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

Metabolites mediate inter-organ communication and this metabolic crosstalk often goes awry in systemic diseases, including chronic kidney disease-mineral bone disorder (CKD-MBD), where CKD disrupts skeletal homeostasis, with significant bone loss and increased fracture risk observed in patients. While metabolites from the injured kidney have been identified to disrupt bone function, whether metabolites from the bone influence kidney function over the course of CKD progression is less-understood. Given that bone-derived factors such as FGF23 and sclerostin influence CKD-MBD disease progression, we hypothesized that identifying skeletal metabolic fluxes disrupted in CKD may reveal other bone-derived metabolites that mediate nephropathy. We employed a combination of in vivo and ex vivo 13C-metabolic flux analysis (13C-MFA) to characterize how the adenine-induced kidney injury murine model of CKD-MBD rewires specific skeletal metabolic fluxes. Through 13C-MFA of bone tissue in vivo, and ex vivo cultures of calvariae and femora, we identified that this murine model of CKD-MBD accelerates osteocytic citrate production. 13C-isotopic tracing in OCY454 osteocytes suggests that this increased citrate flux is in part driven by PTH stimulation of glucose- and glutamine-to-citrate conversion in osteocytes. When citrate production is exacerbated by the loss of function mutation in SLC13A5 (Slc13a5R337*/R337*), a specialized plasma membrane citrate importer, we did not observe a significant worsening of bone loss in mutant mice due to chronic adenine-induced kidney injury. Intriguingly, kidney function appears to be protected, reducing secondary hyperparathyroidism and the severity of nephrolithiasis due to the adenine diet. Our observation on the role of citrate metabolism in CKD both confirms the relevance of citrate in managing patient kidney outcomes and suggests that organismal citrate metabolism may be modulated in the management of CKD-MBD. Altogether, this study reveals a potential new axis of metabolic regulation in the inter-organ communication between the skeleton and the kidneys.