#4377 IMPACT OF TOLVAPTAN ON 24H-URINE VOLUME AND OSMOLALITY DURING THE UP-DOSING PHASE IN ADPKD PATIENTS: A SINGLE-CENTER STUDY
Authors: Todorova Polina , Arjune Sita , Hendrix Claudia , Oehm Simon , Schmidt Johannes , Krauß Denise , Boehm Volker , Grundmann Franziska , Mueller Roman-Ulrich 
Published: June 2023

Abstract

Background and Aims
ADPKD is the most prevalent genetic kidney disease. Tolvaptan is the first proven disease-modifying therapy, but is associated with aquaretic side effects, frequently leading to treatment discontinuation. Therefore, identifying factors, which can ameliorate the aquaretic side effects and facilitate therapy is crucial. Previous data reported 24h-osmolar excretion in urine or GFR as the main determinants of urine volume on tolvaptan but included only few patients. This study's objective was to prospectively examine the 24-hour urine volume and urine osmolality during the up-dosing phase of tolvaptan in a cohort with a moderate sample size and different subgroups in order to identify modifiable and non-modifiable factors for urine volume increase. Finally, quality of life (QoL) during tolvaptan treatment was investigated in relation to urine volume since these data are scarce thus far and provide crucial insights into the therapy burden.

Method
Analysis of 24-h urine collection at baseline and at least once on tolvaptan was carried out for 75 patients (complete cohort). For 35 patients (longitudinal cohort) urine collections were available for baseline and all three tolvaptan doses (45/15 mg, 60/30 mg and 90/30 mg). All patients are participants of the German AD(H)PKD registry. Sodium, protein and potassium intake were calculated from excretion in 24h-urine and QoL was assessed by the Short Form-12 (SF-12) questionnaire. Statistical analyses were computed using R statistical software. A p-value of &lt; 0.05 was regarded as significant.

Results
The mean age of the patients in the complete cohort was 41.3 ± 10.7 (range 18-64 years) with a mean eGFR of 67.3 ± 27.2 ml/min/1.73m2 and was similar to the longitudinal cohort with a mean age of 41.8 ± 10.1 (23-64 years) and eGFR of 69.4 ± 27.5ml/min/1.73m2. A significant increase (p&lt; 0.0001) in 24-h urine volume (138%) occurred only immediately after therapy initiation with no further significant increase during updosing in the complete and longitudinal cohort. In line with this 24h-urine osmolality decreased (57%) significantly (p&lt; 0.0001) only after beginning of treatment and remained almost unchanged after updosing. Total solutes, protein and sodium intake showed non-significant changes across all doses. There were no significant differences in urine volume between gender, age classes (&lt;45 vs. ≥45 years), or Mayo class when examining the various subgroups. Considering modifiable factors, 24h-urine volume was positively correlated with eGFR on tolvaptan reaching significance on 45/15 mg (p = 0.013) and 90/30 mg (p = 0.027). Patients &lt;45 years and patients with an eGFR ≥ 60 ml/min/1.73m2 experienced a significantly higher relative urine volume increase at the beginning (p = 0.0332 vs. ≥45 years and p = 0.0097 vs eGFR &lt; 60 ml/min/1.73m2) in the complete cohort. In multivariable linear regression analyses containing modifiable and non-modifiable covariates only sodium intake had a significant impact in tolvaptan-naive patients (p = 0.0064), while on tolvaptan age (p = 0.0008) and weight (p = 0.0190) became significant together with sodium intake (p = 0.0008) and potassium intake (p = 0.0040). Across the three tolvaptan doses no significant differences between the number of patients reaching pre-defined osmolality goals (&lt; 250 mosmol/kg for spontaneous urine and &lt; 150 mosmol/kg for 24h-urine) could be detected. Before and after tolvaptan treatment, neither the mental nor physical QoL changed significantly.

Conclusion
Our study showed that the significant rise in urine volume occurs immediately after therapy initiation with only minor and non-significant increases upon further updosing. Urine osmolality decreases significantly directly after start of tolvaptan and remains constant with most patients achieving adequate suppression of urine osmolality. Patient counseling should consider that younger patients and patients with better eGFR might experience stronger urine volume increase at the beginning and advising to reduce salt and potassium intake can ameliorate aquaretic side effects. Tolvaptan treatment showed no negative impact on QoL but further investigations in larger cohorts are needed.