Phosphate is emerging as an active mediator of oxidative stress and vascular injury in chronic kidney disease (CKD). This emerging pathophysiological framework, referred to as “Phosphatopathy”, describes the systemic syndrome driven by chronic phosphate overload and characterized by oxidative stress, inflammation, endothelial dysfunction, vascular calcification, cellular senescence, and metabolic imbalance. Beyond being a biochemical marker, phosphate overload triggers NOX-derived reactive oxygen species (ROS), activates Wnt/β-catenin and TGF-β signaling, and disrupts the FGF23–Klotho axis, promoting endothelial dysfunction, vascular calcification, and left ventricular hypertrophy (LVH). These pathways converge with systemic inflammation and energy imbalance, contributing to the malnutrition–inflammation–atherosclerosis (MIA) syndrome. Experimental and clinical data reveal that the phosphate/urinary urea nitrogen (P/UUN) ratio is a sensitive biomarker of inorganic phosphate load, while emerging regulators such as microRNA-125b and calciprotein particles integrate phosphate-driven oxidative and inflammatory responses. Therapeutic strategies targeting phosphate burden—rather than serum phosphate alone—include dietary restriction of inorganic phosphate, non-calcium binders, magnesium and zinc supplementation, and activation of important pathways related to the activation of antioxidant defense such as AMP-activated protein kinase (AMPK) and SIRT1. This integrative framework redefines phosphate as a modifiable upstream trigger of oxidative and metabolic stress in CKD. Controlling phosphate load and redox imbalance emerges as a convergent strategy to prevent vascular calcification, improve arterial stiffness, and reduce cardiovascular risk through personalized, mechanism-based interventions.

Background/Objectives: It would be desirable to reduce the intake of inorganic phosphate (P), which is easily absorbed and is associated with cardiovascular disease. The phosphate-to-urea nitrogen ratio (P/UUN) in urine should reflect the proportion of inorganic P ingested relative to protein intake. In this manuscript, we will refer to this parameter as P/UUN, which is conceptually equivalent to the phosphate-to-urea ratio (P/U). These studies aim to evaluate whether an increased intake of inorganic P translates into an increase in the P/UUN. Methods: A total of 18 healthy volunteers (Study-1) and 18 chronic kidney disease patients (Study-2) were included. At baseline, all participants completed a 3-day dietary survey, and on the third day collected a 24 h urine sample. In Study-2, blood samples were also obtained. Participants were then stratified into three groups (6 per group) for a 3-day dietary intervention: control group: maintained their usual diet; soda group: consumed soda zero, a source of added inorganic P; and processed cheese group: consumed fresh processed cheese, which includes both organic and inorganic P additives. At last visit, all participants again completed a 3-day dietary survey and collected a 24 h urine sample (and blood samples in Study-2). Dietary P intake was estimated using two tools: the diet calibrator and the Spanish Food Composition Database (BEDCA). Results: After the intervention, neither BEDCA nor the diet calibrator was able to provide an accurate measurement of inorganic P ingested. However, only in the soda group, P/UUN increased in both studies (p = 0.046 and 0.047). In Study-2, the levels of FGF23 and klotho remained unchanged (p = 0.9 and p = 0.7, respectively). Conclusions: These findings suggest that urinary P/UUN ratio may be a useful biomarker to monitor changes in inorganic P intake and could help to individualize dietary recommendations to reduce inorganic P exposure without restricting protein intake.