Serhan Tuglular

Evaluation of the angiotensin-converting enzyme insertion/deletion polymorphism and the risk of ischaemic stroke.

Angiotensin-converting enzyme (ACE) gene polymorphism has been associated with increased incidence of stroke in some populations, although contradictory results have been reported. The aim of this study was to determine the allelic frequency and the genotypic distribution for ACE gene polymorphism in Turkish patients with ischemic stroke compared to appropriate healthy controls and to correlate the genetic findings with stoke type. One hundred and eight patients with ischemic stroke versus 79 healthy controls were studied for the presence of ACE gene polymorphism detected by PCR. Genotypes were defined as DD, II and ID according to the presence of the D (deletion) and I (insertion) alleles. There was no statistically significant difference in either the genotypic distribution or allelic frequency between the patients versus healthy controls (chi2 = 0.105; df = 1; p = 0.430). There was also no significant difference for ACE genotype distribution and allelic frequency within the stroke group classified according to Bamford criteria (chi2 = 4.827; df = 3; p = 0.185). Our data supports lack of association between DD genotype and/or D allele and ischemic stroke or subtypes of ischaemic stroke in the Turkish population.

Renal Protective Effects of Leukotriene Receptor Blockers in an Experimental Model of Cyclosporine Nephrotoxicity

BACKGROUND Chronic cyclosporine (CsA) nephrotoxicity is associated with renal fibrosis and hyaline arteriolopathy. Fibrogenic cytokines, such as transforming growth factor-beta (TGF-beta) and vascular endothelial growth factor (VEGF), play a pivotal role in CsA nephrotoxicity. Previous studies have demonstrated the possible role of leukotrienes (LT) in chronic CsA nephrotoxicity. The aim of this study was to examine the possible beneficial effects of LT blockers in attenuating the morphological and histochemical effects induced by CsA in a rat model of CsA nephrotoxicity. MATERIALS AND METHODS Twenty-four male Wistar rats were divided into 3 groups (n = 8). The first group (G1) was treated with vehicle intraperitoneally (IP) for 60 days. The second group (G2) was treated with 15 mg/kg CsA IP for 60 days. The third group (G3) was treated with the same dose of CsA plus 4 mg/kg montelukast administered by oral gavage for 60 days. RESULTS There was a statistically significant decrease in glomerular filtration rate (GFR) among G2 compared with G1 animals: 0.41 +/- 0.03 vs 1.63 +/- 0.12 mL/min (P < .001), or G3 hosts: 0.41 +/- 0.03 vs 0.95 +/- 0.05 mL/min (P < .005), respectively. The percentage of hyaline arteriolopathic changes was higher in G2 than G1 or G3: 81.66% +/- 8.2% vs 11.83% +/- 0.87% (P < .01) or 37.0% +/- 8.8% (P < .01), respectively. Fibrosis score was higher in G2 compared with G1 or G3: 1.5 +/- 0.04 vs 0.16 +/- 0.02 (P < .001) and 1.0 +/- 0.05 (P < .05), respectively. TGF-beta and VEGF immunoexpression were significantly increased in G2 compared with G1 (P < .05) or G3 (P < .05). CONCLUSIONS Our study suggested that LT may play a critical role in the pathogenesis of chronic CsA nephrotoxicity; the administration of montelukast, a LT receptor blocker, may prevent CsA-induced nephrotoxicity.

Association of FMF-related (MEFV) point mutations with secondary and FMF amyloidosis.

Background: Familial Mediterranean fever (FMF) is the major cause of AA amyloidosis in Turkey. M694V mutation in MEFV gene was suggested to be associated with severe clinical features and amyloidosis of FMF. Methods: In this study, the frequencies of three FMF-related MEFV mutations (M694V, M680I and V726A) were investigated in FMF patients with (AA-FMF, n = 37) and without amyloidosis (non-AA-FMF, n = 35), in patients with secondary amyloidosis related to non-FMF inflammatory conditions (S-AA, n = 19) and in a non-inflammatory control group (n = 185) by molecular genetic studies using polymerase chain reaction with the ARMS (amplification refractory mutation system) method. Results: Both AA and non-AA-FMF patients had significantly higher MEFV mutations compared to non-inflammatory controls (81 and 62.7% respectively vs. 4.2%, p = 0.0001). AA-FMF patients carried significantly more MEFV mutations than non-AA-FMF patients (p = 0.01). M694V was the most common mutation in both FMF groups (63.5 vs. 51.4%), however allele frequency (p = 0.17) and the number of homoyzgous patients for this mutation did not differ between the groups (p = 0.77). Although lower compared to FMF patients, S-AA patients also had a significantly higher incidence of MEFV mutations than non-inflammatory controls (21 vs. 4.2%) (p = 0.0002). M694V was the only MEFV mutation in this group. Conclusion: MEFV mutations are found to be increased both in FMF and non-FMF associated secondary amyloidosis in our study; however, no clear association between M694V and amyloidosis is observed, except in the non-FMF group. Our results suggest that MEVF mutations may also serve as a severity marker for other inflammatory conditions.

Effects of spironolactone in an experimental model of chronic cyclosporine nephrotoxicity.

BACKGROUND Cyclosporine (CsA)-associated nephrotoxicity is a long-term complication in transplant patients. Chronic CsA nephrotoxicity is associated with renal fibrosis and hyaline arteriolopathy. The aim of this study was to investigate the effect of spironolactone on functional and structural alterations as well as on platelet-derived growth factor B (PDGF-B) and transforming growth factor (TGF) beta expression induced by CsA in a rat model of chronic CsA nephrotoxicity. MATERIALS AND METHODS Twenty-four rats were divided into 3 groups. Group 1 (G1) received vehicle only (V); G2, CsA (15 mg/kg/d; CsA) by intraperitoneal (IP) injection; and G3, a similar CsA dosage + spironolactone (20 mg/kg/d; CsA + Ald.) by the oral route. At the end of 28 days, glomerular filtration rate (GFR) and blood CsA levels were measured as well as histopathological and immunohistochemical analyses performed on renal tissue. RESULTS Mean CsA trough levels in G2 and G3 were both above 2000 ng/mL. In G2, GFR was lower than G1 and G3 (0.35 +/- 0.05, 1.64 +/- 0.24, and 1.20 +/- 0.25 mL/min, respectively; P < .001). There was a significantly increased number of arteriolopathic changes in G2 and G3 vs G1 (16% +/- 3.7%, 15% +/- 6.8%, 3% +/- 1.2%, respectively; P < .001). Interstitial fibrosis was significantly increased in G2 vs G1 and G3 (52%, 0%, 27%, respectively; P < .05). Marked by up-regulated PDGF-B and TGF beta expressions were observed in G2 vs G1 or G3: 100%, 0%, 37.5%, respectively, for PDGF-B (P < .001) and 87.5%, 0%, 12.5%, respectively, for TGF beta (P < .001). CONCLUSION Our results suggested that chronic CsA nephrotoxicity may be mitigated by aldosterone receptor blockade which seemed to be associated with down-regulation of PDGF-B and TGF beta expression.

Evaluation of Sepsis/Systemic Inflammatory Response Syndrome, Acute Kidney Injury, and RIFLE Criteria in Two Tertiary Hospital Intensive Care Units in Turkey

Sepsis is a common cause of acute renal failure in intensive care units (ICU) with mortality rates as high as 60%. In this study, the clinical and laboratory predictors of acute kidney injury (AKI) in critically ill Turkish patients with sepsis/systemic inflammatory response syndrome were identified. We studied 139 (67 females/72 males) patients admitted to our ICUs with sepsis/systemic inflammatory response syndrome without renal failure. The clinical and laboratory parameters and treatments were recorded. Patients were classified as those without AKI (n = 60; 43.20%) and those with AKI (n = 79; 56.80%) based on the RIFLE (Risk, Injury, Failure, Loss, End-stage renal disease) criteria. Those with AKI were further classified as: risk in 27 (19%), injury in 25 (17.9%), failure in 25 (17.9%), and loss in 2 (1.4%). We found that the mortality rate increased with the severity of renal involvement: 56% in risk, 68% in injury, 72% in failure, and 100% in loss categories. Patients with AKI had a more positive fluid balance, higher central venous pressure, more vasopressor use, and lower systolic blood pressure. In multivariate analysis, the sequential organ failure assessment score, blood pressure, serum creatinine, and fluid balance were risk factors for the development of AKI. In this population, the incidence of AKI was higher and contrary to previous knowledge. A positive fluid balance also carries a risk for AKI and mortality in septic ICU patients. The RIFLE criteria were found to be applicable to our ICU population.

Associations between Apolipoprotein E Gene Polymorphism and Plasminogen Activator Inhibitor-1 and Atherogenic Lipid Profile in Dialysis Patients

Background. Apolipoprotein-E (ApoE) gene polymorphism has an important role in lipoprotein metabolism and could participate in the development of cardiovascular diseases (CVD). Plasminogen activator inhibitor-1 (PAI-1) is also regarded as a risk factor for CVD. The aim of the present study is to further investigate the possible link(s) between ApoE gene polymorphism and plasma PAI-1 antigen and serum lipid profile in peritoneal dialysis (PD) and hemodialysis (HD) patients. Material and Methods. We studied 72 PD patients (38 female, mean age 49.9 ± 16.1 years), 72 HD patients (22 female, mean age 57.4 ± 14.6 years), and 42 healthy subjects (21 female, mean age 50.1 ± 18.6 years). Serum lipid parameters, plasma PAI-1 levels, and ApoE genotypes were determined in all subjects. Results. The distribution of ApoE genotypes and alleles frequencies was similar in dialysis patients and healthy controls. In PD patients, total cholesterol (TC), low-density lipoprotein (LDL)-C, and ApoB levels were significantly higher than that of HD patients. HD patients with E3/4 genotype had elevated TC, LDL-C and ApoB levels compared with E3/3 genotype. TC and triglyceride levels were also higher in E3/4 genotype than that of E2/3 genotype. PD and HD patients showed a significantly increased PAI-1 levels compared with controls, whereas PAI-1 levels were highest in HD patients. There was no significant relation between ApoE genotypes and PAI-1 levels. Conclusions. The present study suggests that ApoE polymorphism significantly affects serum lipid profile in HD patients and ε4 allele carriers are more susceptible to have atherogenic lipid profile.

Elevated Plasma Levels of PAI-1 Predict Cardiovascular Events and Cardiovascular Mortality in Prevalent Peritoneal Dialysis Patients

Background. Elevated plasminogen activator inhibitor-1 (PAI-1) levels are associated with increased cardiovascular (CV) risk in the general population. It has been shown that peritoneal dialysis (PD) patients have increased plasma levels of PAI-1. The aim of this study was to investigate whether PAI-1 independently predicted CV outcome in PD patients. Material and Methods. Seventy-two PD patients (53% females, mean age 49.9 ± 16.1 years) were studied. Twelve patients who underwent kidney transplantation and 14 patients who transferred to hemodialysis during follow-up were excluded from the analysis. The remaining 46 patients (54% female, mean age 54 ± 16 years, dialytic age 42 ± 30 months) were followed a mean time of 45.4 ± 19.4 months (range 8–71 months). Baseline PAI-1, clinical, and laboratory parameters were assessed in all patients. Survival analyses were made with Kaplan-Meier and Cox regression analysis, with all-cause mortality and CV mortality and CV events (CVEs) as clinical end points. Results. During the follow-up, 29 patients died (17 from CV causes), and 28 fatal and non-fatal CVEs were recorded. The patients were divided according to plasma PAI-1 levels (i.e., ≤ or >41 ng/mL). The significant independent predictors of all-cause of mortality were age (60 years; p = 0.018), CRP (5 mg/L; p = 0.015), and serum albumin (<3.5 g/L; p = 0.011). Multivariable Cox regression analysis showed that plasma PAI-1 41 ng/mL was independently predictive of higher CV mortality (p = 0.021) and CVEs (p = 0.001). The only other independent predictor of CV mortality was only CRP (5 mg/L; p = 0.008). Conclusions. Plasma levels of PAI-1 41 ng/mL is a significant predictor of CV mortality and CVEs in PD patients.

Fibroblast Growth Factor–23 Levels Are Associated With Uric Acid But Not Carotid Intima Media Thickness in Renal Transplant Recipients

INTRODUCTION Cardiovascular disease (CVD) is the leading cause of mortality in chronic kidney disease (CKD) patients. Fibroblast growth factor-23 (FGF-23) is associated with atherosclerosis and cardiovascular mortality in CKD patients and healthy subjects. However, data in renal transplant recipients (RTR) are scarce. We aimed to determine factors associated with FGF-23 and to explore its relationship to atherosclerosis. METHODS Forty-six patients and 44 controls were included. FGF-23 was measured from plasma. Carotid intima media thickness (CIMT) was evaluated ultrasonographically. RESULTS Patients had higher waist circumference (WC; 92.2 ± 14.9 vs 85.3 ± 11.0 cm; P < .05), glucose (99.8 ± 17.2 vs 90.3 ± 6.5 mg/dL; P < .01), creatinine (1.43 ± 0.6 vs 0.86 ± 0.1 mg/dL; P < .01), triglyceride (160.4 ± 58.9 vs 135.6 ± 59.8 mg/dL; P < .05), white blood cells (WBC; 7938.6 ± 2105.2 vs 6715.7 ± 1807.5 WBC/mm(3); P < .01), ferritin (217.0 ± 255.8 vs 108.3 ± 142.4 ng/mL; P < .05), uric acid (6.5 ± 1.6 vs 4.7 ± 1.3 mg/dL; P < .01), C-reactive protein (CRP; 8.2 ± 18.2 vs 5.3 ± 7.9 mg/L; P < .01), parathyroid hormone (PTH; 89.7 ± 59.2 vs 44.1 ± 16.7 pg/mL; P < .01), and alkaline phosphatase (ALP; 162.5 ± 86.6 vs 74.2 ± 21.9 U/L; P < .01). FGF-23 was higher in patients (11.7 ± 7.2 vs 9.6 ± 6.8 pg/mL; P < .05). CIMT was similar (0.58 ± 0.09 vs 0.57 ± 0.1 mm; P > .05). WC, creatinine, and uric acid were positively correlated with FGF-23, whereas albumin showed negative correlation. On multivariate analysis only creatinine and uric acid were determinants of FGF-23. CONCLUSION FGF-23 levels are associated with uric acid in RTR. Larger studies are needed to confirm this finding.

Demographic and Clinical Characteristics of Patients with Autosomal Dominant Polycystic Kidney Disease: A Multicenter Experience

Aim: Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease. It accounts for 5–10% of patients with end-stage renal disease (ESRD). The aim of this multicenter study was to investigate the demographic and clinical characteristics of patients with ADPKD. Methods: 1,139 patients with ADPKD who were followed up at 12 different centers were recruited for this study. The investigated demographic and clinical characteristics were gender, age, smoking history, educational status, the existence of hypertension, hematuria, urinary tract infection, urinary tract stones and renal replacement therapy. Patients were considered as hypertensive if they were taking antihypertensive medications or if they had blood pressure (BP) of 140/90 mm Hg or greater. If the patients were currently on antihypertensive drugs, the classes of these agents were noted. Results: 548 male and 591 female patients were included and the mean age at initial diagnosis was 37.1 ± 16.3 years. 20.3% were current smokers whereas 15% were ex-smokers. The mean systolic and diastolic BPs were 136.1 ± 29.8 and 84.9 ± 17.8 mm Hg, respectively. 63.7% used antihypertensive drugs and 73.1% of those used renin-angiotensin system blockers. 11.8% had ESRD, of which 75.8% were treated with hemodialysis. Conclusion: This study showed that hypertension is the most common (72.6%) clinical finding in ADPKD patients in Turkey and renin-angiotensin system blockers are widely used.

Protective effect of the vasopressin agonist terlipressin in a rat model of contrast-induced nephropathy.

Background/Aims: Contrast-induced nephropathy (CIN) remains a leading cause of iatrogenic acute renal failure. Terlipressin, a long-acting analog of vasopressin, may improve renal function. This study aimed to investigate the possible protective effect of terlipressin against the development of experimental CIN in rats. Methods: Wistar albino rats (n = 32) were allocated randomly into four equal groups of 8 each, i.e. control, terlipressin, contrast media (CM), and terlipressin plus contrast media (TCM). CIN was induced by intravenous administration of indomethacin (10 mg/kg), N-nitro L-arginine methyl ester (L-NAME, 10 mg/kg, twice at 15 and 30 min), and high-osmolar contrast media meglumine amidotrizoate 60%. Renal function parameters, kidney histology, and tubular expression of vascular endothelial growth factor (VEGF) were determined. Results: Mean serum creatinine levels were decreased (p < 0.05) and creatinine clearance (p < 0.05) increased in the TCM group compared with the CM group. Notably, rats in the TCM group displayed less tubular necrosis (p < 0.05), medullary congestion (p < 0.05), and a reduced tubular expression of VEGF (p < 0.05) compared with the CM group. Conclusion: These results demonstrate that terlipressin can inhibit the development of CIN.