Nephrogenic Diabetes Insipidus

[Includes: Nephrogenic Diabetes

Insipidus, Autosomal; Nephrogenic
Diabetes Insipidus, X-Linked]
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 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.
o 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.
o 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 g DDAVP intranasally in individuals older than age one year usually
results in a urine osmolality that is:
o Greater than 807 mOsm/kg in normal individuals
o Less than 200 mOsm/kg in individuals with NDI

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
o Sequence analysis of the AVPR2 gene detects almost 95% of disease-
causing mutations in individuals with X-linked NDI.
o 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: (1) to confirm
cosegregation of a potential pathogenic mutation with disease in individual
families and (2) 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].

Table 1 summarizes molecular genetic testing for this disorder.

Table 1. Molecular Genetic Testing Used in NDI

Mutations Test
Test Method Mutation Detection Frequency 1
Detected Availability
Sequence AVPR2 sequence Clinical
~95% of individuals with X-linked NDI
analysis variants
Sequence AQP2 sequence ~95% of individuals with autosomal Clinical
analysis variants recessive or autosomal dominant NDI
1. Proportion of affected individuals with a mutation(s) as classified by gene/locus,
phenotype, population group, genetic mechanism, and/or test method

Interpretation of test results. For issues to consider in interpretation of sequence

analysis results

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.

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 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 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. 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].

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.

Differential Diagnosis
For current information on availability of genetic testing for disorders included in this
section, see GeneTests Laboratory Directory. ED.

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

Management
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., 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.

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.

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

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-fpeptide 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 toxic effect of these antibiotics on the kidney, the application of such a
therapy to NDI in the future is unlikely.

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

Other

Genetics clinics are a source of information for individuals and families regarding the
natural history, treatment, mode of inheritance, and genetic risks to other family members
as well as information about available consumer-oriented resources. See the GeneTests
Clinic Directory.

Support groups have been established for individuals and families to provide
information, support, and contact with other affected individuals. The Resources section
may include disease-specific and/or umbrella support organizations.

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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic
Directory.

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

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

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 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.

Risk to Family Members Autosomal Dominant Inheritance

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.

Related Genetic Counseling Issues

See Testing of Relatives at Risk for information on testing at-risk relatives for the
purpose of early diagnosis and treatment.

Family planning. The optimal time for determination of genetic risk and discussion of
the availability of prenatal testing is before pregnancy.

DNA banking. 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. DNA banking is particularly
relevant in situations in which the sensitivity of currently available testing is less than
100%. See DNA Banking for a list of laboratories offering this service.

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. For laboratories offering PGD, see
. Although technically feasible, PGD may be unacceptable and/or not allowed in
some countries.

Molecular Genetics
Information in the Molecular Genetics tables is current as of initial posting or most
recent update. ED.

Table A. Molecular Genetics of Nephrogenic Diabetes Insipidus

Gene Symbol Chromosomal Locus Protein Name

AQP2 12q13 Aquaporin-2
AVPR2 Xq28 Vasopressin V2 receptor

Data are compiled from the following standard references: Gene symbol from HUGO;
chromosomal locus, locus name, critical region, complementation group from OMIM;
protein name from Swiss-Prot.

Table B. OMIM Entries for Nephrogenic Diabetes Insipidus

107777 AQUAPORIN 2; AQP2

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

Table C. Genomic Databases for Nephrogenic Diabetes Insipidus

Gene Symbol Locus Specific Entrez Gene HGMD

AQP2 AQP2 359 (MIM No. 107777) AQP2
AVPR2 AVPR2 554 (MIM No. 304800) AVPR2
For a description of the genomic databases listed, click here.

AVPR2

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

Pathologic allelic variants: One hundred eighty putative disease-causing mutations have
been identified [Bichet et al 1994, Bichet 1998, Knoers & Monnens 1999, Knoers &
Deen 2001, Morello & Bichet 2001, Robben et al 2006, NDI Database]. The mutations
are not clustered in one domain of the V2R but are scattered throughout the gene [Wildin
et al 1998]. The mutations consist of point mutations, small deletions and insertions,
splice site mutations, or large deletions of the 3' region [Knoers & Monnens 1999]. (For
more information, see Genomic Databases table above.)

Normal gene product: AVPR2 encodes vasopressin V2 receptor (AVPR2). The cDNA
predicts a polypeptide of 371 amino acids with seven transmembrane, four extracellular,
and four cytoplasmic domains. The 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 leads 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 [Bichet
1998].

Abnormal gene product: Most AVPR2 mutations lead to receptors that are trapped
intracellularly and are unable to reach the plasma membrane [Robben et al 2005]. All
AVPR2 alleles from individuals with classic NDI fail to signal with physiologic levels of
AVP [Wildin et al 1998]. A minority of mutant receptors reaches the cell surface but are
unable to bind to AVP or to trigger an intracellular cAMP signal [Bichet 1998, Albertazzi
et al 2000, Pasel et al 2000, Postina et al 2000, Inaba et al 2001].

AQP2

Normal allelic variants: The AQP2 gene has four exons.

Pathologic allelic variants:

Autosomal recessive NDI. Twenty-nine mutations that give rise to autosomal

recessive NDI have been detected in the AQP2 gene. These include 21 missense
mutations, two nonsense mutations, two 1-bp deletions, one 2-bp deletion, and
two splice site mutations [Knoers & Monnens 1999; Knoers & Deen 2001;
Morello & Bichet 2001; Lin et al 2002; Marr, Bichet, Hoefs et al 2002; Tajima et
al 2003; Iolascon et al 2007].
 Autosomal dominant NDI. Mutations identified in eight families with
autosomal dominant NDI are located in the carboxy-terminal region of AQP2, a
region considered to be important for targeting of AQP2 proteins [Kamsteeg et al
1999; Kuwahara et al 2001; Marr, Bichet, Lonergan et al 2002; Sohara et al
2006].

(For more information, see Genomic Databases table above.)

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 [Knoers & Deen 1998]. Vasopression, acting through cyclic AMP
(cAMP) and protein kinase A (PKA) after binding to its V2 receptor (V2R) 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 dominant AQP2 mutants identified in individuals with NDI showed that
all these mutants are functional water channels, but upon 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. Some mutants were reported
to traffick to the basolateral membrane, others to the Golgi complex or late
endosomes/lysosomes [Mulders et al 1998; Marr, Bichet, Lonergan et al 2002;
Asai et al 2003; Kamsteeg et al 2003; de Mattia et al 2005].
Diabetes insipidus
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For the disease most commonly associated with the generic term "diabetes", see Diabetes
mellitus.
Diabeted insipidus
Classification and external
resources
 Vasopressin
ICD-10 E23.2 N25.1
ICD-9 253.5 588.1
OMIM 304800 125800
DiseasesDB 3639
000377
Central000460
MedlinePlus Congenital000461
Nephrogenic
000511
eMedicine med/543 ped/580
MeSH D003919

Diabetes insipidus (DI) (Greek diabainein - to pass through and Latin

insipidus - without taste) is a condition characterized by excretion of large amounts of
severely diluted urine, which cannot be reduced when fluid intake is reduced. It denotes
inability of the kidney to concentrate urine. DI is caused by a deficiency of antidiuretic
hormone (ADH), also known as vasopressin, due to the destruction of the back or
"posterior" part of the pituitary gland where vasopressin is normally released from, or by
an insensitivity of the kidneys to that hormone. It can also be induced iatrogenically by
various drugs.