Battal Altun

Vascular health, systemic inflammation and progressive reduction in kidney function; clinical determinants and impact on cardiovascular outcomes

INTRODUCTION Systemic inflammation, endothelial dysfunction and arterial thickening contribute to the elevated cardiovascular risk of dialysis patients. However, the course of these derangements and their relative contribution to the cardiovascular risk of nondialysed chronic kidney disease (CKD) are scarcely investigated. METHODS Flow-mediated dilatation (FMD) and intima-media thickness (IMT) were assessed in 304 nondialysed CKD patients Stages 1-5 (mean age 46 ± 12 years, 158 men), together with routine biochemical measurements, C-reactive protein (CRP) and insulin resistance. Patients were then followed for time-to-event analysis of cardiovascular outcomes (fatal and nonfatal). RESULTS CRP and IMT increased, while FMD decreased in parallel with estimated glomerular filtration rate (eGFR) decline (P < 0.001 for all). CRP and intact parathormone, as well as eGFR, appeared as strong determinants of FMD and IMT in multivariate analyses. After a median follow-up of 41 (range 6-46) months, 30 fatal and 59 nonfatal cardiovascular events occurred. In univariate analysis, FMD, IMT and CRP were significant predictors of outcome. In a multivariate Cox model excluding IMT, both FMD [hazard ratios 0.52 (95% confidence intervals 0.37-0.73) per %] and CRP [1.07 (1.03-1.11) per mg/L] predicted cardiovascular outcomes independently of confounders. In a model excluding FMD, only CRP (and not IMT) was a significant predictor. CONCLUSIONS Endothelial dysfunction, arterial thickening and inflammation occur in parallel with the decline in eGFR, contributing to the increased cardiovascular risk of nondialysed CKD. Our results support the use of FMD over IMT measurements to monitor nondialysed CKD patients at risk.

Soluble TWEAK and PTX3 in nondialysis CKD patients: impact on endothelial dysfunction and cardiovascular outcomes.

BACKGROUND AND OBJECTIVES Chronic kidney disease (CKD) conveys high mortality rates. Soluble TNF-like weak inducer of apoptosis (sTWEAK) and long pentraxin 3 (PTX3) are predictors of mortality in dialysis patients and determinants of endothelial dysfunction. Now, we hypothesize that both sTWEAK and PTX3 act as biomarkers of cardiovascular outcomes in nondialysis CKD patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Cross-sectional analysis in which flow-mediated dilation (FMD) and intima-media thickness (IMT) were assessed in 257 nondialysis stage 1 to 5 CKD patients (mean age, 52 ± 12 years; 130 men), together with biochemical measurements and sTWEAK and PTX3 assessments. Patients were followed for cardiovascular outcomes. RESULTS PTX3 and IMT increased, whereas FMD and sTWEAK decreased across CKD stages (P<0.001 for all). Both PTX3 and sTWEAK appeared as strong determinants of FMD in multivariate analysis. The univariate associations of sTWEAK and PTX3 with IMT were dependent on estimated GFR. After a median of 39 months (range, 2 to 43 months), 22 fatal and 57 nonfatal cardiovascular events occurred. In a Cox model excluding PTX3, decreasing sTWEAK concentration was associated with increased risk of cardiovascular events independently of basic confounders (age, gender, estimated GFR, C reactive protein, diabetes, and cardiovascular comorbidity) and FMD. In a model excluding sTWEAK, circulating levels of PTX3 were directly associated with cardiovascular outcomes independently of basic confounders, but this association was lost after adjustment for FMD. CONCLUSIONS Both PTX3 and sTWEAK levels associated with the endothelial dysfunction observed with progressive kidney failure. Additionally, both biomarkers impacted the predictability of cardiovascular outcomes.

The Relationship Between Some of the Cardiovascular Risk Factors and Arterial Stiffness Parameters in Essentially Hypertensive Patients

Hypertensive patients have strong evidence of endothelial dysfunction. We aimed to explore the relationships between cardiovascular risk factors and arterial stiffness parameters in hypertensive patients. The study population included 109 hypertensive patients (63 females, 46 males). Arterial stiffness measures including pulse wave velocity, augmentation index, and central aortic pressure were applied. Augmentation index and central aortic pressure were found to be significantly higher (P < .001 and P = .03, respectively) in women. The higher augmentation index and central aortic pressure values were observed in women than in men. These data offer new evidences for the role of sex hormones in the pathogenesis of atherosclerosis in women.

Asymmetric Dimethylarginine and Augmentation Index in Newly Diagnosed Patients With Hypertension

Pulse wave velocity (PWV), augmentation index (Aix), and central aortic pressure (CAP) are arterial stiffness markers of endothelial dysfunction (ED). We investigated the relationship between arterial stiffness parameters and asymmetric dimethylarginine (ADMA; a marker of ED), in newly diagnosed patients with hypertension (n = 101; 61 females). These patients were investigated in accordance with the recommendations of hypertension guidelines. Arterial stiffness was measured, and serum ADMA and C-reactive protein (CRP; a marker of inflammation) levels were determined. In both women and men, there was no difference in terms of age, body mass index, systolic and diastolic blood pressures, PWV, CAP and the levels of ADMA, while Aix and CRP levels were significantly higher in women (P = .004, P = .046, respectively). In the whole group, ADMA levels correlated with Aix (Pearson r = .237, P = .024). Our findings provide further evidence of a link between arterial stiffness and ED in newly diagnosed patients with hypertension.

Serum gamma-glutamyltransferase (GGT) should be evaluated together with other inflammatory markers in clinical practice.

We read the article ‘‘Association of Serum GammaGlutamyltransferase With Arterial Stiffness in Established Coronary Artery Disease’’ written by Zhu et al with interest. The authors concluded that serum g-glutamyltransferase (GGT) activity is independently associated with increased arterial stiffness measured by brachial-ankle pulse wave velocity in both males and females with established coronary artery disease (CAD). We believe that these findings will act as a guide for further studies that will assess arterial stiffness as a surrogate marker of endothelial dysfunction and its relationship with serum markers. Arterial stiffness indicates the viscoelastic properties of the vessel wall. It occurs as a result of atherosclerotic risk factors such as hypertension, diabetes mellitus, smoking, hypercholesterolemia, or due to older age. Increased arterial stiffness is a common indicator of atherosclerotic involvement of the vascular structure indicating CAD, cerebrovascular disease, and peripheral arterial disease. It is a noninvasive method to assess endothelial dysfunction in clinical practice. g-Glutamyltransferase (GGT) is a widely measured serum enzyme and almost specifically shows biliary epithelial damage and generally excessive alcohol intake. g-Glutamyltransferase is released from many tissues such as liver, kidney, cerebrovascular endothelium, pericytes, and, as mentioned in the article, thrombocytes at the sites of atheromatous plaques. Later, it has been investigated as a marker of inflammation. It has been reported that GGT reduces Fe3þ to its bivalent form and oxidizes low-density lipoprotein in the extracellular space. A raised serum GGT activity in a patient leads us to think of a problem with biliary epithelium, cholestasis, or excessive alcohol usage. g-Glutamyltransferase itself without other inflammatory markers may not provide information to clinicians about the endothelial inflammation. So, we think that it should be evaluated together with other serum inflammatory markers. A second challenge is that further studies are needed to define the role of GGT as an inflammatory marker and its association with arterial stiffness in both healthy participants and patients with atherosclerotic disease. Finally, alcohol consumption is a leading cause of serum GGT elevation, as mentioned in the limitations of the study. Therefore, it might be useful if the authors provided information about their patients’ alcohol consumption.

Pentraxin 3 Is a Predictor for Fibrosis and Arterial Stiffness in Patients with Nonalcoholic Fatty Liver Disease

Objective. The aim of the present study was to investigate whether pentraxin 3 (PTX3) can be a new noninvasive marker for prediction of liver fibrosis in patients with NAFLD. We also aimed to evaluate the relationship between PTX3 and atherosclerosis in patients with NAFLD. Method. Fifty-four male patients with biopsy-proven NAFLD and 20 apparently healthy male volunteers were included. PTX3 levels were determined, using an ELISA method (R&D Sysytems, Quantikine ELISA, USA). To detect the presence of subclinical atherosclerosis in NAFLD, measurements of CIMT, FMD, and cf-PWV levels were performed. Results. PTX3 levels in NAFLD patients with fibrosis were higher than both NAFLD patients without fibrosis and controls (P = 0.032 and P = 0.028, respectively), but there was no difference between controls and NAFLD patients without fibrosis in terms of PTX3 levels (P = 0.903). PTX3 levels were strongly correlated with cf-PWV (r = 0.359, P = 0.003), whereas no significant correlation was found with other atherosclerosis markers, CIMT and FMD. Conclusion. Elevated plasma PTX3 levels are associated with the presence of fibrosis in patients with NAFLD, independently of metabolic syndrome components. This study demonstrated that for the first time there is a close association between elevated PTX3 levels and increased arterial stiffness in patients with NAFLD.

Arterial Stiffness Without Other Inflammatory Markers May Not Accurately Provide Information to Clinicians About the Severity of Psoriasis

We read the article ‘‘Aortic Arterial Stiffness is a Moderate Predictor of Cardiovascular Disease in Patient with Psoriasis Vulgaris’’ by Balta et al with interest. This well-presented study investigated the relationship between arterial stiffness and high-sensitivity CRP (hsCRP) in patients with psoriasis. The authors concluded that arterial stiffness correlated positively with age, sex, body mass index, diastolic blood pressure, and hsCRP level. These findings provide further evidence of a link between premature atherosclerosis and psoriasis. Arterial stiffness represents vascular damage and is a measure of the degree of atherosclerosis. Arterial stiffness has received increased attention because of its role as an independent predictor of cardiovascular disease and relationship to the metabolic syndrome. Increased arterial stiffness is a common indicator of atherosclerotic involvement of the vascular structure, indicating cardiovascular diseases, stroke and renal diseases, as well as total mortality. It can also be affected by atherosclerotic risk factors such as smoking, alcohol consumption, hypercholesterolemia, hypothyroidism, plasma homocysteine, and serum gamma-glutamyltransferase (GGT). Furthermore, in recent studies, plasma homocysteine concentrations were found to be significantly higher in patients with psoriasis. In this point of view, in the present study, the authors did not mention about some of the factors affecting arterial stiffness, including alcohol consumption, hypothyroidism, plasma homocysteine, and serum GGT levels. If the authors had described these factors, they would have obtained different results. More severe psoriasis was significantly associated with higher prevalence of concomitant disease, greater involvement (nails, scalp, palm soles), and poorer quality of life. Severe psoriasis is also associated with increased risk of cardiovascular mortality and morbidity due, in part, to shared immune–inflammatory mechanisms. In our opinion, it would have been better if the authors of the present study had included information about disease severity (mild, moderate, or severe), mean Psoriasis Area and Severity Index, and presence of psoriatic arthritis. In conclusion, arterial stiffness was shown as a noninvasive method to assess endothelial dysfunction in clinical practice, which is affected by many factors. Arterial stiffness itself without other inflammatory markers may not provide information to the clinicians about the endothelial inflammation on psoriasis. So we believe that it should be evaluated together with other serum biochemical markers.

Neutrophil-to-lymphocyte ratio for predicting fibrosis in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is not only associated with liver-related mortality and morbidity, but also is linked to an increased cardiovascular disease risk, on the basis of rapidly expanding evidence [1]. Several clinical studies have reported that the neutrophil-tolymphocyte ratio (NLR) is an independent marker of cardiovascular disease-related mortality in the general population and in patients who have cardiovascular risk factors [2]. Recently, we read with great interest the article by Kara et al. [3], evaluating the role of NLR in predicting the liver histology in patients with NAFLD. They reported that NLR is not associated with the severity of liver histology in this large-scale study and suggested that NLR cannot be used as an indicator of liver injury in patients with NAFLD. The results seem important with regard to the relationship between NLR and liver histology. However, we believe that some points should be addressed. The authors did not include patients without cardiovascular risk factors such as diabetes mellitus and hypertension in this study. However, the presence of hyperglycemia was excluded only on the basis of fasting plasma glucose levels, and standard oral glucose tolerance tests (OGTTs) were not performed. OGTT has been accepted as the gold-standard method for the diagnosis of diabetes mellitus and impaired glucose tolerance. Therefore, OGTT would be more appropriate to clarify glucose tolerance in the patients. In addition, there were no data on blood pressure levels. It is well known that NLR is associated independently with different levels of glucose tolerance and blood pressure [4]. In the present study, the authors aimed to investigate the relationship between NLR and liver histology as a predictor of the presence of chronic subclinical inflammation in biopsy-proven NAFLD. C-reactive protein (CRP) has been identified as an independent marker of liver fibrosis in NAFLD and has been shown to be associated with NLR in recent studies [5]. However, levels of CRP and other inflammatory markers were not measured in this study. The use of other inflammatory markers such as CRP and erythrocyte sedimentation rate may accurately support the relationship between histologic findings and NLR in NAFLD. Moreover, healthy individuals were not included for comparison with the patient group in this study. We think that the presence of a control group would increase the reliability of the results of this study. NLR is a cheap and easy-to-reach parameter to show inflammation. However, there can be small but important differences in each measurement in the parameters of complete blood count. The parameter levels can vary even if we measure the same sample again. We believe that taking an average of two to three complete blood count measurements could be better for the study. Consequently, excluding these confounding factors before making certain interpretations would reveal any independent association between NLR and liver injury more accurately and provide the readers of the journal clearer information.

The relationship between microalbuminuria, left ventricular hypertrophy, retinopathy, and sex hormone status in newly diagnosed hypertensive women.

An increased incidence of hypertension (HT) in postmenopausal female population has been shown in previous studies and this has been ascribed to an association with altered status of estrogen (E2) and other female sex hormones. Hypertension is associated with certain target organ damage (TOD) and related clinical conditions. The aim of this study was to determine the relationship between microalbuminuria, left ventricular hypertrophy (LVH), retinopathy, and sex hormone status in newly diagnosed hypertensive women. A total of 66 hypertensive women (39 postmenopausal and 27 premenopausal) were included in the study. Along with the tests recommended in the HT guidelines, LVH, hypertensive retinopathy, and microalbuminuria were investigated in all the patients. Sex hormones (follicle stimulating hormone, luteinizing hormone, progesterone, and E2) of the patients were also measured. The results show that there was no statistically significant difference between the two groups in regard to TOD except microalbuminuria. The frequency of microalbuminuria in premenopausal group patients was higher than that of the postmenopausal group patients (P = .038). This study suggests that TOD caused by HT is a very important health problem, seeming to be related with female sex hormones.

Amlodipine seems to be superior to valsartan in decreasing microalbuminuria in newly diagnosed hypertensive patients: a novel effect to be explained with hyperfiltration?

Background: Microalbuminuria (MA) is common in hypertensive population and is a marker for endothelial dysfunction and a predictor of increased cardiovascular risk. A great body of data shows the importance of MA as a strong predictor of renal and cardiovascular disease (CVD) risk in hypertensive population. Aim: In this study, we aimed to compare the anti-albuminuric effects of an angiotensin II receptor antagonist, valsartan, with a calcium channel blocker, amlodipine, in newly diagnosed hypertensive patients. Material and methods: Totally, 20 patients were recruited into the study. Patients were randomized to one of the following intervention protocols: An (a) angiotensin II receptor blocker (valsartan, 80–320 mg/day) or (b) calcium channel blocker (amlodipine, 5–10 mg/day), for 12 weeks immediately after baseline measurements. Ten patients were randomized into valsartan group and 10 patients into the amlodipine group. Twenty-four-hour urinary albumin excretion (UAE) levels of the patient groups were measured before treatment and on the 12th week. Results: Patients of the two groups were matched for age and body mass index. In the amlodipine group, baseline urine microalbumin levels were higher compared to valsartan group, although the difference was not statistically significant (p = 0.082). At the 12th week, there was a significant decrease in urine microalbumin levels in the amlodipine group, but no significant change was observed in the valsartan group. Conclusion: Amlodipine seems to be superior to valsartan in decreasing UAE. To reduce cardiovascular risks, endothelial dysfunction, and microinflammation, these factors are taken into consideration while prescribing antihypertensive drugs in hypertensive patients.