The association of profilin-1 levels with survival in chronic kidney disease.

BACKGROUND: Profilin-1 is a ubiquitous, actin-binding protein that plays an important role in the regulation of actin polymerization and cytoskeleton remodelling and contributes to vascular dysfunction. We conducted this study to investigate the association of serum profilin-1 levels with fatal and nonfatal CVE in a cohort of patients with stage 1-5 CKD. MATERIALS AND METHODS: Serum concentrations of profilin-1 levels were determined by enzyme-linked immunosorbent assay. Endothelium-dependent vasodilatation (flow-mediated dilatation [FMD]) and endothelium-independent vasodilatation (nitroglycerine-mediated dilatation [NMD]) of the brachial artery were assessed noninvasively, using high-resolution ultrasound. RESULTS: Both fatal and nonfatal CVE were significantly higher in patients with high profilin-1 levels. Kaplan-Meier survival curves showed that patients with profilin-1 below the median value (114 pg/mL) had higher cumulative survival compared with patients who had profilin-1 levels above the median value (log-rank test, P < .001). CONCLUSIONS: This is the first study that demonstrates the serum profilin-1 is independently associated with endothelial dysfunction, cardiovascular events and survival in patients with CKD.

MicroRNA-125b as a new potential biomarker on diagnosis of renal ischemia-reperfusion injury.

BACKGROUND: Acute renal failure is commonly seen in the perioperative period. Ischemia-reperfusion (IR) injury plays a major role in acute renal failure and delayed graft function. MicroRNAs (miRs), which are pivotal modulators of cell activities, offer a major opportunity for affective diagnosis and treatment strategies because they are tissue specific and in the center of gene expression modulation. The effect of bardoxolone methyl (BM) on miR-21, miR-223-5p, and miR-125b in renal IR injury was evaluated in this study. METHODS: Wistar-Albino rats (12-16 wk old, weighing 300-350 g) were used in the study. Rats (n = 6) were randomized into three groups (control, IR, and BM + IR). Tissue levels of miRs were analyzed with reverse transcription polymerase chain reaction. RESULTS: Significant reduction of urea and total oxidant status, increase of total antioxidant status, and oxidative stress index were identified in the IR + BM group compared with the IR group. Significant increases of miR-21 (2842.82-fold) and miR-125b (536.8-fold) were identified in the IR group compared with the control group; however, miR-223-5p levels did not show any significant difference. Also, miR-21 and miR-125b were significantly reduced in the IR + BM group compared with the IR group. Reduced histopathologic changes were observed in the IR + BM group. A significant decrease in the number of tunel-positive cells was identified in the IR + BM group compared with the IR group. CONCLUSIONS: miR-125b was significantly increased in IR injury; thus, miR-125b can be a potential novel marker that can be used in diagnosis and treatment of renal IR injury. BM reduces miR-21 and miR-125b in case of IR injury and makes functional and histopathologic repairs.

Relationship between Fragmented QRS Complex and Aortic Stiffness in Chronic Hemodialysis Patients.

OBJECTIVE: This study aimed to evaluate the correlation between fragmented QRS complex (fQRS), aortic stiffness, and diastolic dysfunction in hemodialysis patients. SUBJECTS AND METHODS: A sample of 56 patients who received hemodialysis treatment was stratified into 2 groups according to their electrocardiography (ECG) patterns with or without fQRS. Baseline characteristics and laboratory parameters of patients were documented. Conventional echocardiographic and Doppler echocardiographic procedures were performed in all patients. The mean early (Em) diastolic and late (Am) diastolic myocardial velocities were calculated. These tests were performed before dialysis. The Student t test, Mann-Whitney U test, χ2 test, Spearman correlation, and multivariate linear regression analysis were used to analyze parameters where appropriate. RESULTS: Of the 56 patients under hemodialysis, fQRS in ECG was detected in 26 (46.4%). Echocardiographic evaluation showed that deceleration time (237.57 ± 40.10 ms; p = 0.030), isovolumic relaxation time (126.84 ± 15.62 ms; p < 0.001), early (E)/late (A) ventricular filling velocity (E/A) ratio (1.15 ± 0.40; p ≤ 0.001), and aortic stiffness index value (9.62 ± 4.53; p = 0.016) exhibited a statistical increase in hemodialysis patients with fQRS compared to patients without fQRS. E (58.23 ± 19.96 m/s; p = 0.004), and Em (5.96 ± 2.08 cm/s; p = 0.023) velocity levels were significantly lower in hemodialysis patients with fQRS than patients without fQRS. Aortic stiffness closely correlated with diastolic dysfunction (deceleration time r = 0.273, p = 0.042; isovolumic relaxation time r = 0.497, p < 0.001; E/A ratio r = -0.449, p = 0.001). On multivariate linear regression analysis, fQRS and aortic stiffness were independently associated in hemodialysis patients (ß = 0.321, p = 0.049). CONCLUSIONS: Increased aortic stiffness and left ventricular systolic dysfunction were observed more frequently in hemodialysis patients with fQRS than in patients without fQRS. fQRS is an important determinant of aortic stiffness in hemodialysis patients.

The Prevalence of Fabry Disease in Patients with Chronic Kidney Disease in Turkey: The TURKFAB Study.

BACKGROUND/AIMS: Fabry disease is a treatable cause of chronic kidney disease (CKD) characterized by a genetic deficiency of α-galactosidase A. European Renal Best Practice (ERBP) recommends screening for Fabry disease in CKD patients. However, this is based on expert opinion and there are no reports of the prevalence of Fabry disease in stage 1-5 CKD. Hence, we investigated the prevalence of Fabry disease in CKD patients not receiving renal replacement therapy. METHODS: This prospective study assessed α-galactosidase activity in dried blood spots in 313 stage 1-5 CKD patients, 167 males, between ages of 18-70 years whose etiology of CKD was unknown and were not receiving renal replacement therapy. The diagnosis was confirmed by GLA gene mutation analysis. RESULTS: Three (all males) of 313 CKD patients (0.95%) were diagnosed of Fabry disease, for a prevalence in males of 1.80%. Family screening identified 8 aditional Fabry patients with CKD. Of a total of 11 Fabry patients, 7 were male and started enzyme replacement therapy and 4 were female. The most frequent manifestations in male patients were fatigue (100%), tinnitus, vertigo, acroparesthesia, hypohidrosis, cornea verticillata and angiokeratoma (all 85%), heat intolerance (71%), and abdominal pain (57%). The most frequent manifestations in female patients were fatigue and cornea verticillata (50%), and tinnitus, vertigo and angiokeratoma (25%). Three patients had severe episodic abdominal pain attacks and proteinuria, and were misdiagnosed as familial Mediterranean fever. CONCLUSIONS: The prevalence of Fabry disease in selected CKD patients is in the range found among renal replacement therapy patients, but the disease is diagnosed at an earlier, treatable stage. These data support the ERBP recommendation to screen for Fabry disease in patients with CKD of unknown origin.

Apoptosis, autophagy & endoplasmic reticulum stress in diabetes mellitus.

The prevalence of diabetes mellitus (DM) is increasing secondary to increased consumption of food and decreased physical activity worldwide. Hyperglycaemia, insulin resistance and hypertrophy of pancreatic beta cells occur in the early phase of diabetes. However, with the progression of diabetes, dysfunction and loss of beta cells occur in both types 1 and 2 DM. Programmed cell death also named apoptosis is found to be associated with diabetes, and apoptosis of beta cells might be the main mechanism of relative insulin deficiency in DM. Autophagic cell death and apoptosis are not entirely distinct programmed cell death mechanisms and share many of the regulator proteins. These processes can occur in both physiologic and pathologic conditions including DM. Besides these two important pathways, endoplasmic reticulum (ER) also acts as a cell sensor to monitor and maintain cellular homeostasis. ER stress has been found to be associated with autophagy and apoptosis. This review was aimed to describe the interactions between apoptosis, autophagy and ER stress pathways in DM.

Micro RNA-320 as a novel potential biomarker in renal ischemia reperfusion.

AIM: MicroRNAs (miR) are important diagnostic and treatment targets due to their different tissue expressions and their central position in the regulation of gene expressions. miR studies might pioneer emerging of new diagnostic tools and treatment goals in kidney diseases. Captopril (CAP) and telmisartan (TEL) were shown to be effective in ischemia reperfusion (IR) injury. There is not any study about the effect of TEL and CAP over miR-21-320-146a. Our aim was to study the effects of CAP and TEL over miR on renal IR model. METHODS: We used 12-16 weeks-old Wistar-Albino rats that weigh 300-350 g. Rats (n, 6) were randomized into four groups (Control, IR, IR + CAP, IR + TEL). Urea, creatinine, total antioxidant status (TAS), total oxidant status (TOS), oxidative stress index (OSI), super oxide dismutase (SOD), and miRs were analyzed. RESULTS: Urea, creatinine, TOS, OSI levels of IR + CAP, and IR + TEL groups were lower comparing to IR group. TAS and SOD levels were higher in IR group than IR + TEL group. miR-21-320-146a showed increase in renal IR injury. miR-320, 146a showed significant decrease in IR + CAP and IR + TEL groups comparing to IR group. We showed histopathological recovery and decreased apoptosis in IR + CAP and IR + T groups than IR group. CONCLUSION: We, for the first time in the literature, showed that miR-320 is increased in IR injury. miR-320 might be a novel diagnosis and treatment target in renal ischemic reperfusion injury. Also, for the first time, we showed that CAP and TEL cause functional and histopathological recovery and lower miR-146a and miR-320.

The effects of grape seed on apoptosis-related gene expression and oxidative stress in streptozotocin-induced diabetic rats.

BACKGROUND: Diabetic nephropathy is the most common cause of end-stage renal disease. Emerging evidences indicate that many mechanistic pathways including apoptosis play an important role in the pathogenesis and progression of macrovascular and microvascular complications of diabetes mellitus. The aim of the present study is to show the effects of grape seed extract (GSE) on oxidative stress and apoptosis in the kidney of streptozotocin-induced diabetic rats. MATERIALS AND METHODS: The study included control group, diabetic group without treatment and diabetic group treated with GSE (n=7) group. GSE was given orally (100 mg/kg/day) for six weeks. Following parameters were evaluated; oxidative stress index, caspase 1, IL1-alpha, caspase 2, IL1-beta, BCL2-associated agonist of cell death (BAD), X-linked inhibitor of apoptosis (XIAP), DNA fragmentation factor, alpha subunit and beta bubunit (DFFA, DFFB), BH3 interacting domain death agonist (BID), caspase 6, Bcl2-like 1 (BCL-XL), caspase 8, tumor necrosis factor receptor superfamily, member 1 b (TNFRSF1B) and IAP-binding mitochondrial protein (DIABLO). RESULTS: Oxidative stress index levels were significantly increased in the kidney of diabetic group without treatment compared to control group, and decreased in diabetic+GSE group compared to diabetic group without treatment. In the kidney of diabetic group without treatment, caspase 1, IL-1 alpha, BAD, DFFA, DFFB and caspase-6 gene expressions were significantly higher compared to control group. In diabetic+GSE group caspase 1, caspase 2, XIAP, DFFA, BID, BCL-XL and TNFRSF1B genes were significantly decreased compared to control group. CONCLUSIONS: Grape seed reduces oxidative stress and apoptosis gene expression suggesting the protective effect on diabetic nephropathy.

Chitotriosidase as a novel biomarker of early atherosclerosis in hemodialysis patients.

INTRODUCTION: Increasing evidence suggests that inflammation and increased macrophage activity have a central role in pathogenesis of atherosclerosis. It is shown that chitotriosidase (CHIT-1) is a marker of macrophage activity in atherosclerotic plaque, and is found associated with severity of atherosclerotic lesion. There is no data about CHIT-1 activity of hemodialysis patients in the literature. Thus, we hypothesized that in hemodialysis patients, CHIT-1 levels might be a novel biomarker in early atherosclerosis. METHODS: Forty-five hemodialysis patients were included in the study (age: 61.93 ± 13.34). Intima media thickness (IMT) was evaluated with high-resolution B-mode ultrasonography. Biomarker levels were measured in serum of patients. FINDINGS: We found positive correlation among IMT, age (R: 0.426, P: 0.004) and, CHIT-1 value (R: 0.462, P: 0.001) in spearman correlation analysis. When age, CRP, creatinine, P, Alb, CHIT-1 were chosen as measures that can effect IMT in multiple regression model, IMT level was related with CHIT-1 (Beta: 0,396, P: 0.012) and age (Beta: 0,313 P: 0,048) independently. DISCUSSION: In conclusion, this is the first report showing that serum CHIT-1 level was related independently with carotid IMT in hemodialysis patients. This biomarker might have an unknown role in the development of atherosclerosis during uremia.

IL-33 and ST2 levels in chronic kidney disease: Associations with inflammation, vascular abnormalities, cardiovascular events, and survival.

OBJECTIVE: Increased inflammation, associated with the increase in chronic kidney disease (CKD) stage, has a very important influence in vascular injury and cardiovascular diseases. In this study, we aimed to investigate the levels of IL-33 and ST2 in the different stages of CKD and to determine their effect on vascular damage and cardiovascular events (CVE). METHODS: This was an observational cohort study in which serum IL-33 and ST2 were obtained from 238 CKD (stages 1-5) patients. We examined the changes in IL-33/ST2 levels in CKD patients, as well as the association with a surrogate of endothelial dysfunction. Fatal and non-fatal CVE were recorded for a mean of 24 months. We also performed a COX regression analysis to determine the association of IL-33/ST2 levels with CVE and survival. RESULTS: IL-33 and ST2 levels were significantly increased and estimated glomerular filtration rates (eGFR) were decreased. Flow-mediated dilatation (FMD) was significantly decreased from stage 1 to stage 5 CKD. IL-33 and ST2 levels were associated with FMD, and ST2 was a predictor. Multivariate Cox analysis showed that the presence of diabetes mellitus, smoking, and proteinuria and haemoglobin, Hs-CRP, IL-33, and ST2 were associated with the risk of CVE. Kaplan-Meier survival curves showed that patients with IL-33 and ST2 levels below the median value (IL-33 = 132.6 ng/L, ST2 = 382.9 pg/mL) had a higher cumulative survival compared with patients who had IL-33 and ST2 levels above the median value (log-rank test, p = 0.000). CONCLUSION: This is the first study that demonstrates that serum IL-33 and ST2 are associated with vascular injury, cardiovascular events, and survival in CKD patients.

Relationship of serum interleukin-6 and tumor necrosis factor alpha levels with abdominal fat distribution evaluated by ultrasonography in overweight or obese postmenopausal women.

BACKGROUND: The objective of this study was to measure associations of circulating interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) levels with anthropometric and abdominal fat distribution in overweight or obese postmenopausal women. METHODS: One hundred eight overweight or obese postmenopausal were evaluated. Demographic and anthropometric measurements were done. Serum IL-6, TNF-alpha, glucose, and insulin levels were measured. Insulin resistance was calculated by using homeostasis model assessment-insulin resistance (HOMA-IR). The assessment of abdominal fat distribution was performed by ultrasonography. Statistical analysis was made with Pearson and partial correlation analysis. RESULTS: There was a positive correlation between serum IL-6 and TNF-alpha (r = .19; p = .047). IL-6 was positively correlated with body mass index (BMI) (r = .43; p = .0001), waist circumference (r = .41; p = .0001), and visceral fat layer (r = .33; p = .0001) measurements and HOMA-IR index (r = .31, p = .001). A positive relationship between HOMA-IR and visceral fat layer thickness was observed (r = .320; p = .0001). TNF-alpha was positively associated with BMI but not with any measures of central obesity. When adjustment for BMI was performed, there were no significant relationships between the studied parameters. CONCLUSIONS: There are no significant correlations between abdominal fat distributions measured by ultrasonography and circulating IL-6 and TNF-alpha levels. BMI may have a stronger association with circulating inflammatory cytokine concentrations than with different measures of central obesity in overweight or obese postmenopausal women.

Increased Mean Platelet Volume in Familial Hypercholesterolemia.

Familial hypercholesterolemia (FH) is a genetic disorder of lipoprotein metabolism and increases the risk of premature cardiovascular diseases. In patients with FH, platelet function may be activated; however, the extent of this activation and its etiology are unclear. We aimed to evaluate the mean platelet volume (MPV), a marker of platelet activation, in patients with FH. The study group consisted of 164 patients with FH and 160 control patients. Controls were matched for age, gender, hypertension, and smoking. The MPV was significantly higher in patients with FH than in controls (9.2 ± 0.4 vs 7.9 ± 0.6 fL, respectively; P < .001). Platelet count was significantly lower among patients with FH when compared to control patients (259 ± 51 vs 272 ± 56 × 10(3)/L, respectively; P = .03). In linear regression analysis, MPV was independently associated only with total cholesterol (ß = .6, 95% confidence interval: 0.004-0.008, P < .001). We have shown that MPV was increased in patients with FH and that it was independently associated with total cholesterol level.

The effects of ozone therapy on caspase pathways, TNF-α, and HIF-1α in diabetic nephropathy.

BACKGROUND: Accelerated apoptosis plays a vital role in the development of diabetic vascular complications. Ozone may attenuate diabetic nephropathy by means of decreased apoptosis-related genes. The aim of our study was to investigate the effect of ozone therapy on streptozotocin-induced diabetic nephropathy in rats. Also the histopathological changes in diabetic kidney tissue with ozone treatment were evaluated. METHODS: The rats were randomly divided into six groups (n = 7): control (C), ozone (O), diabetic (D), ozone-treated diabetic (DO), insulin-treated diabetic (DI), and ozone- and insulin-treated diabetic (DOI). D, DI, and DOI groups were induced by a single intraperitoneal injection of streptozotocin. Ozone was given to the O, DO, and DOI groups. Group DI and DOI received subcutaneous (SC) insulin (3 IU). All animals received daily treatment for 6 weeks. RESULTS: Expressions of caspase-1-3-9, HIF-1α, and TNF-α genes were significantly higher in D group compared to C group (p < 0.05 for all). Ozone treatment resulted in significant decrease in the expressions of these genes in diabetic kidney tissue compared to both C and D group (p < 0.05 for all). Caspase-1-3-9, HIF-1α, and TNF-α gene expressions were found to be lower in DOI group compared to C group (p < 0.05 for all). Also adding ozone treatment to insulin therapy resulted in more significantly decrease in the expressions of these genes in diabetic tissue compared to only insulin-treated diabetic group (p < 0.05 for all). Regarding histological changes, ozone treatment resulted in decrease in the renal corpuscular inflammation and normal kidney morphology was observed. Both insulin and ozone therapies apparently improved kidney histological findings with less degenerated tubules and less inflammation of renal corpuscle compared to D, DO, and DI groups. CONCLUSION: Ozone therapy decreases the expressions of apoptotic genes in diabetic kidney tissue and improves the histopathological changes.

Nephrotoxic effects of varenicline as the most effective drug used for smoking cessation: a preliminary experimental study.

PURPOSE: Varenicline is a new most effective drug for smoking cessation. Its effect on kidney functions remains unclear. This study purposed to investigate whether varenicline causes nephrotoxicity in rats. METHODS: Fifteen rats were randomly assigned to three groups: control, 0.0125 mg kg(-1) varenicline and 0.025 mg kg(-1) varenicline (single dose for 3 days, i.p.). Before and after experimental period, serum neutrophil gelatinase-associated lipocalin, creatinine and urea levels were measured. Total oxidant and antioxidant status were measured in kidney homogenates. Histological examination was performed in kidney. RESULTS: The nephrotoxic effects of varenicline were detected by histopathological and biochemical examinations in the varenicline treatment groups. No change was observed in the control group. CONCLUSIONS: These findings firstly indicate that a 3-day varenicline treatment causes nephrotoxic effects in rats.

Effect of infliximab treatment on QT intervals in patients with ankylosing spondylitis.

BACKGROUND: Cardiovascular complications are one of the most common and the most serious extraskeletal manifestations of ankylosing spondylitis (AS). Infliximab, a monoclonal antibody against tumor necrosis factor, is widely used in the treatment of AS. QT dispersion (QTd), which relates to left ventricular function and is used as an index of cardiac dysrhythmia, may be useful as a prognostic guide. Early detection of possible cardiac involvement may not be clinically evident, whereas it may be detected by electrocardiography. OBJECTIVES: The aim of this prospective study was to assess the effect of infliximab treatment on QT intervals in patients with AS. METHODS: Twenty-one patients (17 females and 4 males) with AS who were in the active phase of disease (Bath Ankylosing Spondylitis Disease Activity Index score >4) were enrolled in the study. Infliximab was administered intravenously at a dosage of 5 mg/kg at weeks 0, 2, and 6 and every 6 weeks thereafter. QT intervals were recorded before and after 6 months of treatment. RESULTS: QT corrected (QTc) for heart rate was significantly reduced in the patients with AS after 6 months of infliximab therapy (406 ± 5.5 vs 388 ± 6.6 milliseconds; P = 0.029). There was no difference in the QTc dispersion (34.3 ± 11.1 vs 34.1 ± 8.6; P = 0.171). Body mass index and lipid profile were slightly increased after the treatment, but the difference was statistically insignificant. CONCLUSION: Inflammation can affect the ventricles with an unknown mechanism, and QTc may be slightly prolonged as a result in the active phase of AS. In our study, QTc was shortened under infliximab therapy by suppressing inflammation. Therefore, this effect may protect patients with AS from fatal arrhythmias and sudden cardiac death.

Angiotensin-converting enzyme gene polymorphism in overweight and obese Turkish patients with insulin resistance.

The aim of this study was to analyze the distribution of the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene in obese Turkish patients with insulin resistance (IR). Sixty-two obese Turkish patients with IR were enrolled in this study. One hundred healthy people without IR were recruited as the control group. ACE amplification was performed by polymerase chain reaction. The frequency of the DD genotype was significantly higher in obese patients with IR than in control subjects. Of sixty-two patients, 1 (1.6%) had an II genotype, 22 (35.5%) had an ID genotype, and 39 (62.9%) had a DD genotype. The frequency of the I allele in the patient group was significantly lower than in controls. We found that the frequency of the DD genotype was higher in obese Turkish patients with IR. ACE gene I/D polymorphism may be associated with obesity in the Turkish population.