Protein-bound Uremic Toxins Research Articles

Displacing the Burden: A Review of Protein-Bound Uremic Toxin Clearance Strategies in Chronic Kidney Disease.

Uremic toxins (UTs), particularly protein-bound uremic toxins (PBUTs), accumulate in chronic kidney disease (CKD) patients, causing significant health complications like uremic syndrome, cardiovascular disease, and immune dysfunction. The binding of PBUTs to plasma proteins such as albumin presents a formidable challenge for clearance, as conventional dialysis is often insufficient. With advancements in the classification and understanding of UTs, spearheaded by the European Uremic Toxins (EUTox) working group, over 120 molecules have been identified, prompting the development of alternative therapeutic strategies. Innovations such as online hemodiafiltration aim to enhance the removal process, while novel adsorptive therapies offer a means to address the high affinity of PBUTs to plasma proteins. Furthermore, the exploration of molecular displacers, designed to increase the free fraction of PBUTs, represents a cutting-edge approach to facilitate their dialytic clearance. Despite these advancements, the clinical application of displacers requires more research to confirm their efficacy and safety. The pursuit of such innovative treatments is crucial for improving the management of uremic toxicity and the overall prognosis of CKD patients, emphasizing the need for ongoing research and clinical trials.

Ibuprofen-Immobilized Thin Films: A Novel Approach to Improve the Clearance of Protein-Bound Uremic Toxins.

Chronic kidney disease (CKD), a pressing global health issue, affects millions and leads to end-stage renal disease (ESRD). Hemodialysis (HD) is a crucial treatment for ESRD, yet its limited efficiency in removing protein-bound uremic toxins (PBUTs) results in high morbidity and mortality rates. A high affinity of pharmaceutical drugs for human serum albumin (HSA) can be leveraged to compete effectively with PBUTs for the same HSA binding sites, thereby enabling them to be capable of displacing these toxins. One such drug is ibuprofen (IBF), known for its very high affinity for HSA and sharing the same binding site as indoxyl sulfate (IS). This study explores the development of IBF-immobilized cellulose acetate-based (CA-based) thin films. The films were created by reacting CA with IBF-modified silica precursors at varying concentrations. The presence of IBF in CA/TEOS/APTES-IBF-3 and CA/TEOS-IBF-25 films, containing 3 and 25 wt % IBF, respectively, was confirmed through 1H NMR spectra. Competitive displacement binding assays indicated that while the incorporation of 3 wt % IBF showed no significant enhancement in IS displacement, the 25 wt % IBF film increased the dialyzed IS by 1.3 when normalized to non-IBF films. Furthermore, there was a 1.2-fold decrease in the total percentage of IS, and the free percentage of IS increased 1.3 to 3.0 times. Although direct systemic infusion of IBF in HD patients achieves a 2.4 times higher removal of IS, it is impractical due to the risks it poses to ESRD patients. The IBF-immobilized films offer the advantage of localized binding, thus eliminating the need for systemic exposure. This innovative approach lays a foundation for developing more efficient HD membranes, aiming to address the challenging issue of PBUT elimination and potentially enhance the quality of life and treatment outcomes for ESRD patients.

Exploring the Relationship between Gut Microbiome Composition and Blood Indole-3-acetic Acid in Hemodialysis Patients.

Indole-3-acetic acid (IAA), a protein-bound uremic toxin resulting from gut microbiota-driven tryptophan metabolism, increases in hemodialysis (HD) patients. IAA may induce endothelial dysfunction, inflammation, and oxidative stress, elevating cardiovascular and cognitive risk in HD patients. However, research on the microbiome-IAA association is limited. This study aimed to explore the gut microbiome's relationship with plasma IAA levels in 72 chronic HD patients aged over 18 (August 2016-January 2017). IAA levels were measured using tandem mass spectrometry, and gut microbiome analysis utilized 16s rRNA next-generation sequencing. Linear discriminative analysis effect size and random forest analysis distinguished microbial species linked to IAA levels. Patients with higher IAA levels had reduced microbial diversity. Six microbial species significantly associated with IAA levels were identified; Bacteroides clarus, Bacteroides coprocola, Bacteroides massiliensi, and Alisteps shahii were enriched in low-IAA individuals, while Bacteroides thetaiotaomicron and Fusobacterium varium were enriched in high-IAA individuals. This study sheds light on specific gut microbiota species influencing IAA levels, enhancing our understanding of the intricate interactions between the gut microbiota and IAA metabolism.

Pruritus and protein-bound uremic toxins in patients undergoing hemodialysis: a cross-sectional study.

Patients undergoing hemodialysis frequently experience pruritus; its severity is associated with poor quality of life and mortality. Recent progress in hemodialysis treatment has improved the removal of small- and middle-molecular-weight molecules; however, the removal of protein-bound uremic toxins (PBUTs) remains difficult. It is possible that pruritus is associated with serum PBUTs in patients undergoing hemodialysis. We conducted a multicenter cross-sectional study in patients undergoing hemodialysis (n=135). The severity of pruritus was assessed using the 5D-itch scale and medication use. Serum PBUTs, including indoxyl sulfate, p-cresyl sulfate, indole acetic acid, phenyl sulfate, and hippuric acid, were measured using mass spectrometry; the PBUT score was calculated from these toxins using principal component analysis. Univariate and multiple regression analyses were performed to examine independent predictors of pruritus. Pruritus was reported by 62.2%, 21.5%, and 13.3%, 1.5% and 0.7% as 5 (not at all), 6-10, 11-15, 16-20, and 21-25 points, respectively. The PBUT score was higher in patients undergoing dialysis having pruritus than those without pruritus (0.201 [-0.021 to 0.424] vs -0.120 [-0.326 to 0.087]; P=0.046). The PBUT score was shown to have an association with the presence of pruritus (coefficient 0.498[Formula: see text]0.225, odds ratio: 1.65 [1.06-2.56]; P=0.027). Uremic pruritus was frequently found and associated with the PBUT score in patients undergoing hemodialysis. Further studies are required to clarify the impact of PBUTs on uremic pruritus and to explore therapeutic strategies in patients undergoing hemodialysis.

The influence of uremic toxins on low bone turnover disease in chronic kidney disease.

Uremic toxins play a crucial role in the development of low bone turnover disease in chronic kidney disease (CKD) through the induction of oxidative stress. This oxidative stress disrupts the delicate balance between bone formation and resorption, resulting in a decline in both bone quantity and quality. Reactive oxygen species (ROS) activate nuclear factor kappa-B and mitogen-activated protein kinase signaling pathways, promoting osteoclastogenesis. Conversely, ROS hinder osteoblast differentiation by facilitating the binding of Forkhead box O proteins (FoxOs) to β-catenin, triggering apoptosis through FoxOs-activating kinase phosphorylation. This results in increased osteoblastic receptor activator of nuclear factor kappa-B ligand (RANKL) expression and decreased nuclear factor erythroid 2-related factor 2 levels, compromising antioxidant defenses against oxidative damage. As CKD progresses, the accumulation of protein-bound uremic toxins such as indoxyl sulfate (IS) and p-cresyl sulfate (PCS) intensifies oxidative stress, primarily affecting osteoblasts. IS and PCS directly inhibit osteoblast viability, induce apoptosis, decrease alkaline phosphatase activity, and impair collagen 1 and osteonectin, impeding bone formation. They also reduce cyclic adenosine 3',5'-monophosphate (cAMP) production and lower parathyroid hormone (PTH) receptor expression in osteoblasts, resulting in PTH hyporesponsiveness. In summary, excessive production of ROS by uremic toxins not only reduces the number and function of osteoblasts but also induces PTH hyporesponsiveness, contributing to the initiation and progression of low bone turnover disease in CKD.

Predictive value of protein-bound uremic toxins for heart failure in patients with chronic kidney disease.

This retrospective cohort study aimed to be the first to evaluate the association between plasma protein-bound uremic toxins (PBUTs) concentrations, echocardiographic parameters of heart failure (HF), and incident HF events in patients with chronic kidney disease (CKD) not on dialysis. Retrospective, single-centre, cohort study at the Ghent University Hospital, Belgium. Adults with CKD stages G1-G5, not on dialysis, could be included. Exclusion criteria were ongoing pregnancy, age <18years, active acute infection, active malignancy, history of transplantation, or a cardiovascular event within 3months prior to inclusion. Free and total concentrations of five PBUTs were quantified at baseline: indoxyl sulfate (IxS), p-cresyl sulfate (pCS), p-cresyl glucuronide (pCG), indole-3 acetic acid (IAA), and hippuric acid (HA). Patients were grouped into three echocardiographic categories: normal left ventricular ejection fraction (LVEF) and normal left ventricular end-diastolic pressure (LVEDP), normal LVEF and increased LVEDP, and reduced LVEF, based on available echocardiographic data in a time interval of ±6months around the plasma sample collection. A total of 523 patients were included between January 2011 and January 2014. Echocardiographic data within the predefined timeframe were available for 210 patients (40% of patients). Levels of pCG and pCS were significantly higher in patients with reduced (<50%) versus normal LVEF (P<0.05). After a median follow-up 5.5years, 43 (8.4%) patients reached the composite endpoint of hospitalization or mortality due to HF. Free fractions of IxS, pCS, and pCG showed the strongest association with clinical outcome: free IxS: HR 1.71 (95% CI 1.11-2.63; P=0.015), free pCS: HR 1.82 (95% CI 1.11-3.01; P=0.019), and free pCG: HR 1.67 (95% CI 1.08-2.58; P=0.020), and these results were independent of age, gender, body mass index, diabetes, and systolic blood pressure. In models that were also adjusted for serum creatinine, the free fractions of these PBUTs remained significant. Elevated free concentrations of IxS, pCG, and pCS were independently associated with an increased risk of HF events in non-dialysed CKD patients. Further research is necessary to confirm these findings and investigate the potential impact of PBUT-lowering interventions on HF events in this patient group.

Effect of Membrane Permeance and System Parameters on the Removal of Protein-Bound Uremic Toxins in Hemodialysis.

Inadequate clearance of protein-bound uremic toxins (PBUTs) during dialysis is associated with morbidities in chronic kidney disease patients. The development of high-permeance membranes made from materials such as graphene raises the question whether they could enable the design of dialyzers with improved PBUT clearance. Here, we develop device-level and multi-compartment (body) system-level models that account for PBUT-albumin binding (specifically indoxyl sulfate and p-cresyl sulfate) and diffusive and convective transport of toxins to investigate how the overall membrane permeance (or area) and system parameters including flow rates and ultrafiltration affect PBUT clearance in hemodialysis. Our simulation results indicate that, in contrast to urea clearance, PBUT clearance in current dialyzers is mass-transfer limited: Assuming that the membrane resistance is dominant, raising PBUT permeance from 3 × 10-6 to 10-5ms-1 (or equivalently, 3.3 × increase in membrane area from ~ 2 to ~ 6m2) increases PBUT removal by 48% (from 22 to 33%, i.e., ~ 0.15 to ~ 0.22g per session), whereas increasing dialysate flow rates or adding adsorptive species have no substantial impact on PBUT removal unless permeance is above ~ 10-5ms-1. Our results guide the future development of membranes, dialyzers, and operational parameters that could enhance PBUT clearance and improve patient outcomes.

Animal Models for Studying Protein-Bound Uremic Toxin Removal

Animal Models for Studying Protein-Bound Uremic Toxin Removal

Kidney Clearances of Protein-Bound Uremic Toxins in Various Stages of CKD and Their Predictive Role for Clinical Prognosis

Kidney Clearances of Protein-Bound Uremic Toxins in Various Stages of CKD and Their Predictive Role for Clinical Prognosis

Indoxyl sulfate induced frailty in patients with end-stage renal disease by disrupting the PGC-1α-FNDC5 axis.

Sarcopenia or frailty is common among patients with chronic kidney disease (CKD). The protein-bound uremic toxin indoxyl sulfate (IS) is associated with frailty. IS induces apoptosis and disruption of mitochondrial activity in skeletal muscle. However, the association of IS with anabolic myokines such as irisin in patients with CKD or end-stage renal disease (ESRD) is unclear. This study aims to elucidate whether IS induces frailty by dysregulating irisin in patients with CKD. The handgrip strength of 53 patients, including 28 patients with ESRD, was examined. Serum concentrations of IS and irisin were analyzed. CKD was established in BALB/c mice through 5/6 nephrectomy. Pathologic analysis of skeletal muscle was assessed through haematoxylin and eosin and Masson's trichrome staining. Expression of peroxisome proliferator-activated receptor-gamma coactivator PGC-1α and irisin were analyzed using real-time polymerase chain reaction and Western blotting. Handgrip strength was lower among patients with ESRD than among those without ESRD. In total, 64.3% and 24% of the patients in the ESRD and control groups had low handgrip strength, respectively (p < 0.05). Serum concentrations of IS were significantly higher in the ESRD group than in the control group (222.81 ± 90.67 μM and 23.19 ± 33.28 μM, respectively, p < 0.05). Concentrations of irisin were lower in the ESRD group than in the control group (64.62 ± 32.64 pg/mL vs. 99.77 ± 93.29 pg/mL, respectively, p < 0.05). ROC curves for low handgrip strength by irisin and IS were 0.298 (95% confidence interval (CI): 0.139-0.457, p < 0.05) and 0.733 (95% CI: 0.575-0.890, p < 0.05), respectively. The percentage of collagen was significantly higher in mice with 5/6 nephrectomy than in the control group. After resveratrol (RSV) treatment, the percentage of collagen significantly decreased. RSV modulates TGF-β signaling. In vitro analysis revealed that IS treatment suppressed expression of PGC-1α and FNDC5 in a dose-dependent manner, whereas RSV treatment attenuated IS-induced phenomena in C2C12 cells. IS was positively correlated with frailty in patients with ESRD through the modulation of the PGC-1α-FNDC5 axis. RSV may be a potential drug for reversing IS-induced suppression of the PGC-1α-FNDC5 axis in skeletal muscle.

Study of the association between serum levels of kynurenine and cardiovascular outcomes and overall mortality in chronic kidney disease.

Kynurenine is a protein-bound uremic toxin. Its circulating levels are increased in chronic kidney disease (CKD). Experimental studies showed that it exerted deleterious cardiovascular effects. We sought to evaluate an association between serum kynurenine levels and adverse fatal or nonfatal cardiovascular events and all-cause mortality in CKD patients. The CKD-REIN study is a prospective cohort of people with CKD having an estimated glomerular filtration rate (eGFR) <60ml/min/1.73m². Baseline frozen samples of total and free fractions of kynurenine and tryptophan were measured using a validated liquid chromatography tandem mass spectrometry technique. Cause-specific Cox models were used to estimate hazard ratios (HRs) for each outcome. Of the 2406 included patients (median age: 68 years; median eGFR: 25ml/min/1.73m2), 52% had a history of cardiovascular disease. A doubling of serum-free kynurenine levels was associated with an 18% increased hazard of cardiovascular events [466 events, HR (95%CI):1.18(1.02,1.33)], independently of eGFR, serum-free tryptophan level or other uremic toxins, cardioprotective drugs, and traditional cardiovascular risk factors. Serum-free kynurenine was significantly associated with non-atheromatous cardiovascular events [HR(95%CI):1.26(1.03,1.50)], but not with atheromatous cardiovascular events [HR(95%CI):1.15(0.89,1.50)]. The association of serum-free kynurenine with cardiovascular mortality was also independently significant [87 events; adjusted HR(95%CI):1.64(1.10,2.40)]. However, the association of serum-free kynurenine with all-cause mortality was no more significant after adjustment on serum-free tryptophan [311 events, HR(95%CI):1.12(0.90, 1.40)]. Our findings imply that serum-free kynurenine, independently of other cardiovascular risk factors (including eGFR), is associated with fatal or nonfatal cardiovascular outcomes, particularly non-atheromatous cardiovascular events; in patients with CKD. Strategies to reduce serum kynurenine levels should be evaluated in further studies.

Immunosenescence and Immune Exhaustion Are Associated with Levels of Protein-Bound Uremic Toxins in Patients on Hemodialysis.

The accumulation of protein-bound uremic toxins (PBUTs) in chronic kidney disease may affect patients' immune status. The aim of the study was to evaluate their potential impacts on lymphocyte alterations in patients on hemodialysis (HD). The plasma levels of PBUTs were assessed in 54 patients on HD and 31 healthy individuals, using ultra-performance liquid chromatography. The results correlated with the senescent and exhausted status of lymphocytes, based on certain surface molecules, analyzed by flow cytometry. The plasma levels of PBUTs were significantly increased in the patients on HD compared with the healthy controls. The patients with residual kidney function had reduced hippuric acid (HA) levels, total (p = 0.03) and free (p = 0.04), and free IxS levels (p = 0.02). The total and free HA levels correlated negatively with less differentiated subpopulations, CD4+CD45RA+CD31+ (p = 0.037 and p = 0.027), CD8+CD28+CD57- (p = 0.01, p = 0.01), and naïve B cells (CD19+IgD+CD27-) (p = 0.04, p = 0.03). Both the total and the free pCS levels correlated positively with exhausted CD4 cells, p = 0.02 and p = 0.01, respectively. A multivariate analysis showed that IxS and age were the main independent parameters implicated in the reduction intotal CD4 and B lymphocytes and their naïve and early differentiated subsets. Increased PBUTs levels are associated with immune disturbances of patients on HD, HA, and IxS in the immunosenescent and pCS in the immunoexhaustion alterations.

Emodin Inhibits the Indoxyl Sulfate-Induced trans-Differentiation of Vascular Smooth Muscle Cells through Upregulating Thrombospondin-1

Background: Indoxyl sulfate (IS) is a protein-bound uremic toxin with vascular toxicity. The primary cause of death in uremic patients on maintenance hemodialysis is vascular disease, and it had been reported that vascular smooth muscle cells (VSMCs) trans-differentiation (VT) plays a vital role in the context of vascular diseases, but the underlying mechanisms remain obscure. Thrombospondin-1 (TSP-1) participates in vascular calcification by keeping the balance of extracellular matrix, but its role in IS-induced VT is unclear. Methods: In this study, clinical specimens, animal models, and in vitro VSMCs were used to investigate the role of TSP-1 in IS induced VT and the potential therapeutic methods. Results: We found that TSP-1 was significantly decreased in arterial samples from uremic patients, animal models, and in VSMCs after IS treatment. Downregulation of TSP-1 sufficiently induced the trans-differentiation genotypes of VSMCs. Conclusion: Emodin, the main monomer extracted from rhubarb, could alleviate IS-induced VT in vitro by upregulating TSP-1. Taken together, IS induces VT by downregulating TSP-1. Emodin might be a candidate drug to alleviate VT under IS treatment.

Impact de l’accumulation sérique des toxines urémiques au cours de l’insuffisance rénale aiguë

AbstractDuring kidney injury, molecules called uremic toxins accumulate in blood. Protein-bound uremic toxins (PBUTs) are not correctly eliminated by conventional techniques of hemodialysis. Their tissue toxicity is well described during chronic kidney disease (CKD). They have specific pathological effects on cardiovascular system which are associated to patients morbi-mortality. In addition, they are correlated to CKD progression and have toxic action on neurologic and immune systems. Their concentrations also raised during acute kidney injury (AKI), even if lower than in CKD. AKI is also frequently associated with organ dysfunction during the episode and to cardiovascular events and mortality at short and long term. Moreover, in recent experimental studies, PBUTs, in particular indoxyl sulfate and para-cresyl sulfate, appear to be also responsible of acute cardiovascular, kidney and neurologic damages. However, these results need to be confirmed in clinical studies in the way to clearly determine the role of PBUTs in organ dysfunction during AKI and to evaluate their association to cardiovascular events and global mortality.

Protein-Bound Uremic Toxins in Senescence and Kidney Fibrosis.

Chronic kidney disease (CKD) is a progressive condition of kidney dysfunction due to diverse causes of injury. In healthy kidneys, protein-bound uremic toxins (PBUTs) are cleared from the systemic circulation by proximal tubule cells through the concerted action of plasma membrane transporters that facilitate their urinary excretion, but the endogenous metabolites are hardly removed with kidney dysfunction and may contribute to CKD progression. Accumulating evidence suggests that senescence of kidney tubule cells influences kidney fibrosis, the common endpoint for CKD with an excessive accumulation of extracellular matrix (ECM). Senescence is a special state of cells characterized by permanent cell cycle arrest and limitation of proliferation, which promotes fibrosis by releasing senescence-associated secretory phenotype (SASP) factors. The accumulation of PBUTs in CKD causes oxidative stress and increases the production of inflammatory (SASP) factors that could trigger fibrosis. Recent studies gave some clues that PBUTs may also promote senescence in kidney tubular cells. This review provides an overview on how senescence contributes to CKD, the involvement of PBUTs in this process, and how kidney senescence can be studied. Finally, some suggestions for future therapeutic options for CKD while targeting senescence are given.

Animal Models for Studying Protein-Bound Uremic Toxin Removal-A Systematic Review.

Protein-bound uremic toxins (PBUTs) are associated with the progression of chronic kidney disease (CKD) and its associated morbidity and mortality. The conventional dialysis techniques are unable to efficiently remove PBUTs due to their plasma protein binding. Therefore, novel approaches are being developed, but these require validation in animals before clinical trials can begin. We conducted a systematic review to document PBUT concentrations in various models and species. The search strategy returned 1163 results for which abstracts were screened, resulting in 65 full-text papers for data extraction (rats (n = 41), mice (n = 17), dogs (n = 3), cats (n = 4), goats (n = 1), and pigs (n = 1)). We performed descriptive and comparative analyses on indoxyl sulfate (IS) concentrations in rats and mice. The data on large animals and on other PBUTs were too heterogeneous for pooled analysis. Most rodent studies reported mean uremic concentrations of plasma IS close to or within the range of those during kidney failure in humans, with the highest in tubular injury models in rats. Compared to nephron loss models in rats, a greater rise in plasma IS compared to creatinine was found in tubular injury models, suggesting tubular secretion was more affected than glomerular filtration. In summary, tubular injury rat models may be most relevant for the in vivo validation of novel PBUT-lowering strategies for kidney failure in humans.

Effects of N-acetyl-L-tryptophan on desorption of the protein-bound uremic toxin indoxyl sulfate and effects on uremic sarcopenia.

Indoxyl sulfate (IS) is a protein-bound uremic toxin that causes uremic sarcopenia. IS has poor dialysis clearance; however, the addition of a binding competitor improves its removal efficiency. Dialysis experiments were performed using N-acetyl-l-tryptophan (L-NAT) instead of l-tryptophan (Trp) using pooled sera obtained from dialysis patients. The molecular structures of L-NAT and Trp were similar to that of IS. Therefore, we examined whether Trp and L-NAT were involved in muscle atrophy in the same manner as IS by performing culture experiments using a human myotube cell line. The removal efficiency of L-NAT was the same as that of Trp. However, L-NAT concentrations in the pooled sera increased at the end of the experiment. Trp (1 mM) decreased the area of human myocytes, similar to IS, whereas L-NAT did not. L-NAT is a binding competitor with the ability to remove protein-bound IS while preventing sarcopenia.

Bioengineered Kidney Tubules Efficiently Clear Uremic Toxins in Experimental Dialysis Conditions.

Patients with end-stage kidney disease (ESKD) suffer from high levels of protein-bound uremic toxins (PBUTs) that contribute to various comorbidities. Conventional dialysis methods are ineffective in removing these PBUTs. A potential solution could be offered by a bioartificial kidney (BAK) composed of porous membranes covered by proximal tubule epithelial cells (PTECs) that actively secrete PBUTs. However, BAK development is currently being hampered by a lack of knowledge regarding the cytocompatibility of the dialysis fluid (DF) that comes in contact with the PTECs. Here, we conducted a comprehensive functional assessment of the DF on human conditionally immortalized PTECs (ciPTECs) cultured as monolayers in well plates, on Transwell® inserts, or on hollow fiber membranes (HFMs) that form functional units of a BAK. We evaluated cell viability markers, monolayer integrity, and PBUT clearance. Our results show that exposure to DF did not affect ciPTECs' viability, membrane integrity, or function. Seven anionic PBUTs were efficiently cleared from the perfusion fluid containing a PBUTs cocktail or uremic plasma, an effect which was enhanced in the presence of albumin. Overall, our findings support that the DF is cytocompatible and does not compromise ciPTECs function, paving the way for further advancements in BAK development and its potential clinical application.

The Potential Influence of Uremic Toxins on the Homeostasis of Bones and Muscles in Chronic Kidney Disease.

Patients with chronic kidney disease (CKD) often experience a high accumulation of protein-bound uremic toxins (PBUTs), specifically indoxyl sulfate (IS) and p-cresyl sulfate (pCS). In the early stages of CKD, the buildup of PBUTs inhibits bone and muscle function. As CKD progresses, elevated PBUT levels further hinder bone turnover and exacerbate muscle wasting. In the late stage of CKD, hyperparathyroidism worsens PBUT-induced muscle damage but can improve low bone turnover. PBUTs play a significant role in reducing both the quantity and quality of bone by affecting osteoblast and osteoclast lineage. IS, in particular, interferes with osteoblastogenesis by activating aryl hydrocarbon receptor (AhR) signaling, which reduces the expression of Runx2 and impedes osteoblast differentiation. High PBUT levels can also reduce calcitriol production, increase the expression of Wnt antagonists (SOST, DKK1), and decrease klotho expression, all of which contribute to low bone turnover disorders. Furthermore, PBUT accumulation leads to continuous muscle protein breakdown through the excessive production of reactive oxygen species (ROS) and inflammatory cytokines. Interactions between muscles and bones, mediated by various factors released from individual tissues, play a crucial role in the mutual modulation of bone and muscle in CKD. Exercise and nutritional therapy have the potential to yield favorable outcomes. Understanding the underlying mechanisms of bone and muscle loss in CKD can aid in developing new therapies for musculoskeletal diseases, particularly those related to bone loss and muscle wasting.

Urinary microbiota and serum metabolite analysis in patients with diabetic kidney disease

BackgroundDiabetic kidney disease (DKD) is a common and potentially fatal consequence of diabetes. Chronic renal failure or end-stage renal disease may result over time. Numerous studies have demonstrated the function of the microbiota in health and disease. The use of advanced urine culture techniques revealed the presence of resident microbiota in the urinary tract, undermining the idea of urine sterility. Studies have demonstrated that the urine microbiota is related with urological illnesses; nevertheless, the fundamental mechanisms by which the urinary microbiota influences the incidence and progression of DKD remain unclear. The purpose of this research was to describe key characteristics of the patients with DKD urinary microbiota in order to facilitate the development of diagnostic and therapeutic for DKD. MethodsWe evaluated the structure and composition of the microbiota extracted from urine samples taken from DKD patients (n = 19) and matched healthy controls (n = 15) using 16S rRNA gene sequencing. Meanwhile, serum metabolite profiles were compared using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Associations between clinical characteristics, urine microbiota, and serum metabolites were also examined. Finally, the interaction between urine microbiota and serum metabolites was clarified based on differential metabolite abundance analysis. ResultsThe findings indicated that the DKD had a distinct urinary microbiota from the healthy controls (HC). Taxonomic investigations indicated that the DKD microbiome had less alpha diversity than a control group. Proteobacteria and Acidobacteria phyla increased in the DKD, while Firmicutes and Bacteroidetes decreased significantly (P < 0.05). Acidobacteria was the most prevalent microbiota in the DKD, as determined by the Linear discriminant analysis Effect Size (LEfSe) plot. Changes in the urinary microbiota of DKD also had an effect on the makeup of metabolites. Short-chain fatty acids (SCFAs) and protein-bound uremic toxins (PBUTs) were shown to be specific. Then we discovered that arginine and proline metabolism was the primary mechanism involved in the regulation of diabetic kidney disease. ConclusionsThis study placed the urinary microbiota and serum metabolite of DKD patients into a functional framework and identified the most abundant microbiota in DKD (Proteobacteria and Acidobacteria). Arginine metabolites may have a major effect on DKD patients, which correlated with the progression of DKD.