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Zhou F, Li H. The association between serum Beta-2 microglobulin and cardiovascular disease in postmenopausal women. Int J Cardiol 2025; 433:133324. [PMID: 40294802 DOI: 10.1016/j.ijcard.2025.133324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2024] [Revised: 04/01/2025] [Accepted: 04/24/2025] [Indexed: 04/30/2025]
Abstract
BACKGROUND Despite evidence indicating that postmenopausal women are at a higher risk of cardiovascular diseases (CVD) than premenopausal women and men, research on monitoring and preventing CVD in this demographic remains incomplete. METHODS Using publicly available 1999-2004 National Health and Nutrition Examination Survey (NHANES) data, serum beta-2-microglobulin (β-2 M) was initially assessed by stratifying it into quartiles. We examined the relationship of β-2 M and other common cardiovascular predictors to CVD using ROC curves. A stratified approach was employed for multifactor weighted logistic regression analyses, followed by sensitivity analyses using propensity score matching and multiple imputation. RESULTS In postmenopausal women, β-2 M was positively and statistically significantly associated with cardiovascular disease (p < 0.05). ROC curves showed that the area under the curve (AUC) for β-2 M was higher than that of other common predictors of cardiovascular disease(p < 0.05). Although second only to N-terminal brain natriuretic peptide (NT-proBNP), there was no significant difference in the predictive efficacy of these two markers (p > 0.05). Subgroup analyses revealed that β-2 M was significantly correlated with an increasing risk of CVD in postmenopausal women with higher education (more than high school), poverty income ratio (PIR) of 1.30-3.50, BMI ≥30.0, and hypertension (p < 0.05). After further adjustment of model 2, sensitivity analyses yielded consistent results, maintaining statistical significance (p < 0.05). CONCLUSIONS In postmenopausal women, β-2 M is strongly associated with CVD, even within specific subgroups. Additionally, β-2 M is a potent indicator of CVD. Further prospective studies are needed to validate these findings in the future.
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Affiliation(s)
- Feng Zhou
- First Clinical College, Hubei University of Chinese Medicine, Wuhan 430000, Hubei Province, China
| | - Hao Li
- Huangjiahu Hospital, Hubei University of Chinese Medicine, Wuhan 430000, Hubei Province, China.
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2
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Jin YX, Zhang S, Xiao J, Wang ZH, Dong C, You LL, Kuai TT, Zhang Y, Liu SX. Association between serum β 2-microglobulin levels and the risk of all-cause and cardiovascular disease mortality in chinese patients undergoing maintenance hemodialysis. BMC Nephrol 2023; 24:170. [PMID: 37312042 DOI: 10.1186/s12882-023-03191-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Accepted: 04/28/2023] [Indexed: 06/15/2023] Open
Abstract
BACKGROUND The association between serum β2-microglobulin (β2M) levels and the risk of all-cause and cardiovascular disease (CVD) mortality and the incidence of cardiovascular events (CVEs) in patients undergoing maintenance hemodialysis (MHD) is inconclusive. Furthermore, no study has been performed in China on the significance of serum β2M levels in MHD patients. Therefore, this study investigated the aforementioned association in MHD patients. METHODS In this prospective cohort study, 521 MHD patients were followed at Dalian Municipal Central Hospital affiliated with Dalian University of Technology from December 2019 to December 2021. The serum β2M levels were categorized into three tertiles, and the lowest tertile served as the reference group. Survival curves were calculated by the Kaplan-Meier method. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazard models. Sensitivity analysis was performed by excluding patients with CVD at baseline. RESULTS During the follow-up period of 21.4 ± 6.3 months, there were 106 all-cause deaths, of which 68 were caused by CVD. When excluding CVD patients at baseline, there were 66 incident CVEs. Kaplan-Meier analysis revealed that the risk of all-cause and CVD mortality in the highest tertile of serum β2M levels was significantly higher than that in the lowest tertile (P < 0.05), but not for the CVEs (P > 0.05). After adjusting for potential confounders, serum β2M levels were positively associated with the risk of all-cause (HR = 2.24, 95% CI = 1.21-4.17) and CVD (HR = 2.54, 95% CI = 1.19-5.43) mortality, and a linear trend was evident (P < 0.05). Besides, the results of sensitivity analysis were consistent with the main findings. However, we didn't observed the significant association between serum β2M levels and CVEs (P > 0.05). CONCLUSION The serum β2M level may be a significant predictor of the risk of all-cause and CVD mortality in MHD patients. Further studies are needed to confirm this finding.
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Affiliation(s)
- Yu-Xin Jin
- Graduate School, Dalian Medical University, Dalian, China
- Dalian Key Laboratory of Intelligent Blood Purifcation, Dalian Municipal Central Hospital affiliated with Dalian University of Technology, Dalian, China
- Department of Nephrology, Dalian Municipal Central Hospital affiliated with Dalian University of Technology, No.826, Xinan Road Dalian, 116033, Liaoning, P. R. China
| | - Shuang Zhang
- Dalian Key Laboratory of Intelligent Blood Purifcation, Dalian Municipal Central Hospital affiliated with Dalian University of Technology, Dalian, China
- Department of Nephrology, Dalian Municipal Central Hospital affiliated with Dalian University of Technology, No.826, Xinan Road Dalian, 116033, Liaoning, P. R. China
| | - Jia Xiao
- Dalian Key Laboratory of Intelligent Blood Purifcation, Dalian Municipal Central Hospital affiliated with Dalian University of Technology, Dalian, China
- Department of Nephrology, Dalian Municipal Central Hospital affiliated with Dalian University of Technology, No.826, Xinan Road Dalian, 116033, Liaoning, P. R. China
| | - Zhi-Hong Wang
- Dalian Key Laboratory of Intelligent Blood Purifcation, Dalian Municipal Central Hospital affiliated with Dalian University of Technology, Dalian, China
- Department of Nephrology, Dalian Municipal Central Hospital affiliated with Dalian University of Technology, No.826, Xinan Road Dalian, 116033, Liaoning, P. R. China
| | - Cui Dong
- Dalian Key Laboratory of Intelligent Blood Purifcation, Dalian Municipal Central Hospital affiliated with Dalian University of Technology, Dalian, China
- Department of Nephrology, Dalian Municipal Central Hospital affiliated with Dalian University of Technology, No.826, Xinan Road Dalian, 116033, Liaoning, P. R. China
| | - Lian-Lian You
- Dalian Key Laboratory of Intelligent Blood Purifcation, Dalian Municipal Central Hospital affiliated with Dalian University of Technology, Dalian, China
- Department of Nephrology, Dalian Municipal Central Hospital affiliated with Dalian University of Technology, No.826, Xinan Road Dalian, 116033, Liaoning, P. R. China
| | - Ting-Ting Kuai
- Dalian Key Laboratory of Intelligent Blood Purifcation, Dalian Municipal Central Hospital affiliated with Dalian University of Technology, Dalian, China
- Department of Nephrology, Dalian Municipal Central Hospital affiliated with Dalian University of Technology, No.826, Xinan Road Dalian, 116033, Liaoning, P. R. China
| | - Yu Zhang
- Dalian Key Laboratory of Intelligent Blood Purifcation, Dalian Municipal Central Hospital affiliated with Dalian University of Technology, Dalian, China
- Department of Nephrology, Dalian Municipal Central Hospital affiliated with Dalian University of Technology, No.826, Xinan Road Dalian, 116033, Liaoning, P. R. China
| | - Shu-Xin Liu
- Dalian Key Laboratory of Intelligent Blood Purifcation, Dalian Municipal Central Hospital affiliated with Dalian University of Technology, Dalian, China.
- Department of Nephrology, Dalian Municipal Central Hospital affiliated with Dalian University of Technology, No.826, Xinan Road Dalian, 116033, Liaoning, P. R. China.
- School of Clinical Medicine, Faculty of Medicine, Dalian University of Technology, Dalian, China.
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Dehghan Niestanak V, Unsworth LD. Detailing Protein-Bound Uremic Toxin Interaction Mechanisms with Human Serum Albumin in the Pursuit of Designing Competitive Binders. Int J Mol Sci 2023; 24:ijms24087452. [PMID: 37108613 PMCID: PMC10139063 DOI: 10.3390/ijms24087452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Revised: 04/12/2023] [Accepted: 04/15/2023] [Indexed: 04/29/2023] Open
Abstract
Chronic kidney disease is the gradual progression of kidney dysfunction and involves numerous co-morbidities, one of the leading causes of mortality. One of the primary complications of kidney dysfunction is the accumulation of toxins in the bloodstream, particularly protein-bound uremic toxins (PBUTs), which have a high affinity for plasma proteins. The buildup of PBUTs in the blood reduces the effectiveness of conventional treatments, such as hemodialysis. Moreover, PBUTs can bind to blood plasma proteins, such as human serum albumin, alter their conformational structure, block binding sites for other valuable endogenous or exogenous substances, and exacerbate the co-existing medical conditions associated with kidney disease. The inadequacy of hemodialysis in clearing PBUTs underscores the significance of researching the binding mechanisms of these toxins with blood proteins, with a critical analysis of the methods used to obtain this information. Here, we gathered the available data on the binding of indoxyl sulfate, p-cresyl sulfate, indole 3-acetic acid, hippuric acid, 3-carboxyl-4-methyl-5-propyl-2-furan propanoic acid, and phenylacetic acid to human serum albumin and reviewed the common techniques used to investigate the thermodynamics and structure of the PBUT-albumin interaction. These findings can be critical in investigating molecules that can displace toxins on HSA and improve their clearance by standard dialysis or designing adsorbents with greater affinity for PBUTs than HSA.
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Affiliation(s)
- Vida Dehghan Niestanak
- Department of Biomedical Engineering, University of Alberta, Edmonton, AB T6G 2G4, Canada
| | - Larry D Unsworth
- Department of Chemical and Materials Engineering, University of Alberta, Edmonton, AB T6G 1H9, Canada
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Solignac J, Lacroix R, Arnaud L, Abdili E, Bouchouareb D, Burtey S, Brunet P, Dignat-George F, Robert T. Rheopheresis Performed in Hemodialysis Patients Targets Endothelium and Has an Acute Anti-Inflammatory Effect. J Clin Med 2022; 12:105. [PMID: 36614906 PMCID: PMC9821709 DOI: 10.3390/jcm12010105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 11/29/2022] [Accepted: 12/20/2022] [Indexed: 12/24/2022] Open
Abstract
Background: Rheopheresis is a double-filtration plasmapheresis that removes a defined spectrum of high-molecular-weight proteins to lower plasma viscosity and improves microcirculation disorders. This technique can be performed in hemodialysis (HD) patients with severe microischemia. Interestingly, some studies showed that rheopheresis sessions improve endothelial function. Methods: Our study evaluated the inflammatory and endothelial biomarker evolution in 23 HD patients treated or not with rheopheresis. A p value ≤ 0.001 was considered statistically significant. Results: Thirteen HD patients treated by rheopheresis either for a severe peripheral arterial disease (N = 8) or calciphylaxis (N = 5) were analyzed. Ten control HD patients were also included in order to avoid any misinterpretation of the rheopheresis effects in regard to the HD circuit. In the HD group without rheopheresis, the circulating endothelial adhesion molecules, cytokines, angiogenic factor concentrations, and circulating levels were not modified. In the HD group with rheopheresis, the circulating endothelial adhesion molecules (sVCAM-1, sP-selectin, and sE-selectin) experienced a significant reduction, except sICAM-1. Among the pro-inflammatory cytokines, TNF-α was significantly reduced by 32.6% [(−42.2)−(−22.5)] (p < 0.0001), while the anti-inflammatory cytokine IL-10 increased by 674% (306−1299) (p < 0.0001). Among the angiogenic factors, only sEndoglin experienced a significant reduction. The CEC level trended to increase from 13 (3−33) cells/mL to 43 (8−140) cells/mL (p = 0.002). We did not observe any difference on the pre-session values of the molecules of interest between the first rheopheresis session and the last rheopheresis session. Conclusion: Rheopheresis immediately modified the inflammation balance and the endothelial injury biomarkers. Further studies are needed to understand the mechanisms underlying these biological observations.
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Affiliation(s)
- Justine Solignac
- Centre de Néphrologie et de Transplantation Rénale, Hôpital de la Conception, Assistance Publique-Hôpitaux de Marseille, 13005 Marseille, France
- Center for CardioVascular and Nutrition Research (C2VN), Faculty of Medical and Paramedical Sciences, Aix-Marseille University, National Institute of Health and Medical Research (INSERM), National Research Institute for Agriculture, Food and Environment (INRAE), 13005 Marseille, France
| | - Romaric Lacroix
- Center for CardioVascular and Nutrition Research (C2VN), Faculty of Medical and Paramedical Sciences, Aix-Marseille University, National Institute of Health and Medical Research (INSERM), National Research Institute for Agriculture, Food and Environment (INRAE), 13005 Marseille, France
- Laboratoire de Biologie, Hôpital de la Timone, Assistance Publique-Hôpitaux de Marseille, 13005 Marseille, France
| | - Laurent Arnaud
- Laboratoire de Biologie, Hôpital de la Timone, Assistance Publique-Hôpitaux de Marseille, 13005 Marseille, France
| | - Evelyne Abdili
- Laboratoire de Biologie, Hôpital de la Timone, Assistance Publique-Hôpitaux de Marseille, 13005 Marseille, France
| | - Dammar Bouchouareb
- Centre de Néphrologie et de Transplantation Rénale, Hôpital de la Conception, Assistance Publique-Hôpitaux de Marseille, 13005 Marseille, France
| | - Stéphane Burtey
- Centre de Néphrologie et de Transplantation Rénale, Hôpital de la Conception, Assistance Publique-Hôpitaux de Marseille, 13005 Marseille, France
- Center for CardioVascular and Nutrition Research (C2VN), Faculty of Medical and Paramedical Sciences, Aix-Marseille University, National Institute of Health and Medical Research (INSERM), National Research Institute for Agriculture, Food and Environment (INRAE), 13005 Marseille, France
| | - Philippe Brunet
- Centre de Néphrologie et de Transplantation Rénale, Hôpital de la Conception, Assistance Publique-Hôpitaux de Marseille, 13005 Marseille, France
- Center for CardioVascular and Nutrition Research (C2VN), Faculty of Medical and Paramedical Sciences, Aix-Marseille University, National Institute of Health and Medical Research (INSERM), National Research Institute for Agriculture, Food and Environment (INRAE), 13005 Marseille, France
| | - Françoise Dignat-George
- Center for CardioVascular and Nutrition Research (C2VN), Faculty of Medical and Paramedical Sciences, Aix-Marseille University, National Institute of Health and Medical Research (INSERM), National Research Institute for Agriculture, Food and Environment (INRAE), 13005 Marseille, France
- Laboratoire de Biologie, Hôpital de la Timone, Assistance Publique-Hôpitaux de Marseille, 13005 Marseille, France
| | - Thomas Robert
- Centre de Néphrologie et de Transplantation Rénale, Hôpital de la Conception, Assistance Publique-Hôpitaux de Marseille, 13005 Marseille, France
- Center for CardioVascular and Nutrition Research (C2VN), Faculty of Medical and Paramedical Sciences, Aix-Marseille University, National Institute of Health and Medical Research (INSERM), National Research Institute for Agriculture, Food and Environment (INRAE), 13005 Marseille, France
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The Role of Gut-Derived, Protein-Bound Uremic Toxins in the Cardiovascular Complications of Acute Kidney Injury. Toxins (Basel) 2022; 14:toxins14050336. [PMID: 35622583 PMCID: PMC9143532 DOI: 10.3390/toxins14050336] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 05/04/2022] [Accepted: 05/07/2022] [Indexed: 02/04/2023] Open
Abstract
Acute kidney injury (AKI) is a frequent disease encountered in the hospital, with a higher incidence in intensive care units. Despite progress in renal replacement therapy, AKI is still associated with early and late complications, especially cardiovascular events and mortality. The role of gut-derived protein-bound uremic toxins (PBUTs) in vascular and cardiac dysfunction has been extensively studied during chronic kidney disease (CKD), in particular, that of indoxyl sulfate (IS), para-cresyl sulfate (PCS), and indole-3-acetic acid (IAA), resulting in both experimental and clinical evidence. PBUTs, which accumulate when the excretory function of the kidneys is impaired, have a deleterious effect on and cause damage to cardiovascular tissues. However, the link between PBUTs and the cardiovascular complications of AKI and the pathophysiological mechanisms potentially involved are unclear. This review aims to summarize available data concerning the participation of PBUTs in the early and late cardiovascular complications of AKI.
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El Chamieh C, Liabeuf S, Massy Z. Uremic Toxins and Cardiovascular Risk in Chronic Kidney Disease: What Have We Learned Recently beyond the Past Findings? Toxins (Basel) 2022; 14:280. [PMID: 35448889 PMCID: PMC9028122 DOI: 10.3390/toxins14040280] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2022] [Revised: 04/10/2022] [Accepted: 04/11/2022] [Indexed: 12/13/2022] Open
Abstract
Patients with chronic kidney disease (CKD) have an elevated prevalence of atheromatous (ATH) and/or non-atheromatous (non-ATH) cardiovascular disease (CVD) due to an array of CKD-related risk factors, such as uremic toxins (UTs). Indeed, UTs have a major role in the emergence of a spectrum of CVDs, which constitute the leading cause of death in patients with end-stage renal disease. The European Uremic Toxin Work Group has identified over 100 UTs, more than 25 of which are dietary or gut-derived. Even though relationships between UTs and CVDs have been described in the literature, there are few reviews on the involvement of the most toxic compounds and the corresponding physiopathologic mechanisms. Here, we review the scientific literature on the dietary and gut-derived UTs with the greatest toxicity in vitro and in vivo. A better understanding of these toxins' roles in the elevated prevalence of CVDs among CKD patients might facilitate the development of targeted treatments. Hence, we review (i) ATH and non-ATH CVDs and the respective levels of risk in patients with CKD and (ii) the mechanisms that underlie the influence of dietary and gut-derived UTs on CVDs.
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Affiliation(s)
- Carolla El Chamieh
- Center for Research in Epidemiology and Population Health (CESP), Paris-Saclay University, Versailles-Saint-Quentin-en-Yvelines University (UVSQ), INSERM UMRS 1018, F-94807 Villejuif, France;
| | - Sophie Liabeuf
- Pharmacology Department, Amiens University Hospital, F-80000 Amiens, France
- MP3CV Laboratory, EA7517, Jules Verne University of Picardie, F-80000 Amiens, France
| | - Ziad Massy
- Nephrology Department, Ambroise Paré University Hospital, APHP, F-92100 Paris, France
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Shao G, Himmelfarb J, Hinds BJ. Strategies for optimizing urea removal to enable portable kidney dialysis: A reappraisal. Artif Organs 2022; 46:997-1011. [PMID: 35383963 DOI: 10.1111/aor.14185] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 12/23/2021] [Accepted: 01/10/2022] [Indexed: 12/01/2022]
Abstract
BACKGROUND Portable hemodialysis has the potential to improve health outcomes and quality of life for patients with kidney failure at reduced costs. Urea removal, required for dialysate regeneration, is a central function of any existing/potential portable dialysis device. Urea in the spent dialysate coexists with non-urea uremic toxins, nutrients, and electrolytes, all of which will interfere with the urea removal efficiency, regardless of whether the underlying urea removal mechanism is based on urease conversion, direct urea adsorption, or oxidation. The aim of the current review is to identify the amount of the most prevalent chemicals being removed during a single dialysis session and evaluate the potential benefits of an urea-selective membrane for portable dialysis. METHODS We have performed a literature search using Web of Science and PubMed databases to find available articles reporting (or be able to calculate from blood plasma concentration) > 5 mg of individually quantified solutes removed during thrice-weekly hemodialysis sessions. If multiple reports of the same solute were available, the reported values were averaged, and the geometric mean of standard deviations was taken. Further critical literature analysis of reported dialysate regeneration methods was performed using Web of Science and PubMed databases. RESULTS On average, 46.0 g uremic retention solutes are removed in a single conventional dialysis session, out of which urea is only 23.6 g. For both urease- and sorbent-based urea removal mechanisms, amino acids, with 7.7 g removal per session, could potentially interfere with urea removal efficiency. Additionally for the oxidation-based urea removal system, plentiful nutrients such as glucose (24.0 g) will interfere with urea removal by competition. Using a nanofiltration membrane between dialysate and oxidation unit with a molecular weight cutoff (MWCO) of ~200 Da, 67.6 g of non-electrolyte species will be removed in a single dialysis session, out of which 44.0 g are non-urea molecules. If the membrane MWCO is further decreased to 120 Da, the mass of non-electrolyte non-urea species will drop to 9.3 g. Reverse osmosis membranes have been shown to be both effective at blocking the transport of non-urea species (creatinine for example with ~90% rejection ratio), and permissive for urea transport (~20% rejection ratio), making them a promising urea selective membrane to increase the efficiency of the oxidative urea removal system. CONCLUSIONS Compiled are quantified solute removal amounts greater than 5 mg per session during conventional hemodialysis treatments, to act as a guide for portable dialysis system design. Analysis shows that multiple chemical species in the dialysate interfere with all proposed portable urea removal systems. This suggests the need for an additional protective dialysate loop coupled to urea removal system and an urea-selective membrane.
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Affiliation(s)
- Guozheng Shao
- Department of Materials Science & Engineering, University of Washington, Seattle, Washington, USA.,Center for Dialysis Innovation, University of Washington, Seattle, Washington, USA
| | - Jonathan Himmelfarb
- Center for Dialysis Innovation, University of Washington, Seattle, Washington, USA.,Division of Nephrology, Department of Medicine, University of Washington, Seattle, Washington, USA
| | - Bruce J Hinds
- Department of Materials Science & Engineering, University of Washington, Seattle, Washington, USA.,Center for Dialysis Innovation, University of Washington, Seattle, Washington, USA
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"The quantitative determination of indolic microbial tryptophan metabolites in human and rodent samples: A systematic review". J Chromatogr B Analyt Technol Biomed Life Sci 2021; 1186:123008. [PMID: 34735972 DOI: 10.1016/j.jchromb.2021.123008] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Accepted: 10/18/2021] [Indexed: 02/08/2023]
Abstract
Concentrations reported for indolic microbial metabolites of tryptophan in human and rodent brain, cerebrospinal fluid, plasma, saliva and feces were compiled and discussed. A systematic review of the literature was accomplished by key word searches of Pubmed, Google Scholar and the Human Metabolome Data Base (HMDB), and by searching bibliographies of identified publications including prior reviews. The review was prompted by the increasing appreciation of the physiological importance of the indolic compounds in human health and disease. The compounds included were indoleacetic acid (IAA), indole propionic acid (IPA), indoleacrylic acid (IACR), indolelactic acid (ILA) indolepyruvic acid (IPY), indoleacetaldehyde (IAALD), indolealdehyde (IALD), tryptamine (TAM), indole (IND) and skatole (SKT). The undertaking aimed to vet and compare existing reports, to resolve apparent discrepancies, to draw biological inferences from the consideration of multiple analytes across sample types, to survey the analytical methodologies used, and to point out areas in need of greater attention.
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Zhang J, Lu X, Zu Y, Li H, Wang S. Prognostic value of beta-2 microglobulin on mortality in chronic kidney disease patients: A systematic review and meta-analysis. Ther Apher Dial 2021; 26:267-274. [PMID: 34459115 DOI: 10.1111/1744-9987.13729] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 06/04/2021] [Accepted: 08/26/2021] [Indexed: 12/30/2022]
Abstract
The aim of this study was to delve into whether beta-2 microglobulin could assess all-cause mortality in patients with chronic kidney disease. PubMed and Embase were systematically searched. Hazard risk and 95% CI were pooled using random-effect models. A total of eight studies were involved according to the inclusion and exclusion criterions. By meta-analysis, each 1 mg/L increase in beta-2 microglobulin displayed positive relationships to the risk of all-cause mortality (hazard risk 1.03, 95% CI = 1.02-1.03) and cardiovascular events (hazard risk 1.04, 95% CI = 1.00-1.08) in patients with dialysis. However, the relationship between elevated level of serum beta-2 microglobulin as a categorical variable and mortality was not significant. The prognostic value of elevated beta-2 microglobulin might be significant in ESRD patients with dialysis and a proper cutoff value to predict mortality should be determined in the future.
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Affiliation(s)
- Jialing Zhang
- Department of Blood Purification, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Xiangxue Lu
- Department of Blood Purification, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Yuan Zu
- Department of Blood Purification, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Han Li
- Department of Blood Purification, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Shixiang Wang
- Department of Blood Purification, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
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10
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Mo Y, Jie X, Wang L, Ji C, Gu Y, Lu Z, Liu X. Bupi Yishen formula attenuates kidney injury in 5/6 nephrectomized rats via the tryptophan-kynurenic acid-aryl hydrocarbon receptor pathway. BMC Complement Med Ther 2021; 21:207. [PMID: 34376166 PMCID: PMC8353787 DOI: 10.1186/s12906-021-03376-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2020] [Accepted: 07/06/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Bupi Yishen Formula (BYF), a patent traditional Chinese medicine (TCM) formulation, has been used in the clinical treatment of chronic kidney disease (CKD). However, the mechanism of action of BYF has not been fully elucidated. METHOD To investigate the variation in the metabolic profile in response to BYF treatment in a rat model of 5/6 nephrectomy (Nx), rats in the treatment groups received low- or high-dose BYF. At the end of the study, serum and kidney samples were collected for biochemical, pathological, and western blotting analysis. Metabolic changes in serum were analyzed by liquid chromatography-tandem mass spectrometry. RESULTS The results showed that BYF treatment could reduce kidney injury, inhibit inflammation and improve renal function in a dose-dependent manner. In total, 405 and 195 metabolites were identified in negative and positive ion modes, respectively. Metabolic pathway enrichment analysis of differential metabolites based on the Kyoto Encyclopedia of Genes and Genomes database identified 35 metabolic pathways, 3 of which were related to tryptophan metabolism. High-dose BYF reduced the level of kynurenic acid (KA) by more than 50%, while increasing melatonin 25-fold and indole-3-acetic acid twofold. Expression levels of aryl hydrocarbon receptor (AhR), Cyp1A1, and CyP1B1 were significantly reduced in the kidney tissue of rats with high-dose BYF, compared to 5/6 Nx rats. CONCLUSION BYF has a reno-protective effect against 5/6 Nx-induced CKD, which may be mediated via inhibition of the tryptophan-KA-AhR pathway.
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Affiliation(s)
- Yenan Mo
- The Second Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, 520120, China
| | - Xina Jie
- The Second Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, 520120, China
| | - Lixin Wang
- Nephrology Department, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, 520120, China
| | - Chunlan Ji
- The Second Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, 520120, China
| | - Yueyu Gu
- Nephrology Department, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, 520120, China
| | - Zhaoyu Lu
- The Second Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, 520120, China. .,Nephrology Department, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, 520120, China.
| | - Xusheng Liu
- Nephrology Department, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, 520120, China.
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11
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Chaves LD, Abyad S, Honan AM, Bryniarski MA, McSkimming DI, Stahura CM, Wells SC, Ruszaj DM, Morris ME, Quigg RJ, Yacoub R. Unconjugated p-cresol activates macrophage macropinocytosis leading to increased LDL uptake. JCI Insight 2021; 6:144410. [PMID: 33914709 PMCID: PMC8262368 DOI: 10.1172/jci.insight.144410] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Accepted: 04/28/2021] [Indexed: 01/03/2023] Open
Abstract
Patients with chronic kidney disease (CKD) and end-stage renal disease suffer from increased cardiovascular events and cardiac mortality. Prior studies have demonstrated that a portion of this enhanced risk can be attributed to the accumulation of microbiota-derived toxic metabolites, with most studies focusing on the sulfonated form of p-cresol (PCS). However, unconjugated p-cresol (uPC) itself was never assessed due to rapid and extensive first-pass metabolism that results in negligible serum concentrations of uPC. These reports thus failed to consider the host exposure to uPC prior to hepatic metabolism. In the current study, not only did we measure the effect of altering the intestinal microbiota on lipid accumulation in coronary arteries, but we also examined macrophage lipid uptake and handling pathways in response to uPC. We found that atherosclerosis-prone mice fed a high-fat diet exhibited significantly higher coronary artery lipid deposits upon receiving fecal material from CKD mice. Furthermore, treatment with uPC increased total cholesterol, triglycerides, and hepatic and aortic fatty deposits in non-CKD mice. Studies employing an in vitro macrophage model demonstrated that uPC exposure increased apoptosis whereas PCS did not. Additionally, uPC exhibited higher potency than PCS to stimulate LDL uptake and only uPC induced endocytosis- and pinocytosis-related genes. Pharmacological inhibition of varying cholesterol influx and efflux systems indicated that uPC increased macrophage LDL uptake by activating macropinocytosis. Overall, these findings indicate that uPC itself had a distinct effect on macrophage biology that might have contributed to increased cardiovascular risk in patients with CKD.
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Affiliation(s)
- Lee D Chaves
- Department of Medicine, Division of Nephrology, Jacobs School of Medicine and Biomedical Sciences, and.,Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, USA
| | - Sham Abyad
- Department of Medicine, Division of Nephrology, Jacobs School of Medicine and Biomedical Sciences, and
| | - Amanda M Honan
- Department of Medicine, Division of Nephrology, Jacobs School of Medicine and Biomedical Sciences, and
| | - Mark A Bryniarski
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, USA
| | - Daniel I McSkimming
- Department of Medicine, Bioinformatics and Computational Biology Core, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA
| | - Corrine M Stahura
- Department of Medicine, Division of Nephrology, Jacobs School of Medicine and Biomedical Sciences, and
| | - Steven C Wells
- Department of Medicine, Division of Nephrology, Jacobs School of Medicine and Biomedical Sciences, and
| | - Donna M Ruszaj
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, USA
| | - Marilyn E Morris
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, USA
| | - Richard J Quigg
- Department of Medicine, Division of Nephrology, Jacobs School of Medicine and Biomedical Sciences, and
| | - Rabi Yacoub
- Department of Medicine, Division of Nephrology, Jacobs School of Medicine and Biomedical Sciences, and
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12
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Targeting Uremic Toxins to Prevent Peripheral Vascular Complications in Chronic Kidney Disease. Toxins (Basel) 2020; 12:toxins12120808. [PMID: 33419312 PMCID: PMC7765928 DOI: 10.3390/toxins12120808] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 12/14/2020] [Accepted: 12/16/2020] [Indexed: 12/24/2022] Open
Abstract
Chronic kidney disease (CKD) exhibits progressive kidney dysfunction and leads to disturbed homeostasis, including accumulation of uremic toxins, activated renin-angiotensin system, and increased oxidative stress and proinflammatory cytokines. Patients with CKD are prone to developing the peripheral vascular disease (PVD), leading to poorer outcomes than those without CKD. Cumulative evidence has showed that the synergy of uremic milieu and PVD could exaggerate vascular complications such as limb ischemia, amputation, stenosis, or thrombosis of a dialysis vascular access, and increase mortality risk. The role of uremic toxins in the pathogenesis of vascular dysfunction in CKD has been investigated. Moreover, growing evidence has shown the promising role of uremic toxins as a therapeutic target for PVD in CKD. This review focused on uremic toxins in the pathophysiology, in vitro and animal models, and current novel clinical approaches in reducing the uremic toxin to prevent peripheral vascular complications in CKD patients.
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13
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Lin TY, Chou HH, Huang HL, Hung SC. Indoxyl Sulfate and Incident Peripheral Artery Disease in Hemodialysis Patients. Toxins (Basel) 2020; 12:toxins12110696. [PMID: 33147880 PMCID: PMC7693838 DOI: 10.3390/toxins12110696] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 10/28/2020] [Accepted: 10/31/2020] [Indexed: 11/17/2022] Open
Abstract
Peripheral artery disease (PAD) is highly prevalent among patients with chronic kidney disease (CKD) and portends a very poor prognosis. Indoxyl sulfate has been shown to induce atherothrombosis and impaired neovascularization in uremic mice. However, there is no clinical evidence regarding the role of indoxyl sulfate in PAD associated with CKD. We examined associations between indoxyl sulfate and incident symptomatic lower extremity PAD events as well as major adverse cardiovascular events (MACE) and all-cause mortality using Cox proportional hazards models in a prospective cohort of 200 hemodialysis patients free of PAD at baseline. Patients were considered as having PAD if they developed PAD symptoms confirmed by an ankle-brachial index with waveforms, duplex ultrasound or angiography, and/or major adverse limb events including revascularization and amputation. During a median follow-up of 6.5 years, 37 patients (18.5%) experienced incident symptomatic PAD. MACE occurred in 52 patients, and a total of 85 patients died. After adjusting for traditional risk factors for PAD, including age, current smoking, diabetes, and cardiovascular disease, indoxyl sulfate was significantly associated with the risk of PAD (hazard ratio (HR), 1.19 for every 10-μg/mL increase in indoxyl sulfate; 95% confidence interval (CI), 1.05–1.35). However, indoxyl sulfate was not associated with risk of MACE (HR, 1.00; 95% CI, 0.90–1.12) or death from any cause (HR, 0.98; 95% CI, 0.90–1.07). Indoxyl sulfate was associated with incident symptomatic PAD but not with MACE or all-cause mortality, suggesting that indoxyl sulfate toxicity may be unique to PAD among hemodialysis patients.
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Affiliation(s)
- Ting-Yun Lin
- Division of Nephrology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, and School of Medicine, Tzu Chi University, Hualien 970, Taiwan;
| | - Hsin-Hua Chou
- Division of Cardiology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, and School of Medicine, Tzu Chi University, Hualien 970, Taiwan;
| | - Hsuan-Li Huang
- Division of Cardiology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, and School of Medicine, Tzu Chi University, Hualien 970, Taiwan;
- Correspondence: (H.-L.H.); (S.-C.H.); Tel.: +886-2-6628-9779 (H.-L.H. & S.-C.H.)
| | - Szu-Chun Hung
- Division of Nephrology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, and School of Medicine, Tzu Chi University, Hualien 970, Taiwan;
- Correspondence: (H.-L.H.); (S.-C.H.); Tel.: +886-2-6628-9779 (H.-L.H. & S.-C.H.)
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14
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Molecular Mechanisms Underlying the Cardiovascular Toxicity of Specific Uremic Solutes. Cells 2020; 9:cells9092024. [PMID: 32887404 PMCID: PMC7565564 DOI: 10.3390/cells9092024] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 08/21/2020] [Accepted: 08/27/2020] [Indexed: 02/07/2023] Open
Abstract
Mounting evidence strongly suggests a causal link between chronic kidney disease (CKD) and cardiovascular disease (CVD). Compared with non-CKD patients, patients with CKD suffer disproportionately from CVD and derive suboptimal benefits from interventions targeting conventional CVD risk factors. Uremic toxins (UTs), whose plasma levels rapidly rise as CKD progresses, represent a unique risk factor in CKD, which has protean manifestations on CVD. Among the known UTs, tryptophan metabolites and trimethylamine N-oxide are well-established cardiovascular toxins. Their molecular mechanisms of effect warrant special consideration to draw translational value. This review surveys current knowledge on the effects of specific UTs on different pathways and cell functions that influence the integrity of cardiovascular health, with implication for CVD progression. The effect of UTs on cardiovascular health is an example of a paradigm in which a cascade of molecular and metabolic events induced by pathology in one organ in turn induces dysfunction in another organ. Deciphering the molecular mechanisms underlying such cross-organ pathologies will help uncover therapeutic targets to improve the management of CVD in patients with CKD.
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15
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Mehta A, Tahhan AS, Liu C, Dhindsa DS, Nayak A, Hooda A, Moazzami K, Islam SJ, Rogers SC, Almuwaqqat Z, Mokhtari A, Hesaroieh I, Ko YA, Waller EK, Quyyumi AA. Circulating Progenitor Cells in Patients With Coronary Artery Disease and Renal Insufficiency. JACC Basic Transl Sci 2020; 5:770-782. [PMID: 32875168 PMCID: PMC7452291 DOI: 10.1016/j.jacbts.2020.06.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 06/04/2020] [Accepted: 06/06/2020] [Indexed: 10/26/2022]
Abstract
Patients with coronary artery disease and renal insufficiency (RI) (estimated glomerular filtration rate <60 ml/min/1.73 m2) are at an increased risk of cardiovascular events. The contribution of regenerative capacity, measured as circulating progenitor cell (CPC) counts, to this increased risk is unclear. CPCs were enumerated as cluster of differentiation (CD) 45med+ mononuclear cells expressing CD34+, CD133+, CXCR4+ (chemokine [C-X-C motif] receptor 4), and VEGF2R+ (vascular endothelial growth factor receptor 2) epitopes in 1,281 subjects with coronary artery disease (35% with RI). Patients with RI and low (<median) hematopoietic CPCs (CD34+, CD34+/CD133+, and CD34+/CXCR4+) were at an increased risk of cardiovascular death or myocardial infarction events (hazard ratios: 1.75 to 1.80) during 3.5-year follow-up, while those with RI and high CPCs (>median) were at a similar risk as those without RI.
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Key Words
- BNP, B-type natriuretic peptide
- CAD, coronary artery disease
- CD, cluster of differentiation
- CI, confidence interval
- CPC, circulating progenitor cell
- CV, cardiovascular
- CXCR4, chemokine (C-X-C motif) receptor 4
- HR, hazard ratio
- IDI, integrated discrimination index
- MI, myocardial infarction
- VEGF2R, vascular endothelial growth factor receptor 2
- coronary artery disease
- eGFR, estimated glomerular filtration rate
- hsTnI, high-sensitivity troponin I
- outcomes
- progenitor cells
- regenerative capacity
- renal insufficiency
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Affiliation(s)
- Anurag Mehta
- Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Ayman S Tahhan
- Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Chang Liu
- Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia.,Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia
| | - Devinder S Dhindsa
- Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Aditi Nayak
- Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Ananya Hooda
- Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Kasra Moazzami
- Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Shabatun J Islam
- Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Steven C Rogers
- Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Zakaria Almuwaqqat
- Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Ali Mokhtari
- Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Iraj Hesaroieh
- Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Yi-An Ko
- Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia.,Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, Georgia
| | - Edmund K Waller
- Department of Hematology and Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia
| | - Arshed A Quyyumi
- Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
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16
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How do Uremic Toxins Affect the Endothelium? Toxins (Basel) 2020; 12:toxins12060412. [PMID: 32575762 PMCID: PMC7354502 DOI: 10.3390/toxins12060412] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 06/15/2020] [Accepted: 06/19/2020] [Indexed: 12/11/2022] Open
Abstract
Uremic toxins can induce endothelial dysfunction in patients with chronic kidney disease (CKD). Indeed, the structure of the endothelial monolayer is damaged in CKD, and studies have shown that the uremic toxins contribute to the loss of cell–cell junctions, increasing permeability. Membrane proteins, such as transporters and receptors, can mediate the interaction between uremic toxins and endothelial cells. In these cells, uremic toxins induce oxidative stress and activation of signaling pathways, including the aryl hydrocarbon receptor (AhR), nuclear factor kappa B (NF-κB), and mitogen-activated protein kinase (MAPK) pathways. The activation of these pathways leads to overexpression of proinflammatory (e.g., monocyte chemoattractant protein-1, E-selectin) and prothrombotic (e.g., tissue factor) proteins. Uremic toxins also induce the formation of endothelial microparticles (EMPs), which can lead to the activation and dysfunction of other cells, and modulate the expression of microRNAs that have an important role in the regulation of cellular processes. The resulting endothelial dysfunction contributes to the pathogenesis of cardiovascular diseases, such as atherosclerosis and thrombotic events. Therefore, uremic toxins as well as the pathways they modulated may be potential targets for therapies in order to improve treatment for patients with CKD.
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17
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Oral Charcoal Adsorbents Attenuate Neointima Formation of Arteriovenous Fistulas. Toxins (Basel) 2020; 12:toxins12040237. [PMID: 32276394 PMCID: PMC7232464 DOI: 10.3390/toxins12040237] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2020] [Revised: 03/31/2020] [Accepted: 04/05/2020] [Indexed: 12/11/2022] Open
Abstract
Chronic kidney disease (CKD) accelerates the development of neointima formation at the anastomosis site of arteriovenous (AV) fistulas. Accumulation of certain uremic toxins has a deleterious effect on the cardiovascular system. The oral charcoal adsorbent, AST-120, reduces circulating and tissue uremic toxins, but its effect on neointima formation at an AV fistula is unknown. To understand the effect of CKD and AST-120 on neointima formation, we created AV fistulas (common carotid artery to the external jugular vein in an end-to-side anastomosis) in mice with and without CKD. AST-120 was administered in chow before and after AV fistula creation. Administration of AST-120 significantly decreased serum indoxyl sulfate levels in CKD mice. CKD mice had a larger neointima area than non-CKD mice, and administration of AST-120 in CKD mice attenuated neointima formation. Both smooth muscle cell and fibrin components were increased in CKD mice, and AST-120 decreased both. RNA expression of MMP-2, MMP-9, TNFα, and TGFβ was increased in neointima tissue of CKD mice, and AST-120 administration neutralized the expression. Our results provided in vivo evidence to support the role of uremic toxin-binding therapy on the prevention of neointima formation. Peri-operative AST-120 administration deserves further investigation as a potential therapy to improve AV fistula patency.
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18
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Protein-Bound Uremic Toxins in Hemodialysis Patients Relate to Residual Kidney Function, Are Not Influenced by Convective Transport, and Do Not Relate to Outcome. Toxins (Basel) 2020; 12:toxins12040234. [PMID: 32272776 PMCID: PMC7232478 DOI: 10.3390/toxins12040234] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Revised: 03/31/2020] [Accepted: 04/05/2020] [Indexed: 01/13/2023] Open
Abstract
Protein-bound uremic toxins (PBUTs) are predominantly excreted by renal tubular secretion and hardly removed by traditional hemodialysis (HD). Accumulation of PBUTs is proposed to contribute to the increased morbidity and mortality of patients with end-stage kidney disease (ESKD). Preserved PBUT excretion in patients with residual kidney function (RKF) and/or increased PBUT clearance with improved dialysis techniques might improve the prognosis of patients with ESKD. The aims of this study are to explore determinants of PBUTs in HD patients, and investigate whether hemodiafiltration (HDF) lowers PBUT plasma concentrations, and whether PBUTs are related to the outcome. Predialysis total plasma concentrations of kynurenine, kynurenic acid, indoxyl sulfate, indole-3-acetic acid, p-cresyl sulfate, p-cresyl glucuronide, and hippuric acid were measured by UHPLC-MS at baseline and after 6 months of follow-up in the first 80 patients participating in the CONvective TRAnsport Study (CONTRAST), a randomized controlled trial that compared the effects of online HDF versus low-flux HD on all-cause mortality and new cardiovascular events. RKF was inversely related to kynurenic acid (p < 0.001), indoxyl sulfate (p = 0.001), indole-3-acetic acid (p = 0.024), p-cresyl glucuronide (p = 0.004) and hippuric acid (p < 0.001) plasma concentrations. Only indoxyl sulfate decreased by 8.0% (−15.3 to 34.6) in patients treated with HDF and increased by 11.9% (−15.4 to 31.9) in HD patients after 6 months of follow-up (HDF vs. HD: p = 0.045). No independent associations were found between PBUT plasma concentrations and either risk of all-cause mortality or new cardiovascular events. In summary, in the current population, RKF is an important determinant of PBUT plasma concentrations in HD patients. The addition of convective transport did not consistently decrease PBUT plasma concentrations and no relation was found between PBUTs and cardiovascular endpoints.
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19
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Indoxyl Sulfate, a Uremic Endotheliotoxin. Toxins (Basel) 2020; 12:toxins12040229. [PMID: 32260489 PMCID: PMC7232210 DOI: 10.3390/toxins12040229] [Citation(s) in RCA: 80] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Revised: 04/02/2020] [Accepted: 04/03/2020] [Indexed: 12/15/2022] Open
Abstract
Chronic kidney disease (CKD) is associated with a high prevalence of cardiovascular diseases. During CKD, the uremic toxin indoxyl sulfate (IS)—derived from tryptophan metabolism—accumulates. IS is involved in the pathophysiology of cardiovascular complications. IS can be described as an endotheliotoxin: IS induces endothelial dysfunction implicated in cardiovascular morbidity and mortality during CKD. In this review, we describe clinical and experimental evidence for IS endothelial toxicity and focus on the various molecular pathways implicated. In patients with CKD, plasma concentrations of IS correlate with cardiovascular events and mortality, with vascular calcification and atherosclerotic markers. Moreover, IS induces a prothrombotic state and impaired neovascularization. IS reduction by AST-120 reverse these abnormalities. In vitro, IS induces endothelial aryl hydrocarbon receptor (AhR) activation and proinflammatory transcription factors as NF-κB or AP-1. IS has a prooxidant effect with reduction of nitric oxide (NO) bioavailability. Finally, IS alters endothelial cell and endothelial progenitor cell migration, regeneration and control vascular smooth muscle cells proliferation. Reducing IS endothelial toxicity appears to be necessary to improve cardiovascular health in CKD patients.
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20
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Wu PH, Lin YT, Wu PY, Lee HH, Lee SC, Hung SC, Chen SC, Kuo MC, Chiu YW. Association between Circulation Indole-3-Acetic Acid Levels and Stem Cell Factor in Maintenance Hemodialysis Patients: A Cross-Sectional Study. J Clin Med 2020; 9:jcm9010124. [PMID: 31906560 PMCID: PMC7019261 DOI: 10.3390/jcm9010124] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2019] [Revised: 12/27/2019] [Accepted: 12/29/2019] [Indexed: 12/17/2022] Open
Abstract
Protein-bound uremic toxin is a cardiovascular (CV) risk factor for patients with end-stage renal disease. Indole-3-acetic acid (IAA) was found to be associated with CV disease but the detailed pathophysiology remains unknown. Moreover, mitogen-activated protein kinase (MAPK) signaling cascades play an important role in the pathogenesis of CV disease. Thus, we explored the association between circulating IAA levels and forty MAPK cascade associated proteins in patients undergoing hemodialysis (HD). Circulating total form IAA was quantified by mass spectrometry and forty MAPK cascade associated proteins by a proximity extension assay in 331 prevalent HD patients. Accounting for multiple testing, and in multivariable-adjusted linear regression models, circulating total form IAA levels were positively associated with stem cell factor (β coefficient 0.13, 95% confidence interval 0.04 to 0.21, p = 0.004). A bioinformatics approach using the search tool for interactions of chemicals (STITCH) tool provided information that IAA may be involved in the regulation of cell proliferation, hematopoietic cells, and the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway. The knowledge gained here can be generalized, thereby impacting the non-traditional CV risk factors in patients with kidney disease. Further in vitro work is necessary to validate the translation of the mechanistic pathways.
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Affiliation(s)
- Ping-Hsun Wu
- Graduate Institute of Clinical Medicine, College of Medicines, Kaohsiung Medical University, Kaohsiung 807, Taiwan; (P.-H.W.); (Y.-T.L.); (P.-Y.W.); (S.-C.C.)
- Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan;
- Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan;
- Department of Medical Sciences, Uppsala University, Uppsala 75105, Sweden
| | - Yi-Ting Lin
- Graduate Institute of Clinical Medicine, College of Medicines, Kaohsiung Medical University, Kaohsiung 807, Taiwan; (P.-H.W.); (Y.-T.L.); (P.-Y.W.); (S.-C.C.)
- Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan;
- Department of Medical Sciences, Uppsala University, Uppsala 75105, Sweden
- Department of Family Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
| | - Pei-Yu Wu
- Graduate Institute of Clinical Medicine, College of Medicines, Kaohsiung Medical University, Kaohsiung 807, Taiwan; (P.-H.W.); (Y.-T.L.); (P.-Y.W.); (S.-C.C.)
- Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan;
- Department of Laboratory Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan;
| | - Hei-Hwa Lee
- Department of Laboratory Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan;
| | - Su-Chu Lee
- Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan;
| | - Szu-Chun Hung
- Division of Nephrology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, and School of Medicine, Tzu Chi University, Hualien 23142, Taiwan;
| | - Szu-Chia Chen
- Graduate Institute of Clinical Medicine, College of Medicines, Kaohsiung Medical University, Kaohsiung 807, Taiwan; (P.-H.W.); (Y.-T.L.); (P.-Y.W.); (S.-C.C.)
- Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan;
- Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan;
- Department of Internal Medicine, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University, Kaohsiung 81267, Taiwan
| | - Mei-Chuan Kuo
- Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan;
- Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan;
- Faculty of Renal Care, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Correspondence: ; Tel.: +886-7-312-1101 (ext. 7351)
| | - Yi-Wen Chiu
- Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan;
- Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan;
- Faculty of Renal Care, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
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21
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Abstract
The kidney harbours different types of endothelia, each with specific structural and functional characteristics. The glomerular endothelium, which is highly fenestrated and covered by a rich glycocalyx, participates in the sieving properties of the glomerular filtration barrier and in the maintenance of podocyte structure. The microvascular endothelium in peritubular capillaries, which is also fenestrated, transports reabsorbed components and participates in epithelial cell function. The endothelium of large and small vessels supports the renal vasculature. These renal endothelia are protected by regulators of thrombosis, inflammation and complement, but endothelial injury (for example, induced by toxins, antibodies, immune cells or inflammatory cytokines) or defects in factors that provide endothelial protection (for example, regulators of complement or angiogenesis) can lead to acute or chronic renal injury. Moreover, renal endothelial cells can transition towards a mesenchymal phenotype, favouring renal fibrosis and the development of chronic kidney disease. Thus, the renal endothelium is both a target and a driver of kidney and systemic cardiovascular complications. Emerging therapeutic strategies that target the renal endothelium may lead to improved outcomes for both rare and common renal diseases.
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22
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Kaihan AB, Hishida M, Imaizumi T, Okazaki M, Kaihan AN, Katsuno T, Taguchi A, Yasuda Y, Tsuboi N, Kosugi T, Maruyama S. Circulating levels of CD34+ cells predict long-term cardiovascular outcomes in patients on maintenance hemodialysis. PLoS One 2019; 14:e0223390. [PMID: 31584974 PMCID: PMC6777758 DOI: 10.1371/journal.pone.0223390] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Accepted: 09/19/2019] [Indexed: 12/12/2022] Open
Abstract
CD34+ cells maintain vascular homeostasis and predict cardiovascular outcomes. We previously evaluated the association of CD34+ cells with cardiovascular disease (CVD) events over 23 months, but long-term CVD outcomes in relation to levels of CD34+ cells in patients on maintenance hemodialysis are unclear. Herein, we analyzed the long-term predictive potential levels of CD34+ cells for CVD outcomes and all-cause mortality. Between March 2005 and May 2005, we enrolled 215 patients on maintenance hemodialysis at Nagoya Kyoritsu Hospital and followed them up to 12.8 years. According to the CD34+ cell counts, patients were classified into the lowest, medium, and highest tertiles. Levels of CD34+ cells were analyzed in association with four-point major adverse CV events (MACEs), CVD death, and all-cause mortality. In univariate analysis age, smoking habit, lower geriatric nutrition risk index, lower calcium × phosphate product, and lower intact parathyroid hormone were significantly associated with the lowest tertile. Whereas, in multivariate analysis, age and smoking habit were significantly associated with the lowest tertile. Among 139 (64.7%) patients who died during a mean follow-up period of 8.0 years, 39 (28.1%) patients died from CVD. Patients in the lowest tertile had a significantly lower survival rate than those in the medium and highest tertiles (p ≤ 0.001). Using multivariable analyses, the lowest tertile was significantly associated with four-point MACEs (hazard ratio 1.80, p = 0.023) and CVD death (hazard ratio 2.50, p = 0.011). In conclusion, our long-term observational study revealed that a low level of CD34+ cells in the circulation predicts CVD outcomes among patients on maintenance hemodialysis.
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Affiliation(s)
- Ahmad Baseer Kaihan
- Department of Nephrology, Graduate School of Medicine, Nagoya University, Nagoya, Japan
- Faculty of Medicine, Balkh University, Mazar-i-Sharif, Afghanistan
| | - Manabu Hishida
- Department of Nephrology, Graduate School of Medicine, Nagoya University, Nagoya, Japan
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America
| | - Takahiro Imaizumi
- Department of Nephrology, Graduate School of Medicine, Nagoya University, Nagoya, Japan
| | - Masaki Okazaki
- Department of Nephrology, Graduate School of Medicine, Nagoya University, Nagoya, Japan
| | | | - Takayuki Katsuno
- Department of Nephrology and Rheumatology, Graduate School of Medicine, Aichi Medical University, Nagakute, Japan
| | - Akihiko Taguchi
- Department of Regenerative Medicine Research, Institute of Biomedical Research and Innovation, Kobe, Japan
| | - Yoshinari Yasuda
- Department of Nephrology, Graduate School of Medicine, Nagoya University, Nagoya, Japan
| | - Naotake Tsuboi
- Department of Nephrology, Graduate School of Medicine, Nagoya University, Nagoya, Japan
- Department of Nephrology, Fujita Health University Graduate School of Medicine, Toyoake, Japan
| | - Tomoki Kosugi
- Department of Nephrology, Graduate School of Medicine, Nagoya University, Nagoya, Japan
| | - Shoichi Maruyama
- Department of Nephrology, Graduate School of Medicine, Nagoya University, Nagoya, Japan
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Emerging Roles of Aryl Hydrocarbon Receptors in the Altered Clearance of Drugs during Chronic Kidney Disease. Toxins (Basel) 2019; 11:toxins11040209. [PMID: 30959953 PMCID: PMC6521271 DOI: 10.3390/toxins11040209] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Revised: 03/12/2019] [Accepted: 04/03/2019] [Indexed: 12/11/2022] Open
Abstract
Chronic kidney disease (CKD) is a major public health problem, since 300,000,000 people in the world display a glomerular filtration rate (GFR) below 60 mL/min/1.73m². Patients with CKD have high rates of complications and comorbidities. Thus, they require the prescription of numerous medications, making the management of patients very complex. The prescription of numerous drugs associated with an altered renal- and non-renal clearance makes dose adjustment challenging in these patients, with frequent drug-related adverse events. However, the mechanisms involved in this abnormal drug clearance during CKD are not still well identified. We propose here that the transcription factor, aryl hydrocarbon receptor, which is the cellular receptor for indolic uremic toxins, could worsen the metabolism and the excretion of drugs in CKD patients.
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Kemp JA, Esgalhado M, Macedo RA, Regis B, Damasceno NRT, da Silva Torres EAF, Gonçalinho GHF, Borges NA, Nakao LS, Fouque D, Mafra D. A possible link between polyunsaturated fatty acids and uremic toxins from the gut microbiota in hemodialysis patients: A hypothesis. Hemodial Int 2019; 23:189-197. [PMID: 30779317 DOI: 10.1111/hdi.12725] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2018] [Revised: 10/30/2018] [Accepted: 12/06/2018] [Indexed: 12/28/2022]
Abstract
INTRODUCTION Indoxyl sulfate (IS) and p-cresyl sulfate (p-CS) are albumin-bound uremic toxins that are difficult to remove by hemodialysis (HD). Human serum albumin (HSA) carries several compounds, including fatty acids that can bind to site II of HSA and represent competing ligands for uremic toxins. The aim of this study was to investigate the association between fatty acids and uremic toxin plasma levels in patients undergoing HD. METHODS Thirty-three HD patients (51.5% male, 54.9 ± 10.2 years old, 44.63 ± 28.4 months on HD, albumin level of 3.8 ± 0.3 g/dL) were evaluated. The erythrocyte fatty acid content (saturated fatty acid [SFA], monounsaturated fatty acid [MUFA], and polyunsaturated fatty acid [PUFA]) was measured by gas chromatography, and total IS and p-CS plasma levels were measured by reversed-phase high-performance liquid chromatography. FINDINGS The mean percentages of docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA) + DHA and gamma-linolenic (GLA) acid in the erythrocyte membrane were 1.35% ± 0.74%, 1.85% ± 0.79%, and 0.33% ± 0.26%, respectively. The mean levels of IS and p-CS were 19.4 ± 11.9 mg/dL and 101.5 ± 57.2 mg/dL, respectively. There was no significant association between SFA and MUFA and IS and p-CS; however, a negative correlation was found between p-CS and specific PUFAs, and the association between GLA and p-CS levels was retained after adjusting for potential confounding variables (β = -0.49, P = 0.007). DISCUSSION Polyunsaturated fatty acids may contribute to the decrease in p-CS uremic toxin plasma levels in patients with chronic kidney disease undergoing HD.
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Affiliation(s)
- Julie Ann Kemp
- Post-Graduate Program in Medical Sciences, Federal University Fluminense (UFF), Niterói, Rio de Janeiro, Brazil
| | - Marta Esgalhado
- Post-Graduate Program in Cardiovascular Sciences, Federal University Fluminense (UFF), Niterói, Rio de Janeiro, Brazil
| | - Renata Azevedo Macedo
- Post-Graduate Program in Cardiovascular Sciences, Federal University Fluminense (UFF), Niterói, Rio de Janeiro, Brazil
| | - Bruna Regis
- Post-Graduate Program in Medical Sciences, Federal University Fluminense (UFF), Niterói, Rio de Janeiro, Brazil
| | | | | | | | - Natália Alvarenga Borges
- Post-Graduate Program in Cardiovascular Sciences, Federal University Fluminense (UFF), Niterói, Rio de Janeiro, Brazil
| | - Lia Sumie Nakao
- Basic Pathology Department, Federal University of Paraná (UFPR), Curitiba, Puerto Rico, Brazil
| | - Denis Fouque
- Department of Nephrology, Centre Hopitalier Lyon Sud, INSERM 1060, CENS, Université de Lyon, France
| | - Denise Mafra
- Post-Graduate Program in Medical Sciences, Federal University Fluminense (UFF), Niterói, Rio de Janeiro, Brazil.,Post-Graduate Program in Cardiovascular Sciences, Federal University Fluminense (UFF), Niterói, Rio de Janeiro, Brazil
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25
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McVey MJ, Kuebler WM. Extracellular vesicles: biomarkers and regulators of vascular function during extracorporeal circulation. Oncotarget 2018; 9:37229-37251. [PMID: 30647856 PMCID: PMC6324688 DOI: 10.18632/oncotarget.26433] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2018] [Accepted: 11/26/2018] [Indexed: 12/12/2022] Open
Abstract
Extracellular vesicles (EVs) are generated at increased rates from parenchymal and circulating blood cells during exposure of the circulation to abnormal flow conditions and foreign materials associated with extracorporeal circuits (ExCors). This review describes types of EVs produced in different ExCors and extracorporeal life support (ECLS) systems including cardiopulmonary bypass circuits, extracorporeal membrane oxygenation (ECMO), extracorporeal carbon dioxide removal (ECCO2R), apheresis, dialysis and ventricular assist devices. Roles of EVs not only as biomarkers of adverse events during ExCor/ECLS use, but also as mediators of vascular dysfunction are explored. Manipulation of the number or subtypes of circulating EVs may prove a means of improving vascular function for individuals requiring ExCor/ECLS support. Strategies for therapeutic manipulation of EVs during ExCor/ECLS use are discussed such as accelerating their clearance, preventing their genesis or pharmacologic options to reduce or select which and how many EVs circulate. Strategies to reduce or select for specific types of EVs may prove beneficial in preventing or treating other EV-related diseases such as cancer.
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Affiliation(s)
- Mark J McVey
- Keenan Research Centre for Biomedical Science, St Michael's Hospital, Toronto, ON, Canada.,Department of Physiology, University of Toronto, Toronto, ON, Canada.,Department of Anesthesia, University of Toronto, Toronto, ON, Canada.,Department of Anesthesia and Pain Medicine, SickKids, Toronto, ON, Canada
| | - Wolfgang M Kuebler
- Keenan Research Centre for Biomedical Science, St Michael's Hospital, Toronto, ON, Canada.,Department of Physiology, University of Toronto, Toronto, ON, Canada.,Department of Surgery, University of Toronto, Toronto, ON, Canada.,Institute of Physiology, Charité-Universitätsmedizin Berlin, Berlin, Germany.,German Heart Institute, Berlin, Germany
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26
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Addi T, Dou L, Burtey S. Tryptophan-Derived Uremic Toxins and Thrombosis in Chronic Kidney Disease. Toxins (Basel) 2018; 10:E412. [PMID: 30322010 PMCID: PMC6215213 DOI: 10.3390/toxins10100412] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2018] [Revised: 10/09/2018] [Accepted: 10/10/2018] [Indexed: 02/07/2023] Open
Abstract
Patients with chronic kidney disease (CKD) display an elevated risk of thrombosis. Thrombosis occurs in cardiovascular events, such as venous thromboembolism, stroke, and acute coronary syndrome, and is a cause of hemodialysis vascular access dysfunction. CKD leads to the accumulation of uremic toxins, which exerts toxic effects on blood and the vessel wall. Some uremic toxins result from tryptophan metabolization in the gut through the indolic and the kynurenine pathways. An increasing number of studies are highlighting the link between such uremic toxins and thrombosis in CKD. In this review, we describe the thrombotic mechanisms induced by tryptophan-derived uremic toxins (TDUT). These mechanisms include an increase in plasma levels of procoagulant factors, induction of platelet hyperactivity, induction of endothelial dysfunction/ impairment of endothelial healing, decrease in nitric oxide (NO) bioavailability, and production of procoagulant microparticles. We focus on one important prothrombotic mechanism: The induction of tissue factor (TF), the initiator of the extrinsic pathway of the blood coagulation. This induction occurs via a new pathway, dependent on the transcription factor Aryl hydrocarbon receptor (AhR), the receptor of TDUT in cells. A better understanding of the prothrombotic mechanisms of uremic toxins could help to find novel therapeutic targets to prevent thrombosis in CKD.
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Affiliation(s)
- Tawfik Addi
- Aix Marseille University, INSERM, INRA, C2VN, 13005 Marseille, France.
- LPNSA, Département de Biologie, Université d'Oran 1 Ahmed Benbella, 31000 Oran, Algérie.
| | - Laetitia Dou
- Aix Marseille University, INSERM, INRA, C2VN, 13005 Marseille, France.
| | - Stéphane Burtey
- Aix Marseille University, INSERM, INRA, C2VN, 13005 Marseille, France.
- Centre de Néphrologie et Transplantation Rénale, AP-HM, 13005 Marseille, France.
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27
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Lekawanvijit S. Cardiotoxicity of Uremic Toxins: A Driver of Cardiorenal Syndrome. Toxins (Basel) 2018; 10:toxins10090352. [PMID: 30200452 PMCID: PMC6162485 DOI: 10.3390/toxins10090352] [Citation(s) in RCA: 80] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2018] [Revised: 08/19/2018] [Accepted: 08/30/2018] [Indexed: 02/07/2023] Open
Abstract
Cardiovascular disease (CVD) is highly prevalent in the setting of chronic kidney disease (CKD). Such coexistence of CVD and CKD—the so-called “cardiorenal or renocardiac syndrome”—contributes to exponentially increased risk of cardiovascular (CV) mortality. Uremic cardiomyopathy is a characteristic cardiac pathology commonly found in CKD. CKD patients are also predisposed to heart rhythm disorders especially atrial fibrillation. Traditional CV risk factors as well as known CKD-associated CV risk factors such as anemia are insufficient to explain CV complications in the CKD population. Accumulation of uremic retention solutes is a hallmark of impaired renal excretory function. Many of them have been considered inert solutes until their biological toxicity is unraveled and they become accepted as “uremic toxins”. Direct cardiotoxicity of uremic toxins has been increasingly demonstrated in recent years. This review offers a mechanistic insight into the pathological cardiac remodeling and dysfunction contributed by uremic toxins with a main focus on fibroblastic growth factor-23, an emerging toxin playing a central role in the chronic kidney disease–mineral bone disorder, and the two most investigated non-dialyzable protein-bound uremic toxins, indoxyl sulfate and p-cresyl sulfate. Potential therapeutic strategies that could address these toxins and their relevant mediated pathways since pre-dialysis stages are also discussed.
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Affiliation(s)
- Suree Lekawanvijit
- Department of Pathology, Faculty of Medicine, Chiang Mai University, 110 Intawaroros Rd, Sribhoom, Chiang Mai 50200, Thailand.
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28
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Ohtake T, Mochida Y, Ishioka K, Oka M, Maesato K, Moriya H, Hidaka S, Higashide S, Ioji T, Fujita Y, Kawamoto A, Fukushima M, Kobayashi S. Autologous Granulocyte Colony-Stimulating Factor-Mobilized Peripheral Blood CD34 Positive Cell Transplantation for Hemodialysis Patients with Critical Limb Ischemia: A Prospective Phase II Clinical Trial. Stem Cells Transl Med 2018; 7:774-782. [PMID: 30059194 PMCID: PMC6216433 DOI: 10.1002/sctm.18-0104] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Revised: 05/22/2018] [Accepted: 06/05/2018] [Indexed: 12/29/2022] Open
Abstract
Critical limb ischemia (CLI) is a devastating disease in patients undergoing hemodialysis (HD). Based on the unsatisfactory results of autologous mononuclear cell transplantation for patients with CLI undergoing HD, we conducted a phase II clinical trial to evaluate the safety and efficacy of granulocyte colony‐stimulating factor (G‐CSF)‐mobilized peripheral blood‐derived autologous purified CD34 positive (CD34+) cell transplantation for CLI in patients undergoing HD. Six patients with CLI (two with Rutherford category 4 and four with Rutherford category 5) were enrolled. As for primary endpoint, there were no major adverse events related to this therapy. As for efficacy, the amputation‐free survival rate was 100% at 1 year after cell therapy. Both rest pain scale and ulcer size were significantly improved as early as 4 weeks after therapy compared with baseline (p < .01), and three out of five ulcers completely healed within 12 weeks after cell transplantation. Clinical severity, including Fontaine scale and Rutherford category, significantly improved at 24 weeks after cell transplantation (p < .05), and further improved at 52 weeks (p < .01) compared with baseline. The improvement rate from CLI stage to non‐CLI stage was 83.3% at 52 weeks. Toe skin perfusion pressure and absolute claudication distance were also significantly improved. In conclusion, G‐CSF‐mobilized peripheral blood CD34+ cell transplantation was safe, feasible, and effective for patients with CLI undergoing HD. stem cells translational medicine2018;7:774–782
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Affiliation(s)
- Takayasu Ohtake
- Department of Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, Kamakura, Japan.,Division of Regenerative Medicine, Department of Center for Clinical and Translational Science, Shonan Kamakura General Hospital, Kamakura, Japan
| | - Yasuhiro Mochida
- Department of Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, Kamakura, Japan
| | - Kunihiro Ishioka
- Department of Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, Kamakura, Japan
| | - Machiko Oka
- Department of Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, Kamakura, Japan
| | - Kyoko Maesato
- Department of Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, Kamakura, Japan
| | - Hidekazu Moriya
- Department of Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, Kamakura, Japan
| | - Sumi Hidaka
- Department of Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, Kamakura, Japan
| | - Satoshi Higashide
- Translational Research Informatics Center, Foundation for Biomedical Research and Innovation, Kobe, Japan
| | - Tetsuya Ioji
- Translational Research Informatics Center, Foundation for Biomedical Research and Innovation, Kobe, Japan
| | - Yasuyuki Fujita
- Translational Research Informatics Center, Foundation for Biomedical Research and Innovation, Kobe, Japan
| | - Atsuhiko Kawamoto
- Translational Research Informatics Center, Foundation for Biomedical Research and Innovation, Kobe, Japan
| | - Masanori Fukushima
- Translational Research Informatics Center, Foundation for Biomedical Research and Innovation, Kobe, Japan
| | - Shuzo Kobayashi
- Department of Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, Kamakura, Japan.,Division of Regenerative Medicine, Department of Center for Clinical and Translational Science, Shonan Kamakura General Hospital, Kamakura, Japan
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29
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Jalal D, Renner B, Laskowski J, Stites E, Cooper J, Valente K, You Z, Perrenoud L, Le Quintrec M, Muhamed I, Christians U, Klawitter J, Lindorfer MA, Taylor RP, Holers VM, Thurman JM. Endothelial Microparticles and Systemic Complement Activation in Patients With Chronic Kidney Disease. J Am Heart Assoc 2018; 7:e007818. [PMID: 30006493 PMCID: PMC6064828 DOI: 10.1161/jaha.117.007818] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2018] [Accepted: 05/28/2018] [Indexed: 01/09/2023]
Abstract
BACKGROUND Endothelial microparticles are associated with chronic kidney disease (CKD) and complement activation. We hypothesized that the complement pathway is activated in patients with CKD via endothelial microparticles and that complement activation correlates with endothelial dysfunction in CKD. METHODS AND RESULTS We analyzed complement data of 30 healthy subjects, 30 patients with stage III/IV CKD, and 30 renal transplant recipients with stage III/IV CKD, evaluating the potential correlation of complement fragments with brachial artery flow-mediated dilation, Chronic Kidney Disease Epidemiology Collaboration glomerular filtration rate, and urinary albumin/creatinine ratio. Endothelial microparticles were characterized via proteomic analysis and compared between study groups. Complement fragment Ba was significantly increased in CKD and post-kidney transplant CKD. Plasma Ba levels correlated significantly with lower brachial artery flow-mediated dilation, lower Chronic Kidney Disease Epidemiology Collaboration glomerular filtration rate, and higher urinary albumin/creatinine ratio. Factor D levels were significantly higher in the plasma microparticles of patients with CKD versus healthy controls. Plasma microparticles isolated from patients with CKD and containing factor D activated the alternative pathway in vitro. CONCLUSION The alternative complement pathway is activated in CKD and correlates with endothelial dysfunction and markers of CKD. Future studies are needed to evaluate whether endothelial microparticles with increased factor D play a pathologic role in CKD-associated vascular disease. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT02230202.
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Affiliation(s)
- Diana Jalal
- Division of Nephrology, Carver College of Medicine University of Iowa, Iowa City, IA
| | - Brandon Renner
- Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Center, Aurora, CO
| | - Jennifer Laskowski
- Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Center, Aurora, CO
| | - Erik Stites
- Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Center, Aurora, CO
| | - James Cooper
- Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Center, Aurora, CO
| | - Karissa Valente
- Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Center, Aurora, CO
| | - Zhiying You
- Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Center, Aurora, CO
| | - Loni Perrenoud
- Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Center, Aurora, CO
| | - Moglie Le Quintrec
- Department of Nephrology and Renal Transplantation, Lapeyronnie Hospital and INSERM U1183 IRMB, Montpellier, France
| | - Ismaeel Muhamed
- Joint Department of Biomedical Engineering and Comparative Medicine Institute, North Carolina State University and University of North Carolina-Chapel Hill, NC
| | - Uwe Christians
- iC42 Clinical Research and Development, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Jelena Klawitter
- iC42 Clinical Research and Development, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Margaret A Lindorfer
- Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA
| | - Ronald P Taylor
- Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA
| | - V Michael Holers
- Division of Rheumatology, University of Colorado Anschutz Medical Center, Aurora, CO
| | - Joshua M Thurman
- Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Center, Aurora, CO
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30
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Cosola C, Rocchetti MT, Cupisti A, Gesualdo L. Microbiota metabolites: Pivotal players of cardiovascular damage in chronic kidney disease. Pharmacol Res 2018. [PMID: 29518493 DOI: 10.1016/j.phrs.2018.03.003] [Citation(s) in RCA: 77] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
In chronic kidney disease (CKD), cardiovascular (CV) damage is present in parallel which leads to an increased risk of CV disease. Both traditional and non-traditional risk factors contribute to CV damage in CKD. The systemic role of the microbiota as a central player in the pathophysiology of many organs is progressively emerging in the literature: the microbiota is indeed involved in a complex, bi-directional network between many organs, including the kidney and heart connection, although many of these relationships still need to be elucidated through in-depth mechanistic studies. The aim of this review is to provide evidence that microbiota metabolites influence non-traditional risk factors, such as inflammation and endothelial dysfunction in CKD-associated CV damage. Here, we report our current understanding and hypotheses on the gut-kidney and gut-heart axes and provide details on the potential mechanisms mediated by microbial metabolites. More specifically, we summarize some novel hypotheses linking the microbiota to blood pressure regulation and hypertension. We also emphasise the idea that the nutritional management of CKD should be redesigned and include the new findings from research on the intrinsic plasticity of the microbiota and its metabolites in response to food intake. The need is felt to integrate the classical salt and protein restriction approach for CKD patients with foods that enhance intestinal wellness. Finally, we discuss the new perspectives, especially the importance of taking care of the microbiota in order to prevent the risk of developing CKD and hypertension, as well as the still not tested but very promising CKD innovative treatments, such as postbiotic supplementation and bacteriotherapy. This interesting area of research offers potential complementary approaches to the management of CKD and CV damage assuming that the causal mechanisms underlying the gut-kidney and gut-heart axes are clarified. This will pave the way to the design of new personalized therapies targeting gut microbiota.
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Affiliation(s)
- Carmela Cosola
- Department of Emergency and Organ Transplantation - Nephrology, Dialysis and Transplantation Unit, University of Bari Aldo Moro, Bari 70124, Italy.
| | - Maria Teresa Rocchetti
- Department of Emergency and Organ Transplantation - Nephrology, Dialysis and Transplantation Unit, University of Bari Aldo Moro, Bari 70124, Italy.
| | - Adamasco Cupisti
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa 56126, Italy.
| | - Loreto Gesualdo
- Department of Emergency and Organ Transplantation - Nephrology, Dialysis and Transplantation Unit, University of Bari Aldo Moro, Bari 70124, Italy.
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31
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Chan D, Green S, Fiatarone Singh MA, Barnard R, Bonder CS, Cheema BS. Effect of intradialytic resistance training on pulse wave velocity and associated cardiovascular disease biomarkers in end stage renal disease. Nephrology (Carlton) 2017; 23:1055-1062. [PMID: 29265637 DOI: 10.1111/nep.13212] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/14/2017] [Indexed: 11/29/2022]
Abstract
AIMS Cardiovascular disease (CVD) is the leading cause of mortality in patients with end-stage renal disease (ESRD) receiving maintenance haemodialysis treatment. This study investigated the effect of a 12-week intradialytic progressive resistance training (PRT) intervention on pulse wave velocity (PWV) and associated haemodynamic, anthropometric, and hematologic outcomes in patients with ESRD. METHODS Twenty-two patients with ESRD (59% men, 71.3 ± 11.0 years) were recruited. Supervised PRT (three sets of 11 exercises) was prescribed three times per week during routine dialysis. The primary outcome was brachial-ankle PWV via applanation tonometry. Secondary outcomes included augmentation index, brachial and aortic blood pressures, endothelial progenitor cells, C-reactive protein, blood lipids and anthropometrics. RESULTS The intradialytic PRT regimen resulted in no significant change in PWV between control and intervention periods [mean difference = 0 (95% CI = -0.1 to 0.1); P = 0.58]. Similarly, no significant change was noted in any secondary outcome measures between the control and intervention periods. Post-hoc analyses limited to high adherers (≥75% attendance; n = 11) did not differ from the primary analysis, indicating no dose-response effect of our intervention. CONCLUSION Our 12-week PRT intervention did not change PWV or any secondary outcomes. Future studies should determine if higher dosages of intradialytic PRT (i.e. longer duration and/or higher intensity) can be applied as a method to improve arterial stiffness to potentially reduce cardiovascular disease and associated mortality this cohort.
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Affiliation(s)
- Danwin Chan
- School of Science and Health, Western Sydney University, Sydney, New South Wales, Australia
| | - Simon Green
- School of Science and Health, Western Sydney University, Sydney, New South Wales, Australia
| | - Maria A Fiatarone Singh
- Exercise, Health & Performance Faculty Research Group, Faculty of Health Sciences and Sydney Medical School, University of Sydney, Sydney, Australia.,Hebrew SeniorLife and Jean Mayer USDA Human Nutrition Center on Aging at Tufts University, Boston, Massachusetts, USA
| | - Robert Barnard
- Centre for Physical Activity in Ageing, Central Adelaide Local Health Network, Adelaide, Australia
| | - Claudine S Bonder
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia, Australia
| | - Birinder S Cheema
- School of Science and Health, Western Sydney University, Sydney, New South Wales, Australia.,The National Institute of Complementary Medicine, Sydney, New South Wales, Australia
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Santana Machado T, Poitevin S, Paul P, McKay N, Jourde-Chiche N, Legris T, Mouly-Bandini A, Dignat-George F, Brunet P, Masereeuw R, Burtey S, Cerini C. Indoxyl Sulfate Upregulates Liver P-Glycoprotein Expression and Activity through Aryl Hydrocarbon Receptor Signaling. J Am Soc Nephrol 2017; 29:906-918. [PMID: 29222397 DOI: 10.1681/asn.2017030361] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Accepted: 11/14/2017] [Indexed: 11/03/2022] Open
Abstract
In patients with CKD, not only renal but also, nonrenal clearance of drugs is altered. Uremic toxins could modify the expression and/or activity of drug transporters in the liver. We tested whether the uremic toxin indoxyl sulfate (IS), an endogenous ligand of the transcription factor aryl hydrocarbon receptor, could change the expression of the following liver transporters involved in drug clearance: SLC10A1, SLC22A1, SLC22A7, SLC47A1, SLCO1B1, SLCO1B3, SLCO2B1, ABCB1, ABCB11, ABCC2, ABCC3, ABCC4, ABCC6, and ABCG2 We showed that IS increases the expression and activity of the efflux transporter P-glycoprotein (P-gp) encoded by ABCB1 in human hepatoma cells (HepG2) without modifying the expression of the other transporters. This effect depended on the aryl hydrocarbon receptor pathway. Presence of human albumin at physiologic concentration in the culture medium did not abolish the effect of IS. In two mouse models of CKD, the decline in renal function associated with the accumulation of IS in serum and the specific upregulation of Abcb1a in the liver. Additionally, among 109 heart or kidney transplant recipients with CKD, those with higher serum levels of IS needed higher doses of cyclosporin, a P-gp substrate, to obtain the cyclosporin target blood concentration. This need associated with serum levels of IS independent of renal function. These findings suggest that increased activity of P-gp could be responsible for increased hepatic cyclosporin clearance. Altogether, these results suggest that uremic toxins, such as IS, through effects on drug transporters, may modify the nonrenal clearance of drugs in patients with CKD.
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Affiliation(s)
- Tacy Santana Machado
- Coordination for the Improvement of Higher Education Personnel (CAPES Foundation), Ministry of Education of Brazil, Brasilia, Brazil.,Aix Marseille University, Faculty of Pharmacy, National Institute of Health and Medical Research (INSERM), Vascular Research Center of Marseille (VRCM), Marseille, France
| | - Stéphane Poitevin
- Aix Marseille University, Faculty of Pharmacy, National Institute of Health and Medical Research (INSERM), Vascular Research Center of Marseille (VRCM), Marseille, France
| | - Pascale Paul
- Aix Marseille University, Faculty of Pharmacy, National Institute of Health and Medical Research (INSERM), Vascular Research Center of Marseille (VRCM), Marseille, France
| | - Nathalie McKay
- Aix Marseille University, Faculty of Pharmacy, National Institute of Health and Medical Research (INSERM), Vascular Research Center of Marseille (VRCM), Marseille, France
| | - Noémie Jourde-Chiche
- Marseille Public University Hospital System (APHM), Conception Hospital, Centre de Néphrologie et Transplantation Rénale, Marseille, France
| | - Tristan Legris
- Marseille Public University Hospital System (APHM), Conception Hospital, Centre de Néphrologie et Transplantation Rénale, Marseille, France
| | - Annick Mouly-Bandini
- Department of Cardiac Surgery, Marseille Public University Hospital System (APHM), La Timone Hospital, Marseille, France
| | - Françoise Dignat-George
- Aix Marseille University, Faculty of Pharmacy, National Institute of Health and Medical Research (INSERM), Vascular Research Center of Marseille (VRCM), Marseille, France
| | - Philippe Brunet
- Marseille Public University Hospital System (APHM), Conception Hospital, Centre de Néphrologie et Transplantation Rénale, Marseille, France.,European Uraemic Toxin Working Group (EUTox) of The European Society for Artificial Organs (ESAO) endorsed by European Renal Association & European Dialysis and Transplant Assiociation (ERA-EDTA), Krems, Austria; and
| | - Rosalinde Masereeuw
- European Uraemic Toxin Working Group (EUTox) of The European Society for Artificial Organs (ESAO) endorsed by European Renal Association & European Dialysis and Transplant Assiociation (ERA-EDTA), Krems, Austria; and.,Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht, The Netherlands
| | - Stéphane Burtey
- Aix Marseille University, Faculty of Pharmacy, National Institute of Health and Medical Research (INSERM), Vascular Research Center of Marseille (VRCM), Marseille, France.,Marseille Public University Hospital System (APHM), Conception Hospital, Centre de Néphrologie et Transplantation Rénale, Marseille, France.,European Uraemic Toxin Working Group (EUTox) of The European Society for Artificial Organs (ESAO) endorsed by European Renal Association & European Dialysis and Transplant Assiociation (ERA-EDTA), Krems, Austria; and
| | - Claire Cerini
- Aix Marseille University, Faculty of Pharmacy, National Institute of Health and Medical Research (INSERM), Vascular Research Center of Marseille (VRCM), Marseille, France;
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Alshahawey M, Shahin SM, Elsaid TW, Sabri NA. Effect of Febuxostat on the Endothelial Dysfunction in Hemodialysis Patients: A Randomized, Placebo-Controlled, Double-Blinded Study. Am J Nephrol 2017; 45:452-459. [PMID: 28463849 DOI: 10.1159/000471893] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2017] [Accepted: 03/03/2017] [Indexed: 01/22/2023]
Abstract
BACKGROUND Endothelial dysfunction is an important risk factor for cardiovascular diseases to occur in end-stage renal disease patients. Febuxostat, being a novel xanthine oxidase inhibitor, is apparently having a beneficial role in improving the endothelial dysfunction; however, data among hemodialysis patients are still limited. METHODS A prospective, placebo-controlled, block-randomized, double-blinded study was carried out to evaluate the effect of oral febuxostat on the endothelial dysfunction in hemodialysis patients. Fifty-seven eligible hemodialysis patients were randomly assigned to either the drug group (40 mg thrice weekly) or the placebo group. Serum Asymmetric dimethylarginine (ADMA), Serum uric acid (UA), and serum high sensitivity C-reactive protein (hsCRP) were measured at baseline and at the end of a 2-month study. Serum alanine aminotransferase (ALT), serum aspartate aminotransferase (AST), and the occurrence of pancytopenia were tested as safety parameters at baseline and at the end of study. RESULTS Serum UA significantly decreased from 7.5 ± 0.8 to 5.1 ± 1.2 mg/dL in the febuxostat group, while it did not change significantly in the placebo group. Treatment with febuxostat resulted in a significant decrease in the serum ADMA level from 1.027 ± 0.116 to 0.944 ± 0.104 µmol/L and the serum hsCRP level from 12.5 ± 1.65 to 12.1 ± 1.70 mg/L. Testing of serum ALT, serum AST, and pancytopenia revealed no significant difference in both groups. CONCLUSION Febuxostat appears to improve hyperuricemia and endothelial dysfunction and ameliorate inflammation in hemodialysis patients with no safety concerns.
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Wu H, Lee L, Wang W. Associations among Serum Beta 2 Microglobulin, Malnutrition, Inflammation, and Advanced Cardiovascular Event in Patients with Chronic Kidney Disease. J Clin Lab Anal 2017; 31:e22056. [PMID: 27645611 PMCID: PMC6817072 DOI: 10.1002/jcla.22056] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2016] [Accepted: 07/28/2016] [Indexed: 11/10/2022] Open
Abstract
OBJECTIVES This study examines the associations among serum β2 microglobulin (B2M), malnutrition, inflammation, and atherosclerosis (MIA) in those with chronic kidney disease (CKD). METHODS CKD patients who were followed in Taoyuan General Hospital from 2009 to 2015 were enrolled. Demographic and biochemical data, including B2M and C-reactive protein (CRP) were reviewed. The participants were stratified according to B2M tertiles. Adjusted hazard ratios (AHRs) and cumulative survival curves for death and MIA syndrome were evaluated by Cox hazard model and Kaplan-Meier method. We also calculated the area under the curve for the receiver operating characteristic curve (AUROC). RESULTS From a total of 312 CKD patients, mean follow-up time was 39.7 months. Compared to those with lowest tertile of B2M, the highest tertile group had lower serum albumin, hemoglobin, and estimated glomerular filtration rate. After multivariate adjustment, the associations among tertiles of B2M, death or dialysis, cardiovascular events (CVEs), and MIA syndrome remained significant. The AHRs for the highest tertile group in death or dialysis, CVEs, and MIA syndrome were 25.91 and 65.84 and 152.50(all Ps <0.05).The AUROC for B2M in death or dialysis, CVEs, and MIA syndrome were greater than that for creatinine. The best cut-off value of B2M for predicting death or dialysis, CVEs, and MIA syndrome were 5.39 mg/dL(sensitivity: 67.1%, specificity 62.5%), 4.21 mg/dL(sensitivity: 85.1%, specificity 52.1%), and 5.40 mg/dL(sensitivity: 79.7%, specificity 64.1%). CONCLUSIONS In those with CKD, serum B2M was more sensitive than creatinine in predicting CVEs and MIA syndrome.
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Affiliation(s)
- Hung‐Chieh Wu
- Division of NephrologyDepartment of Internal MedicineTaoyuan General HospitalMinistry of Health and WelfareTaoyuanTaiwan
| | - Lin‐Chien Lee
- Department of Physical Medicine and RehabilitationCheng Hsin General HospitalTaipeiTaiwan
| | - Wei‐Jie Wang
- Department of Biomedical EngineeringChung Yuan Christian UniversityTaoyuanTaiwan
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Cerezo AB, Hornedo-Ortega R, Álvarez-Fernández MA, Troncoso AM, García-Parrilla MC. Inhibition of VEGF-Induced VEGFR-2 Activation and HUVEC Migration by Melatonin and Other Bioactive Indolic Compounds. Nutrients 2017; 9:nu9030249. [PMID: 28282869 PMCID: PMC5372912 DOI: 10.3390/nu9030249] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2016] [Revised: 03/01/2017] [Accepted: 03/03/2017] [Indexed: 11/17/2022] Open
Abstract
Excessive concentrations of vascular endothelial growth factor (VEGF) trigger angiogenesis, which causes complications such as the destabilization of atherosclerotic plaques and increased growth of tumors. This work focuses on the determination of the inhibitory activity of melatonin and other indolic related compounds on VEGF-induced VEGF receptor-2 (VEGFR-2) activation and an approximation to the molecular mechanism underlying the inhibition. Quantification of phosphorylated VEGFR-2 was measured by ELISA. Migration wound-healing assay was used to determine cell migration of human umbilical vein endothelial cells (HUVECs). This is the first time that melatonin, 3-indolacetic acid, 5-hydroxytryptophol, and serotonin are proved to significantly inhibit VEGF-induced VEGFR-2 activation in human umbilical vein endothelial cells and subsequent angiogenesis. 3-Indolacetic acid showed the highest inhibitory effect (IC50 value of 0.9704 mM), followed by 5-hydroxytryptophol (35% of inhibition at 0.1 mM), melatonin (30% of inhibition at 1 mM), and serotonin (24% of inhibition at 1 mM). An approximation to the molecular mechanism of the inhibition has been proposed, suggesting that indolic compounds might interact with the cell surface components of the endothelial membrane in a way that prevents VEGF from activating the receptor. Additionally, wound-healing assay revealed that exposure of HUVECs to melatonin and 3-indolacetic acid in the presence of VEGF significantly inhibited cell migration by 87% and 99%, respectively, after 24 h. These data demonstrate that melatonin, 3-indolacetic acid, 5-hydroxytryptophol, and serotonin would be good molecules for future exploitation as anti-VEGF signaling agents.
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Affiliation(s)
- Ana B Cerezo
- Departamento de Nutrición y Bromatología, Toxicología y Medicina Legal, Facultad de Farmacia, Universidad de Sevilla, C/P. García González s/n, 41012 Sevilla, Spain.
| | - Ruth Hornedo-Ortega
- Departamento de Nutrición y Bromatología, Toxicología y Medicina Legal, Facultad de Farmacia, Universidad de Sevilla, C/P. García González s/n, 41012 Sevilla, Spain.
| | - M Antonia Álvarez-Fernández
- Departamento de Nutrición y Bromatología, Toxicología y Medicina Legal, Facultad de Farmacia, Universidad de Sevilla, C/P. García González s/n, 41012 Sevilla, Spain.
| | - Ana M Troncoso
- Departamento de Nutrición y Bromatología, Toxicología y Medicina Legal, Facultad de Farmacia, Universidad de Sevilla, C/P. García González s/n, 41012 Sevilla, Spain.
| | - M Carmen García-Parrilla
- Departamento de Nutrición y Bromatología, Toxicología y Medicina Legal, Facultad de Farmacia, Universidad de Sevilla, C/P. García González s/n, 41012 Sevilla, Spain.
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Wu CC, Hung SC, Kuo KL, Tarng DC. Impact of Indoxyl Sulfate on Progenitor Cell-Related Neovascularization of Peripheral Arterial Disease and Post-Angioplasty Thrombosis of Dialysis Vascular Access. Toxins (Basel) 2017; 9:E25. [PMID: 28067862 PMCID: PMC5308257 DOI: 10.3390/toxins9010025] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2016] [Revised: 12/28/2016] [Accepted: 01/04/2017] [Indexed: 01/09/2023] Open
Abstract
Patients with chronic kidney disease (CKD) have an increased risk of vascular disease, which is associated with considerable health care costs. Vascular disease in CKD differs clinically and pathobiologically from that in patients with normal renal function. Besides the traditional risk factors, retention of uremic toxins contributes to the pathogenesis of vascular disease in patients with CKD. Indoxyl sulfate is a protein-bound uremic toxin and is inefficiently removed by conventional dialysis. Accumulating evidence suggests that indoxyl sulfate is a vascular toxin involved in atherosclerosis, arteriosclerosis, vascular calcification and vascular repair. Clinically, indoxyl sulfate is associated with total and cardiovascular mortality in patients with CKD. Recent studies have indicated that in addition to coronary and cerebral arteries, indoxyl sulfate plays a role in peripheral artery disease (PAD) and dialysis graft thrombosis. Emerging evidence suggests that indoxyl sulfate is implicated via novel mechanisms, including progenitor cell-related neovascularization and tissue factor-related hypercoagulability. These findings raise the possibility that strategies targeting serum indoxyl sulfate may have the potential to improve the outcomes of PAD and dialysis vascular access in patients with CKD.
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Affiliation(s)
- Chih-Cheng Wu
- Cardiovascular Center, National Taiwan University Hospital, Hsinchu Branch, Hsinchu 30059, Taiwan.
- National Tsing-Hua University, Institute of Biomedical Engineering, Hsinchu 30013, Taiwan.
- School of Medicine, National Yang-Ming University, Taipei 11217, Taiwan.
| | - Szu-Chun Hung
- Division of Nephrology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and School of Medicine, Tzu Chi University, Hualien 97004, Taiwan.
| | - Ko-Lin Kuo
- Division of Nephrology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and School of Medicine, Tzu Chi University, Hualien 97004, Taiwan.
| | - Der-Cherng Tarng
- Institutes of Physiology and Clinical Medicine, National Yang-Ming University, Taipei 11217, Taiwan.
- Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan.
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Núñez-Gómez E, Pericacho M, Ollauri-Ibáñez C, Bernabéu C, López-Novoa JM. The role of endoglin in post-ischemic revascularization. Angiogenesis 2016; 20:1-24. [PMID: 27943030 DOI: 10.1007/s10456-016-9535-4] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2016] [Accepted: 11/29/2016] [Indexed: 12/12/2022]
Abstract
Following arterial occlusion, blood vessels respond by forming a new network of functional capillaries (angiogenesis), by reorganizing preexisting capillaries through the recruitment of smooth muscle cells to generate new arteries (arteriogenesis) and by growing and remodeling preexisting collateral arterioles into physiologically relevant arteries (collateral development). All these processes result in the recovery of organ perfusion. The importance of endoglin in post-occlusion reperfusion is sustained by several observations: (1) endoglin expression is increased in vessels showing active angiogenesis/remodeling; (2) genetic endoglin haploinsufficiency in humans causes deficient angiogenesis; and (3) the reduction of endoglin expression by gene disruption or the administration of endoglin-neutralizing antibodies reduces angiogenesis and revascularization. However, the precise role of endoglin in the several processes associated with revascularization has not been completely elucidated and, in some cases, the function ascribed to endoglin by different authors is controversial. The purpose of this review is to organize in a critical way the information available for the role of endoglin in several phenomena (angiogenesis, arteriogenesis and collateral development) associated with post-ischemic revascularization.
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Affiliation(s)
- Elena Núñez-Gómez
- Renal and Cardiovascular Research Unit, Department of Physiology and Pharmacology, University of Salamanca, Salamanca, Spain.,Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain
| | - Miguel Pericacho
- Renal and Cardiovascular Research Unit, Department of Physiology and Pharmacology, University of Salamanca, Salamanca, Spain.,Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain
| | - Claudia Ollauri-Ibáñez
- Renal and Cardiovascular Research Unit, Department of Physiology and Pharmacology, University of Salamanca, Salamanca, Spain.,Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain
| | - Carmelo Bernabéu
- Centro de Investigaciones Biológicas, Spanish National Research Council (CIB, CSIC), Madrid, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain
| | - José M López-Novoa
- Renal and Cardiovascular Research Unit, Department of Physiology and Pharmacology, University of Salamanca, Salamanca, Spain. .,Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain.
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Lu CL, Leu JG, Liu WC, Zheng CM, Lin YF, Shyu JF, Wu CC, Lu KC. Endothelial Progenitor Cells Predict Long-Term Mortality in Hemodialysis Patients. Int J Med Sci 2016; 13:240-247. [PMID: 26941585 PMCID: PMC4773289 DOI: 10.7150/ijms.14209] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2015] [Accepted: 01/22/2016] [Indexed: 11/05/2022] Open
Abstract
BACKGROUND The endothelial progenitor cells (EPCs) dysfunction is a critical event in the initiation of atherosclerotic plaque development and the level of circulating EPCs can be considered a biomarker of cardiovascular events. The level and functional change in EPCs has been investigated in hemodialysis patients, but the effect of absolute number of EPCs on risk of death has not yet been explored. We hypothesized that the number of EPCs predicted death from cardiovascular and all-cause mortality in hemodialysis patients. METHODS We evaluate the association between endothelial progenitor cells and clinical outcome in 154 patients on maintenance hemodialysis. The blood sample was drawn at the time of patient enrollment and EPCs were identified by flow cytometry using triple staining for CD34/CD133/KDR. RESULTS The median duration of follow-up was 4.19 years. There were 79 (51.3%) deaths during the follow-up period, 41 of whom died due to a confirmed cardiovascular cause. The cumulative survival was greater in the high-EPC group than the low-EPC group for all-cause and cardiovascular mortality. Decreased EPCs levels were associated with a significant increase in the risk of cardiovascular and all-cause mortality after adjusting for age, gender, current smokers, diabetes mellitus, and hypertension. CONCLUSIONS The level of circulating EPCs independently predicts the clinical outcome in patients on maintenance hemodialysis. Thus, the EPCs levels may be a useful predictive tool for evaluating the risk of death in maintenance hemodialysis patients.
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Affiliation(s)
- Chien-Lin Lu
- 1. Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- 3. Division of Nephrology, Department of Medicine, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan
| | - Jyh-Gang Leu
- 2. School of Medicine, College of Medicine, Fu-Jen Catholic University, New Taipei, Taiwan
- 3. Division of Nephrology, Department of Medicine, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan
| | - Wen-Chih Liu
- 1. Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- 4. Division of Nephrology, Department of Internal Medicine, Yonghe Cardinal Tien Hospital, New Taipei City, Taiwan
| | - Cai-Mei Zheng
- 1. Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- 5. Division of Nephrology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, Taiwan
- 6. Division of Nephrology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University
| | - Yuh-Feng Lin
- 1. Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- 5. Division of Nephrology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, Taiwan
| | - Jia-Fwu Shyu
- 7. Department of Biology and Anatomy, National Defense Medical Center, Taipei, Taiwan
| | - Chia-Chao Wu
- 8. Division of Nephrology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Kuo-Cheng Lu
- 9. Department of Medicine, Cardinal Tien Hospital, School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan
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Challenges and opportunities for stem cell therapy in patients with chronic kidney disease. Kidney Int 2016; 89:767-78. [PMID: 26924058 DOI: 10.1016/j.kint.2015.11.023] [Citation(s) in RCA: 75] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2015] [Revised: 11/10/2015] [Accepted: 11/18/2015] [Indexed: 02/07/2023]
Abstract
Chronic kidney disease (CKD) is a global health care burden affecting billions of individuals worldwide. The kidney has limited regenerative capacity from chronic insults, and for the most common causes of CKD, no effective treatment exists to prevent progression to end-stage kidney failure. Therefore, novel interventions, such as regenerative cell-based therapies, need to be developed for CKD. Given the risk of allosensitization, autologous transplantation of cells to boost regenerative potential is preferred. Therefore, verification of cell function and vitality in CKD patients is imperative. Two cell types have been most commonly applied in regenerative medicine. Endothelial progenitor cells contribute to neovasculogenesis primarily through paracrine angiogenic activity and partly by differentiation into mature endothelial cells in situ. Mesenchymal stem cells also exert paracrine effects, including proangiogenic, anti-inflammatory, and antifibrotic activity. However, in CKD, multiple factors may contribute to reduced cell function, including older age, coexisting cardiovascular disease, diabetes, chronic inflammatory states, and uremia, which may limit the effectiveness of an autologous cell-based therapy approach. This Review highlights current knowledge on stem and progenitor cell function and vitality, aspects of the uremic milieu that may serve as a barrier to therapy, and novel methods to improve stem cell function for potential transplantation.
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Glorieux GLRL, Krieter DH. Effects on the Removal of Uremic Toxins. HEMODIAFILTRATION 2016:165-182. [DOI: 10.1007/978-3-319-23332-1_14] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Stinghen AEM, Massy ZA, Vlassara H, Striker GE, Boullier A. Uremic Toxicity of Advanced Glycation End Products in CKD. J Am Soc Nephrol 2015; 27:354-70. [PMID: 26311460 DOI: 10.1681/asn.2014101047] [Citation(s) in RCA: 173] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Advanced glycation end products (AGEs), a heterogeneous group of compounds formed by nonenzymatic glycation reactions between reducing sugars and amino acids, lipids, or DNA, are formed not only in the presence of hyperglycemia, but also in diseases associated with high levels of oxidative stress, such as CKD. In chronic renal failure, higher circulating AGE levels result from increased formation and decreased renal clearance. Interactions between AGEs and their receptors, including advanced glycation end product-specific receptor (RAGE), trigger various intracellular events, such as oxidative stress and inflammation, leading to cardiovascular complications. Although patients with CKD have a higher burden of cardiovascular disease, the relationship between AGEs and cardiovascular disease in patients with CKD is not fully characterized. In this paper, we review the various deleterious effects of AGEs in CKD that lead to cardiovascular complications and the role of these AGEs in diabetic nephropathy. We also discuss potential pharmacologic approaches to circumvent these deleterious effects by reducing exogenous and endogenous sources of AGEs, increasing the breakdown of existing AGEs, or inhibiting AGE-induced inflammation. Finally, we speculate on preventive and therapeutic strategies that focus on the AGE-RAGE axis to prevent vascular complications in patients with CKD.
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Affiliation(s)
- Andréa E M Stinghen
- Institut National de la Santé et de la Recherche Médicale (INSERM) U-1088, Jules Verne University of Picardie, Amiens, France
| | - Ziad A Massy
- Institut National de la Santé et de la Recherche Médicale (INSERM) U-1088, Jules Verne University of Picardie, Amiens, France; Division of Nephrology, Ambroise Paré University Medical Center, Assistance Publique-Hôpitaux de Paris (APHP), University of Paris Ouest, University Versailles-Saint Quentin, Boulogne Billancourt/Paris, France
| | - Helen Vlassara
- Division of Experimental Diabetes and Aging, Departments of Geriatrics and Palliative Care and Medicine and Division of Experimental Diabetes and Aging, Department of Geriatrics and Aging and Division of Nephrology, Department of Medicine, Icahn School of Medicine, New York, New York; and
| | - Gary E Striker
- Division of Experimental Diabetes and Aging, Departments of Geriatrics and Palliative Care and Medicine and Division of Experimental Diabetes and Aging, Department of Geriatrics and Aging and Division of Nephrology, Department of Medicine, Icahn School of Medicine, New York, New York; and
| | - Agnès Boullier
- Institut National de la Santé et de la Recherche Médicale (INSERM) U-1088, Jules Verne University of Picardie, Amiens, France; Biochemistry Laboratory, Amiens University Medical Center, Amiens, France
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Lee HJ, Kim W, Kim WS, Woo JS, Kim YG, Moon JY, Lee SH, Ihm CG, Lee TW, Jeong KH. Circulating Endothelial Progenitor Cell Levels Predict Cardiovascular Events in End-Stage Renal Disease Patients on Maintenance Hemodialysis. Nephron Clin Pract 2015; 130:151-8. [PMID: 26089157 DOI: 10.1159/000430471] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2014] [Accepted: 04/13/2015] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND The number of circulating endothelial progenitor cells (EPCs) has been identified as a surrogate biologic marker for vascular function and cumulative cardiovascular (CV) risk in the general population. Patients with end-stage renal disease (ESRD) on hemodialysis (HD) have markedly decreased EPC counts and function. We hypothesized that the number of circulating EPCs predicts death from all causes and CV events in patients with ESRD on HD. METHODS We quantified the EPCs in blood samples from 70 patients with ESRD on HD. Circulating EPCs were counted by flow cytometry as the number of CD45(low)CD34(+)VEGFR2(+) cells. Death from all causes and CV events served as outcome variables over a median follow-up period of 20 months. RESULTS It has been postulated that the number of circulating EPCs at baseline ranged from 1 to 350 cells/200 μl, with a mean of ± standard deviation (SD) of 26.0 ± 48.2 cells/200 μl. The median, lowest and highest tertiles of EPC counts were 11.0, 9.0, and 17.0 cells/200 μl, respectively. Patients with the lowest tertile EPC counts had significantly higher rates of CV events, but mortality was similar between the two groups. After adjusting for these risk factors, HbA1c and the lowest tertile EPC count remained as independent predictors of CV events. A cutoff value of 9.5 cells/200 μl maximized the power of the EPC count to predict future CV events as determined by ROC curve analysis. CONCLUSIONS Reduced circulating EPC counts independently predicted CV events in 70 patients with ESRD on maintenance HD. Circulating EPCs may play a role in vascular repair, thereby affecting the clinical course of CV events.
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Affiliation(s)
- Hong Joo Lee
- Department of Nephrology, Seoul Red Cross Hospital, Seoul, South Korea
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Glorieux G, Tattersall J. Uraemic toxins and new methods to control their accumulation: game changers for the concept of dialysis adequacy. Clin Kidney J 2015; 8:353-62. [PMID: 26251699 PMCID: PMC4515890 DOI: 10.1093/ckj/sfv034] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2015] [Revised: 04/21/2015] [Accepted: 04/22/2015] [Indexed: 02/07/2023] Open
Abstract
The current concept of an adequate dialysis based only on the dialysis process itself is rather limited. We now have considerable knowledge of uraemic toxicity and improved tools for limiting uraemic toxin accumulation. It is time to make use of these. A broader concept of adequacy that focusses on uraemic toxicity is required. As discussed in the present review, adequacy could be achieved by many different methods in combination with, or instead of, dialysis. These include preservation of renal function, dietary intake, reducing uraemic toxin generation rate and intestinal absorption, isolated ultrafiltration and extracorporeal adsorption of key uraemic toxins. A better measure of the quality of dialysis treatment would quantify the uraemic state in the patient using levels of a panel of key uraemic toxins. Treatment would focus on controlling uraemic toxicity while reducing harm or inconvenience to the patient. Delivering more dialysis might not be the best way to achieve this.
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Affiliation(s)
- Griet Glorieux
- Department of Internal Medicine, Nephrology Division , Ghent University Hospital , Gent , Belgium
| | - James Tattersall
- Department of Renal Medicine , Leeds Teaching Hospitals , Leeds LS2 7EF , UK
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Stenvinkel P, Carrero JJ, von Walden F, Ikizler TA, Nader GA. Muscle wasting in end-stage renal disease promulgates premature death: established, emerging and potential novel treatment strategies. Nephrol Dial Transplant 2015; 31:1070-7. [PMID: 25910496 DOI: 10.1093/ndt/gfv122] [Citation(s) in RCA: 135] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2015] [Accepted: 03/27/2015] [Indexed: 12/15/2022] Open
Abstract
Muscle wasting (or sarcopenia) is a common feature of the uremic phenotype and predisposes this vulnerable patient population to increased risk of comorbid complications, poor quality of life, frailty and premature death. The old age of dialysis patients is in addition a likely contributor to loss of muscle mass. As recent evidence suggests that assessment of muscle strength (i.e. function) is a better predictor of outcome and comorbidities than muscle mass, this opens new screening, assessment and therapeutic opportunities. Among established treatment strategies, the benefit of resistance exercise and endurance training are increasingly recognized among nephrologists as being effective and should be promoted in sedentary chronic kidney disease patients. Testosterone and growth hormone replacement appear as the most promising among emerging treatments strategies for muscle wasting. As treatment of muscle wasting is difficult and seldom successful in this often old, frail, sedentary and exercise-hesitant patient group, novel treatment strategies are urgently needed. In this review, we summarize recent studies on stimulation of mitochondrial biogenesis, myogenic stem (satellite) cells and manipulation of transforming growth factor family members, all of which hold promise for more effective therapies to target muscle mass loss and function in the future.
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Affiliation(s)
- Peter Stenvinkel
- Department of Renal Medicine, CLINTEC, Karolinska Institutet, Stockholm, Sweden
| | - Juan Jesus Carrero
- Department of Renal Medicine, CLINTEC, Karolinska Institutet, Stockholm, Sweden
| | - Ferdinand von Walden
- Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
| | - T Alp Ikizler
- Division of Nephrology, Vanderbilt University Medical Center, Nashville, USA
| | - Gustavo A Nader
- Department of Kinesiology, The Pennsylvania State University, University Park, USA
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Nelson J, Wu Y, Jiang X, Berretta R, Houser S, Choi E, Wang J, Huang J, Yang X, Wang H. Hyperhomocysteinemia suppresses bone marrow CD34+/VEGF receptor 2+ cells and inhibits progenitor cell mobilization and homing to injured vasculature-a role of β1-integrin in progenitor cell migration and adhesion. FASEB J 2015; 29:3085-99. [PMID: 25854700 DOI: 10.1096/fj.14-267989] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2014] [Accepted: 03/16/2015] [Indexed: 01/18/2023]
Abstract
Hyperhomocysteinemia (HHcy) impairs re-endothelialization and accelerates vascular remodeling. The role of CD34(+)/VEGF receptor (VEGFR) 2(+) progenitor cells (PCs) in vascular repair in HHcy is unknown. We studied the effect of HHcy on PCs and its role in vascular repair in severe HHcy (∼150 μM), which was induced in cystathionine-β synthase heterozygous mice fed a high-methionine diet for 8 weeks. Vascular injury was introduced by carotid air-dry endothelium denudation. CD34(+)/VEGFR2(+) cells were examined by flow cytometry. HHcy reduced bone marrow (BM) CD34(+)/VEGFR2(+) cells and suppressed replenishment of postinjury CD34(+)/VEGFR2(+) cells in peripheral blood (PB). Donor green fluorescent protein-positive PC homing to the injured vessel was reduced in HHcy after CD34(+) PCs from enhanced green fluorescent protein mice were adoptively transferred following carotid injury. CD34(+) PC transfusion partially reversed HHcy-suppressed re-endothelialization and HHcy-induced neointimal formation. Furthermore, homocysteine (Hcy) inhibited proliferation, adhesion, and migration and suppressed β1-integrin expression and activity in human CD34(+) endothelial colony-forming cells (ECFCs) isolated from PBs in a dose-dependent manner. A functional-activating β1-integrin antibody rescued Hcy-suppressed adhesion and migration in CD34(+) ECFCs. In conclusion, HHcy reduces BM CD34(+)/VEGFR2(+) generation and suppresses CD34(+)/VEGFR2(+) cell mobilization and homing to the injured vessel via β1-integrin inhibition, which partially contributes to impaired re-endothelialization and vascular remodeling.
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Affiliation(s)
- Jun Nelson
- *Center for Metabolic Disease Research, Department of Pharmacology, Thrombosis Research Center, Cardiovascular Research Center, Department of Physiology, and Department of Surgery, Temple University School of Medicine, Philadelphia, Pennsylvania, USA; Department of Cardiology, Sun Yixian Memorial Hospital, Zhongshan University School of Medicine, Guangzhou, China; and **Department of Pathology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA
| | - Yi Wu
- *Center for Metabolic Disease Research, Department of Pharmacology, Thrombosis Research Center, Cardiovascular Research Center, Department of Physiology, and Department of Surgery, Temple University School of Medicine, Philadelphia, Pennsylvania, USA; Department of Cardiology, Sun Yixian Memorial Hospital, Zhongshan University School of Medicine, Guangzhou, China; and **Department of Pathology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA
| | - Xiaohua Jiang
- *Center for Metabolic Disease Research, Department of Pharmacology, Thrombosis Research Center, Cardiovascular Research Center, Department of Physiology, and Department of Surgery, Temple University School of Medicine, Philadelphia, Pennsylvania, USA; Department of Cardiology, Sun Yixian Memorial Hospital, Zhongshan University School of Medicine, Guangzhou, China; and **Department of Pathology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA
| | - Remus Berretta
- *Center for Metabolic Disease Research, Department of Pharmacology, Thrombosis Research Center, Cardiovascular Research Center, Department of Physiology, and Department of Surgery, Temple University School of Medicine, Philadelphia, Pennsylvania, USA; Department of Cardiology, Sun Yixian Memorial Hospital, Zhongshan University School of Medicine, Guangzhou, China; and **Department of Pathology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA
| | - Steven Houser
- *Center for Metabolic Disease Research, Department of Pharmacology, Thrombosis Research Center, Cardiovascular Research Center, Department of Physiology, and Department of Surgery, Temple University School of Medicine, Philadelphia, Pennsylvania, USA; Department of Cardiology, Sun Yixian Memorial Hospital, Zhongshan University School of Medicine, Guangzhou, China; and **Department of Pathology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA
| | - Eric Choi
- *Center for Metabolic Disease Research, Department of Pharmacology, Thrombosis Research Center, Cardiovascular Research Center, Department of Physiology, and Department of Surgery, Temple University School of Medicine, Philadelphia, Pennsylvania, USA; Department of Cardiology, Sun Yixian Memorial Hospital, Zhongshan University School of Medicine, Guangzhou, China; and **Department of Pathology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA
| | - Jingfeng Wang
- *Center for Metabolic Disease Research, Department of Pharmacology, Thrombosis Research Center, Cardiovascular Research Center, Department of Physiology, and Department of Surgery, Temple University School of Medicine, Philadelphia, Pennsylvania, USA; Department of Cardiology, Sun Yixian Memorial Hospital, Zhongshan University School of Medicine, Guangzhou, China; and **Department of Pathology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA
| | - Jian Huang
- *Center for Metabolic Disease Research, Department of Pharmacology, Thrombosis Research Center, Cardiovascular Research Center, Department of Physiology, and Department of Surgery, Temple University School of Medicine, Philadelphia, Pennsylvania, USA; Department of Cardiology, Sun Yixian Memorial Hospital, Zhongshan University School of Medicine, Guangzhou, China; and **Department of Pathology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA
| | - Xiaofeng Yang
- *Center for Metabolic Disease Research, Department of Pharmacology, Thrombosis Research Center, Cardiovascular Research Center, Department of Physiology, and Department of Surgery, Temple University School of Medicine, Philadelphia, Pennsylvania, USA; Department of Cardiology, Sun Yixian Memorial Hospital, Zhongshan University School of Medicine, Guangzhou, China; and **Department of Pathology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA
| | - Hong Wang
- *Center for Metabolic Disease Research, Department of Pharmacology, Thrombosis Research Center, Cardiovascular Research Center, Department of Physiology, and Department of Surgery, Temple University School of Medicine, Philadelphia, Pennsylvania, USA; Department of Cardiology, Sun Yixian Memorial Hospital, Zhongshan University School of Medicine, Guangzhou, China; and **Department of Pathology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA
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Sedighi O, Abediankenari S, Omranifar B. Association between plasma Beta-2 microglobulin level and cardiac performance in patients with chronic kidney disease. Nephrourol Mon 2015; 7:e23563. [PMID: 25738124 PMCID: PMC4330690 DOI: 10.5812/numonthly.23563] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2014] [Accepted: 10/01/2014] [Indexed: 11/18/2022] Open
Abstract
Background: Beta-2 microglobulin (B2M) is considered as a surrogate marker for middle molecule uremic toxins and a key component in dialysis-related amyloidosis. However, few studies have evaluated role of B2M in patients with chronic kidney disease (CKD). Objectives: The purpose of this study was to evaluate the association of plasma B2M level with some metabolic and cardiac performance factors in patients with CKD. Patients and Methods: In this case-control study, we measured plasma B2M level in 86 patients with different stages of CKD and 78 age- and sex-matched individuals, as healthy control group. Then we investigated the association between plasma B2M level and left ventricular hypertrophy, ejection fraction (EF), and left ventricular end-diastolic diameter (LVEDD) in echocardiography and some inflammatory and metabolic factors in patients with CKD. Results: Mean plasma B2M level was significantly higher in patients with CKD than in control group (P < 0.001). It was directly correlated with serum C-reactive protein (r = 0.167, P < 0.001), phosphate (r = 0.112, P < 0.001) levels, and left ventricular mass index (r = 0.438, P < 0.001) and LVEDD (r = 0.275, P < 0.001) in echocardiography. It was also inversely correlated with glomerular filtration rate (r = -0.033, P < 0.001), albumin (r = -0.521, P < 0.001), hemoglobin (r = -0.748, P < 0.001), and EF (r = -0.625, P < 0.001). Conclusions: Our findings suggested that plasma B2M level is inversely associated with GFR and EF and directly correlated with some metabolic and cardiac performance factors.
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Affiliation(s)
- Omid Sedighi
- Immunogenetic Research Center, Imam Khomeini Hospital, Mazandaran University of Medical Sciences, Sari, IR Iran
| | - Saeid Abediankenari
- Immunogenetic Research Center, Imam Khomeini Hospital, Mazandaran University of Medical Sciences, Sari, IR Iran
- Diabetes Research Center, Mazandaran University of Medical Sciences, Sari, IR Iran
- Corresponding author: Saeid Abediankenari, Diabetes Research Center, Mazandaran University of Medical Sciences, Sari, IR Iran. Tel: +98-9121985667, Fax: +98-1513543087, E-mail:
| | - Batoul Omranifar
- Department of Cardiology, Imam Khomeini Hospital, Mazandaran University of Medical Sciences, Sari, IR Iran
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Zumrutdal A. Role of β 2-microglobulin in uremic patients may be greater than originally suspected. World J Nephrol 2015; 4:98-104. [PMID: 25664251 PMCID: PMC4317633 DOI: 10.5527/wjn.v4.i1.98] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2014] [Revised: 09/03/2014] [Accepted: 10/10/2014] [Indexed: 02/06/2023] Open
Abstract
The role of beta2-microglobulin (β2M) in dialysis-related amyloidosis as a specific amyloid precursor was defined in the 1980s. Studies in those years were largely related to β2M amyloidosis. In 2005, for what was probably the first time in the available literature, we provided data about the association between β2M and early-onset atherosclerosis in hemodialysis patients without co-morbidities. In recent years, the role of uremic toxins in uremic atherosclerosis and the interest in β2M as a marker of cardiovascular (CV) and/or mortality risk have grown. In the current literature, clinical studies suggest that β2M is an independent, significant predictor of mortality, not only in dialysis patients, but also in predialysis patients and in the high-risk portion of the general population, and it seems to be a factor strongly linked to the presence and severity of CV disease. It is still unknown whether β2M is only a uremic toxin marker or if it also has an active role in vascular damage, but data support that it may reflect an increased burden of systemic atherosclerosis in a setting of underlying chronic kidney disease. Thus, although there have been some inconsistencies among the various analyses relating to β2M, it promises to be a novel risk marker of kidney function in the awareness and detection of high-risk patients. However, more research is required to establish the pathophysiological relationships between retained uremic toxins and further biochemical modifications in the uremic milieu to get answers to the questions of why and how. In this review, the recent literature about the changing role of β2M in uremic patients will be examined.
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48
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Lekawanvijit S. Role of Gut-Derived Protein-Bound Uremic Toxins in Cardiorenal Syndrome and Potential Treatment Modalities. Circ J 2015; 79:2088-97. [DOI: 10.1253/circj.cj-15-0749] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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Bataille S, Burtey S, Decourt A, Frère C, Henneuse A, Aillaud MF, Morange P, Bardin N, Duval A, Sallée M, Jourde-Chiche N, Gondouin B, Samson L, Cohen J, Berland Y, Brunet P. [Antiphospholipids antibodies and hemodialysis: a frequent association linked to arteriovenous fistula thrombosis]. Nephrol Ther 2014; 11:27-33. [PMID: 25457108 DOI: 10.1016/j.nephro.2014.08.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2014] [Revised: 08/19/2014] [Accepted: 08/23/2014] [Indexed: 10/24/2022]
Abstract
Antiphospholipid antibodies (APL) are a heterogeneous family of auto-antibodies that recognize phospholipoproteins bound antigenic epitopes. APL prevalence in patients on chronic hemodialysis ranges from 11 to 37% in the literature. The association of APL with hemodialysis vascular access (VA) thrombosis has already been reported in small studies. In this single center and retrospective study, we defined the APL prevalence and APL risk factors in a large cohort of 192 hemodialysis patients. The association between history of VA thrombosis and APL presence was also analyzed. At least one type of APL was found in 38 patients (19.8%) of which 74% (n=28) had only lupus anticoagulant. Median age of APL positive patients was 68.1years vs. 71.3years in APL negative patients (P=0.02). Smoking history was associated with APL presence: 35.5% of APL positive patients had a smoking history vs only 18.3% of APL negative patients (P=0.04). The multivariate analysis showed an association between the history of VA thrombosis and patient age (HR [IC 95%]=1.04 [1.02-1.06]; P=0.001) or APL presence (HR [IC 95%]=3.03 [1.69-4.42]; P<10(-3)). In conclusion, the prevalence of APL in hemodialysis patients remains high despite hemodialysis techniques improvement: hemodiafiltration, biocompatibility improvements, ultrapure dialysis water. We report that a younger age and past history of smoking are associated with an increased risk of APL presence. The presence of APL, especially lupus anticoagulant, is associated to VA thrombosis in hemodialysis patients.
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Affiliation(s)
- Stanislas Bataille
- Centre de néphrologie et transplantation rénale, hôpital de la Conception, université Aix-Marseille, 147, boulevard Baille, 13385 Marseille cedex 05, France; Institut Phocéen de néphrologie, clinique Bouchard, 13006 Marseille, France.
| | - Stéphane Burtey
- Centre de néphrologie et transplantation rénale, hôpital de la Conception, université Aix-Marseille, 147, boulevard Baille, 13385 Marseille cedex 05, France; UMRS_1076, VRCM, faculté de pharmacie, Aix-Marseille université, 13385 Marseille cedex 05, France
| | - Alexandre Decourt
- Centre de néphrologie et transplantation rénale, hôpital de la Conception, université Aix-Marseille, 147, boulevard Baille, 13385 Marseille cedex 05, France
| | - Corinne Frère
- Laboratoire d'hématologie, hôpital de la Timone, université Aix-Marseille, 13385 Marseille cedex 05, France
| | - Agathe Henneuse
- Laboratoire d'hématologie, hôpital de la Timone, université Aix-Marseille, 13385 Marseille cedex 05, France
| | - Marie-Françoise Aillaud
- Laboratoire d'hématologie, hôpital de la Timone, université Aix-Marseille, 13385 Marseille cedex 05, France
| | - Pierre Morange
- Laboratoire d'hématologie, hôpital de la Timone, université Aix-Marseille, 13385 Marseille cedex 05, France
| | - Nathalie Bardin
- UMRS_1076, VRCM, faculté de pharmacie, Aix-Marseille université, 13385 Marseille cedex 05, France; Medistats, 10, rue de la Conception, 13004 Marseille, France
| | - Ariane Duval
- Centre de néphrologie et transplantation rénale, hôpital de la Conception, université Aix-Marseille, 147, boulevard Baille, 13385 Marseille cedex 05, France
| | - Marion Sallée
- Centre de néphrologie et transplantation rénale, hôpital de la Conception, université Aix-Marseille, 147, boulevard Baille, 13385 Marseille cedex 05, France
| | - Noémie Jourde-Chiche
- Centre de néphrologie et transplantation rénale, hôpital de la Conception, université Aix-Marseille, 147, boulevard Baille, 13385 Marseille cedex 05, France
| | - Bertrand Gondouin
- Centre de néphrologie et transplantation rénale, hôpital de la Conception, université Aix-Marseille, 147, boulevard Baille, 13385 Marseille cedex 05, France
| | - Laurent Samson
- Centre de néphrologie et transplantation rénale, hôpital de la Conception, université Aix-Marseille, 147, boulevard Baille, 13385 Marseille cedex 05, France
| | - Julien Cohen
- Biostatistiques, institut Phocéen de néphrologie, clinique Bouchard, Marseille, France
| | - Yvon Berland
- Centre de néphrologie et transplantation rénale, hôpital de la Conception, université Aix-Marseille, 147, boulevard Baille, 13385 Marseille cedex 05, France
| | - Philippe Brunet
- Centre de néphrologie et transplantation rénale, hôpital de la Conception, université Aix-Marseille, 147, boulevard Baille, 13385 Marseille cedex 05, France
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Lozito TP, Tuan RS. Endothelial and cancer cells interact with mesenchymal stem cells via both microparticles and secreted factors. J Cell Mol Med 2014; 18:2372-84. [PMID: 25250510 PMCID: PMC4302643 DOI: 10.1111/jcmm.12391] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2014] [Accepted: 06/27/2014] [Indexed: 12/13/2022] Open
Abstract
Tightly associated with blood vessels in their perivascular niche, human mesenchymal stem cells (MSCs) closely interact with endothelial cells (ECs). MSCs also home to tumours and interact with cancer cells (CCs). Microparticles (MPs) are cell-derived vesicles released into the extracellular environment along with secreted factors. MPs are capable of intercellular signalling and, as biomolecular shuttles, transfer proteins and RNA from one cell to another. Here, we characterize interactions among ECs, CCs and MSCs via MPs and secreted factors in vitro. MPs and non-MP secreted factors (Sup) were isolated from serum-free medium conditioned by human microvascular ECs (HMEC-1) or by the CC line HT1080. Fluorescently labelled MPs were prepared from cells treated with membrane dyes, and cytosolic GFP-containing MPs were isolated from cells transduced with CMV-GFP lentivirus. MSCs were treated with MPs, Sup, or vehicle controls, and analysed for MP uptake, proliferation, migration, activation of intracellular signalling pathways and cytokine release. Fluorescently labelled MPs fused with MSCs, transferring the fluorescent dyes to the MSC surface. GFP was transferred to and retained in MSCs incubated with GFP-MPs, but not free GFP. Thus, only MP-associated cellular proteins were taken up and retained by MSCs, suggesting that MP biomolecules, but not secreted factors, are shuttled to MSCs. MP and Sup treatment significantly increased MSC proliferation, migration, and MMP-1, MMP-3, CCL-2/MCP-1 and IL-6 secretion compared with vehicle controls. MSCs treated with Sup and MPs also exhibited activated NF-κB signalling. Taken together, these results suggest that MPs act to regulate MSC functions through several mechanisms.
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Affiliation(s)
- Thomas P Lozito
- Department of Orthopaedic Surgery, Center for Cellular and Molecular Engineering, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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