Long-term outcome in inherited nephrogenic diabetes insipidus

Sharma, Sonia; Ashton, Emma; Iancu, Daniela; Arthus, Marie‐Françoise; Hayes, Wesley; Hoff, William van’t; Kleta, Robert; Bichet, Daniel G.; Böckenhauer, Detlef

doi:10.1093/ckj/sfy027

Cited by 23 publications

(26 citation statements)

References 21 publications

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“…This study reported the first Taiwanese CNDI patient with a V279 deletion in the AVPR2 gene. A recent study with long-term follow-up by Sharma et al revealed that the median age of CNDI diagnosis was 0.6 years, which is in agreement with our patient [ 32 ]. The median age of 0.6 years for diagnosis is very often due to the fact that the early severe symptoms of CNDI are very similar to those of other diseases, and they are easily missed by physicians and pediatricians.…”

Section: Discussionsupporting

confidence: 92%

“…This dehydration test should be excluded in the future diagnosis in similar situations. Sharma et al also found that regular treatment favorably affects the long-term prognosis of CNDI regarding growth, as well as renal and intellectual function [ 32 ]. Early diagnosis and rigorous treatment are essential to improve the long-term growth and prognosis of CNDI patients [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

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Valine-279 Deletion–Mutation on Arginine Vasopressin Receptor 2 Causes Obstruction in G-Protein Binding Site: A Clinical Nephrogenic Diabetes Insipidus Case and Its Sub-Molecular Pathogenic Analysis

et al. 2021

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Congenital nephrogenic diabetes insipidus (CNDI) is a genetic disorder caused by mutations in arginine vasopressin receptor 2 (AVPR2) or aquaporin 2 genes, rendering collecting duct cells insensitive to the peptide hormone arginine vasopressin stimulation for water reabsorption. This study reports a first identified AVPR2 mutation in Taiwan and demonstrates our effort to understand the pathogenesis caused by applying computational structural analysis tools. The CNDI condition of an 8-month-old male patient was confirmed according to symptoms, family history, and DNA sequence analysis. The patient was identified to have a valine 279 deletion–mutation in the AVPR2 gene. Cellular experiments using mutant protein transfected cells revealed that mutated AVPR2 is expressed successfully in cells and localized on cell surfaces. We further analyzed the pathogenesis of the mutation at sub-molecular levels via long-term molecular dynamics (MD) simulations and structural analysis. The MD simulations showed while the structure of the extracellular ligand-binding domain remains unchanged, the mutation alters the direction of dynamic motion of AVPR2 transmembrane helix 6 toward the center of the G-protein binding site, obstructing the binding of G-protein, thus likely disabling downstream signaling. This study demonstrated that the computational approaches can be powerful tools for obtaining valuable information on the pathogenesis induced by mutations in G-protein-coupled receptors. These methods can also be helpful in providing clues on potential therapeutic strategies for CNDI.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Valine-279 Deletion–Mutation on Arginine Vasopressin Receptor 2 Causes Obstruction in G-Protein Binding Site: A Clinical Nephrogenic Diabetes Insipidus Case and Its Sub-Molecular Pathogenic Analysis

et al. 2021

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“…The inherited form of NDI is less frequent in children. Only a few clinical data on long-term outcomes exist (8).…”

Section: Introductionmentioning

confidence: 99%

Nephrogenic diabetes insipidus in children (Review)

et al. 2021

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Nephrogenic diabetes insipidus (NDI) is characterized by impaired urinary concentrating ability, despite normal or elevated plasma concentrations of the antidiuretic hormone, arginine vasopressin (AVP). NDI can be inherited or acquired. NDI can result from genetic abnormalities, such as mutations in the vasopressin V2 receptor (AVPR2) or the aquaporin-2 (AQP2) water channel, or acquired causes, such as chronic lithium therapy. Congenital NDI is a rare condition. Mutations in AVPR2 are responsible for approximately 90% of patients with congenital NDI, and they have an X-linked pattern of inheritance. In approximately 10% of patients, congenital NDI has an autosomal recessive or dominant pattern of inheritance with mutations in the AQP2 gene. In 2% of cases, the genetic cause is unknown. The main symptoms at presentation include growth retardation, vomiting or feeding concerns, polyuria plus polydipsia, and dehydration. Without treatment, most patients fail to grow normally, and present with associated constipation, urological complication, megacystis, trabeculated bladder, hydroureter, hydronephrosis, and mental retardation. Treatment of NDI consist of sufficient water intake, low-sodium diet, diuretic thiazide, sometimes in combination with a cyclooxygenase (COX) inhibitor (indomethacin) or nonsteroidal anti-inflammatory drugs (NSAIDs), or hydrochlorothiazide in combination with amiloride. Some authors note a generally favorable long-term outcome and an apparent loss of efficacy of medical treatment during school age.

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“…Persistent polyuria can lead to the development of kidney megacystis, hydroureter, and hydronephrosis. Repeated episodes of dehydration can cause cognitive difficulties ( 5 ), one of the most serious complication of NDI, probably secondary to hypoxic episodes ( 6 ). Establishing the genetic diagnosis is particularly important for NDI in order to enable early detection and a more efficient differential diagnosis in view of its unique associated features and long-term complications.…”

Section: Introductionmentioning

confidence: 99%

Integrating Population Variants and Protein Structural Analysis to Improve Clinical Genetic Diagnosis and Treatment in Nephrogenic Diabetes Insipidus

Liao

Xiang

et al. 2021

Front. Pediatr.

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Congenital nephrogenic diabetes insipidus (NDI) is a rare genetic disorder characterized by renal inability to concentrate urine. We utilized a multicenter strategy to investigate the genotype and phenotype in a cohort of Chinese children clinically diagnosed with NDI from 2014 to 2019. Ten boys from nine families were identified with mutations in AVPR2 or AQP2 along with dehydration, polyuria–polydipsia, and severe hypernatremia. Genetic screening confirmed the diagnosis of seven additional relatives with partial or subclinical NDI. Protein structural analysis revealed a notable clustering of diagnostic mutations in the transmembrane region of AVPR2 and an enrichment of diagnostic mutations in the C-terminal region of AQP2. The pathogenic variants are significantly more likely to be located inside the domain compared with population variants. Through the structural analysis and in silico prediction, the eight mutations identified in this study were presumed to be disease-causing. The most common treatments were thiazide diuretics and non-steroidal anti-inflammatory drugs (NSAIDs). Emergency treatment for hypernatremia dehydration in neonates should not use isotonic saline as a rehydration fluid. Genetic analysis presumably confirmed the diagnosis of NDI in each patient in our study. We outlined methods for the early identification of NDI through phenotype and genotype, and outlined optimized treatment strategies.

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Long-term outcome in inherited nephrogenic diabetes insipidus

Abstract: Background. Inherited nephrogenic diabetes insipidus (NDI) is a rare disorder characterized by impaired urinary concentrating ability. Little clinical data on long-term outcome exists.

Cited by 23 publications

References 21 publications

Valine-279 Deletion–Mutation on Arginine Vasopressin Receptor 2 Causes Obstruction in G-Protein Binding Site: A Clinical Nephrogenic Diabetes Insipidus Case and Its Sub-Molecular Pathogenic Analysis

Valine-279 Deletion–Mutation on Arginine Vasopressin Receptor 2 Causes Obstruction in G-Protein Binding Site: A Clinical Nephrogenic Diabetes Insipidus Case and Its Sub-Molecular Pathogenic Analysis

Nephrogenic diabetes insipidus in children (Review)

Integrating Population Variants and Protein Structural Analysis to Improve Clinical Genetic Diagnosis and Treatment in Nephrogenic Diabetes Insipidus

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