Authors' Reply: A Calciprotein Particle–Centric Framework for Vascular Calcification in CKD Models

We thank Shunsuke Yamada and colleagues for their thoughtful comments1 on our recent JASN article “High Phosphate and Low Protein Mediate Arterial and Cutaneous Vascular Calcification in CKD Mice.”2 We appreciate their insightful discussion of our findings within the context of calciprotein particle biology. We agree that calciprotein particles represent an important systemic mediator linking mineral metabolism, protein nutrition, and vascular calcification in CKD. Indeed, lower fetuin-A and albumin levels, as highlighted by the authors, are likely contributors to increased calciprotein particle formation and maturation under conditions of protein restriction and phosphate loading.3 Although our study did not directly quantify calciprotein particles or serum T50, our data showing enhanced p38 mitogen-activated protein kinase activation and reduced calcification upon its inhibition suggest that downstream cellular responses to calciprotein particles or other mineral stressors may be critical drivers of tissue pathology. Our dietary model could mimic the clinical scenario in which CKD patients with poor nutritional status and high phosphate burden exhibit accelerated vascular and soft tissue calcification. The high-phosphate and low-protein diet combined with 5/6 nephrectomy reproduced both vascular and cutaneous calcification, consistent with the multifactorial perfect storm of uremia described by the authors.4 Their proposed calciprotein particle load framework complements our observations by providing a unifying view of how bone-derived mineral flux, reduced circulating inhibitors, and phosphate excess may converge to promote mineral stress and activate p38-dependent signaling pathways. Future work integrating direct calciprotein particle quantification, T50 kinetics, and cellular signaling analyses will help clarify the relative contributions of calciprotein particles versus other mineral–protein complexes in mediating vascular injury. We fully agree that combining biochemical markers of calciprotein particle dynamics with histologic and molecular end points may enhance the translational relevance of experimental models. We thank the authors again for their constructive comments and for emphasizing the importance of considering systemic calciprotein particle homeostasis in the study of CKD-associated vascular and soft tissue calcification.