Beata Naumnik

The mechanism of vascular calcification – a systematic review

Summary Calcification of vessels reduces their elasticity, affecting hemodynamic parameters of the cardiovascular system. The development of arterial hypertension, cardiac hypertrophy, ischemic heart disease or peripheral arterial disease significantly increases mortality in patients over 60 years of age. Stage of advancement and the extent of accumulation of calcium deposits in vessel walls are key risk factors of ischemic events. Vascular calcification is an active and complex process that involves numerous mechanisms responsible for calcium depositions in arterial walls. They lead to increase in arterial stiffness and in pulse wave velocity, which in turn increases cardiovascular disease morbidity and mortality. In-depth study and thorough understanding of vascular calcification mechanisms may be crucial for establishing an effective vasculoprotective therapy. The aim of this study was to present a comprehensive survey of current state-of-the-art research into the impact of metabolic and hormonal disorders on development of vascular calcification. Due to strong resemblance to the processes occurring in bone tissue, drugs used for osteoporosis treatment (calcitriol, estradiol, bisphosphonates) may interfere with the processes occurring in the vessel wall. On the other hand, drugs used to treat cardiovascular problems (statins, angiotensin convertase inhibitors, warfarin, heparins) may have an effect on bone tissue metabolism. Efforts to optimally control calcium and phosphate concentrations are also beneficial for patients with end-stage renal disease, for whom vessel calcification remains a major problem.

Oxidative Stress – a Link between Endothelial Injury, Coagulation Activation, and Atherosclerosis in Haemodialysis Patients

Background/Aim: Recently emerging evidence suggests that oxidative stress (SOX) may participate in atherogenesis. The aim of the present study was to establish whether enhanced SOX, involving endothelial injury, activation of coagulation, and inflammatory reaction, could be implicated in atherosclerotic diseases in haemodialysis (HD) patients. Methods: Markers of SOX, endothelial injury, coagulation, and cytokines, were measured in the plasma of HD patients with and without cardiovascular disease (CVD), and of healthy controls by ELISA methods. Remodeling of the carotid arteries was assessed by measuring the intima-media thickness (IMT) as a surrogate of atherosclerotic disease in all groups. Results: Markers of SOX, endothelial injury, and extrinsic coagulation pathway activation and IMT values were significantly elevated in HD patients, especially in those with CVD when compared with the control group. The von Willebrand factor antigen (vWF:Ag) levels were more increased in the patients with CVD than in those without. Furthermore, the plasma levels of tumour necrosis factor alpha, monocyte chemo-attractant protein 1, and macrophage inflammatory protein 1 beta were significantly higher only in the HD group with CVD when compared with the controls. The IMT was strongly and directly correlated with Cu/Zn superoxide dismutase. Both IMT and Cu/Zn superoxide dismutase were positively correlated with age, thrombomodulin, vWF:Ag, tissue factor, tissue factor pathway inhibitor, prothrombin fragment F1 + 2, monocte chemo-attractant protein 1, macrophage inflammatory protein 1 beta, and tumour necrosis factor alpha levels. Multivariate analysis identified vWF:Ag as the only independent variable significantly associated with an increased IMT. Conclusions: The present study suggests that enhanced SOX, involved pro-atherogenic cytokine and chemokines levels, endothelial injury, and coagulation activation may constitute a pathway for accelerated atherosclerosis in HD patients. The significant, independent association between IMT and vWF:Ag should be assessed in future studies to determine whether vWF:Ag elevation is causative or a by-product of the increased IMT.

Relationship between oxidative stress and extrinsic coagulation pathway in haemodialyzed patients

Enhanced oxidative stress (SOX), endothelial dysfunction and haemostatic abnormalities are common in end-stage renal failure patients undergoing maintenance haemodialysis (HD). We studied associations among circulating immunoreactive total lipid peroxides as a marker of short-time SOX, autoantibodies against oxidized LDL as a surrogate of prolonged SOX, copper/zinc superoxide dismutase (Cu/Zn SOD) as a major antioxidant enzyme, tissue factor (TF) as a principal initiator of extrinsic coagulation pathway counteracted by its inhibitor (TFPI), and prothrombin fragment 1+2 (F 1+2) as a surrogate of activated haemostasis.Pre-dialysis blood levels of all the markers studied were higher in 24 clinically stable HD patients compared to 11 healthy controls. Spearmans correlations among the three SOX markers were positive but nonsignificant in both HD patients and controls. In HD subjects, increased Cu/Zn SOD levels directly correlated with those of TF (rho=0.551, p=0.005) and TFPI (rho=0.501, p=0.001); the coagulation markers were also positively associated with each other (rho=0.663, p=0.0004). In healthy subjects, the relations between Cu/Zn SOD, TF and TFPI levels were inverse but not significant, and the direct association between TF and TFPI was nonsignificant either. In conclusion, increased plasma levels of Cu/Zn SOD, the antioxidant enzyme with emerging endothelial cell-protective and antithrombotic properties, may be a novel part of the system counteracting activated extrinsic coagulation system in maintenance HD patients.

Tissue Factor and Thrombomodulin in Hemodialysis Patients: Associations with Endothelial Injury, Liver Disease, and Erythropoietin Therapy

Patients receiving maintenance hemodialysis (HD) present with hemostatic abnormalities, which may be aggravated by comorbid conditions, especially liver disease. The factors that influence plasma levels of thrombomodulin (TM), an initiator of the anticoagulant protein C pathway, and those of tissue factor (TF), which triggers the extrinsic coagulation pathway, were assessed. In 63 HD patients, TM and TF levels were higher than those in healthy controls. In bivariate analysis, TF positively correlated with TM, and both were directly associated with the presence of viral hepatitis B or C marker, serum liver enzymes, use of erythropoietin therapy, hemoglobin levels, and duration of HD therapy, and inversely correlated with body mass index. TF was also positively associated with plasma von Willebrand factor (vWF) antigen, and inversely associated with activated partial thromboplastin time. In multivariate analysis, increased vWF, alanine aminotransferase, and use of erythropoietin independently predicted both TF and TM levels. HD patients with vWF and ALT levels lower than middle, and not treated with erythropoietin had normal TF but increased TM concentrations compared with levels in healthy controls. Increased plasma levels of TM and TF in patients on maintenance HD are surrogates of vascular endothelial injury. Liver disease and use of erythropoietin treatment are also important determinants of these markers, and should be considered in further studies.

Serum α1-Antitrypsin But Not Complement C3 and C4 Predicts Chronic Inflammation in Hemodialysis Patients

Background. We studied whether predialysis serum levels of positive acute phase markers such as α1-antitrypsin (AT), and complement components C3 and C4 could identify the presence of chronic inflammation in maintenance hemodialysis (HD) patients. Methods/Results. In 103 stable HD patients, AT directly correlated with C-reactive protein (CRP) (P<0.005), α1 acid-glycoprotein (P<0.005), fibrinogen (P<0.05), lipoprotein (a) (P<0.01) and von Willebrand factor antigen (P<0.05), while C3 and C4 were not related to any of these inflammatory markers. In the patients with elevated CRP and hypoalbuminemia, the mean AT value of 1.74 ± 0.50 g/L was higher (P = 0.008) than that of 1.38 ± 0.27 g/L in the subjects with normal CRP and albumin. Using the above cut-off levels, the positive and negative predictive values of AT on the presence of severe inflammation were 0.86 and 0.62, respectively, and the sensitivity and specificity were 86% and 73%, respectively. Conclusion. Serum AT levels above 1.74 g/L and below 1.38 g/L may select the HD patients with severe inflammation from those without. Measurements of C3 and C4 are not helpful in this situation.

RELATIONS BETWEEN OXIDATIVE STRESS, HEPATOCYTE GROWTH FACTOR, AND LIVER DISEASE IN HEMODIALYSIS PATIENTS

Background: Hepatocyte growth factor (HGF) and copper/zinc superoxide dismutase (Cu/Zn SOD) protect against tissue injury, including that due to oxidative stress (SOX). We studied whether they could be associated with each other, SOX markers, prevalence of viral hepatitis, and cardiovascular disease (CVD) and their laboratory surrogates in maintenance hemodialysis (HD) patients. Methods: In 24 patients, pre-dialysis serum HGF, plasma Cu/Zn SOD, total lipid peroxides, and serum autoantibodies against oxidized LDL were measured by ELISAs. Viral hepatitis B and C markers were determined by third generation microparticle ELISAs, and CVD was identified on a clinical basis. Results: In HD patients, circulating HGF, Cu/Zn SOD, and the other SOX markers were higher than in healthy controls, and HGF directly correlated with Cu/Zn SOD levels (P = 0.0006). Both HGF (P = 0.021) and Cu/Zn SOD (P = 0.017) were positively associated with prevalence of viral hepatitis and serum alanine aminotransferase activity (P = 0.021 and P = 0.040, respectively). Presence of CVD directly correlated with HGF (P = 0.001) but not with Cu/Zn SOD levels (P = 0.087). Circulating HGF positively related to serum C-reactive protein (P = 0.043). In patients without viral hepatitis and CVD, both HGF and Cu/Zn SOD were lower than in those with, and higher than in healthy controls. CVD (P = 0.003) and viral hepatitis (P = 0.024) were independent predictors of increased HGF, while positive viral hepatitis marker predicted increased Cu/Zn SOD levels (P = 0.019) in HD patients. There were no associations between HGF and the SOX markers in controls. Conclusions: In maintenance HD patients, circulating Cu/Zn SOD and HGF levels are increased, likely as a part of the reparatory reaction against liver damage. Viral hepatitis status and liver function should be considered in further studies of Cu/Zn SOD in these subjects.

Effect of Hemodialysis on Plasma Levels of Vascular Endothelial Markers

Vascular endothelial cell dysfunction is linked to hemostatic abnormalities and accelerated atherosclerosis in patients receiving maintenance hemodialysis (HD). The relationships between pre-dialysis plasma levels of immunoreactive thrombomodulin, von Willebrand factor, tissue factor and its inhibitor were studied, and the effects of HD procedure on these endothelial markers were observed. All the markers were higher in 39 HD patients than in 15 healthy controls (p<0.0001). HD treatment resulted in a 50% increase in tissue factor pathway inhibitor (p<0.0001), but did not influence the other markers. This increment directly correlated with the post-dialysis decrease in diastolic (p=0.011) and mean arterial blood pressure (p=0.039), and the surface area of the dialysis membrane (p=0.007). There were no associations between the increase in tissue factor pathway inhibitor and the amount of fluid removed, dose of enoxaparin, or other HD-specific factors. In conclusion, HD is responsible for an increase in plasma tissue pathway factor inhibitor level. The release of tissue factor pathway inhibitor during HD is not only due to heparin injection but also to the contact between blood and artificial dialysis membrane, and to HD-activated hemodynamic forces.

Unfractionated Heparin but Not Enoxaparin Causes Delayed Plasma PAI-1 Depletion in Hemodialysis Patients: A Prospective Study

Background and aims. Heparin modulates function of vascular endothelial cells. We studied the effects of unfractionated heparin (UFH) versus low-molecular-weight heparin (LMWH), enoxaparin, used as anticoagulants during hemodialysis (HD) on plasma levels of circulating endothelium-derived molecules: thrombomodulin (TM), von Willebrand factor (vWF), plasminogen activator inhibitor-1 (PAI-1), cell surface adhesion molecules (E-selectin), intercellular adhesion molecule-1 (ICAM-1), and prothrombin fragment 1+2 (PF 1+2). Methods. Twenty-five patients undergoing enoxaparin-anticoagulated HD were randomly assigned either to continue enoxaparin (n = 13) or receive UFH (n = 12) during HD and followed prospectively for 12 weeks. Plasma immunoreactive TM, vWF, PAI-1, ICAM-1, E-selectin, and PF 1+2 were measured before the randomization procedure and after 12 weeks, at the start, after 10 and 180 minutes of HD. Results. The switch from LMWH to UFH resulted in decreased pre-HD levels of PAI-1 and TM and increased PF 1+2 concentrations. Predialysis PAI-1 negatively correlated with the total dose of UFH/kg/HD. No significant differences were observed in the other variables before and during HD after switching from LMWH to UFH. During enoxaparin-anticoagulated HD, only plasma PAI-1 levels decreased by 32% after 180 minutes compared with the baseline values. This percentage decrease positively correlated with predialysis PAI-1 levels and marginally with PF 1+2 concentrations after 180 minutes of enoxaparin-anticoagulated HD. Conclusion. Enoxaparin-anticoagulated HD is related to transient plasma PAI-1 decrease, whereas UFH anticoagulation may be the cause of delayed PAI-1 and TM depletion, which is an untoward consequence of enhanced coagulation activity in chronic HD patients.

The Status of BK Polyomavirus Replication in Adult Renal Transplant Recipients in Northeastern Poland

PURPOSE BK polyomavirus (BKV) infection and BKV-associated nephropathy (BKVAN) are among the most important problems in renal transplantation. We aimed to determine the incidence of BK viruria, viremia, and BKVAN in renal transplant recipients in the northeastern part of Poland. METHODS Urine and blood samples from 126 cadaveric renal transplant recipients were analyzed for BK viruria and viremia using quantitative real-time polymerase chain reaction and the patients were followed prospectively. The diagnosis of BKVAN was established on the allograft biopsy. RESULTS Based on the BKV DNA analysis, the patients were divided into three groups: group 1 (n=89; 70.6%) without viruria or viremia, group 2 (n=24; 19.1%) with isolated viruria, and group 3 (n=13; 10.3%) with both viruria and viremia. The presence of BK viremia negatively correlated with time after the transplantation. BK viruria was associated with mycophenolate mofetil daily dose. In group 3 there were four patients (3.2%) with high viremia (>10(4) genome equivalents [gEq]/mL) and viruria (>10(7) gEq/mL) loads. Only one patient from this group developed clinical symptoms and had BKVAN in allograft biopsy. In all four cases, the maintenance immunosuppression therapy was based on tacrolimus and steroids. CONCLUSION Prevalence of BKV infection in renal transplant recipients in the northeastern part of Poland is similar to that reported by studies from other countries. We confirm that BK viremia could be predicted by the presence of intense viruria. Time after transplantation and the type of immunosuppression strategy are the most important predictors of BK viremia and viruria in patients after renal transplantation.

Different effects of enoxaparin, nadroparin, and dalteparin on plasma TFPI during hemodialysis: a prospective crossover randomized study.

Background. Low-molecular-weight heparins (LMWHs) are an alternative to unfractionated heparin (UFH) for anticoagulation during hemodialysis (HD). We performed a prospective randomized crossover study of the effect of enoxaparin, nadroparin, and dalteparin on some hemostatic factors, including tissue factor pathway inhibitor (TFPI), in patients with maintenance HD. Methods. Plasma levels (immunoassays) of total TFPI, platelet-derived growth factor-AB (PDGF-AB), and prothrombin fragment 1 + 2 (PF 1 + 2) were evaluated pre-HD, after 10 (T10) and 180 (T180) minutes of HD in 21 patients, who completed a 3-period (for 2 months each) crossover study in 6 groups (Latin-square design). Results. The baseline TFPI, PDGF-AB, and PF 1 + 2 levels were comparable under all LMWH treatments. Tissue factor pathway inhibitor levels, compared with the baseline, significantly increased (all P < 10−4), whereas PDGF-AB levels remained stable at each interval during enoxaparin, nadroparin, and dalteparin anticoagulated HD. Interestingly, TFPI increment at T10 was the highest, dose-dependent, and accompanied by PF 1 + 2 decrease under enoxaparin administration. Conclusion. The switch from enoxaparin to nadroparin and dalteparin used as anticoagulants had no long-term effect on the baseline total TFPI and PF 1 + 2 levels in chronically HD patients. Only short-term, overdialytic differences were noticed, indicating a single bolus of enoxaparin (0.75 mg/kg) as the most potent stimulus for endothelial TFPI