P1392ANALYSIS OF CALCIFYING POTENTIAL OF UREMIC SERUM FROM HAEMODIALYSIS PATIENTS TREATED WITH A MEDIUM CUT-OFF (THERANOVA) DIALYSER: A PROSPECTIVE, CROSS-OVER STUDY

Abstract Background and Aims The retention of a large number of solutes that are normally excreted or metabolized by the kidney is responsible for the classical symptoms of haemodialysis (HD) patients. These molecules are defined as uremic toxins and can be classified into three groups: small water-soluble molecules, middle molecules and protein-bound toxins. Recently, efforts were put in order to develop dialysis membranes that allow the removal of large-middle molecules without clinically relevant albumin loss. These dialysers are the medium cut-off (MCO) membranes, which allow the removal of middle molecules up to approximately 50,000 Da. We performed a prospective, open-label, controlled, cross-over pilot study comparing expanded HD (HDx) with MCO membrane Theranova and conventional HD in 20 patients. Method Ten patients underwent conventional HD high-flux dialyser and 10 patients underwent HDx for 3 months, later the patients switched and received the other treatment for a further 3 months. We then analyzed the pro-calcifying effect of patient uremic serum in a model of high-phosphate (Pi) induced calcification in vascular smooth muscle cells (VSMCs). Results In this study each patient was the control of himself and, interestingly, we found a tendency of less pro-calcifying potential of serum from patients when treated with HDx, in comparison with HD (6.6±1.1, 5.6±0.6 and 6.7±1.0, OD/mg protein, baseline HD, 0-3 HDx and 3-6 HD, months, respectively; and 4.7±0.7 vs 3.2±0.2, OD/mg protein, 0-3 HD vs 3-6 HDx, months, respectively) (Figure). Investigating the major mechanisms involved in high-Pi induced calcium deposition, we found that serum from patients when treated with HDx induced less necrosis in VSMCs, compared with HD (3.2±0.8 vs. 0.9±0.1, necrosis enrichment factor, 0-3 HD vs. 3-6 HDx, months, respectively). Nevertheless, no differences were found between the different dialysis treatment in the serum potential to induce apoptosis and to modulate the expression of a panel of genes involved in VSMC osteoblastic-differentiation such as BMP2, RUNX2, osteocalcin, MGP, OPN, and elastin. In the effort to characterize the difference in uremic toxin profile during the two different dialysis treatments, we measured a panel of protein-bound uremic toxins which have been shown to promote vascular calcification and /or bone loss and shown a significant increased removal by HDx of 3-indoxyl sulfate (30.6±13.2 vs -17.1±10.2 Δ%; 0-3 HD vs 3-6 HDx, months; p<0.05; and -21.1±11.4 vs 54.4±33.2 Δ%; 0-3 HDx vs 3-6 HD, months; p<0.05), indole 3-acetic acid (43.1±16.9 vs -2.3±10.9 Δ%; 0-3 HD vs 3-6 HDx, months; p<0.05), CMPF (61.8±27.6 vs -16.1±9.6 Δ%; 0-3 HD vs 3-6 HDx, months; p<0.05), and kynurenine (44.2±12.9 vs -0.2±6.8 Δ%; 0-3 HD vs 3-6 HDx, months; p<0.05). Conclusion These preliminary data suggest a role for HDx in reducing the calcifying potential of uremic serum. Our findings are promising and they need to be confirmed in larger studies.

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Pro-calcifying analysis of uraemic serum from patients treated with medium cut-off membrane in a prospective, cross-over study

Clinical Kidney Journal ◽

10.1093/ckj/sfaa216 ◽

2020 ◽

Author(s):

Paola Ciceri ◽

Giorgia Tettamanti ◽

Andrea Galassi ◽

Lorenza Magagnoli ◽

Nicolas Fabresse ◽

...

Keyword(s):

Osteoblastic Differentiation ◽

Water Soluble ◽

Matrix Gla Protein ◽

Bone Morphogenetic Protein 2 ◽

Calcium Deposition ◽

Open Label ◽

Small Water ◽

Middle Molecules ◽

Related Transcription Factor ◽

The Difference

Abstract Background The retention of a large number of solutes that are normally excreted or metabolized by the kidney is responsible for the symptoms typical in uraemic patients. These molecules are defined as uraemic toxins and can be classified into three groups: small water-soluble molecules, middle molecules and protein-bound toxins. Recently, efforts were put towards developing dialysis membranes that allow the removal of large middle molecules without clinically relevant albumin loss. These membranes are the medium cut-off (MCO) membranes that allow the removal of middle molecules up to ∼50 000 Da. Methods We performed a prospective, open-label, controlled, cross-over pilot study comparing expanded haemodialysis (HDx) (novel MCO membrane Theranova 400) and conventional haemodialysis (HD) in 20 prevalent HD patients. Ten patients used conventional HD high-flux dialyser and 10 patients used HDx for 3 months; later the patients switched and received the other treatment for a further 3 months. We then analysed the pro-calcifying effect of uraemic serum in a model of high phosphate(Pi)–induced calcification in vascular smooth muscle cells (VSMCs). Results In this study, every patient was the control of himself and, interestingly, we found a tendency of less pro-calcifying potential from HDx-treated patients’ serum compared with HD. Studying pathogenetic processes involved in high Pi–induced calcium deposition, we found that uraemic serum of HDx-treated patients induced less VSMC necrosis compared with uraemic serum of HD patients. Nevertheless, no differences were found between the different dialytic treatments in the serum potential to induce apoptosis and to modulate the expression of a panel of genes involved in VSMC simil-osteoblastic differentiation such as bone morphogenetic protein 2, runt-related transcription factor 2, osteocalcin, matrix Gla protein, osteopontin, elastin and collagen I α1. In an effort to characterize the difference in uraemic toxin profile during the two different dialytic treatments, we measured a panel of 10 uraemic toxins and 3 precursors, finding a significant increased removal during HDx of 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid, tryptophane and some of its metabolites, such as 3-indoxyl sulphate, indole 3-acetic acid and kynurenine. Conclusions These preliminary data are promising, although larger patients’ groups are needed to better understand the effects of HDx on vascular calcification.

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Protein-bound toxins: has the Cinderella of uraemic toxins turned into a princess?

Clinical Science ◽

10.1042/cs20160393 ◽

2016 ◽

Vol 130 (23) ◽

pp. 2209-2216 ◽

Cited By ~ 6

Author(s):

Sophie Liabeuf ◽

Cédric Villain ◽

Ziad A. Massy

Keyword(s):

Kidney Disease ◽

Public Health Problem ◽

Neurological Complications ◽

Water Soluble ◽

Global Public Health ◽

Bone Disorders ◽

Small Water ◽

Middle Molecules ◽

Cv Disease ◽

Stage Renal Disease

Chronic kidney disease (CKD) has emerged as a global public health problem. Although the incidence and prevalence of CKD vary from one country to another, the estimated worldwide prevalence is 8–16%. The complications associated with CKD include progression to end-stage renal disease (ESRD), mineral and bone disorders, anaemia, cognitive decline and elevated all-cause and cardiovascular (CV) mortality. As a result of progressive nephron loss, patients with late-stage CKD are permanently exposed to uraemic toxins. These toxins have been classified into three groups as a function of the molecular mass: small water-soluble molecules, middle molecules and protein-bound uraemic toxins. The compounds can also be classified according to their origin (i.e. microbial or not) or their protein-binding ability. The present review will focus on the best-characterized protein-bound uraemic toxins, namely indoxylsulfate (IS), indole acetic acid (IAA) and p-cresylsulfate (PCS, a cresol metabolite). Recent research suggests that these toxins accelerate the progression of CV disease, kidney disease, bone disorders and neurological complications. Lastly, we review therapeutic approaches that can be used to decrease toxin levels.

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Uremic Patients with Increased Vascular Calcification Score Have Serum with High Calcific Potential: Role of Vascular Smooth Muscle Cell Osteoblastic Differentiation and Apoptosis

Blood Purification ◽

10.1159/000497229 ◽

2019 ◽

Vol 48 (2) ◽

pp. 142-149 ◽

Cited By ~ 5

Author(s):

Paola Ciceri ◽

Andrea Galassi ◽

Carlo Alfieri ◽

Piergiorgio Messa ◽

Mario Cozzolino

Keyword(s):

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Vascular Calcification ◽

Osteoblastic Differentiation ◽

Calcium Deposition ◽

Calcification Score ◽

Uremic Serum ◽

Uremic Patients ◽

Apoptosis And Necrosis

Background/Aims: Uremic patients experience premature vascular ageing that causes cardiovascular morbidity. In this study, we investigated the relationship between uremic serum calcific potential induced by high phosphate (Pi) and vascular calcification score (VCS). Methods: Vascular smooth muscle cells (VSMCs) were cultured with 3.5 mM Na3PO4 (Pi) with 10% uremic serum and calcium deposition, markers of osteoblastic transformation, and apoptosis were evaluated. Results: Culture with uremic serum and high-Pi significantly induced calcification (0.21 ± 0.03 vs. 8.05 ± 0.6; ctr vs. Pi; OD/mg protein; p < 0.01). We next stratified patients with respect of the degree of VCS in 2 groups: absence of vascular calcification (VC) “no VC group” and presence of VC “VC group”. We found that there was a significant correlation between VCS and uremic serum calcific potential induced by high Pi in vitro (p < 0.01). Interestingly, uremic sera of the “VC group” were more effective than sera from the “no VC group”, in downregulating α-actin and SM22α, after treatment with high-Pi (41.3 ± 4.7 vs. 23.3 ± 2.9 and 25.6 ± 6.8 vs. 8.14 ± 2.3; VC vs. no VC group, α-actin and SM22α respectively; Δ intensity area; p < 0.01). Similarly, sera from “VC group” were more effective than sera from “no VC group” in adjuvanting the high-Pi effect of increasing osteoblastic markers, such as bone morphogenic protein 2 (BMP2), osteocalcin (OC), and runt-related transcription factor 2 (RUNX2; 39.1 ± 11.3 vs. 5.0 ± 2.6 BMP2; 12.2 ± 4.2 vs. 1.7 ± 0.3 OC; 2.9 ± 0.4 vs. 1.2 ± 0.2 RUNX2; VC vs. no VC group respectively; p < 0.05). We found a similar pattern with significantly higher apoptosis and necrosis induction by sera from the “VC group” compared to the “no VC group” (2.05 ± 0.33 vs. 1.29 ± 0.13 and 54.1 ± 19.5 vs. 27.4 ± 10.6; Pi; VC group vs. no VC group; enrichment factor of apoptotic or necrotic fragments, respectively; p < 0.05). Conclusions: We conclude that VCS of end-stage renal disease patients significantly correlates with serum-calcific potential induced by high Pi. In addition, uremic patients with higher VCS have sera with a higher potential to induce VSMC osteoblastic trans-differentiation, apoptosis, and necrosis.

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Uremic Toxins and their Relation to Dialysis Efficacy

Blood Purification ◽

10.1159/000502331 ◽

2019 ◽

Vol 48 (4) ◽

pp. 299-314 ◽

Cited By ~ 8

Author(s):

William R. Clark ◽

Nader Laal Dehghani ◽

Vivek Narsimhan ◽

Claudio Ronco

Keyword(s):

Molecular Weight ◽

Water Solubility ◽

Evidence Base ◽

Uremic Toxins ◽

Water Soluble ◽

Renal Elimination ◽

Low Molecular Weight ◽

Middle Molecules ◽

Stage Renal Disease ◽

End Stage

Toxin retention is felt to be a major contributor to the development of uremia in patients with advanced chronic kidney disease and end-stage renal disease (ESRD). Uremic retention compounds are classically divided into 3 categories: small solutes, middle molecules, and protein-bound toxins. Compounds comprising the first category, for which the upper molecular weight limit is generally considered to be 500 Da, possess a high degree of water solubility and minimal or absent protein binding. The second category of middle molecules has largely evolved now to be synonymous with peptides and proteins that accumulate in uremia. Although not precisely defined, low-molecular weight proteins as a class have a molecular weight spectrum ranging from approximately 500 to 60,000 daltons. The final category of uremic retention compounds is protein-bound uremic toxins (PBUTs). As opposed to the above small, highly water-soluble toxins, which are largely by-products of protein metabolism, PBUTs have diverse origins and possess chemical characteristics that preclude the possibility of circulation in an unbound form despite being of low molecular weight. This review is the first in a series of papers designed to provide the current state of the art for extracorporeal treatment of ESRD. Subsequent papers in this series will address membranes, mass transfer mechanisms, and future directions. For small solutes and middle molecules, particular emphasis is placed on the important clinical trials that comprise the evidence base regarding the influence of dialytic solute removal on outcome. Because such trials do not exist for PBUTs, the discussion here is instead focused on solute characteristics and renal elimination mechanisms.

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Randomised controlled trial of the impact of haemodiafiltration on uraemic neuropathy: FINESSE study protocol

BMJ Open ◽

10.1136/bmjopen-2018-023736 ◽

2019 ◽

Vol 9 (1) ◽

pp. e023736

Author(s):

Brendan Smyth ◽

Arun V Krishnan ◽

Martin Gallagher ◽

Matthew Kiernan ◽

Paul Snelling ◽

...

Keyword(s):

Controlled Trial ◽

Randomised Trial ◽

Cumulative Exposure ◽

Open Label ◽

Middle Molecules ◽

Show Evidence ◽

The Difference ◽

Randomised Controlled ◽

End Stage ◽

The Impact

IntroductionThe majority of patients undergoing haemodialysis (HD) show evidence of uraemic neuropathy, a condition with no known disease-modifying treatments. The pathogenesis of uraemic neuropathy is poorly understood, but may be related to cumulative exposure to middle molecules or other solutes such as potassium. It is not known whether haemodiafiltration (HDF) reduces the progression of uraemic neuropathy.Methods and analysisFiltration In the Neuropathy of End-Stage kidney disease Symptom Evolution (FINESSE) is a multicentre, randomised, open-label, blinded endpoint assessment, controlled trial designed to assess the impact of HDF versus HD on uraemic neuropathy. Maintenance HD patients will be randomised in a 1:1 ratio to receive HDF or HD with high-flux membranes for 4 years. The primary endpoint is the difference in the mean change in Total Neuropathy Score (TNS)—a measure of peripheral neuropathy combining symptoms, signs and nerve conduction velocity—over the study period. Secondary outcomes include change at annual timepoints in the TNS and the Neuropathy Symptom Score; and in morbidity, mortality and safety events.Ethics and disseminationThe FINESSE trial has been approved by the Ethics Review Committee of the Sydney South West Area Health Service (HREC/09/RPAH/268) and of Adventist HealthCare Limited (2012–027). When published in a peer-reviewed journal, it will be the largest and longest reported randomised trial aimed at reducing the incidence and severity of uraemic neuropathy. It will advance the understanding of the natural history of uraemic neuropathy and the influence of convective therapies on both neurophysiological and clinical outcomes. It will also allow refinement of current hypotheses surrounding the pathogenesis of uraemic neuropathy and, most importantly, may lead to improvements in the lives of the many patients affected by this debilitating condition.Trial registration numberACTRN12609000615280.

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Removal of Protein-Bound Uremic Toxins by Liposome-Supported Peritoneal Dialysis

Peritoneal Dialysis International ◽

10.3747/pdi.2018.00229 ◽

2019 ◽

Vol 39 (6) ◽

pp. 509-518

Author(s):

Yuanyuan Shi ◽

Huajun Tian ◽

Yifeng Wang ◽

Yue Shen ◽

Qiuyu Zhu ◽

...

Keyword(s):

Peritoneal Dialysis ◽

Uremic Toxins ◽

Water Soluble ◽

Sprague Dawley ◽

Promising Alternative ◽

Small Water ◽

Artificial Plasma ◽

End Stage

Background Protein-bound uremic toxins (PBUTs) are poorly cleared by peritoneal dialysis (PD). This study aimed to enhance PBUT removal in PD by adding a binder to the peritoneal dialysate and to evaluate the feasibility and efficacy of liposome-supported PD (LSPD) to increase the removal of PBUTs compared with albumin PD. Methods Removal of p-cresyl sulfate (PCS), indoxyl sulfate (IS), and indole-3-acetic acid (3-IAA) was first evaluated in an in vitro PD model using artificial plasma preloaded with test solutes. Male Sprague-Dawley rats ( n = 24) were then subjected to 5/6 nephrectomy and fed for 16 weeks to establish end-stage renal failure, after which they were treated with either conventional glucose-based PD, albumin-based PD, or liposome-based PD. Removal of PBUTs and small water-soluble solutes was determined during a 6-hour PD dwell. Results In vitro experiments showed that adding albumin as a toxin binder to the dialysate markedly increased the removal of PCS, IS, and 3-IAA compared with the control. The uptake capacity of liposomes was comparable with that of albumin for PCS and 3-IAA, though slightly inferior for IS. In vivo PD in uremic rats demonstrated that LSPD resulted in higher intraperitoneal concentrations and more total mass removal for PBUTs than the conventional glucose-based PD, which was comparable with albumin PD. Conclusions Supplementing conventional glucose-based PD solutions with a binder could efficiently increase the removal of PBUTs. This preliminary study suggested that LSPD may be a promising alternative to albumin PD for increasing PBUT removal in the development of next-generation PD solutions for PD patients.

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Impact of Uremic Toxins on Endothelial Dysfunction in Chronic Kidney Disease: A Systematic Review

International Journal of Molecular Sciences ◽

10.3390/ijms23010531 ◽

2022 ◽

Vol 23 (1) ◽

pp. 531

Author(s):

Eva Harlacher ◽

Julia Wollenhaupt ◽

Constance C. F. M. J. Baaten ◽

Heidi Noels

Keyword(s):

Systematic Review ◽

Chronic Kidney Disease ◽

Endothelial Dysfunction ◽

Kidney Disease ◽

Molecular Mechanisms ◽

Uremic Toxins ◽

Uremic Toxin ◽

Thrombotic Risk ◽

Increased Risk ◽

Uremic Serum

Patients with chronic kidney disease (CKD) are at a highly increased risk of cardiovascular complications, with increased vascular inflammation, accelerated atherogenesis and enhanced thrombotic risk. Considering the central role of the endothelium in protecting from atherogenesis and thrombosis, as well as its cardioprotective role in regulating vasorelaxation, this study aimed to systematically integrate literature on CKD-associated endothelial dysfunction, including the underlying molecular mechanisms, into a comprehensive overview. Therefore, we conducted a systematic review of literature describing uremic serum or uremic toxin-induced vascular dysfunction with a special focus on the endothelium. This revealed 39 studies analyzing the effects of uremic serum or the uremic toxins indoxyl sulfate, cyanate, modified LDL, the advanced glycation end products N-carboxymethyl-lysine and N-carboxyethyl-lysine, p-cresol and p-cresyl sulfate, phosphate, uric acid and asymmetric dimethylarginine. Most studies described an increase in inflammation, oxidative stress, leukocyte migration and adhesion, cell death and a thrombotic phenotype upon uremic conditions or uremic toxin treatment of endothelial cells. Cellular signaling pathways that were frequently activated included the ROS, MAPK/NF-κB, the Aryl-Hydrocarbon-Receptor and RAGE pathways. Overall, this review provides detailed insights into pathophysiological and molecular mechanisms underlying endothelial dysfunction in CKD. Targeting these pathways may provide new therapeutic strategies reducing increased the cardiovascular risk in CKD.

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MO455LIPID PROFILE AND UREMIC RETENTION SOLUTES IN PATIENTS WITH END-STAGE KIDNEY DISEASE

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfab090.0017 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

Sam Hobson ◽

Jetty De Loor ◽

Karolina Kublickiene ◽

Pieter Evenepoel ◽

Peter Stenvinkel ◽

...

Keyword(s):

Amino Acids ◽

Kidney Disease ◽

Lipid Profile ◽

Density Lipoprotein ◽

Hdl Cholesterol ◽

Uremic Toxins ◽

Water Soluble ◽

Protein Energy Wasting ◽

Small Water ◽

Remnant Cholesterol

Abstract Background and Aims Patients with end-stage kidney disease (ESKD) have an extremely high incidence of cardiovascular (CV) diseases, partly driven by insufficient clearance of uremic toxins. ESKD patients have a characteristically adverse lipid profile, however data investigating the relationship between uremic toxins and lipid profile, potentially contributing to increased CV risk, is scarce. To determine if uremic retention solutes (URS) associate with an adverse lipid profile in ESKD, we studied a large, trinational cohort with a detailed lipid profile, as well as a comprehensive panel of uremic toxins. Method Total, high density lipoprotein (HDL), non-HDL, low density lipoprotein (LDL), and remnant cholesterol, as well as triglyceride, levels were associated with a panel of 15 uremic retention solutes in a combined cohort of 591 European, adult patients with advanced chronic kidney disease (CKD) from UZ Leuven, Belgium (n=150), Karolinska Hospital, Stockholm, Sweden (n=235) or University of Leipzig Medical Center, Leipzig, Germany (n=226). Total and HDL cholesterol, as well as triglycerides, were quantified at each study center, whereas non-HDL cholesterol, LDL cholesterol, and remnant cholesterol were calculated. In all subjects of this trinational study, a selected panel of solutes, including CMPF, TMAO, aromatic amino acids and corresponding end-products of endogenous and microbial metabolism, was centrally quantified in a single lab by liquid chromatography - tandem mass spectrometry. Univariate correlations were assessed using non-parametric Spearman’s rank correlation method. To identify independent associations between solutes and lipid profile, multivariate linear regression models were used with adjustment for age, sex, as well as markers of inflammation, protein energy wasting, renal function, diabetes and dialysis. Results In total, 189 patients in CKD stage 3-5 not on renal replacement therapy (RRT), as well as 402 subjects on RRT, were included. All URS except phenylalanine significantly differed between patients on RRT vs. not on RTT. In univariate analyses, URS negatively correlated with most lipid markers, including LDL and HDL cholesterol. In contrast, the amino acids tryptophan, phenylalanine, and tyrosine were positively correlated with a large majority of lipid markers. After combining URS concentrations based on molecule size, similar associations were observed for the respective groups, i.e. small water-soluble molecules, protein-bound molecules, and amino acids. After adjustment for age, sex, presence of diabetes, dialysis treatment, inflammation, protein energy wasting, and renal function, significant associations were lost for URS and total cholesterol or HDL cholesterol, excluding total cholesterol and phenylacetyl glutamine. However, high triglyceride levels were independently predicted by p-cresyl sulphate, tryptophan, indole-3 acetic acid, phenylalanine, TMAO, small water-soluble molecules combined, and protein-bound molecules combined. Non-HDL cholesterol was independently predicted by phenyl glucuronide, TMAO, phenylacetyl glutamine and small water-soluble molecules combined, while remnant cholesterol was independently associated with 10 out of the 15 URS, as well as small water-soluble molecules combined and amino acids combined. Furthermore, LDL cholesterol independently associated with tryptophan, TMAO, phenylacetyl glutamine and protein-bound molecules combined. Conclusion Significant inverse associations between lipid profile and small water-soluble or protein-bound uremic toxins in advanced CKD highlight the complexity of the uremic environment. Our data suggest that not all URS interactions with conventional CV risk markers may be pathogenic.

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Optical Method and Biochemical Source for the Assessment of the Middle-Molecule Uremic Toxin β2-Microglobulin in Spent Dialysate

Toxins ◽

10.3390/toxins13040255 ◽

2021 ◽

Vol 13 (4) ◽

pp. 255

Author(s):

Joosep Paats ◽

Annika Adoberg ◽

Jürgen Arund ◽

Ivo Fridolin ◽

Kai Lauri ◽

...

Keyword(s):

Optical Method ◽

Optical Signal ◽

Uremic Toxins ◽

Water Soluble ◽

Uremic Toxin ◽

Small Peptides ◽

Entire Cohort ◽

Β2 Microglobulin ◽

Spent Dialysate ◽

End Stage

Optical monitoring of spent dialysate has been used to estimate the removal of water-soluble low molecular weight as well as protein-bound uremic toxins from the blood of end stage kidney disease (ESKD) patients. The aim of this work was to develop an optical method to estimate the removal of β2-microglobulin (β2M), a marker of middle molecule (MM) uremic toxins, during hemodialysis (HD) treatment. Ultraviolet (UV) and fluorescence spectra of dialysate samples were recorded from 88 dialysis sessions of 22 ESKD patients, receiving four different settings of dialysis treatments. Stepwise regression was used to obtain the best model for the assessment of β2M concentration in the spent dialysate. The correlation coefficient 0.958 and an accuracy of 0.000 ± 0.304 mg/L was achieved between laboratory and optically estimated β2M concentrations in spent dialysate for the entire cohort. Optically and laboratory estimated reduction ratio (RR) and total removed solute (TRS) of β2M were not statistically different (p > 0.35). Dialytic elimination of MM uremic toxin β2M can be followed optically during dialysis treatment of ESKD patients. The main contributors to the optical signal of the MM fraction in the spent dialysate were provisionally identified as tryptophan (Trp) in small peptides and proteins, and advanced glycation end-products.

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Uremic Toxins in the Progression of Chronic Kidney Disease and Cardiovascular Disease: Mechanisms and Therapeutic Targets

Toxins ◽

10.3390/toxins13020142 ◽

2021 ◽

Vol 13 (2) ◽

pp. 142

Author(s):

Yong Jin Lim ◽

Nicole A. Sidor ◽

Nicholas C. Tonial ◽

Adrian Che ◽

Bradley L. Urquhart

Keyword(s):

Cardiovascular Disease ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Therapeutic Targets ◽

Free Water ◽

Uremic Toxins ◽

Water Soluble ◽

Therapeutic Interventions ◽

Increased Risk ◽

Middle Molecules

Chronic kidney disease (CKD) is a progressive loss of renal function. The gradual decline in kidney function leads to an accumulation of toxins normally cleared by the kidneys, resulting in uremia. Uremic toxins are classified into three categories: free water-soluble low-molecular-weight solutes, protein-bound solutes, and middle molecules. CKD patients have increased risk of developing cardiovascular disease (CVD), due to an assortment of CKD-specific risk factors. The accumulation of uremic toxins in the circulation and in tissues is associated with the progression of CKD and its co-morbidities, including CVD. Although numerous uremic toxins have been identified to date and many of them are believed to play a role in the progression of CKD and CVD, very few toxins have been extensively studied. The pathophysiological mechanisms of uremic toxins must be investigated further for a better understanding of their roles in disease progression and to develop therapeutic interventions against uremic toxicity. This review discusses the renal and cardiovascular toxicity of uremic toxins indoxyl sulfate, p-cresyl sulfate, hippuric acid, TMAO, ADMA, TNF-α, and IL-6. A focus is also placed on potential therapeutic targets against uremic toxicity.

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