Professor, PhD, overlæge Claus Bistrup MD, PhD Gitte Rye Hinrichs and MD, PhD Line Aas Mortensen Department of Nephrology, Odense University Hospital
Projektet i tal
OPEN undersøgelse/kliniske data
Forventet # af deltagere
Inkluderet antal deltagere
Inkluderede deltagere med prøver
Treatment of congenital nephrogenic diabetes insipidus with fluconazole an antifungal medication
Congenital nephrogenic diabetes insipidus is a rare disease characterized by extreme polyuria (often > 15L / day) and excessive water intake. Currently, no causal treatment exists. An already approved antifungal drug, fluconazole, significantly reduces symptoms in an animal experiment. This study is a national, pharmacological study testing if fluconazole in patients diagnosed with NDI reduce urinary volume, with the perspective to relieve the severe impairment associated with NDI.
study objective is to test, if treatment with the antifungal medication fluconazole in patients diagnosed with NDI ameliorates symptoms (diuresis) by an increase in plasma membrane localization of AQP2 in the absence of a functional V2 receptor caused by a mutation in the AVPR2 gene. Recently, the antifungal drug fluconazole was identified as a candidate for AQP2 modulation, based on screening a library of 17,700 molecules in a cell-based assay. Administration of fluconazole increased plasma membrane localization of AQP2 in the absence of AVP and the abundance of AQP2 was improved caused by alterations in the phosphorylation status and ubiquitination and due to inhibition of RhoA. This was observed in cell and mouse studies. Further in vitro experiments confirmed an increased transepithelial water reabsorption in isolated mouse collecting ducts, and subsequent animal experiment with tolvaptan-induced diuresis (V2 antagonist), which represents a model for X-linked NDI, found that fluconazole reduced urinary output. We now want to pursue this observation in NDI patients.
Description of the cohort
Ten patients with nephrogenic diabetes insipidus caused by V2 receptor defects are recruited in Denmark.
Data and biological material
Medical history, symptoms, age, sex, objective findings, radiology, blood- and urine samples
Collaborating researchers and departments
Cardiovascular and renal research, University of Southern Denmark