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Authorship note: JAT and MR are co-first authors and contributed equally to this work. Conflict of interest: JT and TW are listed inventors on a provisional patent application (62818538) by the University of California Santa Barbara (UCSB) related to discoveries reported in this paper. TW is an inventor on a patent application (15/326296) by UCSB. BC reports consulting fees from Otsuka Pharmaceuticals. MM reports grants and consulting fees from Otsuka Pharmaceuticals, Sanofi, and Chinook Therapeutics. BH is a consultant for Oxthera AB, Alexion Pharmaceuticals, Dicerna Pharmaceuticals, Alnylam Pharmaceuticals, and Allena Pharmaceuticals. RH is on the Advisory Board of Chinook Therapeutics and is an inventor on 2 pending patents (15/545818 and 62/849564) filed by Wake Forest University and UAB. VET reports grant funding from

Mutations in the gene coding for the integral membrane protein polycystin-1 (PC1) are the cause of most cases of autosomal-dominant polycystic kidney disease (ADPKD), a very common disease that leads to kidney failure and currently lacks approved treatment. Recent work has revealed that PC1 can regulate the transcription factor STAT3, and that STAT3 is aberrantly activated in the kidneys of ADPKD patients and PKD mouse models. Recent approaches to directly inhibit STAT3 in PKD mouse models have been promising. Numerous signaling pathways are known to activate STAT3 and many have long been implicated in the pathogenesis of PKD-such as EGF/EGFR, HGF/c-Met, Src. However, a role of STAT3 in the pathogenesis of PKD had never been considered until now. Here, we review the current findings that suggest that STAT3 is a promising target for the treatment of PKD. Polycystic Kidney Disease ADPKD is a very common life-threatening, monogenic disease that is characterized by excessive proliferation and the growth of epithelial-lined cysts that eventually destroy the normal renal parenchyma [1, 2]. Most patients eventually progress to renal failure and will require dialysis or kidney transplantation. No approved treatment is currently available to halt or slow disease progression. However, a recent phase 3 trial using a vasopressin V 2receptor antagonist has shown promise in slowing the decline in kidney function [3]. ADPKD is caused by mutations in the PKD1 or PKD2 genes which encode the proteins polycystin-1 (PC1) and polycystin-2 (PC2), respectively. PC2 is a calcium channel of the TRP family, and forms a complex with PC1. In addition, PC1-which is mutated in most cases of ADPKD-has been shown to interact with a wide variety of signaling proteins and regulates numerous signaling pathways including heterotrimeric G proteins, wnt-, integrinand JAK/STAT-signaling, and the mTOR pathway. It has remained unclear which of these 1

Background Our laboratory published the first evidence that nutritional ketosis, induced by ketogenic diet (KD) or time-restricted diet (TRD), ameliorates disease progression in PKD animal models. We reasoned that, due to their frequent use for numerous health benefits, some ADPKD patients may already have had experience with ketogenic dietary interventions (KDIs). This retrospective case series study is designed to collect first real-life observations of ADPKD patients about safety, feasibility, and possible benefits of KDIs in ADPKD as part of a translational project pipeline. Methods Patients with ADPKD who had already used KDIs were recruited to retrospectively collect observational and medical data about beneficial or adverse effects, the feasibility and safety of KDIs in questionnaire-based interviews. Results 131 ADPKD patients took part in this study. 74 executed a KD and 52 TRD, for 6 months on average. 86% of participants reported that KDIs had improved their overall health. 67% described improvements in ADPKD-associated health issues. 90% observed significant weight loss. 64% of participants with hypertension reported improvements in blood pressure. 66% noticed adverse effects that are frequently observed with KDIs. 22 participants reported safety concerns like hyperlipidemia. 45 participants reported slight improvements in eGFR. 92% experienced KDIs as feasible while 53% reported breaks during their diet. Discussion Our preliminary data indicate that KDIs may be safe, feasible, and potentially beneficial for ADPKD patients highlighting that prospective clinical trials are warranted to confirm these results in a controlled setting and elucidate the impact of KDIs specifically on kidney function and cyst progression.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited cause of renal failure and has limited pharmacological treatment options. Disease progression is relentless, and regression is not a known feature of ADPKD even with pharmacological intervention. Recent research has uncovered underlying pathogenic mechanisms that may be amenable to dietary interventions. Cyst cells in ADPKD are thought to depend on glucose for energy and are unable to metabolize fatty acids and ketones. High-carbohydrate diets and lifestyles leading to hyperglycemia appear to worsen progression of ADPKD. Additionally, renal stressors such as oxalate, phosphate and uric acid, that lead to renal tubular micro-crystal burden appear to accelerate disease progression. Based on these research findings, we have created a remote, dietitian-supervised training program to teach individuals with ADPKD the implementation of dietary and lifestyle changes to avoid factors that may worsen disease progression. Using web-based platforms, digital tools, one-on-one remote meetings, and video group meetings, participants learn to implement a plant-focused ketogenic diet that avoids renal stressors, the science behind these changes, how to self-measure health parameters, and track nutrient intake. Dietary changes are supplemented with a medical food containing the ketone beta-hydroxybutyrate and alkaline citrate, and mindfulness exercises. Here, we report the first experience with this program from a beta test with approximately 24 participants. Most participants completed the program and reported improvements in their health and well-being including pain levels, weight loss, hypertension, and eGFR. Adherence to the program was very high and the feasibility of the dietary and lifestyle changes was rated highly. The Ren.Nu program is now publicly available to individuals with ADPKD.