Effect of Tolvaptan in Combination with Rapamycin in a Rat Model of PKD

Background: Polycystic kidney disease (PKD) is a congenital fibrocystic disorder for which no curative treatment currently exists. Consequently, PKD is classified as a medical condition with high unmet therapeutic need. Animal models with improved clinical translatability are essential for evaluating the efficacy of novel drug candidates for PKD. The polycystic kidney (PCK) rat is a well-established genetic model of PKD recapitulating the natural history and renal histologic abnormalities of human PKD. In this study, we characterized the effect of the vasopressin V2 receptor antagonist Tolvaptan, the only approved drug treatment for PKD, in combination with an immunosuppressant/antiproliferative agent (Rapamycin) previously reported to slow cystogenesis in the PCK rat model. Methods: Male PCK rats (PCK/CrljCrl-Pkhd1pck/Crl, Charles River Laboratories) arrived at 4 weeks of age. Age-matched male Sprague-Dawley rats served as healthy controls. PCK rats were randomized and stratified into groups based on body weight and urine albumin-to-creatinine ratio (uACR). PCK rats received vehicle (IP), or Tolvaptan (0.01 % in diet, ad libitum) + rapamycin (0.15 mg/kg, IP) every third day. Urine was collected in treatment weeks 5 and 10 for uACR analysis. At study termination, kidney and liver weight was obtained. Quantitative cyst counts and volume were assessed by whole-kidney 3D light sheet imaging. Results: PCK rats displayed marked albuminuria and a significantly increased volume and number of renal cysts at 16 weeks of age compared to healthy controls. Notably, Tolvaptan and Rapamycin co-treatment normalized uACR levels concurrent with significantly reduced cyst formation in PCK rats. Conclusion: Combined Tolvaptan and Rapamycin therapy significantly reduces albuminuria and cystogenesis in the PCK rat model of PKD. High-resolution 3D light sheet imaging enables precise, whole-organ assessment of treatment effects in the PCK rat. Our study highlights the nephroprotective potential of the drug combination and supports the utility of the PCK rat as a robust disease model in preclinical drug discovery for PKD.