Combined Pharmacological and Surgical Treatment of Autosomal Recessive Polycystic Kidney Disease: Sex-Dependent Effects of Tolvaptan and Renal Denervation in the PCK Rat

Autosomal recessive polycystic kidney disease (ARPKD) is a rare genetic disease defined by a rapid onset and progression of renal cysts, ultimately leading to severe renal failure by early adulthood. Treatment options remain severely limited for ARPKD progression outside of kidney transplantation. The single FDA-approved treatment option available for the dominant form of the disease (i.e. ADPKD) is tolvaptan (TV), a vasopressin type 2 receptor (V2R) antagonist and is reported to slow cyst progression in the PCK rat model of ARPKD; however, it is not approved for use in ARPKD. Moreover, our laboratory has reported a similar mitigating effect on renal cystogenesis in the PCK rat by surgically ablating the renal nerves (i.e. renal denervation; RDNx), but the mechanisms remain unclear. We aimed to compare the separate and combined effects of TV and RDNx in the PCK rat. We hypothesized that RDNx and TV would similarly blunt cyst progression and improve renal function, and combined TV+RDNx would improve these effects. To test this hypothesis, 48 PCK rats (Age: 4 weeks) were randomly assigned to one of four treatments: Sham/Vehicle, Sham/TV, RDNx/Vehicle, or RDNx/TV (n=12/group; 6M/6F). Surgeries (sham or RDNx) were performed at 4 weeks of age, and animals were assigned to receive either normal chow diet (Teklad 2018) or 0.1% (w/w) TV-supplemented chow ad libitum through age week 10. RDNx was achieved by bilateral renal nerve bundle dissection along the renal artery followed by 10% phenol application. Sham surgeries applied sterile saline to the renal artery without nerve dissection. Renal function was assessed by serum creatinine, blood urea nitrogen (BUN), and 24-hour urine samples collected by metabolic caging. At week 10, animals were euthanized and tissues were collected for morphometric and histological analysis of renal cystogenesis and injury. Renal cystic index (% cystic area) was measured histologically. Renal cell proliferation was assessed by cAMP and ki67 assay. Treatment and sex-dependent effects were analyzed by two-way ANOVA and Dunnet post hoc test (*p<.05) vs. Sham/Vehicle. Data presented as mean±SEM. At end of study, renal cystic progression was similarly reduced (p<.05) in the RDNx, TV, and RDNx-TV males compared to Sham/Vehicle controls (*7.3±1.1 vs. *5.4±0.8 vs. *7.0±0.9 vs. 11.7±1.2 % cystic area). No effects on cystic index with RDNx, TV, or RDNx+TV were detected in the female PCK cohorts (p>.05). 24-hour urine was markedly increased with TV (40.2±3.2 ml/kg bwt) and combined TV+RDNx (72.1±10.2 ml/kg bwt) vs. Sham/Vehicle males (33.9±1.7 ml/kg bwt), which was further increased (p<.05) over two-fold in the females (TV 158.0.1±27.2; RDNx+TV 123.9±9.1 ml/kg bwt) compared to males. No polyuria effects were observed in the RDNx male/female cohorts. No effects of sex or treatment were detected in serum creatinine or BUN. Renal tissue analysis for cell proliferation (cAMP, ki67) is underway. Overall, these findings partially support our hypothesis, RDNx and TV similarly reduced cystic progression in the PCK male rats. In contrast, there was no additive anti-cystic effect with combined RDNx-TV treatment. Moreover, we failed to detect any treatment effect on renal cystic index in females. To our knowledge, this is also the first report to demonstrate a clear sex difference in polyuria response to TV treatment in the PCK rat. Together, these data demonstrate that RDNx was similarly effective as TV treatment in males without the polyuria effects. As no additive effect of RDNx+TV was observed, it remains possible that RDNx and TV treatments share a similar V2R, anti-cystic mechanism. Future studies into the potential relationship between renal nerves and the vasopressin activity in ARPKD are underway. Supporting in part by NIH R01DK135573 (CTB), PKD Foundation Award 1022534 (CTB) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.