Relief of nocturnal enuresis by desmopressin is kidney and Vasopressin type‐2 receptor independent

Nocturnal enuresis is a common problem in childhood and adolescence. Although different medical treatments and mechanical devices are highly effective, a common underlying hypothesis on the pathogenesis is lacking. The success of desmopressin, a synthetic analogue of the pituitary antidiuretic hormone vasopressin, has been attributed to increased renal water reabsorption mediated by the activation of the vasopressin V2 receptor (V2R). However, this effect does not explain other symptoms of PNE like the deep sleep and why patients do not wake up upon a full bladder. Here, we identified a family in which one child displayed co‐existing nephrogenic diabetes insipidus (NDI), due to a novel nonsense mutation in the V2R gene (C358X), and primary nocturnal enuresis. Cell‐biological investigations revealed that this mutation resulted in an instable V2R mutant that was retained in the endoplasmic reticulum, and was causal for NDI. Administration of desmopressin to the patient, however, changed nocturnal enuresis into nocturia, since he now voided unchanged high urinary volumes at night. Withdrawal of desmopressin was accompanied by bedwetting, while reintroduction again relieved the symptoms. Thus, our data clearly demonstrate that neither a functioning renal concentration system nor a functional V2R are needed for the therapeutic benefit of desmopressin in nocturnal enuresis. Rather, it implicates that another vasopressin receptor and other organs must be the target for desmopressin action and represent possibly the aetiology of nocturnal enuresis itself.