Kadriye Altok Reis

An Association Between Inflammatory State and Left Ventricular Hypertrophy in Hemodialysis Patients

This study was performed to investigate the potential relationship between left ventricular hypertrophy (LVH) and proinflammatory cytokines in hemodialysis (HD) patients and the effect of HD on cytokine production. Serum interleukin 1 beta (IL-1 β), interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) measurements and echocardiographic studies were performed in 35 stable HD patients. A variety of probable risk factors for LVH including age, HD duration, blood pressure (BP), body mass index, lipid profile, hemoglobin, albumin, parathormone and homocysteine levels were also investigated. Additionally, the effect of HD procedure on cytokine levels was evaluated. Predialysis serum levels of IL-1β, IL-6, TNF-α, and homocysteine in HD patients were compared with 12 healthy subjects. Left ventricular hypertrophy was demonstrated in 20 (57%) of HD patients by echocardiography. Left ventricular mass index (LVMI) was correlated positively with systolic BP (r = 0.556, p = 0.001), diastolic BP (r = 0.474, p = 0.004), and serum levels of TNF-α (r = 0.446, p = 0.009).Multiple regression analysis showed that systolic BP and TNF-α levels were significant independent predictors of LVH. No relationship was observed between LVH and other parameters. The mean predialysis serum level of IL-6 was significantly higher in HD patients compared to healthy controls (15.7 ± 8.7 vs. 7.3 ± 0.7 pg/mL, p = 0.001). Predialysis serum levels of TNF-α in HD patients were higher when compared to healthy subjects, but the difference was not statistically significant (8.3 ± 3 vs. 7 ± 1.45 pg/mL, respectively, p > 0.05). However, serum levels of IL-6 and TNF-α significantly elevated after HD, when compared to predialysis levels (from 15.7 ± 8.7 to 17.8 ± 9.5 pg/mL, p = 0.001 and from 8.3 ± 3.0 to 9.9 ± 3.5 pg/mL p = 0.004, respectively). As a conclusion, in addition to BP, proinflammatory cytokines, TNF-α in particular, seem to be associated with LVH in ESRD patients.

The relationship of visfatin levels to inflammatory cytokines and left ventricular hypertrophy in hemodialysis and continuous ambulatory peritoneal dialysis patients.

Visfatin was recently defined as an adipocytokine; however, the pathophysiological role of visfatin is not completely understood. A few studies suggest that visfatin may be a new proinflammatory adipocytokine. The aim of the present study was to compare serum visfatin levels between hemodialysis and continuous ambulatory peritoneal dialysis (CAPD) patients and evaluate the relationship between visfatin levels to IL-6, TNF-α, and left ventricular hypertrophy. Serum visfatin, IL-6, and TNF-α levels were measured by using the ELISA method, and echocardiographic evaluations were performed in 31 hemodialysis patients, 30 CAPD patients, and 21 healthy volunteers. Serum visfatin levels were higher in the CAPD group (265.27 ± 387.86 ng/mL) than hemodialysis (97.68 ± 244.96 ng/mL,) and control (41.33 ± 48.87 ng/mL) groups (p = 0.04, p = 0.01, respectively). No significant difference was observed between the hemodialysis and control groups. In univariate analysis, visfatin levels were positively correlated with IL-6 (r = 0.24, p = 0.03), TNF-α (r = 0.34, p = 0.002), and BMI (r = 0.26, p = 0.03) and negatively correlated with some left ventricular diastolic parameters [Em and Em/Am (r = −0.305, p = 0.01), (r = −0.251, p = 0.03), respectively]. No relationship was found between visfatin and left ventricular mass index. In the linear regression analysis, visfatin levels independently related with TNF-( (β = 0.369, p = 0.001) and IL-6 (β = 0.284, p = 0.015). This study has found significantly higher levels of serum visfatin in CAPD patients when compared to healthy individuals. Increased visfatin levels seem to associate with proinflammatory cytokines such as IL-6 or TNF-α. As for the effects of on left ventricular structure and functions, visfatin might have negative effects on left ventricular diastolic function parameters but have no effects on left ventricular mass index.

Angiotensinogen and plasminogen activator inhibitor-1 gene polymorphism in relation to chronic allograft dysfunction

Abstract:  Chronic allograft dysfunction (CAD) is the most common cause of allograft failure in the long‐term, and current immunologic strategies have little effect on this condition. The renin‐angiotensin system (RAS) plays important roles progression of chronic renal disease. It is thought that plasminogen activator inhibitor‐1 (PAI‐1) functions in the RAS, in addition to involvement in thrombotic risk and fibrosis. This study investigated possible links between angiotensinogen (AGT) genotypes (M235T/MM, MT, TT) and PAI‐1 genotypes (4G4G, 4G5G, 5G5G) and CAD assessments of both types of polymorphism were performed in 82 renal allograft recipients. One hundred healthy subjects were also investigated for AGT polymorphism, and 80 healthy subjects for PAI‐1 polymorphism. Genotypes were determined using polymerase chain reaction (PCR) sequence‐specific primers, and PCR followed by restriction fragment length polymorphism analysis. Kidney recipients with CAD had significantly lower frequencies of the MM genotype and the M allele than the recipients without CAD (p < 0.05 and <0.001). The transplant recipients with CAD also had significantly lower frequencies of the 5G5G genotype and the 5G allele than those without CAD (p < 0.001 and <0.05). Determination of AGT M235T and PAI‐1 genotypes prior to transplantation may help identify patients who at risk for chronic renal transplant dysfunction.

Association of the Angiotensinogen M235T and APO E Gene Polymorphisms in Turkish Type 2 Diabetic Patients with and without Nephropathy

Background: Diabetic nephropathy (DN) is a leading cause of diabetes-related morbidity and mortality. The aim of this study was to evaluate the relationship of AGT M235T and apoprotein E (APO E) gene polymorphism with DN in Turkish patients of Type 2 diabetes, and to compare genotype and allele distributions among DN patients, non-DN patients, and healthy controls. Methods: AGT M235T and APO E genotype and allele analysis were performed in 111 DN patients, 108 non-DN patients, 106 healthy control subjects for APO E genotype, and 100 for AGT M235T genotype polymorphism. APO E and AGT M235T genotype were determined by RFLP-PCR. Results: The frequencies of APO E ε2/3, ε 3/3, ε 3/4 genotypes were 22.7%, 60%, 60%, respectively, among DN patients and 6.6%, 80%, 10.4%, respectively (p < 0.001), in the non-DN patients. The frequencies of AGT M235T MM, MT, TT genotypes among the same groups were 17%, 46%, 37% and 21%, 63%, 16%, respectively (p < 0.02). Having the ε2/3 genotype and TT genotype increased the risk for DN nephropathy [4.8-fold (95% CI: 1.94–11.67), 2.9-fold (95% CI: 1.27–6.69), respectively]. Conclusion: Our study has shown that AGT M235T TT genotype and APO E ε 2/3 genotype may be linked to a risk for DN among Turkish population.

Effects of Everolimus on Cytokines, Oxidative Stress, and Renal Histology in Ischemia-Reperfusion Injury of the Kidney

Background. To evaluate the effects of everolimus on renal ischemia-reperfusion injury (IRI). Methods. Wistar albino rats were divided into control, ischemia-reperfusion (IR), and ischemia-reperfusion/everolimus (IR/eve) groups. Everolimus was administered for seven consecutive days to the IR/eve group prior to injury. IR and IR/eve groups underwent forty-five minutes ischemia followed by the application of reperfusion at 2 and 24 hours. Blood samples and kidneys were taken from all animals. Results. Serum blood urea nitrogen and creatinine levels increased at two hours of reperfusion in the IR and IR/eve groups, and decreased at 24 hours of reperfusion in the IR group. In the IR/eve group, we detected significantly high interleukin-6 levels and low tumor necrosis factor-α and malondialdehyde levels at 24 hours. Myeloperoxidase levels increased at two hours of reperfusion in the IR/eve group, but decreased significantly at 24 hours. Everolimus did not improve renal tubular and interstitial injuries in renal IRI. Conclusions. It has been demonstrated that pretreatment with everolimus has beneficial effects on cytokines and oxidative stress in renal IRI. However, these effects are insufficient for the correction of histopathological changes and restoration of normal kidney function.

The Relationship among Asymmetric Dimethylarginine (ADMA) Levels, Residual Renal Function, and Left Ventricular Hypertrophy in Continuous Ambulatory Peritoneal Dialysis Patients

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of endothelial-based nitric oxide synthase. Its level is increased by end stage renal disease. However, most studies showing an increase in ADMA in dialysis patients have focused on hemodialysis. Results with peritoneal dialysis patients have been more inconclusive. Recent studies suggest that ADMA may be a new cardiovascular risk factor. The aim of the present study was to evaluate the relationship between ADMA levels, residual renal function, and left ventricular hypertrophy in peritoneal dialysis patients. Serum ADMA measurements and echocardiographic evaluations were performed in 54 peritoneal dialysis patients and 26 healthy volunteers. Residual renal function was measured in peritoneal dialysis patients by urea clearance from a urine collection. Thirty-two of the 54 peritoneal dialysis patients had residual renal function. ADMA levels of the peritoneal dialysis group were found to be significantly higher than those of healthy individuals (p = 0.03). Within the peritoneal dialysis group, ADMA levels of patients with residual renal function were significantly lower than those without residual renal function (p = 0.01), though they were still higher than the ADMA levels of the control group (p = 0.04). Serum levels of ADMA were positively correlated with left ventricular mass index (r = 0.29, p = 0.01) and negatively correlated with early mitral inflow velocity (Em) (r = −0.28, p = 0.01), Em/Late mitral inflow velocity (Am) (r = −0,32, p = 0.00), and isovolumetric relaxation time (r = −0.30, p = 0.01). In conclusion, increased ADMA levels seem to be associated with left ventricular hypertrophy in peritoneal dialysis patients, and residual renal function may lead to a reduction of serum ADMA levels.

Association between Neopterin and Carotid Intima-Media Thickness in Hemodialysis Patients

Background: Atherosclerotic lesions are heavily infiltrated by macrophages. Neopterin can be used as a marker of the activity of macrophages. Serum neopterin levels were elevated in non-renal patients with atherosclerosis. The intima-media thickness (IMT) of the carotid arteries in hemodialysis patients was significantly higher than in control subjects. In this study, we measured serum neopterin levels in hemodialysis patients and evaluated a possible correlation between neopterin levels and carotid IMT. Patients and Methods: Thirty-seven hemodialysis patients (26 male/11 female, mean age 47 ± 15 years) and 12 healthy subjects (8 male/4 female, mean age 43 ± 10 years) were included in this study. Serum neopterin levels were measured by using a commercial ELISA kit. Carotid IMT of the subjects were measured by high-resolution B-mode ultrasonography. Results: Carotid IMT values were 1.04 ± 0.29 and 0.77 ± 0.25 mm in hemodialysis patients and healthy controls, respectively (p < 0.01). Serum neopterin levels were 110.9 ± 19.1 and 3.8 ± 2.3 ng/ml in hemodialysis patients and healthy controls, respectively (p < 0.01). Serum neopterin levels were 103.2 ± 21.3 ng/ml in hemodialysis patients with IMT <1 mm (n = 15), and 116.7 ± 15.4 ng/ml in hemodialysis patients with IMT ≧1 mm (n = 22) (p < 0.05). Moreover, there was a significant correlation between serum neopterin levels and carotid IMT (p < 0.05, r = 0.363). Conclusion: Our findings suggest that neopterin could be associated with the severity of carotid atherosclerosis in hemodialysis patients.

Cyclosporine – a treatment and a rare complication: Raynaud's phenomenon

To the Editor: Cyclosporine is a potent immunosuppressive agent with a wide range of indications such as psoriasis, glomerulonephritis, tissue and solid organ transplantation. During the therapy, it is necessary to measure the blood levels of the drug. Cyclosporine has several side-effects including nephrotoxicity, neurotoxicity, hypertension, hyperlipidaemia, hypertrichosis, hyperkalaemia, hypomagnesaemia, gingival hyperplasia, hepatotoxicity, haemolytic uremic syndrome and carcinogenicity. Raynaud’s phenomenon is a rare vascular sideeffect associated with cyclosporin treatment (1–5). Although it is known that cyclosporin reduces the blood flow both in microand macrocirculation, mechanisms leading to Raynaud’s phenomenon have not yet been clarified (2,3). In the literature, few cases have been reported with this side effect. We report another case of Raynaud’s phenomenon during cyclosporin therapy. A 17-year-old man was referred to us because of 2.1 g/day proteinuria 5 years ago. Renal biopsy was performed in order to evaluate the aetiology of proteinuria. The histological finding of renal biopsy was compatible with focal segmental glomerulosclerosis. An angiotensinconverting enzyme inhibitor (Lisinopril 5 mg/day) was only prescribed for treatment of proteinuria. In his 4 years of follow-up, the amount of proteinuria was less than 1 g/day; blood urea nitrogen (BUN) and creatinine levels were within the normal range. Five years after the diagnosis, plasma BUN and creatinine levels were still in the normal range but proteinuria increased to 3000 mg/day. Oral prednisolone was started at the dose of 0.5 mg/kg/day. After 3 months of prednisolone therapy, the 24-h urinary protein excretion was detected within high levels again and prednisolone dose was increased to 1 mg/kg/day. Despite this treatment, the amount of proteinuria rose to 5000 mg/day after 1 month. The patient was accepted as unresponsive to steroid therapy, and cyclosporin (3.5 mg/kg/day) was added to his treatment protocol. After 1 month with this new treatment protocol, proteinuria was 3635 mg/day, and blood levels of cyclosporin were between 100 and 182 ng/ml (normal range: 150–350 ng/ ml). During this time, he complained of the colour changing to purple and a sensation of burning in his fingertips, but his lower extremities were normal. His complaints were independent of the cold. Furthermore, gingival hyperplasia and hypertrichosis were observed. On physical examination, upper extremity pulses were found to be normal, but cyanosis of the fingers was apparent. Following cold water test, the cyanotic appearance became a little more prominent (Figure 1). All parameters for connective tissue disorders were evaluated. Plasma cryoglobulin, immunoglobulin M and complement 3 and complement 4 levels were normal and antinuclear autoantibody, antidouble stranded (ds) DNA antibody, anti-Sm-D1, antiribosomal P protein and anticentromer antibody were negative. Pentoxyphyllin (Trental , 1200 mg/day) was added to his therapy. After a week of pentoxyphyllin treatment, there was a progression in his complaints, and cyclosporin treatment was discontinued. The following week cyanosis and the sense of burning in the fingertips completely disappeared. After cessation of cyclosporin therapy, a combined treatment protocol consisting of cyclophosphamide and prednisolone was started. When the Naranjo ADR Probability Scale (6) was applied to this particular report, we found a ‘possible’ relationship between the drug and adverse reaction. The mechanism of Raynaud’s phenomenon occurring as a result of cyclosporin therapy has not yet been clarified. However, cyclosporin has a vasospastic effect on both macroand microcirculation, and this vasospasm, together with the decrease in blood flow can be responsible from Raynaud’s phenomenon (2). Especially, acute vasospastic effect on renal vascular bed and acute reversible nephrotoxicity of cyclosporin are the best explanations of the known vascular effects of this drug (2). It is known that haemolytic uremic

Angiotensinogen and Plasminogen Activator Inhibitor-1 Gene Polymorphism in Relation to Renovascular Disease

The present study was designed to evaluate angiotensinogen (AGT) M235T and plasminogen activator inhibitor-1 (PAI-1) (4G/5G) polymorphisims in relation to the occurrence of atherosclerotic renal artery stenosis (ARAS) and recurrent stenosis. In this study, 30 patients were enrolled after angiographic demonstration of ARAS; 100 healthy subjects for AGT polymorphism and 80 healthy subjects for PAI-1 polymorphism were considered the control group. The patients were followed for a mean 46.1 ± 9.2 months. The patients had significantly higher frequencies of the MT genotype and the T allele than control group (χ2 = 18.2, p < 0.001 and χ2 = 11.5 p < 0.001). There were no significant differences in the PAI-1 genotype and allele findings when the data for all patients were compared with that for the controls (χ2= 2.45, p = 0.29 and χ2 = 0.019, p = 0.89). There were no significant differences in the genotype and allele findings for the patients with and without restenosis (p > 0.05). The C-reactive protein (CRP) level was higher in the patients with restenosis than in the patients without restenosis (7.694 ± 0.39 mg/L and 1.56 ± 1.08 mg/L) (p = 0.001). Our results suggest that the M235T MT genotype and T allele might be associated with increased risk of atherosclerotic renal artery stenosis. The CRP level might be an independent predictor for recurrent stenosis.

TGF-β1 Gene Polymorphisms and Peritoneal Equilibration Test Results in CAPD Patients

Transforming growth factor-β1 (TGF-β1) stimulates the expression of collagen mRNA in cultured human peritoneal mesangial cells, which may predispose them to developing peritoneal fibrosis. Polymorphisms in the signal sequence genetically may be responsible for increased TGF-β1 production (i.e., a substitution at amino acid position 10 and 25, +869 Leu10–Pro and +915 Arg25–Pro, respectively). The aim of this study was to find out whether there is any relation between peritoneal equilibration test (PET) results and TGF-β1 gene polymorphism. Thirty-two CAPD patients and 72 healthy subjects were included into the study. Each CAPD patient had undergone two PET with a two-year interval. The patients were classified according to the results of a baseline PET as high (high-high average) and low (low-low average) transporters. In high transporters group (n = 20), the genotype frequencies were found as 45% Leu/Leu, 55% Leu/Pro for codon 10; and 85% Arg/Arg, 15% Arg/Pro for codon 25. In low transporters group (n = 12), the genotype frequencies were detected as 66.7% Leu/Leu and 33.3% Leu/Pro for codon 10; and 83.3% Arg/Arg, 16.7% Arg/Pro for codon 25. The distribution of the TGF-β1 genotypes in our control population was compatible with a Hardy-Weinberg equilibrium. We found no relation between TGF-β1 genotypes and peritoneal transport group (χ2 test, p > 0.5). There was no relation between TGF-β1 genotype and longitudinal change in peritoneal transport. This study is the first study analyzing the possible link between TGF-βl gene polymorphisms and the characteristics of peritoneal transport and longitudinal change of peritoneal transport characteristics in CAPD patients. Further work is needed to clarify the functional importance of these two polymorphisms in TGF-β1 production and in the development of peritoneal fibrosis.