DiagnosisClinical DiagnosisNephrogenic diabetes insipidus (NDI) is suspected in individuals with:Polyuria (excessive urine production); Polydipsia (excessive drinking).TestingTests 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: >807 mOsm/kg H₂O in normal individuals; <200 mOsm/kg H₂O 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. 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 NDIView in own windowGene SymbolProportion of NDI Attributed to Mutations in This GeneTest MethodMutations DetectedMutation Detection Frequency by Gene and by Test Method ^{1Test AvailabilityAVPR290%Sequence analysisSequence variants 2~95% of individuals with X-linked NDIClinicalDeletion / duplication analysis 3Exonic and whole-gene deletions / duplicationsUnknown 4Linkage analysis 5Not applicableAQP2~10%Sequence analysisSequence variants 2~95% of individuals with autosomal recessive or autosomal dominant NDIClinicalLinkage analysis 5Not applicable1. The ability of the test method used to detect a mutation that is present in the indicated gene2. 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.3. 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.4. Exonic and partial- and whole-gene deletions have been reported (see Table A. Genes and Databases, HGMD).5. 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 Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here. Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing StrategyTo 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.Genetically Related (Allelic) DisordersAVPR2. Gain-of-function mutations in AVPR2 were reported to produce a very rare disorder called "nephrogenic syndrome of inappropriate antidiuresis" [Feldman et al 2005, Knoers 2005, Levtchenko & Monnens 2010]. AQP2. No other phenotypes are known to be associated with mutations in AQP2.}

Natural HistoryNephrogenic 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 CorrelationsX-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 G_s, 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 G_s/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].

Differential DiagnosisDiabetes 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 , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).X-linked NDIAutosomal NDI

ManagementEvaluations Following Initial DiagnosisTo 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 consultationTreatment of ManifestationsManagement 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 ComplicationsPrevention 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. SurveillanceThe 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 AvoidWater intake must not be restricted. Evaluation of Relatives at RiskIt 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 there are no reports of pregnancies in women with NDI resulting from two AQP2 mutations. 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 InvestigationIn 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 V_1a 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 V_1a 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.

Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDAVPR2Xq28Vasopressin V2 receptorAVPR2 @ LOVDAVPR2AQP212q13​.12Aquaporin-2AQP2 homepage - Mendelian genesAQP2Data 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) View in own window 107777AQUAPORIN 2; AQP2 125800DIABETES INSIPIDUS, NEPHROGENIC, AUTOSOMAL 300538ARGININE VASOPRESSIN RECEPTOR 2; AVPR2 304800DIABETES INSIPIDUS, NEPHROGENIC, X-LINKEDAVPR2 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, NDI Database]. 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 GeneReviewView in own windowClass of Variant AlleleDNA Nucleotide ChangeProtein Amino Acid ChangeReference SequencesPathologic alleles resulting in partial phenotype ^{1c.253G>Ap.Asp85AsnNM_000054​.4
NP_000045​.1c.602G>Ap.Gly201Aspc.964C>Tp.Pro322SerSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).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 G_s 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 (G_s), 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 Autosomal recessive NDI. Over 40 mutations that give rise to autosomal recessive NDI have been detected in AQP2. These include 32 missense mutations, two nonsense mutations, two 1-bp deletions, one 2-bp deletion, and three splice site mutations [Knoers & Monnens 1999, Knoers & Deen 2001, Morello & Bichet 2001, Lin et al 2002, Marr et al 2002a, Tajima et al 2003, Iolascon et al 2007, Sahakitrungruang et al 2008, Moon et al 2009, Wesche et al 2012]. Autosomal dominant NDI. Mutations (three missense, one 1-bp insertion, and four small deletions) identified in eight families with autosomal dominant NDI are located in the carboxy-terminal region of aquaporin-2, a region considered to be important for targeting of the protein [Kamsteeg et al 1999, Kuwahara et al 2001, Marr et al 2002b, Sohara et al 2006; Wesche et al 2012]. 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].