Nephrogenic diabetes insipidus

Nephrogenic diabetes insipidus

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Overview

Disease characteristics. Nephrogenic diabetes insipidus (NDI) is characterized by inability to concentrate the urine, which results in polyuria (excessive urine production) and polydipsia (excessive thirst). Affected untreated infants usually have poor feeding and failure to thrive, and rapid onset of severe dehydration with illness, hot environment, or the withholding of water. Short stature and secondary dilatation of the ureters and bladder from the high urine volume is common in untreated individuals. Diagnosis/testing. The clinical diagnosis of NDI relies upon demonstration of subnormal ability to concentrate the urine despite the presence of the antidiuretic hormone, pituitary-derived arginine vasopressin (AVP). The two genes associated with NDI are AVPR2 (X-linked) and AQP2 (autosomal recessive and autosomal dominant). Molecular genetic testing of the AVPR2 gene detects approximately 95% of disease-causing mutations in individuals with X-linked NDI; molecular genetic testing of the AQP2 gene detects about 95% of disease-causing mutations in individuals with autosomal recessive NDI. Such testing is clinically available.

Management

Treatment of manifestations

Management by a team (nutritionist, pediatric nephrologist/endocrinologist, clinical geneticist); provide free access to drinking water and to toilet facilities; reduce polyuria (and thus polydipsia) up to 50% without inducing hypernatremia by use of one of the following: thiazide diuretics (i.e., hydrochlorthiazide, chlorothiazide), dietary restriction of sodium, nonsteroidal anti-inflammatory drugs (NSAIDs); in individuals with dehydration or shock, establish whether the deficit is primarily in free water (through water deprivation or excessive urine, stool, or sweat) or in extracellular fluid (bleeding, fluid extravasation) to avoid inappropriate treatment of dehydration with normal saline (0.9% NaCl); treat hydronephrosis, hydroureter, and megacystis with medical management to reduce urine output and continuous or intermittent bladder catheterization when post-void urinary bladder residuals are significant; when 'NPO' (nothing per ora), individuals with NDI must have intravenous replacement of their usual oral intake of water as 2.5% dextrose in water. Surveillance: monitoring of growth in infants and children; periodic measurement of serum sodium concentration to identify unrecognized hyperosmolality and early dehydration; annual renal ultrasound evaluation to monitor for hydronephrosis and megacystis.

Agents/circumstances to avoid

Restriction of water intake. Testing of relatives at risk: evaluation of at-risk infants as early as possible to allow for prompt diagnosis and treatment to reduce morbidity from hypernatremia, dehydration, and dilation of the urinary tract.

Genetic counseling

NDI is most commonly inherited in an X-linked manner (~90% of individuals). NDI can also be inherited in an autosomal recessive manner (~9% of individuals) or in an autosomal dominant manner (~1% of individuals). The risks to sibs and offspring depend upon the mode of inheritance and the carrier status of the parents, which can be established in most families using molecular genetic testing. Prenatal testing is available for at-risk pregnancies in which the disease-causing mutation(s) have been identified in an affected family member.

Diagnosis

Clinical Diagnosis

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

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

Testing

• Tests of Urine-Concentrating Ability

Affected individuals

• Measurement of serum sodium concentration with simultaneous measurement of urine specific gravity is the most helpful screening test for diabetes insipidus.

• An increased serum sodium concentration (>143 mEq/L) in the presence of a low urine specific gravity and in the absence of excessive sodium intake, is highly suggestive of diabetes insipidus.

• The simultaneous occurrence of a high plasma osmolality and low urine osmolality reflects increased serum sodium concentration and low urine specific gravity.

• Failure to concentrate the urine normally in the presence of high plasma vasopressin concentration and in the presence of parenteral administration of vasopressin or desmopressin (DDAVP) is diagnostic of NDI. Administration of 10 to 40 μg DDAVP intranasally in individuals older than age one year usually results in a urine osmolality that is:

• Greater than 807 mOsm/kg in normal individuals
• Less than 200 mOsm/kg in individuals with NDI [van Lieburg et al 1999]

Note: The results of these tests may be difficult to interpret in individuals with "partial diabetes insipidus," which results from either subnormal amounts of vasopressin secretion (partial neurogenic DI) or partial response of the kidney to normal vasopressin concentrations (partial nephrogenic DI). These two disorders can be distinguished by comparing the ratio of urine osmolarity to plasma vasopressin concentration against normal standards.

Females heterozygous for X-linked NDI

Although an overnight urinary concentration test in female relatives was proposed as a method of carrier detection, it is unreliable.

Molecular Genetic Testing

Genes

• AVPR2is the only gene known to be associated with X-linked nephrogenetic diabetes insipidus.
• AQP2is the only gene known to be associated with autosomal recessive and autosomal dominant nephrogenetic diabetes insipidus.

Clinical uses

• Diagnostic testing
• Carrier testing
• Prenatal diagnosis

Clinical testing

• Sequence analysis

• Sequence analysis of the AVPR2 gene detects almost 95% of disease-causing mutations in individuals with X-linked NDI.
• Sequence analysis of the AQP2 gene detects almost 95% of disease-causing mutations in individuals with autosomal recessive or autosomal dominant NDI.

• Linkage analysis. Linkage analysis may be performed:

• to confirm cosegregation of a potential pathogenic mutation with disease in individual families and
• as an ancillary test to obtain preliminary data prior to the completion of sequence analysis. Linkage testing cannot be used to confirm the diagnosis of NDI [Arthus et al 2000].

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 50^th 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].

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

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.

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.

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).

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:

• 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.

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.

References

Ala Y, Morin D, Mouillac B, Sabatier N, Vargas R, Cotte N, Dechaux M, Antignac C, Arthus MF, Lonergan M, Turner MS, Balestre MN, Alonso G, Hibert M, Barberis C, Hendy GN, Bichet DG, Jard S. Functional studies of twelve mutant V2 vasopressin receptors related to nephrogenic diabetes insipidus: molecular basis of a mild clinical phenotype. J Am Soc Nephrol. 1998; 9: 1861–72.

Albertazzi E, Zanchetta D, Barbier P, Faranda S, Frattini A, Vezzoni P, Procaccio M, Bettinelli A, Guzzi F, Parenti M, Chini B. Nephrogenic diabetes insipidus: functional analysis of new AVPR2 mutations identified in Italian families. J Am Soc Nephrol. 2000; 11: 1033–43.

Arthus MF, Lonergan M, Crumley MJ, Naumova AK, Morin D, De Marco LA, Kaplan BS, Robertson GL, Sasaki S, Morgan K, Bichet DG, Fujiwara TM. Report of 33 novel AVPR2 mutations and analysis of 117 families with X- linked nephrogenic diabetes insipidus. J Am Soc Nephrol. 2000; 11: 1044–54.

Asai T, Kuwahara M, Kurihara H, Sakai T, Terada Y, Marumo F, Sasaki S. Pathogenesis of nephrogenic diabetes insipidus by aquaporin-2 C-terminus mutations. Kidney Int. 2003; 64: 2–10.

Bernier V, Lagace M, Lonergan M, Arthus MF, Bichet DG, Bouvier M. Functional rescue of the constitutively internalized V2 Vasopressin receptor mutant R137H by the pharmacological chaperone action of SR49059. Mol Endocrinol. 2004; 18: 2074–84.

Bernier V, Morello JP, Zarruk A, Debrand N, Salahpour A, Lonergan M, Arthus MF, Laperriere A, Brouard R, Bouvier M, Bichet DG. Pharmacologic chaperones as a potential treatment for X-linked nephrogenic diabetes insipidus. J Am Soc Nephrol. 2006; 17: 232–43.

Bichet DG. Nephrogenic diabetes insipidus. Am J Med. 1998; 105: 431–42.

Bichet DG, Birnbaumer M, Lonergan M, Arthus MF, Rosenthal W, Goodyer P, Nivet H, Benoit S, Giampietro P, Simonetti S. et al. Nature and recurrence of AVPR2 mutations in X-linked nephrogenic diabetes insipidus. Am J Hum Genet. 1994; 55: 278–86.

de Mattia F, Savelkoul PJ, Kamsteeg EJ, Konings IB, van der Sluijs P, Mallmann R, Oksche A, Deen PM. Lack of arginine vasopressin-induced phosphorylation of aquaporin-2 mutant AQP2-R254L explains dominant nephrogenic diabetes insipidus. J Am Soc Nephrol. 2005; 16: 2872–80.

Feldman BJ, Rosenthal SM, Vargas GA, Fenwick RG, Huang EA, Matsuda-Abedini M, Lustig RH, Mathias RS, Portale AA, Miller WL, Gitelman SE. Nephrogenic syndrome of inappropriate antidiuresis. N Engl J Med. 2005; 352: 1884–90.

Garofeanu CG, Weir M, Rosas-Arellano MP, Henson G, Garg AX, Clark WF. Causes of reversible nephrogenic diabetes insipidus: a systematic review. Am J Kidney Dis. 2005; 45: 626–37.

Inaba S, Hatakeyama H, Taniguchi N, Miyamori I. The property of a novel v2 receptor mutant in a patient with nephrogenic diabetes insipidus. J Clin Endocrinol Metab. 2001; 86: 381–5.

Iolascon A, Aglio V, Tamma G, D'Apolito M, Addabbo F, Procino G, Simonetti MC, Montini G, Gesualdo L, Debler EW, Svelto M, Valenti G. Characterization of two novel missense mutations in the AQP2 gene causing nephrogenic diabetes insipidus. Nephron Physiol. 2007; 105: 33–41.

Kamsteeg EJ, Bichet DG, Konings IB, Nivet H, Lonergan M, Arthus MF, van Os CH, Deen PM. Reversed polarized delivery of an aquaporin-2 mutant causes dominant nephrogenic diabetes insipidus. J Cell Biol. 2003; 163: 1099–109.

Kamsteeg EJ, Wormhoudt TA, Rijss JP, van Os CH, Deen PM. An impaired routing of wild-type aquaporin-2 after tetramerization with an aquaporin-2 mutant explains dominant nephrogenic diabetes insipidus. EMBO J. 1999; 18: 2394–400.

Khanna A. Acquired nephrogenic diabetes insipidus. Semin Nephrol. 2006; 26: 244–8.

Kinoshita K, Miura Y, Nagasaki H, Murase T, Bando Y, Oiso Y. A novel deletion mutation in the arginine vasopressin receptor 2 gene and skewed X chromosome inactivation in a female patient with congenital nephrogenic diabetes insipidus. J Endocrinol Invest. 2004; 27: 167–70.

Knoers NV. Hyperactive vasopressin receptors and disturbed water homeostasis. N Engl J Med. 2005; 352: 1847–50.

Knoers NV, Deen PM. Aquaporin molecular biology and clinical abnormalities of the water transport channels. Curr Opin Pediatr. 1998; 10: 428–34.

Knoers NV, Monnens LL. Nephrogenic diabetes insipidus. Semin Nephrol. 1999; 19: 344–52.

Knoers NV, Deen PM. Molecular and cellular defects in nephrogenic diabetes insipidus. Pediatr Nephrol. 2001; 16: 1146–52.

Kuwahara M, Iwai K, Ooeda T, Igarashi T, Ogawa E, Katsushima Y, Shinbo I, Uchida S, Terada Y, Arthus MF, Lonergan M, Fujiwara TM, Bichet DG, Marumo F, Sasaki S. Three families with autosomal dominant nephrogenic diabetes insipidus caused by aquaporin-2 mutations in the C-terminus. Am J Hum Genet. 2001; 69: 738–48.

Lin SH, Bichet DG, Sasaki S, Kuwahara M, Arthus MF, Lonergan M, Lin YF. Two novel aquaporin-2 mutations responsible for congenital nephrogenic diabetes insipidus in Chinese families. J Clin Endocrinol Metab. 2002; 87: 2694–700.

Marr N, Bichet DG, Hoefs S, Savelkoul PJ, Konings IB, De Mattia F, Graat MP, Arthus MF, Lonergan M, Fujiwara TM, Knoers NV, Landau D, Balfe WJ, Oksche A, Rosenthal W, Muller D, Van Os CH, Deen PM. Cell-biologic and functional analyses of five new Aquaporin-2 missense mutations that cause recessive nephrogenic diabetes insipidus. J Am Soc Nephrol. 2002; 13: 2267–77.

Marr N, Bichet DG, Lonergan M, Arthus MF, Jeck N, Seyberth HW, Rosenthal W, van Os CH, Oksche A, Deen PM. Heteroligomerization of an Aquaporin-2 mutant with wild-type Aquaporin- 2 and their misrouting to late endosomes/lysosomes explains dominant nephrogenic diabetes insipidus. Hum Mol Genet. 2002; 11: 779–89.

Mizuno H, Fujimoto S, Sugiyama Y, Kobayashi M, Ohro Y, Uchida S, Sasaki S, Togari H. Successful treatment of partial nephrogenic diabetes insipidus with thiazide and desmopressin. Horm Res. 2003; 59: 297–300.

Morello JP, Bichet DG. Nephrogenic diabetes insipidus. Annu Rev Physiol. 2001; 63: 607–30.

Morello JP, Salahpour A, Laperriere A, Bernier V, Arthus MF, Lonergan M, Petaja-Repo U, Angers S, Morin D, Bichet DG, Bouvier M. Pharmacological chaperones rescue cell-surface expression and function of misfolded V2 vasopressin receptor mutants. J Clin Invest. 2000; 105: 887–95.

Moug SJ, McKee RF, O'Reilly DS, Noble S, Boulton-Jones M. The perioperative challenge of nephrogenic diabetes insipidus: a multidisciplinary approach. Surgeon. 2005; 3: 89–94.

Mulders SM, Bichet DG, Rijss JP, Kamsteeg EJ, Arthus MF, Lonergan M, Fujiwara M, Morgan K, Leijendekker R, van der Sluijs P, van Os CH, Deen PM. An aquaporin-2 water channel mutant which causes autosomal dominant nephrogenic diabetes insipidus is retained in the Golgi complex. J Clin Invest. 1998; 102: 57–66.

Nomura Y, Onigata K, Nagashima T, Yutani S, Mochizuki H, Nagashima K, Morikawa A. Detection of skewed X-inactivation in two female carriers of vasopressin type 2 receptor gene mutation. J Clin Endocrinol Metab. 1997; 82: 3434–7.

Pasel K, Schulz A, Timmermann K, Linnemann K, Hoeltzenbein M, Jaaskelainen J, Gruters A, Filler G, Schoneberg T. Functional characterization of the molecular defects causing nephrogenic diabetes insipidus in eight families. J Clin Endocrinol Metab. 2000; 85: 1703–10.

Pattaragarn A, Alon US. Treatment of congenital nephrogenic diabetes insipidus by hydrochlorothiazide and cyclooxygenase-2 inhibitor. Pediatr Nephrol. 2003; 18: 1073–6.

Postina R, Ufer E, Pfeiffer R, Knoers NV, Fahrenholz F. Misfolded vasopressin V2 receptors caused by extracellular point mutations entail congential nephrogenic diabetes insipidus. Mol Cell Endocrinol. 2000; 164: 31–9.

Rittig S, Robertson GL, Siggaard C, Kovacs L, Gregersen N, Nyborg J, Pedersen EB. Identification of 13 new mutations in the vasopressin-neurophysin II gene in 17 kindreds with familial autosomal dominant neurohypophyseal diabetes insipidus. Am J Hum Genet. 1996; 58: 107–17.

Robben JH, Knoers NV, Deen PM. Characterization of vasopressin V2 receptor mutants in nephrogenic diabetes insipidus in a polarized cell model. Am J Physiol Renal Physiol. 2005; 289: F265–72.

Robben JH, Sze M, Knoers NV, Deen PM. Rescue of vasopressin V2 receptor mutants by chemical chaperones: specificity and mechanism. Mol Biol Cell. 2006; 17: 379–86.

Robertson GL. Differential diagnosis of polyuria. Annu Rev Med. 1988; 39: 425–42.

Robertson GL. Diabetes insipidus. Endocrinol Metab Clin North Am. 1995; 24: 549–72.

Sadeghi H, Robertson GL, Bichet DG, Innamorati G, Birnbaumer M. Biochemical basis of partial nephrogenic diabetes insipidus phenotypes. Mol Endocrinol. 1997; 11: 1806–13.

Schulz A, Sangkuhl K, Lennert T, Wigger M, Price DA, Nuuja A, Gruters A, Schultz G, Schoneberg T. Aminoglycoside pretreatment partially restores the function of truncated V(2) vasopressin receptors found in patients with nephrogenic diabetes insipidus. J Clin Endocrinol Metab. 2002; 87: 5247–57.

Shalev H, Romanovsky I, Knoers NV, Lupa S, Landau D. Bladder function impairment in aquaporin-2 defective nephrogenic diabetes insipidus. Nephrol Dial Transplant. 2004; 19: 608–13.

Sohara E, Rai T, Yang SS, Uchida K, Nitta K, Horita S, Ohno M, Harada A, Sasaki S, Uchida S. Pathogenesis and treatment of autosomal-dominant nephrogenic diabetes insipidus caused by an aquaporin 2 mutation. Proc Natl Acad Sci U S A. 2006; 103: 14217–22.

Soylu A, Kasap B, Ogun N, Ozturk Y, Turkmen M, Hoefsloot L, Kavukcu S. Efficacy of COX-2 inhibitors in a case of congenital nephrogenic diabetes insipidus. Pediatr Nephrol. 2005; 20: 1814–7.

Tajima T, Okuhara K, Satoh K, Nakae J, Fujieda K. Two novel aquaporin-2 mutations in a sporadic Japanese patient with autosomal recessive nephrogenic diabetes insipidus. Endocr J. 2003; 50: 473–6.

Tan CM, Nickols HH, Limbird LE. Appropriate polarization following pharmacological rescue of V2 vasopressin receptors encoded by X-linked nephrogenic diabetes insipidus alleles involves a conformation of the receptor that also attains mature glycosylation. J Biol Chem. 2003; 278: 35678–86.

van Balkom BW, Savelkoul PJ, Markovich D, Hofman E, Nielsen S, van der Sluijs P, Deen PM. The role of putative phosphorylation sites in the targeting and shuttling of the aquaporin-2 water channel. J Biol Chem. 2002; 277: 41473–9.

van Lieburg AF, Knoers NV, Monnens LA. Clinical presentation and follow-up of 30 patients with congenital nephrogenic diabetes insipidus. J Am Soc Nephrol. 1999; 10: 1958–64.

Wildin RS, Cogdell DE, Valadez V. AVPR2 variants and V2 vasopressin receptor function in nephrogenic diabetes insipidus. Kidney Int. 1998; 54: 1909–22.

Yoo TH, Ryu DR, Song YS, Lee SC, Kim HJ, Kim JS, Choi HY, Kang SW. Congenital nephrogenic diabetes insipidus presented with bilateral hydronephrosis: genetic analysis of V2R gene mutations. Yonsei Med J. 2006; 47: 126–30.

Source

GeneReviews at NCBI

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