Ketogenic Communication in Polycystic Kidney Disease

Study objective The objective of this study was to assess the effects of a ketogenic diet (KD) on metabolic changes in patients with autosomal-dominant polycystic kidney disease (ADPKD) and to examine its therapeutic potential. Hypothesis Based on strong animal data showing that ketogenic reprogramming reduces cyst growth by limiting glycolytic fuel to cystic epithelia, we hypothesise that a similar metabolic response may occur in ADPKD patients, leading to reduced cyst enlargement. Methodology Serum and urine from randomised ADPKD and control cohorts on KD or ketone-supplemented diets (KSD), along with samples from PKD rodent models, were examined using metabolomics, proteomics, imaging, ELISA, and kidney function assessment. Data We quantified 156 serum metabolites in ADPKD patients on KD, with 18 remaining consistently altered, including TCA, one-carbon, tryptophan/kynurenine, and urea cycle metabolites. Urine metabolomics showed increased uremic toxins excretion on KD, supported by PKD rodent models, underlying KD’s detoxifying effect. TCA metabolites were reduced, and glycolysis-related metabolites increased. Hypotaurine, carnitine, kynurenine, tryptophan, tyrosine, and phenylalanine decreased in both humans and rodents, indicating shared amino acid responses to ketosis. Given the metabolic similarities between human and rodent data, we performed kidney cortex proteomics in a rodent PKD model. We found that Slc5a8 (ketone transporter), Bhmt, Csad (both one-carbon metabolism), Vnn1 (CoA metabolism), Glud1, Aco1 (both TCA), and Kmo (kynurenine metabolism) increased in PKD animals compared to WT, showing increased expression on KD, indicating potential metabolic pathway normalisation. With ELISA, we confirmed that these changes also significantly reduced oxidative stress, as evidenced by normalisation of the reduced-to-oxidised glutathione ratio in kidney cortex tissue. An integrated proteome-metabolome data from all models suggested a sulfuric sink in PKD metabolism, which is targeted by ketosis. However, the metabolomics data of KSD in healthy and ADPKD patients revealed that ketogenic rewiring is exclusively driven by KD, but not by ketone bodies supplementation. We found that taurine-bile acid conjugation occurs on KD, potentially affecting cyst growth due to taurine depletion. Therefore, we tested mice supplemented with taurine and cysteamine as a precursor of hypotaurine. That led to increased cystic index (CI) in mice on cysteamine diet, however, without changes in kidney weight to body weight. Summary of results KD reverses the glycolytic dependence in ADPKD and reduces oxidative stress, a driver of cyst growth. Dietary ketosis proved superior to exogenous ketones. KD promotes taurine-bile acid conjugation, potentially depleting taurine and influencing cyst progression through altered sulfur metabolism. Conclusions Ketogenic diet induces beneficial metabolic reprogramming in ADPKD by restoring oxidative metabolism. These findings support KD as a therapeutic strategy, emphasising dietary intervention over supplementation. This abstract was presented at the American Physiology Summit 2026 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.