The loss of kidney function entails the development of a positive phosphate balance. The burden of addressing elevated phosphate levels is high. Both parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) are increased to promote phosphaturia, thereby preventing the rise in serum phosphate. However, if the phosphate load is excessive, the corresponding phosphaturia is maximal, kidney function deteriorates and hyperphosphataemia becomes clinically evident in advanced stages of chronic kidney disease (CKD). In addition to its role in CKD progression, hyperphosphataemia has been linked to a multitude of adverse outcomes, including overt inflammation, vascular calcifications, endothelial dysfunction, cardiovascular disease, renal osteodystrophy and secondary hyperparathyroidism. Collectively, these factors contribute to the markedly elevated mortality rates observed among individuals with CKD. Furthermore, hyperphosphataemia has been identified as a significant contributor to the development of inflammatory processes, oxidative stress and fibrosis, which underlie the aetiology of numerous comorbidities. Additionally, elevated levels of PTH and FGF23 have been demonstrated to independently induce organ and tissue injury, which is associated with poor outcomes in CKD. This article provides a concise overview of the current understanding of phosphate handling by the kidney in the context of CKD. It outlines the detrimental effects of phosphate on various organs and the mechanisms through which it contributes to CKD progression. Additionally, we discuss the tools available for clinicians to identify patients at risk of an excessive phosphate load.

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.

Cognitive impairment (CI) is a complication of chronic kidney disease (CKD) that is frequently observed among patients. The aim of this study was to evaluate the potential crosstalk between changes in cognitive function and the levels of Klotho in the brain cortex in an experimental model of CKD. To induce renal damage, Wistar rats received a diet containing 0.25% adenine for six weeks, while the control group was fed a standard diet. The animals underwent different tests for the assessment of cognitive function. At sacrifice, changes in the parameters of mineral metabolism and the expression of Klotho in the kidney and frontal cortex were evaluated. The animals with CKD exhibited impaired behavior in the cognitive tests in comparison with the rats with normal renal function. At sacrifice, CKD-associated mineral disorder was confirmed by the presence of the expected disturbances in the plasma phosphorus, PTH, and both intact and c-terminal FGF23, along with a reduced abundance of renal Klotho. Interestingly, a marked and significant decrease in Klotho was observed in the cerebral cortex of the animals with renal dysfunction. In sum, the loss in cerebral Klotho observed in experimental CKD may contribute to the cognitive dysfunction frequently observed among patients. Although further studies are required, Klotho might have a relevant role in the development of CKD-associated CI and represent a potential target in the management of this complication.

Chronic kidney disease (CKD) is associated with gut microbiota alterations that contribute to increased inflammation and the generation of uremic toxins and may worsen the disease progression. While probiotics may improve the pro-inflammatory cytokine profile, their effects on mineral metabolism, vascular calcification (VC), and CKD progression remain unclear. We aimed to evaluate the impact of a commercial probiotic (Probimel) supplementation on kidney function, mineral metabolism, inflammation and VC in both an experimental rat model and patients with advanced CKD and VC. The experimental model of VC was performed through 5/6 nephrectomy (Nx), a high-phosphate diet, and calcitriol. Animals were divided into three groups: Sham, Nephrectomy, and Nephrectomy + Probiotic. In the exploratory clinical study, 23 patients with advanced stage 5 CKD and VC were randomized and either received or did not receive daily probiotics for 6 months. Kidney function, mineral metabolism, uremic toxins, inflammation, VC, and fecal microbiota were evaluated. Probiotic supplementation decreased interleukin-6 (IL-6) and interpheron-γ (IFN-γ) and levels of the uremic toxin, indoxyl sulfate (IS), in the experimental model. However, no clear evidence of improvement in kidney function or vascular calcification was observed in either rats or patients with this probiotic. Under our experimental and clinical conditions, the selected probiotic did not modify key parameters related to CKD progression or VC.

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.