Long-Term Consequences of Increased Activity of Urine Enzymes After Cardiac Surgery - A Prospective Observational Study.

Introduction: Cardiac surgery associated AKI (CSA-AKI) complicates recovery and may be associated with a greater risk of developing chronic kidney disease and mortality. The aim of this study was to assess long-term clinical consequences of transient increased activity of urinary enzymes after cardiac surgery (CS). Methods: An observational study was conducted in a group of 88 adult patients undergoing planned coronary artery bypass grafting (CABG), but all samples were obtained from 79 patients. The activity of urinary enzymes: N-acetyl-beta-glucosaminidase (NAG), arylsulfatase A (ASA) and beta-glucuronidase was evaluated in sequential urine samples. A comparative analysis of biochemical parameters was performed regarding the occurrence of acute kidney injury (AKI) defined by KIDGO at 24 hours, at day 30 and 5-years after the operation. Results: During the first 24 hours after CS AKI was diagnosed in 13 patients. A comparison of the activity of urinary enzymes in pre-defined time-points showed significant differences for ASA and NAG (post OP-sample p < 0.028 and p < 0.022; POD 1 sample p < 0.004 and p < 0.001 respectively). No patient had any biochemical or clinical features of kidney failure at day 30. In the AKI group kidney failure was diagnosed in 36% of patients within 5 years of follow-up as opposed to 5% in the no AKI group. The activities of tubular enzymes in urine reflect a general injury of kidney tubules during and after the operation. However, they are not ideal biomarkers for prediction of the degree of kidney injury and further poor prognosis of CS-AKI.

Iron excretion in urine in patients with acute kidney injury after cardiac surgery.

BACKGROUND: Hemolysis during cardiopulmonary bypass may lead to acute kidney injury caused by an excessive amount of iron. The clinical usefulness of the measurement of total iron concentration in the urine with the use of the atomic absorption spectrometry method for early identification of patients with postoperative acute kidney injury is not well-established. OBJECTIVES: An observational, prospective study was conducted on a group of 88 pre-selected adult patients undergoing a planned coronary artery bypass grafting (CABG) procedure. MATERIAL AND METHODS: The amount and concentrations of total iron, creatinine and neutrophil gelatinaseassociated lipocalin (NGAL) were evaluated in urine samples. A comparative analysis of the evaluated biochemical parameters was performed in regard to the occurrence of acute kidney injury 48 h postoperatively. RESULTS: Patients in the acute kidney injury group presented more advanced age (p = 0.01), preoperative myocardial infarction (p = 0.02), diuresis reduction (p = 0.04), and lower total iron levels in the 48-hour urine sample (p = 0.01). There was no difference when considering iron concentration in single urine samples in the study group. CONCLUSIONS: The sole result of total iron concentration in single urine samples is unreliable for the diagnosis of acute kidney injury after cardiac surgery. Decreased excretion of iron in the urine seems to be an important additional element in the multifactorial pathogenesis of acute postoperative kidney failure.

Cardiac surgery related cardio-renal syndrome assessed by conventional and novel biomarkers - under or overestimated diagnosis?

INTRODUCTION: Serum creatinine is a 'gold standard' criterion of recognizing and staging of acute kidney injury (AKI) despite it being a suboptimal, delayed indicator. The interpretation of increased values of biomarkers imposes great difficulty regarding cardiac surgery procedures performed with cardiopulmonary bypass and may lead to under- or overestimated diagnosis. The aim of this study was to evaluate the clinical utility of the sole serum creatinine or urine neutrophil gelatinase-associated lipocalin (NGAL) concentration used for identification of patients with AKI after cardiac surgery. MATERIAL AND METHODS: A prospective observational study was conducted on a group of 88 adult patients undergoing a coronary artery bypass grafting procedure. Serum creatinine was evaluated on the day of the operation, and 24 and 48 h post-operatively. Urinary NGAL concentration was measured: immediately after and one hour after cardiopulmonary bypass, and 24 h from the beginning of the operation. We assessed features of kidney injury and 30-day and 5-year mortality. RESULTS: Patients in the AKI group diagnosed with creatinine level and urine output criteria presented more advanced age (p = 0.01), higher body mass index (p = 0.01) and preoperative myocardial infarction (p = 0.02). Elevation of NGAL level was observed in 5 of 13 cases with AKI, based on creatinine criteria and 4 of 75 cases without AKI. Within 5 years after the surgical procedure the recurrence of renal failure was 36% in the AKI group (with perioperative NGAL elevation in 2 cases only). CONCLUSIONS: In the cardiac surgery patients the diagnosis of AKI based on sole serum creatinine or urine NGAL concentration confirmed transient kidney injury. However, the clinical implications of these findings are insufficient for prediction of clinical outcome.

Urinary IL-8 is a marker of early and long-term graft function after renal transplantation.

In this study, we examined whether the IL-8 content of urine sampled on day 1 and day 14 after renal transplantation is a marker of early and long-term renal function. Moreover, we assessed whether its concentration is positively correlated with the matrix metalloproteinase-9 (MMP-9) content of urine sampled on day 1 and day 30 and 12 months after renal transplantation. Our analysis covered 87 patients who underwent a kidney transplant. The patients were observed for an average of 30 months (12-60 months). The IL-8 concentration determined on day 1 was significantly negatively correlated with creatinine clearance early after renal transplantation (on days 1, 7, 14 and 30), as well as during long-term observations. IL-8 concentration in urine sampled on day 1 and day 14 was higher in patients demonstrating DGF than in those without DGF. No relationship was found between IL-8 content and cold ischaemia time. MMP-9 activity determined on day 1 and month 3 after renal transplantation was positively correlated with the IL-8 content determined in urine sampled on day 1, Rs = +0.32, p < .05 and Rs = +0.31, p < .05, respectively. The results of this study suggest that a high IL-8 content in urine sampled on day 1 after renal transplantation is an unfavourable marker of early and long-term (years-long) graft function. A high IL-8 content in urine sampled on day 1 after renal transplantation was positively correlated with the activity of metalloproteinase-9 in urine. This proves that both of these chemokines cooperate in ischaemia-reperfusion injuries in transplanted kidneys.

[Polymorphisms in the oxidative stress-related genes and cancer risk]. / Polimorfizm genów obrony antyoksydacyjnej a ryzyko rozwoju raka.

Oxidative damage induced by the generation of reactive oxygen species (ROS) is thought to be related to human cancer aetiology. Oxidative stress can result in DNA damage, including oxidized bases, formation of DNA adducts and DNA strand breaks, as well as lipid peroxidation, protein modification, membrane disruption and mitochondrial damage. The effect of reactive oxygen species is balanced by the antioxidant action ofnonenzymatic antioxidants (e.g. vitamins A, C, E, glutathione and flavonoids), as well as antioxidant enzymes. There are three main types of antioxidant defence enzymes: superoxide dismutases, catalase and glutathione peroxidases. A variety of cancer cells are known to have lower antioxidant enzyme activity when compared with their normal counterparts. Many studies have examined genetic variation in the genes coding for these enzymes and their relationship to cancer risk. Only a few genetic variants (single nucleotide polymorphisms--SNPs) in genes related to antioxidant defence were found to be associated with breast, prostate, lung, pancreatic, colorectal and bladder cancer. However, the results from these have been contradictory. Moreover, it is believed that environmental as well as genetic factors are implicated in the development of cancers, and consequently it is important to assess both genetic (including gene-gene association) and non-genetic (e.g. diet, supplementation, smoking and alcohol consumption) variability in the activities of defence enzymes in relation to cancer. In this review we focus on the biological function of antioxidant defence enzymes, and relationship between well-known SNPs in SOD1, SOD2, CAT, GPX1 and GPX4 genes and genetic susceptibility to cancer.

Oxidative stress modulates the organization of erythrocyte membrane cytoskeleton.

BACKGROUND: Apart from their main role in transporting oxygen and carbon dioxide, erythrocytes play also an important role in organism antioxidative defence. Direct exposure to reactive oxygen species (ROS) results in shortening of their half-life, even by 50%. The presence of glucose, being the substrate in pentose phosphate pathway (PPP) cycle, is one of the factors that can have influence on the level of oxidative stress. The activity of PPP increases during oxidative stress. Glucose guarantees normal PPP functioning with the production of reductive equivalents in the amounts necessary to reproduction of glutathione--nonenzymatic free radical scavenger. In available literature there are no reports regarding the changes in protein contents of erythrocyte cytoskeleton exposed to t-butyl hydroperoxide in relation to glucose presence in incubation medium. MATERIAL/METHODS: Erythrocytes taken from 10 healthy subjects were used to assess the influence of generated free radicals on erythrocyte proteins and chosen parameters of oxidative stress. Erythrocytes were incubated in the solutions containing deferent concentrations of t-butyl hydroperoxide and glucose. Electrophoresis was performed on polyacrylamide gel in denaturating conditions. The contents of tryptophan in membranes was evaluated spectrofluorometrically. RESULTS/CONCLUSIONS: In vitro conditions oxidative stress leads to protein damage in erythrocyte cytoskeleton, both in proteins inside the cell as well as having contact with extracellular environment. In consequence, the amount of low-molecular proteins--mainly globin, which bind to cytoskeleton, increases. This process takes place independently of glucose presence in incubation medium. One of the element of protein cytoskeleton, tryptophan, also undergoes degradation. The decrease of its contents is higher during erythrocyte exposure to t-BOOH in environment containing glucose, what can suggest prooxidative influence of glucose in conditions in vitro.

Conjugated linoleic acid isomers may diminish human macrophages adhesion to endothelial surface.

Dysfunction of endothelial cells and activation of monocytes in the vascular wall are important pathogenetic factors of atherosclerosis. Conjugated linoleic acids (CLAs) can modulate the function of immune system in humans: reduce the concentration of atherogenic lipoproteins, and the intensity of inflammatory processes in the plasma. In this paper, we focus on macrophage's surface integrins (ß1 integrin CD49d/CD29-(VLA4); Mac-1 as well as endothelial human vein endothelial cell (HUVEC) surface adhesins: vascular cell adhesion molecule-1 (VCAM-1) and intracellular cell adhesion molecule-1 (ICAM-1)) expression in relation to CLA isomer used during cell culture. Both CLA isomers decreased expression of VLA-4 and Mac-1 on macrophages compared with control cells (cultured with bovine serum albumine (BSA) or oxidized form of low-density lipoproteins). cis-9, trans-11 CLA isomer reduced ICAM-1 and VCAM-1 expression on the endothelium surface. Strong tendency to reduce of adhesion of macrophages to HUVEC in the cells cultured with CLA isomers was observed. The potential role of cis-9, trans-11 CLA in the reduction of adhesion of macrophages to the HUVEC--one of the important steps in the inflammatory process, can be considerate. These mechanisms may contribute to the potent anti-atherosclerotic effects of CLA in vivo.

[Metformin - mechanisms of action and use for the treatment of type 2 diabetes mellitus]. / Metformina - mechanizmy dzialania i zastosowanie w terapii cukrzycy typu 2.

Metformin is widely used for the treatment of type 2 diabetes mellitus. Although this biguanide derivative has been used for more than 50 years, its mechanism of action has not been fully elucidated. In this article we describe the latest achievements concerning the mechanisms of antihyperglycemic action of metformin. They include: decrease of glucose absorption in the small intestine, increase of glucose transport into cells, decrease in the plasma free fatty acid concentrations and inhibition of gluconeogenesis. Activation of AMP-activated protein kinase (AMPK) plays an important role in these processes. The latest discoveries have revealed mechanisms of anti-atherosclerotic, hypotensive and anticancer action of metformin and its impact on vein endothelial function. The pleiotropic actions of metformin include impact on plasma lipid profile, decrease of oxidative stress, and increase in plasma fibrinolytic activity. Although metformin is not metabolized, the latest research has shown that it is actively transported into hepatocytes and renal tubular epithelium, by OCT1 (organic cation transporter 1, encoded by the SLC22A1 gene) and OCT2 (organic cation transporter 2, encoded by the SLC22A2 gene), respectively. However, MATE1 transporter (multidrug and toxin extrusion 1 protein) is encoded by the SLC47A1 gene and facilitates metformin excretion from these cells into bile and urine. Metformin transporter gene polymorphisms may contribute to significant variation in drug response. Further studies of mechanisms of metformin action could contribute to its wider use for the prevention of type 2 diabetes mellitus, cancer, and Alzheimer's disease, and for the treatment of type 1 diabetes mellitus, and polycystic ovary syndrome (PCOS).

[Oxidation stress in inflammatory bowel disease]. / Stres oksydacyjny w nieswoistych zapaleniach jelit.

Inflammatory bowel disease (Crohn's disease and ulcerative colitis) has a complex and still largely unknown etiopathology. One of the possible causes can be traced to free radical reactions, and precisely to disorders in the equilibrium between pro-oxidants and antioxidants. This article is a concise review of the literature showing the current state of knowledge of interactions between pro-oxidants and antioxidants in Crohn's disease and ulcerative colitis.

[Cigarette smoking as a promoting factor for nonspecific inflammatory bowel disease]. / Palenie papierosów czynnikiem sprzyjajacym powstawaniu nieswoistych chorób zapalnych jelit.

Nonspecific inflammatory bowel diseases represent serious and chronic pathologies of the gastrointestinal tract. Even though the etiology of these diseases has not been fully elucidated, it is known that environmental factors like cigarette smoking may induce and exacerbate their course. Many substances in cigarette smoke have a modulatory effect on the immune system through a change in the composition of pro-/anti-inflammatory cytokines witch plays its part in the development of inflammation. Moreover, cigarette smoke contains reactive oxygen species which may combine with decreased activity of antioxidant enzymes to produce an additional proinflammatory effect. It is interesting that cigarette smoke has a different effect on the course of Crohn's disease compared with ulcerative colitis.

Conjugated linoleic acids can change phagocytosis of human monocytes/macrophages by reduction in Cox-2 expression.

Prostaglandin E2 produced endogenously (by cyclooxygenases) can regulate macrophage phagocytosis. Cyclooxygenase activity reduction (mainly through inhibition of inducible Cox-2) can induce PGE2 synthesis depression and can activate the phagocytosis process. There are no reports in the literature explaining whether conjugated linoleic acid dienes (trans-10, cis-12 CLA and cis-9, trans-11 CLA) modify the phagocytic activity of human macrophages. For the purpose of this study, monocytes were isolated from venous blood, incubated for 7 days with 30 microM CLAs, and then (in some experiments) LPS (1 microg/mL) was added to the medium. Subsequently, monocyte/macrophage phagocytosis, NF-kappaB transcription factor activity, Cox-2 and PPARgamma mRNA expression (and the amounts of Cox-2 and PPARgamma proteins) and PGE2 synthesis were determined. Both CLA isomers increased macrophage phagocytosis through inhibition of Cox-2 expression (might by inactivation the NF-kappaB pathway). The inhibition of mRNA Cox-2 expression contributed (particularly with respect to trans-10, cis-12 CLA) to a decrease in protein Cox-2 synthesis and to reduction of prostaglandin E2 content in the cell. The inhibition of PGE2 synthesis (by CLA treatment) enhanced the phagocytosis process in macrophages.

Copper modifies the activity of sodium-transporting systems in erythrocyte membrane in patients with essential hypertension.

The aim of the study was to verify the hypothesis if copper could influence the activity of sodium-transporting systems in erythrocyte membrane that could be related to essential hypertension. The examined group of patients consisted of 15 men with hypertension. The control group was 11 healthy male volunteers. The Na+/H+ exchanger (NHE) activity in erythrocytes was determined according to Orlov et al. The activity of transporting systems (ATP-Na+/K+; co-Na+/K+/Cl-; ex-Na+/Li+; free Na+ and K+ outflow [Na+, K+-outflow]) was determined according to Garay's method. The concentration of copper in plasma was assessed using atomic absorption spectrometry. The activity of ATP-Na+/K+ (micromol/L red blood cells [RBCs]/h) in hypertensive patients was 2231.5 +/- 657.6 vs 1750.5 +/- 291 in the control (p < 0.05), the activity of co-Na+/K+/Cl- (micromol/L RBCs/h) in hypertensives was 171.3 +/- 77.9 vs 150.7 +/- 53.9 in the control (NS). Na+-outflow (micromol/L RBCs/h) in hypertensives was 118.3 +/- 51.6 vs 113.3 +/- 24.4 in the control (NS). The K+-outflow (micromol/L RBCs/h) in hypertensives was 1361.7 +/- 545.4 vs 1035.6 +/- 188.3 in the control (NS). The activity of ex-Na+/Li+ (micromol/L RBCs/h) in hypertensive patients was 266.1 +/- 76.1 vs 204.1 +/- 71.6 in the control (p < 0.05). NHE activity (mmol/L RBCs/h) in hypertensives was 9.7 +/- 2.96 vs 7.7 +/- 1.33 in the control (p < 0.05). In hypertensive patients, negative correlation was found between the activity of Na+/K+/Cl- co-transport and plasma copper concentration (Rs = -0.579, p < 0.05) and between the activity of ex-Na+/Li+ and plasma copper concentration (Rs = -0.508, p < 0.05). Plasma copper concentration significantly influences the activity of sodium transporting systems in erythrocyte membrane. Copper supplementation could be expected to provide therapeutic benefits for hypertensive patients.

Is conjugated linoleic acid (CLA) a protective factor in atherosclerosis? Study with the use of neural networks.

PURPOSE: Conjugated linoleic acid (CLA) is a term used for positional and geometrical isomers of linoleic acid whose two unsaturated bonds are separated by one saturated bond (cis9trans11 and trans10cis12). Cooked meat and milk are among the richest dietary sources of CLA. Recently, much attention has been devoted to CLA due to its anti-cancer, anti-atherogenic, and anti-diabetic properties. MATERIAL AND METHODS: Our study group comprised 29 patients aged 45 to 75 years who were operated for atherosclerotic stenosis in the carotid arteries. RESULTS: Venous blood was collected after an overnight fast. Total cholesterol and triglycerides were assayed with enzymatic test kits. HDL-cholesterol was measured after precipitation with sodium magnesium phosphotungstate. LDL-cholesterol was calculated from total cholesterol, triglyceride and HDL-cholesterol concentrations using Friedewald's formula. A Perkin-Elmer gas chromatograph (model 8500) was used to analyze fatty acids methyl esters. Statistical analysis was performed with the Statistica Neural Networks software. Significantly lower plasma content of c9t11 CLA, linoleic, and arachidonic acids was found in the study group as compared with controls. Parametric analysis disclosed that c9t11 CLA concentrations depended on triglycerides and arachidonic acid in the study group and on linoleic acid and triglycerides in controls. An increase in total cholesterol concentration was associated with a decrease in the concentration of c9t11 CLA in the study group and a parallel increase in the control group.

Influence of glucose in dialyzing fluid on purine concentrations in hemodialyzed patients with chronic renal failure.

BACKGROUND: In chronic renal failure the accumulation of some purine nucleotides (in erythrocytes) develops both in patients undergoing conservative treatment and in hemodialyzed patients. The aim of the study was: (1) To find if hemodialysis (HD) sessions using dialyzing fluid containing glucose leads to an increase in ATP concentration and changes in the concentration of other nucleotides, nucleosides and oxypurines in erythrocytes. The potential consequence of such purine concentration changes is the increase of 2,3-DPG concentration and an improved transportation of oxygen in erythrocytes which are more resistant to hemolysis. (2) To compare blood concentrations of purine nucleotides, nucleosides and oxypurines in patients undergoing chronic HD with dialyzing fluid containing or lacking glucose. Significant differences could suggest the long-term influence of glucose in dialyzing fluid on erythrocyte energetic state. METHODS: Whole blood nucleotide concentrations were evaluated with the use of a high-performance liquid chromatography technique. RESULTS: Before the HD session the patients in the 'plus glucose' group had significantly higher concentrations of ATP, ADP, AMP, TAN, NAD, NADP, GTP + GDP, GMP, Urd and HYP than patients in the 'no glucose' group. After the HD the patients in the 'plus glucose' group had significantly higher concentrations of ADP, AMP, TAN, NAD, NADP, Urd and HYP than in the 'no glucose' group. Both before and after the HD session, the uric acid concentrations and AEC were significantly lower in the 'plus glucose' group than in the 'no glucose' group. A significant decrease in the whole blood hypoxanthine (p < 0.05) and uric acid (p < 0.001) concentrations after HD was found in the 'no glucose' group while a significant increase in ADP concentration (p < 0.05) was detected in the patients' erythrocytes in the 'plus glucose' group. In this group a significant decrease of GTP + GDP and GMP (p < 0.05), uric acid concentration (p < 0.001) and adenylate energy charge (p < 0.05) were observed after the dialysis. However, no significant differences in nucleotide concentrations before and after the HD were found in the 'no glucose' group. CONCLUSION: The presence of glucose in the dialyzing fluid causes a significant modification of the energetic state of cells which is reflected by the purines' and their metabolites' concentrations in the erythrocytes. Higher ATP concentrations in patients with renal failure who have been dialyzed with the fluid containing glucose can be considered as an organism adaptation to a decreased amount of RBC and hemoglobin concentration.