Accelerated osteocytic citrate production in chronic kidney disease is associated with protection of the kidney

Har, J. R. G.; Hsu, M. Y.-H.; Saum, K. L.; Singh, A.; Sriram, R.; Kuennen, D. P.; Zhu, E. K.; Pennathur, S.; Antoniewicz, M. R.; Surface, L. E.

doi:10.1101/2025.10.08.681058

bioRxiv · 10.1101/2025.10.08.681058

Accelerated osteocytic citrate production in chronic kidney disease is associated with protection of the kidney

Har, J. R. G.·Hsu, M. Y.-H.·Saum, K. L.·Singh, A.·Sriram, R.·Kuennen, D. P.·Zhu, E. K.·Pennathur, S.·Antoniewicz, M. R.·Surface, L. E.

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Abstract

Patients with chronic kidney disease (CKD) face elevated fracture incidences, but mechanisms underlying CKD-related bone loss remain unclear. Using the adenine-induced chronic kidney injury (AdKI) murine model, we identified that AdKI induces dysregulated glucose metabolism in bones and kidneys via in vivo and ex vivo metabolic tracing. Ex vivo 13C-metabolic tracing of osteocyte-enriched femora revealed accelerated citrate production from [1,2-13C]-glucose and [U-13C]-glutamine in AdKI mice. These metabolic changes were observed together with increased circulating citrate and Slc13a5 overexpression in bones from AdKI mice. Thus, to explore the role of citrate in AdKI, we utilized mice harboring a loss of function mutation in the citrate importer SLC13A5 (Slc13a5R337*/R337*). Mutant mice displayed elevated osteocytic citrate production, and elevated circulating citrate, without significantly worsened AdKI-related bone loss. Coincident with this, Slc13a5R337*/R337* mutant mice were significantly protected from loss of kidney function with attenuated AdKI-induced nephrolithiasis. We also confirmed that Slc13a5 is highly expressed in cortical bone compared to the kidney, suggesting the effect of the mutation is mediated by SLC13A5s function outside the kidney. Altogether, this study finds that accelerated osteocytic citrate production in CKD is associated with protection of kidney function, and modulation of citrate handling may be a site for therapeutic intervention in CKD.

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Har, J. R. G., Hsu, M. Y.-H., Saum, K. L., Singh, A., Sriram, R., Kuennen, D. P., Zhu, E. K., Pennathur, S., Antoniewicz, M. R., Surface, L. E.. 2025-10-09. Accelerated osteocytic citrate production in chronic kidney disease is associated with protection of the kidney. https://doi.org/10.1101/2025.10.08.681058

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