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Chronic kidney disease affects 1 in 10 people globally, with a prevalence twenty times that of cancer. A subset of individuals will progress to end-stage renal disease (ESRD) where renal replacement therapy is required to maintain health. Cutaneous disease, including xerosis and pruritus, are endemic amongst patients with ESRD. In the uraemia-associated immune deficiency of ESRD, impaired circulating immune responses contribute to increased infection risk and poorer vaccination response. Clinical manifestations of dysregulated adaptive immunity within the skin have been well-described and have been posited to play a role in cutaneous features of ESRD. However, our understanding of the mechanisms by which adaptive immunity within the skin is affected by uraemia is relatively limited. We provide an overview of how the cutaneous adaptive immune system is impacted both directly and indirectly by uraemia, highlighting that much work has been extrapolated from the circulating immune system and often has not been directly evaluated in the skin compartment. We identify knowledge gaps which may be addressed by future research. Ultimately, greater understanding of these pathways may facilitate novel therapeutic approaches to ameliorate widespread cutaneous symptomatology in ESRD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zibandeh, Li, Ogg and Bottomley.)

Background: Atherosclerosis is highly prevalent in people with chronic kidney disease (CKD), including those receiving peritoneal dialysis (PD). Although it is lifesaving, PD induces profound systemic inflammation, which may aggravate atherosclerosis. Therefore, the hypothesis is that this PD-induced inflammation aggravates atherosclerosis via immune cell activation., Methods and Results: ApoE -/- mice were subjected to a 5/6 nephrectomy to induce CKD. Three weeks later, mice were fed a high-cholesterol diet. Half of the nephrectomized mice then received daily peritoneal infusions of 3.86% Physioneal for 67 further days (CKD+PD) until the end of the experiment, and were compared with mice without CKD. Sham operated and PD-only mice were additional controls. CKD+PD mice displayed more severe atherosclerotic disease than control mice. Plaque area increased, and plaques were more advanced with a vulnerable phenotype typified by decreased collagen content and decreased fibrous cap thickness. Increased CD3 + T-cell numbers were present in plaques and perivascular adipose tissue of CKD and CKD+PD mice. Plaques of CKD+PD mice contained more iNOS + immune cells. Spleens of CKD+PD mice showed more CD4 + central memory, terminally differentiated type 1 T-helper (Th1), Th17, and CX3C motif chemokine receptor 1 + (CX3CR1) CD4 + T-cells with less regulatory and effector T-cells., Conclusions: PD-fluid exposure in uremic mice potentiates systemic and vascular T-cell-driven inflammation and aggravates atherosclerosis. PD polarized CD4 + T-cells toward an inflammatory Th1/Th17 phenotype, and increased CX3CR1 + CD4 + T-cells, which are associated with vascular homing in CKD-associated atherosclerosis. Targeting CD4 + T-cell activation and CX3CR1 + polarization has the potential to attenuate atherosclerosis in PD patients.

Background: Hemodialysis (HD) patients have an increased risk of acquiring infections due to many health care contacts and may, in addition, have a suboptimal response to vaccination and a high mortality from Covid-19 infection., Methods: In 50 HD patients (mean age 69.4 years, 62% men) administration of SARS-CoV-2BNT162b2 mRNA vaccine began in Dec 2020 and the immune response was evaluated 7-15 weeks after the last dose. Levels of Covid-19 (SARS-CoV-2) IgG antibody against the nucleocapsid antigen (anti-N) and the Spike antigen (anti-S) and T-cell reactivity testing against the Spike protein using ELISPOT technology were evaluated., Results: Out of 50 patients, anti-S IgG antibodies indicating a vaccine effect or previous Covid-19 infection, were detected in 37 (74%), 5 (10%) had a borderline response and 8 (16%) were negative after two doses of vaccine. T-cell responses were detected in 29 (58%). Of the 37 patients with anti-S antibodies, 25 (68%) had a measurable T-cell response. 2 (40%) out of 5 patients with borderline anti-S and 2 (25%) without anti-S had a concomitant T-cell response. Twenty-seven (54%) had both an antibody and T-cell response. IgG antibodies to anti-N indicating a previous Covid-19 disease were detected in 7 (14%) patients., Conclusions: Most HD patients develop a B- and/or T-cell response after vaccination against Covid-19 but approx. 20% had a limited immunological response. T-cell reactivity against Covid-19 was only present in a few of the anti-S antibody negative patients., (© 2021. The Author(s).)

Objectives: This study is to investigate whether the cardiac microvascular endothelial cells (CMECs) can regulate the autophagy of cardiomyocytes (CMs) by secreting lncRNA-ANRIL/miR-181b exosomes, thus participating in the occurrence of uremic cardiovascular disease (CVD)., Methods: A 5/6 nephrectomy uremia model was established, with the mice injected with ANRIL-shRNA lentivirus vector, miR-181b agomir, and related control reagents, containing the serum creatinine and urea nitrogen measured. The renal tissue sections of mice were stained with Periodic Acid-Schiff (PAS), TUNEL, and Hematoxylin-Eosin (HE) performed on myocardial tissue sections of mice. ANRIL-shRNA, miR-181b mimics, and related control reagents were transfected into CMECs, in which the exosomes were extracted and co-cultured with CMs. The expressions of ANRIL, miR-181b and ATG5 were detected by qRT-PCR, and the expressions of autophagy related proteins by Western blot, as well as the binding of ANRIL and miR-181b by the double luciferase reporter gene experiment., Results: ANRIL down-regulation or miR-181b up-regulation can increase the weight of mice with uremia, as well as the expressions of p62 and miR-181b, and reduce the content of serum creatinine and urea nitrogen, the damage of kidney and myocardial tissues, the number of apoptotic cells in myocardial tissues, as well as the expressions of ANRIL, ATG5, Beclin1, and LC3. CMs can absorb the exosomes of CMECs. Compared with IS+ CMEC-Exo group, the expressions of ANRIL and ATG5 in CMs of IS+ CMEC-Exo + sh lncRNA ANRIL and IS+CMEC-Exo+miR-181b mimics groups was down-regulated, as well as the expressions of ATG5, Beclin1, and LC3, while miR-181b expression was up-regulated as well as P62 expression., Conclusions: CMECs can regulate autophagy of CMs by releasing exosomes containing ANRIL and miR-181b., Competing Interests: The authors have declared that no competing interests exist.

Aims: Monocytes are central for atherosclerotic vascular inflammation. The human non-classical, patrolling subtype, which expresses high levels of CD16 and fractalkine receptor CX3CR1, strongly associates with cardiovascular events. This is most marked in renal failure, a condition with excess atherosclerosis morbidity. The underlying mechanism is not understood. This study investigated how human CD16+ monocytes modulate endothelial cell function., Methods and Results: In patients with kidney failure, CD16+ monocyte counts were elevated and dynamically decreased within a year after transplantation, chiefly due to a drop in CD14+CD16+ cells. The CX3CR1 ligand CX3CL1 was similarly elevated in the circulation of humans and mice with renal impairment. CX3CL1 up-regulation was also observed close to macrophage rich human coronary artery plaques. To investigate a mechanistic basis of this association, CD16+CX3CR1HIGH monocytes were co-incubated with primary human endothelium in vitro. Compared to classical CD14+ monocytes or transwell cocultures, CD16+ monocytes enhanced endothelial STAT1 and NF-κB p65 phosphorylation, up-regulated expression of CX3CL1 and interleukin-1β, numerous CCL and CXCL chemokines and molecules promoting leucocyte patrolling and adhesion such as ICAM1 and VCAM1. Genes required for vasodilatation including endothelial nitric oxide synthase decreased while endothelial collagen production increased. Uraemic patients' monocytes enhanced endothelial CX3CL1 even more markedly. Their receptor CX3CR1 was required for enhanced aortic endothelial stiffness in murine atherosclerosis with renal impairment. CX3CR1 dose-dependently modulated monocyte-contact-dependent gene expression in human endothelium., Conclusion: By demonstrating endothelial proatherosclerotic gene regulation in direct contact with CD16+ monocytes, in part via cellular CX3CR1-CX3CL1 interaction, our data delineate a mechanism how this celltype can increase cardiovascular risk., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Only fifteen months after the beginning of the COVID-19 pandemic, several vaccines are already available for clinical use. While the spike protein of SARS-CoV-2 constitutes the main target of all predominant SARS-CoV-2 vaccines, they work by different mechanisms (mRNA-based vaccines vs. vector-based vaccines vs. protein-based vaccines).Though there are slight differences regarding the level of protection against mild COVID-19, all five vaccines that have been through phase 3 trials were nearly 100 % effective in preventing severe or fatal cases of COVID-19. The side effects were of short duration.Patients with chronic kidney disease (or other significant comorbidities) were largely excluded from Phase 3 trials, which makes definite recommendations concerning their vaccination difficult. The vaccine's effectiveness may be reduced in that population due to a uremic immune defect and/or immunosuppressive medication. However, these patients have an increased risk for severe or fatal COVID-19, so that they may particularly benefit from the vaccine., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

In obesity, adipose tissue derived inflammation is associated with unfavorable metabolic consequences. Uremic inflammation is prevalent and contributes to detrimental outcomes. However, the contribution of adipose tissue inflammation in uremia has not been characterized. We studied the contribution of adipose tissue to uremic inflammation in-vitro, in-vivo and in human samples. Exposure to uremic serum resulted in activation of inflammatory pathways including NFκB and HIF1, upregulation of inflammatory cytokines/chemokines and catabolism with lipolysis, and lactate production. Also, co-culture of adipocytes with macrophages primed by uremic serum resulted in higher inflammatory cytokine expression than adipocytes exposed only to uremic serum. Adipose tissue of end stage renal disease subjects revealed increased macrophage infiltration compared to controls after BMI stratification. Similarly, mice with kidney disease recapitulated the inflammatory state observed in uremic patients and additionally demonstrated increased peripheral monocytes and inflammatory polarization of adipose tissue macrophages (ATMS). In contrast, adipose tissue in uremic IL-6 knock out mice showed reduced ATMS density compared to uremic wild-type controls. Differences in ATMS density highlight the necessary role of IL-6 in macrophage infiltration in uremia. Uremia promotes changes in adipocytes and macrophages enhancing production of inflammatory cytokines. We demonstrate an interaction between uremic activated macrophages and adipose tissue that augments inflammation in uremia.

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

Protein-bound uremic toxins (PBUTs) are bioactive microbiota metabolites originated exclusively from protein fermentation of the bacterial community resident within the gut microbiota, whose composition and function is profoundly different in the chronic kidney disease (CKD) population. PBUTs accumulate in the later stages of CKD because they cannot be efficiently removed by conventional hemodialysis due to their high binding affinity for albumin, worsening their toxic effects, especially at the cardiovascular level. The accumulation of uremic toxins, along with oxidative stress products and pro-inflammatory cytokines, characterizes the uremic status of CKD patients which is increasingly associated to a state of immune dysfunction including both immune activation and immunodepression. Furthermore, the links between immune activation and cardiovascular disease (CVD), and between immunodepression and infection diseases, which are the two major complications of CKD, are becoming more and more evident. This review summarizes and discusses the current state of knowledge on the role of the main PBUTs, namely indoxyl sulfate and p-cresyl sulfate, as regulators of immune response in CKD, in order to understand whether a microbiota modulation may be useful in the management of its main complications, CVD, and infections. Summarizing the direct effects of PBUT on immune system we may conclude that PCS seemed to be associated to an immune deficiency status of CKD mainly related to the adaptative immune response, while IS seemed to reflect the activation of both innate and adaptative immune systems likely responsible of the CKD-associated inflammation. However, the exact role of IS and PCS on immunity modulation in physiological and pathological state still needs in-depth investigation, particularly in vivo studies.

Adverse innate immune responses have been implicated in several disease processes, including cardiovascular disease (CVD) and chronic kidney disease (CKD). The monocyte subsets natural killer (NK) cells and natural killer T (NKT) cells are involved in innate immunity. Monocytes subsets are key in atherogenesis and the inflammatory cascade occurring in heart failure. Upregulated activity and counts of proinflammatory CD16+ monocyte subsets are associated with clinical indices of atherosclerosis, heart failure syndromes and CKD. Advanced CKD is a complex state of persistent systemic inflammation characterized by elevated expression of proinflammatory and pro-atherogenic CD14++CD16+ monocytes, which are associated with cardiovascular events and death both in the general population and among patients with CKD. Diminished NK cells and NKT cells counts and aberrant activity are observed in both coronary artery disease and end-stage kidney disease. However, evidence of the roles of NK cells and NKT cells in atherogenesis in advanced CKD is circumstantial and remains to be clarified. This review describes the available evidence regarding the roles of specific immune cell subsets in the pathogenesis of CVD in patients with CKD. Future research is expected to further uncover the links between CKD associated innate immune system dysregulation and accelerated CVD and will ideally be translated into therapeutic targets., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

End-stage renal disease (ESRD) is the final stage of chronic kidney disease, which is increasingly prevalent worldwide and is associated with the progression of cardiovascular disease (CVD). Indoxyl sulfate (IS), a major uremic toxin, plays a key role in the pathology of CVD via adverse effects in endothelial and immune cells. Thus, there is a need for a transcriptomic overview of IS responsive genes in immune cells of ESRD patients. Here, we investigated IS-mediated alterations in gene expression in monocytes from ESRD patients. Transcriptomic analysis of ESRD patient-derived monocytes and IS-stimulated monocytes from healthy controls was performed, followed by analysis of differentially expressed genes (DEGs) and gene ontology (GO). We found that 148 upregulated and 139 downregulated genes were shared between ESRD patient-derived and IS-stimulated monocytes. Interaction network analysis using STRING and ClueGo suggests that mainly metabolic pathways, such as the pentose phosphate pathway, are modified by IS in ESRD patient-derived monocytes. These findings were confirmed in IS-stimulated monocytes by the increased mRNA expression of genes including G6PD, PGD, and TALDO1. Our data suggest that IS causes alteration of metabolic pathways in monocytes of ESRD patients and, thus, these altered genes may be therapeutic targets.

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., Competing Interests: The author declares no conflict of interest.

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., Competing Interests: There is no conflict of interest of the authors related to the contents of this review.

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.

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.

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 H 2 S 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.

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.

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.

Background: Regulatory T (Treg) cells are of critical functionality in immune activation and inflammation in uremic patients undergoing hemodialysis (HD). A disruption in balance of Treg cells has potency to elicit infectious disease progression. Here, we examined possible association between ratio imbalance of Th22/Treg cells and microinflammation in uremic patients undergoing HD., Methods: Peripheral blood mononuclear cells (PBMCs) were isolated to allow measurement of the percentage of Th22 cells and Treg cells using flow cytometry. Subsequently, serum levels of related cytokines, interleukin (IL) 22 (IL-22) and IL-10 and inflammatory factors, C-reactive protein (CRP), (TNF-α), IL-6 were determined via enzyme-linked immunosorbent assay (ELISA). Then relationships among dialysis time, microinflammation status (CRP) and dialysis adequacy (immunoreactive parathyroid hormone (iPTH), urea clearance index (Kt/V), β2-MG, serum calcium, and serum phosphorus) were evaluated. Finally, correlation between microinflammation status and dialysis adequacy was analyzed with Pearson's correlation coefficient., Results: An increased percentage of Th22 and a decreased percentage of Treg cells were evident in uremic patients undergoing HD. Serum levels of IL-22, CRP, TNF-α, and IL-6 were increased, while IL-10 serum level was reduced. An imbalance of Th22/Treg cells was associated with microinflammation status in uremic patients undergoing HD. Furthermore, prolongation of the dialysis time, the microinflammation status and dialysis adequacy were changed. Increased dialysis adequacy was observed to correlate with alleviated microinflammation of uremic patients undergoing HD., Conclusions: Conjointly, an imbalance of Th22/Treg cells may be a potential cause responsible for uremia occurrence, which in turn indicates that uremia could be effectively alleviated by altering the ratio of Th22/Treg cells., (© 2019 The Author(s).)

Intermediate (CD14 ++ CD16 + ) monocytes have important pro-inflammatory and atherogenic features and are increased in patients with chronic kidney disease (CKD). The present study aims to elucidate the role of the uremic milieu and of platelet activation in monocyte differentiation. Monocyte subtypes were analyzed in CKD patients (n = 193) and healthy controls (n = 27). Blood from healthy controls (Ctrl; n = 8) and hemodialysis patients (HD; n = 8) was centrifuged, and plasma (pl) was exchanged between Ctrl and HD (Ctrlcells/HDpl and HDcells/Ctrlpl) or reconstituted as original (Ctrlsham and HDsham) and incubated for 24 h (T24). Monocyte differentiation and platelet aggregation to monocytes (MPA) was assessed by flow cytometry. Especially, a higher proportion of CD14 ++ CD16 + monocytes was found in hemodialysis (HD) patients (p < 0.01). In plasma exchange experiments, Ctrl cells/HD pl T24 showed an increased percentage of CD14 ++ CD16 + monocytes versus Ctrl sham (33.7% ± 15 vs. 15.7% ± 9.6; P < 0.005), comparable to the level of CD14 ++ CD16 + monocytes in the HD sham condition. The percentage of CD14 ++ CD16 + monocytes was lowered by suspending HD cells in Ctrl pl (18.4% ± 7.8 vs. 36.7% ± 15 in HD sham; P < 0.005) reaching the level of the Ctrl sham condition (15.7% ± 9.6). A mixture of uremic sulfates increased CD14 ++ CD16 + monocytes compared to control (19.8 ± 9.6% vs. 15.8 ± 10.9%; P < 0.05), paralleled by a rise MPA. Blocking MPA by abciximab, a potential therapeutic strategy, or anti-CD62P did not inhibit differentiation towards the CD14 ++ CD16 + monocytes. In conclusion, in the present cohort, CD14 ++ CD16 + monocytes are especially increased in HD patients and this can at least in part be attributed to the presence of the uremic milieu, with uremic sulfates inducing a reversible shift towards pro-inflammatory CD14 ++ CD16 + monocytes.

Uraemic syndrome (also known as uremic syndrome) in patients with advanced chronic kidney disease involves the accumulation in plasma of small-molecule uraemic solutes and uraemic toxins (also known as uremic toxins), dysfunction of multiple organs and dysbiosis of the gut microbiota. As such, uraemic syndrome can be viewed as a disease of perturbed inter-organ and inter-organism (host-microbiota) communication. Multiple biological pathways are affected, including those controlled by solute carrier (SLC) and ATP-binding cassette (ABC) transporters and drug-metabolizing enzymes, many of which are also involved in drug absorption, distribution, metabolism and elimination (ADME). The remote sensing and signalling hypothesis identifies SLC and ABC transporter-mediated communication between organs and/or between the host and gut microbiota as key to the homeostasis of metabolites, antioxidants, signalling molecules, microbiota-derived products and dietary components in body tissues and fluid compartments. Thus, this hypothesis provides a useful perspective on the pathobiology of uraemic syndrome. Pathways considered central to drug ADME might be particularly important for the body's attempts to restore homeostasis, including the correction of disturbances due to kidney injury and the accumulation of uraemic solutes and toxins. This Review discusses how the remote sensing and signalling hypothesis helps to provide a systems-level understanding of aspects of uraemia that could lead to novel approaches to its treatment.

Decreased inflammation and cardiovascular mortality are evident in patients with end-stage chronic kidney disease treated by online hemodiafiltration. Extracellular vesicles (EV) are mediators of cell-to-cell communication and contain different RNA types. This study investigated whether mixed online hemodiafiltration (mOL-HDF) beneficial effects associate with changes in the RNA content of plasma EV in chronic kidney disease patients. Thirty bicarbonate hemodialysis (BHD) patients were randomized 1:1 to continue BHD or switch to mOL-HDF. Concentration, size, and microRNA content of plasma EV were evaluated for 9 mo; we then studied EV effects on inflammation, angiogenesis, and apoptosis of endothelial cells (HUVEC) and on osteoblast mineralization of vascular smooth muscle cells (VSMC). mOL-HDF treatment reduced different inflammatory markers, including circulating CRP, IL-6, and NGAL. All hemodialysis patients showed higher plasma levels of endothelial-derived EV than healthy subjects, with no significant differences between BHD and mOL-HDF. However, BHD-derived EV had an increased expression of the proatherogenic miR-223 with respect to healthy subjects or mOL-HDF. Compared with EV from healthy subjects, those from hemodialysis patients reduced angiogenesis and increased HUVEC apoptosis and VSMC calcification; however, all these detrimental effects were reduced with mOL-HDF with respect to BHD. Cell transfection with miR-223 mimic or antagomiR proved the role of this microRNA in EV-induced HUVEC and VSMC dysfunction. The switch from BHD to mOL-HDF significantly reduced systemic inflammation and miR-223 expression in plasma EV, thus improving HUVEC angiogenesis and reducing VSMC calcification., (Copyright © 2019 by The American Association of Immunologists, Inc.)

The anti-inflammatory properties of high-density lipoproteins (HDL) are lost in uremia. These HDL may show pro-inflammatory features partially as a result of changed protein composition. Alterations of polymorphonuclear leukocytes (PMNLs) in chronic kidney disease (CKD) may contribute to chronic inflammation and high vascular risk. We investigated if HDL from uremic patients is related to systemic inflammation by interfering with PMNL function. PMNL apoptosis was investigated by assessing morphological features and DNA content. CD11b surface expression was quantified by flow cytometry. Oxidative burst was measured via cytochrome c reduction assay. Chemotaxis was assessed by using an under-agarose migration assay. We found that HDL from CKD and hemodialysis (HD) patients significantly attenuated PMNL apoptosis, whereas HDL isolated from healthy subjects had no effect on PMNL apoptosis. The use of signal transduction inhibitors indicated that uremic HDL exerts anti-apoptotic effects by activating pathways involving phosphoinositide 3-kinase and extracellular-signal regulated kinase. Healthy HDL attenuated the surface expression of CD11b, whereas HDL from CKD and HD patients had no effect. All tested isolates increased the stimulation of oxidative burst, but did not affect PMNL chemotactic movement. In conclusion, HDL may contribute to the systemic inflammation in uremic patients by modulating PMNL functions.

Severe vascular calcification develops almost invariably in chronic kidney patients posing a substantial risk to quality of life and survival. This unmet medical need demands identification of novel therapeutic modalities. We aimed to pinpoint components of the uremic microenvironment triggering differentiation of vascular progenitors to calcifying osteoblast-like cells. In an unbiased approach, assessing the individual potency of 63 uremic retention solutes to enhance calcific phenotype conversion of vascular progenitor cells, the pro-inflammatory cytokines IL-1β and TNF-α were identified as the strongest inducers followed by FGF-2, and PTH. Pharmacologic targeting of these molecules alone or in combination additively antagonized pro-calcifying properties of sera from uremic patients. Our findings stress the importance of pro-inflammatory cytokines above other characteristic components of the uremic microenvironment as key mediators of calcifying osteoblastic differentiation in vascular progenitors. Belonging to the group of "middle-sized molecules", they are neither effectively removed by conventional dialysis nor influenced by established supportive therapies. Specific pharmacologic interventions or novel extracorporeal approaches may help preserve regenerative capacity and control vascular calcification due to uremic environment.

Increased acetataemia during haemodialysis sessions has been associated with a number of abnormalities, including increased oxidative stress, pro-inflammatory cytokines and nitric oxide synthesis. However, citric acid may play an alternative role to acetate as a dialysate stabiliser given that the effect of citrate on complement and leukocyte activation is different to that of acetate. The purpose of this study was to compare the inflammatory effect in immunocompetent blood cells of acetate dialysate and citrate dialysate., Material and Methods: The effect of acetate and/or citrate was investigated in the whole blood of uraemic patients and in healthy in vitro samples. Four types of dialysate were tested: dialysate 1, acetate-free with 1mmol/L of citrate; dialysate 2, with 0.8mmol/L of citrate and 0.3mmol/L of acetate; dialysate 3, citrate-free with 3mmol/L of acetate; and dialysate 4, citrate-free with 4mmol/L of acetate. The cell types used were: human monocyte culture (THP-1); and peripheral blood mononuclear cells (PBMCs) from healthy subjects and uraemic patients on haemodialysis. ICAM-1 was determined and levels of reactive oxygen species and total microvesicles were quantified., Results: Unlike the citrate dialysates, the dialysates with acetate (dialysate 3 and dialysate 4) induced increased ICAM-1 expression density in THP-1 cells; an increase in ICAM-1 expression was observed in the immunocompetent cells of healthy subjects with acetate dialysate (dialysate 3 and dialysate 4) but not with citrate dialysate (dialysate 1 and dialysate 2). No significant ICAM-1 differences were found between the different dialysates in the cells of haemodialysed patients. Reactive oxygen species expression and the number of microvesicles increased significantly with acetate dialysate but not with citrate dialysate in the cells of both healthy subjects and haemodialysed patients., Conclusions: At the concentrations in which it is generally used in clinical practice, acetate-based dialysate increases oxidative stress and the total number of microvesicles and may induce other pro-inflammatory stimuli typical of uraemic patients on haemodialysis. Citrate dialysates do not induce this activation, which could make them a suitable alternative in clinical practice., (Copyright © 2017 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.)

Systemic inflammation in end-stage renal disease is an established risk factor for mortality and a catalyst for other complications, which are related to a premature aging phenotype, including muscle wasting, vascular calcification, and other forms of premature vascular disease, depression, osteoporosis, and frailty. Uremic inflammation is also mechanistically related to mechanisms involved in the aging process, such as telomere shortening, mitochondrial dysfunction, and altered nutrient sensing, which can have a direct effect on cellular and tissue function. In addition to uremia-specific causes, such as abnormalities in the phosphate-Klotho axis, there are remarkable similarities between the pathophysiology of uremic inflammation and so-called "inflammaging" in the general population. Potentially relevant, but still somewhat unexplored in this respect, are abnormal or misplaced protein structures, as well as abnormalities in tissue homeostasis, which evoke danger signals through damage-associated molecular patterns, as well as the senescence-associated secretory phenotype. Systemic inflammation, in combination with the loss of kidney function, can impair the resilience of the body to external and internal stressors by reduced functional and structural tissue reserves, and by impairing normal organ crosstalk, thus providing an explanation for the greatly increased risk of homeostatic breakdown in this population. In this review, the relationship between uremic inflammation and a premature aging phenotype, as well as potential causes and consequences, are discussed., (Copyright © 2017 the American Physiological Society.)

Patients with end-stage renal disease (ESRD) are at elevated risk of acquiring infectious diseases, including tuberculosis (TB). Inflammation and uremia negatively impact immune function in this population, but specific pathways involved in TB immunity have not been identified. Although γδ T cells are known to contribute to protection from TB, their phenotype and function in patients with ESRD is relatively unknown. To determine this we recruited 20 patients with and 20 without ESRD (controls), with or without latent TB infection to assess γδ T cell frequency, surface phenotype, and cytokine production by flow cytometry in response to stimulation. γδ T cells derived from patients with ESRD exhibited significantly lower expression of CCR5, CXCR3, and CD26 compared to controls. Furthermore, patients with ESRD, particularly the group with latent TB infection, exhibited poor IFNγ, TNFα, and GMCSF responses to stimulation with either phosphoantigen HMB-PP, IL-12/IL-18, E. coli, or phorbol myristate acetate and ionomycin. Similar dysfunctional responses were observed in patients with active TB. Surprisingly, neither the γδ phenotype nor its function was associated with plasma markers of inflammation or microbial translocation. Thus, there is significant perturbation of the γδ T-cell population in patients with ESRD, particularly in those with latent TB infection., (Copyright © 2017 International Society of Nephrology. All rights reserved.)

The reduced number of circulating stem/progenitor cells that is found in chronic kidney disease (CKD) patients may contribute to impaired angiogenic repair and decreased capillary density in the heart. Cell therapy with bone marrow-derived cells (BMDCs) has been shown to induce positive effects on the microvasculature and cardiac function, most likely due to secretion of growth factors and cytokines, all of which are present in the conditioned medium (CM); however, this is controversial. Here we showed that treatment with BMDC or CM restored vascular density and decreased the extent of fibrosis in a rat model of CKD, the 5/6 nephrectomy. Engraftment and differentiation of exogenous BMDCs could not be detected. Yet CM led to the mobilization and infiltration of endogenous circulating cells into the heart. Cell recruitment was facilitated by the local expression of pro-inflammatory factors such as the macrophage chemoattractant protein-1, interleukin-6, and endothelial adhesion molecules. Consistently, in vitro assays showed that CM increased endothelial adhesiveness to circulating cells by upregulating the expression of adhesion molecules, and stimulated angiogenesis/endothelial tube formation. Overall, our results suggest that both treatments exert vasculoprotective effects on the heart of uremic rats by stimulating endogenous repair mechanisms.

Background.: End-stage renal disease (ESRD) is associated with inflammation and increased reactive oxygen species (ROS). Inflammation and oxidative stress are associated with several complications of ESRD. The aim of this study was to determine histological characteristics of adipose tissue and muscle mitochondrial function in uremia and its relationship with inflammation., Methods.: ESRD patients ( n  = 18) and controls ( n  = 6) were enrolled for studies of adipose and muscle tissue by immunohistochemistry and western blot. In a uremic muscle cell model, C2C12 cells were exposed to uremic serum and inflammatory cytokines. Mitochondrial function was studied by MitoTracker Orange, translocase of the mitochondrial outer membrane 20 (TOMM20) and mitochondrial oxidative phosphorylation complex subunit expression., Results.: ESRD patients had increased macrophage infiltration in subcutaneous and visceral adipose tissue compared with controls, even in nonobese ESRD patients (P < 0.05). Compared with controls, TOMM20 expression in muscle tissue was lower in ESRD, consistent with reduced mitochondrial function (P < 0.05). C2C12 exposed to uremia had decreased mitotracker intensity (P < 0.05) and the reduced mitochondrial function was rescued by N-acetyl cysteine (P < 0.01). Similarly, C2C12 cells exposed to tumor necrosis factor α (TNF-α)/interleukin-6 (IL-6) have decreased mitotracker intensity (P < 0.01) that was rescued with adiponectin (P < 0.05). C2C12 exposed to TNF-α, IL-6 and buthionine sulfoximine had decreased TOMM20 expression and cells exposed to TNF-α showed a decrease in subunits of mitochondrial complexes I and III., Conclusion.: Our data indicate that uremia is associated with increased adipose tissue macrophage infiltration and concurrent muscle tissue mitochondrial dysfunction induced by inflammation/ROS. Adipose tissue is a potential source of inflammation in ESRD that is not due to increased adiposity and may contribute to mitochondrial dysfunction in uremia., (© The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

We investigated the hypothesis that the increased concentration of plasma methylguanidine (MG) increases oxidative metabolism and accelerates apoptosis of neutrophils from dogs with chronic kidney disease (CKD). To achieve this, the levels of MG were quantified in healthy (n=16) and uremic dogs with CKD stage 4 of according to the guidelines of the International Renal Interest Society (IRIS, 2015) (n=16) using high performance liquid chromatography (HPLC). To evaluate the isolated effect of MG on neutrophil oxidative metabolism and apoptosis, neutrophils isolated from 12 healthy dogs were incubated with the highest concentration of plasma MG (0.005g/L) observed in dogs with CKD. Neutrophil oxidative metabolism was assessed by flow cytometry, using the probes hydroethidine for superoxide production and 2',7'-dichlorofluorescein diacetate for hydrogen peroxide production, with or without phorbol myristate acetate (PMA) stimulus. Neutrophil apoptosis and viability were also evaluated in flow cytometer using the Annexin V-PE system, with or without the apoptosis-inducing effect of camptothecin. Uremic dogs presented higher concentrations of MG (p<0.0001), increased oxidative stress and primed neutrophils with higher apoptosis rate. The neutrophil abnormalities observed in vivo were also reproduced in vitro, using cells isolated from healthy dogs and incubated with MG. We obtained strong evidence that in dogs with CKD, increased MG levels contributed to oxidative stress and potentially compromised the non-specific immune response by altering the oxidative metabolism and viability of canine neutrophils., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background. Neutrophils are involved in the pathogenesis of atherosclerosis by neutrophil extracellular trap (NET) formation. We hypothesized that the NET formation of neutrophils might be changed in end-stage renal disease (ESRD) patients, explaining their higher incidence of coronary artery diseases (CAD). Method. A cross-sectional study was performed in 60 maintenance hemodialysis (MHD) patients, 30 age- and sex-matched healthy individuals (HV, negative control), and 30 patients with acute infection (positive control). Neutrophil activation and function were measured with reactive oxygen species (ROS) activity, degranulation, NET formation, and phenotypical changes. Result. Compared with HV, neutrophils extracted from MHD patients displayed significantly increased levels of basal NET formation, ROS production, and degranulation, suggesting spontaneous activation in uremia. Also, an increase in citrullinated histone H3 was detected in this group compared to the HV. And neutrophils from HV were normal CD16 bright /CD62L bright cells; however, neutrophils from MHD were CD16 bright /CD62L dim , similar to those from patients with acute infections. Interestingly, multivariate analyses identified the prevalent CAD and neutrophil counts as independent determinants of baseline NET formation ( β = 0.323, p = 0.016 and β = 0.369, p = 0.006, resp.). Conclusions. Uremia-associated-increased NET formation may be a sign of increased burden of atherosclerosis.

Chronic kidney disease (CKD) leads to uremia. CKD is characterized by a gradual increase in kidney fibrosis and loss of kidney function, which is associated with a progressive increase in risk of atherosclerosis and cardiovascular death. To prevent progression of both kidney fibrosis and atherosclerosis in uremic settings, insight into new treatment options with effects on both parameters is warranted. The GLP-1 analogue liraglutide improves glucose homeostasis, and is approved for treatment of type 2 diabetes. Animal studies suggest that GLP-1 also dampens inflammation and atherosclerosis. Our aim was to examine effects of liraglutide on kidney fibrosis and atherosclerosis in a mouse model of moderate uremia (5/6 nephrectomy (NX)). Uremic (n = 29) and sham-operated (n = 14) atherosclerosis-prone low density lipoprotein receptor knockout mice were treated with liraglutide (1000 μg/kg, s.c. once daily) or vehicle for 13 weeks. As expected, uremia increased aortic atherosclerosis. In the remnant kidneys from NX mice, flow cytometry revealed an increase in the number of monocyte-like cells (CD68+F4/80-), CD4+, and CD8+ T-cells, suggesting that moderate uremia induced kidney inflammation. Furthermore, markers of fibrosis (i.e. Col1a1 and Col3a1) were upregulated, and histological examinations showed increased glomerular diameter in NX mice. Importantly, liraglutide treatment attenuated atherosclerosis (~40%, p < 0.05) and reduced kidney inflammation in NX mice. There was no effect of liraglutide on expression of fibrosis markers and/or kidney histology. This study suggests that liraglutide has beneficial effects in a mouse model of moderate uremia by reducing atherosclerosis and attenuating kidney inflammation., Competing Interests: Novo Nordisk markets liraglutide for the treatment of diabetes and obesity. LSB, SER, CM, AR, and LFIN have been or are employed by Novo Nordisk A/S. This affiliation does not alter our adherence to PLOS ONE policies on sharing data and materials. The other authors declared no competing interests.

Background: Patients undergoing conventional hemodialysis (C-HD) present a greater immuno-inflammatory state probably related to uremia, sympathetic nervous system (SNS) activation and /or membrane bioincompatibility, which could improve with a technique-switching to online hemodiafiltration (OL-HD). The antigen-independent pathway activation of this modified immunologic state turns dendritic cells (DC) into an accurate cell model to study these patients. The aim of this study is to further evaluate the immune-inflammatory state of patients in C-HD assessed by DC maturation., Methods: 31 patients were submitted to C-HD and after 4 months switched to the OL-HD technique. Monocytes-derived DCs from HD patients were cultured in the presence of IL-4/GM-CSF. DC-maturation was evaluated by assessing the maturation phenotype by flow cytometry (FACs). DCs-functional capacity to elicit T-cell alloresponse was studied by mixed leucocyte reaction. Cytokine release was assessed by FACs and SNS was evaluated measuring renalase levels by ELISA., Results: An up-regulation of maturation markers was observed in C-HD DCs which induced two fold more T cells proliferation than OL-HD DCs. Also, C-HD-mDCs presented with over-production of pro-inflammatory cytokines (IL-6, IL-1β, IL-8, IL-10 and TNF-α) compared with OL-HD-mDC (P<0·05). Results were correlated with clinical data. When SNS was evaluated, hypotension events and blood pressure were significantly lower and renalase levels were significantly higher after conversion to OL-HD. Diabetes mellitus type 2 patients also found beneficial reduction of mDC when converted to OL-HD compared to non-diabetics., Conclusions: OL-HD could interfere with immuno-inflammatory state in HD patients with an improvement of renalase levels as potential key mediators in the mechanistic pathway of down-regulation of DC maturation., Competing Interests: The authors have declared that no competing interests exist.

The prevention and treatment of type-2 diabetes mellitus (T2DM) and diabetic nephropathy (DN), which are disorders with high incidence rates, is of primary importance. In this study, we analyzed the effect of 1,25-(OH) 2 D 3 and lipopolysaccharide (LPS) in combination with interleukin (IL)-15 on the inflammatory immune response and expression of vitamin D receptor (VDR) in mononuclear cells of T2DM and DN uremia (DNU) patients. The human acute monocytic leukemia cell line THP-1 was treated with peripheral blood serum isolated from 30 healthy controls and T2DM and DNU patients each, cultured in the presence or absence of 1,25-(OH) 2 D 3 , and subsequently treated with LPS and IL-15. The VDR mRNA and protein expression in THP-1 cells was detected by real-time polymerase chain reaction and western blot (and immunofluorescence assay), respectively, and IL-6 and IL-10 concentrations in the culture supernatant were detected by enzyme-linked immunosorbent assay. LPS treatment induced a significant decrease in VDR mRNA expression in T2DM and DNU serum-treated THP-1 cells compared to the control cells (P < 0.05). The VDR protein expression in DNU serum-treated THP-1 cells was also significantly down-regulated (P < 0.05). LPS treatment induced IL-6 secretion in serum-treated THP-1 cells (P < 0.05), while 1,25-(OH) 2 D 3 treatment inhibited IL-6 secretion to some extent. These findings suggested that LPS down-regulates the expression of VDR in mononuclear cells of T2DM and DNU patients and induces an imbalance in the pro-inflammatory and anti-inflammatory cytokine response, while 1,25-(OH) 2 D 3 partially reversed the effect of LPS and protected patients with T2DM and DNU., Competing Interests: The authors declare no conflict of interest.

Background: We tested the effect of uremia on red blood cell (RBC) eryptosis, CD14++/CD16+ monocytes and erythrophagocytosis., Design: RBC and monocytes from chronic kidney disease (CKD) stages 3/4 (P-CKD3/4) or hemodialysis (HD) patients and healthy controls (HCs) cells incubated with sera pools from patients with CKD stages 2/3 (S-CKD2/3) or 4/5 (S-CKD4/5) were evaluated to assess eryptosis, monocyte phenotypes and reactive oxygen species (ROS) by cytometer. Erythrophagocytosis was evaluated by subsequent co-incubation of preincubated HC-monocytes and autologous-RBC., Results: HC-eryptosis (1.3 ± 0.9%) was lower than in HD (4.3 ± 0.5%) and HC-RBC incubated with S-CKD4/5 (5.6 ± 1%). CD14++/CD16+ were augmented in P-CKD3/4 (34.6 ± 8%) and HC-monocytes incubated with S-CKD4/5 (26.4 ± 7%) than in HC (5.4 ± 1%). In these cells, ROS was increased (44.5 ± 9%; control 9.6 ± 2%) and inhibited by N-acetylcysteine (25 ± 13%). Erythrophagocytosis was increased in CD14++/CD16+ (60.8 ± 10%) than in CD14++/CD16- (15.5 ± 2%)., Conclusions: Sera pools from CKD patients increase eryptosis and promote a proinflammatory monocyte phenotype. Both processes increased erythrophagocytosis, thereby suggesting a novel pathway for renal anemia., (© 2016 S. Karger AG, Basel.)

Uremia due to chronic kidney disease (CKD) in humans is associated with immune dysfunction, increased susceptibility to infections, immune-activation-associated inflammation, and poor responses to vaccines. The pathophysiologic basis of these immune defects is hypothesized to be associated with a wide range of immunologic abnormalities, including an inability to sufficiently express the B7 family (B7-1, CD80; B7-2, CD86) of T-cell costimulatory molecules. However, testing the hypothesis that a state of chronic uremia contributes to attenuated expression of CD80 or CD86 has been difficult because few animal models faithfully recapitulate the immune defects observed in human CKD patients. We used a humanized mouse in a model of surgically induced renal failure and secondary chronic uremia to evaluate the effect of uremia on the expression of these markers. In a manner that resembles the changes observed in CKD patients, surgically induced CKD in mice resulted in decreased costimulatory CD86 expression compared with that in sham-operated controls. Immunodeficiency was functionally demonstrated in this mouse model by documenting an attenuated immune response to a cholera-toxin-based hepatitis B vaccine. This model will be useful for investigating the mechanisms involved in chronic uremia-associated immunodeficiency, poor response to vaccination, and problems associated with immunization of CKD patients.

Background/objectives: It is unknown what causes uraemic symptoms in renal disease. Chronic kidney disease (CKD) patients are known to have increased levels of urea, sodium, potassium and phosphate in their saliva compared with those without renal disease. The present cross-sectional study investigated associations between known genetic traits of taste and self-reported upper gastrointestinal (GI) symptoms experienced in CKD patients with the changes in saliva composition found in renal failure., Subjects/methods: Fifty-six CKD patients (35 males, 21 females, age 67±14 years), with stages 4 and 5 renal failure, selected from a tertiary hospital renal outpatient clinic participated in this study. Subjects answered a questionnaire to assess upper GI symptoms and tested for the genetic taste recognition thresholds of thiourea, phenylthiocarbamide and sodium benzoate. Saliva samples were collected to determine biochemical composition. Possible associations between genetic taste variations, saliva composition and upper GI symptoms were investigated., Results: Of the 56 patients enroled, 29 (52%) reported major upper GI uraemic symptoms, whereas 27 (48%) had no symptoms or only minor complaints of dry mouth. There was a strong association between the symptomatic burden a patient experienced and the genetic ability to taste thiourea (P<0.0003). Uraemic symptoms of taste changes (P<0.004) and nausea (P<0.002) were found to be related to a patient's genetic ability to taste thiourea., Conclusions: This study provides evidence that the genetic ability to taste thiourea as bitter, in combination with the increase in active compounds found in CKD patient's saliva, impacts on the uraemic upper GI symptoms experienced.

Patients with chronic kidney disease (CKD) have high incidence rates of cardiovascular disease and malignancy. Several factors contribute to these conditions. Structural characteristics in CKD, loss of renal energy, and uremia result in an imbalance between free radical production and antioxidant defenses. Also, CKD patients usually have multiple cardiovascular risk factors like diabetes mellitus, dyslipidemia, and hypertension. These conditions are associated with oxidative stress, which can trigger the inflammatory process and accelerate renal injury progression. There are some clinical biomarkers to detect oxidative stress and antioxidant status in CKD patients. Antioxidant therapies may be beneficial in reducing oxidative stress, lowering uremic cardiovascular toxicity, and improving survival. Therefore, their roles in CKD patients have been evaluated in several studies as a new target for therapeutic intervention. This review provides an overview of oxidative stress mechanisms, clinical squeals, biomarkers, and possible antioxidant therapies in CKD patients.

Los of renal function is associated with uremia-associated immune deficiency, which contributes significantly to the mortality and morbidity of end-stage renal disease (ESRD) patients. In this review, the effect of ESRD on the adaptive cellular immune system is discussed. Progressive loss of renal function causes a preferential loss of number and function of lymphoid cells. More in depth analysis of these changes reveals a loss of thymic function, attrition of telomeres, and expanded memory T cell population, which is compatible with the concept of premature immunological ageing. Latency for cytomegalovirus is associated with more profound changes and the expansion of a unique pro-inflammatory, cytotoxic subset of CD4-positive CD28null T cells. Epigenetically, modifications in hematopoietic stem cells may underlie uremia-associated immunological ageing, which is not reversed by kidney transplantation. Possible therapeutic options to reverse or halt uremia-associated immunological ageing are discussed.

The uremia-induced inflammatory environment in end-stage renal disease (ESRD) patients is associated with premature T-cell aging resulting in a defective T-cell immunity. As kidney transplantation (KTx) reduces the pro-inflammatory environment, we hypothesized that KTx would rejuvenate the aged T-cell system. As aging parameters, we determined in 70 KTx recipients the differentiation status by immunophenotyping, thymic output by the T-cell receptor excision circle (TREC) content together with CD31(+) naïve T-cell numbers and the relative telomere length (RTL) as a measure for proliferative history at pre-KTx, 3, 6 and 12 months post-KTx. In addition, T-cell function was determined by measuring the proliferative capacity and percentages of cytokine-producing cells. Directly post-KTx, memory T-cell numbers were diminished but restored to pre-KTx values at 12 months, except for CD4(+) EM T cells. The RTL of (memory) CD4(+) and CD8(+) T cells did not change. In contrast, TREC content and CD31(+) naïve T-cell numbers were stable post-KTx although the RTL of naïve CD4(+) and CD8(+) T cells decreased implying homeostatic proliferation of naïve cells, in response to a temporary decrease in memory cells. The T-cell function was not improved post-KTx. Our findings demonstrate that the uremia-associated aged phenotype is stably imprinted in the T-cell system and not reversed by KTx., (© 2014 Steunstichting ESOT.)

Our previous study showed that human herpesvirus type 8 (HHV-8) seroprevalence was significantly higher in patients with end-stage renal disease (ESRD) immediately after haemodialysis than in healthy controls based on an immunofluorescence assay (IFA) and an enzyme-linked immunosorbent assay (ELISA). However, other studies indicated that ESRD patients and healthy controls had similar HHV-8 seroprevalence. This study aimed to investigate whether this discrepancy is due to the effect of uraemic status.Plasma samples from 162 ESRD patients, taken immediately before and after haemodialysis, and 162 age and sex matched healthy controls were analysed for HHV-8 antibodies using both IFA and ELISA.HHV-8 seropositivities based on IFA and ELISA, both before and after haemodialysis, were significantly greater in ESRD patients than in healthy controls (p < 0.008 for all comparisons). The seropositivities and antibody titres of ESRD patients obtained with IFA were similar before and after haemodialysis. Seropositivities based on ELISA were identical before and after haemodialysis. The seropositivities obtained with the IFA markedly exceeded those with ELISA in each group of subjects (p < 0.0001 for all comparisons).Uraemic status did not significantly affect the IFA or ELISA results for HHV-8 antibodies.

Background and Aims: Indoxyl sulfate (IS) and p-cresyl sulfate (PCS) are nephro- and cardiovascular toxins, produced solely by the gut microbiota, which have pro-inflammatory and pro-oxidative properties in vitro. We undertook this study to investigate the associations between IS and PCS and both inflammation and oxidative stress in the chronic kidney disease (CKD) population., Methods: In this cross-sectional observational cohort study, participants with stage 3-4 CKD who enrolled in a randomized controlled trial of cardiovascular risk modification underwent baseline measurements of serum total and free IS and PCS (measured by ultraperformance liquid chromotography), inflammatory markers (interferon gamma [IFN-γ], interleukin-6 [IL-6] and tumor necrosis factor-alpha [TNF-α]), antioxidant and oxidative stress markers (plasma glutathione peroxidase [GPx] activity, total antioxidant capacity [TAC] and F2-isoprostanes) and pulse wave velocity (PWV), a marker of arterial stiffness., Results: There were 149 CKD patients (59% male; age 60 ± 10 years; 44% diabetic) with a mean eGFR of 40 ± 9 mL/min/1.73 m(2) (range 25-59). Serum free and total IS were independently associated with serum IL-6, TNF-α and IFN-γ, whereas serum free and total PCS were independently associated with serum IL-6 and PWV. Free IS and PCS were additionally independently associated with serum GPx but not with TAC or F2-isoprostanes., Conclusions: IS and PCS were associated with elevated levels of selected inflammatory markers and an antioxidant in CKD patients. PCS was also associated with increased arterial stiffness. Inflammation and oxidative stress may contribute to the nephro- and cardiovascular toxicities of IS and PCS. Intervention studies targeting production of IS and PCS by dietary manipulation and the subsequent effect on cardiovascular-related outcomes are warranted in the CKD population., (Copyright © 2014 IMSS. Published by Elsevier Inc. All rights reserved.)

Immune system dysfunctions including the increased Th1/Th2 ratio are common in chronic kidney disease (CKD) patients, and a wide variety of skin diseases including Th1-mediated uremic pruritis are associated with CKD. Although there are more than 90 uremic toxins reported, it is yet to be known which uremic solute is associated with the unbalanced Th1/Th2 ratio and how it works. Indoxyl 3-sulfate (I3S), one of uremic toxins and a potent aryl hydrocarbon receptor (AhR) ligand, accumulates in blood and tissues, increasing up to 81.04 μM in CKD patients, compared with 1.03 μM in healthy subjects. I3S activates NF-κB and AhR. Thus, we investigated roles of I3S in the differentiation of Th1 and Th2 cells. I3S inhibited Th2 differentiation but showed little or no effect on Th1 differentiation. I3S suppressed Th2-mediated ovalbumin-induced allergic asthma in mice and decreased the frequency of IL-4 producing CD4 T cells in the lungs. I3S inhibited phosphorylation of STAT5 and STAT6, transcription factors associated with Th2 differentiation. Effects of I3S on Th2 differentiation were suppressed by α-naphtoflavone, an AhR antagonist, indicating that I3S regulates Th2 differentiation AhR-dependently., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background & Aims: Host and viral factors interplay in the spontaneous clearance of hepatitis C virus (HCV) infection. We aimed to explore the roles of IL28B genotypes and hepatitis B virus (HBV) infections in spontaneous HCV seroclearance., Methods: IL28B rs8099917 genotypes, HCV and HBV markers were determined in 290 patients who were seropositive for HCV antibodies from 1681 total uremic patients on maintenance hemodialysis., Results: Persistent HCV viremia was observed in 74.6% (214/287) of patients. Logistic regression revealed that the strongest factors associated with spontaneous HCV seroclearance were carriage of rs8099917 TT-type (odds ratio/95% confidence intervals [OR/CI]: 6.22/1.41-27.35, p=0.016), followed by concurrent hepatitis B surface antigen (HBsAg) seropositivity (OR/CI: 2.37/1.06-5.26, p=0.035). The clearance rate was highest among patients with both positive HBsAg/rs8099917 TT-type (44.8%, OR/CI: 20.88/3.5-402.5), followed by positive HBsAg/rs8099917 non-TT-type (28.6%, OR/CI: 8.86/1.8-160.8), and negative HBsAg/rs8099917 TT-type (26.7%, OR/CI: 12.75/1.0-319.4), compared to 4% of negative HBsAg/rs8099917 non-TT-type (trend p=0.0002). HBsAg levels, but not HBV DNA levels, were significantly associated with spontaneous HCV seroclearance. Spontaneous HCV seroclearance rate was 58.3% in patients with HBsAg>200IU/ml/rs8099917 TT-type (OR/CI: 42.54/5.7-908.4), 28.0% in patients with HBsAg<200IU/ml/rs8099917 TT-type or HBsAg>200IU/ml/rs8099917 non-TT-type (OR/CI: 11.12/2.3-201.0), compared to only 3.3% in those with HBsAg<200IU/ml/rs8099917 non-TT-type (trend p=0.0004). Five of 214 (2.3%) HCV viremic patients at enrollment had spontaneous HCV seroclearance during one-year follow-up, which was associated with baseline HCV RNA and HBsAg levels., Conclusions: High HBsAg levels and favorable IL28B genotype were additively associated with spontaneous HCV seroclearance in uremic patients., (Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Leukocyte activation and endothelial damage both contribute to cardiovascular disease, a major cause of morbidity and mortality in CKD. Experimental in vitro data link several protein-bound uremic retention solutes to the modulation of inflammatory stimuli, including endothelium and leukocyte responses and cardiovascular damage, corroborating observational in vivo data. However, the impact of these uremic toxins on the crosstalk between endothelium and leukocytes has not been assessed. This study evaluated the effects of acute and continuous exposure to uremic levels of indoxylsulfate (IS), p-cresylsulfate (pCS), and p-cresylglucuronide (pCG) on the recruitment of circulating leukocytes in the rat peritoneal vascular bed using intravital microscopy. Superfusion with IS induced strong leukocyte adhesion, enhanced extravasation, and interrupted blood flow, whereas pCS caused a rapid increase in leukocyte rolling. Superfusion with pCS and pCG combined caused impaired blood flow and vascular leakage but did not further enhance leukocyte rolling over pCS alone. Intravenous infusion with IS confirmed the superfusion results and caused shedding of heparan sulfate, pointing to disruption of the glycocalyx as the mechanism likely mediating IS-induced flow stagnation. These results provide the first clear in vivo evidence that IS, pCS, and pCG exert proinflammatory effects that contribute to vascular damage by stimulating crosstalk between leukocytes and vessels.

Aim: To assess co-stimulatory and co-inhibitory markers of dendritic cells (DCs) in hepatitis C virus (HCV) infected subjects with and without uremia., Methods: Three subject groups were included in the study: group 1 involved 50 control subjects, group 2 involved 50 patients with chronic HCV infection and group 3 involved 50 HCV uremic subjects undergoing hemodialysis. CD83, CD86 and CD40 as co-stimulatory markers and PD-L1 as a co-inhibitory marker were assessed in peripheral blood mononuclear cells by real-time polymerase chain reaction. Interleukin-10 (IL-10) and hyaluronic acid (HA) levels were also assessed. All findings were correlated with disease activity, viral load and fibrogenesis., Results: There was a significant decrease in co-stimulatory markers; CD83, CD86 and CD40 in groups 2 and 3 vs the control group. Co-stimulatory markers were significantly higher in group 3 vs group 2. There was a significant elevation in PD-L1 in both HCV groups vs the control group. PD-L1 was significantly lower in group 3 vs group 2. There was a significant elevation in IL-10 and HA levels in groups 2 and 3, where IL-10 was higher in group 3 and HA was lower in group 3 vs group 2. HA level was significantly correlated with disease activity and fibrosis grade in group 2. IL-10 was significantly correlated with fibrosis grade in group 2. There were significant negative correlations between co-stimulatory markers and viral load in groups 2 and 3, except CD83 in dialysis patients. There was a significant positive correlation between PD-L1 and viral load in both HCV groups., Conclusion: A significant decrease in DC co-stimulatory markers and a significant increase in a DC co-inhibitory marker were observed in HCV subjects and to a lesser extent in dialysis patients.

Objectives: We compared the correlation of regulatory T cell (Treg) and Th17 cell function disequilibrium with calcification in uremic patients on maintenance hemodialysis (MHD) with healthy controls, and investigated if their influence possibly increased the development and outcome of cardiovascular complications in uremic patients after MHD., Methods: The extent of coronary artery calcification was assessed by coronary artery calcification scoring (CACS) in uremic patients with and without adverse cardiovascular events after MHD (MHD group 1 vs. MHD group 2, respectively). Peripheral blood mononuclear cells were incubated with rhBMP-2 as positive control. The Treg/Th17 cell frequencies, Foxp3 ROR-gt mRNA expressions, and MIP 3α/CCL20 concentrations were measured., Results: The CACS score was significantly higher in MHD group 1 as compared group 2. In comparison with controls, rhBMP-2 upregulates Treg/Th17 functional disequilibrium in uremic patients, displayed higher Treg and Th17 frequencies, Foxp3 and ROR-gt expressions, and MIP3α/CCL20 concentrations. However, the up-regulations of Treg frequencies and Foxp3 expressions were significant in controls but not in MHD patients. It was also observed that Treg/Th17 functional disequilibrium was not only correlated with rhBMP-2 state but also consistent with the cardiovascular complications. Moreover, the CACS was negatively correlated with Treg cell frequencies but positively correlated with Th17 cell frequencies and MIP3a/CCL20 concentrations., Conclusions: Function disequilibrium of Treg/Th17 was related to the degree of the rhBMP-2 state. Function disequilibrium of the Treg/Th17 might act synergistically with rhBMP-2 in the high incidence of immune-mediated cardiovascular complications after MHD.

Chronic kidney disease (CKD) and end-stage renal disease (ESRD) are associated with systemic inflammation and acquired immunodeficiency, which promote cardiovascular disease, body wasting, and infections as leading causes of death. This phenomenon persists despite dialysis-related triggers of immune deregulation having been largely eliminated. Here we propose a potential immunoregulatory role of the intestinal microbiota in CKD/ESRD. We discuss how the metabolic alterations of uremia favor pathogen overgrowth (dysbiosis) in the gut and an increased translocation of living bacteria and bacterial components. This process has the potential to activate innate immunity and systemic inflammation. Persistent innate immune activation involves the induction of immunoregulatory mediators that suppress innate and adaptive immunity, similar to the concept of 'endotoxin tolerance' or 'immune paralysis' in advanced sepsis or chronic infections. Renal science has largely neglected the gut as a source of triggers for CKD/ESRD-related immune derangements and complications and lags behind on the evolving microbiota research. Interdisciplinary research activities at all levels are needed to unravel the pathogenic role of the intestinal microbiota in kidney disease and to evaluate if therapeutic interventions that manipulate the microbiota, such as pre- or probiotics, have a therapeutic potential to correct CKD/ESRD-related immune deregulation and to prevent the associated complications.

Uraemia causes inflammation and reduces immune system function as evidenced by an increased risk of viral-associated cancers, increased susceptibility to infections and decreased vaccination responses in patients with end-stage renal disease (ESRD). The substantially increased risk of atherosclerosis in these patients is also probably related to uraemia-associated inflammation. Uraemia is associated with a reduction in the number and function of lymphoid cells, whereas numbers of myeloid cells in uraemic patients are normal or increased with increased production of inflammatory cytokines and reactive oxygen species. Similar to healthy elderly individuals, patients with ESRD have increased numbers of specific proinflammatory subsets of T cells and monocytes, suggesting the presence of premature immunological ageing in these patients. These cells might contribute to inflammation and destabilization of atherosclerotic plaques, and have, therefore, been identified as novel nonclassical cardiovascular risk factors. The cellular composition of the immune system does not normalize after successful kidney transplantation despite a rapid reduction in inflammation and oxidative stress. This finding suggests that premature ageing of the immune system in patients with ESRD might be related to a permanent skewing of the haematopoetic stem cell population towards myeloid-generating subsets, similar to that seen in healthy elderly individuals.