Search Results (11,295)

Background/Objectives: Cardiovascular disease (CVD) in chronic kidney disease (CKD) arises from a multifaceted interplay of pathophysiological processes, including chronic inflammation, oxidative stress (OS), and accelerated vascular calcification (VC). Red blood cell distribution width (RDW) and the neutrophil-to-lymphocyte ratio (NLR) have emerged as simple, inexpensive, and readily available hematological indices that may capture these underlying disturbances. As such, they hold promise as accessible biomarkers for stratifying cardiovascular risk in patients with CKD. Methods: This cross-sectional study enrolled 497 patients, comprising 477 with CKD across all stages and 20 controls. We evaluated the associations of RDW and NLR with both traditional and non-traditional cardiovascular risk factors, as well as with serum calcification propensity (T50). Spearman’s correlation and multivariable regression analysis were used to assess these relationships. Results: Both RDW and NLR were significantly elevated in patients with established CVD (p < 0.001 for both) and demonstrated a progressive increase across advancing CKD stages (p < 0.001). RDW and NLR showed positive correlations with age, CVD duration, urea, phosphorus, parathormone, CRP, FG23, and mean carotid intima–media thickness (cIMT), while exhibiting inverse correlations with eGFR, serum albumin, hemoglobin, lipids, antioxidants such as superoxide dismutase, fetuin-A, and T50. Additionally, NLR correlated positively with the duration of hypertension and diabetes, as well as with albuminuria. Quartile analysis revealed a stepwise decline in T50 across increasing categories of RDW and NLR, supporting the link with impaired calcification defense. In multivariable analysis, T50 independently predicted NLR (β = −0.013; p = 0.018), whereas total cholesterol (β = −0.011; p = 0.019) and cIMT (β = 0.38; p = 0.018) emerged as independent determinants of RDW. Conclusions: RDW and NLR strongly reflect the burden of inflammation, metabolic disturbance, and vascular dysfunction in patients across the CKD spectrum. The consistent associations with impaired calcification defense and with established cardiovascular risk markers underscore the potential value as accessible indicators of cardiovascular vulnerability in CKD. These findings support incorporating RDW and NLR into routine risk assessment and highlight T50 as a mechanistically relevant determinant of hematologic inflammation profiles. Full article

Background/Objectives: Cell-free DNA (cfDNA) is released into the circulation during inflammation-driven cellular injury and regulated cell death. Elevated cfDNA concentrations have been reported in several clinical settings, including chronic kidney disease, hemodialysis, and peritoneal dialysis (PD). We previously demonstrated that PD-related peritonitis induces an increase in circulating cfDNA; however, the mechanisms underlying cfDNA generation remained unclear. This study aimed (i) to confirm peritoneal cfDNA variation following peritonitis in PD patients, and (ii) to elucidate the apoptotic pathways responsible for cfDNA release. Methods: Fifty-four PD patients were enrolled and stratified into the following groups: Group A—no history of peritonitis (n = 25); Group B—remote peritonitis > 3 months prior (n = 21); Group C—recent peritonitis < 3 months prior (n = 8). cfDNA was quantified by qPCR. Apoptosis was assessed qualitatively by DNA laddering and quantitatively using ELISA assays for Caspase-3, Caspase-8 and Caspase-9. Results: cfDNA levels were significantly higher in patients with recent peritonitis compared to both other groups (p < 0.01). DNA laddering showed enhanced nucleosomal fragmentation, consistent with apoptosis. Caspase-3 concentrations were markedly increased in recent peritonitis (<3 months) and significantly correlated with cfDNA levels (ρ = 0.511, p < 0.01). Both Caspase-8 and Caspase-9 correlated with Caspase-3 (ρ = 0.57 and ρ = 0.47, respectively), indicating engagement of both extrinsic and intrinsic apoptotic pathways. Conclusions: In conclusion, peritoneal cfDNA in PD patients with peritonitis originates primarily from apoptosis and reflects dual-pathway caspase activation. cfDNA and Caspase-3 progressively decline with longer time elapsed from peritonitis, supporting their potential use as biomarkers for inflammatory activity and membrane recovery. Full article

Chronic kidney disease is a global public health concern, representing a critical global public health challenge with increasing morbidity and mortality rates. The disease is a long-term condition characterized by the progressive loss of renal function. Early detection of declining kidney health and timely intervention are crucial to slow disease progression and improve prognosis, mitigating complications, including cardiovascular events. Current diagnostic standards are unable to detect early stages of kidney disease, reflecting early signs of glomerular and tubular damage. This creates an urgent need to identify reliable biomarkers for early detection, prognosis and therapeutic monitoring of kidney diseases. Novel biomarkers, including urinary microRNA, exosomal components, proteomic signatures and integrated multi-omics profiles, facilitated by up-to-date technologies offer strong promise for enhancing early diagnosis, risk assessment and monitoring of the disease. We focus on the fundamental biological significance and clinical application of these markers, discussing a critical evaluation of novel methodologies and clinical evidence supporting their potential for earlier and more precise diagnosis. This review summarizes innovative urinary biomarkers and advanced analytical technologies that can provide a more comprehensive and accurate assessment of the kidney status towards early diagnosis, better prognosis and better quality of life for patients with chronic kidney disease. Full article

Objectives: Primary hyperoxaluria type III (PH3) causes kidney stones in children and adults. Gas chromatography/mass spectrometry (GC/MS)-based metabolomics has been applied to study patients with primary hyperoxaluria types I and II, 2,8-dihydroxyadenine lithiasis, and xanthinuria types I to III. This study was performed to verify the usefulness of this technique for the diagnosis of PH3. Specifically, we evaluated an 8-month-old infant with recurrent kidney stones. Methods: GC/MS-based metabolomics was performed on spot urine samples using initial urease pretreatment without fractionation. Results: Metabolomics revealed increased levels of 2,4-dihydroxyglutarate and 4-hydroxyglutamate. No simultaneous elevations of these two critical biomarkers were observed in other patients, except for one case of PH3 confirmed by the identification of HOGA1 mutations. A moderate increase in 4-hydroxyglutamate has been observed only in cases of primary hyperammonemia, in which analytes such as orotate, uridine, glutamine, or proline, but not 2,4-dihydroxyglutarate, are biomarkers, thus distinguishing PH3 from primary hyperammonemia. Conclusions: GC/MS-based urine metabolomics enables the rapid screening and chemical diagnosis of PH3 and other congenital anomalies that cause urolithiasis. This technique can also be used to monitor disease progression, as patients with PH3 benefit from long-term follow-up, particularly when transitioning from childhood to adulthood. The timely identification of patients with hereditary urolithiasis is crucial. To address this, a discussion was had about the current diagnostic criteria. Full article

Early diagnosis of chronic kidney disease (CKD) remains a major clinical challenge. Periostin (POST) and kidney injury molecule-1 (KIM-1) have been proposed as biomarkers of tubular injury and fibrosis. This study aimed to evaluate their utility as markers associated with CKD stage and their associations with renal function and proteinuria in children. Twenty-three children with CKD stages I–IV and 23 healthy controls were enrolled. Serum and urinary POST and KIM-1 were measured together with creatinine (CR), cystatin C (CysC), proteinuria, albuminuria, and urinary α1- and β2-microglobulin. Patients were classified as early stage (ES; CKD I–II) or late stage (LS; CKD III–IV). Serum and urinary POST and KIM-1, uPOST/CR, uKIM-1/CR, fractional excretion indices (FePOST, FeKIM-1), and UPCR were higher in CKD patients than in controls. Absolute biomarker concentrations did not differ between ES and LS and were not associated with eGFR, UPCR, UACR, or tubular protein excretion. In contrast, uPOST/CR, uKIM-1/CR, FePOST, and FeKIM-1 increased with CKD stage, were higher in LS than ES, correlated positively with CysC, and inversely with eGFR. FePOST and FeKIM-1 also correlated strongly with tubular protein markers. The FePOST/FeKIM-1 ratio was elevated in ES patients compared with controls and remained stable across CKD stages. Fractional excretion of POST and KIM-1 is associated with CKD stage and reflects ongoing tubular injury in children. The FePOST/FeKIM-1 ratio may represent a sensitive marker of early CKD. Full article

Background/Objectives: X-linked Alport syndrome (XLAS) arises from pathogenic variants in COL4A5. Truncating variants are generally classified as severe, but whether clinically meaningful heterogeneity exists within this group remains unclear. This study aimed to establish a novel Col4a5 knock-in mouse model based on a clinical variant and to determine whether truncating mutation position influences disease severity. Methods: A de novo COL4A5 frameshift variant, c.2440delG, was identified in a patient with severe early-onset XLAS. A Col4a5-G814fs knock-in mouse was generated by CRISPR/Cas9 on the C57BL/6J inbred mouse strain background and compared with the established Col4a5-G5X nonsense model using survival analysis, serial functional measurements, kidney histopathology, transmission electron microscopy, and RNA sequencing. Results: The Col4a5-G814fs knock-in mouse was successfully generated and showed loss of glomerular α5(IV) collagen chain expression. Compared with G5X mice, G814fs mice exhibited shorter survival (median 141 vs. 161.5 days, p = 0.0004), earlier onset of proteinuria, and more severe kidney functional decline. By 16 weeks, G814fs mice also showed more severe glomerular basement membrane abnormalities and more extensive glomerulosclerosis. RNA sequencing revealed a shared inflammatory gene signature in both models, together with selective upregulation of genes related to the PPAR signaling pathway and fatty acid metabolism in G814fs kidneys. Conclusions: This study reports a novel de novo COL4A5 frameshift variant and establishes the first Col4a5-G814fs knock-in mouse model. Direct comparison with the G5X model shows that distinct truncating COL4A5 mutations can be associated with substantially different disease severity, providing a useful platform for future mechanistic and therapeutic studies in XLAS. Full article

Background and Objectives: Percutaneous coronary intervention (PCI) has markedly improved outcomes in coronary artery disease through the implantation of bare-metal stents (BMS) or drug-eluting stents (DES). However, in-stent restenosis (ISR) remains a significant complication, often necessitating repeat interventions. This study aimed to identify risk factors associated with ISR in patients with ST-elevation myocardial infarction (STEMI) who underwent PCI. Materials and Methods: We conducted a retrospective, non-randomized observational study of 107 STEMI patients treated with PCI between January 2016 and December 2019 who subsequently underwent clinically indicated (predominantly symptom-driven) follow-up coronary angiography within 12 months. ISR was defined as ≥50% luminal narrowing at follow-up angiography. Time-to-event analysis was performed using Cox regression models, incorporating clinical, biochemical, and angiographic variables. Results: In this selected cohort of patients undergoing follow-up angiography, ISR of any degree was identified in 87% of patients, and 52% had restenosis >70%. Advanced age, prior cardiovascular events, diabetes mellitus, chronic kidney disease, and history of stroke significantly increased the hazard of ISR. Smoking, dyslipidemia, and hypertension were prevalent in patients with severe ISR. Women presented with more severe clinical profiles (higher Killip class and troponin levels). DES showed slightly better TIMI flow than BMS, but stent type, dimensions, and number did not significantly impact restenosis risk. Thrombolytic therapy was associated with a significantly reduced ISR hazard. Mortality was 6% in patients with severe ISR. The highest restenosis incidence occurred in the LAD and RCA territories. Conclusions: ISR is a multifactorial process influenced by demographic, clinical, and procedural factors. Despite technological advances, ISR remains a prevalent issue, particularly in high-risk groups undergoing clinically indicated follow-up angiography. Secondary prevention strategies, optimized stent deployment, and targeted therapies addressing inflammation and vascular remodeling are essential to improving long-term PCI outcomes. Full article

Background/Objectives: Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder characterized by immune dysregulation that leads to widespread inflammation and damage across multiple organs. B lymphocytes play a vital role in SLE, with abnormal development and activation leading to autoreactive antibody production and immune complex formation, which damages tissues. Methods: The PPARα agonist WY14643 has anti-inflammatory effects in various inflammatory conditions, including CNS diseases. We investigated whether WY14643 decreases inflammatory mediator production in CD45R⁺ cells in the MRL/lpr mouse model of SLE. Flow cytometry was used to evaluate WY14643’s impact on the expression of IFN-γ, IL-6, iNOS, MCP-1, IL-1α, IL-2, Notch-1, Notch-3, GITR, and NF-κB p65 in splenic CD45R⁺ B cells. Additionally, we assessed the effect of WY14643 on the mRNA levels of these markers in the kidney using RT-PCR. Results: WY14643 decreased inflammatory markers such as CD45R⁺IFN-γ⁺, CD45R⁺IL-6⁺, CD45R⁺iNOS⁺, CD45R⁺MCP-1⁺, CD45R⁺IL-1α⁺, CD45R⁺IL-2⁺, CD45R⁺Notch1⁺, CD45R⁺Notch3⁺, CD45R⁺GITR⁺, and CD45R⁺NF-κB p65⁺ in splenic cells from MRL/lpr mice. Furthermore, WY14643 also lowered mRNA expression of IFN-γ, IL-6, iNOS, MCP-1, IL-2, IL-1α, Notch-1, Notch-3, GITR, and NF-κB p65 in the kidney. Conclusions: This study shows that WY14643 inhibits the production of inflammatory mediators and significantly reduces autoimmune features, including kidney inflammation, in MRL/lpr mice. Our results indicate that WY14643, a PPAR-α agonist, could be a potential therapy for lupus nephritis. Full article

Background/Objectives: Nurses and dialysis technicians are primarily responsible for cannulation in in-center and satellite dialysis units. Despite being a core component of hemodialysis care, existing clinical guidelines offer limited standardization, resulting in practice variability across facilities. Therefore, clinical expertise and adherence to consistent standards are essential to ensure safe and effective vascular access management. The study aimed to investigate the variables related to patients and nurses that contribute to unsuccessful vascular access cannulations, as well as the actions taken in response to cannulation failure, in a tertiary dialysis center in the Eastern Region of Saudi Arabia. Methods: This retrospective analytic study reviewed the records of 228 adult hemodialysis patients at King Fahad Military Medical Complex from 2020 to 2024, analyzing demographic, clinical, vascular access, and nursing variables associated with cannulation failure using descriptive statistics, the chi-square test, and t-tests. Ethical approval was obtained, and data were de-identified and manually extracted from nursing and dialysis documentation. Results: Most patients had hypertension and diabetes, with significant comorbidity burdens. Infiltration (61%) and clot formation (30.7%) were the primary complications of cannulation failure. Significant associations emerged with recurrent stroke and peripheral vascular disease, but not with nurse or patient demographics, suggesting vascular factors outweigh staff variables in cannulation risk. Cannulation failures were most common in patients with vascular comorbidities, while staff experience and education had no significant impact. Conclusions: Recommendations include implementing tailored protocols, providing ongoing nurse education, conducting systematic vascular assessments, and holding regular team reviews to enhance access outcomes and patient safety. Full article

Candida albicans is a ubiquitous commensal fungus that may be lethal once it gains access to the bloodstream, following a breach in protective barriers such as skin or gut lining. Intravenous injection of C. albicans (4.5 × 10⁴ yeasts/gm of mouse) leads reproducibly to systemic infection with a median survival of about 75 h. We studied the effects of two human innate immune effectors on the course of systemic infections. The soluble human pentraxin serum amyloid P component (hSAP) retards death in murine disseminated candidiasis. In contrast, another soluble pentraxin, human C-reactive protein (hCRP), hastens death. To examine the pathological basis for these differences, necropsies were performed, and the right kidney was removed for study. Candidiasis caused abundant collagen deposition (the precursor to fibrosis) and loss of contrast between the kidney medulla and cortex. Daily administration of subcutaneous hSAP following the intravenous injection of C. albicans preserved the discrete histological difference between cortex and medulla and lessened host collagen deposition. Yeasts and hyphae within abscesses were decorated with hSAP. Contrastingly, kidneys from animals administered C. albicans and hCRP showed extensive collagen deposition and loss of the boundary between the cortex and the medulla of the kidney. hCRP did not bind to fungi but bound to damaged tissue surrounding abscesses, leading to a more destructive infection with loss of tissue. Staining cells with antibodies to CD45 (to detect T-lymphocytes, myelocytes, monocytes, and macrophages) and antibodies to Ly-6G (neutrophils, and granulocytes) showed that hSAP retarded infiltration of inflammatory cells into diseased areas. The results are consistent with the hypothesis that early administration of hSAP represses the migration of inflammatory cells, dampens the production of collagen by fibroblasts, and dampens the overall immune response of the host to infection. In doing so, hSAP prolonged life, whereas hCRP facilitated the infectious process and hastened death. Full article

Diabetic kidney disease (DKD) is a severe microvascular complication traditionally attributed to general metabolic derangement and genetic susceptibility. However, this classic pathophysiological approach overlooks the role of red blood cells in the development and the progression of the disease. Prolonged exposure to high blood glucose and oxidative stress compromises the cell’s membrane architecture and ionic homeostasis, resulting in altered rheological properties. By synthesizing these molecular-to-rheological pathways, this review establishes a novel pathophysiological framework for understanding DKD, repositioning erythrocytes to a primary catalyst of renal injury and a highly sensitive target for early diagnostic intervention. Full article

Background: Patients with kidney failure requiring dialysis experience a high burden of vaccine-preventable diseases, and vaccine hypo-responsiveness is a key contributor. Uraemic toxins and gut dysbiosis are potential causes of hypo-responsiveness. Aim: This study aimed to determine whether uraemic toxin concentrations or gut dysbiosis are associated with vaccine response in haemodialysis patients. Methods: This was a single centre, observational cohort study of maintenance dialysis patients receiving a conventional 2-dose primary COVID-19 vaccination course. Demographic, clinical and vaccination data were collected from the eMR. Vaccine response (Elecsys Anti-SARS-CoV-2 immunoassay), serum uraemic toxin concentrations (indoxyl sulphate, p-cresyl sulphate, and trimethylamine N-oxide by liquid chromatography), and stool microbiome (16S rRNA gene sequencing) were measured 8 weeks after the second dose of vaccine. Results: Forty participants (43% female, mean age 66 years; 59% Caucasian) were included, 70% of whom were classified as a vaccine responder. Antibiotic exposure, prednisolone use and lymphopenia were significantly associated with hypo-responsiveness. Microbiome profiling identified differences in beta diversity between responders and non-responders, positively correlated with short-chain fatty acid producers (Parabacteriodes) and negatively with pathobionts (Escherichia/Shigella). Differential abundance analysis identified lower levels of Tyzzerella, Gemmiger, and Hungatella and higher levels of Turicibacter in vaccine responders. Total uraemic toxin burden and individual toxin concentrations did not differ between responders and hypo-responders (all p > 0.05). Stratification by low versus high/very high toxin burden groupings was not associated with response (p > 0.99). Conclusions: Differences in gut microbial composition were observed between vaccine responder groups, while uraemic toxin concentrations were not associated with vaccine responsiveness. These findings suggest gut microbiota composition may contribute to vaccine hypo-responsiveness in individuals receiving dialysis and warrant further investigation in larger mechanistic studies. Full article

Chronic kidney disease (CKD) represents a growing medical, diagnostic and social challenge, and it is estimated to effect 8.5–9.8% of the global population and requires expensive modes of treatment, such as hemodialysis or renal transplants. Currently, a diagnosis of CKD is set based on the level of creatinine in the blood, which is the gold standard of renal function diagnostics. Unfortunately, decrease in GFR is secondary to damage of the kidney parenchyma and indicates that the best time to start more aggressive treatment has already passed. Therefore, several non-invasive methods have been proposed for predicting increased risk of CKD progression; however, in most of the cases kidney biopsy is essential. Currently, the greatest hopes for a method that can confirm CKD are associated with the development of MRI, the most tissue-specific imaging method, and it is already proven to be capable to detect inflammatory and edematous changes, fibrosis, as well as perfusion and oxygenation disturbances. Therefore, in our manuscript we decided to present up-to-date knowledge about kidney MRI from a clinical point of view. Full article

Background/Objectives: Therapeutic drug monitoring (TDM) of immunosuppressants is essential in treating pediatric kidney diseases; however, repeated venipuncture is burdensome in children. We evaluated whether minimally invasive fingerstick capillary sampling combined with liquid chromatography–tandem mass spectrometry (LC-MS/MS) provides results analytically comparable to those of conventional venous sampling. Methods: Capillary whole blood (2.8 µL) was collected via fingersticks from pediatric patients receiving mycophenolate mofetil, with or without tacrolimus (TAC) or cyclosporine A (CsA). Drug concentrations were quantified using a previously validated simultaneous LC-MS/MS method and compared with conventional venous sampling using linear regression and Bland–Altman analyses. Results: Seventy-four paired samples from 21 patients were analyzed. Strong correlations were observed between capillary and venous samples for mycophenolic acid (MPA), TAC, and CsA (R² > 0.90). Hematocrit correction improved agreement for MPA. Bland–Altman analyses demonstrated acceptable bias across analytes. Conclusions: Fingerstick-based microvolume sampling combined with LC-MS/MS provides analytically reliable immunosuppressant quantification in pediatric patients. Although larger clinical validation is required, this minimally invasive approach may reduce procedural burden and may support future outpatient or home-based TDM strategies. Full article

Although medicinal plants possess vast biological properties, crude medicinal plant extracts often show limited therapeutic efficacy due to poor aqueous solubility, instability, and inadequate bioavailability, which restricts efficient intracellular delivery. As cancer is a genetic disease requiring intracellular and nuclear targeting, improved delivery systems are essential. Warburgia salutaris is traditionally used in Southern Africa and possesses reported anticancer and anti-inflammatory properties; however, its crude extracts exhibit suboptimal delivery characteristics. This study comparatively evaluated the anticancer effects of unencapsulated (WSN) and liposomal-encapsulated (WSE) crude leaf extracts, with emphasis on apoptotic mechanisms. Liposomal formulation was confirmed by FTIR, PXRD, and DLS, yielding stable nanoparticles (159.4 nm; PDI 0.114; +79.3 mV). Both WSN and WSE demonstrated efficacy and concentration-dependent cytotoxicity against MCF-7 breast cancer cells (IC₅₀ < 0.0195 mg/mL) with minimal toxicity toward Vero kidney cells and RAW 264.7 macrophages. Mechanistically, WSN induced rapid cytotoxicity with necrotic features, whereas WSE promoted regulated apoptosis. Apoptosis was validated by DAPI/PI staining, Annexin V/PI flow cytometry, mRNA expression levels of Bax, Bcl-2, and caspase-3 measured with RT-PCR and proteome profiling array, confirming activation of intrinsic and extrinsic pathways. Both extracts also reduced LPS-induced ROS production. LC-MS identified multiple bioactive phytochemicals. Overall, liposomal encapsulation enhanced therapeutic precision, stability, and selectivity cytotoxicity, supporting its development as a nanomedicine-based anticancer strategy. Full article