Clinical Heterogeneity of Calcium–Phosphate Disorders in Advanced CKD: A Narrative Review

Disturbances in calcium and phosphate homeostasis are central to chronic kidney disease–mineral and bone disorder (CKD-MBD), yet patients with advanced CKD or end-stage kidney disease may develop different skeletal and extraskeletal phenotypes despite similar circulating mineral and hormonal profiles. In this narrative review, we propose a tissue-specific susceptibility framework: systemic mineral dysregulation creates a permissive background, while local tissue biology, hemodynamic and mechanical forces, inflammation and oxidative stress, altered endogenous calcification inhibition, genetic susceptibility, and secondary clinical modifiers influence where and how individual phenotypes emerge. The most strongly implicated mechanisms differ by phenotype: active osteogenic transformation of resident cells in vascular and valvular calcification, superimposed thrombotic microvasculopathy in calciphylaxis, and predominantly extracellular mineral precipitation shaped by local conditions in tumoral calcinosis, with emerging experimental evidence of an active epithelial response in ocular calcification. Because routine biochemical parameters reflect the systemic milieu rather than tissue-level disease activity, they do not reliably identify which patients will develop specific phenotypes. CKD-MBD may therefore be better understood as a spectrum of organ-specific phenotypes arising from a common systemic disturbance. Progress will require biomarkers and imaging that capture tissue-level activity, and trials that distinguish prevention from treatment of established disease and use phenotype-specific endpoints.