Dijana Stojanovic

Circulating purine compounds, uric acid, and xanthine oxidase/dehydrogenase relationship in essential hypertension and end stage renal disease

Abstract Purine nucleotide liberation and their metabolic rate of interconversion may be important in the development of hypertension and its renal consequences. In the present study, blood triphosphate (ATP), adenosine diphosphate (ADP), and adenosine monophosphate (AMP) breakdown pathway was evaluated in relation to uric acid concentration and xanthine dehydrogenase/xanthine oxidase (XDH/XO) in patients with essential hypertension, patients with chronic renal diseases on dialysis, and control individuals. The pattern of nucleotide catabolism was significantly shifted toward catabolic compounds, including ADP, AMP, and uric acid in patients on dialysis program. A significant fall of ATP was more expressed in a group of patients on dialysis program, compared with the control value (p < 0.001), while ADP and AMP were significantly increased in both groups of patients compared with control healthy individuals (p < 0.001), together with their final degradation product, uric acid (p < 0.001). The index of ATP/ADP and ATP/uric acid showed gradual significant fall in both the groups, compared with the control value (p < 0.001), near five times in a group on dialysis. Total XOD was up-regulated significantly in a group with essential hypertension, more than in a group on dialysis. The activity of XO, which dominantly contributes reactive oxygen species (ROS) production, significantly increased in dialysis group, more than in a group with essential hypertension. In conclusion, the examination of the role of circulating purine nucleotides and uric acid in pathogenesis of hypertension and possible development of renal disease, together with XO role in ROS production, may help in modulating their liberation and ROS production in slowing progression from hypertension to renal failure.

The assessment of renalase: searching for the best predictor of early renal dysfunction by multivariate modeling in stable renal transplant recipients.

BACKGROUND Renal transplant dysfunction has been shown to be an independent risk factor for cardiac, non-cardiovascular, and all-cause mortality in post-transplantation follow-up. MATERIAL AND METHODS We enrolled 73 renal transplant recipients who were more than 12 months post-renal transplant surgery, had stable graft function, and were on standard immunosuppression. The purpose of the study was to observe the relation between renal dysfunction and endothelial dysfunction parameters (nitrates, asymmetric and symmetric dimethylarginine, and endothelial nitric oxide synthase), and renalase, and to hypothesize the best predictor of early renal dysfunction by multivariate modeling. The other aim was to observe differences with regard to immunosuppression. RESULTS Non-adjusted odds ratio showed a significant risk of reduced glomerular filtration rate in transplant recipients with increased renalase concentration (p=0.026); age-adjusted odds ratio showed a significant risk of reduced glomerular filtration rate with increased renalase concentration (p=0.042), also after multivariable adjustment (p=0.032). Increased plasma endothelial nitric oxide synthase concentration was a protective factor for glomerular filtration rate (p=0.011). After adjustment for age (p=0.045), and after multivariate modeling, endothelial nitric oxide synthase was shown to be a protective factor for glomerular filtration rate (p=0.014). Significant differences in immunosuppression were found in plasma renalase in patients maintained on cyclosporine (p=0.027). CONCLUSIONS Renalase was shown to be strong predictor of decreased glomerular filtration rate and was significantly higher in the group of patients on cyclosporine. Endothelial nitric oxide synthase was identified as a strong protective factor for kidney function.

Oxidative and Nitrosative Stress in Stable Renal Transplant Recipients with Respect to the Immunosuppression Protocol – Differences or Similarities? / Oksidativni I Nitrozativni Stres U Odnosu Na Imunosupresivni Protokol Kod Pacijenata Sa Stabilnom Funkcijom Presađenog Bubrega – Razlike I Sličnosti

Summary Background: The aim of the study was to evaluate parameters of oxidative and nitrosative stress as well as antioxidative parameters in a group of renal transplant recipients with stable graft function and no clinical signs of cardiovascular disease. We also aimed to determine the correlations among these parameters and to evaluate potential differences in all the biomarkers with regard to the immunosuppression protocol. Methods: We enrolled 57 renal transplant recipients and 31 controls who were age and sex matched with the renal transplant recipients. All of the patients included in this study had post-renal transplant surgery at least 12 months earlier and were on standard immunosuppressive therapy. In this study, we determined thiobarbituric acid-reactive substances in plasma and red blood cells and advanced oxidation protein products, nitrosative stress parameters (asymmetric and symmetric dimethylarginine - ADMA and SDMA), and antioxidative parameters (total SH groups and catalase activity). Results: The results of our study demonstrated that the levels of oxidative and nitrosative stress were significantly increased compared to the healthy population (p<0.01 except for plasma catalase activity p<0.05). Correlation analysis showed significant positive correlations between: ADMA and SDMA (p<0.01); ADMA and nitrates (p<0.05); SDMA and nitrates (p<0.05); between OS parameters in the experimental group; AOPP and SH groups (p<0.05) and TBARS in plasma and SH groups (p<0.01), SDMA and AOPP (p< 0.05); SDMA and TBARS in plasma (p<0.05); SDMA and SH groups (p<0.01); nitrates and SH groups (p<0.05). Conclusion: There was no significant difference in oxidative and nitrosative stress parameters with respect to the immunosuppressive protocol. Kratok sadrzaj Uvod: Transplantacija bubrega sama po sebi popravlja bubrežnu funkciju, ali ne dovodi do potpunog oporavka. Cilj ovog rada bio je da se odrede parametri oksidativnog i nitrozativnog stresa kao i parametri antioksidativne zastite u populaciji pacijenata sa presacfenim bubregom sa stabilnom funkcijom grafta i bez kliničkih znakova kardiovasku- larne bolesti. Takođe, naš cilj je bio da se utvrdi povezanost među ispitivanim parametrima i procene potencijalne razlike između svih ispitivanih biomarkera u odnosu na imunosupresivni protokol. Metode: U istraživanje jeuključeno 57 pacijenata sa presadenim bubregom i 31 kontrolni subjekt, koji su po go- dinama i polu odgovarali pacijentima sa presađenim bubregom. Svi pacijenti uključeni u istrazivanje imali su transplantaciju bubrega najmanje 12 meseci pre početka istraživanja i bili su na standardnoj imunosupresivnoj terapiji. U ovom radu određivali smo reaktivne supstance tiobar- bituratne kiseline (TBARS) u plazmi i eritrocitima, uznapre- dovale produkte oksidacije proteina (AOPP), parametre nitrozativnog stresa (asimetrični i simetrični dimetilarginin- ADAAA i SDMA) i antioksidativne zastite (ukupne SH grupe i aktivnost katalaze). Rezultati: Rezultati naše studije su pokazali znatno više vrednosti parametara oksidativnog i nitrozativnog stresa kod pacijenata sa presađenim bubregom u odnosu na zdrave dobrovoljce (p<0,01 osim za aktivnost katalaze u plazmi, kada je p<0,05). Korelaciona analiza pokazala je znacajnu pozitivnu korelaciju između ADMA i SDMA (p<0,01); ADMA i nitrata (p<0,05); SDMA i nitrata (p<0,05); između parametara oksidativnog stresa u eksperimentalnoj grupi; AOPP i SH grupe (p<0,05), kao i TBARS u plazmi i SH grupe (p<0,01), SDMA i AOPP (p<0,05); SDMA i TBARS u plazmi (p<0,05); SDMA i SH grupe (p<0,01); nitrata i SH grupe (p<0,05). Zakljudak: Naši rezultati nisu ukazali na statistički značajnu razliku u ispitivanim parametrima među pacijentima na ciklosporinu A i takrolimusu

Crosstalk of inflammatory mediators and lipid parameters as early markers of renal dysfunction in stable renal transplant recipients with regard to immunosuppression

BACKGROUND Kidney transplantation is still the treatment of choice for end-stage renal disease, therefore it is important to establish all modifiable risk factors for initiation of renal dysfunction. MATERIAL/METHODS We enrolled 73 renal transplant recipients, who were more than 12 months post-renal transplant surgery, had a stable graft function, had no clinically present cardiovascular disease, and were on standard immunosuppressive therapy. The concentrations of intracellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), CRP, lipids, and lipoproteins were measured. We used logistic regression to calculate non-adjusted, age, and multivariable-adjusted ORs and 95% confidence intervals for glomerular filtration rate, GFR <60 ml/min/1.73 m(2). RESULTS 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. There were no differences in all evaluated parameters between groups in regard to immunosuppressive therapy. CONCLUSIONS 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.

Crosstalk of Various Biomarkers That Might Provide Prompt Identification of Acute or Chronic Cardiorenal Syndromes

Introduction: Pathophysiological interaction between the heart and kidneys represents the basis for clinical entities called cardiorenal syndromes. The purpose of the study was to assess the relations between acute and chronic cardiorenal syndromes and biomarkers [advanced oxidation protein products, brain natriuretic peptide, malondialdehyde, xanthine oxidoreductase (XOD), xanthine oxidase, xanthine dehydrogenase, interleukin 8, cystatin C, plasminogen activator inhibitor-1, high-sensitive troponin T, C-reactive protein and glomerular filtration rate, measured by the Modification of Diet in Renal Disease (MDRD) formula], to hypothesize biomarkers that might provide a prompt identification of acute or chronic cardiorenal syndromes, and to distinguish acute versus chronic types of these syndromes. Methods: A total of 114 participants were enrolled in this study, i.e. 79 patients divided into subgroups of acute and chronic cardiorenal syndromes and 35 volunteers. Results: Nonadjusted odds ratio (OR) showed that there was a significant risk for acute cardiorenal syndrome with increased XOD activity (p = 0.037), elevated cystatin C concentration (p = 0.038) and MDRD (p = 0.028). Multivariable adjusted OR, on the other hand, revealed that only glomerular filtration rate measured by the MDRD formula had a significance for acute cardiorenal syndrome (p = 0.046). Nonadjusted OR showed a significant risk for chronic cardiorenal syndrome only in elderly (p = 0.002). Multivariable adjusted OR exhibited that age was the only risk factor for chronic cardiorenal syndrome (p = 0.012). Conclusion: Cystatin C, glomerular filtration rate measured by the MDRD equation and XOD were independent risk factors for acute cardiorenal syndrome, while age remained an independent risk factor for chronic cardiorenal syndrome. When comparing ORs of evaluated parameters, the highest significance for acute cardiorenal syndrome was plasma concentration of cystatin C.

Renalase Assessment With Regard to Kidney Function, Lipid Disturbances, and Endothelial Dysfunction Parameters in Stable Renal Transplant Recipients

Background: Renal transplant dysfunction has been shown to be independent predictor for premature cardiovascular disease and mortality. Renalase, a flavoprotein secreted by several tissues, including the kidney, has been found to regulate sympathetic tone and blood pressure. The purpose of this secondary analysis was to explore relationships among parameters of endothelial dysfunction, lipids, glomerular filtration rate, and renalase in 2 groups: renal transplant patients with controlled hypertension and healthy volunteers. Methods: In the parent study, 73 renal transplant recipients and 32 age- and gender-matched controls were enrolled. A fasting sample for endothelial, lipid, and renalase values, along with other clinical parameters, was obtained. Results: We found statistically significant inverse correlation between renalase and estimated glomerular filtration rate (r = −0.552, P < .001), positive correlation between renalase and creatinine (r = 0.364, P = .003), total cholesterol (r = 0.578, P < .001), low-density lipoprotein cholesterol (r = 0.261, P = .046), and non-high-density lipoprotein cholesterol (r = 0.327, P = .01). Renalase inversely correlated with hemoglobin (r = −0.232, P = .032) and positively with white blood cells (r = 0.233, P = .032). There was a significant difference in plasma renalase with regard to chronic kidney disease stages (F = 13.346, P < .001) but did not correlate with C-reactive protein. Renalase did not correlate with any of parameters of endothelial dysfunction, C-reactive protein, neither with some demographic data (gender, age, time or type of transplantation, risk factors). There were no differences in renalase concentration with regard to antihypertensive therapy. Conclusion: Renalase strongly and inversely correlated with kidney function, positively with creatinine and lipid disturbances. Due to that it is very likely that renalase levels are determined mostly by renal function.

Impact of socio-demographic characteristics and long-term complications on quality of life in patients with diabetes mellitus

OBJECTIVE Diabetes mellitus (DM) has been one of the leading chronic diseases worldwide over past decades. The objective of the study was to identify predictors associated with health-related quality of life (HRQOL) in diabetic patients. METHODS A cross-sectional questionnaire-based study was conducted at the General Hospital of the city of Leskovac, between June and November 2015. The Short Form-36 (SF-36) questionnaire, EuroQol-5D (EQ-5D) and EuroQol-VAS (EQ-VAS) questionnaires were used. Univariate and multivariate linear regression analyses were performed. RESULTS The total number of patients was 285, 112 men (39.3%) and 173 women (60.7%), average age 63.92 ± 1.07 years. The results of multiple linear regression of socio-demographic characteristics in relation to dimensions of the quality of life measured by SF-36 and EQ-VAS showed that age, country (rural) life, low level of education, retirement, and poor economic status are predictors of lower quality of life. Our results showed that employment has a significant association with higher Physical Component Score (PCS), Mental Component Score (MCS) and EQ-VAS score, which can be explained with higher incomes, improved economic status and less possibility for the occurrence of depressive mood. Patients without formal education have lower QOL. Univariate multiple regression analysis of the presence of micro- and macrovascular complications of DM showed that angina pectoris, heart failure, diabetic retinopathy, and diabetic nephropathy are the most important factors affecting the quality of life in our population. After including the multivariate model, all tested complications remained statistically significant. CONCLUSION Our results showed that both socioeconomic and chronic complications are relevant factors of HRQOL in type 1 and 2 diabetes mellitus patients. Age, rural lifestyle, retirement, lower level of education and low socioeconomic status, as well as DM complications (angina pectoris, hearth failure, diabetes nephropathy, and diabetes retinopathy) were found to be independent risk factors for the component scores of SF-36 and EQ-VAS score. Taking into consideration the results obtained, health practitioners should be aware not only of the clinical parameters of patients with DM, but also of their educational level and working status.

The influence of type 2 diabetes mellitus on the frequency and complexity of ventricular arrhythmias and heart rate variability in patients after myocardial infarction

Background/Aim After myocardial infarction arrhythmic cardiac deaths are significantly more frequent compared to non-arrhythmic ones. The aim of the study was to investigate the influence of type 2 diabetes mellitus (T2DM) on the frequency and complexity of ventricular arrhythmias after myocardial infarction. Methods The study included 293 patients, mean age 59.5 ± 9.21 years, who were at least six months after acute myocardial infarction with the sinus rhythm, without atrioventricular blocks and branch blocks. In the clinical group 95 (32.42%) patients were with T2DM, while 198 (67.57%) patients were without diabetes. All of the patients were subjected to the following procedures: standard ECG according to which the corrected QT dispersion (QTdc) was calculated, exercise stress test, and 24-hour holter monitoring according to which, the four parameters of time domain of heart rate variability (HRV) were analyzed: standard deviation of all normal RR intervals during 24 hours (SDNN), standard deviation of the averages of normal RR intervals in all five-minute segments during 24 hours (SDANN), the square root of the mean of the sum of the squares of differences between adjacent normal (RMS-SD), and percentage of consequtive RR intervals which differed for more than 50 ms during 24 hours (NN > 50 ms). Results In patients after myocardial infarction, patients with T2DM had significantly higher percentage of frequent and complex ventricular arrhythmias compared to the patients without diabetes (p < 0.001). The patients with T2DM had significantly higher percentage of residual ischemia (p < 0.001), and arterial hypertension (p < 0.001), compared to patients without diabetes. The patients with T2DM had significantly lower values of HRV parameters: SDNN (p < 0.001); SDANN (p < 0.001); RMS-SD (p < 0.001), and NN > 50 ms (p < 0.001), and significantly higher values of QTdc (p < 0.001) compared to the patients without diabetes. Conclusion The study showed that type 2 diabetes mellitus has significant influence on ventricular arrhythmias, HRV parameters and QT dispersion in patients after myocardial infarction.

PS 02-44 URIC ACID CONCENTRATION, XANTHINE OXIDASE ACTIVITY AND SALT SENSITIVITY INDEX AS PREDICTORS FOR PRIMARY ARTERIAL HYPERTENSION – WHICH ONE IS THE BEST?

Objective: The goal of the study was to measure plasma concentration of uric acid and xanthine oxidase (XO) activity and to determine index of sodium sensitivity in the group of patients with primary arterial hypertension, and to hypothesize among them, by multivariate modeling, parameters that represent best risk factors for development of primary arterial hypertension. Design and Method: We included 178 patients, mean age 59 ± 18.2 years. The patients had to have preserved kidney function, to be at least 5 years with diagnosed primary arterial hypertension, to be without a disorder manifested with uric arthropathy and without diuretic therapy for at last 6 months. Salt sensitivity index was calculated by dividing mean arterial pressure with natriuresis for 24 hours. XO activity was measured in plasma according to the liberation of uric acid by using xanthine as substrate in the absence of NADH. Uric acid serum concentration was measured spectrophotometrically. Results: Significant differences were found between groups in all evaluated parameters, acidum uricum (p = 0.002), XO activity (p = 0.002), and salt sensitivity index (p < 0.001). Non-adjusted OR showed that there was a significant risk for primary arterial hypertension with increased XO activity (OR = 1.015, p = 0.037), elevated uric acid concentration (OR = 1.058, p = 0.038), and high salt sensitivity index (OR = 1.821, p = 0.028). Comparing theses predictive values the highest significance for primary arterial hypertension was salt sensitivity index (OR = 1.821). Conclusions: Acidum uricum, XO activity, and salt sensitivity index were independent risk factors for primary arterial hypertension. Comparing OR of evaluated parameters the highest significance for hypertension had measuring salt sensitivity.