Vasopressin V2 receptor antagonists in ADPKD: improving aquaretic side-effects and beyond

Autosomal dominant polycystic kidney disease is a hereditary disease that leads to the formation of numerous cysts in both kidneys of affected patients. These cysts destroy healthy kidney tissue, leading to kidney failure in the majority of patients around 60 years of age. A crucial hormone that is implicated in formation of these cysts is vasopressin. The first part of this thesis aims to identify factors that influence vasopressin, in order to potentially develop strategies that can slow down disease progression. For example, it was found that reduction of salt intake could potentially slow down kidney function decline. The second part of this thesis investigates the only effective drug that is available in polycystic kidney disease: the vasopressin antagonist tolvaptan. Tolvaptan blocks the hormone vasopressin, which leads to less cyst formation and slower kidney function decline. Unfortunately, tolvaptan also has side-effects: it causes massive urine production, up to 10 L per day. This thesis investigates whether this side-effect can be reduced. Potential strategies were investigated in mice with polycystic kidney disease, as well as in a clinical trial with patients. Three effective strategies were found. (1) Reduction of salt and protein intake. (2) The drug hydrochlorothiazide, which can reduce urine production by 25%. (3) The drug metformin, which can reduce urine production by 22%. The results of this thesis can help to make treatment with tolvaptan more tolerable, making it a better treatment option for patients with polycystic kidney disease.