Ferenc Sztanek

The human paraoxonase‐1 phenotype modifies the effect of statins on paraoxonase activity and lipid parameters

AIMS Human serum paraoxonase-1 (PON1) protects lipoproteins against oxidation by hydrolysing lipid peroxides in oxidized low-density lipoprotein, therefore it may protect against atherosclerosis. One of the two common PON1 gene polymorphisms within the PON1 gene is the Q192R, whose prevalence can be estimated by phenotype distribution analysis. The goal of this study was to clarify the role of PON1 phenotypes on the effect of three different statins on paraoxonase activity and lipid parameters. METHODS One hundred and sixty-four patients with type IIb hypercholesterolaemia were involved in the study. We examined the effect of 10 mg day(-1) atorvastatin, 10/20 mg day(-1) simvastatin and 80 mg day(-1) extended-release fluvastatin treatment on lipid levels and paraoxonase activity in patients with different PON1 phenotypes. The phenotype distribution of PON1 was determined by the dual substrate method. RESULTS Three months of statin treatment significantly increased paraoxonase activity in every statin-treated group. In patients with AB+BB phenotype, statin treatment was significantly more effective on paraoxonase activity than in the AA group. Statin treatment more effectively decreased triglyceride levels in the AB+BB group compared with the AA group in the whole study population and in the simvastatin-treated group. Atorvastatin treatment was significantly more effective on apolipoprotein B levels in patients with AB+BB phenotype than in the AA phenotype group. CONCLUSIONS The PON1 phenotype may be a novel predictive factor for the effectiveness of statin treatment on PON1 activity and serum lipid levels; however, different types of statins may exert different effects on these parameters.

Atorvastatin effect on the distribution of high-density lipoprotein subfractions and human paraoxonase activity

Human serum paraoxonase-1 (PON1) protects lipoproteins against oxidation by hydrolyzing lipid peroxides in oxidized low-density lipoprotein (LDL); therefore, it may protect against atherosclerosis. Changes in the ratio of high-density lipoprotein (HDL) subfractions may alter the stability and the antioxidant capacity of PON1. The aim of the study was to examine the effect of atorvastatin treatment on the distribution of HDL subfractions, LDL size, cholesteryl ester transfer protein (CETP), lecithin-cholesterol acyltransferase (LCAT), and PON1 activity. In all, 33 patients with type IIa and IIb hypercholesterolemia were involved in the study. LDL sizes and HDL subfractions were determined by gradient gel electrophoresis. CETP, LCAT, and PON1 activities were measured spectrophotometrically. Three months of treatment with atorvastatin 20 mg daily significantly increased the HDL3 (+8.13%) and decreased the HDL2a and HDL2b subfractions (-1.57% and -6.55%, respectively). The mean LDL size was significantly increased (+3.29%). The level of oxidized LDL was significantly decreased (-46.0%). The PON1 activity was augmented by the atorvastatin treatment (+5.0%). The CETP activity positively correlated with the HDL2b level and negatively correlated with the HDL3 and HDL2a levels. Atorvastatin alters the HDL subfractions, which may improve its antiatherogenic effect via enhancement of the PON1 activity.

Alteration of PON1 Activity in Adult and Childhood Obesity and Its Relation to Adipokine Levels

Obesity as a pathogenic disorder is a predisposing factor for cardiovascular diseases and shows an increasing incidence in the industrialized countries. Adipokines such as leptin, adiponectin and resistin have a great impact on the development of atherosclerosis in obesity. Elevated levels of leptin have been found to be atherogenic whereas decreased levels of adiponectin have been proved to be anti-atherogenic in recent studies. The exact role of resistin in the process of atherosclerosis has so far remained uncertain and controversial. In our recent work, we studied the alteration in human paraoxonase-1 (PON1) activity and adipokine levels; furthermore, we also aimed at identifying the potential correlation between these parameters in this metabolic disorder. We investigated the above-mentioned parameters both in adults and in children, with regard to the emerging role of childhood obesity and to get a clearer view of these factors during a whole lifetime. Investigating the adult population with a broad range of body mass index (BMI) we found significantly increased leptin and significantly decreased adiponectin and resistin levels and PON1 activity in the obese group compared to the lean controls. Adiponectin and resistin levels showed significantly positive correlation, while leptin and BMI showed significantly negative correlation with PON1 activity. Our findings were similar in childhood obesity: leptin showed significantly negative correlation, while adiponectin showed significantly positive correlation with PON1 activity. We found gender differences in the univariate correlations of leptin and adiponectin levels with PON1 activity in the adult population. In multiple regression analysis, adiponectin proved to be an independent factor of PON1 activity both in childhood and adult obesity, furthermore thiobarbituric acid-reactive substances (TBARS) also proved to be an independent predictor of the enzyme in adults, reflecting the important role of oxidative stress in obesity. Investigating PON 192 Q/R polymorphism by phenotypic distribution (A/B isoenzyme) in obese children, we found a significant correlation of PON1 arylesterase activity with leptin and adiponectin levels, and of body fat percentage with PON1 192 B isoenzyme. According to our studies, these metabolic changes in obesity predispose to the early development of atherosclerosis throughout our whole lifetime. Decreased activity of PON1 and alterations in adipokine levels in childhood obesity could contribute to an early commencement of this process, detected only later in adulthood by increased cardiovascular morbidity and mortality. Changed levels of leptin, adiponectin, resistin and PON1 activity at all ages, just like 192 Q/R polymorphism determined by phenotypic distribution, may be useful markers beside the general risk factors.

Decreased paraoxonase 1 (PON1) lactonase activity in hemodialyzed and renal transplanted patients. A novel cardiovascular biomarker in end-stage renal disease

BACKGROUND Human paraoxonase-1 (PON1) has also been described as a lactonase. Decreased PON1 lactonase activity was found to be a predictor of cardiovascular disease. Homocysteine thiolactonase activity may prevent proteins from homocysteinylation and is thought to be a protective factor against the progression of atherosclerosis. Previous studies have demonstrated decreased PON1 paraoxonase activity in hemodialyzed (HD) and renal transplant (TRX) patients; however, lactonase activity has not been investigated. We aimed to determine the paraoxonase and lactonase activities and to clarify the relationship between lactonase activity and a set of cardiovascular risk factors, such as homocysteine, cystatin C and asymmetric dimethylarginine (ADMA) levels, in HD and TRX patients and in healthy controls. METHODS One hundred and eight HD and 78 TRX patients and 63 healthy controls were involved in the study. Paraoxonase and lactonase activities (paraoxon and gamma-thiobutyrolactone as substrates) were measured spectrophotometrically. ADMA level was determined with sandwich enzyme-linked immunosorbent assay. RESULTS Both HD and TRX patients had significantly lower lactonase activities compared to the control group (P<0.05). Significantly lower paraoxonase activities were found in HD patients compared to the TRX group (P<0.05). Significant negative correlation was found between lactonase activity and ADMA level in the whole study population (P<0.001), while paraoxonase and lactonase activities showed significant positive correlation (P<0.001). Multiple regression analysis identified paraoxonase activity and homocysteine level as independent predictors of lactonase activity. CONCLUSION Lactonase activity is a potential new predictor of cardiovascular risk in renal failure. Measurement of lactonase activity is recommended in future studies on HD and TRX patients.

Serum cystatin C is a determinant of paraoxonase activity in hemodialyzed and renal transplanted patients

Background: Human paraoxonase-1 (PON1) inhibits LDL-oxidation and atherogenesis, and possesses lactonase activity. Decreased PON1 activity was found in hemodialyzed and renal transplanted patients. Cystatin C plays a protective role in atherosclerosis, and is a new, sensitive marker of renal function. The relationship between these two markers in renal failure has not been investigated. Aims: The goal of this study was to clarify the relationship between PON1 activity, cystatin C and homocysteine in chronic renal failure. We also determined the levels of oxidatively modified LDL (oxLDL) and thiobarbituric acid reactive substances (TBARS) to characterize lipid peroxidation. Patients and methods: 74 hemodialized (HD), 171 renal transplanted patients (TRX), and 110 healthy controls (C) were involved in the study. PON1 activity and TBARS levels were measured spectrophotometrically. OxLDL level was determined with sandwich ELISA. Results: There was a negative correlation between PON1 activity and cystatin C level. Homocysteine level correlated negatively with PON1 activity, and positively with cystatin C level. OxLDL and TBARS levels were significantly higher in the HD and TRX groups compared to C. Conclusions: Cystatin C may be a good predictive factor not only for homocysteine levels but for the antioxidant status in patients with renal failure and renal transplantation.

Effect of Nutritional Status on Human Paraoxonase-1 Activity in Patients with Chronic Kidney Disease

Background/Methods: The association between nutritional status, antioxidant human paraoxonase-1 (PON1) activity and low grade inflammation in hemodialized (HD) patients with chronic kidney disease (CKD) is unclear. The aim of this study was to determine PON1 paraoxonase and lactonase activities, ADMA, adiponectin and leptin concentrations, and to clarify the relationship between paraoxonase activity and a set of cardiovascular risk factors in malnourished, normal weight and obese HD patients; 114 HD patients with end-stage renal failure were enrolled. Results: Leptin levels were significantly higher and PON1 paraoxonase activities were significantly lower in obese patients compared to the other groups. Plasma adiponectin concentration was significantly lower in obese subjects compared to malnourished patients. Paraoxonase activity was negatively correlated with CRP level in HD and malnourished patients. Furthermore, we found significant inverse correlation between paraoxonase activity and BMI in the whole patient group. In multiple regression analysis, PON1 lactonase activity, CRP level and leptin concentration proved to be independent predictors of paraoxonase activity. Conclusion: Despite the previous findings of reverse epidemiology for the mortality rate of HD patients, further studies are needed to clarify the effects of nutritional state on atherosclerosis in obese and malnourished patients with end-stage renal failure.

Low High-Density Lipoprotein Cholesterol Is Not Responsible for Decreased Paraoxonase Activity in Chronic Renal Failure

Background/Aims: Human paraoxonase-1 (PON1) is responsible for the antioxidant effect of high-density lipoprotein (HDL) by inhibiting low-density lipoprotein oxidation. Previous studies discovered dyslipidemia (DL) and decreased PON1 activity in chronic renal failure (CRF). We aimed to determine PON and arylesterase activity, phenotypic distribution of the PON1 enzyme, and lipid profile in low and normal HDL cholesterol (HDL-C) patients with CRF, and renal transplant (TX), compared to primary DL. Methods: 116 CRF (low or normal HDL-C), 52 TX (low or normal HDL-C), and 62 DL patients (low or normal HDL-C) were included. PON and arylesterase activities were measured spectrophotometrically. Phenotype was determined using the dual substrate method. Results: Aryl/HDL-C was significantly higher in low HDL-C patients. Patients with CRF had significantly lower arylesterase activity compared to DL, independent of HDL-C. PON activity and PON/HDL-C did not differ significantly in CRF compared to TX and DL. Phenotypic distribution was similar in patient groups. Low HDL-C CRF patients had significantly lower cholesterol and triglyceride than DL. Conclusion: Decreased arylesterase activity, correlating with PON1 enzyme protein quantity, is not explicable by decreased HDL-C in CRF. Low HDL-C CRF patients’ increased cardiovascular morbidity is not attributable to changes in PON1 activity, or phenotypic distribution.

Relationship Between Serum Paraoxonase and Homocysteine Thiolactonase Activity, Adipokines, and Asymmetric Dimethyl Arginine Concentrations in Renal Transplant Patients

Paraoxonase lactonase activity protects against homocysteinylation; therefore, it can be a potential contributing factor to prevent atherosclerosis. We aimed to determine paraoxonase and HTLase activities and to clarify the relationship between HTLase activity and some cardiovascular risk factors, such as homocysteine, cystatin C asymmetric dimethylarginine (ADMA), and adipokines both in hemo dialyzed and transplanted patients. Among 114 hemodialyzed, 80 transplanted and 64 healthy control subjects, we investigated body mass index (BMI) as well as fasting serum contents of urea, uric acid, creatinine, cystatin C, homocysteine, glucose, lipids, total protein and albumin. Serum paraoxonase (PON 1) and HTLase activities were measured spectrophotometrically. ADMA, ADPN adiponectin, leptin (LEP) levels was determined with a sandwich enzyme-linked immunosorbent assay method. Dyslipidemic patients showed hypercholesterolemia, and high low-density lipoprotein (LDL); parallel with improved renal function, they displayed decreased cystatin C and homocysteine levels (P < .001). There was a significant negative correlation between PON 1 activity and cystatin C and homocysteine concentrations (P < .05). Obese patients revealed significantly higher LDL (P < .05) and leptin concentrations (P < .01). There was a significant positive correlation between PON 1 activity and adiponectin levels (P = .0276). Both dialyzed and transplanted patients displayed significantly lower HTLase activities compared to the control group (P < .001), particularly lower HTLase and PON 1 activities in dialyzed subjects compared with the transplanted group (P < .05). HTLase activity showed significant negative correlations with ADMA levels among the whole study population (P < .001), whereas positive associations were noted between PON 1 and HTLase activities (P < .001). HTLase activity may be a new predictor of cardiovascular risk in renal failure although it is modulated by other risk factors.

CSN Society News

Nephrology has a long tradition in the Czech Republic. The first acute dialysis was performed in 1955, a chronic dialysis programme started in the early 60ies, and a transplantation programme in 1966. This was reflected by many important international meetings held in Prague: The 2nd Congress of the International Society of Nephrology (1963), 17th Congress of the European Dialysis and Transplantation Association (1980) and the 15th Congress of the European Society of Artificial Organs (1988). More recently, the 17th and 25th meetings of the International Society of Blood Purification (1999 and 2007), 11th ANCA and Vasculitis Workshop (2003), 7th European Peritoneal Dialysis Meeting (2005), 13th Congress of the European Society of Organ Transplantation (2007) and finally, this year, the 48th Congress of ERA-EDTA.