Inflammation In Chronic Kidney Disease Patients Research Articles

Association between Monocyte-to-Lymphocyte Ratio and Inflammation in Chronic Kidney Disease: A Cross-Sectional Study

Introduction: Inflammation plays a key role in chronic kidney disease (CKD). Monocyte-to-lymphocyte ratio (MLR) is a novel inflammatory marker. The purpose of this study was to evaluate the relationship between MLR and inflammation in CKD patients. Methods: In total, 1,809 subjects were recruited from Wanzhai Town, Zhuhai City, between December 2017 and March 2018 for a cross-sectional survey. Patients were categorized based on the absence (hypersensitive C-reactive protein [hsCRP] level ≦3 mg/L) or presence (hsCRP level >3 mg/L) of inflammation. Logistic regression models and MLR quartiles were used to explore the relationship between MLR and inflammation in CKD patients. Results: Among 1,809 subjects, 403 (22.2%) had CKD. Significant differences in systolic blood pressure, estimated glomerular filtration rate, white blood cell (WBC), neutrophil, monocyte, MLR, and interleukin-6 (IL-6) levels were observed between noninflammatory group and inflammatory group. The highest MLR quartile had higher Scr, WBC, neutrophil, monocyte, IL-6, and hsCRP values and lower eGFR and lymphocyte values. Comparing the lowest quartile of MLR, the OR (95% CI) of inflammation risk in the highest quartile was 2.30 (1.24–4.27) after adjustment for confounding factors. The area under the curve of MLR for predicting inflammation was 0.631. The cutoff point for the MLR was 0.153. Conclusion: A high MLR was significantly and independently associated with inflammation in patients with CKD, making MLR a potential marker for inflammation in this demographic. MLR may also predict the severity of CKD.

Knockout of integrin αvβ6 protects against renal inflammation in chronic kidney disease by reduction of pro-inflammatory macrophages

Integrin αvβ6 holds promise as a therapeutic target for organ fibrosis, yet targeted therapies are hampered by concerns over inflammatory-related side effects. The role of αvβ6 in renal inflammation remains unknown, and clarifying this issue is crucial for αvβ6-targeted treatment of chronic kidney disease (CKD). Here, we revealed a remarkable positive correlation between overexpressed αvβ6 in proximal tubule cells (PTCs) and renal inflammation in CKD patients and mouse models. Notably, knockout of αvβ6 not only significantly alleviated renal fibrosis but also reduced inflammatory responses in mice, especially the infiltration of pro-inflammatory macrophages. Furthermore, conditional knockout of αvβ6 in PTCs in vivo and co-culture of PTCs with macrophages in vitro showed that depleting αvβ6 in PTCs suppressed the migration and pro-inflammatory differentiation of macrophages. Screening of macrophage activators showed that αvβ6 in PTCs activates macrophages via secreting IL-34. IL-34 produced by PTCs was significantly diminished by αvβ6 silencing, and reintroduction of IL-34 restored macrophage activities, while anti-IL-34 antibody restrained macrophage activities enhanced by αvβ6 overexpression. Moreover, RNA-sequencing of PTCs and verification experiments demonstrated that silencing αvβ6 in PTCs blocked hypoxia-stimulated IL-34 upregulation and secretion by inhibiting YAP expression, dephosphorylation, and nuclear translocation, which resulted in the activation of Hippo signaling. While application of a YAP agonist effectively recurred IL-34 production by PTCs, enhancing the subsequent macrophage migration and activation. Besides, reduced IL-34 expression and YAP activation were also observed in global or PTCs-specific αvβ6-deficient injured kidneys. Collectively, our research elucidates the pro-inflammatory function and YAP/IL-34/macrophage axis-mediated mechanism of αvβ6 in renal inflammation, providing a solid rationale for the use of αvβ6 inhibition to treat kidney inflammation and fibrosis.

#1815 The neutrophil/lymphocyte, neutrophil/HDL-cholesterol, and monocyte/HDL-cholesterol ratios as simple markers of low-grade inflammation in CKD patients

Abstract Background and Aims Chronic kidney disease (CKD) has been associated with inflammation and oxidative stress, as well as with high cardiovascular (CV) morbidity and mortality. The neutrophil/lymphocyte (NLR), neutrophil/HDL-cholesterol (NHR), and monocyte/HDL-cholesterol (MHR) ratios have been linked both to inflammation and increased CV risk in a variety of diseases. The aim of this study was to investigate changes in these ratios in CKD patients of stage 2-5 without any clinical and laboratory signs of inflammation, and to compare these indicators with those in healthy volunteers. Method A retrospective cross-sectional study was conducted in 88 healthy volunteers and 187 CKD patients (50 of stage 2, 44 of stage 3a, 45 of stage 3b and 48 of stage 4-5). Patients with acute renal impairment, nephrotic proteinuria, infections, systemic inflammation, malignancies and hematologic diseases were excluded, as were those receiving hypolipidemic, corticosteroid, immunosuppressive or immunostimulant drugs. The whole blood samples were collected and the absolute numbers of neutrophils, lymphocytes, and monocytes were used for calculation of NLR, NHR and MHR, respectively. Serum creatinine, HDL-cholesterol, C-reactive protein (CRP) and albumin were measured and eGFR calculated according to the CKD EPI equation. Statistical analysis was performed with the Mann-Whitney, Shapiro–Wilk, Kruskal-Wallis, and Spearman's correlation tests using the SPSS software. Results The NLR, NHR and MHR were higher in CKD patients when compared to healthy volunteers (P < 0,001), but only NLR and NHR increased significantly across CKD stages (P < 0,01). The ratio differences between CKD stages were more evident for NHR which was also in best correlation with eGFR (ρ = −0,406, P < 0,001). The CRP values increased across CKD stages as well (P < 0,01) although remaining within the reference range. The NLR, NHR and MHR were significantly related to CRP with NHR providing the best correlation (ρ = 0,289, P < 0,001). Conclusion This study showed that NLR and NHR increased across CKD stages 2-5 and could be used to identify low-grade inflammation in this population even within normal CRP values.

Correlation between Neutrophil-Lymphocyte Ratio and Urea Serum in Hemodialysis Patients at Dr. Doris Sylvanus Hospital

Chronic Kidney Disease (CKD) is a condition characterized by kidney damage for > 3 months, as well as structural or functional abnormalities with or without a decrease in Glomerular Filtration Rate (GFR) < 60 mL/minute/1.73. This damage leads to increased urea levels in the blood, also known as uremia, which can increase the risk of inflammation in CKD patients undergoing hemodialysis (HD). Previous studies revealed that increased urea and Neutrophil-Lymphocyte Ratio (NLR) can be used as inflammatory biomarkers to replace CRP, IL-6, and other indicators. This study aimed to determine the correlation between NLR and serum urea levels in pre- and post-HD CKD patients at Dr. Doris Sylvanus Hospital. An analytical survey method was used with a retrospective design.The process started by taking medical records of patients currently undergoing HD who were selected as respondents. The sample population consisted of 50 (70.4%) males and 21 (29.6%) females. Based on the age group, 43.7% of patients were aged 51-60. The results showed that the average NLR pre- and post-HD were 5.24±4.88 and 10.41±12.31, respectively. The average urea pre- and post-HD were 195.97±77.88 and 120.97±47.4, respectively. The bivariate analysis showed a significant weak correlation between NLR and serum urea level pre-HD (p=0.004 with r =0.338) and post-HD (p=0.039 with r =0.246) in patients.

NLR and PLR as Available and Inexpensive markers for Evaluation of Subclinical Inflammation in patients with Chronic Kidney Disease

Chronic kidney disease (CKD) is associated with high morbidity and increased cardiovascular mortality. Chronic inflammation was found to be correlated with cardiovascular disease (CVD) in CKD population. High-sensitivity C-reactive protein (hs-CRP), is one of biomarkers of subclinical inflammation, and widely used as an independent predictor of cardiovascular risk. Neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) were introduced as potential markers for evaluation of inflammation in several diseases. However, there are a few studies in CKD patients. We aimed to evaluate the relationship of NLR and PLR with hs-CRP levels in Syrian patients with CKD. The study included 100 CKD patients in stages 3 to 5 seen at Tishreen University Hospital, and 22 subjects served as control. CKD patients were divided into two groups, according to the presence or absence of inflammation, based on the high-sensitivity C-reactive protein (hs-CRP) cut off value of 3 mg/l. Blood samples were collected for blood count and hs-CRP levels determination. hs-CRP concentration was measured by immunoturbidimetry assay kit. NLR and PLR were calculated based on the absolute number of neutrophils, lymphocytes and platelets. We used the SPSS 25.0 program for the statistical analysis. Probability (P) value<0.05 was considered statistically significant. NLR as well as PLR and hs-CRP levels were significantly higher in all CKD groups compared to control subjects (p<0.05, for all). NLR and PLR values were significantly different between CKD groups with and without inflammation (for both, p<0.001). Both NLR and PLR were positively correlated with hs-CRP (r=0.50, p<0.001 for NLR; r=0.43, p<0.001 for PLR) in CKD patients. The best cutoff point for NLR to detect inflammation was ≥3.06, with 70% sensitivity and 81.1% specificity. For PLR, the cut off was ≥144.78, with 59% sensitivity and 73% specificity. There was no significant difference between the area under the NLR and PLR curve (0.77 vs. 0.70, p=0.19) for this population. Our findings suggests that NLR and PLR are available, simple and less expensive methods that could be used as markers of inflammation in CKD patients instead of hs-CRP.

MCP1 Could Mediate FGF23 and Omega 6/Omega 3 Correlation Inversion in CKD.

Fibroblast growth factor 23 (FGF23) concentrations rise after the early stages of chronic kidney disease (CKD). FGF23 is involved in inflammatory reactions closely associated with an incremented risk of cardiovascular disease (CVD). There is growing evidence that omega-6 (n-6) and n-3 polyunsaturated fatty acids (PUFA) can modulate inflammation through several mediators producing an opposite effect on cardiovascular (CV) risks. In this study, we explore whether there is any correlation between PUFA, FGF23, and inflammation in CKD patients. We evaluated, cross-sectionally, 56 patients at different stages of CKD. Monocyte chemoattractant protein 1 (MCP1), and intact and c-terminal FGF23 (iFGF23, cFGF23) were quantified by the ELISA, and the fatty acids (FA) profile was analyzed by gas chromatography. Concurrently with an eGFR decrease (p < 0.01) and an MCP1 increase (p = 0.031), we observed an inversion of the correlation between FGF23 and the n-6/n-3 ratio. This last correlation was inversed in CKD stage 3 (r2 (−) 0.502 p = 0.029) and direct in stage 5 (r2 0.657 p = 0.020). The increase in MCP1 seems to trigger events in the inversion of the correlation between FGF23 and the n-6/n-3 PUFA ratio. This result strongly encourages future studies on basal pathways, on possible pharmacological interventions, and on managing kidney transplant patients treated with immunosuppressive therapy.

Statins Have an Anti-Inflammation in CKD Patients: A Meta-Analysis of Randomized Trials.

Background Persistent inflammation has been recognized as an important comorbid condition in patients with chronic kidney disease (CKD) and is associated with many complications, mortality, and progression of CKD. Previous studies have not drawn a clear conclusion about the anti-inflammatory effects of statins in CKD. This meta-analysis is aimed at assessing the anti-inflammatory effects of statins therapy in patients with CKD. Methods A comprehensive literature search was conducted in these databases (Medline, Embase, Cochrane library, and clinical trials) to identify the randomized controlled trials that assess the anti-inflammatory effects of statins. Subgroup, sensitivity, and trim-and-fill analysis were conducted to determine the robustness of pooled results of the primary outcome. Results 25 eligible studies with 7921 participants were included in this meta-analysis. The present study showed that statins therapy was associated with a decreased C-reactive protein (CRP) (-2.06 mg/L; 95% CI: -2.85 to -1.27, p < 0.01). Subgroup, sensitivity, and trim-and-fill analysis showed that the pooled results of CPR were stable. Conclusion This meta-analysis demonstrates that statins supplementation has anti-inflammatory effects in patients with CKD. Statins exert an anti-inflammatory effect that is clinically important in improving complications, reducing mortality, and slowing progression in CKD. We believe that the benefits of statins to CKD are partly due to their anti-inflammatory effects. However, stains usually are prescribed in the CKD patients with dyslipidemia, whether statins can reduce inflammation in CKD patients with normal serum lipid needed to explore in the future. Therefore, we suggest that randomized clinical trials need to assess the effect of statins in CKD patients with normal serum lipid. Whether statins can be prescribed for aiming to inhibit inflammation in CKD also needed further study. Trial Registration. The study protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO); registration number: CRD42022310334.

Brain-derived neurotrophic factor (BDNF): a multifaceted marker in chronic kidney disease.

Despite advances in diagnostic tools and therapeutic options, chronic kidney disease (CKD) is still a global health problem associated with increased morbidity and mortality. Insulin resistance, muscle wasting, malnutrition and chronic inflammation are highly prevalent in CKD patients. Brain-derived neurotrophic factor (BDNF) is a member of the nerve growth factor-related family and with its receptor tropomyosin-related kinase receptor B impacts cell differentiation, synaptic connectivity and plasticity of the brain. BDNF is well studied in various populations especially in the area of neurology and psychiatry. Recently, there is also an acceleration of BDNF research in CKD and accumulating evidence suggests that BDNF may be a potential prognostic marker in CKD patients. Specifically, studies have shown that BDNF is associated with insulin resistance, muscle wasting, depression, oxidative stress and inflammation in CKD patients. However, the data regarding BDNF in CKD is only in its first steps and various issues must be highlighted in upcoming studies. In this review, we have summarized the findings regarding BDNF and its relationship between insulin resistance, muscle wasting, depression, oxidative stress and inflammation in CKD patients. We also mentioned controversies and possible causes for diverse findings and suggest perspectives in the context of BDNF and CKD.

Vascular Calcification and the Gut and Blood Microbiome in Chronic Kidney Disease Patients on Peritoneal Dialysis: A Pilot Study.

Vascular calcification (VC) is a frequent condition in chronic kidney disease (CKD) and a well-established risk factor for the development of cardiovascular disease (CVD). Gut dysbiosis may contribute to CVD and inflammation in CKD patients. Nonetheless, the role of gut and blood microbiomes in CKD-associated VC remains unknown. Therefore, this pilot study aimed to explore the link between gut and blood microbiomes and VC in CKD patients on peritoneal dialysis (CKD-PD). Our results showed relative changes in specific taxa between CKD-PD patients with and without VC, namely Coprobacter, Coprococcus 3, Lactobacillus, and Eubacterium eligens group in the gut, and Cutibacterium, Pajaroellobacter, Devosia, Hyphomicrobium, and Pelomonas in the blood. An association between VC and all-cause mortality risk in CKD-PD patients was also observed, and patients with higher mortality risk corroborate the changes of Eubacterium eligens in the gut and Devosia genus in the blood. Although we did not find differences in uremic toxins, intestinal translocation markers, and inflammatory parameters among CKD-PD patients with and without VC, soluble CD14 (sCD14), a nonspecific marker of monocyte activation, positively correlated with VC severity. Therefore, gut Eubacterium eligens group, blood Devosia, and circulating sCD14 should be further explored as biomarkers for VC, CVD, and mortality risk in CKD.

Exploring Mechanisms by Which Danggui Buxue Decoction Regulates Inflammation and Improves Renal Anemia Based on Network Pharmacology

Background: Renal anemia occurs frequently in patients with chronic kidney disease (CKD) and is related to chronic inflammation. Danggui Buxue Decoction (DBD) can treat anemia and improve the chronic inflammation. However, whether DBD treatment attenuates anemia by regulating inflammation in CKD patients with renal anemia is unknown. Therefore, this study explored inflammation-related network targets of DBD in renal anemia therapy and verified the interaction between DBD active ingredients and inflammatory proteins by molecular docking. Methods: The main effective components and targets of DBD were screened using the Traditional Chinese Medicine System Pharmacology Database and Analysis Platform. Renal anemia-related biomolecules were searched in the GeneCards, OMIM, TTD, Pharmgkb, and DrugBank databases. Protein-protein interaction (PPI) data were downloaded from the STRING database and core targets were obtained. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses for core targets were performed. Finally, active ingredients and core biomolecules were determined using molecular docking. Results: Twenty-two active components and 158 targets for DBD treatment of renal anemia were screened, and an “ingredient-target” network was constructed. Twenty core target genes were screened from the PPI data. Vascular endothelial growth factor A, Signal Transducer and Activator of transcription 1, C-X-C motif chemokine ligand 8, post-transcriptional gene silencing 2, and interleukin (IL)-1β were identified as inflammatory proteins. GO items related to inflammation and DBD included lipopolysaccharide, cellular response to chemical stress, and oxidative stress-related reactions. KEGG enrichment analyses showed that core inflammatory pathways mainly involved the IL-17 signaling pathway, tumor necrosis factor signaling pathway, and phosphoinositide 3-kinase-protein kinase B signaling pathway. Molecular docking results indicated that the binding energy of quercetin, an active ingredient of DBD, to the 5 core proteins was less than −6 kcal·mol−1. Conclusion: DBD might have protective effects against renal anemia by improving inflammation. Quercetin might modulate multiple inflammatory proteins and pathways.

Inflammation and Cardiovascular Disease Associated With Hemodialysis for End-Stage Renal Disease.

Chronic kidney disease (CKD) and cardiac insufficiency often co-exist, particularly in uremic patients on hemodialysis (HD). The occurrence of abnormal renal function in patients with cardiac insufficiency is often indicative of a poor prognosis. It has long been established that in patients with cardiac insufficiency, poorer renal function tends to indicate poorer cardiac mechanics, including left atrial reserve strain, left ventricular longitudinal strain, and right ventricular free wall strain (Unger et al., Eur J Heart Fail, 2016, 18(1), 103–12). Similarly, patients with chronic kidney disease, particularly uremic patients on HD, often have cardiovascular complications in addition to abnormal endothelial function with volume overload, persistent inflammatory states, calcium overload, and imbalances in redox responses. Cardiac insufficiency due to uremia is therefore mainly due to multifaceted non-specific pathological changes rather than pure renal insufficiency. Several studies have shown that the risk of adverse cardiovascular events is greatly increased and persistent in all patients treated with HD, especially in those who have just started HD treatment. Inflammation, as an important intersection between CKD and cardiovascular disease, is involved in the development of cardiovascular complications in patients with CKD and is indicative of prognosis (Chan et al., Eur Heart J, 2021, 42(13), 1244–1253). Therefore, only by understanding the mechanisms underlying the sequential development of inflammation in CKD patients and breaking the vicious circle between inflammation-mediated renal and cardiac insufficiency is it possible to improve the prognosis of patients with end-stage renal disease (ESRD). This review highlights the mechanisms of inflammation and the oxidative stress that co-exists with inflammation in uremic patients on dialysis, as well as the mechanisms of cardiovascular complications in the inflammatory state, and provides clinical recommendations for the anti-inflammatory treatment of cardiovascular complications in such patients.

Effects of non-surgical periodontal therapy on serum inflammatory factor high-sensitive C-reactive protein, periodontal parameters and renal biomarkers in patients with chronic periodontitis and chronic kidney disease.

Chronic kidney disease (CKD) is associated with significant morbidity and mortality, and there are various risk factors for this disease. Although the association between CKD and periodontal disease (PD) has been reported in various cross-sectional studies, longitudinal intervention studies are scarce. This study aimed to evaluate the effects of non-surgical periodontal therapy (NSPT) on periodontal clinical parameters, serum inflammatory factor high-sensitivity C-reactive protein (hs-CRP) and renal biomarkers in patients with CKD and chronic periodontitis (CP). A total of 80 patients with confirmed CKD aged 22-65 years, attending the Institute of Kidney Diseases Research Centre (IKDRC) in Ahmedabad, India, and referred to the Government Dental College and Hospital, Ahmedabad (GDCHA), were enrolled in this study. The patients were divided into 2 groups: group 1 received NSPT, including scaling and root planing (SRP), as well as oral hygiene instructions; and group 2 received oral hygiene instructions without NSPT. Periodontal clinical parameters, such as probing pocket depth (PPD), clinical attachment loss (CAL), bleeding on probing (BoP), the periodontal inflamed surface area (PISA) score, and the Simplified Oral Hygiene Index (OHI-S), were recorded. Biomarkers, including hs-CRP, the estimated glomerular filtration rate (eGFR) and the urine albumin-to-creatinine ratio (UACR), were obtained from medical records. The comparisons of periodontal parameters, hs‑CRP and renal biomarkers within and between the groups were performed at baseline, and 3 and 6 months after treatment. The periodontal parameter scores as well as the serum levels of hs‑CRP and UACR significantly decreased while eGFR significantly increased in group 1 after treatment as compared to baseline (p < 0.001). Six months after treatment, group 1 showed significantly lower values than group 2 for periodontal parameters, the serum levels of hs‑CRP and renal biomarkers except for eGFR, which improved and increased (p < 0.001). Periodontitis is an important source of chronic inflammation and the treatment of periodontitis can hinder systemic inflammation in CKD patients. Non-surgical periodontal therapy resulted in improved periodontal health, with significant decreases in hs‑CRP and UACR, and an increase in eGFR in CKD patients with CP in comparison with CKD patients not receiving NSPT.

Sex Differences in Patients With Non-dialysis Dependent Chronic Kidney Disease on Serum Cytokines

ObjectivesCardiovascular (CV) mortality is higher in male compared to female patients with chronic kidney disease (CKD), but biological mechanisms for sex-specific differences are not established. Inflammation and high body fat are both associated with the development of CKD and CV diseases. Yet, little is known about the relationship between sex, body composition, and inflammation in CKD patients. The purpose of this study was to examine cytokines differences between male and female patients with CKD according to body composition. MethodsThis is a single center, cross-sectional study of patients with non-dialysis dependent CKD stages 3–5. Body composition was assessed by dual energy x-ray absorptiometry. Glomerular filtration rate (eGFR) was estimated by the CKD-EPI equation. Cytokines were measured using an ELISA multiplex assay kit for interleukin (IL) 4, IL6, IL8, IL10, IL12p70, IL17, monocyte chemoattractant protein-1, tumour necrosis factor alpha (TNFɑ), and interferon gamma (IFNγ). High fat mass and low appendicular muscle mass (ASM) was defined for females and males, respectively as ≥32%, ≥25%; and <20 kg, <15 kg. ResultsPatients with CKD (n = 167; 53.3%males) aged 60.4 ± 11.3 years, eGFR 30.9 ± 30.2 mL/min, and BMI 26.7 ± 5.0 kg/m2 were included. Age, eGFR, and BMI were similar in both sexes. IL4 was higher in males compared to females (6.5 ± 1.0 vs 3.8 ± 0.9 pg/mL, P = 0.04). After stratifying according to body composition, IL4 remained higher (P = 0.04) in lean males compared to lean females, both with adequate ASM, but this difference disappeared in patients with high fat mass (male versus female). Within sex comparison, females with high fat mass have higher concentrations of IL4, IL8, and IL17 compared with lean females, whereas IL6, IL8, IL17, TNFɑ, and INFγ were higher in males with high fat mass. ConclusionsMale and female patients with CKD present a different cytokine profile according to body composition. The higher levels of IL4 observed in males in the present study is consistent with recent evidence that IL4 exerts pro-inflammatory effects on vascular endothelium and is associated with an increase of CV events in CKD. Thus, IL4 might be a cytokine of interest to explain sex differences of CV events and mortality in CKD. Funding SourcesFundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro.

MO441CALPROTECTIN IS A NOVEL CONTRIBUTING FACTOR IN VASCULAR CALCIFICATION AND A PREDICTOR OF CARDIOVASCULAR OUTCOME IN CKD PATIENTS*

Abstract Background and Aims Vascular calcification, leading to aortic stiffening and heart failure, is decisive risk factor for cardiovascular (CV) mortality in patients with chronic kidney disease (CKD). Promoted by bone mineral disorder and systemic inflammation in CKD patients, vascular calcification is a complex mechanism involving osteochondrogenic differentiation of vascular smooth muscle cells (VSMCs) and abnormal deposition of minerals in the vascular wall. Despite intensive research efforts in recent years, available treatments have limited effect and none of them prevent or reverse vascular calcification. The aim of this study was to analyse the serum proteome of CKD stage 3-4 patients in order to unravel new molecular changes associated to CV morbid-mortality and to decipher the role of novel candidates on vascular calcification to provide potential new therapeutic agents. Method In this study we used serum samples from two independent cohorts: 112 CKD stage 3-4 patients with a 4 years follow-up for CV events and 222 CKD stage 5 patients exhibiting a broad range of calcification degree determined by histological quantification in the epigastric and/or iliac artery. Serum proteome analysis was performed using tandem mass-spectrometry in a subcohort of 66 CKD3-4 patients and validation of protein candidates was performed using ELISA in the two full cohorts. Human primary vascular smooth muscle cells and mouse aortic rings were used for calcification assays. Calcium content was quantified using QuantiChrom calcium assay kit and calcium deposition was visualized by Alizarin Red and Von Kossa staining. Results Among 443 proteins detected in the serum of CKD3-4 patients, 134 displayed significant modified abundance in patients with CV events (n=32) compared to patients without (n=34). One of the most prominent changes was increased level of calprotectin (up to 8.6 fold, P&amp;lt;.0001). Using ELISA, we validated that higher serum calprotectin levels were strongly associated with higher probability of developing CV complications and increased mortality in CKD stage 3-4 patients (Figure A). Moreover, we showed that higher serum calprotectin was associated with increased vascular calcification levels in CKD stage 5 patients (Figure B). In vitro, calprotectin promoted calcification of human VSMCs (p&amp;lt;0.0001) (Figures C-D) and in mouse aortic rings (p&amp;lt;0.0001) (Figure E-F). Interestingly, these effects were significantly attenuated by paquinimod, a calprotectin inhibitor (Figures C-F). Conclusion Circulating calprotectin is a novel predictor of CV outcome and mortality in CKD patients. Calprotectin also shows calcification-inducing properties and its blockade by paquinimod alleviates its effects. Future experiments will consist in deciphering the signalling pathways involved in the regulation of calcification by calprotectin and evaluating in vivo the therapeutic potential of paquinimod on the development of medial vascular calcification lesions associated with CKD.

Effect of Ramadan Fasting on Chronic Inflammation and Body Composition in Patients with Chronic Kidney Disease.

Chronic kidney disease (CKD) is associated with a state of chronic inflammation which is responsible for many of the pathophysiological changes detected in these patients. Many studies have evaluated the effect of Ramadan fasting on renal function and cardiovascular morbidity in CKD patients, but the effect of Ramadan fasting on markers of chronic inflammation was not previously assessed. This study aimed to evaluate the effect of Ramadan fasting on some markers of chronic inflammation in CKD patients with estimated glomerular filtration rate (eGFR) less than 60 mL/min/1.73 m2 body surface area and not on dialysis. This was a pilot study that included 20 patients (8 males and 12 females), mean age 61.9 years with CKD (eGFR <60 mL/min/1.73 m2 body surface area not on dialysis) who fasted the whole lunar month of Ramadan. Complete blood count, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), high-sensitive C-reactive protein (hs-CRP), serum creatinine (SCr), eGFR, serum albumin, body weight, body mass index (BMI), and body composition assessed by bioimpedance analysis were assessed before and after Ramadan fasting. Ramadan fasting was not associated with significant change of SCr (P = 0.132), eGFR (P = 0.097), serum albumin (P = 0.352), body weight (P = 0.445), BMI (P = 0.168), body fat (P = 0.979), visceral fat (P = 0.163), muscle mass (P = 0.662), or body water (P = 0.815). There was a statistically significant decrease of markers of chronic inflammation including NLR (P = 0.003), PLR (P = 0.005), and hs-CRP (P = 0.000) after Ramadan fasting. Ramadan fasting was associated with improvement of the state of chronic inflammation in CKD patients (eGFR below 60 mL/min/1.73 m2 body surface area). Ramadan fasting was not associated with a significant change of body composition or deterioration of renal function tests in CKD patients.

Kronik Böbrek Yetmezliğinde Antioksidan Vitaminlerin İnflamasyon ve Oksidatif Stres Üzerine Etkisi

Kronik böbrek yetmezliği (KBY), inflamasyonun ve oksidatif stresin sıklıkla eşlik ettiği bir süreç olarak bilinmektedir. Kronik böbrek yetmezliği hastalarında artan oksidatif stres düzeyleri, azalmış antioksidan savunma ve ortaya çıkan kronik inflamasyon kardiyovasküler hastalıklar başta olmak üzere birçok sağlık sorunu için risk faktörü olabilmektedir. Bu nedenle hastalarda antioksidan tedavinin uygun kullanımı oldukça önem taşımaktadır. Antioksidan vitaminlerin sürece etkisi değerlendirildiğinde, KBY hastalarında retinol bağlayıcı protein katabolizmasındaki azalmalar nedeniyle serum A vitamini konsantrasyonlarının sıklıkla yüksek olduğu düşünülmektedir. Buna bağlı olarak KBY hastalarına ek A vitamini suplemantasyonu önerilmemektedir. Diğer bir antioksidan olan C vitamininin, prooksidan etki gösterebilme ve oksalat oluşumunu artırma riski nedeniyle bu hastalara yönelik öneri konusu tartışmalıdır. Ancak diyaliz tedavisi alan hastalar değerlendirilirken C vitamininde gözlenen önemli kayıplar ve diyet kısıtlılıkları nedeniyle alımdaki azalmalar dikkate alınmalıdır. Kronik böbrek yetmezliği hastalarında E vitamininin birçok olumlu etkisi bildirilmekle birlikte suplemantasyonun dozu, süresi ve uygulama yolu gibi farklılıklar nedeniyle net öneri vermek mümkün olmamaktadır. Bununla birlikte özellikle E vitamini kaplı diyaliz membran kullanımının oksidatif stresi azaltabileceği düşünülmektedir. Kronik böbrek yetmezliği hastalarında antioksidan vitamin desteğine yönelik çalışmaların devam etmesi gerekmekle birlikte, hastaların diyet antioksidan vitamin alımlarının iyi değerlendirilmesi oldukça önem taşımaktadır.

THE EFFECT OF VITAMIN D LEVELS ON INFLAMMATION IN PATIENTS WITH CHRONIC RENAL FAILURE

It is suggested that a number of environmental and genetic factors trigger the formation of progressive kidney damage and complications. One of these factors is inflammation, it occurs as a result of a series of mechanisms included within a number of cytokines. Vitamin-D, IL-6, PCT and hs-CRP are also valuable biomarkers in terms of mortality in dialysis patients in this sense. Vitamin D deficiency is common in patients with chronic kidney disease (CKD) and is associated with inflammation. In recent years, some randomized controlled trials have revealed the effect of Vitamin D on inflammation in CKD patients, but the results are conflicting. The aim of this study is to investigate the relationship between Vitamin D, high-sensitivity C Reactive Protein (hs-CRP), procalcitonin and IL-6, and to evaluate the relation of Vitamin D levels with inflammation in PD patients, HD patients and controls. This study was carried on with 40 patients receiving on hemodialysis treatment, 40 patients receiving peritoneal treatment with renal failure disease and with a control group consisting of 40 healthy individuals. Vitamin D levels were measured by HPLC, PCT and IL-6 levels were measured by chemiluminescent method, hs-CRP is measured by nephelometric method. For Vitamin D, there was no differences between the groups. For PCT, there was a significant difference between all groups. For IL-6, while there was no difference between peritoneal and hemodialysis groups, a significant difference was determined between the peritoneal dialysis and control groups. For hs-CRP, there was a significant difference among all groups. While correlation was found between serum PCT levels with IL-6 and hs-CRP, no correlations were found between serum PCT with Vitamin D levels. Although a correlation was found between serum IL-6 levels and hs-CRP, no correlation was detected between serum IL-6 and Vitamin D levels. No correlations were detected between Vitamin D andPCT, IL-6 and hs-CRP.

Pilot Study of Probiotic Supplementation on Uremic Toxicity and Inflammatory Cytokines in Chronic Kidney Patients

Background: Bacterial metabolism contributes to the generation of uremic toxins in patients with chronic kidney disease (CKD). It has been investigated the use of probiotics in the reduction of uremic toxins intestinal production. Objective: The aim of this pilot study was to evaluate the effect of probiotic supplementation on reducing the production of uremic toxins and the inflammatory profile of CKD patients. Methods: We performed a randomized, blind, placebo-controlled, crossover study on patients with CKD stages 3 and 4. The intervention was a probiotic formulation composed of Lactobacillus acidophilus strains given orally three times a day for 3 months. Changes in uremic toxins (p-Cresylsulfate and Indoxyl Sulfate) and serum inflammatory cytokines were the primary endpoints. Results: Of the 44 patients randomized, 25 completed the study (mean age 51 ± 9.34, 64% female, mean eGFR 36 ± 14.26 mL/min/1.73m², mean BMI 28.5 ± 5.75 kg/m²). At 3 months, there were no significant changes in any of the studied biomarkers including p-cresylsulfate (p = 0.57), Indoxyl sulfate (p = 0.08) and interleukin-6 (p = 0.55). Conclusion: Lactobacillus acidophilus strains given as probiotic were not able to reduce serum levels of uremic toxins and biomarkers of inflammation in CKD patients in stage 3 and 4.

Transcriptome Profiling Reveals Indoxyl Sulfate Should Be Culpable of Impaired T Cell Function in Chronic Kidney Disease

Introduction: Chronic inflammation and immune system dysfunction have been evaluated as major factors in the pathogenesis of chronic kidney disease (CKD), contributing to the high mortality rates observed in these populations. Uremic toxins seem to be the potential “missing link.” Indoxyl sulfate (IS) is one of the protein-bound renal toxins. It participates in multiple pathologies of CKD complications, yet its effect on immune cell has not been studied. This study aimed to explore the genome-wide expression profile in human peripheral blood T cells under stimulation by IS.Methods: In this study, we employed RNA-sequencing transcriptome profiling to identify differentially expressed genes (DEGs) responding to IS stimulation in human peripheral T cells in vitro. Flow cytometry and western blot were used to verify the discovery in RNA-sequencing analysis.Results: Our results yielded a total of 5129 DEGs that were at least twofold up-regulated or down-regulated significantly by IS stimulation and half of them were concentration-specific. Analysis of T cell functional markers revealed a quite different transcription profile under various IS concentration. Transcription factors analysis showed the similar pattern. Aryl hydrocarbon receptor (AhR) target genes CYP1A1, CYP1B1, NQO1, and AhRR were up-regulated by IS stimulation. Pro-inflammatory genes TNF-α and IFN-γ were up-regulated as verified by flow cytometry analysis. DNA damage was induced by IS stimulation as confirmed by elevated protein level of p-ATM, p-ATR, p-BRCA1, and p-p53 in T cells.Conclusion: The toxicity of IS to T cells could be an important source of chronic inflammation in CKD patients. As an endogenous ligand of AhR, IS may influence multiple biological functions of T cells including inflammatory response and cell cycle regulation. Further researches are required to promulgate the underling mechanism and explore effective method of reserving T cell function in CKD.

Elevated serum procalcitonin level in patients with chronic kidney disease without infection: A case-control study.

BackgroundInflammation is a necessary component of chronic kidney disease (CKD) that can be attributed to an accumulation of toxins and a reduced clearance of proinflammatory cytokines. Procalcitonin (PCT) is a widely applied biomarker in the diagnosis of infection, and considering the presence of pre‐existing inflammation in CKD patients, the PCT level could be high in such a population; however, no reference value for PCT in CKD patients has been available to date.MethodsDuring the present study period, 361 CKD patients and 119 healthy controls were included. The PCT level and other biochemistry parameters were assayed by using a COBAS system. Statistical analysis was conducted to compare the differences in PCT levels and other biochemistry parameters between the two groups, and linear regression was used to assess the correlation between two variables. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the performance of PCT and the optimal cutoff value to differentiate between CKD patients and healthy controls.ResultsThe PCT level in CKD patients was significantly higher than that in healthy controls, and among the CKD patients, the PCT level was increased with advanced clinical stage. Moreover, PCT was moderately correlated with CysC. The optimal off‐value was 0.075 with a sensitivity of 94.7% and specificity of 90.8%.ConclusionThe PCT level was significantly higher in CKD patients than in healthy controls, and the reference value for CKD patients should be adjusted to avoid unnecessary antibiotic treatments which may pose a negative impact on residual renal function.