Chronic Kidney Disease-Associated Immune Dysfunctions: Impact of Protein-Bound Uremic Retention Solutes on Immune Cells.
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ABSTRACT:
SUBMITTER: Espi M
PROVIDER: S-EPMC7291164 | biostudies-literature | 2020 May
REPOSITORIES: biostudies-literature
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Chronic Kidney Disease-Associated Immune Dysfunctions: Impact of Protein-Bound Uremic Retention Solutes on Immune Cells.
Espi Maxime M Koppe Laetitia L Fouque Denis D Thaunat Olivier O
Toxins 20200506 5
Regardless of the primary disease responsible for kidney failure, patients suffering from chronic kidney disease (CKD) have in common multiple impairments of both the innate and adaptive immune systems, the pathophysiology of which has long remained enigmatic. CKD-associated immune dysfunction includes chronic low-grade activation of monocytes and neutrophils, which induces endothelial damage and increases cardiovascular risk. Although innate immune effectors are activated during CKD, their anti ...[more]
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Project description:In this narrative review, the biological/biochemical impact (toxicity) of a large array of known individual uremic retention solutes and groups of solutes is summarized. We classified these compounds along their physico-chemical characteristics as small water-soluble compounds or groups, protein bound compounds and middle molecules. All but one solute (glomerulopressin) affected at least one mechanism with the potential to contribute to the uremic syndrome. In general, several mechanisms were influenced for each individual solute or group of solutes, with some impacting up to 7 different biological systems of the 11 considered. The inflammatory, cardio-vascular and fibrogenic systems were those most frequently affected and they are one by one major actors in the high morbidity and mortality of CKD but also the mechanisms that have most frequently been studied. A scoring system was built with the intention to classify the reviewed compounds according to the experimental evidence of their toxicity (number of systems affected) and overall experimental and clinical evidence. Among the highest globally scoring solutes were 3 small water-soluble compounds [asymmetric dimethylarginine (ADMA); trimethylamine-N-oxide (TMAO); uric acid], 6 protein bound compounds or groups of protein bound compounds [advanced glycation end products (AGEs); p-cresyl sulfate; indoxyl sulfate; indole acetic acid; the kynurenines; phenyl acetic acid;] and 3 middle molecules [??-microglobulin; ghrelin; parathyroid hormone). In general, more experimental data were provided for the protein bound molecules but for almost half of them clinical evidence was missing in spite of robust experimental data. The picture emanating is one of a complex disorder, where multiple factors contribute to a multisystem complication profile, so that it seems of not much use to pursue a decrease of concentration of a single compound.
| S-EPMC5793120 | biostudies-literature
Project description:BackgroundTo date, over 150 possible uremic solutes have been listed, but their role in the progression of CKD is largely unknown. Here, the association between a selected panel of uremic solutes and progression in CKD patients was investigated.MethodsPatients from the MASTERPLAN study, a randomized controlled trial in CKD patients with a creatinine clearance between 20 and 70 ml/min per 1.73m2, were selected based on their rate of eGFR decline during the first five years of follow-up. They were categorized as rapid (decline >5 ml/min per year) or slow progressors. Concentrations of eleven uremic solutes were obtained at baseline and after one year of follow-up. Logistic regression was used to compare the odds for rapid to slow progression by uremic solute concentrations at baseline. Variability in uremic solute levels was assessed using scatter plots, and limits of variability were calculated.ResultsIn total, 40 rapidly and 40 slowly progressing patients were included. Uremic solutes were elevated in all patients compared to reference values for healthy persons. The serum levels of uremic solutes were not associated with rapid progression. Moreover, we observed substantial variability in solute levels over time.ConclusionsElevated concentrations of uremic solutes measured in this study did not explain differences in rate of eGFR decline in CKD patients, possibly due to lack of power as a result of the small sample size, substantial between patient variability, and variability in solute concentrations over time. The etiology of intra-individual variation in uremic solute levels remains to be elucidated.
| S-EPMC5199014 | biostudies-literature
Project description:UNLABELLED:The colonic microbial metabolism is a key contributor to uremic retention solutes accumulating in patients with CKD, relating to adverse outcomes and insulin resistance. Whether prebiotics can reduce intestinal generation of these microbial metabolites and improve insulin resistance in CKD patients not yet on dialysis remains unknown. We performed a randomized, placebo-controlled, double-blind, cross-over study in 40 patients with eGFR between 15 and 45 ml/min/1.73 m2. Patients were randomized to sequential treatment with prebiotic arabinoxylan oligosaccharides (AXOS) (10 g twice daily) and maltodextrin for 4 weeks, or vice versa, with a 4-week wash-out period between both intervention periods. Serum levels and 24h urinary excretion of p-cresyl sulfate, p-cresyl glucuronide, indoxyl sulfate, trimethylamine N-oxide and phenylacetylglutamine were determined at each time point using liquid chromatography-tandem mass spectrometry. In addition, insulin resistance was estimated by the homeostatic model assessment (HOMA-IR). A total of 39 patients completed the study. We observed no significant effect of AXOS on serum p-cresyl sulfate (P 0.42), p-cresyl glucuronide (P 0.59), indoxyl sulfate (P 0.70) and phenylacetylglutamine (P 0.41) and a small, albeit significant decreasing effect on serum trimethylamine N-oxide (P 0.04). There were neither effect of AXOS on 24h urinary excretion of p-cresyl sulfate (P 0.31), p-cresyl glucuronide (P 0.23), indoxyl sulfate (P 0.87) and phenylacetylglutamine (P 0.43), nor on 24h urinary excretion of trimethylamine N-oxide (P 0.97). In addition, we observed no significant change in HOMA-IR (P 0.93). In conclusion, we could not demonstrate an influence of prebiotic AXOS on microbiota derived uremic retention solutes and insulin resistance in patients with CKD not yet on dialysis. Further study is necessary to elucidate whether prebiotic therapy with other characteristics, higher cumulative exposure or in different patient populations may be of benefit. TRIAL REGISTRATION:Clinicaltrials.gov NCT02141815.
| S-EPMC4839737 | biostudies-literature
Project description:BACKGROUND: Chronic kidney disease (CKD) is characterized by the progressive accumulation of various potential toxic solutes. Furthermore, uremic plasma is a complex mixture hampering accurate determination of uremic toxin levels and the identification of novel uremic solutes. METHODS: In this study, we applied (1)H-nuclear magnetic resonance (NMR) spectroscopy, following three distinct deproteinization strategies, to determine differences in the plasma metabolic status of stage 3-4 CKD patients and healthy controls. Moreover, the human renal proximal tubule cell line (ciPTEC) was used to study the influence of newly indentified uremic solutes on renal phenotype and functionality. RESULTS: Protein removal via ultrafiltration and acetonitrile precipitation are complementary techniques and both are required to obtain a clear metabolome profile. This new approach, revealed that a total of 14 metabolites were elevated in uremic plasma. In addition to confirming the retention of several previously identified uremic toxins, including p-cresyl sulphate, two novel uremic retentions solutes were detected, namely dimethyl sulphone (DMSO2) and 2-hydroxyisobutyric acid (2-HIBA). Our results show that these metabolites accumulate in non-dialysis CKD patients from 9±7 µM (control) to 51±29 µM and from 7 (0-9) µM (control) to 32±15 µM, respectively. Furthermore, exposure of ciPTEC to clinically relevant concentrations of both solutes resulted in an increased protein expression of the mesenchymal marker vimentin with more than 10% (p<0.05). Moreover, the loss of epithelial characteristics significantly correlated with a loss of glucuronidation activity (Pearson r?=?-0.63; p<0.05). In addition, both solutes did not affect cell viability nor mitochondrial activity. CONCLUSIONS: This study demonstrates the importance of sample preparation techniques in the identification of uremic retention solutes using (1)H-NMR spectroscopy, and provide insight into the negative impact of DMSO2 and 2-HIBA on ciPTEC, which could aid in understanding the progressive nature of renal disease.
| S-EPMC3732267 | biostudies-literature
Project description:The aim of this study was to evaluate the contribution and removal dynamics of the main fluorophores during dialysis by analyzing the spent dialysate samples to prove the hypothesis whether the fluorescence of spent dialysate can be utilized for monitoring removal of any of the protein bound uremic solute. A high performance liquid chromatography system was used to separate and quantify fluorophoric solutes in the spent dialysate sampled at the start and the end of 99 dialysis sessions, including 57 hemodialysis and 42 hemodiafiltration treatments. Fluorescence was acquired at excitation 280 nm and emission 360 nm. The main fluorophores found in samples were identified as indole derivatives: tryptophan, indoxyl glucuronide, indoxyl sulfate, 5-hydroxy-indoleacetic acid, indoleacetyl glutamine, and indoleacetic acid. The highest contribution (35 ± 11%) was found to arise from indoxyl sulfate. Strong correlation between contribution values at the start and end of dialysis (R2 = 0.90) indicated to the stable contribution during the course of the dialysis. The reduction ratio of indoxyl sulfate was very close to the decrease of the total fluorescence signal of the spent dialysate (49 ± 14% vs 51 ± 13% respectively, P = 0.30, N = 99) and there was strong correlation between these reduction ratio values (R2 = 0.86). On-line fluorescence measurements were carried out to illustrate the technological possibility for real-time dialysis fluorescence monitoring reflecting the removal of the main fluorophores from blood into spent dialysate. In summary, since a predominant part of the fluorescence signal at excitation 280 nm and emission 360 nm in the spent dialysate originates from protein bound derivatives of indoles, metabolites of tryptophan and indole, the fluorescence signal at this wavelength region has high potential to be utilized for monitoring the removal of slowly dialyzed uremic toxin indoxyl sulfate.
| S-EPMC4882071 | biostudies-literature
Project description:BACKGROUND:There is growing evidence that the accumulation of protein- bound uremic retention solutes, such as indoxyl sulfate, p-cresyl sulfate and kynurenic acid, play a role in the accelerated cardiovascular disease seen in patients undergoing chronic hemodialysis. Protein-binding, presumably to albumin, renders these solutes poor-dialyzable. We previously observed that the free fraction of indoxyl sulfate was markedly reduced at the end of hemodialysis. We hypothesized that solute binding might be pH-dependent and attributed the changes in free solute concentration to the higher serum pH observed at the end of standard hemodialysis with dialysis buffer bicarbonate concentration greater than 35 mmol/L. We observed that acidification of uremic plasma to pH 6 in vitro greatly increased the proportion of freeIS. METHODS:We tested our hypothesis by reducing the dialysate bicarbonate buffer concentration to 25 mmol/L for the initial half of the hemodialysis treatment ("isohydric dialysis"). Eight stable hemodialysis patients underwent "isohydric dialysis" for 90 minutes and then were switched to standard buffer (bicarbonate = 37mmol/L). A second dialysis, 2 days later, employed standard buffer throughout. RESULTS:We found a clearcut separation of blood pH and bicarbonate concentrations after 90 minutes of "isohydric dialysis" (pH = 7.37, bicarbonate = 22.4 mmol/L) and standard dialysis (pH = 7.49, bicarbonate = 29.0 mmol/L). Binding affinity varied widely among the 10 uremic retention solutes analyzed. Kynurenic acid (0.05 free), p-cresyl sulfate (0.12 free) and indoxyl sulfate (0.13 free) demonstrated the greatest degree of binding. Three solutes (indoxyl glucuronide, p-cresyl glucuronide, and phenyl glucuronide) were virtually unbound. Analysis of free and bound concentrations of uremic retention solutes confirmed our prediction that binding of solute is affected by pH. However, in a mixed models analysis, we found that the reduction in total uremic solute concentration during dialysis accounted for a greater proportion of the variation in free concentration, presumably an effect of saturation binding to albumin, than did the relatively small change in pH produced by isohydric dialysis. The effect of pH on binding appeared to be restricted to those solutes most highly protein-bound. The solutes most tightly bound exhibited the lowest dialyzer clearances. An increase in dialyzer clearance during isohydric and standard dialyses was statistically significant only for kynurenic acid. CONCLUSION:These findings provide evidence that the binding of uremic retention solutes is influenced by pH. The effect of reducing buffer bicarbonate concentration ("isohydric dialysis:"), though significant, was small but may be taken to suggest that further modification of dialysis technique that would expose blood to a greater decrease in pH would lead to a greater increase the free fraction of solute and enhance the efficacy of hemodialysis in the removal of highly protein-bound uremic retention solutes.
| S-EPMC5823377 | biostudies-literature
Project description:BACKGROUND:Residual kidney function (RKF) is thought to exert beneficial effects through clearance of uremic toxins. However, the level of native kidney function where clearance becomes negligible is not known. METHODS:We aimed to assess whether levels of nonurea solutes differed among patients with 'clinically negligible' RKF compared with those with no RKF. The hemodialysis study excluded patients with urinary urea clearance >1.5?mL/min, below which RKF was considered to be 'clinically negligible'. We measured eight nonurea solutes from 1280 patients participating in this study and calculated the relative difference in solute levels among patients with and without RKF based on measured urinary urea clearance. RESULTS:The mean age of the participants was 57?years and 57% were female. At baseline, 34% of the included participants had clinically negligible RKF (mean 0.7?±?0.4?mL/min) and 66% had no RKF. Seven of the eight nonurea solute levels measured were significantly lower in patients with RKF than in those without RKF, ranging from -24% [95% confidence interval (CI) -31 to -16] for hippurate, -7% (-14 to -1) for trimethylamine-N-oxide and -4% (-6 to -1) for asymmetric dimethylarginine. The effect of RKF on plasma levels was comparable or more pronounced than that achieved with a 31% higher dialysis dose (spKt/Vurea 1.7 versus 1.3). Preserved RKF at 1-year follow-up was associated with a lower risk of cardiac death and first cardiovascular event. CONCLUSIONS:Even at very low levels, RKF is not 'negligible', as it continues to provide nonurea solute clearance. Management of patients with RKF should consider these differences.
| S-EPMC7203561 | biostudies-literature
Project description:Better knowledge of the uremic solutes that accumulate when the kidneys fail could lead to improved renal replacement therapy. This study employed the largest widely available metabolomic platform to identify such solutes. Plasma and plasma ultrafiltrate from 6 maintenance hemodialysis (HD) patients and 6 normal controls were first compared using a platform combining gas and liquid chromatography with mass spectrometry. Further studies compared plasma from 6 HD patients who had undergone total colectomy and 9 with intact colons. We identified 120 solutes as uremic including 48 that had not been previously reported to accumulate in renal failure. Combination of the 48 newly identified solutes with those identified in previous reports yielded an extended list of more than 270 uremic solutes. Among the solutes identified as uremic in the current study, 9 were shown to be colon-derived, including 6 not previously identified as such. Literature search revealed that many uremic phenyl and indole solutes, including most of those shown to be colon-derived, come from plant foods. Some of these compounds can be absorbed directly from plant foods and others are produced by colon microbial metabolism of plant polyphenols that escape digestion in the small intestine. A limitation of the metabolomic method was that it underestimated the elevation in concentration of uremic solutes which were measured using more quantitative assays.
| S-EPMC4552739 | biostudies-literature
Project description:BackgroundUremic solute concentration increases as Glomerular Filtration Rate (GFR) declines. Weak associations were demonstrated between estimated GFR (eGFR) and the concentrations of several small water-soluble and protein-bound uremic solutes (MW<500 Da). Since also middle molecular weight proteins have been associated with mortality and cardiovascular damage in Chronic Kidney Disease (CKD), we investigated the association between several eGFR formulae and the concentration of Low Molecular Weight Proteins (LMWP) (MW>500 Da).Materials and methodsIn 95 CKD-patients (CKD-stage 2-5 not on dialysis), associations between different eGFR-formulae (creatinine, Cystatin C-based or both) and the natural logarithm of the concentration of several LMWP's were analyzed: i.e. parathyroid hormone (PTH), Cystatin C (CystC), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-?), leptin, retinol binding protein (RbP), immunoglobin light chains kappa and lambda (Ig-? and Ig-?), beta-2-microglobulin (?(2)M), myoglobin and fibroblast growth factor-23 (FGF-23)).ResultsThe regression coefficients (R(2)) between eGFR, based on the CKD-EPI-Crea-CystC-formula as reference, and the examined LMWP's could be divided into three groups. Most of the LMWP's associated weakly (R(2) <0.2) (FGF-23, leptin, IL-6, TNF-?, Ig-?, Ig-?) or intermediately (R(2) 0.2-0.7) (RbP, myoglobin, PTH). Only ?(2)M and CystC showed a strong association (R(2) >0.7). Almost identical R(2)-values were found per LMWP for all eGFR-formulae, with exception of CystC and ?(2)M which showed weaker associations with creatinine-based than with CystC-based eGFR.ConclusionThe association between eGFR and the concentration of several LMWP's is inconsistent, with in general low R(2)-values. Thus, the use of eGFR to evaluate kidney function does not reflect the concentration of several LMWP's with proven toxic impact in CKD.
| S-EPMC3432070 | biostudies-literature
Project description:Although the relationship between protein-bound uremic toxins (PBUTs) and cardiac structure and cardiac mortality in chronic kidney disease (CKD) has been studied in the past, the association between cardiac dysfunction and PBUTs has not yet been studied. We therefore evaluated the association between impaired peak cardiac performance and the serum free and total concentrations of potentially cardiotoxic PBUTs. In a cross-sectional study of 56 male CKD patients (stages 2⁻5 (pre-dialysis)) who were asymptomatic with no known cardiac diseases or diabetes we measured peak cardiac power (CPOmax), aerobic exercise capacity (VO2max), and echocardiographic parameters of cardiac morphology and evaluated their association with PBUTs. The serum total and free concentrations of indoxyl sulfate (IXS), p-cresyl sulfate (PCS), p-cresyl glucuronide, indole acetic acid, and hippuric acid showed significant negative correlation with CPOmax and VO2max. IXS and PCS were independently associated with CPOmax and VO2max even after controlling for eGFR. No correlation between left ventricular mass index (LVMI) and PBUTs was seen. The present study for the first time has demonstrated the association between subclinical cardiac dysfunction in CKD and serum levels of a panel of PBUTs. Further studies are required to evaluate the mechanism of cardiotoxicity of the individual uremic toxins.
| S-EPMC6316640 | biostudies-literature