Juul KV, Bichet DG, Nielsen S, Nørgaard JP. The physiological and pathophysiological functions of renal and extrarenal vasopressin V2 receptors. Am J Physiol Renal Physiol 306: F931-F940, 2014. First published March 5, 2014 doi:10.1152/ajprenal.00604.2013.-The arginine vasopressin (AVP) type 2 receptor (V2R) is unique among AVP receptor subtypes in signaling through cAMP. Its key function is in the kidneys, facilitating the urine concentrating mechanism through the AVP/V2 type receptor/aquaporin 2 system in the medullary and cortical collecting ducts. Recent clinical and research observations strongly support the existence of an extrarenal V2R. The clinical importance of the extrarenal V2R spans widely from stimulation of coagulation factor in the endothelium to as yet untested potential therapeutic targets. These include V2R-regulated membranous fluid turnover in the inner ear, V2R-regulated mitogensis and apoptosis in certain tumor tissues, and numerous other cell types where the physiological role of V2Rs still requires further research. Here, we review current evidence on the physiological and pathophysiological functions of renal and extrarenal V2Rs. These functions of V2R are important, not only in rare diseases with loss or gain of function of V2R but also in relation to the recent use of nonpeptide V2R antagonists to treat hyponatremia and possibly retard the growth of cysts and development of renal failure in autosomal dominant polycystic kidney disease. The main functions of V2R in principal cells of the collecting duct are water, salt, and urea transport by modifying the trafficking of aquaporin 2, epithelial Na ϩ channels, and urea transporters and vasodilation and stimulation of coagulation factor properties, mainly seen with pharmacological doses of 1-desamino-8-D-AVP. The AVPR2 gene is located on the X chromosome, in a region with high probability of escape from inactivation; this may lead to phenotypic sex differences, with females expressing higher levels of transcript than males. vasopressin V 2 receptor; arginine vasopressin V2 receptor; arginine vasopressin; desmopressin; extrarenal vasopressin V 2 receptor THE PURPOSE OF THIS REPORT is to review current evidence on the physiological and pathophysiogical functions of renal and extrarenal arginine vasopressin (AVP) type 2 receptors, referred to as V2Rs (Fig. 1).AVP is an important neurohypophyseal nonapeptide that, via its three receptor types, is primarily responsible for regulating osmotic homeostasis of body fluids, volume homeostasis, and vasoconstriction in addition to an array of central functions such as memory and learning (17,29). In addition to these endocrine functions, AVP also contributes to regulating mitogenesis, cell survival, and death (apoptosis) (77).AVP is released from its storage site in the posterior pituitary (Fig. 2) by highly sensitive osmotic stimuli, specifically by a Ͻ1-2% increase in plasma osmolarity, as originally detailed in the 1940s through classic research by Prof. E. B. Verney (125). AVP release may also ...

Increased age and female gender are well-known risk factors for the development of desmopressin-induced hyponatremia. However, little focus has been on exploring gender differences in the antidiuretic response to desmopressin. Based on an exploratory analysis from three clinical trials, we report a significant gender difference in the effects of desmopressin on nocturnal urine volume that could not be explained by pharmacokinetic differences. Mean desmopressin concentration profiles were tested for covariates, and age and gender were not statistically significant and only weight was significant for log(C(max)) (P = 0.0183) and borderline significant for log(AUC) (P = 0.0571). The decrease in nocturnal urine volume in nocturia patients treated with desmopressin over 28 days was significantly larger for women at the lower desmopressin melt doses of 10 and 25 μg than for men. The ED(50) for men was modeled to be 43.2 μg and 16.1 μg for women, with the ED(50) men/women estimated to be 2.7 (1.3-8.1 95% CI), corresponding to significantly higher sensitivity to desmopressin in women. An increasing incidence of hyponatremia with increasing dose was found, and at the highest dose level of 100 μg decreases in serum sodium were approximately twofold greater in women over 50 yr of age than in men. A new dose recommendation stratified by gender is suggested in the treatment of nocturia: for men, 50- to 100-μg melt is an efficacious and safe dose, while for women a dose of 25 μg melt is recommended as efficacious with no observed incidences of hyponatremia. Areas for further research are proposed to uncover pathophysiological mechanism(s) behind these gender differences.

QoL evaluated with a general and disease-specific instrument (SHS) was significantly impaired in patients with bulging around a sigmoidostomy. The Stoma-QoL questionnaire showed a small but statistically significant difference between patients with and those without bulging but the clinical significance is uncertain. Further studies are required to evaluate the role of some of the individual items in the Stoma-QoL questionnaire.

BackgroundQuality of life of stoma patients is increasingly being addressed in clinical trials. However, the instruments used in the majority of these studies have not been validated specifically for stoma patients. The aim of this paper is to describe the development and validation of a quality-of-life instrument, "Stoma-QOL", specifically for patients with colostomy or ileostomy.MethodsPotential items were formulated in English on the basis of the results of a series of semi-structured interviews with 169 adult stoma patients. The process resulted in a preliminary 37-item version, which was translated into French, German, Spanish and Danish, and administered repeatedly to 182 patients with colostomy or ileostomy. A psychometric selection of items was performed through Rasch Analysis. The measurement properties of the final questionnaire version were subsequently tested.ResultsThe 20 items in the final questionnaire covered four domains – sleep, sexual activity, relations to family and close friends, and social relations to other than family and close friends. These items were found to define a unidimensional variable according to Rasch specifications (Infit MNSQ < 1.3). Internal consistency reliability calculated as Cronbach's alpha was 0.92, i.e., highly reliable. Spearman's correlation coefficients of scores across times of administration was >0.88 (p < 0.01), indicating a high test-retest reliability. Item calibrations by country calculated as ICC were 0.81 (0.67–0.91 95% CI), confirming cross-cultural comparability across the European countries included in the study.ConclusionGiven the adequacy of the metric properties of the Stoma-QOL suggested by the psychometric analyses, this study confirms the suitability of the instrument in clinical practice and in clinical research.

CENTRAL DIABETES INSIPIDUS (CDI)is a chronic, heterogeneous condition characterised by polyuria and polydipsia due to a deficiency of arginine vasopressin (AVP) secretion [1]. The most frequent aetiology is the destruction or degeneration of the neurons that originate in the supraoptic and paraventricular nuclei of the hypothalamus [1]. Mutations in the gene that encodes AVP have also been shown to be responsible for CDI [1,2]. However, 30-50% of cases are considered idiopathic [3].Desmopressin is a synthetic analogue of AVP used in the treatment of CDI as a physiological replacement to maintain water balance and normal urine output. In Abstract. Central diabetes insipidus (CDI) is associated with arginine vasopressin (AVP) deficiency with resultant polyuria and polydipsia. Intranasal desmopressin provides physiological replacement but oral formulations are preferred for their ease of administration. This study aimed to demonstrate the efficacy and safety of desmopressin orally disintegrating tablet (ODT) in the treatment of Japanese patients with CDI, and confirm that antidiuresis is maintained on switching from intranasal desmopressin to desmopressin ODT. A total of 20 patients aged 6-75 years with CDI were included in this 4-week multicenter, open-label study. Following observation, patients switched from intranasal desmopressin to desmopressin ODT with titration to optimal dose over ≤5 days at the study site. Following three consecutive doses with stable patient fluid balance, patients were discharged with visits at Weeks 2 and 4. Following titration from intranasal desmopressin to ODT, the mean 24-hour urine volume was unchanged, indicating similar antidiuresis with both formulations. The proportion of patients with endpoint measurements (urine osmolality, 24-hour urine volume, hourly diuresis rate and urine-specific gravity) within normal range at Days 1-2 (intranasal desmopressin) and Week 4 (desmopressin ODT) was similar. The mean daily dose ratio of intranasal desmopressin to desmopressin ODT (Week 4) was 1:24 but a wide range was observed across individuals to maintain adequate antidiuretic effect. Hyponatraemia was generally mild and managed by dose titration. Desmopressin ODT achieved sufficient antidiuretic control compared to intranasal therapy and was well tolerated over longterm treatment. The wide range of intranasal:ODT dose ratios underline the importance of individual titration.