Background: Vascular calcification (VC) affects up to 90% of patients with end-stage renal disease and increases cardiovascular mortality 3- to 5-fold. Once considered passive mineral deposition, VC is now recognized as an active, toxin-driven process orchestrating vascular smooth muscle cell transdifferentiation, endothelial dysfunction, and matrix remodeling. However, current uremic toxin classifications remain biochemically oriented, providing limited clinical guidance for risk stratification and therapeutic selection. Methods: This comprehensive review reframes uremic toxin-driven VC through an integrated phenotypic lens, synthesizing molecular mechanisms, clinical biomarkers, and therapeutic targets into a unified translational framework. Results: We propose five mechanistic-clinical phenotypes representing distinct biological trajectories of vascular injury. These include (1) inflammatory-oxidative (dominated by indoxyl sulfate, p-cresyl sulfate, NLRP3 inflammasome activation), (2) mineral-metabolic (hyperphosphatemia, FGF23 excess, Klotho deficiency), (3) epigenetic-senescent (histone modifications, microRNA dysregulation, cellular senescence), (4) endocrine cross-talk (vitamin D, PTH, gut-derived metabolites), and (5) integrated toxic continuum (convergence of multiple pathways in advanced disease). A comprehensive biomarker panel spanning inflammatory markers, mineral metabolism parameters, epigenetic indicators, and endocrine-gut metabolites enables phenotypic stratification and therapeutic monitoring. Emerging therapies—including tissue-nonspecific alkaline phosphatase inhibition, ectonucleotide pyrophosphatase/phosphodiesterase 1 enzyme replacement, vitamin K₂ activation, senolytic agents, and SNF472 crystal-growth blockade—are mapped to their optimal phenotypic contexts. Conclusions: This phenotype-oriented paradigm transforms VC from an inevitable complication into a targetable and potentially reversible manifestation of uremic toxicity, establishing a translational foundation for precision-based vascular medicine in chronic kidney disease. The framework enables biomarker-guided patient stratification, rational therapeutic selection, and phenotype-enriched clinical trial design.

Burosumab is a monoclonal anti-FGF23 antibody used to treat patients with X-linked hypophosphatemic rickets (XLH). Its effect on serum phosphate and physical performance was compared in patients during a 6-month treatment with burosumab. Eight adult patients with XHL were treated with burosumab (1 mg/kg s.c. every 28 days). In the first 6 months of treatment, calcium-phosphate metabolism variables were measured, and muscle performance (tested with chair and walking test) and quality of life (tested with fatigue, BPI-pain and BPI-life questionnaires) were estimated. A significant increase in serum phosphate was observed during the treatment. From the 16th week, serum phosphate became significantly lower than its value in the 4th week. No patients had serum phosphate below the normal range at the 10th week, but seven patients were hypophosphatemic in the 20th and 24th week. All patients improved the execution time of the chair test and walking test, which reached a plateau after the 12th week. BPI-pain and BPI-life scores significantly decreased from baseline to the 24th week. In conclusion, a six-month burosumab treatment may significantly improve the general condition and physical performance of adult patients with XLH; this improvement was more stable and more indicative of treatment efficacy than that of serum phosphate.

Objective: X-linked hypophosphatemia (XLH) is the most common congenital phosphate disorder affecting individuals throughout the lifespan. We investigated the skeletal burden, the cardiovascular involvement, the diagnostic performance and the therapeutic management in a cohort of Italian adults with XLH. Design: Cross-sectional study involving 15 Italian tertiary centers. Methods: Retrospective study. Results: In total, 170 adults (110 females and 60 males), aged 44.6 ± 14.6 (19–83) years, were identified. i) Skeletal deformities were detected in 87.1% of individuals, fractures/pseudofractures in 44.7%, osteophytosis in 65.4% and enthesopathies in 57.6%. Dental disease affected 72.4% of individuals. The skeletal burden was heavier in males than in females. ii) Hypertension occurred in 14.7% of individuals and was associated with elevated plasma intact FGF23 levels; dyslipidemia, diabetes and cerebrovascular events occurred in very few individuals. iii) FGF23 levels were measured in 30.0% of individuals; they were >30 pg/mL (nv 23–95) in nearly all individuals but overtly elevated in 58.8%. Genetic analysis has been performed in 86.5% of the cohort, and PHEX mutations were identified in 95.2% of the individuals without evidence of genotype/phenotype correlation. iv) 44.2% of individuals were on conventional therapy, 32.5% were on burosumab, and 23.3% were untreated. Individuals having received diagnosis in the adulthood (n = 14) were neither medically nor surgically treated during their childhood. Conclusion: The burden of XLH disease in adulthood is determined by skeletal manifestations and dental disease and may be more severe in males. Additionally, cardiometabolic impairment may not be common. The disease burden impacts most of the individuals, beyond those presenting the criteria for burosumab reimbursement. Significance statement: Data from a consistent cohort of adults with XLH highlighted that skeletal and dental disease-related complications significantly affect XLH individuals during adulthood and aging. Skeletal features associated with aging occur earlier in adults with XLH, being more evident when untreated or poorly treated with conventional therapy. The disease burden impacts most of individuals, beyond those presenting the criteria for burosumab reimbursement. The study contributes in increasing awareness toward adult XLH individuals and provides data for implementing the disease management and the health policy planning.

Purpose Ectonucleotide pyrophosphate/phosphodiesterase family member 1 (ENPP1) deficiency is a rare genetic disorder caused by loss-of-function ENPP1 gene mutations. Characterized by abnormally low circulating inorganic pyrophosphate concentrations, bone hypomineralization, soft tissue calcification, and arterial stenosis, ENPP1 deficiency is associated with a phenotypic spectrum that includes generalized arterial calcification of infancy type 1 (GACI1) and autosomal recessive hypophosphatemic rickets type 2 (ARHR2). Despite phenotypic differences, patients with GACI1 and ARHR2 have a marked, lifelong physical and emotional burden, with a negative impact on quality of life. Methods A scientific board, comprising seven specialist physicians (endocrinologists, nephrologists, and pediatricians) practicing in Italy, held two virtual meetings to exchange knowledge regarding real-world clinical experience of GACI1 and ARHR2 using case examples, and to discuss strategies on how to increase disease awareness and optimize the diagnosis and management of these patients. Results Five real-world clinical cases are described. The specialist physicians also provide guidance for optimizing the management pathway for patients with ENPP1 deficiency. Early identification of the clinical signs of disease, in combination with comprehensive diagnostic and follow-up testing, is essential for effective patient management. Conclusion Early and accurate identification of ENPP1 deficiency by healthcare providers and comprehensive diagnostic testing is essential for the effective management of patients with GACI1 and ARHR2. Consistent follow-up is key to preventing complications and adverse outcomes. Although treatment options are limited, novel therapies are currently under clinical development.