Search Results (735)

Short-chain fatty acids (SCFAs) and medium-chain fatty acids (MCFAs) include small organic anions derived from the gut microbiome that interact with organic anion transporters of the SLC22 family, many of which are expressed in the kidney proximal tubule. According to the Remote Sensing and Signaling Theory (RSST), crosstalk between organs (e.g., gut–liver–kidney axis, gut–brain axis) and the gut microbiome is mediated by metabolites and signaling molecules transported by multi-specific “drug” transporters. The renal drug transporter OAT1 (SLC22A6) is also a major transporter of gut-microbiome products and uremic toxins (e.g., indoxyl sulfate); it has been shown to act as part of a regulatory feedback loop involving the gut microbiome. SCFAs, especially propionate and butyrate, have been shown to play a central role in the transcriptional regulation of OAT1 through HDAC inhibition. By fecal metagenomics analyses of Oat1 knockout mice, we now find that propionate synthesis is among the most altered pathways in the gut microbiome. In contrast, these pathways were only minimally altered in the Oat3 (Slc22a8) knockout. Metabolomics analyses indicate that serum propionate derivatives (e.g., propionyl glycine) and 3-hydroxybutyrate are dependent on OAT1 in the knockout mice and in humans treated with probenecid, an OAT1 inhibitor. The gut microbiome of the Oat1 knockout mice also exhibited greater fatty acid synthesis, which generates odd-chain-length fatty acids (e.g. heptanoate) when propionate is available. Overall, the data, especially when considered in light of in vitro experiments of others, indicates the in vivo existence of a feedback loop connecting gut-microbiome-derived SCFAs and MCFAs to kidney proximal tubule uptake via OAT1. This bidirectional feedback loop in turn regulates OAT1 expression through HDAC inhibition. The feedback loop is clearly consistent with the Remote Sensing and Signaling Theory—in particular, the centrality of multi-specific “drug” transporters in organ crosstalk and host–microbiome interactions via small molecules with “high information content.” The key role of OAT1 function in maintaining tubular secretion in CKD supports the importance of this RSST loop in renal pathophysiology. Modulating this RSST loop could have therapeutic value in chronic kidney disease and other contexts. Full article

Chronic kidney disease (CKD) is characterized by the progressive accumulation of uremic toxins (UTs), which contribute to systemic complications, increased cardiovascular risk, and disease progression. Epidemiological and experimental evidence demonstrate pronounced sex differences in CKD progression and outcomes, yet the mechanisms underlying sex-specific uremic toxicity remain unclear. This review synthesizes current knowledge on sex differences in the origin, metabolism, transport, and biological effects of UTs, with a focus on sex-dependent regulatory mechanisms along the gut–liver–kidney axis. Sex hormones influence key determinants of toxin handling, including gut microbiota composition, hepatic enzyme activity, plasma protein binding, membrane transporter expression, and intracellular signaling pathways. Together, these factors regulate systemic toxin exposure and tissue susceptibility to injury. CKD also disrupts endocrine homeostasis, creating bidirectional interactions between hormonal regulation and toxin accumulation. Experimental and limited clinical evidence suggest that sex may influence circulating toxin profiles and susceptibility to toxin-associated complications. Collectively, sex is an important modulator of uremic toxicity, with sex hormones mediating at least part of the sex differences. A sex-informed framework may improve fundamental understanding through mechanistic studies and future clinical research may help clarify its relevance for biomarker development and support the development of personalized therapeutic strategies for CKD. Full article

There is a bidirectional relationship between chronic kidney disease (CKD) and an altered gut microbiome, with gut-derived uremic toxins contributing to cardiovascular-kidney-metabolic effects. In this review, we summarize the interplay between diet, the intestinal microbiota and systemic sequelae including CKD progression, cardiovascular morbidity and cognitive decline. We discuss the current state of knowledge regarding microbiota-modulating therapies that have the potential to delay CKD complications such as plant-dominant diets, oral adsorbents, prebiotics/probiotics, fecal microbiota transplantation and exercise. Full article

Background: Certain metabolites of the tryptophan-kynurenine (Trp-KYN) pathway, which are primarily cleared via tubular transport, have been linked to end-stage kidney disease (ESKD). Uromodulin—a protein expressed exclusively in the kidneys—is a key regulator of renal structure and function, as well as a direct marker of tubular health. This preliminary study explores the hypothesis that serum uromodulin correlates with Trp-KYN metabolites, potentially revealing new pathophysiological pathways in patients undergoing kidney replacement therapy (KRT). Given the link between serum uromodulin, Trp-KYN metabolites, and tubular function, we examined their correlation in KRT patients. Furthermore, we assessed how various clinical and dialysis parameters influence serum uromodulin levels. Methods: A total of 64 stable patients from a single dialysis center receiving hemodialysis (HD) or hemodiafiltration (HDF) were enrolled. Pre- and post-dialysis concentrations of uromodulin, Trp, KYN, kynurenic acid (KYNA), 3-hydroxykynurenine (3-OHKYN), and their reduction ratios (RRs) were established. High-performance liquid chromatography (HPLC) was used to estimate the KYN pathway metabolite levels, whereas uromodulin concentration was measured using an immunoenzymatic assay. Results: Detectable serum uromodulin was found in only 30 patients. This group was predominantly male (p < 0.001) and characterized by shorter dialysis vintage (p < 0.001), a higher prevalence of residual kidney function (RKF) (p = 0.001) and diabetes mellitus (p = 0.028), higher pre-dialysis serum phosphorus levels (p = 0.015), and more frequent use of loop diuretics (p = 0.004). Furthermore, univariate analysis revealed significantly higher pre-dialysis (p = 0.004) and post-dialysis (p = 0.025) serum Trp concentrations in the uromodulin-positive group. Pre-dialysis serum uromodulin concentration correlated positively with pre-dialysis Trp level (p < 0.001) and negatively with the pre-dialysis KYN/Trp ratio (p = 0.008), but not with other metabolites that are also subject to tubular transport mechanisms. Post-dialysis uromodulin levels correlated positively only with post-dialysis Trp level (p = 0.005). Patients treated with HDF had significantly higher RR for uromodulin than those treated with HD (p = 0.01). Conclusions: The presented data indicate that serum uromodulin levels are correlated with RKF. Additionally, the presence of detectable serum uromodulin may indicate reduced immunological activation, leading to diminished activity within the Trp-KYN pathway. Full article

Chronic kidney disease (CKD) affects nearly 10% of the global population, yet diagnosis and disease monitoring still rely primarily on plasma creatinine. Because creatinine levels are strongly influenced by non–renal factors, such as age, sex, muscle mass, and diet, its accuracy as a kidney function marker is limited. To identify plasma biomarkers that reflect kidney injury, we applied untargeted and targeted metabolomics in the adenine-induced CKD mouse model, a well-known tubular damage model, and validated the findings in plasma from patients with advanced CKD and healthy controls. We identified five metabolites that showed altered plasma levels in both experimental and human CKD, of which galactonic acid, pipecolic acid, and N-acetylneuraminic acid were significantly associated with measured glomerular filtration rate (GFR). As a proof-of-concept, we demonstrated that integrating these metabolites into a biomarker panel alongside creatinine could improve GFR estimation compared with creatinine alone. Our study introduces a promising metabolite-based biomarker panel that might enhance the accuracy of kidney function assessment and could potentially support diagnosis, risk stratification, and monitoring of disease progression; however, validation in a broader CKD cohort is needed. Full article

Chronic kidney disease (CKD) is characterized by persistent exposure to uremic toxins (UTs), many of which originate from gut microbial metabolism and contribute to renal, cardiovascular, and metabolic complications. Current evidence indicates that CKD is associated with dysbiosis and the enrichment of microbial taxa carrying genes involved in UT precursor production. Diet is a major modulator of the gut microbiota and therefore represents a promising lever to reduce UT generation in synergy with current nephroprotective therapies. Beyond simple protein restriction, more specific dietary approaches, particularly plant-based low-protein diets, appear especially relevant. Additional factors, including amino acid composition, lipid quality, food processing, constipation, transit time, meal timing, and circadian rhythms, may also influence microbial metabolism and UT production. This review examines the role of nutrition in shaping the gut microbiota–UT–kidney axis and discusses how dietary modulation may support precision nutrition in the context of CKD. It also highlights future directions based on multidimensional phenotyping and robust biomarkers to capture interindividual variability, guide personalized interventions, and ultimately improve renal and cardiovascular outcomes in CKD. Full article

Background: Vancomycin (VAN)-induced nephrotoxicity limits its clinical application. Licorice (Glycyrrhiza uralensis Fisch.) and its bioactive constituents have been reported to protect against nephrotoxicity induced by various nephrotoxic agents. This study aimed to evaluate the protective effects of licorice against VAN-induced nephrotoxicity and to explore the underlying mechanisms both in vivo and in vitro. Methods: Seven groups of male C57BL/6 mice received different treatments for 7 consecutive days. Blood, fecal and renal tissue samples were collected for the assessment of serum creatinine, renal histopathology, mitochondrial ultrastructure, oxidative stress markers, kidney injury molecule-1 (Kim-1), short-chain fatty acids (SCFAs), and uremic toxins. In human proximal tubular epithelial cells (HK-2 cells), the effects of licorice on cell viability, oxidative stress, inflammatory markers, and mitochondrial membrane potential (MMP) were further investigated. Results: Licorice significantly attenuated VAN-induced nephrotoxicity and restored glutathione peroxidase (GSH-Px) activity while reducing malondialdehyde (MDA) levels. In addition, licorice markedly ameliorated VAN-induced renal histopathological injury, as demonstrated by hematoxylin and eosin staining and transmission electron microscopy. Licorice also reversed VAN-induced intestinal microbiota dysbiosis and increased the relative abundance of SCFA-producing bacteria, including Bacteroides. Moreover, licorice treatment increased fecal SCFA contents and modulated multiple uremic toxins in both serum and renal tissue. Consistently, licorice protected HK-2 cells against VAN-induced cytotoxicity by regulating GSH, interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and MMP. Conclusions: These findings demonstrate that licorice exerts protective effects against VAN-induced nephrotoxicity in vivo and in vitro, suggesting the potential involvement of oxidative stress, mitochondrial structure and function, inflammation, intestinal microbiota-SCFAs and uremic toxins. Full article

Chronic kidney disease (CKD) is associated with a markedly increased risk of cardiovascular (CV) morbidity and mortality that cannot be fully explained by traditional risk factors. Emerging evidence highlights the central role of the gut–kidney–heart axis, whereby gut microbiota dysbiosis promotes the generation and systemic accumulation of uremic toxins, including indoxyl sulfate (IS), p-cresyl sulfate (PCS), and trimethylamine N-oxide (TMAO). These metabolites contribute to endothelial dysfunction, oxidative stress, inflammation, and vascular remodeling, thereby accelerating CV disease progression in CKD. Dietary patterns represent a key modifiable factor influencing gut microbiota composition and metabolic activity. The Mediterranean diet, characterized by high intake of plant-based foods, dietary fiber, and polyphenols, and low consumption of red and processed meats, has emerged as a promising microbiota-targeted strategy. It promotes saccharolytic fermentation, enhances short-chain fatty acid production, and reduces proteolytic pathways responsible for uremic toxin generation. Accumulating evidence from observational studies, meta-analyses, and dietary intervention trials suggests that adherence to Mediterranean and plant-based dietary patterns is associated with reduced uremic toxin burden, improved renal outcomes, and lower CV risk in CKD populations. However, direct interventional evidence linking Mediterranean diet adherence to changes in specific uremic toxin levels remains limited. This narrative review summarizes current evidence on diet–microbiota interactions in CKD and highlights the Mediterranean diet as a biologically plausible strategy for targeting the gut–kidney–heart axis. Future well-designed randomized controlled trials (RCTs) are needed to confirm causal relationships and support clinical implementation. Full article

Acute kidney injury (AKI) is a frequent complication in critically ill patients and is associated with high morbidity, mortality, and an increased risk of progression to chronic kidney disease (CKD). In this context, nutritional management represents a key component of supportive therapy, as AKI is commonly characterized by hypercatabolism, negative nitrogen balance, and protein-energy wasting. Current nutritional strategies primarily focus on the quantity of protein intake required to compensate for catabolic losses, particularly in patients undergoing renal replacement therapy (RRT). However, growing evidence suggests that the quality and metabolic effects of dietary protein sources may also influence renal physiology and recovery. Plant-based proteins have recently gained attention as a potentially advantageous nutritional strategy in kidney disease. Compared with animal-derived proteins, plant-based proteins are associated with a lower dietary acid load, reduced production of gut-derived uremic toxins, and beneficial effects on the intestinal microbiota. In addition, their amino acid profile may modulate oxidative stress, inflammatory pathways, and renal hemodynamics. These characteristics may contribute to a more favorable metabolic environment in patients with AKI, potentially supporting renal recovery and reducing the risk of AKI-to-CKD transition. This review examines the pathophysiological mechanisms linking protein metabolism, renal injury, and nutritional support in AKI. Particular attention is given to the role of plant-based proteins, their amino acid composition, and their potential nephroprotective effects. Understanding the interaction between dietary protein sources, metabolic pathways, and the gut–kidney axis may help guide future nutritional strategies aimed at improving outcomes in critically ill patients with AKI. Full article

Background: p-Cresyl sulfate (PCS) has been linked to vascular dysfunction through endothelial injury and vascular remodeling. Peripheral artery disease (PAD), identified by a low ankle–brachial index (ABI), is associated with increased mortality in kidney transplant (KT) recipients. This study investigated the association between serum PCS levels and PAD (as defined by ABI) in KT recipients. Methods: This cross-sectional, single-center study included 90 KT recipients. Serum total PCS levels were quantified using liquid chromatography–mass spectrometry. ABI was measured using an automated oscillometric device, and PAD was defined as ABI < 0.9. Results: Among the 90 KT recipients, 20 (22.2%) met the ABI for PAD. Patients with ABI-defined PAD had a significantly higher prevalence of diabetes mellitus (p = 0.036) and serum PCS levels (p = 0.001). Multivariate logistic regression analysis adjusting for potential confounders revealed that serum PCS levels remained independently associated with PAD (odds ratio 1.254, 95% confidence interval 1.108–1.419; p < 0.001). PCS levels were inversely correlated with both left (r = −0.339, p = 0.001) and right (r = −0.357, p < 0.001) ABIs. The association remained consistent in penalized regression models. Conclusions: Higher serum PCS levels were independently associated with ABI-defined PAD in KT recipients. The findings indicate that residual uremic toxin burden may contribute to peripheral vascular disease despite the restoration of renal function following transplantation. 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

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