Two distinct pathophysiological mechanisms in congenital nephrogenic diabetes insipidus

V1 and V2 vasopressin receptor functions were studied in 2 patients with congenital nephrogenic diabetes insipidus. V1 receptor-mediated functions (increase in urinary prostaglandin E2 excretion and plasma cortisol levels) and Gs (guanine nucleotide-binding stimulatory protein) activity of erythrocyte membranes were normal in both patients. After infusion of 0.4 micrograms/kg dDAVP, a 57-yr-old male patient had no increase in plasma factor VIII coagulant, ristocetin cofactor, or fibrinolytic activity or change in von Willebrand factor multimers. In addition, he had no vasodilatory response to dDAVP, a response that occurs in normal subjects and patients with central diabetes insipidus. In contrast, a 25-yr-old female patient had normal hemostatic and vasodilatory responses to the infusion of dDAVP. These observations indicate that the cellular abnormalities in patients with congenital nephrogenic diabetes insipidus may be either at the V2 receptor or in the postreceptor (and Gs activity) cascade of events that mediate vasopressin-induced antidiuresis. Therefore, heterogeneity exists in the biochemical cause(s) of congenital nephrogenic diabetes insipidus in man.