Inflammation In End-stage Renal Disease Research Articles

#2728 THROMBOINFLAMMATORY BIOMARKERS AND THEIR RELATIONSHIP WITH CIRCULATING GLYCOSAMINOGLYCANS IN END-STAGE RENAL DISEASE PATIENTS

Abstract Background and Aims End stage renal disease (ESRD) is a complex progressive medical condition that affects multiple organ systems. Given the high risk of morbidity and mortality of ESRD as well as its rising incidence, it is critical to understand the relevance of thromboinflammatory biomarkers in disease development and progression of kidney dysfunction. The purpose of this study is to profile the levels of thromboinflammatory biomarkers in ESRD patients including D-Dimer, C-reactive protein (CRP), von Willebrand factor (vWF), plasminogen activator inhibitor 1 (PAI-1), and thrombin activatable fibrinolysis inhibitor (TAFI). In addition, the levels of anti-PF4 IgG and endogenous circulating glycosaminoglycans (GAGs) were measured. Method Citrated plasma samples were collected from seventy-three ESRD patients. Control plasma samples (NHP) from healthy, non-smoking adults aged 19 to 53 were obtained commercially. Validated ELISA methods have been used to profile each of the biomarkers. The levels of endogenous GAGs were determined (Redprobes UG, Germany). To compare the levels of thromboinflammatory biomarkers, anti-PF4 IgG, and endogenous GAGs in different groups, appropriate statistical methods included Mann-Whitney U, t-tests, Kruskal-Wallis ANOVA and experiment correlation analysis methods were performed. Results All of the biomarkers and GAGs were significantly elevated, with the exception of TAFI, in ESRD patients. The ESRD patients exhibited varying levels of increase in the D-Dimer, CRP, vWF, PAI-1, anti-PF4 IgG, and GAGs as shown in Figure 1 (p < 0.05). D-Dimer showed the most pronounced increase (1075%) followed by PAI-1 (361.31%), anti-PF4 IgG (209.78%), CRP (101.77%) and endogenous GAGs (17.29%). The correlation analysis revealed varying degrees of association among these biomarkers (Figure 2). Conclusion These results suggest that thromboinflammatory biomarkers offer the potential utility of identifying inflammation in end-stage renal disease. Marked increase in thromboinflammatory mediators due to endothelial damage may result in the upregulation of glycosaminoglycans and anti-PF4 IgG antibodies in the ESRD patients.

IDF21-0092 Influence of the NLRP3 inflammasome in podocytes on the pathogenesis of diabetes dependent hyperfiltration-induced CKD

Background: Diabetic nephropathy (DN) is one of the most severe complications of Type 1 diabetes mellitus (T1) that is accounting for about 40% of end-stage renal disease (ESRD). The pathology is seen to correlate with inflammation. Amongst others, pattern recognition receptors are important mediators of disease progression, e.g. nucleotide-binding oligomerization domain receptors, together with inflammasomes. Especially the Nod-like receptor protein 3 (NLRP3) inflammasome multiprotein complex seems to be a key mediator in DN. The assembly of this promotes the maturation of proinflammatory cytokines (canonical pathway) such as IL-1β and IL-18. It is assumed that there are non-canonical pathways, that trigger innate inflammatory response. Whereas the role of NLRP3 in specialized immune cells is well understood, its contribution to processes of disease and homeostasis in renal parenchymal cells is controversially discussed in literature. Aim: With this project we expect to get a better understanding of the role of canonical and non-canonical NLRP3 signaling in podocytes. Furthermore, we aim to investigate if an inhibition of the NLRP3 signaling may lead to an ameliorated or even absent hyperfiltration-induced CKD. Method: To verify, if the NLRP3 inflammasome is involved in canonical, proinflammatory signaling, primary human podocytes derived from renal progenitor cells were stimulated in vitro. By using different concentrations of LPS, ATP, glucose and nigericin, metabolic stress was imitated. IL-1β and IL-18 ELISAs were used to verify canonical pathway activation. We further introduced podocyte-specific NLRP3 inflammasome modulations and Streptozotocin dependent diabetes in mice with a NLRP3 overactive variant (Nlrp3A350V fl/wt) to investigate, if NLRP3 overactivation leads to an aggravated phenotype of hyperfiltration-induced CKD. By using pharmaceuticals such as Oridonine and beta-Hydroxybutyrate we examined, if the inhibition of NLRP3 signaling in C57BL/6J wildtype mice with diabetes leads to an ameliorated outcome. To investigate if it is possible to reverse diabetes dependent hyperfiltration-induced CKD in NLRP3 overactive mice, we treated them with beta-Hydroxybutyrate. The primary endpoint of all in vivo experiments was defined as urinary albumin-creatinine-ratio. Furthermore, relevant histopathological alterations were observed. Results: Our data suggest that human derived podocytes are not susceptible for metabolic stress dependent canonical NLRP3 inflammasome signaling compared with THP-1 + PMA cells. Even though mice presented with severe diabetes and polyuria, we did not observe a significant difference in mice with NLRP3 overactivation regarding urinary albumin excretion and histological changes. So far, also the treatment with NLRP3 inhibitors did not ameliorate hyperfiltration-induced CKD. Discussion: Investigation of the NLRP3 functionality in podocytes provided a deeper insight and better understanding of the pathogenesis of diabetes dependent hyperfiltration-induced CKD. Even though it might have been possible that the specific inhibition of the inflammasome associated proteins should have synergistic effects in inflammation in ESRD and might be a future therapeutic target beyond IL-1β inhibition, our data do not support this hypothesis.

The association between platelet to lymphocyte ratio and neutrophil to lymphocyte ratio with inflammatory factors in hemodialysis patients

Introduction: Chronic inflammation is a major factor in the pathogenesis of atherosclerosis in hemodialysis patients compared to healthy individuals. Chronic inflammation is part of the malnutrition, atherosclerosis, and inflammation syndrome in advanced renal failure. Objectives: In this study, the relationships of platelet to lymphocyte ratio (PLR) and neutrophil to lymphocyte ratio (NLR) with the inflammatory factors were investigated. Patients and Methods: This cross-sectional study was conducted on 108 hemodialysis patients who were on dialysis for more than three months. For patients, serum levels of urea, creatinine (Cr), sodium, potassium, calcium, phosphate, parathyroid hormone, total cholesterol, triglyceride, ferritin, 25-hydroxy vitamin D, albumin, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and complete blood cell count were assessed before dialysis since serum urea was examined again after dialysis too. Results: The mean age of the patients (58 male and 50 female) was 63.43±14.65 years. The median values for NLR and PLR were 2.25 and 114.7, respectively. ESR was significantly higher in hemodialysis patients with NLR >2.25 (46.7±29.7 versus 36±22.7) and in those with PLR >114.7 (47.09±27.8 versus 35.6±24.8). Plasma hemoglobin and serum 25-hydroxy vitamin D levels were observed to be lower (10.37±1.6 versus 11.7±1.8 and 33.1±2.5 versus 37.9±15.2) in patients with PLR >114.7. Bivariate correlation showed that PLR and NLR had positive significant correlation with ESR while PLR had a significant negative correlation with values of blood 25-hydroxy vitamin D hemoglobin and Cr. Conclusion: Due to availability and affordability of PLR and NLR, they could be used for early assessment of inflammation in end-stage renal disease (ESRD) patients. PLR may be better predictor than NLR (to detect inflammation.

Neutrophil Lymphocyte Ratio and C-Reactive Protein in Nondialysis Chronic Kidney Disease

Background: Chronic kidney disease (CKD) occurs when a disease or condition impairs kidney function, causing kidney damage to worsen over several months. Inflammatory markers such as C-reactive protein (CRP), Interleukine are widely used in CKD. However, those traditional biomarkers have their limitations because of its measurement is costly or inaccessible. Recently, the Neutrophil-to-lymphocyte ratio (NLR) was reported to be associated with inflammation in End-stage renal disease (ESRD). Its measurement is simpler and cheaper4.5. The aim of the present study was to determine whether NLR is associated with CRP in CKD patients.
 Methods: This cross-sectional and observational analytic study was conducted 12 consecutive Pre Hemodialysis patients ESRD between Mei 2021 and Augustus 2021. Subjects were divided into two groups according to the results of the examination of the CRP and NLR levels. Then analyzed whether there is have a correlation.
 Results: The composite endpoint was observed in 12 patients with ESRD; it was found that both of the values of NLR and CRP were equally increased in ESRD patients, although they were not statistically significant.
 Conclusion: The present study demonstrated that a high NLR in ESDR and suggesting that NLR may be a useful marker for the prediction of infection in patients with CKD.

Association of CX3CR1 Gene Polymorphisms with Fractalkine, Fractalkine Receptor, and C-Reactive Protein Levels in Patients with Kidney Failure.

Fractalkine (CX3CL1) is a chemokine that plays a significant role in inflammation, one of the pathophysiological processes underlying end-stage renal disease (ESRD). Genetic factors are significantly involved in cytokine expression and have been studied as potential risk factors for chronic kidney disease (CKD). Objectives: We aimed to elucidate the association of CX3CR1 gene polymorphisms rs3732378 and rs3732379 with the levels of CX3CL1, CX3CL1 receptor (CX3CR1), as well as C-reactive protein (CRP). Patients and methods: We enrolled 198 participants, including 106 patients with ESRD and 92 controls. Peripheral blood samples were collected from each patient for genetic (rs3732378 and rs3732379 polymorphisms) and immunoenzymatic (fractalkine, CX3CR1, CRP) tests. Results: CX3CR1 and CRP levels were higher in patients with ESRD than in controls (p < 0.05). Fractalkine levels were significantly higher in ESRD patients who were homozygous for the G allele of the rs3732378 polymorphism and for the C allele of the rs3732379 polymorphism than in homozygous controls. Moreover, carriers of these alleles among patients with ESRD had significantly higher CX3CR1 levels than controls. Conclusions: The G allele of the rs3732378 polymorphism and the C allele of the rs3732379 polymorphism of the CX3CR1 gene are associated with higher CX3CL1 and CX3CR1 levels. Our study suggests that CX3CR1 gene polymorphisms could be potentially involved in the pathogenesis of ESRD, but the study needs to be replicated in a larger population with a longitudinal follow-up study. Identification of genetic factors associated with inflammation in ESRD may contribute to the development of targeted gene therapies in the future.

Neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio in evaluation of inflammation in non-dialysis patients with end-stage renal disease (ESRD)

BackgroundNeutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been reported to be associated with inflammation in end-stage renal disease (ESRD) receiving dialysis. However, the value of NLR and PLR in non-dialysis patients with ESRD remains unclear.MethodsAmong 611 non-dialysis patients with ESRD in The First Affiliated Hospital of University of South China (2012–2018), we compared NLR and PLR in patients with high-sensitivity C-reactive protein (hs-CRP) levels of ≤3 mg/L vs. > 3 mg/L. Correlation of NLR and PLR to hs-CRP, PCT, ferritin were analyzed. Receiver operating characteristics (ROC) analysis was used for estimating sensitivity and specificity of NLR and PLR.ResultsNLR was higher in the patients with high hs-CRP levels (> 3 mg/L), compared to patients with low hs-CRP levels (≤ 3 mg/L) [5.74 (3.54–9.01) vs. 3.96 (2.86–5.85), p < 0.0001]. Additionally, PLR was higher in high hs-CRP group than in low group [175.28 (116.67–252.26) vs. 140.65 (110.51–235.17), p = 0.022]. In the current study, NLR and PLR were both positively correlated with hs-CRP (rs = 0.377, p = 0.000 for NLR; rs = 0.161, p = 0.001 for PLR), PCT, leukocytes, neutrophils, platelets, and age. NLR or PLR with a cut-off value of 5.07 or 163.80 indicated sensitivity and specificity were 65.67 and 66.37% (AUC = 0.69) or 57.21 and 57.52% (AUC = 0.55), respectively.ConclusionsNLR or PLR was positively correlated with hs-CRP in non-dialysis patients with ESRD. NLR might be better for identifying inflammation than PLR in this population.

Effects of resistance training on hepcidin levels and iron bioavailability in older individuals with end-stage renal disease: A randomized controlled trial.

Anemia is an inherent complication of older individuals with end-stage renal disease (ESRD) that is associated with inflammation which in turn is an important factor in the activation of hepcidin that contributes to the decrease in serum iron. Athough resistance training (RT) seems to reduce inflammation in ESRD, its influence on hepcidin and iron availability in hemodialysis patients is unclear. Therefore, the aim of this study was to exemine the effects of RT in on inflammatory profile, hepcidin, and iron status in older individuals with ESRD. End-stage renal disease patients (N: 157, age: 66.8±3.6; body mass: 73±15 body mass index:27±3), were assigned to control (CTL n: 76) and exercise groups (RT n: 81). RT consisted of 24weeks/3days per week of a moderate intensity. There was an increase in the bioavailability of iron (ΔRT: 22.2; ΔCTL: -1μg/dL, p<0.0001), a decrease in hepcidin levels (ΔRT: -7.9; ΔCTL: 0.2ng/mL, p<0.0001),and an improvement of the inflammatory profile. These novel findings show that RT is a potential coadjuvant to reduce iron deficiency by decreasing the levels of hepcidin and pro-inflammatory markers in older patients undergoing hemodialysis.

P1379PLATELET/LYMPHOCYTE RATIO AS A MARKER OF ERYTHROPOIETIN RESPONSIVENESS IN END-STAGE RENAL DISEASE

Abstract Background and Aims Neutrophil/Lymphocyte Ratio (NLR) and Platelet/Lymphocyte Ratio (PLR) are closely associated with increased inflammation in end-stage renal disease, which often contributes to the severity of anemia in these patients. Erythropoiesis stimulating agents (ESA) have become a standard treatment of anemia in hemodialysis patients. Since some patients do not respond well to erythropoietin therapy (EPO) the aim of this study is to investigate if NLR and PLR as markers of increased inflammation, could be associated with resistance to EPO therapy. Method A total of 90 patients (36 females, 54 males; mean age 60,45 ±11,58) undergoing maintenance hemodialysis and who received recombinant human EPO therapy were examined. Patients' clinical characteristics, laboratory data, dialysis adequacy and the applied doses os EPO were examined in a period of 3 months. EPO hyporesponsiveness index (EHRI) was calculated as the weekly dose of EPO divided by kilograms of body weight divided by the hemoglobin level. Results Obtained results show a statistically significant correlation of moderate-intensity between EHRI and NLR ( r = 0.497, p &amp;lt; 0.01) as well as a negative correlation of moderate-intensity between EHRI and hemoglobin levels (Hgb) (r = -0.403, p &amp;lt; 0.01). When it comes to the connection of NLR and PLR with logarithmically converted EHRI values, the results show that there is no statistically significant correlation between NLR and EHRI. Comparison of PLR among 25th, 50th and 75th percentile of EHRI showed that PLR levels increased going from the 25th towards the 75th percentile (p &amp;lt; 0.01). Post hoc analysis indicated that there is also a statistically strong connection for the 25th i 50th percentile (&amp;lt;0 .05) and furthermore for the 50th and 75th percentile (&amp;lt; 0.05). Conclusion PLR was found to be superior to NLR in terms of evaluating ESA therapy resistance. PLR could be used as a predictor of ESA therapy response.

End-Stage Renal Disease-Associated Gut Bacterial Translocation: Evolution and Impact on Chronic Inflammation and Acute Rejection After Renal Transplantation.

Chronic inflammation in end-stage renal disease (ESRD) is partly attributed to gut bacterial translocation (GBT) due to loss of intestinal epithelium integrity. Increased levels of circulating lipopolysaccharide (LPS) –a surrogate marker of GBT– contribute to maintain a chronic inflammatory state. However, circulating LPS can be neutralized by lipoproteins and transported to the liver for elimination. While ESRD-associated GBT has been widely described, less is known about its changes and impact on clinical outcome after kidney transplantation (KT). One hundred and forty-six renal transplant recipients with serum samples obtained immediately before and 1 year after transplantation (1-Year post KT) were included. Intestinal epithelium integrity (iFABP), total LPS (by measuring 3-hydroxymyristate), LPS activity (biologically active LPS measured by the LAL assay), inflammatory biomarkers (sCD14 and cytokines), lipoproteins and LPS-binding proteins (LBP and phospholipid transfer protein [PLTP] activity) were simultaneously measured. At 1-Year post KT, iFABP decreased but remained higher than in normal volunteers. Total LPS concentration remained stable while LPS activity decreased. Inflammation biomarkers decreased 1-Year post KT. We concomitantly observed an increase in lipoproteins. Higher sCD14 levels before transplantation was associated with lower incidence of acute rejection. Although GBT remained stable after KT, the contemporary increase in lipoproteins could bind circulating LPS and contribute concomitantly to neutralization of LPS activity, as well as improvement in ESRD-associated chronic inflammation. Chronic exposure to LPS in ESRD could promote endotoxin tolerance and explain why patients with higher pre-transplant sCD14 are less prompt to develop acute rejection after transplantation.

Long Pentraxin 3 as a Broader Biomarker for Multiple Risk Factors in End-Stage Renal Disease: Association with All-Cause Mortality

Persistent inflammation in end-stage renal disease (ESRD) patients is known to underlie the progression of chronic kidney disease and to be associated with multiple risk factors including malnutrition, atherosclerosis, and cardiovascular disease (CVD). The acute-phase protein pentraxin 3 (PTX3) has a proven potential as a local inflammatory biomarker, but its clinical utility in ESRD remains unclear. Circulating levels of PTX3 and classical inflammatory mediators, including the clinical prototypical C-reactive protein (CRP), were assessed in 246 ESRD patients on dialysis and analysed in relation to the lipid profile, adipokine levels, and nutritional, cardiac, and renal fibrosis markers. Occurrence of deaths was recorded for the following year. Contrarily to the classical inflammatory markers, PTX3 levels were negatively correlated with nutritional markers and associated with a less atherogenic lipid profile. Levels of the cardiac and renal fibrosis markers and of the oxidized LDL/LDL-C ratio were found to be independent determinants of PTX3 concentration. When comparing inflammatory mediators, the increase in the PTX3 levels was the only predictor of all-cause mortality in dialysis patients in a survival model adjusted to all markers under study, other than the inflammatory ones, besides common confounding factors in dialysis. Data support the clinical applicability of PTX3 as a broader inflammatory biomarker than the classical ones, presenting a close association with inflammation, malnutrition, CVD, and renal fibrosis and a great potential to predict all-cause mortality in dialysis patients. The pleiotropic character of PTX3 may be of clinical relevance, and it could be targeted to ameliorate the high morbidity and mortality associated with ESRD.

Endothelial injury is closely related to osteopontin and TNF receptor-mediated inflammation in end-stage renal disease

BackgroundEndothelial dysfunction, inflammation and active mineralization are key processes involved in cardiovascular burden in end stage renal disease (ESRD). Serum (soluble) thrombomodulin (sTM) is an established marker of endothelial injury. Patients80 patients in ESRD were recruited consecutively. Baseline distribution of sex, age, main comorbidities and Framingham score was similar. A biochemical panel including sTM, intact PTH (iPTH), interleukin-6 (IL-6), pentraxin 3 (PTX3), fibroblast growth factor 23 (FGF-23), osteopontin (OPN), osteoprotegerin (OPG), osteocalcin (OC), osteonectin (ON), soluble tumor necrosis factor receptor type 2 (TNFR2), transforming growth factor-β (TGF-β), hepatocyte growth factor (HGF), vascular endothelial growth factor receptor type 2 (sVEGFR2) and stromal cell-derived factor 1α (SDF1α) was investigated in each patient. Samples obtained while establishing haemodialysis (HD) access were stained for radial artery calcifications (RACs) with Alizarin red and examined histologically. ResultsAfter adjustment for HD status, sTM showed a significant positive correlation with serum creatinine, TNFR2, OPN, HGF, SDF1α, sVEGFR2, Pi, iPTH, FGF-23, OPG, OC and ON. In forward stepwise multiple regression, serum creatinine, TNFR2, and OPN were identified as significant, independent predictors of sTM. Grades 1–3 of RACs correlated with sTM (R = 0.50, p = 0.017), while grade 3 RACs were significantly associated with higher sTM (p = 0.02) than less advanced lesions. ConclusionAmong novel renal and cardiovascular biomarkers, OPN and TNFR2 are closely related to sTM. This may link endothelial damage, vascular remodeling and inflammation. Progression of RAC parallels a presumed compensatory rise in sTM, reflecting endothelial injury. sTM has an intricate role in endothelial function and potential clinical and prognostic applications.

Chronic inflammation in end-stage renal disease and dialysis.

Under normal conditions, inflammation is a protective and physiological response to various harmful stimuli. However, in several chronic debilitating disorders, such as chronic kidney disease, inflammation becomes maladaptive, uncontrolled and persistent. Systemic persistent inflammation has, for almost 20 years, been recognized as a major contributor to the uraemic phenotype (such as cardiovascular disease, protein energy wasting, depression, osteoporosis and frailty), and a predictor of cardiovascular and total mortality. Since inflammation is mechanistically related to several ageing processes (inflammageing), it may be a major driver of a progeric phenotype in the uraemic milieu. Inflammation is likely the consequence of a multifactorial aetiology and interacts with a number of factors that emerge when uraemic toxins accumulate. Beside interventions aiming to decrease the production of inflammatory molecules in the uraemic milieu, novel strategies to increase the removal of large middle molecules, such as expanded haemodialysis, may be an opportunity to decrease the inflammatory allostatic load associated with retention of middle molecular weight uraemic toxins.

Novel PAradigm to improve Inflammatory burden in end stage Renal disease (rePAIR): study protocol for a randomized controlled trial

BackgroundGiven the importance of inflammation as a predictor of poor outcomes in End Stage Renal Disease (ESRD), reductions in inflammatory biomarkers have been proposed as a critical target in this population. This study targets chronic periodontitis, an oral inflammatory disease of microbial etiology causing persistent inflammation in ESRD. Unlike the previously reported episodic periodontal interventions, we propose to control periodontal inflammation with a continuous maintenance and oral health behavior modifications. We hypothesize that this strategy will improve systemic inflammation and oxidative stress, oral health and quality of life within the 6-month observation period.MethodsThe rePAIR (novel PAradigm to improve Inflammatory burden in ESRD) study is a pilot and feasibility, parallel-arm, and randomized controlled clinical trial that will recruit 72 ESRD subjects with periodontitis in a model of computerized block randomization. This trial aims to compare the effect of standard-of-care vs. repeated non-surgical periodontal therapy on systemic and oral inflammatory burden. This trial will recruit ESRD adult patients with periodontitis older than 21 years old with a minimum of 12 teeth and no history of periodontal treatment within a year. The trial will examine serum C-reactive protein (CRP) (primary outcome) as a biomarker of inflammation as well as interleukin-6 (IL-6), F2 isofurans and F2 isoprostanes (secondary outcomes) and compare their difference between groups from baseline to 6 months. The trial will also compare the difference between groups in patient-centered and clinical oral outcomes from baseline to 6 months.DiscussionThe trial follows a rigorous and transparent study design capturing elements such as pre-specified eligibility criteria, pre-specified primary and secondary outcomes, detailed intervention description to allow replication, intervention random allocation and concealment, blinding in outcome assessment, appropriate sample size calculations, explanation of interim analysis, as per CONSORT Guidelines. Further, gender diversity is secured not only at recruitment but also throughout the trial and during the analysis. Therefore, treatment response outcomes will be examined per gender category. In order to manage anticipated problems, the protocol has included alternative approaches.Trial registrationClinicalTrials.gov, NCT03241511. Registered on 7 August 2017.

Inflammation and premature aging in advanced chronic kidney disease.

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.

Uremia induces adipose tissue inflammation and muscle mitochondrial dysfunction.

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. 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. 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. 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.

Plasma protein-bound di-tyrosines as biomarkers of oxidative stress in end stage renal disease patients on maintenance haemodialysis

BackgroundPatients with end-stage renal disease (ESRD) undergoing haemodialysis (HD) experience enhanced oxidative stress and systemic inflammation, which are risk factors for cardiovascular disease, the most common cause of excess morbidity and mortality for these patients. Different pathways producing different types of oxidative stress occur in ESRD. The purpose of our study was to determine the effect of HD on plasma levels of protein-bound dityrosine (di-Tyr), a biomarker of protein oxidation. MethodsProtein-bound di-Tyr formation was measured by size exclusion HPLC coupled to fluorescence detector. Clinical laboratory parameters were measured by standardized methods. ResultsIn most ESRD patients, a single HD session decreased significantly the plasma protein-bound di-Tyr level, although the mean post-HD level remained significantly greater than the one in healthy people. Furthermore, pre-HD plasma protein-bound di-Tyr level was positively correlated with pre-HD serum creatinine and albumin concentrations. No significant correlation was found between plasma protein-bound di-Tyr level and serum concentration of C-reactive protein, a biomarker of systemic inflammation. ConclusionsThis study demonstrates that a single HD session does not increase, rather partially decreases, oxidative pathways producing di-Tyr in the haemodialyzed patient. General significanceThe choice of the most pertinent biomarkers of oxidative stress is critical for the development of novel treatments for ESRD. However, the relative importance of oxidative stress and inflammation in ESRD remains largely undetermined, and several questions concerning oxidative stress and inflammation remain poorly defined. These results could stimulate further studies on the use of plasma protein-bound di-Tyr as a long-lasting oxidative stress biomarker in ESRD.

End-Stage Renal Disease, Inflammation and Cardiovascular Outcomes.

Despite marked improvements in renal replacement therapy during the last 30 years, the age-adjusted mortality rate in end-stage renal disease (ESRD) patients is still unacceptably high and comparable to that of many malignancies. Cardiovascular disease (CVD) remains the major cause of morbidity and mortality in ESRD patients. However, traditional risk factors can only partially explain the high premature cardiovascular burden in this population. Nontraditional risk factors, including persistent low-grade inflammation, are critical in the pathogenesis of atherosclerosis, vascular calcification, and other causes of CVD and may also contribute to protein-energy wasting and other complications in chronic kidney disease (CKD) patients. Inflammatory biomarkers, such as high sensitivity C-reactive protein and interleukin-6, independently predict mortality in these patients. The causes of inflammation in CKD are multifactorial and include imbalance between increased production (due to multiple sources of inflammatory stimuli such as oxidative stress, acidosis, volume overload, co-morbidities, especially infections, genetic and epigenetic influences, and the dialysis procedure) and inadequate removal (due to decreased glomerular filtration rate or in ESRD patients, inadequate dialytic clearance) of pro-inflammatory cytokines. Though there are currently no established guidelines for the treatment of low-grade inflammation in ESRD patients, several strategies have been proposed, such as lifestyle modifications, pharmacological treatment, and optimization of dialysis. Further studies on pathways involved in pathogenic processes of inflammation in ESRD, and long-term effects of anti-inflammatory interventions targeting production or removal of cytokines or both on premature CVD and clinical outcomes in this patient group are warranted.

Neutrophil-to-lymphocyte ratio and platelet-tolymphocyte ratio in evaluation of inflammation in end-stage renal disease

To evaluate the relationship between neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and inflammation in end-stage renal disease (ESRD) patients on maintenance hemodialysis (HD). 100 ESRD patients on maintenance HD (mean ± SD age: 52.3 ± 1.7 years, 52% were males) were included in this cross-sectional study. Data on patient demographics, dry weight, body mass index, duration of HD (months), etiology of ESRD, delivered dose of dialysis (spKt/V), complete blood count, blood biochemistry and inflammatory markers including hs-CRP (mg/L), TNF-α (pg/mL), NLR, and PLR were recorded in all patients and compared in patients with hs-CRP levels of ≤ 3 mg/L vs. > 3 mg/L. other study parameters were also recorded. Compared to patients with lower hs-CRP levels, patients with hs-CRP levels of > 3 mg/L had significantly higher values for NLR (3.7 ± 0.2 vs. 2.7 ± 0.2, p < 0.01) and PLR (150.7 ± 6.9 vs. 111.8 ± 7.0, p < 0.001). Both NLR and PLR were positively correlated with hs-CRP (r = 0.333, p = 0.01 and r = 0.262, p = 0.001, respectively) and negatively correlated with transferrin saturation (%) (r = -0.418, p = 0.001 and r = -0.309, p = 0.002, respectively). Our findings in a cohort of ESRD patients on maintenance HD revealed higher values for NLR and PLR in patients with higher levels of inflammation along with a significant positive correlation of both NLR and PLR with hs-CRP levels. Being a simple, relatively inexpensive and universally available method, whether or not calculation of NLR and PLR offers a plausible strategy in the evaluation of inflammation in ESRD patients in the clinical practice should be addressed in larger scale randomized and controlled studies.

Platelet‐to‐lymphocyte ratio better predicts inflammation than neutrophil‐to‐lymphocyte ratio in end‐stage renal disease patients

Neutrophil-to-lymphocyte ratio (NLR) was introduced as a potential marker to determine inflammation in end-stage renal disease (ESRD) patients. Recently, platelet-to-lymphocyte ratio (PLR) and NLR were found to positively correlated with inflammatory markers including tumor necrosis factor-α (TNF-α) and interleukin (IL)-6 in cardiac and noncardiac patients. Data regarding PLR and its association with inflammation are lacking in hemodialysis (HD) and peritoneal dialysis (PD) patients. Hence, we aimed to determine the relationship between PLR, NLR, and inflammation in ESRD patients. This was a cross-sectional study involving 62 ESRD patients (29 females, 33 males; mean age, 49.6 ± 14.6 years) receiving PD or HD for ≥6 months in the Dialysis Unit of Necmettin Erbakan University. PLR, NLR, C-reactive protein, TNF-α, IL-6 levels were measured. PLR, NLR, serum high sensitive C-reactive protein, IL-6, and TNF-α levels were significantly higher in PD patients when compared with HD patients. ESRD patients with PLR ≥ 140 had significantly higher NLR, IL-6, and TNF-α levels when compared to patients with PLR < 139. In the bivariate correlation analysis, PLR was positively correlated with NLR, IL-6, and TNF-α in this population. When we compared the association of PLR and NLR with IL-6 (r = 0.371, P = 0.003 vs. r = 0.263, P = 0.04, respectively) and TNF-α (r = 0.334, P = 0.008 vs. r = 0.273, P = 0.032, respectively), PLR was found to be superior to NLR in terms of inflammation in ESRD patients. Simple calculation of PLR can predict inflammation better than NLR in ESRD patients.

Immune cell dysfunction and inflammation in end-stage renal disease

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.