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: 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.
 * 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., hydrochlorothiazide, 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.

Nomenclature
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."

Prevalence
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.

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.

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].

Testing Strategy
To establish the diagnosis in a proband:


 * 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.
 * 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.

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].
 * AQP2. No other phenotypes are known to be associated with mutations in AQP2.

Natural History
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.

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 increases or decreases in plasma osmolality. Occasionally, the presenting sign is hydronephrosis, hydroureter, or megacystis.

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.

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.

Affected individuals are almost always less than 50th 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].

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.

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].

Genotype-Phenotype Correlations
X-linked and recessive NDI are similar with respect to initial symptoms and, with a few exceptions, age of onset.

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].

Differential Diagnosis
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:


 * 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).


 * Acquired causes include trauma, malignancy, granulomatous disease, infection, vascular disease, and autoimmune disease.


 * 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].


 * 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].


 * 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.


 * Diabetes mellitus. Polyuria associated with diabetes mellitus is associated with glucose in the urine and increased urine specific gravity.


 * 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.

Evaluations Following Initial Diagnosis
To establish the extent of disease in an individual diagnosed with nephrogenic dianetes insipidus (NDI):


 * Renal ultrasound examination to evaluate for hydronephrosis, dilatation of the urinary tract, and megacystis

Treatment of Manifestations
Management is usually best accomplished by a team consisting of a nutritionist, a pediatric nephrologist or endocrinologist, and a clinical geneticist.

General management
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.

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.


 * Thiazide diuretics (i.e., hydrochlorothiazide, 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.


 * 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.


 * 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.

Emergency treatment for dehydration
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.


 * 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.
 * 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.

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.

Special situations
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].

Hydronephrosis, hydroureter, and megacystis
Treatment involves medical management to reduce urine output and continuous or intermittent bladder catheterization when significant post-void urinary bladder residuals are present.

Psychomotor development
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.

Prevention of Secondary Complications
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.

Surveillance

 * Monitoring of growth in infants and children
 * 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.
 * Annual renal ultrasound evaluation to monitor for hydronephrosis and megacystis [Shalev et al 2004]

Agents/Circumstances to Avoid
Restriction of water intake

Testing of Relatives at Risk
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.

Therapies Under Investigation
In an individual with a milder V2R mutation resulting in a partial response to AVP and DDAVP, high doses of DDAVP in combination with a thiazide diuretic significantly decreased urinary volume [Mizuno et al 2003]. Effectiveness of this treatment in partial NDI needs to be explored further.

Because of the known gastrointestinal safety of selective cyclooxygenase (COX)-2 inhibitors compared to nonselective COX-inhibitors (such as indomethacin), use of these drugs has been proposed for the treatment of NDI. The effectiveness of a specific COX-2 inhibitor in decreasing free water losses was demonstrated in male infants with NDI [Pattaragarn & Alon 2003, Soylu et al 2005]. However, in view of the recent discovery that prolonged use of this COX-2 inhibitor can cause severe cardiac side effects, it is not appropriate to use these inhibitors in the treatment of NDI until it has been determined which of the specific COX-2 inhibitors are completely safe.

Because in vitro expression studies reveal that the majority of V2R mutations in X-linked NDI and all AQP2 mutations in autosomal recessive NDI result in normal protein that is retained within the endoplasmic reticulum (ER), agents that restore plasma routing are under investigation as potential treatments. Promising agents for X-linked NDI are cell-permeable V2R antagonists or agonists that in vitro rescue the intracellular retention of several V2R mutants [Morello et al 2000, Tan et al 2003, Bernier et al 2004, Robben et al 2006]. The feasibility of treatment with these so-called pharmacologic "chaperones" has recently been tested in vivo. In individuals with NDI who have missense AVPR2 mutations, Bernier et al (2006) showed that treatment with a non-f peptide V1a receptor antagonist had beneficial effects on urine volume and osmolality starting a few hours after administration. However, the long-term effect of this drug could not be tested because the clinical development of this V1a receptor antagonist was interrupted during the course of this study as a result of possible interference with the cytochrome P450 metabolic pathway. Confirmation of the putative beneficial effect of pharmacologic chaperones in NDI awaits further in vivo testing.

Aminoglycosides, such as gentamicin, allow read-through of stop codon V2R mutants in vitro, resulting in the production of full-length proteins [Schulz et al 2002]. However, in view of the toxiceffect of these antibiotics on the kidney, the application of such a therapy to NDI in the future is unlikely.

Genetic Counseling
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members.

Mode of Inheritance
Nephrogenic diabetes insipidus (NDI) may be transmitted in an X-linked recessive manner (90% of families), an autosomal recessive manner (~9% of families), or an autosomal dominant manner (~1% of families).

Parents of a proband

 * The father of an affected male will not have NDI nor will he be a carrier of the mutation.


 * Women who have an affected son and another affected male relative are obligate heterozygotes.


 * A positive family history consistent with X-linked inheritance is observed in about half of X-linked cases [Arthus et al 2000].


 * Pedigree analysis reveals that in about half of families with an affected male, he represents a simplex case (i.e., an affected individual with no known family history of NDI); several possibilities regarding his mother's carrier status need to be considered:


 * The proband has a de novo disease-causing mutation in the AVPR2 gene and his mother is not a carrier;


 * His mother has a de novo disease-causing mutation in the AVPR2 gene, either (a) as a "germline mutation" (i.e., present at the time of her conception and therefore in every cell of her body) or (b) as "germline mosaicism" (i.e., in some of her germ cells only);


 * His maternal grandmother has a de novo disease-causing mutation in the AVPR2 gene.

Sibs of a proband

 * The risk to sibs depends upon the genetic status of the proband's mother.


 * If the mother of the proband has a disease-causing mutation, the chance of transmitting it in each pregnancy is 50%. Male sibs who inherit the mutation will be affected; female sibs who inherit the mutation will be carriers and will usually not be affected.


 * If the disease-causing mutation cannot be detected in the DNA of the mother of the only affected male in the family, the risk to sibs is low but greater than that of the general population because the possibility of germline mosaicism exists.

Offspring of a proband
All the daughters of an affected male are carriers; none of his sons will be affected.

Carrier Detection
Carrier testing by molecular analysis of at-risk female relatives is available if the mutation has been identified in the proband.

Parents of a proband

 * The parents are obligate heterozygotes and, therefore, carry a single copy of a disease-causing mutation in the AQP2 gene.
 * Heterozygotes are asymptomatic.

Sibs of a proband

 * At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
 * Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3.
 * Heterozygotes (carriers) are asymptomatic.

Offspring of a proband.

 * The offspring of an individual with autosomal recessive NDI are obligate heterozygotes (carriers) for a disease-causing mutation in the AQP2 gene.

Other family members
Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection
Carrier testing by molecular analysis for at-risk family members is available once the mutations have been identified in the proband.

Parents of a proband

 * The proportion of individuals with autosomal dominant NDI who have an affected parent is unknown because the number of reported cases is small.


 * A proband with autosomal dominant NDI may have the disorder as the result of a de novo gene mutation. The proportion of cases caused by de novo mutations is unknown.

Sibs of a proband

 * The risk to sibs depends upon the genetic status of the proband's parent.
 * If a parent of a proband is affected, the risk to the sibs is 50%.


 * When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.

Offspring of a proband

 * Each child of an individual with autosomal dominant NDI has a 50% chance of inheriting the AQP2 mutation.

Other family members of a proband

 * The risk to other family members depends upon the status of the proband's parents. If a parent is found to be affected, his or her family members are at risk.

Prenatal Testing
X-linked NDI. Prenatal testing is available for pregnancies at increased risk if the AVPR2 mutation has been identified in an affected family member. The usual procedure is to determine fetal sex by performing chromosome analysis on fetal cells obtained by chorionic villus sampling (CVS) at about ten to 12 weeks' gestation or by amniocentesis usually performed at about 15-18 weeks' gestation. If the karyotype is 46,XY, DNA from fetal cells can be analyzed for the known disease-causing mutation.

Autosomal recessive NDI. Prenatal diagnosis is available for pregnancies at increased risk. Analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15-18 weeks' gestation or chorionic villus sampling (CVS) at about ten to 12 weeks' gestation. Both disease-causing alleles of an affected family member must be identified before prenatal testing can be performed. Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for conditions such as NDI that do not affect intellect and have treatment available are not common. Differences in perspective may exist among medical professionals and in families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, careful discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation(s) has/have been identified. Although technically feasible, PGD may be unacceptable and/or not allowed in some countries.

Source
GeneReviews at NCBI (an article by Nine Knoers, MD)