Chronic kidney disease (CKD) is a global epidemic affecting more than 10% of the world's population and projected to become the fifth leading cause of death worldwide by 2040 1. Its progression is driven by hemodynamic and inflammatory injuries, as well as metabolic derangements that compromise the energy-demanding renal tubular epithelium. Among these, the abnormal accumulation of lipids within tubular cells, ectopic lipid deposition (ELD), has emerged as a consistent and mechanistically important feature of advanced CKD, even in patients without obesity or diabetes 2. A recent study in Acta Physiologica by Sanz-Gómez and colleagues 3 identifies a previously unrecognized metabolic axis linking elevated circulating citrate to renal lipotoxicity and opens an exciting new chapter in our understanding of the pathophysiology of CKD. The metabolic logic underpinning ELD in CKD centers on an imbalance between fatty acid synthesis and oxidation. Acetyl-CoA carboxylase (ACC) sits at center stage: it catalyzes the conversion of acetyl-CoA to malonyl-CoA, simultaneously fueling de novo lipogenesis and suppressing fatty acid oxidation (FAO) by inhibiting carnitine palmitoyl transferase 1 (CPT-1) 4. Under healthy conditions, AMP-activated protein kinase (AMPK) phosphorylates ACC at Ser79, holding it in an inactive monomeric form and maintaining the balance between lipid synthesis and FAO. In CKD, AMPK signaling is disrupted and ACC becomes overactive, promoting lipid accumulation and fibrosis 5. Pharmacological AMPK activation with metformin reduces renal fibrosis precisely through its downstream inhibitory phosphorylation of ACC 6, underscoring ACC as a central therapeutic node. It has remained unclear; however, why the AMPK-ACC axis decouples in CKD. Sanz-Gómez and colleagues provide a compelling answer to this important problem. Using the Munich Wistar Frömter (MWF) rat, a well-validated polygenic model of progressive CKD, and human embryonic kidney (HEK293) cells, they demonstrate that elevated plasma citrate drives ACC into an active polymerized state through an allosteric mechanism that is independent of AMPK phosphorylation. In the MWF model, plasma citrate was elevated 1.5-fold compared with age-matched controls, a finding that mirrors conditions in CKD patients 7. The authors propose that this hypercitratemia reflects two converging processes characteristic of advanced CKD: reduced urinary citrate excretion as glomerular filtration rate falls 8, and increased release of citrate from bone, where more than 90% of body citrate resides, driven by vitamin D deficiency-associated bone resorption. Consistent with this, MWF rats showed significantly reduced femoral bone mineral density and circulating vitamin D alongside their elevated plasma citrate. The mechanistic core of the study lies in what elevated citrate does inside renal tubular cells. ACC exists in equilibrium between an inactive monomer and an active polymer; citrate shifts this equilibrium toward polymerization, activating the enzyme allosterically. The authors demonstrate this directly using native gel electrophoresis in both kidney lysates and citrate-treated cells, showing that MWF kidneys and HEK293 cells exposed to 1.5 mM citrate both display a higher proportion of polymerized ACC. Crucially, the normal positive correlation between AMPK phosphorylation and ACC inhibitory phosphorylation remained intact in Wistar controls, but was entirely lost in MWF kidneys and in citrate-treated cells, even when AMPK was pharmacologically stimulated with AICAR, a well-known AMPK activator. Citrate, it appears, can override the kinase-mediated braking system. The downstream consequences are predictable and severe: upregulation of ATP-citrate lyase and fatty acid synthase, downregulation of CPT-1, accumulation of lipid droplets in tubular parenchyma, impaired mitochondrial respiratory chain complexes, and increased superoxide production. Untargeted lipidomics of MWF kidneys confirmed a coordinated increase in long-chain fatty acid species, alongside depletion of membrane-associated glycerophospholipids, a pattern consistent with lipid redistribution toward pathological storage. Importantly, the significance of this lipid burden for tubular cell fate has been powerfully illustrated in a recent study by Pierre and colleagues 9, which showed that palmitate-induced AMPK activity decline is the proximate cause of lysosomal alkalinization, autophagosome accumulation, and dedifferentiation in primary mouse proximal tubular epithelial cells. AMPK activators preserved lysosomal acidification and the differentiated phenotype, with protection dependent on ACC phosphorylation at the same Ser79 residue. Taken together, citrate-driven ACC polymerization removes the AMPK brake, unleashing a lipotoxic cascade in which lysosomal dysfunction possibly is a critical intermediate step on the way to tubular dedifferentiation and fibrosis (Figure 1). This concept is further reinforced by work from Nakamura et al., who demonstrated that activation of TFEB-mediated lysosomal exocytosis alleviates renal lipotoxicity and restores tubular function, underscoring that lysosomal homeostasis is a central determinant of tubular cell fate in CKD 10. The study Sanz-Gómez and colleagues may have two translational implications. First, ACC and its upstream regulator ATP-citrate lyase emerge as potential therapeutic targets. Bempedoic acid, an ATP-citrate lyase inhibitor already in clinical use for cholesterol lowering, could in principle interrupt this pathway in the kidney, a hypothesis that merits dedicated study. Pharmacological AMPK activation, which Pierre et al. showed can restore lysosomal function and tubular differentiation even under lipid stress 9, represents a further avenue that may act downstream of citrate to rescue the tubular phenotype. Second, the authors raise a thought-provoking concern about regional citrate anticoagulation in dialysis: patients receiving citrate as an anticoagulant during renal replacement therapy are already vulnerable to citrate accumulation, and the present data suggest this exposure could amplify rather than mitigate renal metabolic injury. The causal relationship between hypercitratemia and ACC-driven ELD is supported by compelling in vivo correlations and direct in vitro evidence, but future studies employing dietary citrate loading, transporter-specific knockouts, or isotopic flux measurements are needed to establish causality with full rigor. Nevertheless, by connecting CKD-mineral bone disorder to renal lipotoxicity through the allosteric regulation of a central metabolic enzyme, Sanz-Gómez and colleagues have identified citrate, a molecule long considered a benign TCA cycle intermediate, as an unexpected driver of kidney disease progression. This finding adds a new dimension to the emerging view of CKD as a fundamentally metabolic disorder, in which the interplay between lipid dysmetabolism, energy sensing, and organelle homeostasis determines tubular fate 11. The author declares no conflicts of interest. This article is linked to Sanz-Gómez et al. paper. To view this article, visit https://doi.org/10.1111/apha.70219. Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.
Nils J. Færgeman (Tue,) studied this question.