#2225 The effect of fluconazole on polyuria and urine concentration ability in nephrogenic diabetes insipidus

Abstract Background and Aims Congenital nephrogenic diabetes insipidus (NDI) is a rare disease with severe polyuria, often >10L/day, polydipsia and risk of life threatening dehydration upon water deprivation. It is primarily caused by loss-of function mutations of the vasopressin-2 receptor gene, causing inability to insert otherwise functional aquaporin 2 (AQP2) in the apical membrane of the principal cells in the renal collecting ducts. No causal treatment exists. Administration of fluconazole, an antimycotic drug, increased plasma membrane localization of AQP2 and reduced urinary output in the absence of vasopressin in tolvaptan treated mice. We aimed to test if fluconazole reduces diuresis and improves urinary concentration ability in patients with NDI. We present the interim analysis of the first four patients to complete the study as defined in the protocol. Method The study is an ongoing Danish-German, open-label, non-randomized intervention study. The aim is to include 10 male patients with X-linked NDI due to a verified mutation in AVPR2. The patients were treated with fluconazole 400 mg per day for two weeks. This was extended to three weeks if there were indications of a beneficial effect. 24-hour urine samples, blood samples, body weight and body composition monitoring (BCM) were performed weekly during the intervention. A water deprivation test was performed before and after two weeks of treatment. During the water deprivation test, blood and urine samples were obtained hourly along with body weight and BCM measurements. Plasma sodium concentration above 150 mmol/L or a weight loss of 3% body weight from baseline during the water deprivation test were defined as stop criteria. The primary outcomes were 24-hour urinary volume and the urinary concentration ability evaluated urine osmolality and time to reach the stop criteria in the water deprivation test. Secondary outcomes were urine- and plasma osmolality, plasma vasopressin, co-peptin and electrolyte concentrations, micturition frequency and the abundance of AQP2 in urinary exosomes. Results Four patients have completed the study. Median age was 39 years (range 32 to 57). One patient terminated the treatment after two weeks (ID2) due to increasing diuresis after initiating fluconazole, whereas the remaining patients completed three weeks of treatment. Baseline 24-hour diuresis ranged from 4846 mL/day to 13270 mL/day. Fluconazole did not decrease diuresis in any of the four participants (Fig. 1A) nor impact 24-hour urinary osmolality (Fig. 1B). Two patients completed 8 hours of water deprivation without fulfilling the stop criteria at baseline and their maximal urine osmolality during water deprivation did not increase after two weeks of fluconazole. Of the remaining two participants, one increased his urinary concentration ability to a maximum of 179 mOsm/L after fluconazole compared to 101 mOsm/L at baseline (ID4, Fig. 1C and D) and completed 7 hours of water deprivation before fulfilling the stop criteria compared to 4 hours at baseline. The other participant (ID1) did not increase his maximal urinary osmolality nor the tolerated water deprivation time. Fluconazole was well tolerated in all participants with no reported side effects. Analyses of plasma osmolality, vasopressin, co-peptin and urinary AQP2 are pending. Conclusion Fluconazole for two to three weeks did not reduce polyuria in four patients with NDI. Two participants had a weak phenotype allowing 8 hours of water deprivation without severe dehydration or hypernatremia despite genetically proven mutations in the AVPR2 gene. One patient had a clinically meaningful improvement of his urine concentration ability albeit still far from normal level. Based on the results of this interim analysis, a beneficial effect of fluconazole in selected patients cannot be ruled out. The study will aim to include the planned 10 participants to further evaluate the potential benefits of fluconazole in the management of patients with NDI.