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Purpose Indoxyl sulfate (IS) is one of the most potent uremic toxins involved in chronic kidney disease (CKD) progression, induction of inflammation, oxidative stress, and cardiovascular diseases occurrence. It is proved that hypertension is a common CVD complication and a major death risk factor as well as contributes for decline in a renal function. The aim of our study was to investigate how implementing of antihypertensive therapy impact IS concentrations and the associations between IS and markers of renal function, inflammation and oxidative stress. Methods Study was conducted on 50 patients diagnosed with CKD and hypertension, divided into three groups: without hypotensive therapy (CKD-NONE), hypotensive monotherapy (CKD-MONO), and hypotensive polypharmacotherapy (CKD-POLI), and 18 healthy volunteers. The markers of inflammation [interleukin-6, tumor necrosis factor-alpha (TNF-α), high-sensitive C-reactive protein (hs-CRP), neopterin, ferritin], oxidative status [superoxide dismutase (Cu/Zn-SOD), antibodies against oxidized low-density lipoprotein (oxLDL-abs)], and selectins were determinate using immunoenzymatic methods. IS levels were assayed using high-performance liquid chromatography and other parameters were analysed using routine laboratory techniques. Then cross-sectional analysis was performed. Results Elevated levels of IS, indicators of kidney function, markers of inflammation and blood pressure values were observed in each CKD subgroups. There was no effect of antihypertensive therapy on IS levels between studied groups, as well as there was no clear relationship between IS and blood pressure values in each studied group. The positive associations between IS and Cu/Zn SOD, neopterin, hs-CRP, creatinine and neutrophils/lymphocytes ratio were observed in CKD-NONE and CKD-POLI subgroups. Additionally, in CKD-POLI group IS positively correlated with TNF-α, ferritin and neutrophils. In CKD-MONO group, IS was positively related to oxLDL-abs, neopterin, E-selectin and creatinine, whereas it was inversely associated with hs-CRP. Conclusions Our study showed for the first time that the antihypertensive therapy has no impact on IS levels in CKD patients with hypertension. However, the introduction of the antihypertensive therapy modified the dependencies between IS and the studied markers of kidney function, inflammation, oxidative stress and hematological parameters that are crucial for mortality and morbidity amongst the CKD patients with hypertension. Electronic supplementary material The online version of this article (10.1007/s11255-018-02064-3) contains supplementary material, which is available to authorized users.

Heparin (both unfractionated and low molecular weight) is not only a potent anticoagulant but also has many pleiotropic effects, some of which are mediated by cytokine release. We compared the effect of hemodialysis (HD) with enoxaparin as an anticoagulant and without systemic anticoagulation (heparin-grafted membrane—Evodial) on the release of monocyte chemoattractant protein 1 (MCP-1), endostatin (ES) and activin A (Act-A). Nineteen stable HD patients were dialyzed with or without heparin, and plasma levels of MCP-1, ES and Act-A were measured after such a dialysis. During HD with Evodial, the intradialytic levels of all three cytokines were 2–3 folds lower. The between-anticoagulant differences were significant over time for all three cytokines: MCP-1 (P

Chronic kidney disease (CKD) occurrence is rising all over the world. Its presence is associated with an increased risk of premature death from cardiovascular disease (CVD). Several explanations of this link have been put forward. It is known that in renal failure, an array of metabolites cannot be excreted, and they accumulate in the organism. Among them, some are metabolites of tryptophan (TRP), such as indoxyl sulfate and kynurenine. Scientists have become interested in them in the context of inducing vascular damage in the course of chronic kidney impairment. Experimental evidence suggests the involvement of TRP metabolites in the progression of chronic kidney disease and atherosclerosis separately and point to oxidative stress generation as one of the main mechanisms that is responsible for worsening those states. Since it is known that blood levels of those metabolites increase significantly in renal failure and that they generate reactive oxygen species (ROS), which lead to endothelial injury, it is reasonable to suspect that products of TRP metabolism are the missing link in frequently occurring atherosclerosis in CKD patients. This review focuses on reports that shed a light on TRP metabolites as contributing factors to vascular damage in the progression of impaired kidney function.

Deterioration of glomerular filtration rate (GFR) is associated with alterations of bone metabolism. It translates clinically to bone fragility and increased fractures rate among patients with impaired GFR. Recently, sclerostin (SCL) gained much attention as an important factor in pathogenesis of mineral and bone disturbances in patients with renal diseases. There is no data about SCL behaviour in patients with acute GFR decline. The aim of this study was to evaluate the renal handling of SCL. This is a prospective, single-centre observational study in patients undergoing nephrectomy due to urological indications. Serum and urinary SCL levels were measured prior and after nephrectomy. 25 patients were enrolled. After surgery, eGFR significantly declined (from 87.4±19.7 to 67.7±25.7 ml/min/1.73 m(2), p0.0001). Nephrectomy caused more than 20 times higher renal fractional excretion of SCL [0.15 (interquartile range, IQR 0.09-0.40) vs. 2.78 (IQR 1.51-4.02)%, p0.001], while its serum level remained intact [0.69 (IQR 0.57-0.90 vs. 0.65 (IQR 0.53-0.88) ng/ml, p=0.4]. The magnitude of eGFR reduction was associated inversely with change in urinary SCL fractional excretion (r=-0.6, p=0.001) and with alteration in serum SCL level (r=-0.5, p=0.01). Our results suggest that increased serum SCL concentrations at moderately reduced GFR are not due to diminished renal clearance. At more severely decreased GFR, elevated SCL concentration results from both increased production and reduced renal elimination.

Objectives Endocan is a new marker of endothelial cell activation that mediates adhesion of leukocytes into endothelium. Soluble intercellular (sICAM-1) and vascular cellular (sVCAM-1) adhesion molecules play an important role in the prevalence of cardiovascular disease (CVD) in chronic kidney disease (CKD) patients. The aim of this study is to investigate whether endocan could affect the concentrations of sICAM-1 and sVCAM-1 in CKD patients, particularly in those with CVD. Design and methods We evaluated plasma endocan, sICAM-1, sVCAM-1 and the markers of inflammation: high sensitivity C-reactive protein (hs CRP), interleukin-6, tumor necrosis factor-α (TNF-α) and their interrelationships in 53 CKD patients (both with and without CVD) and 29 healthy controls. Results Endocan, sICAM-1, sVCAM-1 and inflammatory markers were significantly higher in CKD patients than in controls, and patients with CVD had levels significantly higher (except interleukin-6 and TNF-α) than those without CVD. The presence of CVD, ferritin, TNF-α and SBP were the independent predictors of endocan levels in the whole CKD group. In this group, the weak relationship was between endocan and sICAM-1 and sVCAM-1, but age was the only independent predictor of these adhesion molecules. The strong association between endocan and sICAM-1 and sVCAM-1 was exclusively observed in subgroup with CVD, and the low % of lymphocytes followed by increased endocan was identified as the independent variables significantly associated with these soluble molecule levels. Conclusions This study shows that plasma endocan is significantly increased and independently associated with sICAM-1 and sVCAM-1 levels in CKD patients with cardiovascular complications.

Purpose Chronic kidney disease (CKD) is an estimated risk factor for increased mortality and morbidity due to fibrinolytic system disturbances. Progressive loss of renal function leads to retention of uremic toxins. Anthranilic acid (AA) is a tryptophan-derived uremic toxin with multidirectional properties that can affect the hemostatic system. The goal of this study was to examine the association between AA and the parameters of fibrinolysis at different stages of CKD. Methods Patients with CKD were divided into two groups: mild-to-moderate (n = 20) and severe-to-end-stage CKD (n = 28). Seventeen healthy volunteers served as an additional control group. Parameters of fibrinolysis, inflammation, and monocytes activation were determined by ELISA immune-enzymatic kits. AA levels were evaluated using high-performance liquid chromatography. Results AA concentration and parameters of fibrinolysis: urokinase-type plasminogen activator (uPA), its soluble receptor (suPAR), tissue plasminogen activator (tPA), tissue plasminogen activator inhibitor-1 (PAI-1) and plasmin-antiplasmin complex (PAP) were significantly elevated in the CKD groups compared with the controls. The markers of inflammation, monocyte activation, and impaired kidney function were also increased in those with CKD. AA was positively correlated with the uPA/suPAR system in the early stages of CKD, whereas during severe-to-end-stage CKD, inverse relationships were observed between AA, tPA and PAI-1. Additionally, AA was an independent variable associated with tPA in patients with CKD overall and with uPA levels in the mild-to-moderate CKD group. Conclusions Obtained results suggest for the first time the association between AA and the fibrinolytic system in CKD patients. The distinct relationship between AA and individual parameters of fibrinolysis appears to be dependent on CKD stage.

Patients with end-stage renal disease (ESRD) exhibit features of a hypercoagulable state, which may contribute to cardiovascular complications. Data from "in vitro" studies suggest that cell-free plasma lipids and lipoproteins may be capable to support thrombin generation. The aim of this study has been to establish the role of plasma oxidized LDL (oxLDL) in the coagulation activation in hemodialyzed (HD) patients with and without cardiovascular disease (CVD).We examined relationship between a marker of coagulation activation - prothrombin fragments 1+2 (F1+2), and plasma oxLDL levels in 60 HD patients with and without CVD and in 20 healthy controls.F1+2 levels were significantly higher in HD patients than in controls, and they were higher in HD patients with CVD compared to those without CVD (p0.001). Conversely, oxLDL levels were similar in HD patients with CVD and healthy controls, whereas this parameter was lower in HD patients without CVD when compared to controls and patients with CVD (both p0.01). Close positive and independent association was between F1+2 and oxLDL levels in HD patients. Nitrates treatment and the presence of pyelonephritis were associated with reduced oxLDL as well as hypercoagulability in HD patients with cardiovascular complications.This study demonstrates the independent association between oxLDL and the marker of coagulation activation - F1+2 in HD patients. This new observation may offer a better understanding of the complex mechanism leading to hypercoagulability, which is markedly intensified in these patients, particularly in those with CVD.

Myeloperoxidase (MPO) is a proteolytic and prooxidant enzyme largely assembled with the vascular wall, and a heparin-binding protein. We studied if low-molecular-weight heparin enoxaparin administered for hemodialysis (HD) anticoagulation causes systemic MPO activation. Plasma MPO levels were measured in patients undergoing maintenance HD with an intravenous bolus of enoxaparin. Patients were retested during HD employing dialyzers with heparin-grafted polyacrylonitrile membrane and no systemic enoxaparin administration. During enoxaparin-anticoagulated HD plasma MPO levels strikingly increased in all patients (8.6-fold at 10 minutes and 3.3-fold at 120 minutes, both P

VAP-1 (vascular adhesion protein-1) possesses semicarbazide-sensitive amine oxidase (SSAO) activity. It has also been found that serum VAP-1 was elevated in acute and chronic hyperglycemia and in patients with diabetes as well as in chronic kidney disease. Renalase, with possible monoamine oxidase activity, which breaks down catecholamines such as SSAO, is expressed in the endothelium as well as in the kidney. The aim of the study was to assess serum VAP-1 levels in peritoneally dialyzed (PD) patients and factors explaining its variability. This pilot study was performed on 25 peritoneally dialyzed patients, including 4 patients with type 2 diabetes. We found that the mean VAP-1 was significantly higher in chronic ambulatory peritoneal dialysis (CAPD) patients when compared to the control group (p

Background YKL-40 is a new biomarker of inflammation, which is expressed by several cell types of the immune system. The aim of the present study was to evaluate plasma YKL-40 levels in hemodialysis (HD) patients and to establish its potential role as a new inflammatory biomarker of cardiovascular disease (CVD) in this population. Methods YKL-40 and two other inflammatory markers: high sensitivity C-reactive protein (hsCRP) and neopterin levels were measured in 70 HD patients both with and without CVD and in 38 healthy controls. Results Median YKL-40, hsCRP and neopterin levels were significantly elevated in HD patients, particularly those with CVD, compared to controls. YKL-40 was no associated with hsCRP, but it is strongly and independently associated with plasma neopterin levels in HD patients. The coexistence of the seropositivity against hepatitis C virus (anti-HCV) infection increased both YKL-40 and neopterin levels in these patients. This effect was particularly seen in subjects with CVD. Moreover, high neopterin levels were exclusively associated with anti-HCV seropositivity, whereas hsCRP values were only associated with the presence of CVD. Conclusions This study indicated for the first time that plasma YKL-40 level is increased in HD patients, especially in those with CVD, and it is independently associated with neopterin – an biomarker of monocyte/macrophage activation. There was no association between YKL-40 and hsCRP, the common indicator of an inflammatory state. Moreover, the coexistence of anti-HCV seropositivity had an important impact on plasma YKL-40 levels in HD patients particularly those with cardiovascular complications.

hRenalase may degrade catecholamines and regulate sympathetic tone and blood pressure (BP). The aim of the study was to assess dopamine (DA), norepinephrine (NE), and renalase in 75 hemodialysis (HD) and 26 peritoneal dialysis (PD) patients and their correlations with heart rate (HR), BP, a type of hypotensive therapy, and residual renal function.Renalase, DA, NE were studied using commercially available assays.Renalase and NE were higher and DA was lower in dialyzed groups comparing to healthy volunteers. Hemodialysis patients had lower NE and higher renalase level. Norepinephrine was higher in anuric patients in HD group. Renalase correlated with dialysis vintage and inversely with residual diuresis. Dopamine correlated with residual diuresis in the whole study cohort, with HR in PD patients, with renalase in HD patients. Norepinephrine correlated with aortic diameter in PD patients. Norepinephrine was significantly higher in patients with coronary artery disease (CAD) in HD group. Hemodialysis population with CAD had lower NE and higher DA and renalase level than their PD counterparts. In the follow up, 27% of HD group died. Cardiac death was diagnosed in 17% and there was higher renalase level than in noncardiac death.Elevated level of circulating renalase in dialysis patients is rather related to kidney function and the sympathetic nervous system hyperactivity found in this population. The real excess of renalase in the pathogenesis of cardiovascular disorders in patients with chronic kidney disease still remains to be proven. If confirmed, it may give a new way for pathophysiological therapy.

Anemia is more prevalent in allograft recipients compared with glomerular filtration rate (GFR) matched patients with chronic kidney diseases. There is a paucity of data concerning the correction of anemia in the posttransplant period with erythropoietin-stimulating agents (ESA). The aim of this study was to compare the iron status, kidney function, inflammatory state, use of drugs affecting erythropoiesis (immunosuppressants ACEi/ARB) and correction of anemia using ESA in a chronic kidney disease (CKD) population versus kidney transplant recipients. We included 67 patients treated with ESA including 17 after kidney transplantation. CKD Patients with native kidneys were significantly older than allograft recipients (mean age 69 versus 51 years; P < .001, and despite similar serum creatinine and iron parameters showed an estimated lower GFR (19 mL/min versus 23 mL/min; P < .05). Median time of ESA therapy was similar among patients with native kidney CKD versus kidney recipients, but they achieved a significantly higher hemoglobin (11.04 versus 10.36 g/dL; P < .05). There was no difference between patients administered or not a mammalian target of rapamycin antagonist. None of the patients with native kidney CKD received immunosuppressive therapy, but they were prescribed ACEi more often than kidney recipients. The higher degree of anemia in kidney allograft recipient is the most probably attributed to the use of immunosuppressive drugs, despite their better kidney function and comparable iron status. This study suggested that higher doses of ESA should be employed to anemia in kidney transplant recipients.

Objective To investigate the role of autoantibodies against oxidized LDL (oxLDL-Ab) in clearing of oxLDL from circulation in dialyzed uremic patients, as well as the significance of this process in the carotid atherosclerosis and cardiovascular complications. Methods oxLDL, oxLDL-Ab and intima-media thickness (IMT) were measured in 132 uremic patients on hemodialysis (HD), peritoneal dialysis (PD) or conservative treatment both with and without cardiovascular disease (CVD) and in 29 healthy controls. The ratio of oxLDL to oxLDL-Ab (oxLDL/oxLDL-Ab), reflecting the balance between in vivo oxidative LDL modification and the clearance of oxLDL from circulation was also calculated. Results oxLDL were lower, whereas oxLDL-Ab were higher in patients without CVD compared to those with CVD. oxLDL/oxLDL-Ab ratio was also significantly lower in dialyzed subjects without CVD compared to their counterparts with CVD and healthy controls. IMT values were significantly higher in uremic patients compared with controls, and patients with CVD had particularly elevated IMT compared with those without CVD. The inverse correlation was between IMT and oxLDL-Ab, whereas the IMT was strongly and positively associated with oxLDL/oxLDL-Ab ratio. There was the weak inverse relationship between oxLDL and oxLDL-Ab levels in dialyzed patients. Multiple stepwise regression analysis identified oxLDL/oxLDL-Ab ratio as one of the predictors of IMT in the whole dialyzed group. Conclusions oxLDL/oxLDL-Ab ratio could be a new biomarker significantly and independently associated with carotid atherosclerosis in dialyzed patients. A titer of oxLDL-Ab and oxLDL/oxLDL-Ab ratio seem to play an important role for distinguishing patients with and without cardiovascular complications.

Purpose It is advocated to delay the start of peritoneal dialysis (PD) at least 10–14 days after insertion of peritoneal catheter. The aim of this study was to investigate factors associated with catheter-related complications (CRC) in patients starting PD early (1–13 days) (ES) and late (14 days or more) (LS) after catheter implantation. Material/Methods Single center, retrospective analysis of CRC occurring within 14 days of follow up after peritoneal dialysis initiation in ES and LS group of patients. Results A total of 97 patients were analyzed. Seventy percent of them were ES. There were significantly more CRC in ES vs. LS (31% vs. 3%, p=0.01). Significantly more mechanical CRC occurred in ES than in LS (21% vs. 0%, p=0.01). Occurrence of infectious CRC did not differ between the groups. In multivariate analysis the only predictor of CRC development was the time elapsed between catheter insertion and beginning of PD (Odds Ratio [OR] 0.80 95% Confidence Interval [95% CI] 0.70–0.91; p=0.001). Conclusions Each day of delay of PD initiation following peritoneal catheter insertion decreases the odds for development of mechanical CRC.

Hyperhomocysteinemia and the activation of kynurenine (KYN) pathway have been reported as the factors participated in atherosclerosis in uraemic patients. The objective of this study was to verify whether hyperhomocysteinemia may be involved in atherosclerotic cardiovascular disease (CVD) in patients undergoing continuous ambulatory peritoneal dialysis (CAPD).We determined the plasma concentrations of KYN, KYNA, KYNA/KYN ratio, homocysteine (Hcy) and intima-media thickness (IMT) - an early reflection of the systemic atherosclerosis in CAPD patients both with and without CVD and healthy controls.KYNA concentrations and KYNA/KYN ratio were about 3 times higher in the patients with hyperhomocysteinemia (Hcy15μM) compared to those with normal Hcy levels (15μM), and they were significantly lower in CVD[+] than in CVD[-] patients in these studied groups. The presence of CVD was associated with higher Hcy levels only in the patients with Hcy15μM. The positive association was between Hcy and KYNA, KYNA/KYN ratio in all CAPD patients and in CVD[+] patients with hyperhomocysteinemia. IMT was positively associated with Hcy levels in patients with hyperhomocysteinemia, whereas there was no relationship between IMT and KYNA concentrations in the studied groups.These results showed the association between hyperhomocysteinemia and carotid atherosclerosis as well as the possible role of hyperhomocysteinemia in the activation of KYNA production in CAPD patients. The elevated KYNA levels observed in patients with hyperhomocysteinemia seem to be protective against Hcy-mediated atherosclerosis in these patients.

Hypertension and kidney disease have been associated with increased incidence of stroke. Renalase, a newly discovered hormone, is secreted by the kidney and circulates in blood. The aim of this study was to assess possible correlations between renalase, blood pressure, stroke, and cardiovascular status in prevalent hemodialyzed patients.Renalase was assessed using commercially available assay. Echocardiography was performed in each patient.Serum renalase was significantly lower in patients with a history of stroke (21%) than in patients without it. Similarly, renalase was significantly lower in hypertensive patients (82%) when compared with normotensives. Serum renalase correlated with creatinine, residual renal function, and transferrin saturation. The only predictor of renalase in multiple regression analysis was the presence of hypertension explaining 90% of the renalase variations.Our preliminary results suggest that renalase, probably due to the sympathetic nervous system hyperactivity, could be associated with hypertension and cardiovascular complications, including stroke in hemodialyzed patients. However, further studies are needed to establish the possible role of renalase in these complications. Renalase is "a new postulated therapeutic target."

Fibroblast growth factor (FGF)-23 inhibits PTH production. Elevated FGF-23 and parathyroid hormone (PTH) levels are characteristic of hemodialyzed patients. Iron polymaltose was shown to increase FGF-23 concentration. The effect of intravenous low molecular weight iron dextran (LMID) on these hormones and bone metabolism has not been studied in hemodialysis (HD). Twelve HD patients were prospectively followed up for 3 weeks after a single infusion of LMID. Calcium, phosphate, FGF-23, PTH, degradation products of C-terminal telopeptides of type I collagen (CTX) and procollagen I N-terminal propeptide (PINP) were measured prior to, and at week 1 and week 3 after the LMID administration. FGF-23 increased significantly from 453.4 (68.6–3971.5) pg/mL at baseline to 971.8 (779.5–3361.4) pg/mL (P = 0.001) at week 1 and started to decrease toward the initial value at week 3. The changes were accompanied by a significant decline in PTH from 367.6 (21.4–1487.4) pg/mL at baseline to 315.7 (16.4–1339.8) pg/mL (P = 0.018) at week 1 and subsequently began to increase toward the initial values. Phosphate, calcium, CTX and PINP did not change over the study course. LMID causes an increase in FGF-23 concentration together with a decrease in PTH. Our study highlights a pathophysiological element, which may connect suppression of parathyroid glands with intravenous iron supplementation.

Renalase, secreted by the kidney, degrades catecholamines and may play a role in the regulation of sympathetic tone and blood pressure. The aim of this study was to assess serum renalase levels in hemodialysis patients and their relationship to blood pressure control, type of antihypertensive therapy and the presence of residual renal function. Results: The mean serum renalase in the study cohort was significantly higher than in the control group (27.53 ± 7.18 vs. 3.86 ± 0.73 µg/ml, p < 0.001). The serum renalase concentration was significantly lower in patients with residual renal function when compared to the anuric patients. The type of hypotensive treatment (β-blockers, ACE inhibitors or AT1 receptor blockers) did not affect renalase levels. There was a significant inverse correlation between the serum renalase and age (r = –0.28, p = 0.023) and residual renal function (r = –0.327, p = 0.001). Renalase was not related to blood pressure, heart rate or hemodialysis vintage. Conclusion: Elevated renalase levels in HD patients may be due to impaired kidney function. Further studies are needed to prove or disprove the possible role of renalase in the pathogenesis of hypertension in patients with kidney diseases.

Introduction Vascular adhesion protein-1 (VAP-1) is a copper-containing semicarbazide-sensitive amine oxidase (SSAO) secreted by vascular smooth muscle cells, adipocytes, and endothelial cells with functional monoamine oxidase activity. Renalase, with possible monoamine oxidase activity, which breaks down catecholamines like SSAO, is also expressed in the endothelium as well as in the kidney. The aim of the study was to assess VAP-1 level and its correlation with renalase level in 60 hemodialyzed (HD) patients. Material and methods Complete blood count, urea, serum lipids, fasting glucose and creatinine were studied by the standard laboratory method in the hospital central laboratory. We assessed VAP-1 and renalase with commercially available assays. Results The mean level of VAP-1 as well as renalase was significantly higher in HD patients when compared to the control group (291.01 ±94.91 ng/ml vs. 158.34 ±56.89 ng/ml, p < 0.01; 27.53 ±9.394.91 µg/ml vs. 4.00 ±1.37 µg/ml, p < 0.001, respectively). In hemodialysis patients VAP-1 correlated with presence of diabetes (r = 0.27, p < 0.05), presence of hypertension (r = 0.32, p < 0.05), use of calcium channel blockers (r = 0.30, p < 0.05), use of β-blockers (r = 0.25, p < 0.05), ejection fraction (r = –0.38, p < 0.01), systolic blood pressure before (r = 0.52, p < 0.001) and after hemodialysis (r = 0.30, p < 0.01), and weight gain (r = 0.41, p < 0.01). Renalase was not significantly different in diabetic and non-diabetic patients or between hypertensive and normotensive patients. In multiple regression analysis VAP-1 was predicted 77% by serum ejection fraction and fibrinogen. Conclusions Vascular adhesion protein-1, elevated in patients on hemodialysis, was predominantly dependent on blood pressure and diabetes, both factors associated with endothelial damage and promoting cardiovascular complications. Renalase appeared to be unrelated to VAP, at least in the HD population.

VAP-1 (vascular adhesion protein-1) is a copper-containing SSAO (semicarbazide sensitive amine oxidase) secreted by vascular smooth muscle cells, adipocytes, endothelial cells with functional monoamine oxidase activity. The oxidation process generates harmful products that may be involved in atherosclerosis and vascular damage. Elevation of SSAO activity is observed in atherosclerosis, diabetes mellitus and obesity. On the other hand, renalase, with possible monoamine oxidase activity, which breaks down catecholamines like SSAO, is also expressed in the endothelium as well as in the kidney. The aim of the study was to assess VAP-1 levels and its correlations with endothelial injury markers and renalase in 50 kidney allograft recipients.Hemoglobin, urea, creatinine, rate were studied by standard laboratory method in the hospital central laboratory. We assessed markers of endothelial function/injury: vWF, thrombomodulin, ICAM, VCAM, CD40L, CD44, CD146, inflammation: hsCRP, and IL-6 and adipocytokines: leptin, adiponectin, visfatin, apelin with commercially available assays.The mean serum VAP-1 in Tx was significantly higher comparing to the control group. In kidney transplant recipients VAP-1 correlated with BMI (r=0.39, p0.01), CD44 (r=0.27, p0.05), hsCRP (r=0.28, p0.05), serum creatinine (r=0.29, p0.05), eGFR (CKD-EPI formula r=-0.27, p0.05, MDRD r=-0.27,p0.05, Cockcroft-Gault r=-0.35,p0.01), serum urea (r=0.27, p0.05), CD146 (r=0.49, p0.001), CD40L (r=0.26, p0.06), and renalase (r=0.34, p0.05). In multiple regression analysis VAP-1 was predicted 80% by serum creatinine (beta value 0.33, p=0.01), and CD146 (beta value 43, p=0.0005).VAP-1, elevated in kidney transplant recipients, is predominantly dependent on endothelial damage and kidney function, which deteriorated with time after kidney transplantation.

Morbidity in end-stage renal disease (ESRD) diabetic patients is worse than in patients without diabetes mellitus (DM). This study aims to compare clinical, laboratory, and echocardiographic features between the ESRD patients with and without DM. Fifty-eight ESRD patients on dialysis were prospectively divided into two groups according to the presence of DM. Demographic, clinical, laboratory, and echocardiographic features (ejection fraction and wall motion score index) were compared between the two groups. Overall, 20 out of 58 patients (37.8%) with ESRD had DM. There were no significant differences between the patients with DM and those without DM when it comes to age (60.6 ± 10.6 vs. 59.0 ± 10.6 years, P = 0.665), ejection fraction (52.6% ± 12.8% vs. 54.2% ± 12.8%, P = 0.59), and wall motion score index (1.21 ± 0.3 vs.1.15 ± 0.3, P = 0.37). In multivariant analysis of the interventricular septum, posterior wall thickness and left atrium size correlated positively with DM. There was also no statistical difference in myocardial perfusion disturbances on real-time contrast echocardiography between the groups with and without DM (12 (60%) patients vs. 14 patients (36.8%), P = 0.079). Among diabetics 77.8% had significant atherosclerotic changes, while in the group without DM, only 38.1%, P = 0.01. From the laboratory parameters ferritin and high-sensitivity C-reactive protein levels were significantly higher in the group with DM, P = 0.014 and P = 0.026, respectively. Patients with ESRD and DM have significantly bigger left atrial size, thicker left ventricular walls, and higher serum ferritin and high-sensitivity C-reactive protein levels than the patients without DM. The aforementioned features may be possible risk factors for the development of adverse cardiac events in patients on hemodialysis.

Objectives IL-21 is a new pleiotropic cytokine involved in immune system regulation. Design and methods We determined IL-21 in the plasma of hemodialyzed (HD) patients and healthy controls, and we tried to identify the factors which could affect its levels. Results Detectable levels of IL-21 were observed in the similar percent of HD patients and controls, but its concentration was twice lower in HD patients. The patients with detectable IL-21 had lower inflammatory state, reflected by IL-6 and TNF-α, compared to those with undetectable IL-21. The association was between IL-21 and the presence of glomerulonephritis (p Conclusions IL-21 is decreased in HD patients and is not affected by gender, age, inflammation, the vintage of HD, type of medication and type of used dialysis membrane. The etiology of chronic kidney disease and anti-HCV seropositivity independently affect its plasma levels in these patients.

Renalase is an enzyme that catabolizes catecholamines such as adrenaline and noradrenaline in the circulation. The human kidney releases this protein into the bloodstream to regulate blood pressure. In kidney transplant recipients, the prevalence of hypertension is 60%-80%.The aim of our study was to assess possible correlations between renalase, blood pressure, and kidney function among 89 prevalent kidney allograft recipients. To obtain normal ranges, we also studied renalase levels in 27 healthy volunteers.Complete blood counts, urea, serum lipids, fasting glucose, and creatinine were measured by standard laboratory methods in the hospital central laboratory. Renalase was assessed with the use of a commercially available kit.In kidney transplant recipients renalase was significantly higher than in healthy volunteers (P.001). In kidney transplant recipients, renalase correlated with age (r=0.29; P.05), time after transplantation (r=0.34; P.01), systolic blood pressure (r=0.28; P.05), diastolic blood pressure (r=0.27; P.05), serum creatinine (r=0.49; P.001), estimated glomerular filtration rate (Chronic Kidney Disease Endemiology collaboration: r=-0.44; P.0001; Modification of Diet in Renal Disease: r=-0.43; P.001; Cockcroft-Gault r=-0.39; P.01), serum phosphate (r=0.34; P.05). Upon multiple regression analysis renalase was predicted by 70% using age (beta value 0.21, P=0.043), time after transplantation (beta value, 0.22; P=.037), serum creatinine (beta value, 0.50; P=.016), and diastolic blood pressure (beta value, 0.33; P=.027).Renalase is highly elevated in kidney transplant recipients, predominantly dependent on kidney function, which deteriorates with time after kidney transplantation and age. Further studies are needed to establish its putative role in the pathogenesis of hypertension after transplantation and possible novel targeted therapies.

Objectives Data concerning the levels of metalloproteinase-2 (MMP-2) and MMP-9 in uremia and dialysis are conflicting and incomplete. Design and methods We measured the serum MMP levels in patients with chronic kidney disease (CKD) and undergoing maintenance hemodialysis (HD), and we tried to identify factors that could affect their levels. Results MMP-2 and the high sensitivity C-reactive protein (hsCRP) were inversely correlated with hematological parameters in the whole CKD group. CKD patients with stages 3 + 4 showed a significant increase in the MMP-9 levels compared to the other studied groups; this metalloproteinase was inversely correlated with lymphocyte count, and positively correlated with the hsCRP. The MMP-2 levels were higher in pre and post HD patients compared to the control group and CKD stage 1 + 2. In contrast, there was no difference in the MMP-9 levels. Both MMP-2 and MMP-9 were associated with the leukocyte count in pre HD group. Conclusions This study suggests a connection between an inflammatory state, biochemical response and the MMP levels in uremic and dialysis patients.

We evaluated the impact of residual renal function (RRF) on oxidative stress (SOX) and CD40/CD40L system in haemodialysis (HD) patients.We determined sCD40, sCD40L and SOX marker-Cu/Zn superoxide dismutase (Cu/Zn SOD) levels in HD patients with RRF, with anuria (A) and in healthy controls.sCD40 and Cu/Zn SOD plasma levels were higher in both groups of dialyzed patients compared to controls (all p0.001), and they were higher in A than in RRF patients (all p0.01). In RRF group, sCD40/sCD40L and Cu/Zn SOD were significantly higher in anti-HCV-seropositive (anti-HCV[+]) patients than in their anti-HCV[-] counterparts. This phenomenon was not observed in A group. Multiple regression analysis showed that Cu/Zn SOD, kt/V and low fibrinogen were the independent factors affecting sCD40 levels in the whole HD group.The loss of RRF and HCV seropositivity increased plasma levels of sCD40/sCD40L and oxidative status in HD patients.

The production by hepatocytes of hepcidin, a small defensin-like peptide, is modulated in response to anemia, hypoxia, or inflammation. We studied hepcidin as a marker of iron status (serum iron, ferritin, and soluble receptor of transferrin [sTfR], and as a marker of inflammation among 170 prevalent kidney transplantation (KT) patients and 168 prevalent orthotopic heart transplant (OHT) patients. In addition, we assessed the prevalence of anemia and its relation to measurements of hepcidin, sTfR, and high-sensitivity C-reactive protein, using commercially available enzyme-linked immunosorbent assay (ELISA) kits. Prevalence of anemia was 37% in KT patients and 34% in OHT patients according to the World Health Organisation (WHO) definition. Anemic KT patients displayed significantly higher values of serum creatinine, hepcidin, hsCRP, ferritin, and proteinuria associated with greater use of mTOR and significantly lower CSA therapy. The hemoglobin and estimated glomerular filtration rate (eGFR). Upon multiple regression analysis eGFR, ferritin, and hsCRP independently predicted hepcidin levels, explaining 78% of the variation in hepcidin. Anemic OHT patients showed significantly lower GFR, red blood cell (RBC), and hemoglobin values and significantly higher creatinine and NT-proBNP content. Upon multiple regression analysis the predictors of serum hepcidin were eGFR and ferritin, which explained 68% of the variation in hepcidin. The prevalence of anemia is relatively high and not adequately treated (mainly due to reimbursement regulations) among heart and kidney allograft recipients. In conclusion, elevated hepcidin levels in heart and kidney transplant recipients suggest subclinical inflammation and impaired kidney function.

Introduction Hepatitis C virus (HCV) infection occurs frequently among haemodialysis (HD) patients and increases the risk of atherosclerosis. CD40 and Fas belong to tumor necrosis factor receptor (TNFR) superfamily, which play a role in hepatocyte apoptosis during HCV infection. The aim of the present study was to determine whether anti-HCV-seropositivity constitutes an additional risk factor for endothelial dysfunction in HD patients, and whether sCD40 and sFas could be associated with endothelial dysfunction. Materials and methods A total of 69 stable HD patients and 28 healthy controls were included in this study. Patients were divided into anti-HCV-seropositive (HCV[+], n = 18) and anti-HCV- seronegative (HCV[-], n = 51). The plasma endothelial markers: von Willebrand factor (vWF), thrombomodulin (TM), soluble adhesion molecules – sICAM-1, sVCAM-1 and TNFRs were assayed. Results HD patients showed a significant increase in the levels of TM, sVCAM-1, sCD40 and sFas compared to controls, and all these parameters were higher in HCV[+] than in HCV[-] patients. sICAM-1 concentrations were higher in the HCV[+] group compared to controls and the HCV[-] group. vWF levels were higher in HD patients than in the controls, however there was no difference in this parameter between HCV[+] and HCV[-] group. The anti-HCV-seropositivity and sCD40 were determined as an independent variables of TM, whereas anti-HCV-seropositivity and sFas were found as independent determinants of sICAM-1 and sVCAM-1 levels. Conclusions This study showed that anti-HCV-seropositivity and TNF superfamily receptors: sCD40 and sFas are the novel determinants of the increased plasma endothelial dysfunction markers in haemodialysis patients.

Objectives CC-chemokines and kynurenine pathway (KP) metabolites are associated with accelerated atherosclerosis in chronic kidney disease (CKD) patients. Design and methods We evaluate the plasma levels of anthranilic acid (AA), 3-hydroxyanthranilic acid (3-HAA) and their possible relationship with CC-chemokines, Cu/Zn superoxide dismutase (Cu/Zn SOD) as the marker of oxidative status and high sensitivity C-reactive protein (hsCRP) as an index of inflammation in the population of 48 CKD patients. Results Compared with controls, CKD patients showed a significant increase in plasma concentrations of CCL2, CCL4, AA, 3-HAA, Cu/Zn SOD and hsCRP. Multiple stepwise regression analysis identified inflammation, renal function and 3-HAA levels as the independent variables significantly associated with increased CCL2; whereas age, 3-HAA and renal function as independent variables associated with CCL4. Conclusions These results suggest a relationship between CC-chemokine system and KP activation, which may represent one of the mechanisms involved in the accelerated atherosclerosis in CKD population.

Introduction Anaemia is one of the arms of the cardio-renal-anaemia syndrome (CRA) in chronic kidney disease (CKD) patients. The correction of anaemia was effective in the amelioration of both cardiac and renal failure. We studied the relationship between the severity of CRA syndrome in peritoneally dialyzed patients and their survival probability. Material and methods Fifty-six patients on peritoneal dialysis were followed for 1 year. Definition of the severity of the CRA in dialysis patients: cardiac arm – NYHA class I-IV = 1-4 points, renal arm – non-diabetic patients age < 65 =1 point, non-diabetic patients age>65 = 2 points, diabetic patients age < 65 = 3 points, diabetic patients age>65 = 4 points, anaemia arm – Hb 11-13 g/dl (male), 11-12 g/dl (female) = 1 point, Hb 10-11 g/dl = 2 points, Hb 9-10 g/dl = 3 points, Hb < 9 g/dl = 4 points. The severity score = cardiac + renal + anaemia arms score divided by 3 (maximum 4 points). Results A total of 10/56 patients (18%) died during the study. The median value for the severity score of the whole group was 1.69. In Kaplan-Meier analysis CRA severity score was strongly associated with mortality (p < 0.001). It also correlated with albumin, CRP, erythropoietin treatment, Hb and fasting glucose. In the multivariate regression analysis age, Hb, albumin, and presence of diabetes remained significant predictors of death. Conclusions The severity score of CRA syndrome in peritoneally dialyzed patients is an independent and very significant predictor of death. The patients with a high severity score had more hypoalbuminaemia, higher inflammation markers and higher prevalence of diabetes and chronic heart failure. Cardio-renal-anaemia syndrome severity scoring as defined by us could be an easy tool to predict outcome of dialysis patients.

Cellular adhesion molecules and oxidative stress play a role in the pathogenesis of atherosclerosis in patients with chronic kidney disease (CKD). Recently, it has been postulated that the kynurenine (KYN) pathway could be involved in the pathogenesis of atherosclerosis.We evaluated the KYN, kynurenic acid (KYNA), anthranilic acid (AA), and their relations with cellular adhesion molecules: soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular adhesion molecule-1 (sVCAM-1), sE-selectin, sP-selectin, and Cu/Zn superoxide dismutase (Cu/Zn SOD) levels as the markers of oxidative stress in the population of 132 patients with CKD and 28 healthy controls.Compared with the controls, 2 groups of dialyzed patients had significantly increased KYN (both P0.01), KYNA, AA, sICAM-1, sVCAM-1, and Cu/Zn SOD levels (all P0.001, respectively). KYN, AA, sICAM-1, and sVCAM-1 concentrations were significantly higher in undialyzed patients with CKD compared with healthy subjects (P0.001, P0.01, and both P0.05, respectively). sICAM-1 and sVCAM-1 were positively associated with KYN (P0.0001 and P0.01), KYNA (P0.05 and P0.0001), AA (P0.01 and P0.0001), and with Cu/Zn SOD (both P0.0001, respectively) in the whole CKD group. The positive relationship existed between sICAM-1, sVCAM-1 and age, high-sensitivity C-reactive protein, creatinine, and the duration of dialysis therapy. Multivariable analysis showed that KYN was a strong independent correlate of sICAM-1, whereas Cu/Zn SOD and platelets independently and significantly predicted sVCAM-1 in patients with CKD.This study demonstrated that KYN is independently and significantly associated with elevated sICAM-1, whereas oxidative status and platelets independently and significantly predicted increased sVCAM-1 levels in patients with CKD.

The abnormalities of tissue factor (TF) and its inhibitor (TFPI) system could potentially contribute to high incidence of thrombotic complications and atherosclerosis in patients with chronic kidney disease (CKD). Recently, the role of the kynurenine (KYN) pathway of tryptophan (TRP) degradation has been postulated in the progression of cardiovascular complications. We compared the plasma TF, TFPI and the metabolites of TRP degradation: KYN and 3-hydroxykynurenine (3-HKYN) levels in 55 CKD patients on conservative treatment and 19 healthy controls; and we tried to establish whether or not there is an association between TF/TFPI system and above-mentioned metabolites in these patients. Compared with the controls, the patients with CKD showed a significant increase in plasma concentrations of TF (P < 0.01), KYN, 3-HKYN (both P < 0.0001), KYN-to-TRP (kyn/trp) ratio (P < 0.001) and 3-HKYN-to-KYN (3-hkyn/kyn) ratio (P < 0.05). In contrast, TRP concentrations were significantly decreased in the CKD group compared with controls (P < 0.001). The difference in TFPI levels between CKD patients and controls was not statistically significant. TF/TFPI system was inversely correlated with TRP, whereas it was positively related to the 3-HKYN, kyn/trp and 3-hkyn/kyn ratios. Moreover, both the TF/TFPI system and KYNs were associated with the markers of kidney function. These data suggested for the first time a significant relationship between TF/TFPI system and KYN pathway in CKD patients on conservative treatment.

Increased oxidative stress (SOX) is one of the most potent inductors of endothelial dysfunction in end-stage renal disease (ESRD) patients. Kynurenines are the metabolites of tryptophan (TRP) degradation in mammals. However, the role of kynurenines in the function of the endothelium is still not recognized.We determined the plasma concentrations of TRP, kynurenine (KYN), 3-hydroxykynurenine (3-HKYN), quinolinic acid (QA); markers of SOX: Cu/Zn superoxide dismutase (Cu/Zn SOD), malondialdehyde (MDA); and endothelial dysfunction markers: thrombomodulin (TM) and von Willebrand factor (vWF) levels in 148 ESRD patients and healthy controls.TM, vWF, KYN, 3-HKYN and QA levels were significantly elevated in ESRD patients compared to controls. TRP concentrations in uremics were significantly lower than in healthy people. Both dialyzed groups showed a significant increase Cu/Zn SOD and MDA levels compared to controls. TM and vWF were positively associated with kynurenine pathway metabolites: KYN, 3-HKYN, QA (all p0.001), and with SOX markers: Cu/Zn SOD (both p0.0001) and MDA levels (p0.05, and p0.0001; respectively) in the whole ESRD group. The positive relationship were between Cu/Zn SOD and KYN (p0.010), 3-HKYN and QA levels (both p0.0001), whereas MDA was correlated with 3-HKYN and QA concentrations (both p0.05). Multiple stepwise regression analysis showed that KYN metabolites and oxidative status were the independent variables significantly associated with increased both TM and vWF levels in uremic patients.Our study demonstrated that kynurenine metabolites and increased oxidative status are independently and significantly associated with endothelial dysfunction in ESRD patients.

Background/Aims: Impaired renal function is a strong risk factor for cardiovascular diseases and worsens a patient’s prognosis. Renal dysfunction predicts mortality after acute stroke in the long term. On the other hand, in-hospital mortality after acute stroke is strongly associated with disorders of consciousness at the onset of stroke, severity of stroke, body temperature, blood sugar and some other comorbidities. The aim of the study was to analyze the possible role of renal dysfunction and/or signs of renal disease (proteinuria) on 30-day mortality after acute ischaemic stroke (AIS) based on the hospital medical records of one county. Methods: Medical records of 312 consecutive patients admitted to Ostrołęka County Hospital (Department of Neurology) between March 2000 and October 2002 for AIS were retrieved retrospectively to determine factors influencing 30-day survival. None of patients received thrombolytic therapy. Results: Among the patients analyzed, 74 (23.7%) died during the 30-day period. In a simple Cox proportional hazards regression model, negative predictive factors were: older age, higher pulse rate, lower estimated glomerular filtration rate (eGFR), proteinuria, elevated plasma glucose level, diabetes mellitus, atrial fibrillation and chronic heart failure. In a multivariate analysis, independent negative predictors of 30-day morbidity were: age hazard ratio (HR) 1.05 (95% CI 1.02–1.08), eGFR 100 mg/dl HR 2.96 (95% CI 2.22–3.70). Conclusion: The results of this study identify decreased eGFR and presence of dipstick proteinuria as a strong negative predictor of 30-day survival after AIS in patients not treated with thrombolytic agents.

Hepcidin is the key regulator of iron metabolism. Iron supplementation is often introduced in dialyzed patients to replete or to maintain iron stores, particularly in patients treated with erythropoietic-stimulating agents. The present study was aimed to assess possible relation between hepcidin and erythropoietin therapy, with particular attention being paid to erythropoietin-hyporesponsiveness in hemodialyzed patients. Prohepcidin and hepcidin were studied using commercially available kits from DRG Instruments GmbH, Germany (ELISA method) and Bachem, UK (RIA method). TNFalpha and IL-6 were studied using kits from and RD (Abington, UK), and hsCRP was studied using kits from American Diagnostica, USA. Hyporesponsive patients to erythropoietin therapy had significantly lower serum albumin, cholesterol, LDL, hemoglobin, hematocrit, and residual renal function, and significantly higher serum ferritin, hsCRP, IL-6, TNFalpha, and erythropoietin dose. The difference in serum prohepcidin and hepcidin did not reach statistical significance; however, there was a tendency toward higher values of both prohepcidin and hepcidin in hyporesponsive patients. In conclusion, though hyporesponsiveness to erythropoietin therapy occur in dialyzed patients, it is mainly associated with subclinical inflammation than with hepcidin excess. Further studies are needed to develop a reliable and reproducible assay to elucidate the potential contribution of hepcidin to hyporesponsiveness during erythropoietin therapy.

It is unknown whether the glycosaminoglycan drug sulodexide interferes with transforming growth factorβ1—a member of heparin-binding family and a potent regulator of human biology and diseases. Hence, a 2-week pilot study was performed in 11 healthy men. Sulodexide was initially administered intravenously in a single dose, then—orally for 12 days and—again intravenously on study completion. Initial injection had no effect on activated form of the growth factor measured in plasma after 10 and 120 min; no change was also observed after 120 min from drug ingestion on day 7. On final intravenous administration, the growth factor levels increased by almost 60% after 10 min and remained elevated; the 120-min levels directly correlated with sulodexide dosage. Baseline cytokine levels decreased during the 2-week trial by more than 50%. In conclusion, transforming growth factor-β1 release and likely downregulation of its expression may constitute novel pharmacological effects of sulodexide.

Disturbances in hemostasis and endothelial damage are common complications of kidney disease. Endothelial dysfunction may link these 2 processes and inflammation is closely related to endothelial dysfunction.This cross-sectional study on serum concentrations of markers of endothelial damage and inflammation in relation to adhesion molecules was performed in 90 kidney allograft recipients and 30 healthy volunteers. We measured markers of endothelial damage-von Willebrand factor (vWF), thrombomodulin, intracellular adhesion molecule (ICAM), vascular adhesion molecule (VCAM), CD146, CD44, and CD40L; markers of inflammation-high-sensitivity C-reactive protein (hsCRP), tumor necrosis factor alpha (TNFalpha), and interleukin-6 (IL-6); and other hemostatic parameters-thrombin-antithrombin complexes (TAT), plasmin-antiplasmin complexes, and thrombin activatable fibrinolysis inhibitor (TAFI) using commercially available kits.Markers of endothelial dysfunction and inflammation were significantly elevated in kidney allograft recipients compared with control subjects. CD44 was independently related to hsCRP (r = .37; P.01), ICAM (r = .23; P.05), eGFR (r = -.37; P.01), thrombomodulin (r = .43; P.001), VCAM (r = -.44; P.001), hemoglobin (r = -.26; P.01), red blood cell count (r = -.25; P.05), creatinine (r = .37; P.01), CD146 (r = .34; P.01), and CD40L (r = .23; P.05). Upon multiple regression analysis the predictors of elevated CD44 were hsCRP concentration (beta = .25; P.05), CD146 (beta = .39; P.05), creatinine (beta = .55; P.01), and thrombomodulin (beta = .39; P.05) with an adjusted R(2) = .40 (F = 4.12; P.00028; SE of estimate = 151.19).As demonstrated in multiple regression analysis, kidney function was strictly linked to the degree of inflammation and endothelial injury. Endothelial cell injury and the presence of an inflammatory state, as reflected by elevated marker concentrations, and endothelial activation/injury may play roles in the pathogenesis of atherosclerosis and cardiovascular complications among kidney allograft recipients.

Elevated VEGF levels has been reported in patients with chronic renal failure (CRF), but the reasons for its higher level in renal insufficiency remain unknown. We assessed VEGF, SOX markers: total peroxide, Cu/Zn superoxide dismutase (Cu/Zn SOD), the levels of autoantibodies against oxidized LDL (OxLDL-Ab), and inflammation markers: high sensitivity C-reactive protein (hs CRP), interleukine-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) in 55 CRF patients and 18 controls. The patients with CRF showed a significant increase in plasma levels of VEGF, markers of inflammation, total peroxide and Cu/Zn SOD levels compared with controls. The strong positive associations were between VEGF and creatinine, urea, phosphate and CaxP product (all p

Possible correlations between adiponectin, leptin, CD146, a novel adhesion molecule localized at the endothelial junction, and other markers of endothelial cell injury, von Willebrand factor, thrombomodulin, vascular cell adhesion molecule, and intracellular adhesion molecule, and markers of inflammation, tumor necrosis factor-α, interleukin-6, and high-sensitivity C-reactive protein in nondiabetic hemodialyzed patients with and without coronary artery disease were studied. Markers of endothelial dysfunction were elevated in hemodialyzed patients, predominantly with coronary artery disease. In multivariate analysis, kinetic urea modeling and plasminogen activator inhibitor-1 remained the only positive predictors of adiponectin. In multivariate analysis, predictors of leptin were triglycerides, tissue plasminogen activator, CD146, and coronary artery disease. In multivariate analysis, predictors of CD146 were age, hemoglobin, and adiponectin. Elevated adiponectin correlated to CD146 may be the expression of a counterregulatory response aimed at mitigating the consequences in endothelial damage and increased cardiovascular risk in renal failure. The data provide further support for a link between adipocytokines, endothelial dysfunction, cardiovascular risk, and renal failure.

Introduction Recombinant human erythropoietin (rHuEPO) is the cornerstone of anaemia therapy in uraemic patients however the effects of this hormone on fibrinolytic system are difficult to interpret. Materials and methods Assessment of fibrinolytic parameters: tissue-type plasminogen activator (tPA) antigen, urokinase-type plasminogen activator (uPA) and its soluble receptor (suPAR), plasminogen activator inhibitor 1 (PAI-1) and plasmin/antiplasmin (PAP) complexes were performed in haemodialyzed (HD) patients without rHuEPO therapy: Group I ( n = 8, Hg n = 12, Hg > 10 g/dl); and in HD patients treated with rHuEPO for more than 6 months (Group III, n = 10) or for more than 12 months (Group IV, n = 9) in relation to the healthy controls. Results Patients of Group I had the significantly lower haematological parameters than those of Groups II, III and IV. All the fibrinolytic parameters studied, except PAI-1, were significantly higher in HD patients without rHuEPO therapy when compared to the controls. There were no significant differences in fibrinolytic system between the Groups I and II. Erythropoietin therapy resulted in progressive decrease in antigenic tPA levels, which reach normal range values after 6 months rHuEPO administration. uPA and PAP concentrations were also decreased and reached normal values after 12 months of rHuEPO therapy. In these patients a significant decrease in uPAR levels was also observed. Therapy with rHuEPO did not alter PAI-1 concentrations in HD patients. Conclusions These results suggest that long-term rHuEPO therapy can correct fibrinolytic parameters in patients undergoing regular HD irrespective from haemoglobin levels and in the absence of concomitant iron supplementation.

Aims: We designed a study to evaluate whether erythropoietin (EPO), given to patients on continuousambulatory peritoneal dialysis (CAPD) both with and without diabetes mellitus (DM), influences tissue factor (TF), tissue factor pathway inhibitor (TFPI) and oxidative stress (SOX). Methods: We assessed TF, TFPI and a marker of SOX, Cu/Zn superoxide dismutase (Cu/Zn SOD) in 16 diabetic CAPD patients (8 with EPO therapy), 39 non-diabetic CAPD patients (23 with EPO therapy) and 18 healthy controls. Results: Patients on CAPD showed a significant increase in plasma concentrations of TF, TFPI and Cu/Zn SOD as compared to controls. EPO therapy was related to a decrease in these parameters in diabetic patients, whereas in non-diabetic patients EPO did not affect their levels. In diabetics, TF was positively correlated with TFPI and Cu/Zn SOD levels. There was a positive relationship between TFPI and Cu/Zn SOD, whereas inverse relationships existed between TFPI and haemoglobin, haematocrit (Ht), EPO dose and triglycerides. Multivariate analysis showed that independent variables linked to TFPI levels in diabetic patients were Cu/Zn SOD, Ht and EPO dose. Conclusion: Our data suggest that correction of anaemia with EPO therapy is associated with a significant decrease in TF, TFPI and SOX in diabetic CAPD patients.

Heparin influences numerous pleiotropic growth factors, including hepatocyte growth factor (HGF), partially by their release from endothelial and extracellular matrix stores. The effects of sulodexide, a heparin-like glycosaminoglycan medication of growing importance in medicine, on HGF liberation are not known. We performed a 2-week open-label sulodexide trial in healthy male volunteers. The drug was initially administered intravenously (i.v.) in a single dose of 1200 Lipoprotein Lipase Releasing Units (LRU), then -- orally for 12 days (500 LRU twice a day), and -- again by i.v. route (1200 LRU) on day 14. Intravenous sulodexide injections were repeatedly found to induce marked and reproducible increases in immunoreactive plasma HGF levels (more than 3500% vs baseline after 10 min, and more than 1200% after 120 min), and remained unchanged when measured 120 min following oral sulodexide administration. The percentage increments in plasma HGF evoked by i.v. sulodexide at both time points and on both days inversely correlated with baseline levels of the growth factor. On day 14, the HGF levels after 120 min and their percentage increase vs baseline were strongly and directly dependent on i.v. sulodexide dose per kg of body weight. This study shows that sulodexide has a novel, remarkable and plausibly biologically important stimulating effect on the release of pleiotropic hepatocyte growth factor in humans.

The disturbances of haemostasis and enhanced oxidative stress (SOX) appear to contribute to the cardiovascular disease (CVD) in hemodialysis (HD) patients. The aim of the present study was to investigate if the disorders of coagulation/fibrinolysis system are associated with the presence of CVD in these patients.We compared pre-dialysis levels of uPA, suPAR, tissue factor (TF) and its inhibitor (TFPI), prothrombin fragment F1+2 (F1+2); a marker of SOX-Cu/Zn superoxide dismutase (Cu/Zn SOD) and a surrogate of inflammation-high sensitivity C-reactive protein (hs CRP) in HD patients with and without CVD.The uPA/suPAR system and hs CRP values were significantly greater in patients with CVD than in those without CVD; whereas TF, TFPI, F1+2 and Cu/Zn SOD levels were comparable in both patient groups. TF was positively correlated with both uPA (p0.001) and suPAR levels (p0.05). Logistic regression analysis showed that elevated levels of suPAR, TF and uPA were independently associated with the presence of CVD in HD patients.The association between TF and uPA/suPAR system is significantly related to the presence of CVD in HD patients.

Increased oxidative stress (SOX) has been reported in continuous ambulatory peritoneal dialysis (CAPD) patients, but its influence on beta-chemokine levels and progression of atherosclerosis remains unknown. We determined three distinct SOX markers: Cu/Zn superoxide dismutase (Cu/Zn SOD), total peroxide and autoantibodies against oxidized LDL (OxLDL-Ab); high sensitivity C-reactive protein (hs CRP); beta-chemokines: monocyte chemoattractant protein-1 (CCL2), macrophage inflammatory proteins (CCL3 and CCL4) and regulated upon activation, normal T cell expressed and secreted (CCL5) and the intima-media thickness (IMT) values in CAPD patients both with and without cardiovascular disease (CVD) and healthy controls. CAPD patients both with and without CVD had significantly increased IMT (p

Enhanced oxidative stress (SOX) and changes in the fibrinolytic system are common in end-stage renal failure patients undergoing maintenance dialysis. This study attempted to verify the existence of a relationship between SOX documented by Cu/Zn superoxide dismutase (Cu/Zn SOD) and fibrinolysis analyzed by tissue-type plasminogen activator (tPA), urokinase-type plasminogen activator (uPA), plasminogen activator inhibitor 1 (PAI-1) and plasmin/antiplasmin (PAP) complexes in dialysis patients.Twenty-seven patients on maintenance haemodialysis (HD) and 16 on maintenance peritoneal dialysis (CAPD) were examined together with 18 healthy controls. Pre-dialysis blood levels of all the parameters were determined using commercially ELISA kits.Cu/Zn SOD, uPA and PAP levels were increased in both groups of dialyzed patients compared to the controls. PAI-1 was significantly lower in CAPD subjects compared to HD subjects and control group. PAI-1/uPA ratio and PAI-1/tPA ratio were significantly decreased in CAPD and HD compared to controls, being significantly lower in CAPD patients relative to HD patients. In the patients, increased Cu/Zn SOD levels directly correlated with those of uPA (r=0.565, p0.0001) and PAP (r=0.335, p0.05); the fibrinolytic markers were also positively associated with each other (r=0.377, p0.05).The positive association between Cu/Zn SOD and both uPA as well as PAP levels suggests a link between SOX and the fibrinolytic activity in dialysis patients. We hypothesize that increased SOX-mediated fibrinolytic activity may be a part of the counter-system against activation of blood coagulation in these patients.

Background: CC-chemokines are now widely accepted in the recruitment of leukocytes from the blood compartment into tissues, and their role in the progression of atherosclerosis has been documented. Recombinant human erythropoietin (EPO) has become widely used to treat anemic HD patients. However, little is known about the effect of EPO on the plasma CC-chemokine levels and intima-media thickness (IMT) in HD patients. Methods: Assessment of CC-chemokines: monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory proteins (MIP-1α, MIP-1β), regulated upon activation, normal T cell expressed and secreted (RANTES) and IMT were performed in 26 stable HD patients and 15 healthy controls. The patients were divided into 3 groups: group I (n = 8, without EPO), group II (n = 9, EPO at a mean dose of 76 ± 48 U/kg/week for more than 4 months), and group III (n = 9, EPO at a mean dose of 110.5 ± 21 U/kg/week for more than 12 months), none of them on iron therapy. Results: MCP-1, MIP-1α, MIP-1β and IMT values were significantly higher, whereas RANTES were significantly lower in HD patients without EPO therapy than those in healthy controls. CC-chemokine levels were found to be significantly lower in patients administered EPO when compared to subjects without EPO. In the patients treated with EPO for more than 12 months IMT values were significantly decreased compared to patients not receiving this hormone. Conclusion: These results suggest that long-term EPO therapy decreased CC-chemokine and IMT values in patients undergoing regular HD in the absence of concomitant iron supplementation.