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Contribution of the uremic milieu to an increased pro-inflammatory monocytic phenotype in chronic kidney disease.

ABSTRACT: 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?++CD16⁺ monocytes versus Ctrl sham (33.7%?±?15 vs. 15.7%?±?9.6; P?++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?++CD16⁺ monocytes compared to control (19.8?±?9.6% vs. 15.8?±?10.9%; P?++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.

SUBMITTER: Borges Bonan N

PROVIDER: S-EPMC6629661 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Contribution of the uremic milieu to an increased pro-inflammatory monocytic phenotype in chronic kidney disease.

Borges Bonan Natalia N Schepers Eva E Pecoits-Filho Roberto R Dhondt Annemieke A Pletinck Anneleen A De Somer Filip F Vanholder Raymond R Van Biesen Wim W Moreno-Amaral Andréa A Glorieux Griet G

Scientific reports 20190715 1

Intermediate (CD14<sup>++</sup>CD16<sup>+</sup>) 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 ...[more]

PMID: 31308443

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Project description:Deletion polymorphism of glutathione S-transferase M1 (GSTM1), a phase II detoxification and antioxidant enzyme, increases susceptibility to end-stage renal disease (ESRD) as well as the development of cardiovascular diseases (CVD) among ESRD patients and leads to their shorter cardiovascular survival. The mechanisms by which GSTM1 downregulation contributes to oxidative stress and inflammation in endothelial cells in uremic conditions have not been investigated so far. Therefore, the aim of the present study was to elucidate the effects of GSTM1 knockdown on oxidative stress and expression of a panel of inflammatory markers in human umbilical vein endothelial cells (HUVECs) exposed to uremic serum. Additionally, we aimed to discern whether GSTM1-null genotype is associated with serum levels of adhesion molecules in ESRD patients. HUVECs treated with uremic serum exhibited impaired redox balance characterized by enhanced lipid peroxidation and decreased antioxidant enzyme activities, independently of the GSTM1 knockdown. In response to uremic injury, HUVECs exhibited alteration in the expression of a series of inflammatory cytokines including retinol-binding protein 4 (RBP4), regulated on activation, normal T cell expressed and secreted (RANTES), C-reactive protein (CRP), angiogenin, dickkopf-1 (Dkk-1), and platelet factor 4 (PF4). GSTM1 knockdown in HUVECs showed upregulation of monocyte chemoattractant protein-1 (MCP-1), a cytokine involved in the regulation of monocyte migration and adhesion. These cells also have shown upregulated intracellular and vascular cell adhesion molecules (ICAM-1 and VCAM-1). In accordance with these findings, the levels of serum ICAM-1 and VCAM-1 (sICAM-1 and sVCAM-1) were increased in ESRD patients lacking GSTM1, in comparison with patients with the GSTM1-active genotype. Based on these results, it may be concluded that incubation of endothelial cells in uremic serum induces redox imbalance accompanied with altered expression of a series of cytokines involved in arteriosclerosis and atherosclerosis. The association of GSTM1 downregulation with the altered expression of adhesion molecules might be at least partly responsible for the increased susceptibility of ESRD patients to CVD.

Project description:Background and objectivesUremic symptoms, including fatigue, anorexia, pruritus, nausea, paresthesia, and pain, are attributed to the accumulation of organic waste products normally cleared by the kidneys, but whether kidney function is the primary driver of changes in symptom severity over time is not known. The goal of our study was to evaluate the association between eGFR and uremic symptom severity score in patients with CKD.Design, setting, participants, and measurementsWe identified 3685 participants with CKD not on dialysis in the prospective, observational Chronic Renal Insufficiency Cohort (CRIC) Study with baseline assessment of eGFR and uremic symptom severity. Symptoms were assessed by separate questions on the Kidney Disease Quality of Life-36 instrument (zero- to 100-point scale). The longitudinal association between eGFR and uremic symptom severity score was examined with multivariable adjusted linear mixed-effects models with random intercepts and random slopes.ResultsThe mean±SD eGFR at baseline was 44±15 ml/min per 1.73 m2, and participants had a median of six (interquartile range 3-11) simultaneous assessments of eGFR and uremic symptoms over the duration of follow-up. The most prevalent symptoms at baseline were pain (57%), fatigue (52%), paresthesia (45%), and pruritus (42%). In adjusted models, a decrease in eGFR of 5 ml/min per 1.73 m2 was associated with a worsening of the symptom severity score by two points or less for each uremic symptom (P<0.01; zero- to 100-point scale). The association between eGFR and uremic symptom severity score was nonlinear. When starting from a lower initial eGFR, a 5 ml/min per 1.73 m2 decrease in eGFR was associated with a greater magnitude of uremic symptom worsening.ConclusionsThe prevalence of uremic symptoms in CKD is high, with significant variability in patient symptom change over time. Declines in eGFR were associated with worsening of uremic symptom severity, but the magnitude of these changes is small and of uncertain clinical significance.

Dataset Information

Contribution of the uremic milieu to an increased pro-inflammatory monocytic phenotype in chronic kidney disease.

Publications

Contribution of the uremic milieu to an increased pro-inflammatory monocytic phenotype in chronic kidney disease.

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