Fariza Mukhammedova
1* 
, Shaxlo Orziqulova
2 , Lobar Shukurova
3 , Nargiza Pulatova
4 , Sergey Kityan
5 , Elena Akhmedova
6 , Mukhammad Amonov
7 , Rabbim Raxmatov
8 , Malika Saidova
9 , Faxriddin Madolimov
10 1 Department of Obstetrics and Gynecology №2, Samarkand State Medical University, Samarkand, Uzbekistan
2 Department of Clinical Sciences, Asia International University, Bukhara, Uzbekistan
3 Department of Family Medicine No. 2, Clinical Pharmacology, Tashkent State Medical University, Tashkent, Uzbekistan
4 Department of Clinical Pharmacology, Tashkent State Medical University, Tashkent, Uzbekistan
5 Department of Propaedeutics of Internal Diseases, Andijan State Medical Institute, Andijan, Uzbekistan
6 Department of Pediatrics, Fergana Medical Institute of Public Health, Fergana, Uzbekistan
7 Department of Hematology, Clinical Laboratory Diagnostics, Nephrology and Hemodialysis, Bukhara, Uzbekistan
8 Department of Higher Mathematics, Tashkent University of Information Technologies named after Muhammad Al-Khwarizmi, Tashkent, Uzbekistan
9 Department оf Metallurgy, Tashkent State Technical University named after Islam Karimov, Tashkent, Uzbekistan
10 Department of Software Engineering, Andijan State University, Andijan, Uzbekistan
Abstract
Chronic kidney disease-mineral and bone disorder (CKD-MBD) represents a complex systemic syndrome linking mineral metabolism abnormalities with extra-skeletal calcification and profound bone fragility. Whilst traditionally viewed through the lens of hormonal dysregulation involving parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF-23), emerging evidence highlights the pivotal role of immune-metabolic crosstalk in driving pathology. This overview considers how accumulated uremic toxins, such as indoxyl sulfate and p-cresyl sulfate, act as the potent inflammatory mediators that critically and directly disrupt the bone-vascular axis. These toxins trigger chronic low-grade inflammation by activating innate and adaptive immune cells, including macrophages and T-lymphocytes, which subsequently alter osteoblast and osteoclast function through pro-inflammatory cytokine release. Concurrently, metabolic disturbances characterized by oxidative stress and mitochondrial dysfunction exacerbate vascular smooth muscle cell (VSMC) transdifferentiation into osteogenic phenotypes, directly promoting arterial calcification. Then, the interplay between immune activation and metabolic reprogramming creates a vicious cycle where accelerated bone resorption releases minerals that deposit in the vasculature, further worsening cardiovascular outcomes. Meanwhile, the distinction between renal bone disease and vascular calcification blurs, unified by shared inflammatory pathways and metabolic derangements involving NF-κB signaling and RANKL pathways. Identification of these mechanistic links is necessary for developing novel therapeutic strategies beyond conventional phosphate binders. Targeting specific uremic toxins or modulating immune-metabolic signaling pathways offers highly significant promise. Finally, addressing the inflammatory milieu induced by uremia may mitigate the high cardiovascular mortality associated with CKD-MBD, necessitating a paradigm shift towards integrated immune-metabolic interventions in contemporary nephrology practice to improve overall patient survival and reduce fracture risk significantly.
Implication for health policy/practice/research/medical education:
Chronic kidney disease-mineral and bone disorder (CKD-MBD) represents a systemic syndrome linking mineral metabolism with vascular calcification and bone fragility. Though traditional views emphasize hormonal dysregulation, emerging evidence highlights critical immune-metabolic crosstalk driving pathology. This review explores how uremic toxins, such as indoxyl sulfate, act as potent inflammatory mediators. These toxins activate immune cells, fostering chronic inflammation that disrupts osteoblast differentiation and vascular smooth muscle cell phenotypic switching. This condition promotes bone resorption while simultaneously driving vascular calcification, illustrating significant bone-vascular axis dysregulation. We examine molecular pathways connecting metabolic waste retention to immune activation and tissue mineralization. Identification of these interactions is imperative, since current therapies often fail to address underlying inflammatory drivers linked to mortality. Targeting uremic toxins or inflammatory cytokines may offer novel strategies to decouple bone loss from vascular stiffening. Finally, integrating immune-metabolic perspectives into CKD-MBD management could improve cardiovascular outcomes and bone health in this high-risk population.
Please cite this paper as: Mukhammedova F, Orziqulova Sh, Shukurova L, Pulatova N, Kityan S, Akhmedova E, Amonov M, Raxmatov R, Saidova M, Madolimov F. Immune-metabolic crosstalk in chronic kidney disease-mineral and bone disorder; uremic toxins, inflammation, and bone-vascular axis dysregulation. J Nephropharmacol. 2026;15(x):e12879. DOI: 10.34172/npj.12879.