Search Results (16,249)

Background/Objectives: Type 2 diabetes mellitus (T2DM) is a multisystemic disease with overlapping metabolic, renal, and cardiovascular effects. Within the Diabetic@ project, which aims to characterize individuals with T2DM using real-world data extracted from electronic health records (EHRs), this substudy sought to develop a predictive model for two-year heart failure (HF) risk. Methods: Multicenter, retrospective study including T2DM individuals across eight Spanish hospitals (2013–2018). Data were extracted exclusively from EHRs’ unstructured free text using clinical natural language processing (cNLP) and mapped to SNOMED CT. At inclusion, individuals were categorized as having or not prevalent HF (pHF). Predictive modeling was performed in non-pHF to assess two-year risk of developing HF, termed incident HF (iHF). Logistic regression (LR), decision trees, random forest, and XGBoost were compared, selecting for accuracy and interpretability. Results: Of 588,756 individuals with T2DM, 84,197 (14.3%) had pHF. Among non-pHF, 353,371 (60%) were used for model development (90.7% training, 9.3% validation). iHF occurred in 13.6% of the training set and 11.4% of the validation set. Ischemic heart disease was present in 16.2% overall, 37.9% in pHF, and 12.6% in non-pHF. Glycosylated hemoglobin data was rarely reported (<15%). LR achieved the best performance (AUC-ROC 0.73) using 27 predictors. Reduced 12- and clinically refined 9-predictor models performed similarly, with the latter implemented in a web-based tool. Conclusions: Unstructured data from EHRs enabled development of a two-year HF risk model for individuals with T2DM, underscoring the potential of cNLP for risk stratification across the cardiovascular–renal–metabolic spectrum. Full article

Background/Objectives: Clear cell renal cell carcinoma (ccRCC) involves complex interactions between immune evasion and metabolic reprogramming. This study aimed to characterize ccRCC through integrated immunometabolic profiling, develop a prognostic signature, and investigate the functional role of the key driver gene UCN using in vitro and in vivo approaches. Methods: Integrated immunometabolic profiling was performed to identify molecular subtypes and establish a prognostic gene signature. Two distinct molecular subtypes were identified, and a 9-gene Immune Metabolic Index (IMI) was constructed. The functional role of the key driver gene UCN was investigated through in vitro functional assays and in vivo xenograft models in BALB/c mice, including combination with PD-1 blockade. Results: Two molecular subtypes with significant survival differences (p < 0.001) were identified. The established IMI demonstrated high prognostic accuracy, with Area Under the Curve (AUC) values of 0.813, 0.751, and 0.779 at 1-, 3-, and 5-year intervals, respectively. UCN was identified as the highest-risk gene in the signature. Functional assays showed that UCN silencing significantly inhibited cell proliferation and migration (p < 0.05). In BALB/c mouse xenograft models, UCN silencing remodeled the tumor microenvironment by increasing CD8+ T cell infiltration and reducing regulatory T cells (p < 0.01). Furthermore, UCN knockdown significantly suppressed tumor growth and synergized with PD-1 blockade to enhance antitumor efficacy (p < 0.001). Conclusions: The IMI is a robust tool for risk stratification in ccRCC. Targeting the UCN-driven immunometabolic axis represents a promising therapeutic strategy to overcome immune resistance in ccRCC. Full article

Clear cell renal cell carcinoma (ccRCC) is characterized by marked biological heterogeneity, which limits the prognostic accuracy of conventional clinicopathological models. Increasing attention has therefore focused on identification of biomarkers that can enhance risk stratification throughout all stages of the disease. Starting from the current state of the art, this narrative review summarizes and critically appraises the evidence published over the past decade regarding prognostic biomarkers in ccRCC. The analysis is structured into four overarching domains: (i) genomic biomarkers, covering somatic alterations and transcriptomic signatures; (ii) tissue-based biomarkers, including immunohistochemical surrogates and immune microenvironment features; (iii) circulating biomarkers, such as systemic inflammation parameters and indices; and (iv) integrated predictive models, represented by emerging multi-omic approaches. Going through the broad framework of potential prognostic biomarkers, emphasis is placed on their individual and integrative value in relation to classic clinical-pathological factors and survival parameters. At the tissue level, chromosome 3p-related alterations constitute a central molecular feature of ccRCC. Among these, BAP1 loss has emerged as one of the most consistently validated indicators of aggressive tumor behavior. Disruption of the SETD2/H3K36me3 axis and immune-related biomarkers, including PD-L1 expression, have demonstrated prognostic associations in selected settings, although with variable and context-dependent performance. In the circulating compartment, plasma KIM-1 has shown prognostic relevance following nephrectomy, while postoperative detection of circulating tumor DNA (ctDNA) may identify patients at increased risk of recurrence. However, limited analytical sensitivity and methodological heterogeneity currently restrict the broader clinical applicability of ctDNA-based strategies. Systemic inflammatory indices, such as the neutrophil-to-lymphocyte ratio, show reproducible associations with outcomes but largely reflect host inflammatory status rather than tumor-specific biology. However, no single biomarker currently supports routine prognostic implementation in ccRCC. Future progress will likely depend on integrative models combining genomic, tissue-based, immune, and circulating parameters with established clinical variables. Prospective validation and clear demonstration of incremental clinical utility will be essential before such strategies can meaningfully inform therapeutic decision-making. Full article

Background and Objectives: Anemia is a frequent complication of chronic kidney disease (CKD), primarily attributed to erythropoietin deficiency. Interstitial fibrosis (IF), which disrupts the renal interstitium where erythropoietin-producing cells reside, may contribute to anemia independent of glomerular filtration rate (GFR). However, data in primary glomerulonephritis (PGN) are limited and conflicting. Materials and Methods: In this nationwide multicenter registry analysis (TSN-GOLD), 2794 adults with biopsy-proven PGN were included. Interstitial fibrosis was graded semi quantitatively (0–3). Anemia was defined according to KDIGO/WHO criteria. Multivariable logistic regression models were constructed to evaluate the independent association between IF severity and anemia, adjusting for age, sex, eGFR, log-transformed proteinuria, hypertension, diabetes mellitus, and biopsy diagnosis. Interaction between IF and eGFR was assessed. A predefined subgroup analysis was performed in patients with preserved renal function (eGFR ≥ 60 mL/min/1.73 m²). Results: Anemia was present in 34.4% of patients. Although moderate-to-severe IF was more frequent among anemic patients (p < 0.001), IF severity was not independently associated with anemia in multivariable analysis (p-trend = 0.72). Female sex and lower eGFR were independently associated with anemia. A statistically significant IF×eGFR interaction was observed (p = 0.0029), indicating effect modification across renal function levels. The model demonstrated moderate discrimination (AUC = 0.705). In patients with preserved renal function, IF severity was not associated with anemia. Conclusions: In this large multicenter cohort of PGN patients, interstitial fibrosis severity was not independently associated with anemia after adjustment for renal function and clinical covariates. These findings suggest that the association between interstitial fibrosis and anemia in PGN appears largely mediated by renal functional status rather than fibrosis severity alone. Full article

Infectious bronchitis virus (IBV) is an avian coronavirus associated with respiratory, renal, and reproductive disease in chickens, with important economic consequences in intensive poultry production. This study aimed to estimate the seroprevalence of anti-IBV antibodies in vaccinated broiler flocks reared in south-western Romania and to characterize its distribution across counties and study years. Between 2018 and 2021, a total of 2466 blood samples were collected from Ross 308 broilers aged 35–45 days originating from five commercial farms (one per county) located in Caraș-Severin, Dolj, Gorj, Hunedoara, and Vâlcea. Samples were obtained from 137 production halls/series. Sera were tested using a commercial indirect ELISA kit and classified according to the manufacturer’s criteria based on the sample-to-positive (S/P) ratio and the corresponding antibody titer threshold. Overall, 2115/2466 sera were positive (85.77%) and 351/2466 were negative (14.23%). Anti-IBV antibodies were detected in all halls (137/137, 100%), although negative sera were recorded in 87/137 halls (63%). Seroprevalence by county ranged from 78.67% (Vâlcea) to 89.24% (Hunedoara). Significant differences in the proportions of positive and negative sera were identified between several county pairs by Fisher’s exact test. These findings indicate widespread serological evidence of anti-IBV antibodies in vaccinated broiler flocks from south-western Romania, which may reflect vaccine-induced immunity and/or field exposure. The results support the need for continued serological monitoring, alongside targeted molecular investigations to differentiate vaccine strains from circulating field variants. Full article

Background: The combined prognostic value of the fibrinogen-to-albumin ratio (FAR) and uric acid-to-albumin ratio (UAR) in acute kidney injury patients undergoing continuous renal replacement therapy remains unclear. Methods: This retrospective cohort study utilized the MIMIC-IV database. Adult patients with AKI receiving CRRT were included and stratified into four groups based on optimal FAR and UAR cut-offs. Multivariable Cox proportional hazards regression and restricted cubic spline analyses were employed to examine associations with 30-, 90-, and 360-day all-cause mortality. Results: Patients with high FAR/high UAR had the poorest survival (log-rank p < 0.001). After multivariable adjustment, high FAR/high UAR was associated with higher 30-day (HR = 2.17, 95%CI: 1.61–2.92) and 360-day mortality (HR = 1.50, 95%CI: 1.18–1.90) vs. low FAR/low UAR. The association was stronger in patients with an SOFA score >12 or vasopressin use (interaction p < 0.05). Conclusions: In critically ill AKI patients undergoing CRRT, the combined assessment of the FAR and UAR is associated with elevated mortality risk. These readily obtainable composite markers may support risk stratification in clinical practice. Full article

Background: Elevated anticardiolipin IgG (aCL IgG) has been reported in end-stage renal disease (ESRD), but its association with specific etiologies of kidney failure remains unexplored. The unique pathophysiology of diabetic–hypertensive nephropathy may be associated with a microenvironment that could potentially contribute to antiphospholipid antibody production and thrombotic complications. This study aimed to investigate whether aCL IgG elevation in hemodialysis (HD) patients is associated with combined diabetes–hypertension (DM + HTN) etiology and thrombocytopenia, thereby identifying a clinically distinct potential high-risk subgroup. In this hypothesis-generating study, we focused on within-HD patient comparisons rather than healthy controls. Methods: We enrolled 242 participants: 150 healthy controls (included only to establish local reference ranges) and 92 patients with maintenance HD. The study was conducted from 01 September to 20 November 2025 in Madinah, Saudi Arabia. Serum aCL IgG was measured by chemiluminescence immunoassay (positive ≥ 12 GPL units). Comprehensive hematological and biochemical parameters were analyzed. Multivariable logistic regression identified predictors of aCL positivity. Results: In the HD cohort, 21% demonstrated aCL positivity; this represents a substantially higher rate than the 2% observed in local healthy controls (p < 0.001). This elevation was not uniform across etiologies. Strikingly, 94.7% (18/19) of aCL-positive HD patients had DM + HTN aetiology, compared with only 17.8% of aCL-negative patients (p < 0.001). Thrombocytopenia was significantly more severe in aCL-positive patients (median platelets: 100 vs. 191 × 10⁹/L, p < 0.001). In multivariable analysis, DM + HTN etiology (HTN-alone vs. DM + HTN odds ratio [OR]: 0.0013, 95% confidence interval [CI]: 0.00002–0.0999, p = 0.003; confirmed by Firth’s penalized logistic regression sensitivity analysis, and lower platelet count (OR: 0.92 per 1 × 10⁹/L increase, 95% CI: 0.87–0.98, p = 0.006) independently predicted aCL positivity. Conclusions: These hypothesis-generating findings suggest a potential association between metabolic–vascular disease and antiphospholipid immunity in ESRD. Causality cannot be inferred from this cross-sectional design. At present, routine aCL screening is not recommended outside of research protocols; prospective studies are needed to confirm these associations. Full article

Cardiac surgery represents a cornerstone of modern cardiovascular medicine, yet it is intrinsically linked to significant systemic stress responses that can compromise remote organ function. Among postoperative complications, cardiac surgery-associated acute kidney injury (CSA-AKI) remains a significant clinical challenge characterized by high morbidity and complex pathophysiology. While hemodynamic instability and ischemia–reperfusion injury are established risk factors, renal dysfunction frequently persists despite optimal perfusion. This observation suggests the involvement of potent circulating mediators in cellular injury. Extracellular vesicles (EVs) are essential for intercellular communication and serve as central hubs for transporting bioactive lipids, proteins, and genetic material. Accumulating evidence indicates that the mechanical and oxidative stress inherent to cardiopulmonary bypass triggers substantial release of EVs from platelets, erythrocytes, and injured vascular tissues. These vesicles may function as vectors that traffic oxidized mitochondrial components and pro-inflammatory cargo to the renal parenchyma. This signaling cascade appears to disrupt renal homeostasis through a proposed “dual-hit” mechanism involving the induction of endothelial dysfunction and endothelial-to-mesenchymal transition (EndMT), followed by tubular epithelial injury via mitochondrial fragmentation, redox imbalance, and downregulation of anti-aging factors. The complexity of these EV-mediated interactions may contribute to an incomplete understanding of why specific patient phenotypes fail to recover. This narrative review examines the mechanisms of surgery-induced EV biogenesis, the molecular pathogenesis of endothelial and tubular damage, and the role of intercellular crosstalk. Additionally, we discuss future perspectives on targeting the “EV vector” through therapeutic apheresis and mitochondrial pharmacotherapy to potentially improve clinical outcomes in high-risk surgical patients. Full article

Background: Despite advances in reperfusion therapy, ST-segment elevation myocardial infarction (STEMI) remains associated with substantial morbidity and mortality. Early identification of predictors of adverse outcomes is essential for improving risk stratification. Methods: This retrospective study included 512 STEMI patients who underwent coronary revascularization within 6 h of symptom onset. Clinical, laboratory, angiographic and echocardiographic variables were analyzed. The primary endpoint was in-hospital mortality. Secondary outcomes included reduced left ventricular ejection fraction (LVEF < 40%) and moderate-to-severe ischemic mitral regurgitation (IMR). Independent predictors of in-hospital mortality were identified using multivariable logistic regression, while secondary outcomes were described to characterize the study population. Model performance was evaluated using ROC analysis. Results: In-hospital mortality occurred in 9.4% of patients. Reduced LVEF was present in 26.2%, and IMR in 10.9%. Independent predictors of mortality included LVEF < 40% (OR 5.72, 95% CI 2.77–11.80, p < 0.001), IMR (OR 2.61, 95% CI 1.14–5.97, p = 0.023), lower hemoglobin levels (OR 0.74, 95% CI 0.61–0.91, p = 0.003), and reduced glomerular filtration rate (OR 0.96, 95% CI 0.95–0.98, p < 0.001). The model demonstrated good discrimination (AUC 0.88). Complete revascularization was not independently associated with mortality. Conclusions: Left ventricular dysfunction, IMR, anemia, and renal impairment are strong predictors of in-hospital mortality in STEMI patients. Integrating echocardiographic and laboratory parameters may improve early risk stratification and guide clinical decision-making. Full article

Dysregulated iron handling—including catalytic iron and ferroptosis, hepcidin–ferroportin signaling, ferritin dynamics, and neutrophil gelatinase-associated lipocalin (NGAL)-mediated siderophore transport—has been implicated in the initiation and propagation of acute kidney injury (AKI) across ischemia–reperfusion, sepsis, and nephrotoxic contexts. To provide a SANRA-aligned narrative synthesis of mechanistic and translational evidence on iron biology in AKI, clarifying biomarker readiness and therapeutic prospects while explicitly separating preclinical from human findings. PubMed, Scopus, and Web of Science (1 January 2000 to 30 September 2025), plus appraised grey literature (guidelines/registries) using predefined criteria (authority, update recency, and methodological transparency). Narrative review with comprehensive database searches, single-reviewer screening/extraction (acknowledged as a limitation), and qualitative synthesis. Evidence is organized by pathway (catalytic iron/ferroptosis, transferrin (Tf)/transferrin receptor (/TfR), ferritin/ferritin heavy chain (FtH), hepcidin–ferroportin and NGAL) and translational domain (biomarkers and therapeutics). Statements are tagged as [Preclinical] or [Human]. [Preclinical] Robust signals support roles for catalytic iron and ferroptosis, protection by iron chelation, hepcidin modulation, heme oxygenase 1 (HO-1)/FtH induction, and apotransferrin/NGAL-based strategies. [Human] Biomarkers such as NGAL show clinical utility for kidney injury detection, whereas catalytic iron assays (labile plasma iron [LPI]/bleomycin-detectable iron [BDI]) remain investigational with limited standardization. Observational links between iron-regulatory pathways and AKI risk exist, but interventional trials are sparse; dose, timing, and safety of iron-targeted strategies in defined AKI settings remain to be established. Iron-handling pathways are compelling targets for AKI prevention/mitigation, yet high-quality human trials are limited. Priorities include standardized catalytic-iron assays, biomarker-guided enrichment, and pragmatic trials of tractable interventions (e.g., peri-contrast or cardiopulmonary bypass settings). Until such evidence accumulates, recommendations beyond standard care should be avoided. Full article

Sarcopenia, defined as the progressive loss of skeletal muscle mass and strength, is increasingly recognized as a significant concern in patients with chronic kidney disease (CKD) and particularly in kidney transplant recipients (KTx-ps). This review explores the complex interplay of pathophysiological mechanisms, prevalence, and management strategies of sarcopenia in the context of kidney transplantation. CKD contributes to sarcopenia through systemic inflammation, malnutrition, uremic toxin accumulation, and metabolic imbalances, all of which persist or are exacerbated after transplantation due to immunosuppressive therapies especially corticosteroids. Notably, the post-transplant period may introduce additional risks, such as altered body composition and reduced physical activity, further aggravating muscle wasting. Sarcopenia affects approximately 26% of KTx-ps, leading to adverse outcomes including decreased quality of life, increased risk of infection, frailty, delayed recovery, and graft loss. The diagnosis remains challenging due to variability in assessment tools and a lack of standardized criteria. Management strategies must be multifactorial, including personalized nutritional support, targeted physical activity, and, where appropriate, pharmacological interventions. Early identification through imaging and functional testing is critical, especially in older patients and those with prolonged dialysis vintage. Emerging therapies, such as myostatin inhibitors, offer promise but require further validation. Additionally, early steroid withdrawal may mitigate muscle loss without compromising graft survival in selected patients. This review underscores the need for heightened awareness and standardized protocols to identify and manage sarcopenia in kidney transplantation, ultimately improving long-term outcomes and patient-centered care. Full article

Phenylketonuria (PKU) is an autosomal recessive disorder characterised by an inborn error of phenylalanine (Phe) metabolism. Such errors are attributed to pathogenic gene variants causing phenylalanine hydroxylase (PAH) deficiency, impairing the hydroxylation of phenylalanine to tyrosine in the Phe metabolic pathway. This defect leads to plasma Phe concentrations above the normal range. If untreated, hyperphenylalaninemia can adversely affect brain function, leading to severe intellectual disability and seizures. Since 1969, the newborn dried blood spot test has remained the main method of early screening and diagnosis for PKU. The primary therapeutic management is a lifelong phenylalanine-restricted diet with the aim of decreasing plasma Phe levels. The recommended diet consists of avoiding high-protein foods such as meat, fish, eggs and nuts, and can be supplemented with high-protein medical formulas which are low in phenylalanine. Pharmacological interventions such as sapropterin, sepiapterin and pegvaliase can also be used as treatment adjuncts in patients with PKU. Currently, small-molecule inhibitors reducing renal phenylalanine reabsorption are being explored as a potential therapeutic intervention. Furthermore, novel gene-editing techniques are under evaluation as potential curative strategies, with preclinical studies showing promising results in correcting pathogenic phenylalanine hydroxylase variants. This non-systematic review synthesises current literature on the management of PKU, with a focus on dietary interventions and recommendations. Full article

Epidemiological studies have demonstrated that kidney aging is a risk factor for acute kidney injury (AKI) and chronic kidney disease (CKD). Therefore, understanding the mechanisms of kidney aging is key to designing novel anti-kidney aging strategies. In this regard, animal models of kidney aging are essential tools. In this review article, we focus on D-galactose (D-gal)-induced accelerated aging in rodents. This animal aging model is a popular and widely used experimental method in the field of aging and aging-related degenerative disorders. It has been shown that the major characteristics of the D-gal-induced aging process are increased oxidative stress, decreased antioxidant enzymes, elevated cell death, increased tissue fibrosis, and accumulation of inflammatory mediators. This review focuses on D-gal-induced kidney aging in mice and rats, with discussions on both kidney aging mechanisms and anti-kidney aging regimens using this model. It is our belief that D-gal induction of accelerated kidney aging will continue to be used as a convenient platform for elucidating kidney aging mechanisms and exploring novel anti-kidney aging targets that may slow down kidney aging and retard the development of aging-related renal disorders. Full article

Cardiovascular disease represents the primary cause of morbidity and mortality among patients with chronic kidney disease (CKD). Emerging evidence suggests that coronary artery pathology in CKD diverges from the traditional atherosclerotic phenotype seen in individuals with maintained renal function. This review delineates coronary artery-specific alterations in CKD, focusing on mechanisms that expedite atherogenesis, characteristics of plaques, calcific remodeling, and dysfunction of the coronary microvasculature. CKD fosters a pro-inflammatory, pro-oxidative, and pro-calcific environment, which results in endothelial damage and vascular calcification remodeling. Furthermore, coronary plaques in CKD are more likely to exhibit larger lipid-rich necrotic cores, heightened inflammatory cell infiltration, a significant calcific burden, and vulnerability indicators such as cholesterol crystals and microdisruptions. Impaired coronary microvascular function is also prevalent and may account for ischemia with non-obstructive coronary arteries. In summary, CKD is linked to a rapid, calcification- and inflammation-driven form of coronary disease characterized by both macrovascular plaque remodeling and microvascular dysfunction. This underscores the necessity of early identification and prevention of cardiovascular risk, targeting CKD-specific mechanisms in conjunction with conventional risk factors. Full article

Background/Objectives: Pregnancy is associated with increased renal secretory clearance of drugs mediated by organic anion transporters (OATs) and organic cation transporter 2 (OCT2). Circulating concentrations of pregnancy-related hormones (PRHs) increase with gestational age, providing a plausible mechanism for renal OAT and OCT2 regulation. Methods: Using primary human proximal tubular epithelial cells (PTECs), we quantified the effects of PRHs, at trimester-specific concentrations, on the mRNA expression of renal drug transporters (apical and basal) and metabolizing enzymes (DMETs), as well as endocytic receptors. PTECs from three female, premenopausal donors were cultured in an optimized Transwell system that maintains measurable OAT activity. PTECs were then exposed for 72 h to trimester-matched PRH cocktails at physiologic (1×) or supraphysiologic (10×) concentrations, with medium replaced every 24 h. DMET and endocytic receptor mRNA were quantified by RT-qPCR, and uptake activities of OAT1/2/3, OCT2, OAT4, and OCTN1 were measured with selective substrates or substrate–inhibitor pairs. Results: At 1× PRHs, renal DMET and endocytic receptor mRNA expression was unchanged across trimester-related PRH concentration except for consistent downregulation of PEPT2. Uptake activity for all measured transporters was unchanged. At 10× PRHs, selective changes in mRNA expression of transporters were observed (e.g., induction of OAT1), but these changes did not translate into changes in activity. Conclusions: Our data argue against PRHs as the main driver of the increase in OAT-mediated drug secretion during pregnancy. Alternative mechanisms (e.g., flow-dependent mechanotransduction and untested hormones [e.g., prolactin, hCG]) should be evaluated to explain gestation-dependent changes in renal secretory clearance of drugs. Full article