Removal of Protein-Bound Uremic Toxins during Hemodialysis Using a Binding Competitor

Background and objectivesCurrent hemodialysis techniques fail to efficiently remove the protein-bound uremic toxins p-cresyl sulfate and indoxyl sulfate due to their high degree of albumin binding. Ibuprofen, which shares the same primary albumin binding site with p-cresyl sulfate and indoxyl sulfate, can be infused during hemodialysis to displace these toxins, thereby augmenting their removal.Design, setting, participants, & measurementsWe infused 800 mg ibuprofen into the arterial bloodline between minutes 21 and 40 of a conventional 4-hour high-flux hemodialysis treatment. We measured arterial, venous, and dialysate outlet concentrations of indoxyl sulfate, p-cresyl sulfate, tryptophan, ibuprofen, urea, and creatinine before, during, and after the ibuprofen infusion. We report clearances of p-cresyl sulfate and indoxyl sulfate before and during ibuprofen infusion and dialysate concentrations of protein-bound uremic toxins normalized to each patient’s average preinfusion concentrations.ResultsWe studied 18 patients on maintenance hemodialysis: age 36±11 years old, ten women, and mean vintage of 37±37 months. Compared with during the preinfusion period, the median (interquartile range) clearances of indoxyl sulfate and p-cresyl sulfate increased during ibuprofen infusion from 6.0 (6.5) to 20.2 (27.1) ml/min and from 4.4 (6.7) to 14.9 (27.1) ml/min (each P<0.001), respectively. Relative median (interquartile range) protein-bound uremic toxin dialysate outlet levels increased from preinfusion 1.0 (reference) to 2.4 (1.2) for indoxyl sulfate and to 2.4 (1.0) for p-cresyl sulfate (each P<0.001). Although median serum post- and predialyzer levels in the preinfusion period were similar, infusion led to a marked drop in serum postdialyzer levels for both indoxyl sulfate and p-cresyl sulfate (−1.0 and −0.3 mg/dl, respectively; each P<0.001). The removal of the nonprotein-bound solutes creatinine and urea was not increased by the ibuprofen infusion.ConclusionsInfusion of ibuprofen into the arterial bloodline during hemodialysis significantly increases the dialytic removal of indoxyl sulfate and p-cresyl sulfate and thereby, leads to greater reduction in their serum levels.

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MO660INTERRELATIONSHIP BETWEEN PROTEIN BOUND UREMIC TOXIN INDOXYL SULFATE CONCENTRATION IN BLOOD AND SPENT DIALYSATE DURING HEMODIALYSIS TREATMENT

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfab099.005 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

Joosep Paats ◽

Annika Adoberg ◽

Jürgen Arund ◽

Ivo Fridolin ◽

Kai Lauri ◽

...

Keyword(s):

Strong Correlation ◽

Uremic Toxins ◽

Interquartile Range ◽

Indoxyl Sulfate ◽

Total Serum ◽

Uremic Toxin ◽

Optical Monitoring ◽

On Line ◽

Spent Dialysate ◽

Treatment Settings

Abstract Background and Aims Indoxyl sulfate (IS) is a representative of the protein-bound uremic retention solutes [1]. Among CKD patients, high serum levels of IS are associated with high cardiovascular and all-cause mortality – IS is linked to cardiovascular outcomes, induces acceleration of atherosclerosis and abnormal bone metabolism [2,3]. Optical monitoring of the uremic marker molecules in the spent dialysate has been proposed [4] to estimate on-line concentration and removal of uremic toxins, allowing to assess total removed solute and removal rate of uremic toxins. Although several studies have been published covering the on-line optical monitoring of the spent dialysate, there is scarce knowledge about relation between spent dialysate and blood concentrations for protein-bound uremic solutes. The aim of this study was to evaluate the relationship between protein bound uremic toxin IS concentration in blood and spent dialysate during hemodialysis (HD) and hemodiafiltration (HDF) with different treatment settings, with the potential of evaluating uremic toxins’ levels in blood by assessing uremic toxins’ concentration in spent dialysate. Method 22 ESKD patients (16 male and 8 female, 55±17 years) on chronic HDF were enrolled into the study (fistula N=15, graft N=7). For each patient 4 midweek dialysis sessions (length 240min, HD: N=1, Qb=200ml/min, Qd=300ml/min, 1,5m2; HDF: N=3, median (interquartile range) Qb = 298 (296-356) ml/min, Qd= 795 (500-800) ml/min, Vsubst = 21.8 (15-24.5) L, 1,8m2 and 2,2m2) were included. During each dialysis session, blood samples were taken at 0 min (start) and 240 min from the arterial blood line, and dialysate samples were taken at 7 min and 240 min from the outlet of the dialysis machine. After sample processing, serum total, serum free and spent dialysate IS concentrations were determined by HPLC. Regression analysis was carried out. Results Median (interquartile range) IS concentrations in blood were 10.02 (6.68 - 14.68) µmol/L for free IS, 101.33 (56.99- 125.66) µmol/L for total IS, and 3.74 (2.35- 5.93) µmol/L in dialysate at the beginning of dialysis, and 6.07 (3.58- 9.00) µmol/L, 56.70 (28.91-80.67) µmol/L, 1.94 (1.15-2.98) µmol/L at the end of dialysis, respectively. There was a strong correlation between IS concentration in blood and dialysate at the beginning and at the end of dialysis even without data normalization by treatment settings (Fig. 1), with the strongest correlation between free IS concentration and IS in dialysate at 240 min (R2 = 0,976) and at the beginning of dialysis (R2 = 0,962). The reason for the higher correlation between free IS in blood and IS in dialysate is that only protein non-bound fraction of IS is available for removal by dialysis from blood into dialysate. Conclusion There is a strong correlation between IS concentrations in blood and dialysate with different treatment settings during whole dialysis. Assessment of protein bound uremic toxins’ concentration in the spent dialysate by optical sensor could thus also provide information about the concentration of uremic toxins in blood. [1] Vanholder et al 2018; [2] Yamamoto et al 2020; [3] Barreto et al 2009; [4] Lauri et al 2019;

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Pilot Study of Probiotic Supplementation on Uremic Toxicity and Inflammatory Cytokines in Chronic Kidney Patients

Current Nutrition & Food Science ◽

10.2174/1573401315666190215111402 ◽

2020 ◽

Vol 16 (4) ◽

pp. 470-480

Author(s):

Cristina T. Roth-Stefanski ◽

Carla Dolenga ◽

Lia S. Nakao ◽

Roberto Pecoits-Filho ◽

Thyago P. de Moraes ◽

...

Keyword(s):

Pilot Study ◽

Inflammatory Cytokines ◽

Lactobacillus Acidophilus ◽

Serum Levels ◽

Uremic Toxins ◽

Indoxyl Sulfate ◽

Bacterial Metabolism ◽

Probiotic Supplementation ◽

Primary Endpoints ◽

Inflammatory Profile

Background: Bacterial metabolism contributes to the generation of uremic toxins in patients with chronic kidney disease (CKD). It has been investigated the use of probiotics in the reduction of uremic toxins intestinal production. Objective: The aim of this pilot study was to evaluate the effect of probiotic supplementation on reducing the production of uremic toxins and the inflammatory profile of CKD patients. Methods: We performed a randomized, blind, placebo-controlled, crossover study on patients with CKD stages 3 and 4. The intervention was a probiotic formulation composed of Lactobacillus acidophilus strains given orally three times a day for 3 months. Changes in uremic toxins (p-Cresylsulfate and Indoxyl Sulfate) and serum inflammatory cytokines were the primary endpoints. Results: Of the 44 patients randomized, 25 completed the study (mean age 51 ± 9.34, 64% female, mean eGFR 36 ± 14.26 mL/min/1.73m², mean BMI 28.5 ± 5.75 kg/m²). At 3 months, there were no significant changes in any of the studied biomarkers including p-cresylsulfate (p = 0.57), Indoxyl sulfate (p = 0.08) and interleukin-6 (p = 0.55). Conclusion: Lactobacillus acidophilus strains given as probiotic were not able to reduce serum levels of uremic toxins and biomarkers of inflammation in CKD patients in stage 3 and 4.

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Positive correlation of serum indoxyl sulfate level with peripheral arterial disease in hemodialysis patients

Vascular ◽

10.1177/17085381211039941 ◽

2021 ◽

pp. 170853812110399

Author(s):

Liang-Te Chiu ◽

Lin Lin ◽

Huei-Jhen Lin ◽

Yu-Hsien Lai ◽

Bang-Gee Hsu

Keyword(s):

Peripheral Arterial Disease ◽

Ankle Brachial Index ◽

Serum Levels ◽

Arterial Disease ◽

Indoxyl Sulfate ◽

Maintenance Hemodialysis ◽

C Reactive Protein ◽

Reactive Protein ◽

Index Group ◽

Peripheral Arterial

Objectives Indoxyl sulfate, known for its cardiovascular toxicity, is associated with vascular and coronary artery diseases and increased mortality. Peripheral arterial disease, defined by low ankle–brachial index, is associated with increased mortality in patients on hemodialysis. The present study aimed to determine the relationship between the serum indoxyl sulfate level and peripheral arterial disease in patients on maintenance hemodialysis. Methods The present cross-sectional, single-center study included 75 patients on maintenance hemodialysis. Serum indoxyl sulfate levels were determined by high-performance liquid chromatography–mass spectrometry. Ankle–brachial index values were measured using an automated oscillometric device. Patients with ankle–brachial indexes of < 0.9 were categorized into the low ankle–brachial index group. Results In the study cohort, 12 of the 75 patients (16.0%) had low ankle–brachial indexes. The rates of diabetes mellitus ( p = 0.010) as well as the serum levels of C-reactive protein ( p < 0.001) and indoxyl sulfate ( p < 0.001) were higher in the low ankle–brachial index group than the normal ankle–brachial index group. The multivariable logistic regression analysis revealed that serum levels of indoxyl sulfate (odds ratio = 1.123, 95% confidence interval 1.011–1.249, p = 0.031) and C-reactive protein (each 0.1 mg/dL increase, odds ratio = 1.169, 95% confidence interval 1.018–1.343, p = 0.027) were independently associated with peripheral arterial disease in patients on maintenance hemodialysis. Conclusions Serum indoxyl sulfate levels were associated with peripheral arterial disease in patients on maintenance hemodialysis.

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The uremic toxin indoxyl sulfate reflects cardio-renal risk and intestinal-renal relationship

Orvosi Hetilap ◽

10.1556/oh.2011.29223 ◽

2011 ◽

Vol 152 (43) ◽

pp. 1724-1730 ◽

Cited By ~ 2

Author(s):

István Kiss

Keyword(s):

Renal Failure ◽

Chronic Renal Failure ◽

Uremic Toxins ◽

Indoxyl Sulfate ◽

Morbidity And Mortality ◽

Renal Diseases ◽

Uremic Toxin ◽

Cardiovascular Risks ◽

Endogenous Protein ◽

Uremic Syndrome

Uremic syndrome and condition is primarily a result of kidney failure in which uremic toxins are accumulated. More and more attention is paid to possibilities for removal of uremic toxins, which not only means dialysis, but also takes into account special dietary considerations and treatments, which aim to absorb the toxins or reduce their production. These uremic toxins, which also increase the cardiovascular risks, play a major part in morbidity and mortality of patients suffering from chronic renal failure and those receiving renal replacement therapy. One of them is a member of the indol group, the indoxyl sulfate. This toxin is difficult to remove with dialysis and is an endogenous protein-bound uremic toxin. Today we know that indoxyl sulfate is a vascular-nephrotoxic agent, which is able to enhance progression of cardiovascular and renal diseases. It is of particular importance that because of its redox potency, this toxin causes oxidative stress and antioxidant effects at the same time and, on top of that, it is formed in the intestinal system. Its serum concentration depends on the nutrition and the tubular function and, therefore, it can also signal the progression of chronic renal failure independently of glomerular filtration rate. Successful removal of indoxyl sulfate reduces the morbidity and mortality and improves survival. Therefore, it could be a possible target or area to facilitate the reduction of uremia in chronic renal failure. The use of probiotics and prebiotics with oral adsorbents may prove to be a promising opportunity to reduce indoxyl sulfate accumulation. Orv. Hetil., 2011, 152, 1724–1730.

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P-Cresylsulfate, the Protein-Bound Uremic Toxin, Increased Endothelial Permeability Partly Mediated by Src-Induced Phosphorylation of VE-Cadherin

Toxins ◽

10.3390/toxins12020062 ◽

2020 ◽

Vol 12 (2) ◽

pp. 62 ◽

Cited By ~ 2

Author(s):

Shih-Chieh Chen ◽

Shin-Yin Huang ◽

Chia-Chun Wu ◽

Chiung-Fang Hsu

Keyword(s):

Umbilical Vein ◽

Endothelial Permeability ◽

Serum Levels ◽

Uremic Toxins ◽

Endothelial Barrier ◽

Uremic Toxin ◽

Barrier Dysfunction ◽

Endothelial Barrier Dysfunction ◽

Endothelial Gaps ◽

The Impact

The goal of our study was to investigate the impact of p-cresylsulfate (PCS) on the barrier integrity in human umbilical vein endothelial cell (HUVEC) monolayers and the renal artery of chronic kidney disease (CKD) patients. We measured changes in the transendothelial electrical resistance (TEER) of HUVEC monolayers treated with PCS (0.1–0.2 mM) similar to serum levels of CKD patients. A PCS dose (0.2 mM) significantly decreased TEER over a 48-h period. Both PCS doses (0.1 and 0.2 mM) significantly decreased TEER over a 72-h period. Inter-endothelial gaps were observed in HUVECs following 48 h of PCS treatment by immunofluorescence microscopy. We also determined whether PCS induced the phosphorylation of VE-cadherin at tyrosine 658 (Y658) mediated by the phosphorylation of Src. Phosphorylated VE-cadherin (Y658) and phosphorylated Src levels were significantly higher when the cells were treated with 0.1 and 0.2 mM PCS, respectively, compared to the controls. The endothelial barrier dysfunction in the arterial intima in CKD patients was evaluated by endothelial leakage of immunoglobulin G (IgG). Increased endothelial leakage of IgG was related to the declining kidney function in CKD patients. Increased endothelial permeability induced by uremic toxins, including PCS, suggests that uremic toxins induce endothelial barrier dysfunction in CKD patients and Src-mediated phosphorylation of VE-cadherin is involved in increased endothelial permeability induced by PCS exposure.

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Effect of dietary synbiotic supplementation on serum indoxyl sulfate in prevalent hemodialysis patients

The Egyptian Journal of Internal Medicine ◽

10.1186/s43162-021-00096-3 ◽

2022 ◽

Vol 34 (1) ◽

Author(s):

Mohamed Saeed Hassan ◽

Yasser Soliman Ahmed ◽

Eman Ibrahim Sarhaan ◽

Nayra Shaker Mehanna ◽

Norhan Nagdy Madbouli ◽

...

Keyword(s):

Controlled Trial ◽

Intestinal Flora ◽

Serum Levels ◽

Indoxyl Sulfate ◽

University Hospital ◽

Blood Levels ◽

Uremic Toxin ◽

Cardiovascular Morbidity And Mortality ◽

Group 2 ◽

Group 1

Abstract Background Indoxyl sulfate (IS) is produced by action of the intestinal flora on tryptophan in protein diet, and it is normally excreted by the kidney. IS is a protein-bound uremic toxin, and it is difficult to be removed by conventional hemodialysis (HD) methods; so, it accumulates in HD patients and may contribute to major cardiovascular morbidity and mortality. Aim To study the effect of dietary synbiotic (prebiotic and probiotic) supplementation on IS level in prevalent HD patients. Patients and methods This single-blind, placebo-controlled trial was conducted on 80 prevalent HD patients (between January 2017 and March 2017) in Ain Shams University Hospital. Patients were divided into 2 groups: group 1 was given synbiotic (SYN) and group 2 was given placebo for 6 weeks. Blood levels of IS, CRP, creatinine, blood urea nitrogen (BUN), sodium, potassium, calcium, and phosphorus were measured at baseline and after 6 weeks. Results There was a significant reduction in serum IS level in groups 1 and 2 in comparison to their baselines (P value = 0.000 and 0.019 respectively); however, the change in IS level in group 1 after SYN supplementation (64% with IR 72.38–33.33) was more than that shown in group 2 (did not receive SYN) (18.47% with IR 26.75–26.75) with a highly significant P value, 0.000. Also, there were significant reductions in the levels of creatinine, BUN, phosphorus (P values < 0.001), and CRP (P values 0.002) in group 1 respectively with no similar changes noticed in group 2. Conclusion SYN supplementation in HD patients can reduce serum levels of IS and other uremic toxins like BUN and creatinine. Also, it may help to reduce serum phosphorus and CRP levels.

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Indoxyl sulfate has a dominant role regarding the risks during different stages of chronic kidney disease

10.21203/rs.3.rs-41393/v1 ◽

2020 ◽

Author(s):

Cheng-Hsu Chen ◽

Shih-Chien Huang ◽

Pei-Chih Lin ◽

Shang-Feng Tsai ◽

Yi-Chia Huang

Keyword(s):

Chronic Kidney Disease ◽

Renal Function ◽

Kidney Disease ◽

Dominant Role ◽

Plasma Homocysteine ◽

Uremic Toxins ◽

Indoxyl Sulfate ◽

Antioxidant Enzyme Activities ◽

Uremic Toxin ◽

Ckd Stage

Abstract Background: Increased levels of uremic toxins and decreased antioxidant capacities have a significant impact on the progression of chronic kidney disease (CKD). However, it is unclear whether they interact with each other in order to mediate the damage of renal function. The purpose of this study was to determine whether uremic toxins [i.e., homocysteine and indoxyl sulfate (IS)] and glutathione-dependent antioxidant enzyme activities are dependently or independently associated with each other in affecting renal function during different stages of CKD patients.Methods: One hundred thirty-two patients diagnosed with CKD stage 1 to 5 participated in this cross-sectional study.Results: Patients who had reached an advanced CKD stage experienced a gradual increase in plasma uremic toxin levels, along with decreased glutathione peroxidase (GSH-Px) activities. Plasma homocysteine, cysteine and IS concentrations were positively associated with each other, but negatively correlated to GSH-Px activity levels after adjusting potential confounders in all CKD patients. Although plasma homocysteine, cysteine, IS and GSH-Px levels were significantly associated with renal function, only plasma IS levels still had a significant association with renal function after these parameters were simultaneously adjusted.Conclusions: IS plays a more dominant role than other factors in affecting renal function, where a higher IS concentration needs to be controlled in order to defer the progressive loss of renal function.

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P1112COMPARISON OF EFFICACY BETWEEN MAINTENANCE HEMODIALYSIS AND THEIR COMBINATION WITH HEMOPERFUSION IN PATIENTS UNDERGOING CHRONIC HEMODIALYSIS TREATMENT

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p1112 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Amela Beciragic ◽

Alma Mutevelic-Turkovic ◽

Badema Äœengiä† Roljiä† ◽

Fahrudin Masnic ◽

Aida Coric ◽

...

Keyword(s):

Statistical Difference ◽

Combined Treatment ◽

Serum Levels ◽

Uremic Toxins ◽

Maintenance Hemodialysis ◽

Significant Difference ◽

Group 3 ◽

Group 2 ◽

Group 1

Abstract Background and Aims The occurance of mid- and longterm uremic complications is related to the low clearance rate of middle and large molecule uremic toxins when hemodialysis (HD) alone is adopted. As the uremic toxins and their corresponding biological effects become increasingly clear, blood purification treatment that aims to remove these toxins, has developed from a stage of life-sustaining to improving the quality of life. The objective of this study was to evaluated demographic, clinical and laboratory data in patients who underwent the combination of maintenance hemodialysis with hemoperfusion (HP) and in those who recieved HD alone and to investigate whether this combination could improve the clearance rate of middle and large molecule uremic toxins. Method A total of 26 patients, who underwent routine hemodialysis, were assessed in this study. Those patients were randomly divided into three groups: Group 1 (7 patients) received combined treatment of HD with HP biweekly (HD 2 times a week with HD+HP once a week), whereas Group 2 (10 patients) was given HD with high flux dialyzer and Group 3 (9 patients) was given HD with low flux dialyzer 3 times a week. This study was followed for 4 months. Before and after the observational period demographic and clinical data were taken from the medical history and blood samples were taken for hemoglobin (Hb), iron (Fe), total iron binding capacity (TIBC), albumin (Alb), calcium (Ca), phosphorus (P04) and parathyroid hormone (PTH). Results This study included 13 female and 13 male patients with a mean age of 41, 62 + 11.12 and a mean dialysis duration of 62, 78+53, 33 months. When it comes to baseline characteristics, patients of the group 3 were significantly older than patients in other groups (p=0.001). At the end of the four months observation period, the same difference according to age was noticed (p=0.01). Also, HD+HP group had significantly higher values of TIBC (p=0.006) and significantly lower serum levels of P04 (p=0.001). EPO doses were very similar in group 1 and 2, but in group 3 there were noticeably lower than in those two groups but without a significant difference. The serum levels of albumin were higher in group 3 compared to the other two groups but also without statistical difference. No statistical difference between groups after the follow up period was observed in terms of Hb, Fe, PTH, Ca, BMI, duration of dialysis treatment and vascular access. When groups are viewed individually, in the HD+HP group serum P04 levels were significantly lower after the 4 months off the follow up period than it was at the beginning (p=0.031) and also TIBC was significantly higher (p=0.018). In group 2 the values of TIBC were significantly lower after the follow up period than it was at the beginning (p=0.025). No significant difference was noticed in group 3 but serum PTH levels tends to decrease after 4 months compared to baseline measurement. Conclusion This combination treatment of HD with HP was superior to HD in reducing levels of phosphorus. These findings suggests a potential role of reducing the risk of cardiovascular events in this population especially when it is known that hyperphosphatemia has been pointed out as the primary culprit in the process of cardiovascular calcification. Also, patients who underwent the combined treatment showed higher values of TIBC but unfortunately no difference was noticed between Hb levels and EPO doses. These results eventually demonstrates their role in the improvement of renal disease anemia, which opens up the possibility of further research on a larger sample and over a longer period of time.

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Efficacy of Divinylbenzenic Resin in Removing Indoxyl Sulfate and P-cresol Sulfate in Hemodialysis Patients: Results from an In Vitro Study and an In Vivo Pilot Trial (xuanro4-Nature 3.2)

Toxins ◽

10.3390/toxins12030170 ◽

2020 ◽

Vol 12 (3) ◽

pp. 170

Author(s):

Maria Teresa Rocchetti ◽

Carmela Cosola ◽

Ighli di Bari ◽

Stefania Magnani ◽

Vanessa Galleggiante ◽

...

Keyword(s):

Plasma Levels ◽

Pilot Trial ◽

In Vitro Study ◽

Serum Levels ◽

Cardiovascular Complications ◽

High Serum ◽

Uremic Toxins ◽

Indoxyl Sulfate

High serum levels of microbiota-derived uremic toxins, indoxyl sulfate (IS) and p-cresyl sulfate (PCS), are associated with chronic kidney disease (CKD) progression and cardiovascular complications. IS and PCS cannot be efficiently removed by conventional hemodialysis (HD), due to their high binding affinity for albumin. This study evaluates the efficacy of a divinylbenzene-polyvinylpyrrolidone (DVB-PVP) cartridge and a synbiotic to reduce uremic toxins in HD patients. First, the in vitro efficacy of DVB-PVP in adsorbing IS and PCS was evaluated. Second, a randomized, placebo-controlled pilot study in HD patients was carried out to establish whether the administration of a synbiotic, either individually and in association with DVB-PVP-HD, could reduce the production of uremic toxins. In vitro data showed that DVB-PVP resin removed a mean of 56% PCS and around 54% IS, after 6 h of perfusion. While, in the in vivo study, the DVB-PVP cartridge showed its adsorbing efficacy only for IS plasma levels. The combination of synbiotic treatment with DVB-PVP HD decreased IS and PCS both at pre- and post-dialysis levels. In conclusion, this study provides the first line of evidence on the synergistic action of gut microbiota modulation and an innovative absorption-based approach in HD patients, aimed at reducing plasma levels of IS and PCS.

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