Search Results (284)

Background: Cardiovascular disease remains a leading cause of morbidity and mortality after kidney transplantation. The relative contribution of metabolic abnormalities and inflammatory burden to cardiac remodeling and subsequent clinical outcomes in kidney transplant recipients (KTRs) remains incompletely understood. Methods: In this retrospective cohort study, 152 KTRs underwent comprehensive cardiovascular evaluation at a stable post-transplant time point (12 ± 4 months after transplantation). Metabolic phenotype was assessed using metabolic syndrome and indices of insulin resistance and atherogenic dyslipidemia (TyG index, TG/HDL ratio, and atherogenic index of plasma [AIP]). Inflammatory status was evaluated using hs-CRP and complete blood count-derived indices. Echocardiographic damage composite (EDC) was defined as the presence of left ventricular hypertrophy, diastolic dysfunction, or left atrial enlargement. Patients were followed for major adverse clinical outcome (MACO), defined as cardiovascular event, graft failure, or death, and major adverse cardiovascular and cerebrovascular events (MACCE). Results: At baseline, 78 patients (51.3%) met criteria for EDC. EDC was strongly associated with higher TyG, AIP, TG/HDL, LDL/HDL ratio, and metabolic syndrome, whereas inflammatory markers showed no association. In multivariable logistic regression adjusted for age, sex, eGFR, and proteinuria, TyG remained independently associated with EDC (OR 1.13 per 0.1 increase, 95% CI 1.05–1.21; p = 0.001), independent of hs-CRP. Similar results were observed when AIP was evaluated in place of TyG (OR 10.39, 95% CI 2.22–48.71; p = 0.003). During follow-up, 78 patients developed MACO and 49 developed MACCE. In Cox regression analysis, graft dysfunction and inflammatory markers independently predicted MACO, whereas TyG was no longer significant. In contrast, TyG remained an independent predictor of MACCE after adjustment for confounders and inflammatory markers (HR 1.10 per 0.1 increase, 95% CI 1.04–1.16; p < 0.001). Similar results were observed when AIP was tested in place of TyG (HR 10.8, 95% CI 3.06–38.11; p < 0.001). Echocardiographic damage did not independently predict outcomes after adjustment. Conclusions: In KTRs, metabolic abnormalities reflecting insulin resistance and atherogenic dyslipidemia are closely associated with cardiac remodeling one year after transplantation and remain specifically linked to subsequent cardiovascular events. In contrast, systemic inflammation and graft dysfunction are the primary determinants of overall adverse clinical outcomes. Simple metabolic indices such as TyG and AIP may provide practical tools for cardiovascular risk stratification in this population. In Cox proportional hazards models, TyG (HR 1.102, 95% CI 1.043–1.164, p = 0.001) and AIP (HR 10.8, 95% CI 3.06–38.11, p < 0.001) were independently associated with cardiovascular events during follow-up, underscoring the role of atherogenic dyslipidemia in cardiovascular risk. Full article

Background: Chronic kidney disease (CKD) is associated with increased cardiovascular morbidity and mortality, even at early stages. Postmenopausal women represent a particularly vulnerable population due to estrogen deficiency, which promotes adverse cardiovascular remodeling. However, data specifically characterizing the cardiac phenotype of hypertensive postmenopausal women with mild-to-moderate CKD remain limited. Methods: We conducted a prospective observational cohort study including 413 hypertensive postmenopausal women consecutively referred to a tertiary center between 2019 and 2022. Participants were stratified into a CKD group with stage 3 CKD (estimated glomerular filtration rate of 30–59 mL/min/1.73 m²; n = 213) and a control group without CKD (n = 200). All subjects underwent comprehensive clinical evaluation, laboratory testing, and standardized transthoracic echocardiography. The prevalence of left ventricular hypertrophy (LVH), left ventricular diastolic dysfunction (LVDD), and chronic coronary syndromes (CCS) was assessed. Multivariable logistic regression analyses were performed to evaluate independent associations between CKD and cardiovascular abnormalities. Results: Compared with controls, women with CKD showed a significantly higher prevalence of LVH (46.7% vs. 21.5%), LVDD (55.8% vs. 36.0%), and CCS (15.5% vs. 7.5%) (all p < 0.01). The coexistence of LVH and LVDD identified a high-risk cardiac phenotype that was markedly more frequent in the CKD group (41.3% vs. 12.5%). After adjustment for age, body mass index, blood pressure, duration of hypertension, smoking status, and antihypertensive therapy, stage 3 CKD remained independently associated with LVH, LVDD, and CCS. Conclusions: In hypertensive postmenopausal women, mild-to-moderate CKD is associated with a substantial burden of cardiac structural and functional abnormalities exceeding that attributable to hypertension alone, supporting early cardiovascular screening and an integrated cardiorenal approach. Full article

Atherosclerosis remains the leading cause of death worldwide and imposes a major healthcare burden. Physiologically, elimination of cholesterol from the arterial wall depends on reverse cholesterol transport (RCT). RCT requires access to HDL and apolipoprotein A-I (ApoA-I) to lesional macrophages/foam cells. The endothelial glycocalyx is a dynamic and injury-sensitive layer of proteoglycans and glycosaminoglycans (including hyaluronan). It contributes to vascular barrier properties, leukocyte adhesion, mechanotransduction, and macromolecular transport. In atherosclerosis, glycocalyx structure and function are altered; this may facilitate entry/retention of atherogenic lipoproteins and may also alter transport conditions relevant to cholesterol efflux pathways. This article presents a mechanistic hypothesis: short, transient, systemic hyaluronidase exposure could temporarily remodel glycocalyx/extracellular matrix components and thereby facilitate conditions permissive for regulated transport processes relevant to RCT. However, the proposed link between glycocalyx remodeling and improved lesional cholesterol efflux remains theoretical. Direct in vivo evidence that the endothelial glycocalyx is a dominant barrier limiting HDL- or ApoA-I-mediated cholesterol efflux from plaque macrophages is currently limited. Moreover, glycocalyx degradation is widely associated with endothelial dysfunction, increased permeability, inflammation, and thrombosis, all of which could aggravate rather than ameliorate atherosclerosis. Human pharmacokinetic data indicate a very short plasma half-life of circulating hyaluronidase activity, suggesting that any systemic enzymatic effect is brief. Nevertheless, the biological consequences of repeated degradation–regeneration cycles, especially in high-risk states such as diabetes, inflammation, oxidative stress, or chronic kidney disease, remain incompletely understood. Evidence supporting clinical benefit in atherosclerosis is currently limited to heterogeneous animal experiments, historical uncontrolled reports, and a small number of anecdotal case observations, whereas randomized trials have only been performed in other settings such as acute myocardial infarction and do not establish efficacy for plaque regression. We therefore provide a balanced evaluation of knowns, uncertainties, alternative interpretations, potential risks, dosing unknowns, and a translational research agenda including mechanistic preclinical studies, biomarker development, imaging, and carefully designed early-phase clinical investigation. Full article

The transition from acute kidney injury (AKI) to chronic kidney disease (CKD) represents a dynamic and multistage pathological process driven by maladaptive intercellular communication. Rather than resulting from isolated cellular injury, AKI-CKD progression unfolds through a spatially and temporally coordinated dysregulation of cellular networks. In the acute phase, damaged tubular epithelial cells act as instigators, releasing damage-associated molecular patterns (DAMPs) and activating a storm of inflammatory crosstalk among immune cells, endothelium, and fibroblasts. During the subacute repair phase, imbalance in macrophage polarization (M1 persistence/M2 dysfunction) and the emergence of senescent tubular cells with a senescence-associated secretory phenotype (SASP) together create a pro-fibrotic microenvironment. In the chronic phase, activated myofibroblasts—derived from multiple sources—establish self-sustaining feedback loops via autocrine signaling, mechanical memory from the stiffened extracellular matrix (ECM), and ongoing dialogue with immune and resident cells, ultimately leading to irreversible fibrosis. Current therapeutic strategies focused on single molecular targets often fail to disrupt this resilient network homeostasis. Therefore, we propose a paradigm shift toward spatiotemporally precise network-remodeling therapies, which require integrated use of liquid biopsy-based staging, smart nanocarriers for cell-specific delivery, and AI-powered multi-omics modeling. This review systematically delineates the evolving cell-to-cell communication networks across AKI-CKD continuum and highlights innovative strategies to intercept disease progression by targeting the pathophysiology of cellular crosstalk. Full article

Cardiovascular–kidney–metabolic (CKM) syndrome has emerged as a broader clinical and pathophysiological framework than traditional metabolic syndrome, addressing the limitations of a purely factor-clustering approach by integrating dysfunctional adiposity, metabolic dysfunction, chronic kidney disease, and cardiovascular disease within a dynamic multiorgan continuum. This narrative review critically examines the transition from metabolic syndrome to CKM syndrome, emphasizing why the newer framework may better reflect real-world cardiorenometabolic multimorbidity and provide more clinically meaningful risk stratification through the incorporation of renal markers, subclinical cardiovascular disease, and stage-based progression. The review synthesizes the epidemiological burden of the CKM continuum and discusses the main biological mechanisms linking adipose tissue dysfunction, insulin resistance, inflammation, oxidative stress, endothelial injury, MASLD as the hepatic component of the continuum, renal vulnerability, and cardiovascular remodeling. It also considers the role of social determinants of health and the life-course perspective in shaping disease onset, progression, and access to care. Particular attention is given to the clinical implications of CKM syndrome as an interpretive and organizational model that may support earlier recognition of multiorgan risk, more integrated prevention, and less fragmented multidisciplinary management, while remaining distinct from a self-sufficient diagnostic or therapeutic algorithm. Overall, CKM syndrome should be regarded not as a new nosological entity, but as a clinically useful framework for reclassifying and managing the interconnected progression from metabolic dysfunction to renal and cardiovascular disease. Full article

Congenital anomalies of the kidney and urinary tract (CAKUT) constitute the most common underlying cause of chronic kidney disease in pediatric populations. Maternal hypovitaminosis D links to mesoderm-related birth defects, leading to our hypothesis that maternal vitamin D deficiency (VDD) impairs renal development (a mesoderm-derived process) and induces offspring CAKUT. To investigate whether a low-vitamin D level can cause CAKUT, we used vitamin D-free diets to induce a maternal vitamin D deficiency mice model. The maternal vitamin D deficiency (VDD) mice models and normal vitamin D status (CON) were successfully established by administering a vitamin D-free or vitamin D-sufficient diet for 4 weeks prior to pregnancy. The overall incidence of CAKUT was significantly increased in VDD neonatal mice (19.4% vs. 2.44%; p = 0.0006), with a higher incidence of early duplicated budding in E11.5. E11.5 ureteric bud tissue revealed significantly increased activity of Gdnf-Ret-p-Erk1/2 signaling in the VDD group. In vivo intervention with the p-Erk1/2 antagonist U0126 in the pregnant VDD mice model at E10.5 improved CAKUT occurrence in offspring with p-Erk1/2 expression decreasing toward normal levels. Early metanephric ureteric bud H3K4me3 CUT&TAG analysis at E12.5 revealed chromatin activation patterns, which revealed that the downregulation of Hnf1β promoter region peaks was accompanied by reduced Hnf1β expression, and Robo2 promoter region peak was upregulated with increased Robo2 expression in the VDD group. Maternal vitamin D deficiency in mice significantly increased offspring CAKUT incidence. This phenotype was mediated by enhanced Gdnf-Ret-p-Erk1/2 signaling and reversed by p-Erk1/2 inhibition, with VDD inducing epigenetic remodeling of Hnf1β and Robo2 promoters. Full article

Osteocalcin (OCN) is increasingly recognized as a multifunctional hormone whose actions extend far beyond its traditional role as a marker of bone turnover. This review provides an integrated examination of the molecular, endocrine, and translational dimensions of osteocalcin biology, with emphasis on its bioactive undercarboxylated form (ucOCN), which links skeletal remodeling to systemic physiological processes. The structural determinants, biosynthetic pathways, and vitamin K-dependent carboxylation mechanisms underlying OCN isoform diversity are summarized, together with analytical limitations arising from assay variability and differences between N-MID and ucOCN-specific measurements. Mechanistic evidence demonstrates that ucOCN signals through GPRC6A and GPR158 to modulate insulin secretion, muscle glucose uptake, adipokine production, testosterone synthesis, neurocognitive function, hepatic lipid metabolism, and acute stress response. These receptor-level pathways position osteocalcin as a central regulator at the intersection of bone metabolism and whole-body homeostasis. The review synthesizes data across major clinical contexts, including metabolic syndrome, type 2 diabetes (T2DM), non-alcoholic fatty liver disease (NAFLD), chronic kidney disease–mineral and bone disorder (CKD-MBD), cardiovascular dysfunction, and neurodegeneration, highlighting the modifying influence of vitamin K status, circadian rhythms, renal clearance, and local tissue microenvironments. The need for biomarker standardization, methodological harmonization, and receptor-targeted translational strategies is emphasized, alongside emerging therapeutic concepts involving vitamin K supplementation and exercise-induced activation of OCN. Collectively, the evidence reframes osteocalcin as a versatile endocrine mediator at the interface of bone physiology, systemic metabolic regulation, and disease mechanisms. Full article

Snakebite envenoming remains a major global health challenge. Naja atra (N. atra) envenomation induces severe acute kidney injury (AKI), largely driven by snake venom phospholipase A₂ (SVPLA₂). Increasing evidence suggests that immune dysregulation, in addition to direct cytotoxicity, contributes to delayed renal injury. Here, we investigated whether N. atra SVPLA₂ exposure is associated with macrophage immunometabolic remodeling and functional changes relevant to AKI progression. In vivo, AKI was induced in C57BL/6J mice by intraperitoneal administration of N. atra venom, followed by treatment with the SVPLA₂ inhibitor varespladib. In vitro, bone marrow–derived macrophages were exposed to venom with or without varespladib. N. atra venom exposure was associated with extensive tubular apoptosis, increased renal macrophage abundance, and elevated kidney injury biomarkers. Macrophages exhibited a shift toward a pro-inflammatory polarization signature accompanied by reduced efferocytic capacity. Targeted metabolomics revealed coordinated increases in glycolytic intermediates together with upregulation of key glycolytic enzymes. Pharmacological inhibition of SVPLA₂ partially restored macrophage metabolic features and efferocytic capacity and was accompanied by attenuation of renal injury. Together, these findings support a model in which SVPLA₂ exposure is associated with macrophage immunometabolic remodeling and impaired apoptotic cell clearance during venom-induced AKI. Full article

Hypertension-induced renal injury is a major cause of chronic kidney disease and end-stage renal disease. Increasing evidence indicates that disease progression is not driven solely by hemodynamic stress but results from the interplay of multiple molecular mechanisms. In this review, we propose a stage-structured and network-based framework to systematically integrate current mechanistic insights into hypertension-induced renal injury. Early events, mainly including endothelial dysfunction and renal hypoxia, establish a permissive microenvironment for disease progression. These insults activate amplifying pathways such as the renin–angiotensin–aldosterone system (RAAS) overactivation, oxidative stress, immune and inflammatory responses, and sympathetic nervous system hyperactivity, which interact through cross-talk and positive feedback loops. Ultimately, these signals converge on fibrotic programs characterized by epithelial–mesenchymal transition (EMT), fibroblast activation, and extracellular matrix deposition, leading to irreversible structural remodeling and functional decline. Furthermore, epigenetics, the gut–kidney axis, autophagy dysfunction and renal aging also contribute to this process. We highlight two critical and underappreciated aspects: the existence of a permissive ‘early-window’ dominated by endothelial dysfunction and hypoxia, which sets the stage for later amplification; and the hierarchical interplay between amplifying mechanisms where cross talk creates self-reinforcing loops that may explain therapeutic resistance. In addition, this review highlights emerging biomarkers for early diagnosis and disease monitoring, and discusses therapeutic advances that extend beyond blood pressure control to disease-modifying interventions that confer renoprotective effects. By integrating molecular mechanisms with diagnostic and therapeutic perspectives, this review provides a comprehensive framework for early detection and precision intervention in hypertension-induced renal injury. Full article

Vitamin D, a fat-soluble vitamin functioning as a hormone via the vitamin D receptor (VDR), is critical for calcium homeostasis and bone health. Vitamin D deficiency is linked to nutritional rickets, osteomalacia, and increased risk of non-communicable diseases such as cancer and diabetes. While serum 25(OH)D₃ is used to assess vitamin D status, its active form, 1α,25(OH)₂D₃, exerts context-dependent effects on calcium metabolism. Nonetheless, the therapeutic utility of native vitamin D is limited in certain pathologies. In chronic kidney disease (CKD), the renal conversion of 25(OH)D₃ to active 1α,25(OH)₂D₃ is compromised, necessitating the use of active synthetic analogs to bypass this metabolic defect. Furthermore, for dermatological and oncological disorders requiring supraphysiological dosing, synthetic analogs have been designed to dissociate beneficial anti-proliferative effects from the severe hypercalcemia induced by high-dose 1α,25(OH)₂D₃. VDR mediates transcriptional responses, modulated by co-regulators and chromatin remodeling complexes. Recent discoveries include non-genomic VDR pathways and SCAP (SREBP cleavage-activating protein)-dependent signaling that modulate lipid metabolism. Despite promising preclinical results, most synthetic VDR agonists fail to show efficacy in cancer therapy due to calcemic toxicity. However, compounds like eldecalcitol are effective in osteoporosis, especially in low-calcium-intake populations. Selective VDR modulators, akin to SERMs, exhibit tissue-specific effects. Moreover, novel VDR antagonists such as ZK168281 demonstrate potential to suppress hypercalcemia and vitamin D toxicity by inhibiting transcriptional activity and altering VDR localization. These agents may enable anti-inflammatory or anti-proliferative actions without calcemic risks. Understanding the nuanced biology of vitamin D and its analogs offers new avenues for therapeutic intervention beyond bone metabolism, including managing hyperparathyroidism, granulomatous diseases, and inflammation-associated disorders. Full article

One of the key pathological features of Diabetic Kidney Disease (DKD) progression is the accumulation of extracellular matrix (ECM) proteins in kidneys, leading to thickening of the glomerular and tubular basement membranes, subsequently resulting in mesangial expansion, sclerosis, and tubulointerstitial fibrosis. Given the high prevalence of DKD among both T2DM and T1DM patients, as well as the complexity of its underlying molecular mechanisms, this study provides a comparative analysis of published urinary proteomics datasets in DKD (n = 4). By integrating these data with published tissue proteomics (n = 2) and published transcriptomics datasets (n = 5), the study further aims to link urinary findings to tissue pathophysiology. Through integrative proteomic and transcriptomic analysis, DKD was associated with distinct alterations in the urinary proteome, particularly involving proteins related to ECM turnover. Using multiple validation datasets, several upregulated proteins with potential biological significance were identified, including annexins, collagens, cathepsins, and glycoproteins. Overall, our findings underscore the critical role of ECM remodeling in DKD progression and further validation could open new avenues for biomarker development and targeted therapy in early stages of DKD. Full article

Background: Obstructive sleep apnea (OSA) is a major modifiable risk factor for atrial fibrillation (AF), promoting arrhythmogenesis through intermittent hypoxia, autonomic activation, and atrial remodeling. Although continuous positive airway pressure (CPAP) effectively treats OSA, real-world evidence linking objectively measured CPAP exposure to clinically relevant AF recurrence remains limited. Aims: We aimed to evaluate the association between CPAP adherence and risk of recurrent paroxysmal AF, and to compare time to first recurrence between patients with mean nightly CPAP use ≥4 h/night versus <4 h/night. Materials and Methods: In this prospective observational cohort (2017–2024), consecutive hospitalized and outpatient adults with severe obstructive sleep apnea (OSA; apnea–hypopnea index > 30 events/h) and documented paroxysmal atrial fibrillation (AF) were enrolled. Persistent and long-standing persistent AF were excluded to ensure a homogeneous population with respect to atrial substrate. OSA was assessed using home sleep apnea testing (ResMed ApneaLink), and all patients initiated continuous positive airway pressure (CPAP) therapy (ResMed AirSense 10). Objective adherence data were obtained via the ResMed AirView telemonitoring platform. Exclusion criteria included permanent AF, prior pulmonary vein isolation, central sleep apnea, left ventricular ejection fraction < 50%, end-stage chronic kidney disease (eGFR < 15 mL/min/1.73 m² or dialysis), or inability to initiate or maintain CPAP therapy. Patients were followed for 12 months. The primary endpoint was time to first documented recurrence of paroxysmal AF (≥30 s on 12-lead electrocardiography or 24-h Holter monitoring). Progression to permanent AF, defined after unsuccessful rhythm control attempts and subsequent transition to a rate control strategy, was assessed as a secondary endpoint. Time-to-event analyses used Kaplan–Meier estimates with log-rank testing, and Cox proportional hazards regression adjusted for age, body mass index, apnea–hypopnea index, heart failure, left atrial volume index, and antiarrhythmic drug therapy. Results: The final analysis included 91 patients (mean age 62.15 ± 8.29 years; 68.13% men). Mean nightly CPAP use was ≥4 h/night in 49 patients and <4 h/night in 42 patients. During follow-up, paroxysmal AF recurrence occurred in 12/49 (24.5%) patients in the ≥4 h/night group and 16/42 (38.1%) in the <4 h/night group. Mean arrhythmia-free survival at 12 months was numerically higher in the ≥4 h/night group (11.25 vs. 10.51 months), without a statistically significant difference in Kaplan–Meier curves (log-rank p = 0.11). In multivariable Cox regression, binary adherence (≥4 h/night) was not independently associated with recurrence (HR 0.52, p = 0.13), whereas mean nightly CPAP use analyzed as a continuous variable remained independently associated with delayed recurrence (per 1-h increase: HR 0.66, 95% CI 0.48–0.91, p = 0.01). Progression to permanent AF occurred in 4/49 (10.0%) versus 9/42 (17.6%) patients, respectively (p = 0.29). Conclusions: In this real-world cohort of patients with severe OSA and paroxysmal AF, higher objectively measured CPAP exposure was independently associated with delayed AF recurrence when analyzed as a continuous variable, suggesting a graded association between objectively measured CPAP exposure and AF recurrence. Larger studies with extended follow-up and continuous rhythm monitoring are warranted to confirm long-term rhythm benefits and effects on AF progression. Full article

Background: Metalloproteinases (MMPs), together with their tissue inhibitors (TIMPs), regulate the extracellular matrix (ECM) in various tissues. MMP-2 and TIMP-2 maintain this process in renal tissue. An imbalance in the MMP-2/TIMP-2 ratio alters the abundance and proportions of specific extracellular matrix components, leading to kidney fibrosis. We aimed to assess differences in the morphometric parameters of the kidney and the immunohistochemical (IHC) expression of MMP-2 and TIMP-2 in kidney biopsies according to their fibrotic state. Methods: The histological slides were scanned using the 3DHISTECH Pannoramic MIDI II Scanner, and the resulting digital images of the sections were analyzed using Pattern Quant software; the morphometric analyses were performed with the Slide Viewer application. Results: In the current manuscript, we have investigated the significant enlargement of the diameter of the urinary space and renal corpuscle, as well as the reduced height of the epithelial lining of the proximal and distal convoluted tubules, of grafted kidneys with fibrosis when compared to the non-fibrotic kidneys. Moreover, we have noticed a rising MMP-2/TIMP-2 ratio in the immunohistochemical reaction in the renal tissue of fibrotic grafted kidneys in comparison to healthy kidneys. Conclusions: These results suggest that the MMP-2/TIMP-2 ratio, together with the lower inhibition of MMP-2, may promote an increased extracellular matrix remodeling, which accompanies the development of fibrosis. Full article

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. Full article

Phosphorus is an essential mineral involved in bone mineralization, energy metabolism, and cellular signaling, whose serum concentration is tightly regulated by an endocrine network including fibroblast growth factor 23 (FGF23), parathyroid hormone (PTH), vitamin D and Klotho. Disruption of this balance, particularly in chronic kidney disease (CKD), leads to hyperphosphatemia, which is strongly associated with bone fragility, vascular calcification, and increased mortality. In CKD, impaired phosphorus homeostasis triggers endocrine dysregulation characterized by elevated PTH and FGF23 levels, Klotho deficiency, and altered vitamin D metabolism, resulting in major skeletal and vascular consequences. Experimental and clinical evidence indicates that phosphorus overload contributes directly to skeletal deterioration and early vascular remodeling, even prior to clinically detectable renal impairment. Moreover, high dietary phosphorus intake under conditions of normal renal function reproduces several molecular and structural alterations typically observed in CKD, supporting a pathogenic role for chronic phosphorus excess. The dietary source of phosphorus has gained increasing relevance, as inorganic phosphate additives exhibit high intestinal bioavailability and impose a greater systemic phosphorus burden. Current management strategies rely on dietary restriction, phosphate binders, modulation of intestinal phosphorus transport and optimization of mineral-regulating hormones, although evidence for improved clinical outcomes remains limited. A deeper understanding of the molecular mechanisms linking phosphorus overload to bone and vascular pathology may facilitate the development of more effective preventive and therapeutic strategies. Full article