Search Results (725)

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

Background/Objectives: Protein-bound uremic toxins (PBUTs), particularly p-cresyl sulfate (PCS) and indoxyl sulfate (IS), are associated with cardiovascular toxicity and increased mortality. Conventional hemodialysis (HD) removes PBUTs poorly, and the efficacy of medium cut-off (MCO) dialyzer membranes remains uncertain. Furthermore, PBUT production is influenced by gut microbial metabolism and can be modified through diet. We hypothesized that MCO dialysis would provide superior clearance of PCS and IS compared with online hemodiafiltration (OL-HDF), and that combining MCO dialysis with increased dietary fiber and short-chain fatty acid (SCFA) intake would further reduce PBUT levels. Methods: In this prospective randomized trial, 62 maintenance HD patients underwent a 2-week wash-in period with high-flux HD (HF-HD) and were then randomized to MCO-HD (EXP) or OL-HDF (CON). After a 4-week intervention with the assigned dialysis modality, both groups continued with the same dialysis treatment and received an 8-week dietary intervention consisting of 19 g/day fiber and 1 g/day sodium propionate. The study concluded with a 4-week wash-out period on HF-HD. Primary outcomes were total serum PCS and IS levels measured at four timepoints. Results: Fifty-two patients completed the study. No significant changes in PCS or IS were observed after the dialysis-only intervention. PCS levels remained stable throughout the study. When the aligned dialysis regimen was combined with the dietary intervention, IS levels were significantly lower in the CON than in the EXP group (31.5 ± 10.3 vs. 42.0 ± 15.8 µmol/L; p = 0.006), with a partial rebound after wash-out in the CON group (39.6 ± 20.9 µmol/L; p = 0.003). Conclusions: While MCO-HD and OL-HDF had a similar effect on serum PCS and IS concentrations, only OL-HDF combined with the dietary intervention significantly reduced IS levels. Full article

Oxidative stress and gut microbiota dysbiosis establish a self-perpetuating loop that disrupts epithelial barrier integrity and fuels chronic inflammatory and metabolic disorders, including inflammatory bowel disease (IBD), metabolic syndrome (MS), and chronic kidney disease (CKD). This systematic review synthesizes mechanistic, preclinical, and clinical evidence linking reactive oxygen species (ROS), microbiota-derived metabolites, and host redox homeostasis, with a focus on probiotic-based interventions. Comprehensive searches of PubMed, Scopus, Web of Science, and Google Scholar (2000–March 2026) identified in vitro, animal, and human studies, as well as systematic reviews and meta-analyses, assessing oxidative biomarkers, microbiome profiles, and barrier function outcomes. Probiotic strains, predominantly Lactiplantibacillus, Bifidobacterium, and emerging next-generation taxa, attenuate oxidative stress by inducing antioxidant enzymes [superoxide dismutase (SOD), glutathione peroxidase (GPx)], activating Nrf2 signaling, and restoring short-chain fatty acid (SCFAs) production, thereby lowering malondialdehyde (MDA) and 8-hydroxy-2′-deoxyguanosine (8-OHdG) while enhancing total antioxidant capacity (TAC). At the mucosal interface, probiotics strengthen tight junction proteins, suppress NF-κB-mediated cytokine release, and mitigate dysbiosis, contributing to clinically meaningful improvements in disease activity, insulin sensitivity, and uremic toxin burden along gut–liver, gut–kidney, and other gut–organ axes. Overall, current evidence supports probiotics and synbiotics as promising adjuncts for nutrition-driven redox modulation, while highlighting the need for strain-resolved, multi-omics, multicenter trials with standardized redox and microbiome endpoints to optimize dosing strategies and long-term safety. Full article

Background/Objectives: Cardiovascular complications remain the leading cause of mortality among patients with end-stage renal disease (ESRD) treated with maintenance hemodialysis (HD). Global longitudinal strain (GLS) is a sensitive echocardiographic marker of left ventricular systolic dysfunction that enables the detection of transient contractile abnormalities consistent with intradialytic myocardial stunning. This study aimed to assess intradialytic GLS dynamics during a single HD session and to identify predictors of GLS deterioration. Methods: Forty-three patients were enrolled. Transthoracic echocardiography, electrocardiography, and pulse wave analysis were performed before HD, at mid-session, and after HD. Biochemical assessment included, among others, plasma osmolality, electrolytes, and biomarkers of oxidative stress and endothelial dysfunction. Results: Three distinct intradialytic GLS trajectories were identified: GLS worsening (GLSw, 46.5%), GLS stable (GLSs, 34.9%), and GLS improvement (GLSi, 18.6%). In the GLSw group, independent predictors of GLS deterioration included a decrease in left atrial volume index (LAVI, p = 0.0002), an increase in left ventricular end-systolic volume index (LVESVI, p = 0.0067), diabetes mellitus (p = 0.0094), and an increase in the malondialdehyde-to-creatinine ratio (MDA/CREA, p = 0.0055). In the GLSi group, GLS improvement was associated with a decrease in plasma osmolality (p = 0.0326) and asymmetric dimethylarginine (ADMA, p = 0.0279), as well as an increase in the subendocardial viability ratio index (SEVRI, p = 0.0004) and caspase-1 (p = 0.0005). Conclusions: Intradialytic GLS trajectories are heterogeneous and reflect individual susceptibility to GLS deterioration. Modifiable adverse factors likely include oxidative stress, osmotic stress, fluid overload, uremic toxin- and ion-disturbance-related stress, and impaired coronary microvascular reserve. Future prospective studies are needed. Full article

Patients with chronic kidney disease (CKD) have a markedly increased cardiovascular risk that is not fully explained by traditional risk factors. Gut-derived uremic toxins, indoxyl sulfate (IS), indole-3-acetic acid (IAA), and p-cresyl sulfate (pCS), are poorly cleared by dialysis and may contribute to vascular damage. This cross-sectional observational study included 70 patients with CKD under different clinical conditions (pre-dialysis, peritoneal dialysis, hemodialysis, and kidney transplantation) and 17 healthy controls. Serum levels of IS, IAA, pCS and Klotho were measured, and vascular damage was assessed by carotid intima–media thickness (IMT) using ultrasound. CKD patients showed higher concentrations of IS, IAA, and pCS compared with controls, with the highest levels observed in hemodialysis patients. Peritoneal dialysis was associated with elevated IS and pCS, whereas in kidney transplantation, IS and IAA levels did not differ significantly from controls, and pCS remained elevated. Carotid IMT was higher in patients with diabetes and those undergoing hemodialysis. IAA correlated significantly with left/mean IMT, and mean IMT was the only parameter associated with previous cardiovascular events. These findings suggest that gut-derived uremic toxins, particularly IAA, might be associated with subclinical vascular damage in advanced CKD, although larger studies are needed to confirm these associations. Full article

Chronic kidney disease (CKD), especially diabetic kidney disease (DKD), is characterized not only by progressive loss of renal function but also by profound metabolic disturbances, including insulin resistance (IR). Emerging evidence implicates gut-derived uremic toxins as mediators linking intestinal dysbiosis to metabolic and renal injury. Several microbial metabolites, for example, indoxyl sulfate, p-cresyl sulfate, and trimethylamine-N-oxide, are known to accumulate in CKD due to decreased renal excretion and altered tubular secretion. In vitro and in vivo experiments indicate that these gut-derived nephrotoxins impair insulin signaling pathways in cells. This results in increased production of reactive oxygen species, activation of stress kinases, higher levels of inflammatory cytokines, and inhibitory serine phosphorylation of insulin receptor substrates. Consequently, phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling is impaired, reducing cellular glucose uptake. At the same time, these toxins induce endothelial dysfunction and mitochondrial damage, not only causing systemic IR but also contributing to the progression of kidney disease. Observational data link higher plasma toxin levels with components of IR, rapid loss of renal function as measured by estimated glomerular filtration rate, and a high risk of cardiovascular events in CKD patients. Although causality in humans remains unproven, interventions targeting the microbiota, toxin binding, and oxidative stress pathways show promise. We propose an integrated gut–kidney–metabolic framework in which dysbiosis-driven toxin production may amplify IR and DKD progression. Full article

Chronic kidney disease (CKD) is a progressive condition associated with metabolic disturbances, systemic inflammation, and the accumulation of gut-derived uremic toxins. Increasing evidence highlights the role of gut microbiota dysbiosis in the progression of CKD through the gut–kidney axis. Consequently, microbiome-targeted nutritional strategies, including probiotics, prebiotics, and synbiotics, have emerged as promising complementary approaches to modulate intestinal microbial composition and metabolic functions. This review summarizes and critically evaluates the current clinical evidence regarding the use of these interventions in CKD patients. Clinical studies indicate that supplementation with probiotics, prebiotics, and synbiotic formulations may promote beneficial shifts in the composition of the gut microbiota, enhance saccharolytic fermentation, and increase the production of short-chain fatty acids (SCFAs). These changes have been associated with reduced circulating levels of gut-derived uremic toxins such as indoxyl sulfate and p-cresyl sulfate, as well as with the attenuation of systemic inflammation and oxidative stress. However, available trials remain heterogeneous in terms of study design, probiotic strains, prebiotic substrates, dosing regimens, and patient populations, and are frequently limited by small sample sizes and short intervention durations. As a result, evidence for improvements in renal function and long-term clinical outcomes remains inconclusive. While synbiotics may offer theoretical advantages by combining microbial supplementation with targeted substrates that support microbial growth and metabolic activity, current evidence does not consistently demonstrate superior clinical efficacy. Overall, these interventions often improve surrogate biomarkers, but their effects on renal function and hard clinical outcomes remain uncertain. Larger, longer-duration multicenter randomized controlled trials with standardized formulations are needed to establish their clinical utility and to better elucidate microbiota–host interactions in CKD. Advancing this field may support the development of personalized microbiome-based therapeutic strategies aimed at modulating the gut–kidney axis and ultimately improving clinical outcomes in CKD patients. Full article

Background: Chronic kidney disease (CKD) represents an escalating global health burden, fundamentally altering morbidity and mortality trajectories across the world, particularly as it advances into end-stage renal disease (ESRD). Beyond the primary decline in renal filtration and excretion, a wide spectrum of endocrine and metabolic derangements frequently accompanies kidney failure, with thyroid dysfunction emerging as a critical complication. Methods: The current study was designed to rigorously evaluate the nuanced association between thyroid hormone dynamics—specifically thyrotropin (TSH), triiodothyronine (T3), and thyroxine (T4)—and renal status in three distinct cohorts: individuals with suspected thyroid issues but normal renal function (NPs), non-dialysis kidney disease patients (NDKPs), and patients undergoing maintenance hemodialysis (DPs). Data were collected from a clinical setting in Bangladesh, involving 161 subjects. Results: The results demonstrated that patients in the DP cohort exhibited slightly elevated thyroid hormone levels relative to those in the NDKP cohort. Specifically, within the subgroups of patients exhibiting normal or sub-reference hormonal levels, dialysis patients maintained higher concentrations than their non-dialysis counterparts. Demographic stratification further revealed that males, females, and individuals younger than 45 years were more likely to demonstrate restorative hormonal profiles in the DP group than in the NDKP group. Conclusions: These collective outcomes suggest that renal replacement therapy, specifically hemodialysis, may serve to stabilize or improve thyroid function in ESRD patients by potentially mitigating the suppressive effects of uremic toxins and normalizing homeostatic feedback loops. Full article

Chronic kidney disease (CKD) is on the rise, with sarcopenia accompanying CKD in an estimated 25% of patients, featuring as a potentially debilitating issue that should not be overlooked. Sarcopenia, characterized by a loss of skeletal muscle mass and strength, is multifactorial. The aging process, uremic toxins, systemic inflammation, oxidative stress, gut dysbiosis, hormonal dysregulation, dietary deficits, and even air pollution are among the major parameters being implicated in sarcopenia among patients with CKD. Additionally, the existence of various comorbidities, such as type 2 diabetes mellitus (T2DM), depression, and cardiovascular diseases (CVD), also contribute to the chronic low-grade inflammation associated with skeletal muscle inflammation and atrophy. The purpose of this review is to delve into the complex interplay of multiple factors being involved in the pathogenesis of sarcopenia in patients with CKD. Moreover, we aim to shed light upon nutritional aspects that could delay the development and progression of sarcopenia among patients with CKD. To address vitamin D deficiency, micronutrients and macronutrients together with physical activity remain the cornerstone of delaying the progression of sarcopenia in this sub-population. Additionally, experimental drugs exhibiting therapeutic potential are also being discussed. As sarcopenia and quality of life are interconnected, the timely recognition of sarcopenia, together with nutritional and therapeutic interventions, is of the utmost importance in our crusade for a better quality of life (QoL) in patients with CKD. Full article

Phage-encoded Shiga toxin (Stx) released by Shiga toxin-producing E. coli (STEC) can kill multiple eukaryotic bacterial predators, including Acanthamoeba castellanii, Tetrahymena thermophila and Caenorhabditis elegans. However, the impact of Stx type, Stx amount, and the serogroup of the E. coli on the effectiveness of this exotoxin are poorly understood. These factors impact the severity of Stx-mediated disease in humans and therefore, by studying their role in modulating predator–prey interactions, we may gain insight into how these virulence factors evolved to contribute to human pathogenicity. Herein, we investigated the effects of these factors on predator killing by measuring the efficiency with which five different hemolytic uremic syndrome (HUS)-causing STEC strains consume and/or kill A. castellanii and C. elegans. These strains express various combinations of Stx types and amounts and O-antigens. We found that variations in Stx types and amounts significantly affect the ability of a given bacterial strain to kill predator A. castellanii and C. elegans, with higher Stx1 titers (HUSEC 31 vs. 19) and the presence of Stx2 alone (HUSEC 20) correlating with significantly greater predator killing. These attributes also affect STEC pathogenicity in humans, suggesting that ecological selective pressures for anti-predator defense inadvertently drive the evolution of strains with higher virulence potential in humans. Full article

Chronic kidney disease (CKD) involves uremic toxin-driven tubular injury and systemic vascular dysfunction, in which mitochondrial impairment and apoptotic cell loss contribute to progressive tissue deterioration. Accordingly, a targeted EV platform is required to enable efficient miRNA delivery to the toxin-stressed tubular–endothelial compartment. Based on our previous study showing that melatonin restores miR-4516 levels under CKD-related stress, we directly loaded miR-4516 into engineered extracellular vesicles (EVs) to evaluate its effects on mitochondrial function and cell survival. Here, we engineered EVs with a G3-C12/RGD surface modification and established a miR-4516 loading strategy to enhance delivery to kidney proximal tubule cells and vascular endothelial cells. miR-4516 loading increased EV-associated miR-4516 levels without major changes in particle size distribution, and EV identity was supported by CD9 and CD81 expression. Confocal microscopy and flow cytometry demonstrated increased cellular uptake of miR-4516-loaded G3-C12/RGD-EVs compared with control EVs in TH1 proximal tubule cells and HUVECs. Under indoxyl sulfate stress, engineered EV treatment restored intracellular miR-4516 and improved mitochondrial function, as indicated by recovery of respiratory Complex I and Complex IV activities and improved Seahorse bioenergetic parameters (OCR/ECAR, basal and maximal respiration, ATP-linked respiration, and spare respiratory capacity). Annexin V staining further indicated reduced toxin-induced apoptosis. In an adenine diet-induced CKD mouse model, intravenous administration of miR-4516-loaded G3-C12/RGD-EVs improved urinary albumin-to-creatinine ratio (UACR), blood urea nitrogen (BUN), and serum creatinine. These findings indicate that miR-4516-loaded, targeting-engineered EVs may mitigate uremic toxin-associated mitochondrial dysfunction and renal impairment in CKD. Full article

Extracorporeal dialysis for uremic toxin removal and fluid regulation relies on specialized dialyzers whose membranes differ markedly in polymer chemistry, pore architecture, adsorption capacity, surface bioactivity, and convective performance. These structural and material distinctions result in wide variation in the clearance of chemically diverse uremic solutes. Despite the expanding range of dialyzer options, membrane selection in clinical practice remains largely non-individualized. In this review, we propose a phenotype-based model for dialyzer membrane selection. We outline how distinct membrane families achieve differential solute clearance and integrate these functional characteristics into a framework that considers residual kidney function, nutritional and inflammatory status, cardiovascular physiology, protein-bound toxin burden, and hemodynamic vulnerability. Because access to advanced membranes varies across regions and dialysis providers, implementation will require adaptation to local formulary constraints. Nevertheless, aligning membrane properties with patient-specific toxin profiles offers a promising strategy to optimize extracorporeal therapy and improve outcomes in chronic dialysis. Full article

Fetal bovine serum (FBS) is the standard supplement for cell culture, yet we previously demonstrated that it drives hyper-proliferation and phenotypic drift in Madin–Darby canine kidney (MDCK) cells, compromising their epithelial identity and ciliogenesis. In contrast, a modified chicken embryo extract (CEE) preserved these intrinsic properties, maintaining a stable and physiologically relevant phenotype. To elucidate the metabolic mechanisms driving these distinct cellular fates, we performed a comparative analysis of redox status and metabolomic profiles. We found that FBS forces a metabolic shift toward oxidative phosphorylation, resulting in mitochondrial stress characterized by elevated mitochondrial reactive oxygen species (mtROS), calcium overload, and the accumulation of uremic toxins like hippuric acid. Conversely, CEE established a balanced redox environment. Although CEE induced higher intracellular signaling ROS via NADPH oxidase 1/2, it prevented oxidative damage by upregulating antioxidant transcription factors, such as nuclear factor erythroid 2-related factor 2, and enzymes such as Mn superoxide dismutase. Additionally, metabolomic analysis revealed that CEE is enriched with antioxidants (ascorbic acid, proline) and signaling molecules (5-hydroxyindole-3-acetic acid). These findings indicate that while FBS imposes a metabolic burden leading to cellular stress, CEE provides a favorable metabolic microenvironment that supports homeostasis and epithelial integrity, validating its superiority as a culture supplement. Full article

Background: Cardiorenal syndrome (CRS) represents a complex clinical entity characterized by the bidirectional dysfunction of the heart and kidneys. Despite advances in pharmacological therapy, CRS remains associated with high morbidity and mortality. Pathophysiological drivers, including oxidative stress, chronic inflammation, and mitochondrial derangements, create a self-perpetuating cycle of organ damage that necessitates multitarget therapeutic approaches. Objective: This review synthesizes current preclinical evidence regarding the protective roles of plant-derived polyphenols—specifically bergamot, curcumin, quercetin, catechins, and resveratrol—in mitigating the cardiorenal continuum. Methods: An analysis of recent literature was conducted, focusing on the molecular mechanisms by which these bioactives modulate redox balance, inflammatory signaling, and mitochondrial homeostasis in experimental models of CRS. Results: Polyphenols act at the crossroads of several stress-response pathways. Key mechanisms include the activation of the Nrf2/HO-1 axis to enhance endogenous antioxidant defenses, the suppression of the NLRP3 inflammasome to attenuate systemic “inflammaging”, and the preservation of mitochondrial quality through SIRT1/PINK1/Parkin-mediated mitophagy. Furthermore, emerging evidence highlights the role of polyphenols in modulating the gut-kidney-heart axis by reducing microbiota-derived uremic toxins. Conclusions: Preclinical data suggest that polyphenols are potent multifunctional agents capable of breaking the feedback loops of cardiorenal injury. While bioavailability remains a significant translational challenge, novel nano-delivery systems and synthetic analogs offer promising strategies for clinical application. Integrating these bioactives into CRS management could provide a decisive adjunctive strategy to improve metabolic homeostasis and prevent end-stage organ failure. Full article

Background: Hyperuricemia (HUA) is a metabolic disorder that severely threatens human health. Chronic uric acid (UA) overload promotes the progression of tubulointerstitial fibrosis (TIF), leading to impaired UA excretion. Our previous studies identified HIPK2 inhibitor XRF-1021, which exhibits robust anti-TIF activity and lowers UA levels in vivo. This study aimed to elucidate its UA-lowering mechanism and therapeutic potential for HUA. Methods: Uricase and xanthine oxidase (XOD) assays were performed to assess effects on UA degradation/production. HEK293T cells transiently expressing UA transporters and gene-knockdown rats were used to evaluate transporter inhibition, while HK-2 cells were analyzed by Western blot. Pharmacokinetics were characterized in rats. Efficacy was tested in potassium oxonate-induced acute HUA rats, diet/adenine-induced chronic HUA quails, and adenine-induced mice with HUA secondary to TIF. Maximum tolerated dose and long-term toxicity were assessed in rats. Results: XRF-1021 neither activated uricase nor inhibited XOD, indicating no direct effect on UA catabolism or synthesis. Instead, XRF-1021 inhibited URAT1 and GLUT9, reducing renal UA reabsorption, while sparing OAT3, OAT4, and ABCG2 activity and upregulating OAT3 and NPT4, suggesting minimal risk of disrupting drug or uremic toxin handling. XRF-1021 showed dose-dependent systemic exposure in rats, lowered serum UA, and provided renal protection in vivo. LD₅₀ values were 2345.4 mg/kg (male) and 1078.9 mg/kg (female), with no obvious toxicity after long-term dosing. Conclusions: XRF-1021 lowers UA by inhibiting URAT1 and GLUT9 to enhance renal UA excretion and provides kidney protection, supporting XRF-1021 as a promising candidate for HUA therapy. Full article