Relief of Nocturnal Enuresis by Desmopressin is Kidney and Vasopressin Type 2 Receptor Independent

Title: Relief of Nocturnal Enuresis by Desmopressin is Kidney and Vasopressin Type 2 Receptor Independent
Authors: Robben, Joris; Sze, Mozes; Knoers, Nine; Eggert, Paul; Deen, Peter M.T.; Muller, Dominik
Publisher: Journal of American Society of Nephrology
Date Published: March 27, 2007
Reference Number: 718

Primary nocturnal enuresis (PNE) is a common problem in childhood and adolescence. Although various treatments are highly effective, a common underlying hypothesis on the pathogenesis is lacking. The success of desmopressin, a synthetic analogue of the antidiuretic hormone vasopressin, has been attributed to increased renal water reabsorption that is mediated by activation of the renal vasopressin V2 receptor (V2R). However, this effect does not explain other symptoms of PNE, such as the failure to arouse upon bladder distension. This study identified a family in which one child displayed PNE and coexisting nephrogenic diabetes insipidus, as a result of a novel nonsense mutation in the V2R gene (C358X). Cell-biologic investigations revealed that V2R-C358X is retained in the endoplasmic reticulum and is unstable, which explains his nephrogenic diabetes insipidus. Consistently, extrarenal V2R-mediated responses were absent in the patient who was treated with desmopressin. Administration of desmopressin, however, changed his PNE into nocturia, because he now still voided unchanged high urinary volumes at night but woke up and went to the bathroom. Withdrawal of desmopressin was accompanied by bedwetting, whereas reintroduction again relieved the symptoms. Therefore, these data indicate that neither a functioning renal concentration system nor a functional V2R is needed for the therapeutic benefit of desmopressin in PNE. Rather, it suggests that another vasopressin receptor and other organ(s) is the target for desmopressin to relieve PNE.

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This translation by the NDI Foundation is to assist the lay reader. To provide a clear, accessible interpretation of the original article, we eliminated or simplified some technical detail and complicated scientific language. We concentrated our translation on those aspects of the article dealing directly with NDI. The NDI Foundation thanks the researchers for their work toward understanding and more effectively treating this disorder.
© Copyright NDI Foundation 2007 (JC)

Nephrogenic Diabetes Insipidus (NDI) is a disorder in which patients are unable to concentrate their urine in response to the antidiuretic hormone, arginine vasopressin (AVP) or a synthetic analogue of AVP, Desmopressin. Congenital NDI is due to either a mutation of the vasopressin-2 receptor (V2R) gene or the aquaporin-2 (AQP2) gene, with the former accounting for the vast majority of the cases. V2R mutants cannot bind with AVP, therefore the chemical sequence which leads to the insertion of AQP2 into the apical membrane of the principal cells in the kidney collecting duct cannot occur. AQP2 mutants cannot travel from the cell interior to the cell’s apical membrane. In both cases, the NDI patient will express the two major symptoms of NDI: excessive urination (polyuria) and excessive thirst (polydypsia).

Primary nocturnal enuresis (PNE) is the persistence of nightly bedwetting in children who are at least five years old. If a child wets his bed at least three times per week and has never had a period of six months where he did not wet the bed, and if he generally does not wake up before, during or after urinating in the night, then he is likely to be diagnosed for PNE. There is as yet no scientific consensus on the causes or mechanics of PNE.

Robben, et al., were presented with a unique opportunity to explore the workings of PNE when they were presented with two brothers whom they diagnosed with congenital NDI. In this instance, the NDI was due to a mutation of the V2R gene. One of the brothers experienced PNE, the other did not, though the latter did have to get up during the night to urinate. Administering Desmopressin to a PNE patient is one of three primary therapeutic options in use. The other two are alarm treatment and tricyclic antidepressants.

A patient with NDI resulting from a V2R mutation cannot concentrate urine in response to either AVP or Desmopressin. Still, the research team administered Desmopressin to its PNE NDI patient on the strength of its history of effectiveness with PNE patients, and because the mechanics of PNE were not clear enough to discount Desmopressin’s potential out of hand. Robben, et al., noted that their patient ceased his PNE when placed on Desmopressin. The patient still had to void high volumes of dilute urine during the night, but while taking Desmopressin, he was able to wake up in response to his bladder and urinate in the bathroom. When he was taken off Desmopressin, the patient experienced PNE. The researchers concluded that even if a person with PNE has neither functional V2Rs nor the ability to concentrate urine, Desmopressin may still prove effective in treating his or her PNE.