Special Issue "Immune Dysfunction in Uremia"

A special issue of Toxins (ISSN 2072-6651). This special issue belongs to the section "Uremic Toxins".

Deadline for manuscript submissions: closed (31 March 2020).

Special Issue Editors

Prof. Dr. R. Vanholder

Guest Editor
Nephrology Section, 0K12, Department of Internal Medicine, Ghent University Hospital, 9000 Ghent, Belgium
Interests: uremia, chronic kidney disease, hemodialysis, adequacy of dialysis, acute kidney injury
Special Issues and Collections in MDPI journals
Prof. Dr. Gerald Cohen

Guest Editor
Division of Nephrology and Dialysis, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
Interests: uremic toxins, neutrophils, apoptosis, NETosis

Special Issue Information

Dear Colleagues,

Cardiovascular disease as a consequence of inflammation and infections is the main cause for the increased occurrence of morbidity and mortality among patients with chronic kidney disease (CKD). Both complications are directly or indirectly linked to a compromised immune defense, innate as well as adaptive. The specific coordinated roles of neutrophils, monocytes/macrophages, lymphocytes, and antigen-presenting cells in maintaining an efficient immune response are affected. Furthermore, a state of genomic instability with declining kidney function may lead to the genomic damage and dysfunction of immune cells.
Kidney dysfunction leads to impaired glomerular filtration, resulting in the retention of toxic solutes affecting all organs of the body, inducing both primary activation of the immune system and lack of responsiveness when confronted with infection or other foreign stimuli. In CKD, proteins may become irreversibly changed by posttranslational modifications, resulting in an altered effect on the immune response. Uremic toxins may also be generated or introduced into the body via the intestine. Acute renal failure has a severe impact on the immune system as well, both on the molecular (e.g., complement, cytokines, and lymphocytes) and the cellular level (e.g., neutrophils, macrophages, lymphocytes).
Kidney replacement therapies per se may adversely affect the immune system. Critical evaluation and systematic design of preventive and therapeutic interventions for patients with kidney disease will help to develop novel therapeutic strategies to improve immune response. Kidney transplantation may reverse uremia-related defects but also induce immune dysfunction by immunosuppressive therapy. In addition to impaired glomerular filtration, disturbed metabolic activities of the kidney per se may be involved in manifestations of the uremic syndrome. Several substances that are produced by the kidneys, such as erythropoietin, calcitriol, and renin, affect the immune system.
The focus of this Special Issue of Toxins will be on the interrelated factors interfering with the immune response in patients with kidney dysfunction.

Prof. Dr. R. Vanholder
Prof. Dr. Gerald Cohen
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a double-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Toxins is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2000 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Acute renal failure
  • Antigen-presenting cells
  • Calcitriol
  • Cardiovascular disease
  • Chronic kidney disease
  • Complement
  • Cytokines
  • Epigenetics
  • Erythropoietin
  • Hemodialysis
  • Immunosuppression
  • Infection
  • Inflammation
  • Intestine/microbiota
  • Kidney transplantation
  • Lymphocytes
  • Monocytes/macrophages
  • Neutrophils
  • Peritoneal dialysis
  • Posttranslational
  • modifications
  • Renin
  • Uremic toxins
  • Brain

Published Papers (8 papers)

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Research

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Open AccessArticle
A Pharmacokinetic Study Comparing the Clearance of Vancomycin during Haemodialysis Using Medium Cut-Off Membrane (Theranova) and High-Flux Membranes (Revaclear)
Toxins 2020, 12(5), 317; https://doi.org/10.3390/toxins12050317 - 12 May 2020
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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Open AccessArticle
Hypervolemia-Induced Immune Disturbances Do Not Involve IL-1ß but IL-6 and IL-10 Activation in Haemodialysis Patients
Toxins 2020, 12(3), 159; https://doi.org/10.3390/toxins12030159 - 03 Mar 2020
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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Open AccessArticle
Association of Nrf2, SOD2 and GPX1 Polymorphisms with Biomarkers of Oxidative Distress and Survival in End-Stage Renal Disease Patients
Toxins 2019, 11(7), 431; https://doi.org/10.3390/toxins11070431 - 23 Jul 2019
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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Open AccessReview
Endothelial Damage, Inflammation and Immunity in Chronic Kidney Disease
Toxins 2020, 12(6), 361; https://doi.org/10.3390/toxins12060361 (registering DOI) - 01 Jun 2020
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)
Open AccessReview
Monocytes in Uremia
Toxins 2020, 12(5), 340; https://doi.org/10.3390/toxins12050340 - 21 May 2020
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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Open AccessReview
Chronic Kidney Disease-Associated Immune Dysfunctions: Impact of Protein-Bound Uremic Retention Solutes on Immune Cells
Toxins 2020, 12(5), 300; https://doi.org/10.3390/toxins12050300 - 06 May 2020
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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Open AccessReview
Gut-Derived Metabolites and Their Role in Immune Dysfunction in Chronic Kidney Disease
Toxins 2020, 12(4), 245; https://doi.org/10.3390/toxins12040245 - 11 Apr 2020
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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Open AccessReview
Uremia-Associated Ageing of the Thymus and Adaptive Immune Responses
Toxins 2020, 12(4), 224; https://doi.org/10.3390/toxins12040224 - 03 Apr 2020
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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