Yalcin Solak

A Randomized Study of Allopurinol on Endothelial Function and Estimated Glomular Filtration Rate in Asymptomatic Hyperuricemic Subjects with Normal Renal Function

BACKGROUND AND OBJECTIVES Endothelial dysfunction is an early manifestation of vascular injury and contributes to the development of atherosclerotic cardiovascular disease. Recent studies have implicated hyperuricemia as a risk factor for cardiovascular disease. We hypothesized that lowering uric acid in subjects with asymptomatic hyperuricemia with allopurinol might improve endothelial dysfunction, BP, estimated GFR (eGFR), and inflammatory markers. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Subjects with asymptomatic hyperuricemia and no history of gout and 30 normouricemic control subjects were enrolled in this 4-month randomized prospective study. Thirty hyperuricemic patients received 300 mg/d allopurinol and were compared with 37 hyperuricemic patients and 30 normouricemic subjects in matched control groups. Flow-mediated dilation (FMD), eGFR, ambulatory BP monitoring, spot urine protein-creatine ratio, and highly sensitive C-reactive protein were measured at baseline and at 4 months. RESULTS Age, gender, lipid profile, eGFR, hemoglobin, glucose, and level of proteinuria were similar in hyperuricemic subjects and controls at baseline. As expected, hyperuricemic patients had higher levels of highly sensitive C-reactive protein and lower FMD compared with normouricemic patients. Allopurinol treatment resulted in a decrease in serum uric acid, a decrease in systolic BP, an increase in FMD, and an increase in eGFR compared with baseline. No significant difference was observed in the control hyperuricemic and normouricemic groups. In a multiple regression analysis, FMD levels were independently related to uric acid both before (beta = -0.55) and after (beta = -0.40) treatment. CONCLUSIONS Treatment of hyperuricemia with allopurinol improves endothelial dysfunction and eGFR in subjects with asymptomatic hyperuricemia.

Uric acid in metabolic syndrome: From an innocent bystander to a central player

Uric acid, once viewed as an inert metabolic end-product of purine metabolism, has been recently incriminated in a number of chronic disease states, including hypertension, metabolic syndrome, diabetes, non-alcoholic fatty liver disease, and chronic kidney disease. Several experimental and clinical studies support a role for uric acid as a contributory causal factor in these conditions. Here we discuss some of the major mechanisms linking uric acid to metabolic and cardiovascular diseases. At this time the key to understanding the importance of uric acid in these diseases will be the conduct of large clinical trials in which the effect of lowering uric acid on hard clinical outcomes is assessed. Elevated uric acid may turn out to be one of the more important remediable risk factors for metabolic and cardiovascular diseases.

Microvascular disease and its role in the brain and cardiovascular system: a potential role for uric acid as a cardiorenal toxin

Arteriolosclerosis (microvascular disease) may have a key role not only in driving salt-sensitive hypertension but also in mediating the development of chronic kidney disease, vascular dementia, stroke and coronary heart disease. In this paper, we review the evidence that these latter conditions result from the altered autoregulation that occurs when arterioles become diseased. We also discuss the increasing evidence that dietary intake of sugars rich in fructose may be driving the development of microvascular disease as a consequence of raising intracellular uric acid. We hypothesize that the treatment of microvascular disease may require a multifaceted approach by utilizing agents which aim at blocking of the renin-angiotensin system, reducing oxidative stress, stimulating endothelial nitric oxide production and lowering uric acid levels. Paradoxically, agents that only stimulate nitric oxide, such as oestrogens, may increase the risk of poor outcomes if microvascular disease is not reversed.

Blood neutrophil-to-lymphocyte ratio independently predicts survival in patients with liver cirrhosis.

Objectives Neutrophil-to-lymphocyte ratio (NLR) is a novel inflammation index that has been shown to independently predict poor clinical outcomes. We aimed to evaluate the role of NLR in the prediction of long-term mortality in patients with stable liver cirrhosis. Materials and methods This is a retrospective observational cohort study in which 145 stable cirrhotic patients without infection, hepatocellular carcinoma, and ongoing steroid therapy were enrolled between January 2009 and December 2011. The primary end point was survival during follow-up. NLR along with Child–Turcotte–Pugh (CTP), Model for End-Stage Liver Disease (MELD) scores, and Charlson comorbidity index were assessed for the prediction of mortality. Results There were 86 men and 59 women, mean age 58.9±13.4 years. The etiologies of liver cirrhosis included viral hepatitis (n=73), cryptogenic (50), alcoholic (12), and other (10). The mean follow-up duration was 27.8±6.8 months, during which 40 patients died. The mean NLRs were 2.08±0.99 and 4.39±3.0 in surviving and nonsurviving patients, respectively (P<0.001). Kaplan–Meier survival analysis was carried out according to the median NLR above and below 2.72. Patients with NLR of at least 2.72 had a significantly lower survival (log rank, P<0.001). NLR was found to be an independent predictor of mortality in all Cox Regression models (odds ratio 1.2; 95% confidence interval 1.2–1.3; P<0.001). Receiver operating characteristic analysis showed that cut-off values of 4.22, 3.07, and 2.96 for NLR predicted 12, 24, and 36-month mortality, respectively (AUC: 0.806, P=0.0029; 0.841, P<0.0001 and 0.783, P<0.0001, respectively). Conclusion NLR is a predictor of mortality independent of CTP and MELD scores in patients with liver cirrhosis. NLR could predict mortality in the subgroup of patients with low MELD scores as well.

Red cell distribution width is independently related to endothelial dysfunction in patients with chronic kidney disease.

Background:Red cell distribution width (RDW) is a measure of erythrocyte size variability and has been shown as an independent predictor of mortality. The aim of this article was to evaluate the association of RDW with endothelial dysfunction in patients with chronic kidney disease (CKD). Methods:Patients with 1 to 5 stages of CKD were included in the study. Endothelial function was assessed with flow-mediated dilatation (FMD). Estimated glomerular filtration rate (eGFR) and carotid intima media thickness (CIMT) were determined. Clinicodemographic characteristics, biochemical values, complete blood counts, ferritin, C-reactive protein (CRP) and cholesterol levels were recorded. Spearmans correlation was used to determine correlates of RDW. Multivariate linear regression model was used to assess independent associates of FMD. Results:Overall, 367 patients with CKD 1 to 5 were included in the study. RDW showed a significant increase from stage 1 to stage 5 CKD. Median RDW was 13.5. Patients with RDW values higher than median had significantly lower hemoglobin, eGFR and FMD values and higher CIMT and CRP values compared with patients who had RDW values below median. RDW showed a significant positive correlation with the presence of diabetes mellitus, CIMT and CRP, whereas a significant negative correlation with eGFR, ferritin and FMD. Multivariate analysis showed independent predictors of FMD as RDW, presence of diabetes, hemoglobin, eGFR, CRP, and serum albumin. Conclusions:Multivariate regression model revealed RDW as a significant predictor of FMD independent of major confounding factors, such as diabetes, inflammation, anemia and kidney function in CKD.

Pregabalin versus gabapentin in the treatment of neuropathic pruritus in maintenance haemodialysis patients: a prospective, crossover study.

Aim:  Pruritus is common in dialysis patients. Peripheral neuropathy is also prevalent in this patient population. However, the role of neuropathy in the genesis of uraemic itch has not been adequately studied to date. Therefore, we aimed to investigate the effects of gabapentin and pregabalin on uraemic pruritus along with neuropathic pain in patients receiving haemodialysis.

Mechanisms and consequences of salt sensitivity and dietary salt intake.

Purpose of reviewInvestigation into the underlying mechanisms of salt sensitivity has made important advances in recent years. This review examines in particular the effects of sodium and potassium on vascular function. Recent findingsSodium chloride (salt) intake promotes cutaneous lymphangiogenesis mediated through tissue macrophages and directly alters endothelial cell function, promoting increased production of transforming growth factor-β (TGF-β) and nitric oxide. In the setting of endothelial dysfunction, such as occurs with aging, diminished nitric oxide production exacerbates the vascular effects of TGF-β, promoting decreased arterial compliance and hypertension. Dietary potassium intake may serve as an important countervailing influence on the effects of salt in the vasculature. SummaryThere is growing appreciation that, independently of alterations in blood pressure, dietary intake of sodium and potassium promotes functional changes in the vasculature and lymphatic system. These changes may protect against development of salt-sensitive hypertension. While salt sensitivity cannot be ascribed exclusively to these factors, perturbation of these processes promotes hypertension during high-salt intake. These studies add to the list of genetic and environmental factors that are associated with salt sensitivity, but in particular provide insight into adaptive mechanisms during high salt intake.

The Relationship between Epicardial Adipose Tissue and Malnutrition, Inflammation, Atherosclerosis/Calcification Syndrome in ESRD Patients

BACKGROUND AND OBJECTIVES Malnutrition, inflammation, atherosclerosis/calcification (MIAC) and endothelial dysfunction are the most commonly encountered risk factors in the pathogenesis of cardiovascular disease in ESRD patients. Epicardial adipose tissue (EAT) is the true visceral fat depot of the heart. The relationship between CAD and EAT was shown in patients with high risk of coronary artery disease. In this study, we aimed to investigate the relationship between EAT and MIAC syndrome in ESRD patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Eighty ESRD patients and 27 healthy subjects enrolled in this cross-sectional study. EAT and coronary artery calcification score were measured by a multidetector computed tomography (MDCT) scanner. Patients with serum albumin <3.5 mg/dl were defined as patients with malnutrition; those with serum C-reactive protein level >10 ng/dl (normal range, 0-5 ng/dl) had inflammation; and those with CACS >10 had atheroscleosis/calcification. RESULTS Total CACS and EAT measurements were significantly higher in ESRD patients when compared with healthy subjects. There was a statistically significant relationship between EAT and CACS in ESRD patients (r = 0.48). EAT measurements were higher in PD patients than HD patients. Twenty-four of the patients had no component, 31 had one component, 17 had two components, and nine had all of the MIAC components. EAT was found to be significantly increased when the presence of MIAC components increased. EAT was positively correlated with age, body mass index, and presence of MIAC. These parameters were also found as independent predictors of increased EAT. CONCLUSIONS We found a relationship between EAT and components of MIAC syndrome in ESRD patients.

Serum uric acid independently predicts cardiovascular events in advanced nephropathy.

Background: Chronic kidney disease (CKD) is associated with increased risk for cardiovascular (CV) disease and is also associated with elevated uric acid, which is emerging as a nontraditional CV risk factor. We therefore evaluated uric acid as a risk factor for CV disease in subjects presenting to nephrologists with CKD who were not on medications known to alter endothelial function. Methods: 303 subjects with stage 3–5 CKD were followed for a mean of 39 months (range 6–46) and assessed for fatal and nonfatal CV events. Hyperuricemia was defined as uric acid >6.0 mg/dl for women and >7.0 mg/dl for men. In addition to other CV risk factors, endothelial function (flow-mediated dilatation), inflammatory markers (hsCRP), and insulin resistance (HOMA index and fasting insulin levels) were included in the analysis. We evaluated the association between uric acid and flow-mediated dilatation with linear regression. The impact of uric acid on composite CV events was assessed with Cox regression analysis. Results: Of a total of 303 patients, 89 had normouricemia and 214 had hyperuricemia. Both fatal (32 of 214 vs. 1 of 89 subjects) and combined fatal and nonfatal (100 of 214 vs. 13 of 89 subjects) CV events were more common in subjects with hyperuricemia compared with normal uric acid levels, and this was independent of estimated glomerular filtration rate, traditional CV risk factors including diabetes, hypertension and BMI, and nontraditional risk factors (hsCRP and endothelial function). The 46-month survival rate was 98.7% in the group with low uric acid compared to 85.8% in patients with high uric acid (p = 0.002). Conclusions: Hyperuricemia is an independent risk factor for CV events in subjects presenting with CKD who are not on medications known to alter endothelial function.

Hypertension as an autoimmune and inflammatory disease

Hypertension that is considered idiopathic is called essential hypertension and accordingly has no clear culprit for its cause. However, basic research and clinical studies in recent years have expanded our understanding of the mechanisms underlying the development of essential hypertension. Of these, increased oxidative stress, both in the kidney and arterial wall, closely coupled with inflammatory infiltration now appear to have a prominent role. Discovery of regulatory and interleukin-17-producing T cells has enabled us to better understand the mechanism by which inflammation and autoimmunity, or autoinflammation, lead to the development of hypertension. Despite achieving considerable progress, the intricate interactions between oxidative stress, the immune system and the development of hypertension remain to be fully elucidated. In this review, we summarize recent developments in the pathophysiology of hypertension with a focus on the oxidant stress–autoimmunity–inflammation interaction.