Nephrogenic diabetes insipidus: Difference between revisions
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:* Sequence analysis of the AVPR2 gene detects almost 95% of disease-causing mutations in individuals with X-linked NDI. | :* Sequence analysis of the AVPR2 gene detects almost 95% of disease-causing mutations in individuals with X-linked NDI. | ||
:* Sequence analysis of the AQP2 gene detects almost 95% of disease-causing mutations in individuals with autosomal recessive or autosomal dominant NDI. | :* Sequence analysis of the AQP2 gene detects almost 95% of disease-causing mutations in individuals with autosomal recessive or autosomal dominant NDI. | ||
* Linkage analysis. Linkage analysis may be performed: | * Linkage analysis. Linkage analysis may be performed: | ||
::* to confirm cosegregation of a potential pathogenic mutation with disease in individual families and | |||
::* 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]. | |||
Revision as of 13:21, 10 January 2009
| Nephrogenic diabetes insipidus |
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Overview
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. 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.
Management
Treatment of manifestations
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.
Agents/circumstances to avoid
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.
Genetic counseling
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.
Diagnosis
Clinical Diagnosis
Nephrogenic diabetes inspidus (NDI) is suspected in individuals with:
- Polyuria (excessive urine production)
- Polydipsia (excessive thirst)
Testing
- Tests of Urine-Concentrating Ability
Affected individuals
- Measurement of serum sodium concentration with simultaneous measurement of urine specific gravity is the most helpful screening test for 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.
- The simultaneous occurrence of a high plasma osmolality and low urine osmolality reflects increased serum sodium concentration and low urine specific gravity.
- 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:
- Greater than 807 mOsm/kg in normal individuals
- Less than 200 mOsm/kg in individuals with NDI [van Lieburg et al 1999]
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.
Females heterozygous for X-linked NDI
Although an overnight urinary concentration test in female relatives was proposed as a method of carrier detection, it is unreliable.
Molecular Genetic Testing
Genes
- AVPR2is the only gene known to be associated with X-linked nephrogenetic diabetes insipidus.
- AQP2is the only gene known to be associated with autosomal recessive and autosomal dominant nephrogenetic diabetes insipidus.
Clinical uses
- Diagnostic testing
- Carrier testing
- Prenatal diagnosis
Clinical testing
- Sequence analysis
- Sequence analysis of the AVPR2 gene detects almost 95% of disease-causing mutations in individuals with X-linked NDI.
- Sequence analysis of the AQP2 gene detects almost 95% of disease-causing mutations in individuals with autosomal recessive or autosomal dominant NDI.
- Linkage analysis. Linkage analysis may be performed:
- to confirm cosegregation of a potential pathogenic mutation with disease in individual families and
- 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].