Congenital Nephrogenic Diabetes Insipidus Research Articles

The Benefit Of A Mitrofanoff Stoma In Patients With Unusual Indications. Case Report Of Two Patients Before And After Mitrofanoff Operation

PURPOSE It is sometimes difficult to motivate a child or adolescent to undergo a urine diversion and CIC. The aim of this report is to describe quality of life and renal function for two patients before and after Mitrofanoff diversion without bladder augmentation. MATERIAL AND METHODS Two boys,born 1994 and 1995. One boy presented at our clinic with severe incontinence, poor bladder emptying, increasing hydronephrosis and recurrent uti:s that affected his renal function. He was later diagnosed with Hinman bladder. The other boy has a congenital nephrogenic diabetes insipidus with a urine production of about 10 l/day. He expressed problems with drousiness because of lack of sleep, having to empty his bladder several times every night. He also failed to grow according to his age. Both were followed by urotherapist and urologist/nephrologist about two years before the operation and are continiously followed afterwards with urotherapy coaching, kidney function tests, blood tests etc. Both patients use a night drainage catheter. The boy with Hinman is doing CIC every four hours. RESULTS Both patients had their Mitrofanoff deviation performed in our department. One boy visited the psychologist before surgery, wich helped him cope with his fear of the operation and the CIC procedure. He also met another patient with Mitrofanoff. Today he is continent and has no more uti:s. The other patient uses his deviation only for night drainage, which has given him the possibility to sleep the whole night, something he never did before surgery. GFR improved in both boys. CONCLUSIONS Mitrofanof deviation and CIC can improve life quality and renal function for patients with unusual diagnoses. Good coaching and follow up by urotherapist and doctors are necessary for a good outcome.

Congenital nephrogenic diabetes insipidus: what can we learn from mouse models?

Aquaporins (AQPs) are central players in mammalian physiology, allowing efficient water transport through cellular membranes. To date, 13 different aquaporins have been identified in mammals (AQP0-AQP12). Knocking out genes in mice and identification of mutations in the human genes provided important information on the role of AQPs in normal physiology. While the physiological role of many AQPs only becomes clear when the putative function is challenged, the lack of AQP2 directly results in a disease phenotype. Aquaporin 2 is highly expressed in the principal cells of the renal collecting duct, where it shuttles between intracellular storage vesicles and the apical membrane. Upon hypernatraemia or hypovolaemia, the antidiuretic hormone vasopressin (AVP) is released from the pituitary into blood and binds to its type 2 receptor on renal principal cells. This initiates a cAMP signalling cascade resulting in the translocation of AQP2-bearing vesicles to the apical membrane. Subsequently, pro-urinary water reabsorption and urine concentration occurs. This process is reversed by a reduction in circulating AVP levels, which is obtained with the establishment of isotonicity. In humans, mutations in the AQP2 gene cause congenital nephrogenic diabetes insipidus (NDI), a disorder characterized by an inability to concentrate urine in response to vasopressin. Until the recent development of several congenital NDI mouse models, our knowledge on AQP2 regulation was primarily based on in vitro studies. This review focuses on the similarities between the in vitro and in vivo studies and discusses new insights into congenital NDI obtained from the mouse models.

Novel Mutation of Aquaporin-2 Gene in a Patient with Congenital Nephrogenic Diabetes Insipidus

Congenital nephrogenic diabetes insipidus (CNDI) is a rare inherited disease, characterized by an inability of the kidney to concentrate urine in response to vasopressin. Three different inheritance patterns have been described, i.e., the X-linked recessive form associated with arginine vasopressin V2 receptor (AVPR2) gene mutations, the autosomal recessive and dominant forms of CNDI associated with mutations in the aquaporin-2 (AQP2) gene encoding the vasopressin-regulated water channel of the renal collecting duct. Our case is an 18-year-old male patient who complained of severe polyuria since his infancy. But his developmental and growth status were normal. He was diagnosed as CNDI by water deprivation test and genomic DNA sequencing, which revealed high plasma AVP levels but persistently low urine osmolalities to 6 h-water deprivation and the novel missense mutation S216F in exon4 of the AQP2 gene. Immunohistochemistry of renal biopsied tissue revealed that most of the AQP2 labeling was seen intracellularly in a dotted pattern in the collecting duct principal cells. Immunoblotting of urine samples revealed significantly decreased urinary excretion of AQP2 (approximately 7% of normal control). Here, we report a new case of CNDI associated with the novel missense mutation of the AQP2 gene.

Compound Heterozygous Mutation of Aquaporin 2 Gene in Woman Patient with Congenital Nephrogenic Diabetes Insipidus

We performed mutational analyses of a woman patient with congenital nephrogenic diabetes insipidus referred to us during pregnancy. The diagnosis was made during the neonatal period, after which she was treated with spironolactone and hydrochlorothiazide. Our examination showed the patient to be apparently in good health without definite evidence of dehydration. Serum and urine osmolality were 220 mOsm/L and 50 mOsm/L, respectively, and the serum concentration of AVP was 2.7 pg/mL. Results of a water-deprivation test performed after delivery were compatible with nephrogenic diabetes insipidus. Mutational analyses showed that the patient was a compound heterozygote with point mutations at nucleotide position 298 (G to A; G100R) in exon 1 and nucleotide position 374 (C to T; T125M) in exon 2 of the aquaporin 2 gene, which have been previously described.

Novel Treatment for Lithium-Induced Nephrogenic Diabetes Insipidus Rat Model Using the Sendai-Virus Vector Carrying Aquaporin 2 Gene

Congenital nephrogenic diabetes insipidus (NDI) is a chronic disorder involving polyuria and polydipsia that results from unresponsiveness of the renal collecting ducts to the antidiuretic hormone vasopressin. Either of the genetic defects in vasopressin V2 receptor or the water channel aquaporin 2 (AQP2) cause the disease, which interfere the water reabsorption at the epithelium of the collecting duct. An unconscious state including a perioperative situation can be life threatening because of the difficulty to regulate their water balance. The Sendai virus (SeV) vector system deleting fusion protein (F) gene (SeV/DeltaF) is considered most suitable because of the short replication cycle and nontransmissible character. An animal model for NDI with reduced AQP2 by lithium chloride was used to develop the therapy. When the SeV/DeltaF vector carrying a human AQP2 gene (AQP2-SeV/DeltaF) was administered retrogradely via ureter to renal pelvis, AQP2 was expressed in the renal collecting duct to reduce urine output and water intake by up to 40%. In combination with the retorograde administration to pelvis, this system could be the cornerstone for the applicable therapies on not only NDI patients but also other diseases associate with the medullary collecting duct.

Mutation Analysis of AVPR2 and AQP2 Gene in Chinese Patients with Congenital Nephrogenic Diabetes Insipidus

Abstract To detect mutations of the aquaporin 2 gene(AQP2) and the arginine vasopressin V2 receptor gene(AVPR2) of Chinese congenital nephrogenic diabetes insipidus, and to establish the foundation for further studying the emergence mechanism of the disease and clinical diagnosis, all the exons and part of introns of AQP2 and AVPR2 genes were amplified with intronic primers, using genomic DNA extracted from three patients with congenital nephrogenic diabetes insipidus and two mothers as template, PCR product was ligated into a T-vector and then sequenced. The result was compared with the database sequence to identify the mutable sites via a BLAST search, the incidence of every mutation was analyzed, and the putative transcription factor binding sites that maybe disturbed were analyzed by MAPPER. Mutation g.1394A>G in exon 3 of AVPR2 was detected in all the subjects, g.861C>T(S167L) in exon 2 of AVPR2 and IVS1+3G>A in intron of AQP2 were detected, respectively, in two patients, and c.836A>C in 3′ untranslated region of AQP2 was detected in two patients and one mother. Four mutations were identified. g.1394A>G of AVPR2 and c.836A>C of AQP2 have high incidence in patients with nephrogenic diabetes insipidus. Detection on the two sites may become auxiliary diagnosis index of congenital nephrogenic diabetes insipidus.

Identification of two novel aquaporin-2 mutations in a Thai girl with congenital nephrogenic diabetes insipidus

To describe a Thai girl with congenital nephrogenic diabetes insipidus (NDI) and perform mutation analysis of the AQP2 gene. Case report. A 6-year old girl with a history of failure to thrive, polydipsia and polyuria was studied. Polyuria and polydipsia were observed within the first few months of life. Despite normal serum osmolality and electrolyte, the result of water deprivation test was compatible with a diagnosis of NDI. The entire coding regions of the AQP2 gene were assessed by polymerase chain reaction and sequencing analysis. The presence of mutations was also confirmed by restriction enzyme digestion analysis. Two heterozygous novel missense mutations were identified. Both were located in exon 1; a guanine-to-thymine substitution at nucleotide position 3 (c.3G-->T) inherited from her mother and a guanine-to-adenine at position 85 (c.85G-->A) inherited from her father, resulting in a methionine to isoleucine at codon 1 (p.M1I) and glycine to serine at codon 29 (p.G29S), respectively. These mutations have never been previously described and were not detected in 100 ethnic-matched unaffected control chromosomes. We report two novel mutations of the AQP2 gene, p.M1I and p.G29S, associated with autosomal recessive congenital NDI. This study expands the genotypic spectrum of AQP2 mutations and emphasizes an important role of genetic testing for definite diagnosis and genetic counseling.

Correlation between Clinical Phenotypes and X-inactivation Patterns in Six Female Carriers with Heterozygote Vasopressin Type 2 Receptor Gene Mutations

About 90% of patients with congenital nephrogenic diabetes insipidus (NDI) have vasopressin type 2 receptor (V2R) gene mutations that are inherited in an X-linked recessive manner. Although most female carriers are asymptomatic, some female carriers show polydipsia and polyuria. The reason why female carriers show NDI symptoms is explained by skewed X-inactivation. We studied X-inactivation patterns of six female carriers with heterozygote V2R gene mutations. The X-inactivation pattern in peripheral blood leukocytes was examined using methylation analysis of the polymorphic CAG repeat in the androgen receptor gene. Two asymptomatic female carriers showed random X-inactivation (61.9% and 60.7%). Skewed X-inactivation patterns (71.6%, 79.4%, and 91.2%) occurring preferentially to normal X alleles were recognized in three female carriers who showed clinical NDI symptoms. However, in one female carrier who showed clinical NDI symptoms, random X-inactivation (55.4%) was recognized. In conclusion, the clinical NDI phenotypes may correlate with the X-inactivation patterns in female carriers with heterozygote V2R gene mutations. However, in some female carriers, we cannot predict the clinical phenotypes by the evaluation of the X-inactivation patterns in peripheral blood leukocytes, because X-inactivation ratios within an individual are sometimes different between tissues.

Partial nephrogenic diabetes insipidus caused by a novel mutation in the AVPR2 gene

To identify the molecular basis and clinical characteristics of X-linked congenital nephrogenic diabetes insipidus (CNDI) presenting with an unusual phenotype characterized by partial resistance to AVP. The proband was admitted at the age of 4 years with a history of polydipsia and polyuria since infancy. Initial clinical testing confirmed a diagnosis of diabetes insipidus (DI). Urine osmolarity rose during fluid deprivation and after 20 microg of intranasal desmopressin [1-deamino-8-D-arginine-vasopressin (dDAVP)]. A similar DI phenotype was found in his brother. The coding regions of the AVP gene and the AVP receptor 2 (AVPR2) genes were sequenced in two affected and three unaffected family members. Clinical studies included a fluid deprivation test, intranasal dDAVP challenge, infusion of graded doses of dDAVP and AVP, and measurements of 24-h urine output before and at the end of a 7-day therapeutic trial of intranasal dDAVP. A novel missense mutation (1454C > A) in exon 3 of the AVPR2 gene predicting a Ser329Arg substitution was identified in the X-chromosome of the two affected brothers and in one of the X-chromosomes in the mother. The AVPR2 gene was normal in two unaffected siblings. Under basal conditions, the 24-h urine volumes of the two affected boys were 5.5 l (229 ml/kg) and 3.5 l (192 ml/kg), the urine osmolalities were 78 and 90 mosm/kg, and plasma AVP 13.5 and 19.0 pg/ml. Urine osmolalities increased to 573 and 720 mosm/kg while plasma AVP levels were practically unchanged, 13.6 and 8.8 pg/ml, during fluid deprivation. Infusion of AVP resulted in urine osmolalities of 523 and 623 mosm/kg at plasma AVP levels of 58 and 42 pg/ml. Infusion of dDAVP had a similar effect, while treatment with standard doses of intranasal dDAVP had no effect on urine output. The affected members of this Belgian kindred have CNDI with partial resistance to AVP caused by a mutation in the AVPR2 gene that differs from any of the six mutations reported previously to produce this phenotype. Because the resistance to AVP is partial, this form of CNDI can be difficult to distinguish by indirect diagnostic tests from partial pituitary and dipsogenic DI.

Nephrogenic Diabetes Insipidus

Congenital nephrogenic diabetes insipidus is a rare disorder of resistance to Anti Diuretic Hormone (ADH), characterized by polyuria, polydipsia, low urine osmolality and high serum osmolality. Diagnosis is established by measuring serum and urine osmolality, water deprivation test and vasopressin challenge test. This report describes a 4½-year-old boy who presented to us with fever, polydipsia, polyuria and delayed language development and was diagnosed as a case of congenital nephrogenic diabetes insipidus.

Hyponatremia resulting from Arginine Vasopressin Receptor 2 gene mutation

Chronic hyponatremia, unless associated with extracellular fluid volume expansion, is an infrequent electrolyte imbalance in pediatrics. We report an infant with chronic hyponatremia suggestive of a syndrome of inappropriate secretion of antidiuretic hormone (SIADH), in the absence of ADH secretion. A mutation was found in the same codon of the gene that results in a loss-of- function of arginine vasopressin receptor 2 (AVPR2) observed in congenital nephrogenic diabetes insipidus. In this case, a gain-of- function of AVPR 2 was found to be responsible for a SIADH-like state.

Molecular genetic study of congenital nephrogenic diabetes insipidus and rescue of mutant vasopressin V2 receptor by chemical chaperones

X-linked nephrogenic diabetes insipidus is a rare disease caused by mutations in the arginine vasopressin V2 receptor (AVPR2) gene, which encodes vasopressin V2 receptor (V2R). More than a half of reported mutations in AVPR2 are missense mutations, and a large number of missense mutant receptors fail to fold properly and therefore are not routed to the cell surface. We analysed the AVPR2 gene in 14 unrelated patients with X-linked nephrogenic diabetes insipidus, and found 13 different mutations including eight missense point mutations. The cellular expression patterns of three missense mutant (A98P, L274P and R113W) and wild-type V2R were determined in transfected COS-7 cells. In contrast to wild-type V2R, the cell-surface expressions of mutant receptors were totally (A98P and L274P) or partially (R113W) absent. Instead, they were retained intracellularly. However, treatment of cells with two chemical chaperones (100 mmol/L trimethylamine oxide or 2% dimethyl sulfoxide) or incubation at 26 degrees C restored the cell-surface expressions of mutant receptors. These data show that some chemical chaperones correct the mistrafficking of misfolded A98P, L274P and R113W V2R. Thus, we believe that a therapeutic strategy based on chemical chaperones in patients with these mutations is worth trying.

Mouse models for congenital nephrogenic diabetes insipidus: what can we learn from them?

Mouse models for congenital nephrogenic diabetes insipidus: what can we learn from them?

Growth failure in an infant with congenital nephrogenic diabetes insipidus during sodium restriction.

Congenital nephrogenic diabetes insipidus (CNDI) is an inherited disorder characterized by renal tubular insensitivity to antidiuretic hormone, resulting in an inability to concentrate urine. We report on an infant boy with CNDI who showed growth failure during treatment with sodium restriction. At the age of 4 mo, he was diagnosed as having CNDI, judging from fever with hypernatremia (serum Na 153 mEq/L), diluted urine (urine osmolarity 193 mOsm/kg), high antidiuretic hormone (plasma antidiuretic hormone 53 pg/mL), and normal renal function (serum creatinine 0.3 mg/dL). His length and weight were mean +0.4 and –1.1 SD, respectively, at that time. He was treated with sodium restriction (sodium intake; 0.53 mEq/kg/day) using low sodium formula in addition to trichlormethiazide, spironolactone, and mefenamic acid. Growth failure developed: his length and weight were mean –2.4 and –3.3 SD, respectively, at the age of 10 mo. After withdrawal of sodium restriction to 1.5 mEq/kg/day of sodium intake without any change of caloric intake and medication, catch-up growth was observed. At the age of 39 mo, the patient’s height and weight were mean –0.8 and –0.6 SD, respectively. We conclude that excessive sodium restriction can cause growth failure in infants with CNDI.

Correlation Between AVPR2 Mutations and Urinary AQP2 Excretion in Patients with Nephrogenic Diabetes Insipidus

Activation of the V2 receptor by arginine vasopressin (AVP) results in trafficking of the water channel AQP2 to the luminal plasma membrane and a small amount into the urine. Mutations in the A VPR2 gene, encoding the AVP V2 receptor, result in congenital nephrogenic diabetes insipidus (CNDI). To determine a correlation between A VPR2 mutations and urinary AQP2 excretion, immunobloting was used to detect AQP2 in the urine of patients with CNDI before and after a dehydration test. The patients' genotype was determined using PCR amplification and direct sequencing of the complete A VPR2 gene. Urinary AQP2 excretion was absent in patients with severely debilitating mutations, a novel total deletion of the A VPR2 gene, and a novel nonsense mutation W296X. However, it was detected in siblings with a V88M missense mutation. Urinary AQP2 excretion correlated well with other tested phenotype markers. Urinary AQP2 excretion could be used to evaluate the remaining in vivo integrity of the AVP-V2 receptor-AQP2 cascade in patients with CNDI.

Urological complications of congenital nephrogenic diabetes insipidus––long-term follow-up of one patient

A male with a severe form of congenital nephrogenic diabetes insipidus (diuresis 10 l per day) had megaureters, megavesica, large residuum and a history of three traumatic ruptures of the megavesica and a recurrent urinary tract infection (RUTI). Hemodialysis was introduced at 41 years of age. At age of 42, he underwent a bilateral retroperitoneoscopic nephrectomy to prevent further RUTI and 8 months later transplantation of a cadaver kidney. Intermittent catheterization is necessary due to residual urine in the urinary bladder.

Deletion of the V2 vasopressin receptor gene in two Chinese patients with nephrogenic diabetes insipidus.

BackgroundCongenital nephrogenic diabetes insipidus (NDI) is a rare X-linked inherited disorder characterized by the excretion of large volumes of diluted urine and caused by mutations in arginine vasopressin receptor 2 (AVPR2) gene. To investigate the mutation of AVPR2 gene in a Chinese family with congenital NDI, we screened AVPR2 gene in two NDI patients and eight family members by PCR amplification and direct sequencing.ResultsFive specific fragments, covering entire coding sequence and their flanking intronic sequences of AVPR2 gene, were not observed in both patients, while those fragments were all detected in the control subjects. Several different fragments around the AVPR2 locus were amplified step by step. It was revealed that a genomic fragment of 5,995-bp, which contained the entire AVPR2 gene and the last exon (exon 22) of the C1 gene, was deleted and a 3-bp (GAG) was inserted. Examination of the other family members showed that the mothers and the grandmother were carriers for this deletion.ConclusionOur findings suggest that the two patients in a Chinese family suffering from congenital NDI had a 5,995-bp deletion and 3-bp (GAG) insertion at Xq28. The deletion contained the entire AVPR2 gene and exon 22 of the C1 gene.

Diabètes insipides néphrogéniques

Nephrogenic diabetes insipidus which can be inherited or acquired, is characterized by an inability to concentrate urine despite normal or elevated plasma concentrations of the antidiuretic hormone, arginine–vasopressine (AVP). Polyuria, with hyposthenuria and polydipsia are the cardinal clinical manifestations of the disease. Hypercalcemia, hypokaliemia, lithium administration and chronic renal failure are the principal causes of acquired nephrogenic diabetes insipidus. About 90 percent of patients with congenital nephrogenic diabetes insipidus are males with X-linked recessive nephrogenic diabetes insipidus who have mutations in the arginine–vasopressin receptor 2 ( AVPR2) gene that codes for the vasopressin V2 receptor. The gene is located in chromosome region Xq28. In about 10 percent of the families studied, congenital nephrogenic diabetes insipidus has an autosomal recessive or autosomal dominant mode of inheritance. In these cases, mutations have been identified in the aquaporin-2 gene ( AQP2), which is located in chromosome region 12q13 and codes for the vasopressin-sensitive water channel. Other inherited disorders with mild, moderate or severe inability to concentrate urine include Bartter's syndrome and Cystinosis. Identification of the molecular defect underlying congenital nephrogenic diabetes insipidus is of immediate clinical significance because early diagnosis and treatment of affected infants can avert the physical and mental retardation associated with episodes of dehydration.

Functional rescue of vasopressin V2 receptor mutants in MDCK cells by pharmacochaperones: relevance to therapy of nephrogenic diabetes insipidus

Intracellular retention of a functional vasopressin V2 receptor (V2R) is a major cause of congenital nephrogenic diabetes insipidus (NDI) and rescue of V2R mutants by nonpeptide antagonists may restore their basolateral membrane (BM) localization and function. However, the criteria for efficient functional rescue of G protein-coupled receptor (GPCR) mutants at clinically feasible antagonist concentrations are unknown. We found that the four nonpeptide antagonists SR49059, OPC31260, OPC41061, and SR121463B induced maturation and rescued the BM expression of eight of nine different V2R mutants, stably expressed in physiologically relevant polarized cells. The extent of maturation and rescued BM expression correlated with the antagonists' concentration and affinity for the V2R. Displacement of the antagonists by AVP and subsequent cAMP generation inversely correlated with the antagonists' affinities for the V2R but is partially influenced by antagonist-specific aspects. Despite limited increases in maturation and cell-surface expression of V2R mutants, the low-affinity SR49059 optimally induced functional rescue at high concentrations, due to its easy displacement by vasopressin. At clinically feasible antagonist concentrations, however, only the high-affinity antagonists OPC31260 and OPC41061 induced functional rescue, as at these concentrations the extent of BM expression became limited. In conclusion, functional rescue of mutant V2Rs at clinically feasible concentrations is most effective with high-affinity antagonists. As OPC31260 and OPC41061 are clinically safe, they are promising candidates to relieve NDI. Moreover, as numerous other diseases are caused by endoplasmic reticulum-retained GPCRs for which cell-permeable antagonists become available, our finding that high-affinity antagonists are superior is anticipated to be important for pharmacotherapy development of these diseases.

Hereditary Polyuric Disorders: New Concepts and Differential Diagnosis

The identification, characterization, and mutational analysis of genes coding for key proteins to the mechanisms of urine concentration provide the basis for understanding the 2 types of hereditary nephrogenic diabetes insipidus (NDI): a pure type characterized by loss of water only, and a complex type characterized by loss of water and ions. Patients with hereditary NDI bearing mutations in AVPR2, the gene coding for the arginine vasopressin 2 receptor, or in AQP2, the gene coding for the vasopressin-sensitive water channel, have a pure NDI phenotype with loss of water, but normal conservation of sodium, potassium, chloride, and calcium. Patients bearing inactivating mutations in 1 of the 5 genes (SLC12A1, KCNJ1, CLCNKB, CLCNKA, and CLCNKB in combination, or BSND) that encode the membrane proteins of the thick ascending limb of the loop of Henle have a complex polyuro-polydipsic syndrome with loss of water, sodium, chloride, calcium, magnesium, and potassium. The purpose of this article is to increase the general awareness of these congenital NDI patients to prevent severe episodes of dehydration and provide precise molecular diagnosis and treatment.