agents is indicated because of demonstrated hypokalemia. Has a potassium-sparing effect. In addition. gout. diabetes mellitus. migraines. digitalis.73 m2/d PO divided bid/tid. renal disease. renal decompensation Thiazides may decrease effects of anticoagulants. not to exceed 100 mg/d Documented hypersensitivity. Use with care in seizure disorders. natriuretic.5 mEq/L). vascular disease. Monitor urine output and serum electrolytes carefully. anuria. not to exceed 20 mg/d Titrate dose gradually. and thiazide diuretics when used concomitantly. anesthetics. thiazides may increase toxicity of allopurinol. and arteriosclerosis Drug Category: Diuretic agents -. and systemic lupus erythematosus Amiloride (Midamor) -. not to exceed 20 mg/1. observe patient closely to determine if desired effect of diuretic is obtained. hepatic disease. indomethacin and potassium-sparing diuretics.. may be associated with increased serum potassium levels. which causes enhanced reabsorption of isoosmotic sodium chloride from the glomerular filtrate. including amiloride. acute or chronic renal insufficiency. impaired renal function. consider potential effects on potassium kinetics and renal function B . 25-50 mg/d PO <2 years: 2-4 mg/kg/d PO bid/qd. Reduction in urine volume derives from a concomitant action on the proximal tubule. The net result of both processes is a smaller volume and a higher concentration of the urine.

gemfibrozil. cholestyramine. MAOIs. diazoxide. histamine (H2) antagonists. nicotinic acid. may decrease diuretic effects of furosemide and thiazides.These compounds are an alternative therapy to desmopressin and can be used in combination with thiazide diuretics. corticosteroids. chloramphenicol. may increase by 50 mg/d increments q3-5d. azole antifungals. may increase PT when taking anticoagulants (instruct patients to watch for signs of bleeding). betablockers. granulocytopenia. ketoacidosis. increases risk of acute renal failure in patients with preexisting renal disease or compromised renal perfusion.Promotes renal response to ADH. Dosage must be individualized. 150-250 mg/d PO initially. magnesium salts. Available only in tablet form. and sulfonamides may enhance hypoglycemic effects. methyldopa.5 mg/100 mL Drug Category: Nonsteroidal anti-inflammatory agents -. may increase effects of digitalis glycosides C . GI bleeding. rifampin. salicylates. urinary acidifiers. interaction of the receptors with sulfonylurea compounds can produce a physiologic antidiuresis. and sympathomimetics may decrease hypoglycemic effects. not to exceed 150 mg/d Documented hypersensitivity. renal insufficiency Coadministration with aspirin increases risk of inducing serious NSAID-related adverse effects. acute renal insufficiency. and renal papillary necrosis may occur. probenecid.These agents act synergistically with thiazides to diminish urine volume. PO contraceptives. ie. possibly. thiazide diuretics. slowly increase in 50 mg/d increments q3-5d if hypoglycemia does not supervene. may decrease effect of hydralazine. hyponatremia.Usually safe but benefits must outweigh the risks. not to exceed 750 mg/d Not established.Nonsteroidal prostaglandin inhibitor with antipyretic properties. isoniazid. hyperkalemia. Thus. reversible leukopenia may occur (discontinue if persistent leukopenia. sulfinpyrazone. limited data suggests a starting dose of 50 mg/d PO. not to exceed 200 mg/d <2 years: Do not use >2 years: 2 mg/kg/d PO divided bid/qid doses. phenothiazines. and beta-blockers. carefully monitor blood sugar Documented hypersensitivity. not to exceed 150 mg/d.Safety for use during pregnancy has not been established. 25 mg PO bid/tid. interstitial nephritis. type 1 DM Clofibrate. toxicity of NSAIDs. androgens. BUN >30 mg/100 mL or serum creatinine levels >1. Chlorpropamide (Diabinese) -. probenecid may increase concentrations and. Sulfonylurea compounds have the reported property of causing a syndrome identical to inappropriate ADH secretion. ADH secretion is absent. although ADH receptor sites remain present in the kidney. Drug Name Adult Dose Pediatric Dose Contraindications Interactions Pregnancy . Drug Name Adult Dose Pediatric Dose Contraindications Indomethacin (Indocin) -. anticoagulants. may increase risk of methotrexate toxicity. Category D in third trimester of pregnancy. fluconazole. fenfluramine. hydantoins. urinary alkalinizers. phenytoin levels may be increased when administered concurrently B . calcium channel blockers. or thrombocytopenia is present) Interactions Pregnancy Precautions Drug Category: Sulfonylurea compounds -.Precautions Monitor electrolytes and renal function carefully if evidence of renal functional impairment is present. captopril. estrogens. In CDI. although precise mechanism is unknown.

the prognosis is excellent with early recognition and appropriate DDAVP therapy. Complications: • • • • • Growth failure Nocturia and enuresis Hypernatremic dehydration Seizures Mental retardation Prognosis: • Long-term survival in cases of CDI depends on the precipitating cause. Transfer: • Transfer to an academic center is highly advised for initial diagnosis and treatment. When indomethacin is used in long-term therapy. • Deterrence/Prevention: • • Reduce or eliminate activities resulting in increased insensible fluid losses. and fluid overload.Precautions Monitor carefully for hypoglycemia. especially during intercurrent gastrointestinal illnesses. . • In/Out Patient Meds: • In addition to the medications already listed. Further Outpatient Care: • Regular follow-up visits with an endocrinologist (for central diabetes insipidus [CDI]) or a nephrologist (for NDI) are necessary for dosage adjustment. Avoid creating barriers to drinking water. caution in hepatic and renal impairment. hyponatremia. Subsequent episodes requiring intravenous rehydration can be treated by routine admission. cardiovascular disorders may occur FOLLOW-UP Further Inpatient Care: • Subsequent admissions are determined by the need for intravenous rehydration. In primary CDI. carefully observe renal function for any signs of toxicity. especially because CDI may require involved diagnostic studies and neurosurgical or oncologic treatment. aqueous vasopressin (Pitressin) and desmopressin (DDAVP) preparations are available for intravenous use in emergency circumstances.

Pivonello R. Garofeanu CG. Horm Res 2005. 5(1): 9-13[Medline]. hyperactivity. 102(1): 57-66[Medline][Full Text]. long-term survival is not in question. Leung AK. Gastrointestinal illnesses that cause decreased intake. et al: Nephrogenic diabetes insipidus: an X chromosome-linked dominant inheritance pattern with a vasopressin type 2 receptor gene that is structurally normal. 92(3): 1262-8[Medline][Full Text]. Rosas-Arellano MP. 64(5): 231-7[Medline]. Am J Med Sci 1983 Nov-Dec. Rijss JP. 83(7): 2275-80[Medline][Full Text]. inattention to this may result in serious consequences. 108(2): 305-11[Medline]. MISCELLANEOUS Medical/Legal Pitfalls: • • • Failure to recognize excessive fluid losses Failure to diagnose an underlying condition causing secondary central diabetes insipidus Overtreatment with DDAVP resulting in hyponatremia and seizures • Special Concerns: • Surgical procedures of any kind require replacement of fluids at a much higher rate than normal maintenance. et al: Impairment of bone status in patients with central diabetes insipidus. Seif SM. Colao A. DiSomma C. J Clin Invest 1998 Jul 1. 286(3): 42-6[Medline]. et al: X-linked nephrogenic diabetes insipidus mutations in North America and the Hopewell hypothesis. increased stool losses. Proc Natl Acad Sci U S A 1994 Aug 30. Blackett PR. diagnosis and molecular studies of familial central diabetes insipidus. and psychomotor delay. 45(4): 626-37[Medline]. Libber S. Arthus MF. J Clin Invest 1993 Sep. Lonergan M. Am J Kidney Dis 2005 Apr.• The earlier onset of NDI and the reduced ability to treat this variety of the disease renders the child more prone to attention deficits. Penney M. J Pediatr 1986 Feb. Mulders SM. J Clin Endocrinol Metab 1998 Jul. Robinson AG: Familial central diabetes insipidus: vasopressin and nicotine stimulated neurophysin deficiency with subnormal oxytocin and estrogen stimulated neurophysin. Davies JH. et al: Clinical features. • Patient Education: • Parents must replace water in infants and young children who cannot express thirst or access fluids without assistance. or both must receive early and serious attention to prevent life-threatening electrolyte and fluid balance abnormalities. Clin Pediatr (Phila) 1991 Nov. learning disorders. Bichet DG. Weir M. 91(18): 8457-61[Medline][Full Text]. Robson WL. Abbes AP. Harrison H. Bale AE. . et al: Causes of reversible nephrogenic diabetes insipidus: a systematic review. et al: An aquaporin-2 water channel mutant which causes autosomal dominant nephrogenic diabetes insipidus is retained in the Golgi complex. BIBLIOGRAPHY • • • • • • • • • • Alon U. Bichet DG. Halperin ML: Polyuria in childhood. Carson E. Friedman E. 30(11): 63440[Medline]. Spector D: Treatment of nephrogenic diabetes insipidus with prostaglandin synthesis inhibitors. Am J Nephrol 1985. Altmiller DH. Chan JC: Hydrochlorothiazide-amiloride in the treatment of congenital nephrogenic diabetes insipidus. As long as water remains available at all times to replace the massive losses.

54(4): 104151[Medline]. Am J Hum Genet 1994 Aug. Pediatr Nephrol 2005 Dec. et al: Efficacy of COX-2 inhibitors in a case of congenital nephrogenic diabetes insipidus. Bennett RL: Heterogeneous AVPR2 gene mutations in congenital nephrogenic diabetes insipidus.• • • Soylu A. Kasap B. Antush MJ. Ogun N. Wildin RS. . 55(2): 266-77[Medline]. 20(12): 1814-7[Medline]. Yamamoto T. Kidney Int 1998 Oct. Sasaki S: Aquaporins in the kidney: emerging new aspects.