Toxins

Editorial

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3 pages, 197 KiB

Open AccessEditorial

Special Issue: Immune Dysfunction in Uremia

by Gerald Cohen and Raymond Vanholder

Toxins 2021, 13(1), 70; https://doi.org/10.3390/toxins13010070 - 19 Jan 2021

Cited by 6 | Viewed by 1833

Abstract

This Special Issue of Toxins focusses on the interconnected factors interfering with the immune response in uremic patients [...] Full article

(This article belongs to the Special Issue Immune Dysfunction in Uremia)

Research

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14 pages, 1506 KiB

Open AccessArticle

A Pharmacokinetic Study Comparing the Clearance of Vancomycin during Haemodialysis Using Medium Cut-Off Membrane (Theranova) and High-Flux Membranes (Revaclear)

by Hussain Allawati, Linda Dallas, Sreejith Nair, Janine Palmer, Shaiju Thaikandy and Colin Hutchison

Toxins 2020, 12(5), 317; https://doi.org/10.3390/toxins12050317 - 12 May 2020

Cited by 10 | Viewed by 3992

Abstract

Medium cut-off membrane (MCO) dialysers have been shown to remove a range of middle molecules, which are associated with adverse outcomes in haemodialysis (HD) patients, more effectively than high-flux HD. Vancomycin is widely used in HD patients for treating a variety of infections. [...] Read more.

Medium cut-off membrane (MCO) dialysers have been shown to remove a range of middle molecules, which are associated with adverse outcomes in haemodialysis (HD) patients, more effectively than high-flux HD. Vancomycin is widely used in HD patients for treating a variety of infections. To avoid subtherapeutic trough concentrations, it is important to understand vancomycin clearance in patients undergoing HD with the MCO membrane. This open label single centre, cross-over clinical study compared the vancomycin pharmacokinetics in chronic HD patients using MCO membrane (Theranova) and high-flux membrane (Revaclear). Five patients established on chronic HD who were due to receive vancomycin were enrolled. The study used alternating Theranova and Revaclear dialysis membranes over six consecutive sessions. Vancomycin was administered over the last one to two hours of each HD session. The maintenance dose was adjusted based on pre-HD serum concentrations. Over the 210 study samples, vancomycin clearance was higher with MCO-HD compared to high-flux HD but not statistically significant. Median percentage of vancomycin removal at 120 min by MCO membrane was 39% (20.6–51.5%) compared with 34.1% (21.3–48.4%) with high-flux HD. MCO-HD removes a slightly higher percentage of vancomycin at 120 min into dialysis compared to high-flux membrane dialysis in HD patients with infections. Application of vancomycin during the last one to two hours of each dialysis is required to maintain therapeutic concentrations to minimise loss through the dialyser and maintain therapeutic levels. Full article

(This article belongs to the Special Issue Immune Dysfunction in Uremia)

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11 pages, 1277 KiB

Open AccessArticle

Hypervolemia-Induced Immune Disturbances Do Not Involve IL-1ß but IL-6 and IL-10 Activation in Haemodialysis Patients

by Christof Ulrich, Annegret Wilke, Nadja Schleicher, Matthias Girndt and Roman Fiedler

Toxins 2020, 12(3), 159; https://doi.org/10.3390/toxins12030159 - 03 Mar 2020

Cited by 6 | Viewed by 2434

Abstract

Dysregulated fluid homeostasis is frequent in haemodialysis (HD) patients and is linked to inflammation which may be elicited by endotoxemia. The impact of hypervolemia on immune cells has not been studied in detail. Therefore, we analysed the hypervolemic activation of peripheral blood mononuclear [...] Read more.

Dysregulated fluid homeostasis is frequent in haemodialysis (HD) patients and is linked to inflammation which may be elicited by endotoxemia. The impact of hypervolemia on immune cells has not been studied in detail. Therefore, we analysed the hypervolemic activation of peripheral blood mononuclear cells (PBMCs) in HD with special focus on the NLRP3 inflammasome response. First, 45 HD were included in the observational study. Immune parameters including cell counts, caspase-1, oxidative stress, cytokine gene expression and serum analysis (IL-1ß, IL-6, IL-10) were all measured at two time points. Fluid status was evaluated by electrical bioimpedance vector analysis, defining hypervolemia (H) as >75 vector percentile. Then, 17 patients were classified as hypervolemic (H-HD), 19 as normovolemic (N-HD) and 9 failed to meet the inclusion criteria. Monocytes were elevated and lymphocytes were decreased by hypervolemia. NLRP3 inflammasome components, caspase-1 and IL-1ß expression were not statistically different between the two groups. Serum IL-6 levels were significantly elevated in H-HD. IL-10 mRNA transcripts were elevated by 2-fold in H-HD but were not efficiently translated. We conclude that the NLRP3 inflammasome is not activated by hypervolemia thus refuting the thesis that endotoxemia may be a main driver for inflammation in H-HD. Nevertheless, inflammation is generally higher in H-HD compared to N-HD patients and is not sufficiently balanced by anti-inflammatory mechanisms. Full article

(This article belongs to the Special Issue Immune Dysfunction in Uremia)

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15 pages, 1544 KiB

Open AccessEditor’s ChoiceArticle

Association of Nrf2, SOD2 and GPX1 Polymorphisms with Biomarkers of Oxidative Distress and Survival in End-Stage Renal Disease Patients

by Djurdja Jerotic, Marija Matic, Sonja Suvakov, Katarina Vucicevic, Tatjana Damjanovic, Ana Savic-Radojevic, Marija Pljesa-Ercegovac, Vesna Coric, Aleksandra Stefanovic, Jasmina Ivanisevic, Zorana Jelic-Ivanovic, Lana McClements, Nada Dimkovic and Tatjana Simic

Toxins 2019, 11(7), 431; https://doi.org/10.3390/toxins11070431 - 23 Jul 2019

Cited by 22 | Viewed by 4193

Abstract

The oxidative stress response via Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) interlinks inflammation- and metabolism-related pathways in chronic kidney disease. We assessed the association between polymorphisms in Nrf2, superoxide dismutase (SOD2), glutathione peroxidase (GPX1), and the risk of end-stage renal disease (ESRD). The [...] Read more.

The oxidative stress response via Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) interlinks inflammation- and metabolism-related pathways in chronic kidney disease. We assessed the association between polymorphisms in Nrf2, superoxide dismutase (SOD2), glutathione peroxidase (GPX1), and the risk of end-stage renal disease (ESRD). The modifying effect of these polymorphisms on both oxidative phenotype and ESRD prognosis, both independently and/or in combination with the glutathione S-transferase M1 (GSTM1) deletion polymorphism, was further analyzed. Polymorphisms in Nrf2 (rs6721961), SOD2 (rs4880), GPX1 (rs1050450), and GSTM1 were determined by PCR in 256 ESRD patients undergoing hemodialysis and 374 controls. Byproducts of oxidative stress were analyzed spectrophotometically or by ELISA. Time-to-event modeling was performed to evaluate overall survival and cardiovascular survival. The SOD2 Val/Val genotype increased ESRD risk (OR = 2.01, p = 0.002), which was even higher in combination with the GPX1 Leu/Leu genotype (OR = 3.27, p = 0.019). Polymorphism in SOD2 also showed an effect on oxidative phenotypes. Overall survival in ESRD patients was dependent on a combination of the Nrf2 (C/C) and GPX1 (Leu/Leu) genotypes in addition to a patients’ age and GSTM1 polymorphism. Similarly, the GPX1 (Leu/Leu) genotype contributed to longer cardiovascular survival. Conclusions: Our results show that SOD2, GPX1, and Nrf2 polymorphisms are associated with ESRD development and can predict survival. Full article

(This article belongs to the Special Issue Immune Dysfunction in Uremia)

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Review

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27 pages, 901 KiB

Open AccessEditor’s ChoiceReview

Immune Dysfunction in Uremia 2020

by Gerald Cohen

Toxins 2020, 12(7), 439; https://doi.org/10.3390/toxins12070439 - 05 Jul 2020

Cited by 75 | Viewed by 6060

Abstract

Cardiovascular disease and infections are major causes for the high incidence of morbidity and mortality of patients with chronic kidney disease. Both complications are directly or indirectly associated with disturbed functions or altered apoptotic rates of polymorphonuclear leukocytes, monocytes, lymphocytes, and dendritic cells. [...] Read more.

Cardiovascular disease and infections are major causes for the high incidence of morbidity and mortality of patients with chronic kidney disease. Both complications are directly or indirectly associated with disturbed functions or altered apoptotic rates of polymorphonuclear leukocytes, monocytes, lymphocytes, and dendritic cells. Normal responses of immune cells can be reduced, leading to infectious diseases or pre-activated/primed, giving rise to inflammation and subsequently to cardiovascular disease. This review summarizes the impact of kidney dysfunction on the immune system. Renal failure results in disturbed renal metabolic activities with reduced renin, erythropoietin, and vitamin D production, which adversely affects the immune system. Decreased kidney function also leads to reduced glomerular filtration and the retention of uremic toxins. A large number of uremic toxins with detrimental effects on immune cells have been identified. Besides small water-soluble and protein-bound compounds originating from the intestinal microbiome, several molecules in the middle molecular range, e.g., immunoglobulin light chains, retinol-binding protein, the neuropeptides Met-enkephalin and neuropeptide Y, endothelin-1, and the adipokines leptin and resistin, adversely affect immune cells. Posttranslational modifications such as carbamoylation, advanced glycation products, and oxidative modifications contribute to uremic toxicity. Furthermore, high-density lipoprotein from uremic patients has an altered protein profile and thereby loses its anti-inflammatory properties. Full article

(This article belongs to the Special Issue Immune Dysfunction in Uremia)

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22 pages, 1550 KiB

Open AccessEditor’s ChoiceReview

Endothelial Damage, Inflammation and Immunity in Chronic Kidney Disease

by Maribel Diaz-Ricart, Sergi Torramade-Moix, Georgina Pascual, Marta Palomo, Ana Belen Moreno-Castaño, Julia Martinez-Sanchez, Manel Vera, Aleix Cases and Gines Escolar

Toxins 2020, 12(6), 361; https://doi.org/10.3390/toxins12060361 - 01 Jun 2020

Cited by 44 | Viewed by 4872

Abstract

Chronic kidney disease (CKD) patients have an accelerated atherosclerosis, increased risk of thrombotic-ischemic complications, and excessive mortality rates when compared with the general population. There is also evidence of an endothelial damage in which the proinflammatory state, the enhanced oxidative stress, or the [...] Read more.

Chronic kidney disease (CKD) patients have an accelerated atherosclerosis, increased risk of thrombotic-ischemic complications, and excessive mortality rates when compared with the general population. There is also evidence of an endothelial damage in which the proinflammatory state, the enhanced oxidative stress, or the accumulation of toxins due to their reduced renal clearance in uremia play a role. Further, there is evidence that uremic endothelial cells are both involved in and victims of the activation of the innate immunity. Uremic endothelial cells produce danger associated molecular patterns (DAMPS), which by binding to specific pattern recognition receptors expressed in multiple cells, including endothelial cells, induce the expression of adhesion molecules, the production of proinflammatory cytokines and an enhanced production of reactive oxygen species in endothelial cells, which constitute a link between immunity and inflammation. The connection between endothelial damage, inflammation and defective immunity in uremia will be reviewed here. Full article

(This article belongs to the Special Issue Immune Dysfunction in Uremia)

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20 pages, 1724 KiB

Open AccessReview

Monocytes in Uremia

by Matthias Girndt, Bogusz Trojanowicz and Christof Ulrich

Toxins 2020, 12(5), 340; https://doi.org/10.3390/toxins12050340 - 21 May 2020

Cited by 29 | Viewed by 3927

Abstract

Monocytes play an important role in both innate immunity and antigen presentation for specific cellular immune defense. In patients with chronic renal failure, as well as those treated with maintenance hemodialysis, these cells are largely dysregulated. There is a large body of literature [...] Read more.

Monocytes play an important role in both innate immunity and antigen presentation for specific cellular immune defense. In patients with chronic renal failure, as well as those treated with maintenance hemodialysis, these cells are largely dysregulated. There is a large body of literature on monocyte alterations in such patients. However, most of the publications report on small series, there is a vast spectrum of different methods and the heterogeneity of the data prevents any meta-analytic approach. Thus, a narrative review was performed to describe the current knowledge. Monocytes from patients with chronic renal failure differ from those of healthy individuals in the pattern of surface molecule expression, cytokine and mediator production, and function. If these findings can be summarized at all, they might be subsumed as showing chronic inflammation in resting cells together with limited activation upon immunologic challenge. The picture is complicated by the fact that monocytes fall into morphologically and functionally different populations and population shifts interact heavily with dysregulation of the individual cells. Severe complications of chronic renal failure such as impaired immune defense, inflammation, and atherosclerosis can be related to several aspects of monocyte dysfunction. Therefore, this review aims to provide an overview about the impairment and activation of monocytes by uremia and the resulting clinical consequences for renal failure patients. Full article

(This article belongs to the Special Issue Immune Dysfunction in Uremia)

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16 pages, 1434 KiB

Open AccessEditor’s ChoiceReview

Chronic Kidney Disease-Associated Immune Dysfunctions: Impact of Protein-Bound Uremic Retention Solutes on Immune Cells

by Maxime Espi, Laetitia Koppe, Denis Fouque and Olivier Thaunat

Toxins 2020, 12(5), 300; https://doi.org/10.3390/toxins12050300 - 06 May 2020

Cited by 61 | Viewed by 13024

Abstract

Regardless of the primary disease responsible for kidney failure, patients suffering from chronic kidney disease (CKD) have in common multiple impairments of both the innate and adaptive immune systems, the pathophysiology of which has long remained enigmatic. CKD-associated immune dysfunction includes chronic low-grade [...] Read more.

Regardless of the primary disease responsible for kidney failure, patients suffering from chronic kidney disease (CKD) have in common multiple impairments of both the innate and adaptive immune systems, the pathophysiology of which has long remained enigmatic. CKD-associated immune dysfunction includes chronic low-grade activation of monocytes and neutrophils, which induces endothelial damage and increases cardiovascular risk. Although innate immune effectors are activated during CKD, their anti-bacterial capacity is impaired, leading to increased susceptibility to extracellular bacterial infections. Finally, CKD patients are also characterized by profound alterations of cellular and humoral adaptive immune responses, which account for an increased risk for malignancies and viral infections. This review summarizes the recent emerging data that link the pathophysiology of CKD-associated immune dysfunctions with the accumulation of microbiota-derived metabolites, including indoxyl sulfate and p-cresyl sulfate, the two best characterized protein-bound uremic retention solutes. Full article

(This article belongs to the Special Issue Immune Dysfunction in Uremia)

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16 pages, 688 KiB

Open AccessEditor’s ChoiceReview

Gut-Derived Metabolites and Their Role in Immune Dysfunction in Chronic Kidney Disease

by Griet Glorieux, Tessa Gryp and Alessandra Perna

Toxins 2020, 12(4), 245; https://doi.org/10.3390/toxins12040245 - 11 Apr 2020

Cited by 45 | Viewed by 5357

Abstract

Several of the uremic toxins, which are difficult to remove by dialysis, originate from the gut bacterial metabolism. This opens opportunities for novel targets trying to decrease circulating levels of these toxins and their pathophysiological effects. The current review focuses on immunomodulatory effects [...] Read more.

Several of the uremic toxins, which are difficult to remove by dialysis, originate from the gut bacterial metabolism. This opens opportunities for novel targets trying to decrease circulating levels of these toxins and their pathophysiological effects. The current review focuses on immunomodulatory effects of these toxins both at their side of origin and in the circulation. In the gut end products of the bacterial metabolism such as p-cresol, trimethylamine and H₂S affect the intestinal barrier structure and function while in the circulation the related uremic toxins stimulate cells of the immune system. Both conditions contribute to the pro-inflammatory status of patients with chronic kidney disease (CKD). Generation and/or absorption of these toxin precursors could be targeted to decrease plasma levels of their respective uremic toxins and to reduce micro-inflammation in CKD. Full article

(This article belongs to the Special Issue Immune Dysfunction in Uremia)

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14 pages, 803 KiB

Open AccessReview

Uremia-Associated Ageing of the Thymus and Adaptive Immune Responses

by Michiel GH Betjes

Toxins 2020, 12(4), 224; https://doi.org/10.3390/toxins12040224 - 03 Apr 2020

Cited by 34 | Viewed by 4772

Abstract

Progressive loss of renal function is associated with a series of changes of the adaptive immune system which collectively constitute premature immunological ageing. This phenomenon contributes significantly to the mortality and morbidity of end-stage renal disease (ESRD) patients. In this review, the effect [...] Read more.

Progressive loss of renal function is associated with a series of changes of the adaptive immune system which collectively constitute premature immunological ageing. This phenomenon contributes significantly to the mortality and morbidity of end-stage renal disease (ESRD) patients. In this review, the effect of ESRD on the T cell part of the adaptive immune system is highlighted. Naïve T cell lymphopenia, in combination with the expansion of highly differentiated memory T cells, are the hallmarks of immunological ageing. The decreased production of newly formed T cells by the thymus is critically involved. This affects both the CD4 and CD8 T cell compartment and may contribute to the expansion of memory T cells. The expanding populations of memory T cells have a pro-inflammatory phenotype, add to low-grade inflammation already present in ESRD patients and destabilize atherosclerotic plaques. The effect of loss of renal function on the thymus is not reversed after restoring renal function by kidney transplantation and constitutes a long-term mortality risk factor. Promising results from animal experiments have shown that rejuvenation of the thymus is a possibility, although not yet applicable in humans. Full article

(This article belongs to the Special Issue Immune Dysfunction in Uremia)

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