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| {{SI}} | | {{Nephrogenic diabetes insipidus}} |
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| {{Editor Help}} | | '''For patient information page click [[{{PAGENAME}} (patient information)|here]]''' |
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| ==Overview==
| | {{CMG}}; '''Associate Editor in Chief:''' {{CZ}} |
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| Disease characteristics. Nephrogenic diabetes insipidus (NDI) is characterized by inability to concentrate the urine, which results in polyuria (excessive urine production) and polydipsia (excessive thirst). Affected untreated infants usually have poor feeding and failure to thrive, and rapid onset of severe dehydration with illness, hot environment, or the withholding of water. Short stature and secondary dilatation of the ureters and bladder from the high urine volume is common in untreated individuals.
| | ==[[Nephrogenic diabetes insipidus overview|Overview]]== |
| Diagnosis/testing. The clinical diagnosis of NDI relies upon demonstration of subnormal ability to concentrate the urine despite the presence of the antidiuretic hormone, pituitary-derived arginine vasopressin (AVP). The two genes associated with NDI are AVPR2 (X-linked) and AQP2 (autosomal recessive and autosomal dominant). Molecular genetic testing of the AVPR2 gene detects approximately 95% of disease-causing mutations in individuals with X-linked NDI; molecular genetic testing of the AQP2 gene detects about 95% of disease-causing mutations in individuals with autosomal recessive NDI. Such testing is clinically available.
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| ==Management == | | ==[[Nephrogenic diabetes insipidus historical perspective|Historical Perspective]]== |
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| ===Treatment of manifestations=== | | ==[[Nephrogenic diabetes insipidus pathophysiology|Pathophysiology]]== |
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| Management by a team (nutritionist, pediatric nephrologist/endocrinologist, clinical geneticist); provide free access to drinking water and to toilet facilities; reduce polyuria (and thus polydipsia) up to 50% without inducing hypernatremia by use of one of the following: thiazide diuretics (i.e., hydrochlorthiazide, chlorothiazide), dietary restriction of sodium, nonsteroidal anti-inflammatory drugs (NSAIDs); in individuals with dehydration or shock, establish whether the deficit is primarily in free water (through water deprivation or excessive urine, stool, or sweat) or in extracellular fluid (bleeding, fluid extravasation) to avoid inappropriate treatment of dehydration with normal saline (0.9% NaCl); treat hydronephrosis, hydroureter, and megacystis with medical management to reduce urine output and continuous or intermittent bladder catheterization when post-void urinary bladder residuals are significant; when 'NPO' (nothing per ora), individuals with NDI must have intravenous replacement of their usual oral intake of water as 2.5% dextrose in water. Surveillance: monitoring of growth in infants and children; periodic measurement of serum sodium concentration to identify unrecognized hyperosmolality and early dehydration; annual renal ultrasound evaluation to monitor for hydronephrosis and megacystis.
| | ==[[Nephrogenic diabetes insipidus causes|Causes]]== |
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| ===Agents/circumstances to avoid=== | | ==[[Nephrogenic diabetes insipidus differential diagnosis|Differentiating Nephrogenic diabetes insipidus from other Diseases]]== |
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| Restriction of water intake. Testing of relatives at risk: evaluation of at-risk infants as early as possible to allow for prompt diagnosis and treatment to reduce morbidity from hypernatremia, dehydration, and dilation of the urinary tract.
| | ==[[Nephrogenic diabetes insipidus epidemiology and demographics|Epidemiology and Demographics]]== |
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| ===Genetic counseling=== | | ==[[Nephrogenic diabetes insipidus risk factors|Risk Factors]]== |
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| NDI is most commonly inherited in an X-linked manner (~90% of individuals). NDI can also be inherited in an autosomal recessive manner (~9% of individuals) or in an autosomal dominant manner (~1% of individuals). The risks to sibs and offspring depend upon the mode of inheritance and the carrier status of the parents, which can be established in most families using molecular genetic testing. Prenatal testing is available for at-risk pregnancies in which the disease-causing mutation(s) have been identified in an affected family member.
| | ==[[Nephrogenic diabetes insipidus natural history, complications and prognosis|Natural History, Complications and Prognosis]]== |
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| ==Diagnosis== | | ==Diagnosis== |
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| ===Clinical Diagnosis===
| | [[Nephrogenic diabetes insipidus history and symptoms|History and Symptoms ]] | [[ Nephrogenic diabetes insipidus physical examination|Physical Examination]] | [[Nephrogenic diabetes insipidus laboratory findings|Laboratory Findings]] | [[Nephrogenic diabetes insipidus electrocardiogram|Electrocardiogram]] | [[Nephrogenic diabetes insipidus ultrasound|Ultrasound]] | [[Nephrogenic diabetes insipidus other imaging findings|Other Imaging Findings]] | [[Nephrogenic diabetes insipidus other diagnostic studies|Other Diagnostic Studies]] |
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| Nephrogenic diabetes inspidus (NDI) is suspected in individuals with: | | ==Treatment== |
| *Polyuria (excessive urine production)
| | [[Nephrogenic diabetes insipidus medical therapy|Medical Therapy]] | [[Nephrogenic diabetes insipidus surgery |Surgery]] | [[Nephrogenic diabetes insipidus primary prevention|Primary Prevention]] | [[Nephrogenic diabetes insipidus secondary prevention|Secondary Prevention]] | [[Nephrogenic diabetes insipidus cost-effectiveness of therapy|Cost-Effectiveness of Therapy]] | [[Nephrogenic diabetes insipidus future or investigational therapies|Future or Investigational Therapies]] |
| *Polydipsia (excessive thirst)
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| ===Testing=== | | ==Case Studies== |
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| * Tests of Urine-Concentrating Ability
| | [[Nephrogenic diabetes insipidus case study one|Case #1]] |
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| ===Affected individuals=== | | ==Sources== |
| | [http://www.ncbi.nlm.nih.gov GeneReviews at NCBI (an article by Nine Knoers, MD)] |
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| :* Measurement of serum sodium concentration with simultaneous measurement of urine specific gravity is the most helpful screening test for diabetes insipidus.
| | ==Related Chapters== |
| | | * [[Diabetes insipidus]] |
| ::* An increased serum sodium concentration (>143 mEq/L) in the presence of a low urine specific gravity and in the absence of excessive sodium intake, is highly suggestive of diabetes insipidus.
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| ::* The simultaneous occurrence of a high plasma osmolality and low urine osmolality reflects increased serum sodium concentration and low urine specific gravity.
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| :* Failure to concentrate the urine normally in the presence of high plasma vasopressin concentration and in the presence of parenteral administration of vasopressin or desmopressin (DDAVP) is diagnostic of NDI. Administration of 10 to 40 μg DDAVP intranasally in individuals older than age one year usually results in a urine osmolality that is:
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| ::*Greater than 807 mOsm/kg in normal individuals
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| ::*Less than 200 mOsm/kg in individuals with NDI [van Lieburg et al 1999]
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| Note: The results of these tests may be difficult to interpret in individuals with "partial diabetes insipidus," which results from either subnormal amounts of vasopressin secretion (partial neurogenic DI) or partial response of the kidney to normal vasopressin concentrations (partial nephrogenic DI). These two disorders can be distinguished by comparing the ratio of urine osmolarity to plasma vasopressin concentration against normal standards.
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| ===Females heterozygous for X-linked NDI===
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| Although an overnight urinary concentration test in female relatives was proposed as a method of carrier detection, it is unreliable.
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| ==Molecular Genetic Testing==
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| ===Genes===
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| * AVPR2is the only gene known to be associated with X-linked nephrogenetic diabetes insipidus.
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| * AQP2is the only gene known to be associated with autosomal recessive and autosomal dominant nephrogenetic diabetes insipidus.
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| ===Clinical uses===
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| * Diagnostic testing
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| * Carrier testing
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| * Prenatal diagnosis
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| ===Clinical testing===
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| * Sequence analysis
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| :* Sequence analysis of the AVPR2 gene detects almost 95% of disease-causing mutations in individuals with X-linked NDI.
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| :* Sequence analysis of the AQP2 gene detects almost 95% of disease-causing mutations in individuals with autosomal recessive or autosomal dominant NDI.
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| * Linkage analysis. Linkage analysis may be performed:
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| ::* to confirm cosegregation of a potential pathogenic mutation with disease in individual families and
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| ::* as an ancillary test to obtain preliminary data prior to the completion of sequence analysis. Linkage testing cannot be used to confirm the diagnosis of NDI [Arthus et al 2000].
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| ===Testing Strategy===
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| To establish the diagnosis in a proband:
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| :*Since most NDI is caused by AVPR2 mutations, molecular genetic testing of a symptomatic individual, male or female, usually starts with AVPR2 sequencing. If no mutations are found, AQP2 sequencing is performed.
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| :*In affected children (male or female) from consanguineous parents, AQP2 sequencing is performed first, followed by AVPR2 sequencing if no mutation in AQP2 is identified.
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| ===Genetically Related (Allelic) Disorders=== | |
| * AVPR2. A gain-of-function mutation in AVPR2 was reported to produce an abnormality called "nephrogenic syndrome of inappropriate antidiuresis" [Feldman et al 2005, Knoers 2005].
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| * AQP2. No other phenotypes are known to be associated with mutations in AQP2.
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| ==Clinical Description==
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| ===Natural History===
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| Nephrogenic diabetes insipidus (NDI). Individuals with NDI typically have polyuria and polydipsia. However, in some infants, polydipsia and polyuria are often unappreciated or unimpressive. These infants may present with vomiting, gagging or retching, poor feeding, constipation or diarrhea, failure to thrive, unexplained fevers, and lethargy or irritability. The majority of affected individuals are diagnosed in the first year of life [van Lieburg et al 1999]. The initial symptoms in autosomal dominant NDI usually appear later, in some cases not before early adulthood.
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| Other infants, as well as older individuals, may present with rapid onset of severe dehydration associated with water deprivation, a hot environment, or intercurrent illnesses associated with decreased water intake and/or increased free water losses through vomiting, diarrhea, or fever. Seizures and/or coma may occur with rapid
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| increases or decreases in plasma osmolality. Occasionally, the presenting sign is hydronephrosis, hydroureter, or megacystis.
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| Dehydrated individuals who have not been diagnosed to have NDI or who are unable to communicate their complaints run the risk of being improperly treated with IV administration of normal saline, especially in emergency situations. This may exacerbate hypernatremia. Prolonged, unrecognized, or repeated episodes of hypernatremic dehydration may result in seizures, permanent brain damage, developmental delay, and mental retardation. With early diagnosis and proper management, intelligence and life span are usually normal.
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| Chronic excretion of large volumes of urine in untreated persons results in hydronephrosis, hydroureter, and megacystis (huge bladder). Some degree of urinary tract distension may be seen on ultrasound examination even in infants [Yoo et al 2006]. Potential complications of urinary tract dilatation are rupture of the urinary tract, infection, intractable pain, improper bladder function, and/or kidney failure. These complications may occur as early as the second decade of life [Shalev et al 2004]. Lifestyle is substantially affected by the need to have constant access to potable water and by the increased frequency of urination. The unavailability of restroom facilities, even for a short time, is a problem in societies in which public urination is taboo. School and other social or group activities may be disrupted.
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| Affected individuals are almost always less than 50<sup>th</sup> percentile for height; most are more than one standard deviation below the mean. Failure to thrive or short stature may result from unsuccessful management or inadequate nutrition related to polydipsia. Catch-up growth does not occur later in childhood [van Lieburg et al 1999].
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| Partial nephrogenic diabetes insipidus. Individuals with partial NDI tend to be diagnosed in later childhood. They usually do not have growth or developmental delay and are able to concentrate the urine in response to dehydration or DDAVP administration, but to a lesser extent than unaffected individuals.
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| Heterozygotes for X-linked NDI. Female carriers of X-linked NDI may have no symptoms or a variable degree of polyuria and polydipsia, or they may be as severely affected as males. In females heterozygous for AVPR2 mutations, a correlation between urine-concentrating ability (and symptoms) and skewed X-chromosome inactivation in leukocytes has been reported in one family [Nomura et al 1997, Kinoshita et al. 2004].
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| ==Genotype-Phenotype Correlations==
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| X-linked and recessive NDI are similar with respect to initial symptoms and, with a few exceptions, age of onset.
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| In the minority of individuals with X-linked NDI and a V2 receptor mutation resulting in partial insensitivity to AVP or DDAVP, the disease onset may be later in childhood. Thus, three families had the missense mutation D85N associated with decreased ligand-binding affinity and decreased coupling to Gs, and one had the missense mutation G201D associated with a decreased number of cell surface AVPR2 receptors [Sadeghi et al 1997]. An individual representing a simplex case (a single affected individual in a family) had the mutation P322S, which was able to partly activate the Gs/adenylyl cyclase system [Ala et al 1998].
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| ==Nomenclature==
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| The name "nephrogenic diabetes insipidus" was coined by Williams and Henry in 1947. In the literature the name "nephrogenic diabetes insipidus" has been used synonymously with the terms "vasopressin- or ADH-resistant diabetes insipidus" or "diabetes insipidus renalis."
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| ==Prevalence==
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| The exact prevalence of NDI is not known but it is assumed to be rare. The most recent estimate of the prevalence of NDI in Quebec, Canada is 8.8:1,000,000 males [Arthus et al 2000]. In the Dutch population of about 16 million, 40 affected families are known.
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| ==Differential Diagnosis==
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| Diabetes insipidus is the excretion of abnormally large volumes (i.e., >50 mL/kg body weight in 24 hours) of dilute urine (i.e., specific gravity <1.010 or osmolality <300 mOsm/kg) [Robertson 1988, Robertson 1995]. In addition to inherited forms of nephrogenic diabetes insipidus (NDI), causes of diabetes insipidus include the following:
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| * Deficiency in synthesis of the antidiuretic hormone arginine vasopressin (AVP) in the supraoptic nuclei or secretion by the posterior pituitary (also called neurogenic, hypothalamic, cranial, central, or vasopression-responsive diabetes insipidus).
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| :* Acquired causes include trauma, malignancy, granulomatous disease, infection, vascular disease, and autoimmune disease.
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| :* Autosomal dominant neurogenic diabetes insipidus is caused by mutations in the gene encoding prepro-arginine-vasopressin-neurophysin II (prepro-AVP-NPII) [Rittig et al 1996].
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| * Acquired nephrogenic diabetes insipidus is much more common than the hereditary form of NDI, is usually less severe, and is associated with down-regulation of AQP2 [Bichet 1998]. Known causes include lithium treatment; hypokalemia; hypercalcemia; vascular, granulomatous, and cystic kidney disease; infection; and urinary tract obstruction [Khanna et al 2006]. Rarer reported causes include antibiotics and antifungal, antineoplastic, and antiviral agents [Garofeanu et al 2005]. | |
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| * Primary polydipsia may result from mental illness (called psychogenic polydipsia or compulsive water drinking) or disturbance of the thirst mechanism (called dipsogenic diabetes insipidus). The presence of plasma osmolarity greater than 295 mOsm/kg or serum sodium concentration greater than 143 mEq/L in the context of ad libitum fluid intake effectively excludes primary polydipsia.
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| * Diabetes mellitus. Polyuria associated with diabetes mellitus is associated with glucose in the urine and increased urine specific gravity.
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| * Other. Because of the nonspecific nature of the presenting signs of NDI, infants with NDI may go undiagnosed or be misdiagnosed while under care for failure to thrive, unexplained fever, urinary reflux, or other symptoms.
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| ==Management==
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| ===Evaluations Following Initial Diagnosis===
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| To establish the extent of disease in an individual diagnosed with nephrogenic dianetes insipidus (NDI):
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| * Renal ultrasound examination to evaluate for hydronephrosis, dilatation of the urinary tract, and megacystis
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| ===Treatment of Manifestations===
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| Management is usually best accomplished by a team consisting of a nutritionist, a pediatric nephrologist or endocrinologist, and a clinical geneticist.
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| ====General management====
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| The essence of management is the provision of free access to drinking water and to toilet facilities. Infants, who are naturally unable to seek out water when thirsty, must be offered water between regular feedings. Children and adults who are heavy sleepers may need to be awakened at night by a family member or an alarm clock in order to drink water and to urinate. As long as an individual's thirst mechanism remains intact and the person is otherwise well, these measures prevent hypernatremic dehydration. Education of friends, teachers, caretakers, and neighbors and a willingness to find creative solutions are helpful.
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| Polyuria (and thus polydipsia) can be reduced by up to 50% without inducing hypernatremia by the use of one of the following. Therapy is considered effective when urine output declines below a documented baseline in individuals with ad libitum water intake. Objective measurements of 24-hour urine volume are more valuable than subjective reports of the volume or frequency of voiding, although reduction in the latter provides a benefit to lifestyle.
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| * Thiazide diuretics (i.e., hydrochlorthiazide, chlorothiazide) in standard to high doses. Since these diuretics cause potassium wasting, serum potassium concentration should be monitored and supplemental potassium provided in the diet or pharmacologically as needed. Thiazides are often used in combination with either amiloride or indomethacin. Note: When thiazide diuretic therapy is initiated, a transient increase in urine output may occur as a result of salt diuresis.
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| * Dietary restriction of sodium to 300 mg/day to maximize the effectiveness of thiazide diuretics in reducing urine output. Although previously a diet low in protein (2 g/kg/day) to reduce the renal osmolar load and obligatory water excretion was recommended, severe limitation of dietary protein may introduce nutritional deficiencies. Thus, it is preferable to prescribe dietary restriction of sodium only.
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| * Nonsteroidal anti-inflammatory drugs (NSAIDs) , such as indomethacin, to potentially improve urine concentrating ability and reduce urine output. NSAIDs have been used individually and in combination with thiazide diuretics (with or without amiloride). Because NSAIDs have undesirable effects, such as gastric and renal tubular damage, and because the incidence of complications has not been studied in individuals with NDI, caution is warranted in the chronic use of NSAIDs for treatment of NDI.
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| ====Emergency treatment for dehydration====
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| When individuals with NDI present with dehydration or shock, it is essential to establish whether the deficit is primarily in free water (through water deprivation or excessive urine, stool, or sweat) or in extracellular fluid (bleeding, fluid extravasation). The natural tendency of healthcare providers to treat dehydration with normal saline (0.9% NaCl) is dangerous in individuals with NDI if the deficit is primarily in free water.
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| * Acute blood loss or shock may be treated with isotonic fluid until the blood pressure and heart rate are stabilized, after which 2.5% dextrose in water is the preferred solution.
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| * Dehydration associated with free water deficit is treated by gradually replacing the deficit water as well as ongoing urinary losses. Whenever possible, rehydration should occur with the oral intake of drinking water. If administration of IV fluids is required, 2.5% dextrose in water and/or quarter-normal saline should be used.
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| If significant hypernatremia is present, serum sodium concentration should be monitored and the hydration solution modified to avoid reducing serum sodium concentration faster than 1 mEq/L per hour. Rapid increases or decreases in plasma osmolality can cause seizures, coma, brain damage, and death.
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| ====Special situations====
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| Individuals being prepared for surgery are often denied oral intake for many hours and are described as having 'NPO' (nothing per ora) status. In individuals with NDI, an IV must be provided from the beginning of NPO status, and the person's oral intake of water for that period, which is typically much larger than that of an individual who does not have NDI, should be given intravenously as 2.5% dextrose in water [Moug et al 2005].
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| ====Hydronephrosis, hydroureter, and megacystis====
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| Treatment involves medical management to reduce urine output and continuous or intermittent bladder catheterization when significant post-void urinary bladder
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| residuals are present.
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| ====Psychomotor development====
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| Children with a history of an episode of severe dehydration, delayed developmental milestones, or a delay in establishing the correct diagnosis and management warrant a formal developmental evaluation and intervention before school age.
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| ==Prevention of Secondary Complications==
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| Prevention or reduction of serious renal, ureteral, or bladder dilatation may be achieved by reduction of urine production by drug therapy and voiding at two-hour intervals.
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| ===Surveillance===
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| * Monitoring of growth in infants and children
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| * Periodic measurement of serum sodium concentration to identify unrecognized hyperosmolality and early dehydration. Note: Urine output and urine specific gravity are useless as indicators of hydration status.
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| * Annual renal ultrasound evaluation to monitor for hydronephrosis and megacystis [Shalev et al 2004]
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| ===Agents/Circumstances to Avoid===
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| Restriction of water intake
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| ===Testing of Relatives at Risk===
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| It is appropriate to evaluate at-risk infants as early as possible to allow for prompt diagnosis and treatment to reduce morbidity from hypernatremia, dehydration, and dilation of the urinary tract.
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| ==References==
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| {{Reflist|2}}
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| ==Source==
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| [http://www.ncbi.nlm.nih.gov GeneReviews at NCBI]
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| {{SIB}}
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| | [[Category:Disease]] |
| [[Category:Nephrology]] | | [[Category:Nephrology]] |
| [[Category:Endocrinology]] | | [[Category:Endocrinology]] |