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Nephrogenic Diabetes Insipidus

Includes: Nephrogenic Diabetes Insipidus, Autosomal; Nephrogenic Diabetes Insipidus, X-Linked
, MD, PhD
Medical Genetics
University Medical Center
Utrecht, The Netherlands

Initial Posting: ; Last Update: June 14, 2012.

Summary

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 on demonstration of subnormal ability to concentrate the urine despite the presence of the antidiuretic hormone pituitary-derived arginine vasopressin (AVP). Mutations in two genes are known to cause NDI – AVPR2 (X-linked) and AQP2 (autosomal recessive and autosomal dominant).

Management. Treatment of manifestations: Management by a team (nutritionist, pediatric nephrologist/endocrinologist, clinical geneticist); free access to drinking water and to toilet facilities; reduction of polyuria (and thus polydipsia) up to 50% without inducing hypernatremia by use of one of the following: thiazide diuretics (i.e., hydrochlorothiazide, chlorothiazide) and/or other diuretics (i.e., potassium-sparing diuretic amiloride), dietary restriction of sodium, use of nonsteroidal anti-inflammatory drugs; 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 and development 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: Water intake must not be restricted.

Evaluation 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 on 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 possible for at-risk pregnancies if the disease-causing mutation(s) in the family have been identified.

Diagnosis

Clinical Diagnosis

Nephrogenic diabetes insipidus (NDI) is suspected in individuals with:

  • Polyuria (excessive urine production)
  • Polydipsia (excessive drinking)

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.
  • Failure to concentrate the urine normally in the presence of high plasma vasopressin concentration and after 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:

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. However, direct measurement of vasopressin is hampered by technical difficulties. Recently, it has been shown that copeptin, which is the C-terminal component of the AVP-precursor and co-secreted with AVP, is much easier to measure than AVP and a valuable surrogate of AVP. As such, it holds promise as a diagnostic tool in polyuria-polydipsia syndromes [Fenske et al 2011].

Females heterozygous for X-linked NDI. An overnight urinary concentration test in female relatives, proposed as a method of carrier detection, is unreliable.

Molecular Genetic Testing

Genes

  • AVPR2 is the only gene in which mutations are known to cause X-linked nephrogenic diabetes insipidus.
  • AQP2 is the only gene in which mutations are known to cause autosomal recessive and autosomal dominant nephrogenic diabetes insipidus.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in NDI

Gene 1Proportion of NDI Attributed to Mutations in This GeneTest MethodMutations Detected 2Mutation Detection Frequency by Gene and by Test Method 3
AVPR290%Sequence analysisSequence variants 4~95% of individuals with X-linked NDI
Deletion / duplication analysis 5Exonic and whole-gene deletions / duplicationsUnknown 6
Linkage analysis 7Not applicable
AQP2~10%Sequence analysisSequence variants 4~95% of individuals with autosomal recessive or autosomal dominant NDI
Linkage analysis 7Not applicable

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

6. Exonic and partial- and whole-gene deletions have been reported (see Table A. Genes and Databases, HGMD).

7. Linkage testing cannot be used to confirm the diagnosis of NDI [Arthus et al 2000]. However, if the family pedigree structure is sufficient and family members are cooperative with the testing process, linkage analysis may be performed to confirm co-segregation of a potential pathogenic mutation identified by sequence analysis with the disease phenotype in individual families.

Testing Strategy

To confirm/establish the diagnosis in a proband

  • Because 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, deletion/duplication analysis is performed, followed by AQP2 sequencing
  • In affected children (male or female) from consanguineous parents, AQP2 sequencing is performed first. If no mutation in AQP2 is identified, AVPR2 sequencing is performed.

Carrier testing for female relatives at risk for X-linked NDI requires prior identification of the disease-causing mutation in the family.

Note: (1) Carriers are heterozygotes for this X-linked disorder and may develop clinical findings related to the disorder. (2) Identification of female carriers requires either (a) prior identification of the disease-causing mutation in the family or, (b) if an affected male is not available for testing, molecular genetic testing by sequence analysis.

Carrier testing for relatives at risk for autosomal recessive NDI requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Clinical Description

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 unremarkable. 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 cognitive impairment. 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 centile 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. In the majority of cases 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 [Kinoshita et al 2004, Faerch et al 2010].

Genotype-Phenotype Correlations

X-linked and autosomal 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 an AVPR2 mutation resulting in partial insensitivity to AVP or DDAVP®, disease onset may be later in childhood. Thus, three families had the missense mutation p.Asp85Asn associated with decreased ligand-binding affinity and decreased coupling to Gs, and one had the missense mutation p.Gly201Asn associated with a decreased number of cell surface AVPR2 receptors. An individual representing a simplex case (a single affected individual in a family) had the missense mutation p.Pro322Ser, which was able to partially activate the Gs/adenylyl cyclase system.

Recently, two other mutations (p.Ser-333del and p.Tyr128Ser) were shown to result in a partial NDI phenotype. The partial loss of function of these mutations results from defective membrane trafficking [Takahashi et al 2012].

Nomenclature

The name "nephrogenic diabetes insipidus" was coined by Williams and Henry in 1947. In the literature it 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 approximately 16 million, 50 affected families are known.

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). 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 vasopressin-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).
  • Acquired nephrogenic diabetes insipidus is much more common than the hereditary form of NDI, is usually less severe, and is associated with downregulation of AQP2. Known causes include prolonged lithium treatment; hypokalemia; hypercalcemia; vascular, granulomatous, and cystic kidney disease; infection; and urinary tract obstruction [Khanna 2006, Wesche et al 2012]. 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 characterized by 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.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with nephrogenic diabetes insipidus (NDI), the following evaluations are recommended:

  • Renal ultrasound examination to evaluate for hydronephrosis, dilatation of the urinary tract, and megacystis
  • Medical genetics consultation

Treatment of Manifestations

Management is usually best accomplished by a team consisting of a nutritionist, a pediatric (or adult) 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 drugs/combinations. 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 (a potassium-sparing diuretic) 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, 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 Primary Manifestations

Prevention of primary manifestations (see Treatment of Manifestations) is possible when the diagnosis is made promptly after birth via molecular genetic testing. A genetic diagnosis may be performed after a few days; treatment and monitoring may then start immediately.

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

The following are appropriate:

  • Monitoring of growth and development 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

Water intake must not be restricted.

Evaluation of Relatives at Risk

It is appropriate to test at-risk infants for the family-specific mutation(s) as early as possible to allow for prompt diagnosis and treatment to reduce morbidity from hypernatremia, dehydration, and dilation of the urinary tract.

Since autosomal dominant NDI is usually less severe than X-linked or autosomal recessive NDI, genetic testing of sibs of affected children may be performed at a later stage.

Asymptomatic female family members of a male with X-linked NDI who are at risk of being a carrier of the gene mutation may undergo genetic counseling and genetic testing when they are of reproductive age.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Carriers of X-linked nephrogenic diabetes insipidus may experience a mild increase in urinary output and associated thirst during pregnancy.

As yet pregnancies in women with NDI resulting from two AQP2 mutations have been reported.

Polyhydramnios is found in a minority of pregnancies in which the fetus is affected by NDI. In cases of severe polyhydramnios and maternal discomfort, frequent amniotic fluid drainage may be necessary [Kollamparambil et al 2011].

Therapies Under Investigation

In an individual with a milder AVPR2 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 and safety 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 AVPR2 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 AVPR2 antagonists or agonists that in vitro rescue the intracellular retention of several AVPR2 mutants [Morello et al 2000, Tan et al 2003, Bernier et al 2004, Robben et al 2006, Robben et al 2007, Robben et al 2009]. 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-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 mutations in AVPR2 in vitro, resulting in the production of full-length vasopressin V2 receptor proteins [Schulz et al 2002]. However, in view of the toxic effect of these antibiotics on the kidney, the application of such a therapy to NDI in the future is unlikely.

Another mechanism circumventing the vasopressin type-2 receptor has been tested in vitro. By stimulation of the E-prostanoid receptor EP4, NDI symptoms were greatly reduced in a conditional AVPR2-deletion mouse model [Li et al 2009]. This was due to raised AQP2 levels, most probably as a consequence of cAMP production caused by EP4 stimulation. Recently, a similar effect was seen after stimulation of the EP2 receptor by the agonist butaprost [Olesen et al 2011]. The EP2 receptor is a more interesting candidate for treatment of NDI than the EP4 receptor since EP2 agonists have already been tested in clinical studies for other diseases and have shown promising results concerning safety issues. However, clinical trials in NDI have not yet been performed and are necessary to evaluate the effects and safety of EP2 agonists for this disorder.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

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. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

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).

Risk to Family Members — X-Linked Inheritance

Parents of a proband

Sibs of a proband. The risk to sibs depends on 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 of the possibility of germline mosaicism.

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 possible if the mutation has been identified in the proband.

Risk to Family Members — Autosomal Recessive Inheritance

Parents of a proband

  • The parents are obligate heterozygotes and therefore carry a single copy of a disease-causing mutation in AQP2.
  • 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 AQP2.

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 possible once the mutations have been identified in the family.

Risk to Family Members — Autosomal Dominant Inheritance

Parents of a proband

Sibs of a proband. The risk to sibs depends on 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 is at a 50% risk of inheriting the AQP2 mutation.

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

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

X-linked NDI. If the disease-causing mutation has been identified in the family, prenatal testing is possible for pregnancies at increased risk. The usual procedure is to determine fetal sex first. Noninvasive prenatal diagnosis for fetal sex determination for women who are carriers of sex-linked conditions, such as NDI, is possible in some countries [Devaney et al 2011]. Fetal sex is determined on the presence/absence of Y chromosome sequences in maternal blood. Fetal sex may also be determined by performing chromosome analysis on fetal cells obtained by chorionic villus sampling (usually performed at ~10-12 weeks' gestation) or by amniocentesis (usually performed at ~15-18 weeks' gestation). In case of a male fetus, fetal DNA can be analyzed for the known disease-causing mutation.

Autosomal recessive NDI. If the disease-causing mutations have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

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 which (like NDI) 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, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Diabetes Insipidus Foundation, Inc
    1232 24th Street
    Ames IA 50010
    Phone: 706-323-7576
    Email: ndi-support@diabetesinsipidus.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Nephrogenic Diabetes Insipidus: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Nephrogenic Diabetes Insipidus (View All in OMIM)

107777AQUAPORIN 2; AQP2
125800DIABETES INSIPIDUS, NEPHROGENIC, AUTOSOMAL
300538ARGININE VASOPRESSIN RECEPTOR 2; AVPR2
304800DIABETES INSIPIDUS, NEPHROGENIC, X-LINKED

AVPR2

Normal allelic variants. AVPR2 has three exons and two small introns.

Pathologic allelic variants (mutations). Over 220 putative disease-causing mutations have been identified [Knoers & Monnens 1999, Knoers & Deen 2001, Morello & Bichet 2001, Robben et al 2006] (update summarized in Wesche et al [2012]). The mutations are not clustered in one domain of AVPR2R but are scattered throughout the gene. The mutations consist of point mutations, small deletions and insertions, splice site mutations, or large deletions of the 3' region [Knoers & Monnens 1999, Wesche et al 2012] or of the entire gene. For more information, see Table A.

Table 2. AVPR2 Allelic Variants Discussed in This GeneReview

Class of Variant AlleleDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
Pathologic alleles resulting in partial phenotype 1c.253G>Ap.Asp85AsnNM_000054​.4
NP_000045​.1
c.602G>Ap.Gly201Asp
c.964C>Tp.Pro322Ser

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. See Genotype-Phenotype Correlations.

Normal gene product. AVPR2 encodes vasopressin V2 receptor. The cDNA predicts a polypeptide of 371 amino acids with seven transmembrane, four extracellular, and four cytoplasmic domains. The vasopressin V2 receptor, a member of the G protein-coupled receptor superfamily, preferentially activates the G protein Gs resulting in the activation of adenylyl cyclase. The first step in the antidiuretic action of AVP is binding the vasopressin V2 receptor on the basolateral membrane of collecting duct cells. This step initiates a cascade of events — receptor-linked activation of G protein (Gs), activation of adenylyl cyclase, production of cyclic adenosine-monophosphate (cAMP), and stimulation of protein kinase A (PKA) — that lead to the final step in the antidiuretic action of AVP, i.e., the exocytic insertion of specific water channels AQP2, into the luminal membrane, thereby increasing the water permeability of that membrane.

Abnormal gene product. Most AVPR2 mutations result in a receptor that is trapped intracellularly and unable to reach the plasma membrane [Robben et al 2005]. All AVPR2 mutant alleles of individuals with classic NDI fail to signal with physiologic levels of AVP. A minority of mutant receptors reach the cell surface but are unable to bind to AVP or to trigger an intracellular cAMP signal [Albertazzi et al 2000, Pasel et al 2000, Postina et al 2000, Inaba et al 2001].

AQP2

Normal allelic variants. AQP2 has four exons (NM_000486.5).

Pathologic allelic variants

For more information, see Table A.

Normal gene product. AQP2 encodes aquaporin-2, the vasopressin-sensitive water channel of the renal collecting duct cells. Aquaporin-2 (AQP2) is one of a family of water-transporting proteins that facilitates osmotically driven water movement across plasma cell membranes. Vasopression, acting through cyclic AMP (cAMP) and protein kinase A (PKA) after binding to its V2 receptor at the basolateral membrane of collecting duct cells, triggers the insertion of intracellular vesicles containing AQP2 proteins in the apical membrane, resulting in increased water permeability of this membrane. Phosphorylation of a PKA consensus site in AQP2 (serine at position 256 in the carboxy terminus) is essential for AQP2 delivery to the apical membrane [van Balkom et al 2002]. Upon dissociation of AQP2 from its receptor, this process is rapidly reversed. This shuttling of AQP2 into and out of the apical membrane is responsible for the short-term regulation of collecting duct water permeability. Long-term regulation is a consequence of an increase in the expression level of AQP2 mRNA and protein.

Abnormal gene product

  • Autosomal recessive NDI. AQP2 mutant proteins show impaired transport from the endoplasmic reticulum to the plasma membrane, indicating that the major cause of autosomal recessive NDI is misrouting of mutant AQP2 proteins.
  • Autosomal dominant NDI. Expression studies in Xenopus oocytes of the different AQP2 mutant proteins identified in individuals with the autosomal dominant form of NDI showed that all these AQP2 mutant proteins are functional water channels, but on expression in polarized cells, it appeared that all mutants mistargeted to destinations in the cell other than the apical membrane destination of wild-type AQP2. The AQP2 mutants form heterotetramers with the wild-type AQP2 and are inappropriately trafficked. Some heterotetramers were reported to traffick to the basolateral membrane, others to the Golgi complex, or to late endosomes/lysosomes. Formation of heterotetramers of mutant with wild-type AQP2 provides an explanation for the dominant behavior of these mutants. The fact that one sixteenth of all tetramers formed are wild-type-AQP2-only tetramers (which are normally trafficked to the apical membrane) explains the relatively milder phenotype in dominant NDI as compared to the recessive form [Kamsteeg et al 1999, Marr et al 2002b, Asai et al 2003, Kamsteeg et al 2003, de Mattia et al 2005].

References

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Suggested Reading

  1. Bichet DG. Nephrogenic diabetes insipidus. Adv Chronic Kidney Dis. 2006;13:96–104. [PubMed: 16580609]
  2. Sands JM, Bichet DG. Nephrogenic diabetes insipidus. Ann Intern Med. 2006;144:186–94. [PubMed: 16461963]
  3. Bichet DG, Fujiwara TM. Nephrogenic diabetes insipidus. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). Chap 163. New York, NY: McGraw-Hill. Available online. Accessed 6-8-12.

Chapter Notes

Author History

Nine Knoers, MD (2003-present)
Robert S Wildin, MD; Oregon Health and Science University (2000-2003)

Revision History

  • 14 June 2012 (me) Comprehensive update posted live
  • 4 March 2010 (me) Comprehensive update posted live
  • 8 June 2007 (cd) Revision: deletion/duplication analysis no longer available on a clinical basis
  • 8 March 2007 (me) Comprehensive update posted to live Web site
  • 5 January 2005 (me) Comprehensive update posted to live Web site
  • 28 February 2003 (me) Comprehensive update posted to live Web site
  • 12 February 2000 (pb) Review posted to live Web site
  • 13 January 1999 (rw) Original submission
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