Impact of fluconazole in vasopressin 2 receptor-related congenital arginine vasopressin resistance

INTRODUCTION: Arginine vasopressin resistance (AVP-R), previously called nephrogenic diabetes insipidus is a rare inherited disorder characterized by excessive urine output (often over 10 l/d) and a risk of life-threatening dehydration, resulting from kidney collecting duct insensitivity to arginine vasopressin. Currently, no curative treatment exists. Preclinical studies suggest that repurposing of anti-fungal fluconazole enhances AQP2-mediated water transport. Here, we present results from a clinical intervention study evaluating the effect of fluconazole on 24-hour urine output and urine concentrating ability in patients with congenital AVP-R caused by a pathogenic variant in the AVPR2 gene encoding the receptor of AVP. METHODS: We performed an open-label, non-randomized intervention in five adult males with AVPR2-related AVP-R. Participants received oral fluconazole 400 mg daily for 14 days, with baseline and follow-up assessments including water deprivation test. The primary endpoints were 24-hour urine output and urinary concentrating ability. Secondary endpoints included urinary and plasma osmolality, surrogate copeptin secretion, electrolytes, and micturition frequency. Safety and treatment adherence were evaluated weekly. RESULTS: Median fluconazole concentration following treatment were 13.7 µg/ml (range 12.1–24.4) in plasma and 28.6 µg/ml (range 22.4–34.7) in urine, respectively. Median change in 24-h urine output was +0.8 l (range −3.6 to +5.7) and in urine osmolality −3 mOsm/kg (range −78 to +25), with no change in micturition frequency. During water deprivation, body weight decreased −2.0 to −2.8 kg at baseline vs. −2.1 to −3.1 kg after treatment, urine osmolality changed −91 to +222 vs. −12 to +193 mOsm/kg, and plasma copeptin increased 4.8 to 16.8 vs. 4.2 to 12.9 pmol/l. CONCLUSIONS: Fluconazole treatment did not reduce urine output or improve urine concentrating ability in adult patients with congenital AVP-R.