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Introduction: The prevalence of cardiovascular (CV) comorbidity in patients with chronic kidney disease (CKD) is high, particularly in end‑stage renal disease (ESRD). There is an ongoing search for novel biomarkers of CV disease in this population., Objectives: We aimed to investigate the associations of matrix proteoglycans (PGs) and glycosaminoglycans (GAGs), collagen, and arterial calcifications with selected serum and plasma markers of endothelial dysfunction, inflammation, oxidative stress, and bone turnover in patients with ESRD., Patients and Methods: We enrolled 47 adult patients (32 men) with stage 5 CKD. The following parameters were investigated: fibrinogen, soluble thrombomodulin (sTM), plasminogen activator inhibitor 1 (PAI‑1), stromal cell‑derived factor 1α (SDF‑1α), calcium (Ca), phosphate (Pi), intact parathormone, interleukin 6, high‑sensitivity C‑reactive protein (hs‑CRP), ferric reducing ability of plasma, 2,2‑diphenyl‑1‑picrylhydrazyl scavenging, ferric reducing ability of ascorbate in plasma, fetuin‑A, fibroblast growth factor 23, osteopontin, osteoprotegerin, osteocalcin, transforming growth factor β (TGF‑β), hepatocyte growth factor, secreted protein acidic and rich in cysteine, as well as matrix metalloproteinase 2. Radial artery specimens were stained with alizarin red for calcifications, alcian blue for PGs and GAGs, and sirius red for collagen., Results: We observed positive correlations between PG and GAG, collagen, and calcification staining. The most intense (grade 3) alcian blue staining was significantly correlated with diabetes as well as higher levels of Ca × Pi product, hs‑CRP, fibrinogen, SDF‑1α, PAI‑1, and sTM. However, PAI‑1 was the only significant predictor of grade 3 alcian blue staining in a multiple logistic regression model adjusted for hemodialysis, Ca× Pi product, and hs‑CRP levels., Conclusions: Coagulation disorders and endothelial dysfunction are the hallmarks of ESRD. The levels of SDF‑1α, PAI‑1, sTM, and fibrinogen may be novel predictors of early vascular wall alterations and may serve as CV risk markers.

Background: Endothelial 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., Patients: 80 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., Results: After 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., Conclusion: Among 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., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Introduction: Fetuin-A plays an important role in bone turnover and vascular calcification., Aim: The aim of the study was to assess the relationship between serum fetuin-A concentrations, inflammatory and bone turnover markers of patients on maintenance hemodialysis., Materials and Methods: The study was performed in 71 patients (21 women, 40 men) aged 60 ± 12 years on chronic dialysis because of end-stage renal failure for a period of 75 ± 57.2 months. The routine laboratory tests were performed with Modular P analyzer (Roche Diagnostics), serum concentrations of iPTH were measured using Nichols method, hsCRP and IL-6 using nephelometric techniques while fetuin-A, bone-specific alkaline phosphatase (bALP), fully carboxylated osteocalcin (cOC), undercarboxylated osteocalcin (ucOC), and fibroblast growth factor-23 (FGF-23) were measured using commercially available ELISA kits., Results: Concentrations of fetuin-A were significantly positively correlated with albumin (r=0.37, p=0.003) and negatively associated with patients age (r=26, p=0.04), log (iPTH) (r=0.31, p=0.02), log (CRP) (r=0.31, p=0.02), log (IL-6) (r=0.41, p=0.001), log (ucOC) (r=-0.29, p=0.02), and log (FGF-23) (r=0.27, p=0.04)., Conclusions: 1. Patients on maintenance hemodialysis suffer from severe disturbances of bone turnover. 2. Low serum fetuin-A levels are associated with increase markers of bone turnover and inflammation.

Background: The objective of the study was to determine the relationship between common carotid artery intima-media thickness (CCA-IMT) and histologically assessed calcification of radial artery in relation to clinical features and laboratory markers of bone and mineral metabolism, inflammation, and oxidative stress in patients with stage 5 chronic kidney disease (CKD)., Methods: The study comprised 59 patients (36 hemodialyzed, 23 predialysis). CCA-IMT was measured by ultrasonography; the biochemical parameters examined were assessed using routine laboratory methods, ELISA micro-plate immunoassays and spectrophotometry. Fragments of radial artery obtained during creation of hemodialysis access were cryosectioned and stained for calcifications using von Kossa method and alizarin red., Results: Glucose, osteoprotegerin, pentraxin 3 and Framingham risk score significantly correlated with CCA-IMT. In multiple regression analysis, OPG positively predicted CCA-IMT. Radial artery calcifications were found in 34 patients who showed higher CCA-IMT (0.98 ± 0.13 vs 0.86 ± 0.14 mm; P = 0.006). Higher CCA-IMT values were also associated with more advanced calcifications. CCA-IMT and the presence of plaques in common carotid artery were positive predictors of radial artery calcifications, independent of dialysis status, Framingham risk score, CRP and Ca x Pi [OR for calcifications 2.19 (1.08-4.45) per 0.1 mm increase in CCA-IMT]. The presence of radial artery calcifications was a significant predictor of mortality, independent of dialysis status and Framingham risk score [HR 3.16 (1.03-9.64)]., Conclusions: In CKD patients, CCA-IMT examination can be used as a surrogate measure to assess the incidence and severity of arterial medial calcification which is associated with poor clinical outcome in these patients.

Purpose: Identification of vulnerable plaques remains crucial for better cardiovascular risk assessment. At least 20% of inflammatory cells within unstable (vulnerable) plaques comprise T lymphocytes, which contain receptors for interleukin-2 (IL-2); those receptors can be identified by scintigraphy with radiolabelled IL-2.The aim of this study was to identify the "inflamed" (vulnerable) plaques by scintigraphy using IL-2 labelled with (99m)Tc in the selected, high cardiovascular risk group of end-stage renal disease (ESRD) patients., Methods: A total of 28 patients (18 men, 10 women, aged 55.2 ± 9.6 years, 17 on peritoneal dialysis, 11 on haemodialysis) underwent common carotid artery (CCA) scintigraphy with the use of (99m)Tc-hydrazinonicotinamide (HYNIC)-IL-2. In all cases, ultrasound examination of the CCA was performed and levels of selected proinflammatory factors, atherogenic markers and calcium-phosphate balance parameters were measured. Finally, the target to non-target (T/nT) ratio of IL-2 uptake in atherosclerotic plaques with intima-media thickness (IMT), classic cardiovascular risk factors and concentrations of the measured factors were compared., Results: Increased (99m)Tc-HYNIC-IL-2 uptake in atherosclerotic plaques in 38/41 (91%) cases was detected. The median T/nT ratio of focal (99m)Tc-HYNIC-IL-2 uptake in atherosclerotic plaques was 2.35 (range 1.23-3.63). The mean IMT value on the side of plaques assessed by scintigraphy was 0.79 ± 0.18 mm (median 0.8, range 0.5-1.275). Correlations between T/nT ratio and homocysteine (R = 0.22, p = 0.037), apolipoprotein B (apoB) (R = 0.31, p = 0.008), apoB to apoA-I ratio (R = 0.29, p = 0.012) and triglyceride concentration (R = 0.26, p = 0.021) were detected. A lower T/nT ratio in patients with better parameters of nutritional status (haemoglobin, albumin, adiponectin) in comparison with patients with worse nutritional parameters (3.20 ± 0.5 vs 2.16 ± 0.68, p = 0.025) was revealed as well as a difference between values of T/nT ratio in groups of patients with values of apoB, soluble CD40 ligand and asymmetric dimethylarginine above and below median (3.18 ± 0.52 vs 2.16 ± 0.68, p = 0.031). No statistically significant association was found between T/nT ratio and mean value of either IMT or classic cardiovascular risk factors., Conclusion: Scintigraphy with the use of (99m)Tc-HYNIC-IL-2 can be a tool for inflamed atherosclerotic (vulnerable) plaque visualization within CCA in ESRD patients. Quantitative results of carotid artery scintigraphy with (99m)Tc-HYNIC-IL-2 correlate with serum concentration of selected cardiovascular risk markers.

Fibroblast growth factor-23 (FGF-23) is a phosphatonine of important value in maintenance of mineral homeostasis. In the 1st part of this review dealing with FGF-23 its composition, mode of action, and regulatory mechanisms of its secretion were described. In the 2nd part of this work, regulatory activity in the calcium-phosphate homeostasis in different stages of chronic kidney disease (CKD) with special attention to increased synthesis of FGF-23 in the course of declined glomerular filtration rate were elucidated. The FGF-23 concentration in dialyzed patients, subjects after parathyroidectomy and patients after kidney transplantation were characterized. The relationship between FGF-23 serum concentaration and cardiovascular morbidity and mortality will be presented in the 3rd part of this review.

In the 1st part of this review dealing with FGF-23 its composition, mode of action, and regulatory mechanisms of its secretion were described. In the 2nd part of this review, regulatory activity in the calcium-phosphate homeo-stasis in different stages of chronic kidney disease (CKD) including dialyzed patients, subjects after parathyreoidectomy and patients after kidney transplantation were characterized. The aim of this part was to analyze the relationship between FGF-23 and left ventricular hypertrophy, vascular calcification and increased morbidity and mortality in patients with CKD. The current knowledge on FGF-23 has lead to suspect that in the nearest future it may serve as sensitive marker of early calcium-phosphate disturbances in patients with CKD.

Background: Low-molecular-weight proteins (LMWPs) are substances of molecular weights 10-35 kDa, which accumulate in plasma of patients with end-stage renal disease (ESRD) due to the abolishment of plasma renal filtration. LMWPs are considered as a separate group of uremic toxins., Aim: The influence of hemodialysis (HD) on the release of some LMWPs from leukocytes was assessed by comparing levels of serum pancreatic-type alkaline RNase and leukocyte-type acid RNase as well as polymorphonuclear (PMN) elastase., Methods: The mentioned proteins were assayed in 58 ESRD patients on HD prior and after the dialysis session and compared with the results obtained from 36 healthy subjects. The levels of elastase and acid and alkaline RNase were correlated with HD parameters, residual diuresis, predialysis concentrations of serum creatinine, urea and albumin as well as pre- and postdialysis granulocyte count., Results: Changes in PMN elastase produced by the dialysis session positively correlate with changes in acid RNase levels (r = 0.3650; p = 0.0061), while there is no such correlation for alkaline RNase. There is a negative correlation between pre- and postdialysis differences in levels of acid and alkaline RNases (r = -0.3542; p = 0.008), indicating that HD induces liberation of a factor suppressing alkaline RNase. Levels of acid and alkaline RNase negatively correlate with residual diuresis, indicating its significance in control of LMWP accumulation (r = -0.3970; p = 0.0025; r = -0.2596; p = 0.0533, respectively)., Conclusions: Dialysis treatment causes an increase in both acid leukocyte-type and alkaline pancreatic-type RNase activity in plasma. Dialysis-related increases in acid RNase activity correlate with the respective changes in PMN elastase, which suggests that leukocyte activation during dialysis contributes to an increase in plasma LMWPs., (Copyright 2009 S. Karger AG, Basel.)