Clinical and biochemical assessment of endothelial dysfunction and inflammation in renal transplant recipients : PhD dissertation
Kliničko-biohemijski pokazatelji endotelne disfunkcije i inflamacije kod pacijenata sa transplantiranim bubregom
Committee membersRadenković, Sonja
Živančević Simonović, Snežana
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Introduction. Renal replacement therapy remains the treatment of option for patients in end stage renal disease. The most frequent cause of late allograft loss is cardiovascular disease, which constitutes the leading cause of death of renal transplant recipients (RTR). When compared with the general population, RTR show a four-fold greater risk for CVD, and a two-fold higher risk for cardiovascular death. Renal transplant dysfunction can be considered as a traditional risk factor, while high sympathetic activity and accumulation of the endogenous inhibitor of endothelial NO synthase (eNOS), asymmetric dimethylarginine (ADMA) are factors peculiar to chronic renal failure. eNOS can be strongly inhibited by ADMA, whose accumulation in plasma may play an important role in endothelial dysfunction. ADMA is an uremic toxin that can be considered as parameter of endothelial dysfunction. ADMA, also, causes local vasoconstriction when infused intra-arterially. Symmetric dimethylaginine (SDMA) do...es not inhibit NOS directly, and is also elevated in patients with renal failure, its levels, better than ADMA, correlate with glomerular filtration rate (GFR). ADMA was proposed to be a marker for atherosclerotic changes, and for the assessment of cardiovascular morbidity and mortality. Atherosclerosis is today described as a disease where inflammation is the dominant pathological and biochemical alteration. The development of the atherosclerotic plaque is closely linked to expression of different cellular adhesion molecules (CAMs), that are essential mediators, playing a central role in the recruitment of inflammatory cells to the site development. Many factors were demonstrated to increase concentration of cellular adhesion molecules: hypertension, immunosuppressive therapy, autoimmune disease and cell mediated allograft rejection. These CAMs can be measured in plasma and therefore may represent promising biomarkers that may reflect underlying endothelial activation and vascular inflammation. Besides inflammation many studies have generally suggested a positive association between dyslipidemia and end stage renal disease and advanced chronic kidney failure. Renal disease is associated with profound abnormalities in lipids and lipoprotein metabolism and in renal transplant recipients hyperlipidemia is a well known feature. It has been suggested that dyslipoproteinemia observed in kidney disease contributes to the progression of glomerular and tubular lesions, with deterioration to end stage renal disease. Factors that induce post-transplant dyslipidemia include age, body weight, pre-transplant lipid levels, presence of proteinuria and allograft dysfunction. Standard immunosuppressive therapy usually consists of triple drug therapy of three drug classes: calcineurin inhibitors, anti-proliferative agents and corticosteroids. Corticosteroids and cyclosporine, besides the nephrotoxic effect, seem to be one of the main contributing factors that influence the post-transplant lipidemic profile. Cyclosporine plays an independent role in elevating cholesterol levels by modulating the low density lipoprotein (LDL) receptors. Corticosteroids, cyclosporine and tacrolimus (to a lesser degree than cyclosporine) increase post-transplant cholesterol and triglycerides levels, usually in dose dependent fashion. Elevated total and LDL cholesterol occur in about 60% and hypertriglyceridemia in about 35%, whereas low high density (HDL) cholesterol is present in only 15% of renal transplant recipients. Enhanced sympathetic activity is frequently reported in end stage renal disease, and such activation declines, but does not normalize, after successful kidney transplantation. Renalase is a new flavoprotein that regulates sympathetic tone and blood pressure. It is secreted by the kidney and is reported that has monoamine oxidase (MAO) activity, therefore may metabolize catecholamines. Cardiomyocytes, liver and skeletal muscles also secrete renalase, and it was found in peripheral nerves, central nervous system, adrenals, adipose tissue, 12.5-day-old embryo and endothelium. It circulates in the blood as a proenzyme waiting for elevated catecholamines for activation. The purpose of the study was to observe parameters of endothelial dysfunction (parameters of chronic inlammation and nitrosative stress), lipid profile disturbances and the level of sympathetic activity in the stable renal transplant recipients, to assess correlations between renal dysfunction and inflammatory biomarkers, lipid profile disturbances, nitrosative stress and sympathetic activity, as well as potential differences in these parameters in regard to immunosuppressive protocol, and among them to hypothesize the best independent predictor, and predictors of early renal dysfunction after multivariate modeling (adjustment for age, body mass index, hypertension, smoking and diabetes mellitus). Methods. We enrolled 73 renal transplant recipients, who were greater than 12 months post-renal transplant surgery, had a stable graft function, no clinically present cardiovascular disease and were on standard immunosuppression. The study was conducted between March and November 2012 at the Clinic for Nephrology, Dialysis and Transplantation, Clinical Centre Nis. Ethics Committee of Medical Faculty Nis approved the study and fully informed written consent was obtained from each patient. Results. Significant differences were found between clinical and control group in sistolic blood pressure, (p<0.001), diastolic blood pressure, (p<0.001), urea (p<0.001), creatinine (p<0.001), creatinine clearance (p<0.001), hemoglobin (p=0.003), white blood cells, (p=0.003), total cholesterol (p<0.001), non-HDL (p<0.001) and Tg (p<0.001). Plasma concentration of nitrates (p<0.001), eNOS (p<0.001), ADMA (p=0.001), SDMA (p<0.001), renalase (p<0.0001), ICAM-1 (p<0.001), and VCAM-1 (p<0.001), were statistically increased with regard to controls. Non-adjusted OR showed that there was a significant risk of reduced GFR in patients with total cholesterol higher than 5.19 mmol/L, LDL cholesterol≥4.1 mmol/L, non-HDL≥4.2 mmol/L and higher VCAM-1 concentration. After adjustment for age and in multivariable model OR showed a significant risk for reduced GFR in patients with total cholesterol ≥5.2 mmol/L, LDL≥4.1 mmol/L, non-HDL≥4.2 mmol/L and higher VCAM-1 concentration. HDL, triglycerides, CRP and lipoprotein ratios did not have any significance as predictors of renal dysfunction. Finally, there were no differences in all evaluated parameters between groups in regard to immunosuppressive therapy. Total cholesterol, LDL, non-HDL and VCAM-1 are strong and independent predictors of renal dysfunction in stable renal transplant recipients. In contrast HDL, CRP, triglycerides and ICAM-1 did not seem to have any impact on renal dysfunction. Non-adjusted OR showed that there was a significant risk of reduced eGFR in transplant recipients with increased renalase activity (p=0.026); age-adjusted OR showed a significant risk of reduced eGFR with increased renalase activity (p=0.042), also after multivariable adjustment (p=0.032). Increased plasma eNOS activity was protective factor for eGFR (p=0.011), also after adjustment for age (p=0.045), and after multivariate modeling, eNOS was shown to be protective factor for eGFR (p=0.014). Significant differences with respect to immunosuppression were in plasma renalase in patients maintained on cyclosporine (p=0.027), as well as differences in eGFR (p=0.034). We found statistically significant inverse correlation between renalase and eGFR (p<0.001), positive correlation between renalase and creatinine (p=0.003), total cholesterol (p<0.001), LDL-cholesterol (p=0.046), and non-HDL cholesterol (p=0.01). There was a significant difference in plasma renalase with regard to chronic kidney disease stages (p<0.001). Renalase correlated with leukocytes, but did not correlate with C-reactive protein. Renalase did not correlate with any of parameters of endothelial dysfunction, neither with some demographic data (gender, age, time or type of transplantation, risk factors). There were no differences in renalase activity with regard to antihypertensive therapy. Conclusion. Renalase was shown to be strong predictor for decreased eGFR in stable renal recipients. eNOS was identified as a strong protective factor for eGFR. Renalase strongly and inversely correlated with eGFR, positively with creatinine and lipid disturbances, but did not correlate with endothelial dysfunction parameters, and is most probably determined by kidney function. Total cholesterol, LDL, non-HDL and VCAM-1 strongly and inversely correlated with glomerular filtration rate and were shown to be independent predictors for decreased GFR, as well as predictors by multivariate modeling. In contrast there was no correlation of HDL, CRP, triglycerides and ICAM-1 with glomerular filtration rate. All evaluated lipid and inflammation parameters did not differ between the groups in respect to immunosuppression therapy protocol. Renalase was significantly higher in the group of patients on cyclosporine.
Faculty:University of Niš, Faculty of Medicine
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