Michał Myśliwiec

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.

Lipids, blood pressure, kidney - what was new in 2011?

The year 2011 was very interesting regarding new studies, trials and guidelines in the field of lipidology, hypertensiology and nephrology. Suffice it to mention the new European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guidelines on the management of dyslipidaemias, American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) guidelines on hypertension in the elderly, and many important trials presented among others during the American Society of Nephrology (ASN) Annual Congress in Philadelphia and the AHA Annual Congress in Orlando. The paper is an attempt to summarize the most important events and reports in the mentioned areas in the passing year.

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.

Endothelial Cell Injury Markers in Chronic Renal Failure on Conservative Treatment and Continuous Ambulatory Peritoneal Dialysis

Aim: In chronic renal failure in dialyzed patients vascular damage is frequently observed and it is probable that disturbances in fibrinolytic activity and endothelial dysfunction may play a role in vascular complications such as stroke or ischemic heart disease. There have been a few data concerning hemostasis in chronic renal failure. Since hemostatic disturbances in nephrotic syndrome mimick those observed in patients maintained on chronic ambulatory peritoneal dialyses (CAPD), the aim of the study was to assess adhesion molecules (P-selectin, E-selectin, ICAM, VCAM and markers of endothelial cell injury), von Willebrand factor, thrombomodulin, and TFPI (tissue factor pathway inhibitor) in CAPD patients as well as in subjects with chronic renal failure (CRF) treated conservatively. Methods: The studies were performed on 23 CAPD patients, 24 patients with nephrotic syndrome and 24 sex- and age-matched healthy volunteers. TFPI total, full length, truncated, von Willebrand factor, trombomodulin, P-selectin, E-selectin, ICAM, VCAM and vascular endothelial growth factor (VEGF) and its receptor sFlt3 were assayed using commercially available kits. We evaluated also thrombin activity (thrombin-antithrombin complexes (TAT), prothrombin fragments 1 and 2) and the degree of plasmin generation. Results: In CAPD and CRF patients, concentrations of the adhesion molecules P-selectin, E-selectin, ICAM and VCAM were significantly higher when compared to the control group. Concentrations of total, free and truncated TFPI were significantly higher in CAPD and CRF patients when compared to the healthy volunteers. Concentrations of ‘classical’ markers of endothelial cell injury, von Willebrand factor and thrombomodulin, were significantly higher in CAPD and CRF patients when compared to the control group. In CAPD patients, VCAM and thrombomodulin were significantly elevated when compared to the CRF patients. Conclusions: The elevated levels of adhesion molecules in CAPD patients probably reflect inadequate clearance as well as enhanced synthesis/release. They may also indicate endothelial cell injury as well as elevated levels of von Willebrand factor and trombomodulin and increased ICAM and VCAM in CAPD patients. Our studies indicate that in renal failure patients, particularly on CAPD, there is evidence of endothelial cell injury and a high degree of hypercoagulation relative to healthy subjects. It may lead to fibrin deposition in the vascular wall, thrombus formation, and development and progression of atherosclerosis with its complications.

Kynurenine pathway – a new link between endothelial dysfunction and carotid atherosclerosis in chronic kidney disease patients

PURPOSE The endothelium dysfunction is an important component of atherosclertic cardiovascular disease. It has been also suggested that kynurenine pathway activation may be involved in the pathogenesis of this disease. MATERIAL/METHODS This is a cross-sectional study in chronic kidney disease (CKD) patients (n=106; 60 Males). The plasma markers of endothelial dysfunction and kynurenine (KYN), 3-hydroxykynurenine (3-HKYN), kynurenic acid (KYNA), anthranilic acid (AA) and quinolinic acid (QA) were measured in relation to an early indicator of the systemic atherosclerosis - intima-media thickness (IMT). RESULTS Kynurenines, von Willebrand factor (vWF), thrombomodulin (TM), soluble adhesion molecules (sICAM-1, sVCAM-1) and IMT in each uraemic group were significantly higher than in healthy people. In contrast, no significant differences in sE-selectin and sP-selectin concentrations were observed between CKD patients and controls. Kynurenines were positively associated with vWF, TM, sICAM-1 and sVCAM-1, whereas sP-selectin was inversely associated with the most of kynurenines. IMT was positively correlated both with kynurenines: KYN, 3-HKYN, QA as well as with endothelial markers: TM, vWF, sICAM-1 and sVCAM-1 (all p<0.01). Finally, multiple regression analysis identified age, vWF, sVCAM-1 and QA levels as the independent variables significantly associated with increased IMT in this population (adjusted r² = 0.51). CONCLUSIONS This study suggests a relationship between kynurenine pathway activation, endothelial dysfunction and the progression of atherosclerosis in CKD patients. It opens a new idea that the inhibition of kynurenine pathway may provide an effective strategy to slow down endothelial dysfunction and thereby the prevalence of atherosclerosis in this population.

Apelin and Cardiac Function in Hemodialyzed Patients: Possible Relations?

Background: Apelin, a newly discovered adipocytokine, is produced by white adipose tissue and is also expressed in the kidney and heart. Increasing evidence suggests a role for apelin in the pathology of the cardiovascular system. Cardiovascular disease is a major contributor to the mortality and morbidity in patients with chronic renal failure. The aim of this study was to assess associations between apelin, coronary artery disease (CAD) and echocardiographic parameters in hemodialyzed patients. Patients and Methods: We investigated plasma apelin levels (using commercially available kits) in 81 nondiabetic, clinically stable hemodialyzed patients (38 females, 43 males) with and without CAD. Results: Patients with CAD were significantly older, with significantly increased left ventricular internal end-diastolic dimension (LVIDd), left ventricular internal end-systolic dimension (LVISd), right ventricle (RV), left atrium (LA), interventricular septum in diastole, left ventricle posterior wall in diastole (LVPW), aorta, pulmonary artery, significantly lower ejection fraction and apelin than patients without CAD. We observed statistically significant correlations between apelin and echocardiographic parameters: LVIDd, LVISd, RV, LA, right atrium, LVPW, aorta, and serum lipids: cholesterol, LDL, triglycerides. In multiple logistic regression analysis, the only associate of apelin was LVIDd. Conclusions: Apelin level was significantly lower in dialyzed patients with CAD and it was associated with cardiac function. Apelin might be involved in the pathophysiology of cardiovascular disease in chronic renal failure. Since apelin is an inotrope in normal and failing hearts, this finding may have clinical implications for future use of apelin as a novel inotropic agent also for patients with uremic cardiomyopathy.

Vitamin K Status in Relation to Bone Metabolism in Patients with Renal Failure

Vitamin K abnormalities may be involved in the pathogenesis of bone disease in patients with advanced renal failure since vitamin K plays a role in the synthesis of osteocalcin, a marker of bone formation. Vitamin K may also indirectly suppress parathyroid function. The aim of this study was to evaluate vitamin K status in patients with renal failure and in healthy volunteers in relation to some biochemical markers of bone turnover. The studies were performed on: patients with chronic renal failure (CRF) on conservative treatment; hemodialyzed patients treated with continuous ambulatory peritoneal dialysis (CAPD); kidney transplant patients, and a control group. Intact PTH, osteocalcin, vitamin 1,25-(OH)2D3, 25-OH-D3, bone-specific alkaline phosphatase, procollagen type-I cross-linked carboxyterminal telopeptide, deoxypyridinoline, and osteonectin were assayed using commercially available kits, and the vitamin K concentration by HPLC. We found that vitamin K concentrations did not differ significantly between all the groups studied. Only in CRF patients was the vitamin K concentation low, almost reaching statistical significance when compared to the healthy volunteers (p = 0.05) and correlated positively with age, serum calcium and osteonectin. No statistically significant correlations were found between vitamin K and osteocalcin, PTH or other biochemical parameters of bone metabolism studied in patients with CRF and renal replacement therapy. In patients after renal replacement therapy, the only significant positive correlation was found between phylloquinone and osteonectin (r = 0.027, p = 0.004). The same applied when we also included healthy volunteers. The correlations of osteonectin and vitamin K are of unknown clinical relevance. Our study does not support the hypotheses of a possible role of vitamin K deficiency in patients with CRF and the influence of vitamin K on bone metabolism.

Importance of Serotonergic Mechanisms in the Thrombotic Complications in Hemodialyzed Patients Treated with Erythropoietin

So far it is not clear how erythropoietin affects the anticoagulant properties of vascular endothelium in uremia. Since serotonin is also thought to play a role in the pathogenesis of thrombosis, the aim of the study was to evaluate major components of extrinsic coagulation pathway, markers of endothelial cell injury, lipoprotein (a) and peripheral serotonergic mechanisms during rHuEPO therapy in hemodialyzed patients. The study was performed on chronically hemodialyzed patients divided into two groups: with rHuEPO treatment and without rHuEPO therapy in relation to the control group. In uremic patients, thrombomodulin and von Willebrand factor, activity of factor VII, tissue factor pathway inhibitor (TFPI) activity, TFPI and tissue factor (TF) concentrations, lipoprotein (a) level were significantly higher when compared to healthy volunteers. Treatment with rHuEPO resulted in a further significant rise in markers of endothelial cell injury: thrombomodulin and von Willebrand factor and TFPI concentration. Extrinsic coagulation factors: activities of factor VII and X, TFPI activity and TF activity and concentration, lipoprotein (a) and vitronectin remained unchanged during rHuEPO therapy. Platelet serotonin content and whole blood serotonin were significantly lower in uremic patients relative to healthy volunteers and during rHuEPO treatment they increased significantly. Whole blood serotonin reached normal values. Plasma serotonin, significantly elevated in uremia, did not change during rHuEPO therapy. Serotonin uptake by uremic platelets was significantly impaired and remained unaltered during rHuEPO administration. Serotonin release by uremic platelets was also significantly depressed but a significant improvement was observed in rHuEPO-treated patients. Our data suggest that endothelial injury, TF pathway components and peripheral serotonergic system disturbances may predispose to thromboembolic complications and play a role in the pathogenesis of atherosclerosis in uremic patients, particularly treated with rHuEPO. Increase in TFPI may compensate the increase in TF in these patients.

Markers of Endothelial Cell Activation/Injury: CD146 and Thrombomodulin Are Related to Adiponectin in Kidney Allograft Recipients

Background: Adiponectin may be used for assessing the risk of coronary artery disease (CAD) and may be related to the development of acute coronary syndrome. Decreased adiponectin has been associated with some risk factors for cardiovascular diseases such as male sex, obesity and diabetes mellitus. Adiponectin has antiatherogenic properties and attenuates endothelial inflammatory responses. CD146, a novel cell adhesion molecule, is localized at the endothelial junction. In kidney allograft recipients, endothelial dysfunction and atherosclerosis are almost universal. The aim of this cross-sectional study was to evaluate possible relations between adiponectin, CD146, and other markers of endothelial cell injury in 82 stable kidney transplant recipients (mean age 45 years, mean time after transplantation 47 months) with and without CAD. Methods: Adiponectin and markers of endothelial injury: CD146, von Willebrand factor, thrombomodulin, ICAM, CD40L, P-selectin and other hemostatic markers were assessed using commercially available kits. Results: Patients with CAD had evidence of more pronounced endothelial dysfunction, procoagulant state and lower adiponectin than patients without CAD. Adiponectin correlated significantly, in univariate analysis, with CD146 (r = 0.29, p = 0.009), thrombomodulin (r = 0.37, p = 0.001), protein Z (r = –0.25, p = 0.03), BMI (r = –0.26, p = 0.047), serum creatinine (r = 0.26, p = 0.02) and urea (r = 0.38, p = 0.001). CD146 correlated significantly with von Willebrand factor (r = 0.33, p = 0.002), thrombomodulin (r = 0.25, p = 0.025), age (r = 0.34, p = 0.001), platelets (r = –0.33, p = 0.002), serum urea (r = 0.24, p = 0.039), cholesterol (r = 0.24, p = 0.046), ICAM (r = 0.23, p = 0.036), protein C activity (r = –0.26, p = 0.019) and tended to correlate with serum creatinine and time after transplantation. In multivariate linear regression, independent predictors of adiponectin were CD146, thrombomodulin and urea, and of CD146 was mainly age of patients. Conclusions: Endothelial dysfunction and procoagulant state are more pronounced in kidney transplant recipients with CAD, particularly in those with lower GFR. In kidney transplant recipients, markers of endothelial cell injury are significantly increased relative to healthy volunteers. Elevation of adiponectin may be a defense mechanism against endothelial damage, reflected by elevated CD146 and thrombomodulin.

The Hematocrit-Corrected Erythrocyte Sedimentation Rate Can Be Useful in Diagnosing Inflammation in Hemodialysis Patients

Background/Aims: We aimed to determine predictors of erythrocyte sedimentation rate (ESR), and the ESR level pointing to the presence of inflammation in 60 chronic hemodialysis (HD) patients. Methods/Results: On bivariate analysis, increased Westergren ESR of 62 (4–160) mm/h correlated inversely with hematocrit (Hct) and serum albumin, and positively with age, plasma fibrinogen, serum C-reactive protein (CRP), immunoglobulins A and G, α1-acid-glycoprotein and α1-antitrypsin. On multivariable analysis, independent predictors of the ESR were raised CRP (p < 0.0001), low Hct (p < 0.0001), increased fibrinogen (p < 0.0001) and immunoglobulin A (p = 0.009), and older age (p = 0.015). The Hct-corrected ESR level [ESR × (Hct/45)] of 38 (4–91) mm/h was independently predicted by CRP (p < 0.0001), fibrinogen (p < 0.0001), and age (p = 0.001). In the patients with normal CRP and albumin, the Hct-corrected ESR value was normal (23 mm/h) and lower than that of 59 mm/h in the subjects with elevated CRP and hypoalbuminemia. Using these cut-off points, the positive and negative predictive values of the Hct-corrected ESR on the presence of inflammation were 1.0, and its sensitivity and specificity were 100%. Conclusion: Increased Westergren ESR in HD patients is associated with activated acute-phase response, anemia, and aging. The Hct-corrected ESR values of 23 and 59 mm/h precisely select the HD patients with severe inflammation from those without.