Metabolites Associated With Uremic Symptoms in Patients With CKD: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study.

RATIONALE & OBJECTIVE: The toxins that contribute to uremic symptoms in patients with chronic kidney disease (CKD) are unknown. We sought to apply complementary statistical modeling approaches to data from untargeted plasma metabolomic profiling to identify solutes associated with uremic symptoms in patients with CKD. STUDY DESIGN: Cross-sectional. SETTING & PARTICIPANTS: 1,761 Chronic Renal Insufficiency Cohort (CRIC) participants with CKD not treated with dialysis. PREDICTORS: Measurement of 448 known plasma metabolites. OUTCOMES: The uremic symptoms of fatigue, anorexia, pruritus, nausea, paresthesia, and pain were assessed by single items on the Kidney Disease Quality of Life-36 instrument. ANALYTICAL APPROACH: Multivariable adjusted linear regression, least absolute shrinkage and selection operator linear regression, and random forest models were used to identify metabolites associated with symptom severity. After adjustment for multiple comparisons, metabolites selected in at least 2 of the 3 modeling approaches were deemed "overall significant." RESULTS: Participant mean estimated glomerular filtration rate was 43mL/min/1.73m2, with 44% self-identifying as female and 41% as non-Hispanic Black. The prevalence of uremic symptoms ranged from 22% to 55%. We identified 17 metabolites for which a higher level was associated with greater severity of at least one uremic symptom and 9 metabolites inversely associated with uremic symptom severity. Many of these metabolites exhibited at least a moderate correlation with estimated glomerular filtration rate (Pearson's r≥0.5), and some were also associated with the risk of developing kidney failure or death in multivariable adjusted Cox regression models. LIMITATIONS: Lack of a second independent cohort for external validation of our findings. CONCLUSIONS: Metabolomic profiling was used to identify multiple solutes associated with uremic symptoms in adults with CKD, but future validation and mechanistic studies are needed. PLAIN-LANGUAGE SUMMARY: Individuals living with chronic kidney disease (CKD) often experience symptoms related to CKD, traditionally called uremic symptoms. It is likely that CKD results in alterations in the levels of numerous circulating substances that, in turn, cause uremic symptoms; however, the identity of these solutes is not known. In this study, we used metabolomic profiling in patients with CKD to gain insights into the pathophysiology of uremic symptoms. We identified 26 metabolites whose levels were significantly associated with at least one of the symptoms of fatigue, anorexia, itchiness, nausea, paresthesia, and pain. The results of this study lay the groundwork for future research into the biological causes of symptoms in patients with CKD.

Effectiveness of Combined Hemodialysis-Hemadsorption Therapy in Improving Uremic Toxin Clearance, Inflammatory Markers, and Symptoms in Maintenance Hemodialysis Patients.

INTRODUCTION: Combined hemodialysis (HD) and hemadsorption (HA) therapy has shown the highest clearance rates for middle and large-sized uremic toxin molecules and reduced mortality rates among maintenance HD (MHD) patients. This study aimed to investigate the effectiveness of combined HD and HA therapy in patients undergoing MHD. METHODS: Forty patients with end-stage renal disease (ESRD) were divided into three groups: HD only (14), HD + biweekly HA (14), and HD + weekly HA (12). The duration of the study was 8 weeks. Uremic toxins (ß2-microglobulin, leptin, parathyroid hormone), inflammatory markers (interleukin-6, C-reactive protein), and symptoms (appetite, pruritus, sleep quality) were assessed before the start and at the completion of therapy. Changes in the parameters were compared between the three groups. Mean differences of parameters in each group were also compared between before and after therapy. RESULTS: Decrease in BUN level (-61.34 mg/dL [95% CI: -71.33 to -51.34], p < 0.0001) and pruritus score (-3.93 [95% CI: -6.89 to -0.97], p = 0.013) was significantly larger in HD + biweekly HA group compared to the others. Only HD + biweekly HA group showed significant reductions in CRP level (-0.10 mg/L [95%: -0.18 to -0.01], p = 0.034), VAS appetite score (10.43 [95% CI: 4.99-15.87], p = 0.001), and pruritus score (-3.93 [95% CI: -6.89 to -0.97], p = 0.013) after therapy. Both HD + biweekly HA (-2.79 [95% CI: -4.97 to -0.60], p = 0.016) and HD + weekly HA group (-2.33 [95% CI: -4.59 to -0.08], p = 0.044) exhibited a significant improvement in sleep quality score after therapy. CONCLUSIONS: HD combined with a biweekly HA is associated with a greater reduction in BUN level and better improvement of pruritus in ESRD patients compared to HD alone. HD + biweekly HA can significantly reduce CRP levels, alleviate pruritus, improve appetite, and enhance sleep quality.

Indoleamine 2,3-dioxygenase-1, a Novel Therapeutic Target for Post-Vascular Injury Thrombosis in CKD.

BACKGROUND: CKD, characterized by retained uremic solutes, is a strong and independent risk factor for thrombosis after vascular procedures . Urem ic solutes such as indoxyl sulfate (IS) and kynurenine (Kyn) mediate prothrombotic effect through tissue factor (TF). IS and Kyn biogenesis depends on multiple enzymes, with therapeutic implications unexplored. We examined the role of indoleamine 2,3-dioxygenase-1 (IDO-1), a rate-limiting enzyme of kynurenine biogenesis, in CKD-associated thrombosis after vascular injury. METHODS: IDO-1 expression in mice and human vessels was examined. IDO-1-/- mice, IDO-1 inhibitors, an adenine-induced CKD, and carotid artery injury models were used. RESULTS: Both global IDO-1-/- CKD mice and IDO-1 inhibitor in wild-type CKD mice showed reduced blood Kyn levels, TF expression in their arteries, and thrombogenicity compared with respective controls. Several advanced IDO-1 inhibitors downregulated TF expression in primary human aortic vascular smooth muscle cells specifically in response to uremic serum. Further mechanistic probing of arteries from an IS-specific mouse model, and CKD mice, showed upregulation of IDO-1 protein, which was due to inhibition of its polyubiquitination and degradation by IS in vascular smooth muscle cells. In two cohorts of patients with advanced CKD, blood IDO-1 activity was significantly higher in sera of study participants who subsequently developed thrombosis after endovascular interventions or vascular surgery. CONCLUSION: Leveraging genetic and pharmacologic manipulation in experimental models and data from human studies implicate IS as an inducer of IDO-1 and a perpetuator of the thrombotic milieu and supports IDO-1 as an antithrombotic target in CKD.

Uremia and Inadequate Oxygen Supply Induce Eryptosis and Intracellular Hypoxia in Red Blood Cells.

BACKGROUND/AIMS: Chronic kidney disease is frequently accompanied by anemia, hypoxemia, and hypoxia. It has become clear that the impaired erythropoietin production and altered iron homeostasis are not the sole causes of renal anemia. Eryptosis is a process of red blood cells (RBC) death, like apoptosis of nucleated cells, characterized by Ca2+ influx and phosphatidylserine (PS) exposure to the outer RBC membrane leaflet. Eryptosis can be induced by uremic toxins and occurs before senescence, thus shortening RBC lifespan and aggravating renal anemia. We aimed to assess eryptosis and intracellular oxygen levels of RBC from hemodialysis patients (HD-RBC) and their response to hypoxia, uremia, and uremic toxins uptake inhibition. METHODS: Using flow cytometry, RBC from healthy individuals (CON-RBC) and HD-RBC were subjected to PS (Annexin-V), intracellular Ca2+ (Fluo-3/AM) and intracellular oxygen (Hypoxia Green) measurements, at baseline and after incubation with uremic serum and/or hypoxia (5% O2), with or without ketoprofen. Baseline levels of uremic toxins were quantified in serum and cytosol by high performance liquid chromatography. RESULTS: Here, we show that HD-RBC have less intracellular oxygen and that it is further decreased post-HD. Also, incubation in 5% O2 and uremia triggered eryptosis in vitro by exposing PS. Hypoxia itself increased the PS exposure in HD-RBC and CON-RBC, and the addition of uremic serum aggravated it. Furthermore, inhibition of the organic anion transporter 2 with ketoprofen reverted eryptosis and restored the levels of intracellular oxygen. Cytosolic levels of the uremic toxins pCS and IAA were decreased after dialysis. CONCLUSION: These findings suggest the participation of uremic toxins and hypoxia in the process of eryptosis and intracellular oxygenation.

Elevated interleukin 31 serum levels in hemodialysis patients are associated with uremic pruritus.

INTRODUCTION: Uremic pruritus is a multifactorial devastating complication of renal failure, which has a significant negative impact on patients' quality of life including medical, psychological, as well as social aspects. It is also associated with an increased mortality in dialysis patients. METHODS: A cross sectional study evaluating the traditional risk factors for uremic pruritus (UP) - using pruritus grading system (PGS) and visual analogue scale (VAS) - as well as measuring the serum levels of different inflammatory cytokines (ILs 13, 31 and 33) in chronic hemodialysis and healthy controls, in a tertiary referral hospital. RESULTS: 65 hemodialysis (HD) patients and 49 heathy controls were enrolled in the study. The mean age for the HD patients was 43.4 years (SD ± 21.3), and 31.5 years (SD ± 11.1) for the control group. The most common cause for End Stage Renal Disease (ESRD) was diabetes mellitus (DM) 27.7%. The mean PGS score in HD patients was 5.92 (SD ± 2.9); 50% had mild itch, 43.8% moderate itch and 6.2% had severe itch. The mean serum levels for IL-13 was 8674.3 pg/ml (SD ± 4353.9), serum levels of IL-31 were 150.7 pg/ml (SD ± 178.2) and for IL-33 it was 42850.5 pg/ml (SD ± 11370.7) in hemodialysis patients; in comparison to serum levels of 7913.4 pg/ml (SD ± 3454.1), 67.1 pg/ml (SD ± 71.9) and 44875.9 pg/ml (SD ± 12114.6), respectively in the control group. IL-31 level was significantly higher in HD patients than in the control group (P = 0.0001), while the difference in the levels of IL-13 and IL-33 between the two groups were not statistically significant (P = 0.41 and 0.18, respectively). IL-13 had a statistically significant relationship with the itch score (P = 0.014) and the severity of itch (P = 0.03), while IL-31 and IL-33 were not statistically significant. CONCLUSION: UP is a complex and multifactorial problem. In patients with UP the high levels of IL-31 indicates a possible role in pathogenesis. IL-13 serum level on the other hand may be related to the severity of itch in these patients. Optimizing dialysis and targeting these cytokines may provide a potential therapeutic option especially in refractory UP. Further studies addressing these cytokines and their levels in response to various treatments may provide additional information on UP.

Online Hemodiafiltration Inhibits Inflammation-Related Endothelial Dysfunction and Vascular Calcification of Uremic Patients Modulating miR-223 Expression in Plasma Extracellular Vesicles.

Decreased inflammation and cardiovascular mortality are evident in patients with end-stage chronic kidney disease treated by online hemodiafiltration. Extracellular vesicles (EV) are mediators of cell-to-cell communication and contain different RNA types. This study investigated whether mixed online hemodiafiltration (mOL-HDF) beneficial effects associate with changes in the RNA content of plasma EV in chronic kidney disease patients. Thirty bicarbonate hemodialysis (BHD) patients were randomized 1:1 to continue BHD or switch to mOL-HDF. Concentration, size, and microRNA content of plasma EV were evaluated for 9 mo; we then studied EV effects on inflammation, angiogenesis, and apoptosis of endothelial cells (HUVEC) and on osteoblast mineralization of vascular smooth muscle cells (VSMC). mOL-HDF treatment reduced different inflammatory markers, including circulating CRP, IL-6, and NGAL. All hemodialysis patients showed higher plasma levels of endothelial-derived EV than healthy subjects, with no significant differences between BHD and mOL-HDF. However, BHD-derived EV had an increased expression of the proatherogenic miR-223 with respect to healthy subjects or mOL-HDF. Compared with EV from healthy subjects, those from hemodialysis patients reduced angiogenesis and increased HUVEC apoptosis and VSMC calcification; however, all these detrimental effects were reduced with mOL-HDF with respect to BHD. Cell transfection with miR-223 mimic or antagomiR proved the role of this microRNA in EV-induced HUVEC and VSMC dysfunction. The switch from BHD to mOL-HDF significantly reduced systemic inflammation and miR-223 expression in plasma EV, thus improving HUVEC angiogenesis and reducing VSMC calcification.

Endothelial glycocalyx damage in kidney disease correlates with uraemic toxins and endothelial dysfunction.

BACKGROUND: Damage to the endothelial glycocalyx is an early indicator of vascular damage and a potential marker of endothelial dysfunction. This study aimed to assess the relationship between markers of glycocalyx damage, endothelial dysfunction, and uraemic toxins in patients with chronic kidney disease. METHODS: Healthy controls, CKD patients, dialysis patients, and kidney transplant recipients had biochemical markers of glycocalyx damage (syndecan-1 and hyaluronan), endothelial dysfunction (von Willebrand factor; vWF and vascular cell adhesion molecule; VCAM-1), and uraemic toxins (indoxyl sulphate and p-cresyl sulphate) measured. In addition, Sidestream Darkfield imaging was performed using the novel GlycoCheck™ device to measure glycocalyx width by the perfused boundary region (PBR) in the sublingual microcirculation. RESULTS: Serum markers of glycocalyx damage were highest in the dialysis group (n = 33), followed by CKD patients (n = 32) and kidney transplant recipients (n = 30) compared to controls (n = 30): hyaluronan: 137 (16-1414), 79 (11-257), 57 (14-218) and 23 (8-116) ng/mL, respectively, p < 0.0001; syndecan-1: 81 (40-529), 46 (21-134), 39 (23-72), and 30 (12-138) ng/mL, respectively, p < 0.0001. Markers of endothelial dysfunction followed a similar pattern. No difference in the width of the PBR was detected between these groups (2.01 ± 0.35, 2.07 ± 0.27, 2.06 ± 0.28, and 2.05 ± 0.3 µm, respectively, p = 0.89). Glycocalyx damage correlated with markers of endothelial dysfunction (log-hyaluronan and log-VCAM-1: r = 0.64, p < 0.001) and levels of uraemic toxins (log-hyaluronan and log-indoxyl sulphate: r = 0.48, p < 0.001). CONCLUSIONS: Levels of biochemical markers of glycocalyx and endothelial cell damage are highest in patients receiving dialysis. Glycocalyx and endothelial damage markers correlated with each other, and with uraemic toxins. Although we could not demonstrate a change in PBR, the biochemical markers suggest that glycocalyx damage is most marked in patients with higher levels of uraemic toxins.

Uremic Toxic Blood-Brain Barrier Disruption Mediated by AhR Activation Leads to Cognitive Impairment during Experimental Renal Dysfunction.

BACKGROUND: Uremic toxicity may play a role in the elevated risk of developing cognitive impairment found among patients with CKD. Some uremic toxins, like indoxyl sulfate, are agonists of the transcription factor aryl hydrocarbon receptor (AhR), which is widely expressed in the central nervous system and which we previously identified as the receptor of indoxyl sulfate in endothelial cells. METHODS: To characterize involvement of uremic toxins in cerebral and neurobehavioral abnormalities in three rat models of CKD, we induced CKD in rats by an adenine-rich diet or by 5/6 nephrectomy; we also used AhR-/- knockout mice overloaded with indoxyl sulfate in drinking water. We assessed neurologic deficits by neurobehavioral tests and blood-brain barrier disruption by SPECT/CT imaging after injection of 99mTc-DTPA, an imaging marker of blood-brain barrier permeability. RESULTS: In CKD rats, we found cognitive impairment in the novel object recognition test, the object location task, and social memory tests and an increase of blood-brain barrier permeability associated with renal dysfunction. We found a significant correlation between 99mTc-DTPA content in brain and both the discrimination index in the novel object recognition test and indoxyl sulfate concentrations in serum. When we added indoxyl sulfate to the drinking water of rats fed an adenine-rich diet, we found an increase in indoxyl sulfate concentrations in serum associated with a stronger impairment in cognition and a higher permeability of the blood-brain barrier. In addition, non-CKD AhR-/- knockout mice were protected against indoxyl sulfate-induced blood-brain barrier disruption and cognitive impairment. CONCLUSIONS: AhR activation by indoxyl sulfate, a uremic toxin, leads to blood-brain barrier disruption associated with cognitive impairment in animal models of CKD.

Uremic serum induces prothrombotic changes in venous endothelial cells and inflammatory changes in aortic endothelial cells.

BACKGROUND: Uremia induces various pathologic changes in the endothelium. However, there is limited information about the differences of these effects in endothelial cells originating from different parts of the vascular tree. METHODS: The effect of uremic serum obtained from patients with end stage renal failure on the gene expression and secretory activity of venous endothelial cells (VEC) and aortic endothelial cells (AEC) was studied in in vitro culture. RESULTS: In VEC, the expression of genes regulating the synthesis of von Willebrand factor (vWF) was increased by 254% (p<.005), vascular endothelial growth factor (VEGF) synthesis by 150% (p<.001), tissue plasminogen activator (t-PA) synthesis by 62% (p<.005), platelet endothelial cell adhesion molecule by 89% (p<.005), and the expression of gene regulating interleukin-6 (IL-6) synthesis was reduced. In AEC, the expression of the gene regulating synthesis of IL-6 was increased by 174% (p<.001), and the expression of the other genes was reduced. The secretion of IL-6 was reduced in VEC by 38% (p<.01) and increased in AEC by 55% (p<.005). In VEC, increased synthesis of VEGF 64% (p<.001) vWF (+34%, p<.01), and t-PA (+53%, p<.002) was observed, and in AEC it was reduced. CONCLUSIONS: VEC and AEC respond in different ways after exposure to uremic serum. VEC acquires the prothrombotic phenotype, whereas in AEC the inflammatory phenotype appears.

Predialysis and Dialysis Therapies Differently Affect Nitric Oxide Synthetic Pathway in Red Blood Cells from Uremic Patients: Focus on Peritoneal Dialysis.

Red blood cells (RBCs) have been found to synthesize and release both nitric oxide (NO) and cyclic guanosine monophosphate (cGMP), contributing to systemic NO bioavailability. These RBC functions resulted impaired in chronic kidney disease (CKD). This study aimed to evaluate whether predialysis (conservative therapy, CT) and dialysis (peritoneal dialysis, PD; hemodialysis, HD) therapies used during CKD progression may differently affect NO-synthetic pathway in RBCs. Our data demonstrated that compared to PD, although endothelial-NO-synthase activation was similarly increased, HD and CT were associated to cGMP RBCs accumulation, caused by reduced activity of cGMP membrane transporter (MRP4). In parallel, plasma cGMP levels were increased by both CT and HD and they significantly decreased after hemodialysis, suggesting that this might be caused by reduced cGMP renal clearance. As conceivable, compared to healthy subjects, plasma nitrite levels were significantly reduced by HD and CT but not in patients on PD. Additionally, the increased carotid intima-media thickness (IMT) values did not reach the significance exclusively in patients on PD. Therefore, our results show that PD might better preserve the synthetic NO-pathway in CKD-erythrocytes. Whether this translates into a reduced development of uremic vascular complications requires further investigation.

Up-regulation of HDACs, a harbinger of uraemic endothelial dysfunction, is prevented by defibrotide.

Endothelial dysfunction is an earlier contributor to the development of atherosclerosis in chronic kidney disease (CKD), in which the role of epigenetic triggers cannot be ruled out. Endothelial protective strategies, such as defibrotide (DF), may be useful in this scenario. We evaluated changes induced by CKD on endothelial cell proteome and explored the effect of DF and the mechanisms involved. Human umbilical cord vein endothelial cells were exposed to sera from healthy donors (n = 20) and patients with end-stage renal disease on haemodialysis (n = 20). Differential protein expression was investigated by using a proteomic approach, Western blot and immunofluorescence. HDAC1 and HDAC2 overexpression was detected. Increased HDAC1 expression occurred at both cytoplasm and nucleus. These effects were dose-dependently inhibited by DF. Both the HDACs inhibitor trichostatin A and DF prevented the up-regulation of the endothelial dysfunction markers induced by the uraemic milieu: intercellular adhesion molecule-1, surface Toll-like receptor-4, von Willebrand Factor and reactive oxygen species. Moreover, DF down-regulated HDACs expression through the PI3/AKT signalling pathway. HDACs appear as key modulators of the CKD-induced endothelial dysfunction as specific blockade by trichostatin A or by DF prevents endothelial dysfunction responses to the CKD insult. Moreover, DF exerts its endothelial protective effect by inhibiting HDAC up-regulation likely through PI3K/AKT.

Resveratrol Reduces Kidney Injury in a Rat Model of Uremia and is Associated with Increased Expression of Heat Shock Protein 70 (Hsp70).

BACKGROUND This study aimed to investigate the effects of resveratrol on kidney function in a rat model of uremia and the expression of heat shock proteins. MATERIAL AND METHODS The rat model of uremia was developed by 5/6 nephrectomy of Sprague-Dawley rats. The Hsp70 inhibitor MKT-077, a rhodacyanine dye, was used. The study groups included rats with sham surgery (the sham group), the rat model of uremia (the model group), the solvent-treated control group (the control group), the rat model treated with resveratrol group (the resveratrol group), the rat model treated with MKT-077 (the MKT-077 group), and the resveratrol+MKT-077 group. Kidney tissues were studied histologically. Renal cell apoptosis was detected by the TUNEL method. Expression of p53, Bax, and Bcl-2 mRNA and protein were detected by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and immunohistochemistry, respectively. RESULTS Compared with the sham group, the expression levels of heat shock proteins Hsp70, Hsp90, Hsp27, Hsp25, Hsp40, and Hsp60 in the kidney of the rat model group increased to different degrees. Compared with the model group, the Hsp70 levels in the resveratrol group were significantly increased (p<0.05). Compared with the model group, treatment with MKT-077 reduced the survival rate of rats, which was increased following resveratrol treatment. Compared with the resveratrol group, renal function in the resveratrol+MKT-077 group was significantly reduced (p<0.05). CONCLUSIONS In a rat model of uremia, resveratrol reduced renal injury and improved both renal function and survival, which were associated with increased expression of Hsp70.

Simultaneous multielement analysis by ICP-MS with simple whole blood sample dilution and its application to uremic patients undergoing long-term hemodialysis.

Few studies were reported on trace elements' alterations in uremic patients undergoing long-term (>24 months) hemodialysis (HD), especially by using the whole blood as the biological fluid for the measuring purpose. Our objective was to develop an improved micro-sampling inductively coupled plasma-mass spectrometry (ICP-MS) method to determine the levels of Ca, Mg, Cu, Zn, Fe, Mn, Se and Pb in uremic patients receiving long-term HD. A ICP-MS method with a modified whole blood sample preparation procedure with small volumes was established and applied for the simultaneous quantification of the various elements in uremic patients undergoing long-term HD. 124 eligible uremic patients receiving long-term HD (75 males and 49 females) and 77 healthy subjects (54 males and 23 females) were recruited and Ca, Mg, Cu, Zn, Fe, Mn, Se and Pb levels were further determined. Our results revealed that uremic patients with HD had significantly higher blood levels of Ca, Mg, Zn and Pb and lower Cu, Fe, Se and Mn concentrations than healthy controls. In conclusion, a reproducible and reliable ICP-MS method using minimal whole blood sample volume (50 µL) with a simple dilution-based preparation procedure was successfully improved, validated and applied. Uremic patients undergoing long-term HD might be at increased risk of some essential trace elements deficiency (especially for Cu, Fe and Se) or toxic trace element excess (Pb) in respect to healthy subjects. Monitoring of blood levels and supplementation of some trace elements may be indicated in uremic patients undergoing long-term HD.

Comparison of Circulating Levels of Uremic Toxins in Hemodialysis Patients Treated with Medium Cut-Off Membranes and High-Flux Membranes: Theranova in Sisli Hamidiye Etfal (THE SHE) Randomized Control Study.

INTRODUCTION: Removal of uremic toxins is a main objective of hemodialysis; however, whether high-flux and medium cut-off (MCO) membranes differ as regards removal of middle and large uremic toxins is not clear. OBJECTIVE: To compare medium cut-off and high-flux dialyzers as regards their intra- and interdialysis effect on circulating levels of middle and large uremic toxins and serum albumin. METHODS: Fifty-two patients were randomized to have hemodialysis with either 3 months of high-flux dialyzer followed by 3 months of MCO or vice versa. Blood samples were taken before and after dialysis at the first and last sessions of each dialyzer for analyses of middle and large uremic toxins including inflammatory mediators and vascular endothelial growth factor (VEGF), and serum albumin. RESULTS: Reduction rates were higher, and postdialysis levels of ß-2 microglobulin, free kappa and lambda light chains, and myoglobulin were lower at the first and last sessions with MCO dialyzers compared to high-flux dialyzers (p < 0.05 for all). Last session predialysis levels of ß-2 microglobulin, free kappa light chain, and free lambda light chain were lower than first session predialysis levels in MCO dialyzers as compared to high-flux dialyzers (p < 0.05 for all). Last session levels of interleukin-6, interleukin-10, interleukin-17, and interferon-gamma did not differ between dialyzers (p > 0.05 for all). VEGF level was lower in the MCO group compared to the high-flux group (p = 0.043). Last session level of serum albumin with MCO dialyzers was lower than that with high-flux dialyzers (3.62 [3.45-3.88] vs. 3.78 [3.58-4.02] g/L) (p = 0.04) and 6.7% lower (p < 0.001) than at the first session of MCO dialyzers. CONCLUSION: The decline in circulating levels of several middle and large uremic toxins including VEGF following hemodialysis was more pronounced when using MCO membranes as compared to high-flux membranes while their effect on inflammatory molecules was similar.

The Efficacy of Prebiotic, Probiotic, and Synbiotic Supplementation in Modulating Gut-Derived Circulatory Particles Associated With Cardiovascular Disease in Individuals Receiving Dialysis: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

OBJECTIVE: This systematic review and meta-analyses provide an up-to-date synthesis on the effects of supplementation on circulating levels of toxic metabolites, markers of uremia and inflammation, blood lipids, and other clinical outcomes. METHODS: Seventeen databases were searched, supplemented with internet and hand searching. Randomized controlled trials of adult end-stage renal-disease individuals receiving either hemodialysis or peritoneal dialysis were eligible. Trials were restricted to those which had administered a prebiotic, probiotic, or synbiotic as an oral supplement. Primary outcomes were measures of circulating endotoxin, indoxyl-sulphate, and p-cresyl sulfate. RESULTS: Twenty-one trials were eligible (1152 randomized participants), of which 16 trials were considered to have a high risk of bias. The number of trials available for meta-analysis varied for each primary outcome. Synthesized data indicated that supplementation significantly reduced circulating levels of endotoxin (standardized mean difference, -0.61; 95% confidence interval, -1.03 to -0.20; P = .004; I2 = 0%), indoxyl-sulphate (-0.34; -0.64 to -0.04; P = .02; I2 = 0%), and p-cresyl sulfate (-0.34; -0.61 to -0.07; P = .01; I2 = 0%). For secondary outcomes, supplementation significantly reduced gastrointestinal symptoms (-0.54; -1.02 to -0.07; P = .02; I2 = 0%). CONCLUSIONS: Supplementation reduces toxic metabolites associated with cardiovascular disease and mortality in individuals receiving dialysis. However, the majority of trials included were low in quality.

Therapeutic effect of intravenous sodium thiosulfate for uremic pruritus in hemodialysis patients.

OBJECTIVES: This study aimed to compare the efficacy of intravenous sodium thiosulfate (IV STS) with that of loratadine in the treatment of uremic pruritus in hemodialysis (HD) patients. METHODS: This retrospective study included 44 HD patients with pruritus aged over 18 years between June 2018 and January 2020 at the Aerospace Center Hospital of China. Twenty-four HD patients received 3.2 g IV STS treatment three times per week at the end of each HD session for 8 weeks. Twenty HD patients received loratadine (10 mg/day) for 8 weeks. Pruritus intensity was measured using a visual analog scale (VAS) and the detailed pruritus score (DPS) at three time points. The safety of STS was evaluated according to adverse event symptoms and biological variable changes. RESULTS: There was no significant difference between the STS and loratadine groups in age, sex, characteristics of pruritus, or other clinical variables before treatment. After 8 weeks of treatment, the VAS score (7.07 ± 2.56 and 2.67 ± 2.01) and DPS (30.72 ± 4.81 and 8.04 ± 2.86) decreased significantly in the STS group (p < 0.05). The mean decrease in VAS score (6.89 ± 1.98 and 6.34 ± 2.35) and DPS (28.90 ± 3.24 and 26.92 ± 2.41) in the loratadine group was not statistically significant (p > 0.05). There were no morbidities or mortalities associated with the use of either drug. All biological variables remained stable after therapy. CONCLUSIONS: STS can improve uremic pruritus in HD patients. However, literature on the subject remains lacking. Close monitoring for adverse effects is advised.

CharXgen-Activated Bamboo Charcoal Encapsulated in Sodium Alginate Microsphere as the Absorbent of Uremic Toxins to Retard Kidney Function Deterioration.

Indoxyl sulphate (IS) and p-cresyl sulphate (PCS) are two protein bound uraemic toxins accumulated in chronic kidney disease (CKD) and associated with adverse outcomes. The purpose of this study isto evaluate the effect of the new activated charcoal, CharXgen, on renal function protection and lowering serum uraemic toxins in CKD animal model. The physical character of CharXgen was analyzed before and after activation procedure by Scanning Electron Microscope (SEM) and X-ray diffractometer (XRD). The effect of CharXgen on biochemistry and lowering uremic toxins was evaluated by in vitro binding assay and CKD animal model. CharXgen have high interior surface area analyzed by SEM and XRD and have been produced from local bamboo after an activation process. CharXgen was able to effectively absorb IS, p-cresol and phosphate in an in vitro gastrointestinal tract simulation study. The animal study showed that CharXgen did not cause intestine blackening. Serum albuminand liver function did not change after feeding with CharXgen. Moreover, renal function was improved in CKD rats fed with CharXgen as compared to the CKD group, and there were no significant differences in the CKD and the CKD + AST-120 groups. Serum IS and PCS were higher in the CKD group and lower in rats treated with CharXgen and AST-120. In rats treated with CharXgen, Fibroblast growth factor 23 was significantly decreased as compared to the CKD group. This change cannot be found in rats fed with AST-120.It indicates that CharXgen is a new safe and non-toxic activated charcoal having potential in attenuating renal function deterioration and lowering protein-bound uraemic toxins. Whether the introduction of this new charcoal could further have renal protection in CKD patients will need to be investigated further.

Circadian rhythm of activin A and related parameters of mineral metabolism in normal and uremic rats.

Activin A is a new fascinating player in chronic kidney disease-mineral and bone disorder (CKD-MBD), which is implicated in progressive renal disease, vascular calcification, and osteodystrophy. Plasma activin A rises early in the progression of renal disease. Disruption of circadian rhythms is related to increased risk of several diseases and circadian rhythms are observed in mineral homeostasis, bone parameters, and plasma levels of phosphate and PTH. Therefore, we examined the circadian rhythm of activin A and CKD-MBD-related parameters (phosphate, PTH, FGF23, and klotho) in healthy controls and CKD rats (5/6 nephrectomy) on high-, standard- and low-dietary phosphate contents as well as during fasting conditions. Plasma activin A exhibited circadian rhythmicity in healthy control rats with fourfold higher values at acrophase compared with nadir. The rhythm was obliterated in CKD. Activin A was higher in CKD rats compared with controls when measured at daytime but not significantly when measured at evening/nighttime, stressing the importance of time-specific reference intervals when interpreting plasma values. Plasma phosphate, PTH, and FGF23 all showed circadian rhythms in control rats, which were abolished or disrupted in CKD. Plasma klotho did not show circadian rhythm. Thus, the present investigation shows, for the first time, circadian rhythm of plasma activin A. The rhythmicity is severely disturbed by CKD and is associated with disturbed rhythms of phosphate and phosphate-regulating hormones PTH and FGF23, indicating that disturbed circadian rhythmicity is an important feature of CKD-MBD.

Plasma metabolite biomarkers related to secondary hyperparathyroidism and parathyroid hormone.

BACKGROUND: Hyperphosphatemia, hypocalcemia, and elevation of parathyroid hormone (PTH) are typical abnormalities of uremic patients with Secondary hyperparathyroidism (SHPT). However, metabolic imbalance associated with SHPT is not well understood. METHODS: A total of 15 SHPT patients with an intact parathyroid hormone (iPTH) level > 600 pg/mL were set as preoperative (PR) group, 15 age- and gender-matched controls who had undergone parathyroidectomy plus forearm transplantation because of hyperparathyroidism and achieved an iPTH level <150 pg/mL were set as postoperative (PO) group. Metabolite profiling of these 30 uremic patients and five healthy controls (HC) was performed using ultra performance liquid chromatography-mass spectrometry. RESULTS: Five differential metabolites, including allyl isothiocyanate, L-phenylalanine, D-Aspartic acid, indoleacetaldehyde, and D-galactose correlated with PTH were identified in this study. Taking them as a biomarker signature, PR group can be distinguished from HC group with an area under the curve (AUC) of 0.947 (95% CI, 0.76-1) and PO group with an AUC of 0.6 (95% CI, 0.38-0.807). CONCLUSIONS: The serum metabolome correlated with PTH is successfully demonstrated for a better understanding of the pathogenesis of SHPT.

Accumulation of uremic solutes in the cerebrospinal fluid in experimental acute renal failure.

The accumulation of uremic solutes in kidney failure may impair mental function. The present study profiled the accumulation of uremic solutes in the cerebrospinal fluid (CSF) in acute renal failure. CSF and plasma ultrafiltrate were obtained from rats at 48 h after sham operation (control; n = 10) or bilateral nephrectomy (n = 10) and analyzed using an established metabolomic platform. Two hundred forty-eight solutes were identified as uremic based on their accumulation in the plasma ultrafiltrate of nephrectomized compared with control rats. CSF levels of 124 of these solutes were sufficient to allow calculation of CSF-to-plasma ultrafiltrate concentration ratios. Levels of many of the uremic solutes were normally lower in the CSF than in the plasma ultrafiltrate, indicating exclusion of these solutes from the brain. CSF levels of the great majority of the uremic solutes increased in renal failure. The increase in the CSF was, however, relatively less than in the plasma ultrafiltrate for most solutes. In particular, for the 31 uremic solutes with CSF-to-plasma ultrafiltrate ratios of <0.25 in control rats, the average CSF-to-plasma ultrafiltrate ratio decreased from 0.13 ± 0.07 in control rats to 0.09 ± 0.06 in nephrectomized rats, revealing sustained ability to exclude these solutes from the brain. In summary, levels of many uremic solutes are normally kept lower in the CSF than in the plasma ultrafiltrate by the action of the blood-brain and blood-CSF barriers. These barriers remain functional but cannot prevent accumulation of uremic solutes in the CSF when the kidneys fail.