Ibolya Haszon

Platelet aggregation, blood viscosity and serum lipids in hypertensive and obese children

A group of 35 patients (median age 15.5 years, range 8–17 years) with juvenile essential hypertension, 15 with body mass index (BMI kg/m2) <25 and 20 with BMI >25, as well as 35 age and sex matched controls (BMI <25 n=20; BMI >25 n=15) were investigated to study the role of hypertension and obesity, separately and in combination, on in vitro platelet aggregation, blood and plasma viscosity, plasma lipid concentrations and lipid peroxidation as well as nitric oxide (NO) production. Obese children (hypertensive and controls) had significantly higher concentrations of total cholesterol and triglycerides. The levels of high density lipoprotein (HDL)-cholesterol were lower in obese hypertensive children than their non-obese counterparts. There was a significant increase in platelet aggregation and a decrease in NO levels in hypertensive patients (obese and non-obese) reflecting a significant negative correlation (r=−0.553 and −0.530, n=35; P<0.01, respectively). However, an increased tendency to aggregation was also evident in obese normotensive patients. A significant positive correlation was observed between the platelet aggregation and BMI (r=0.501, n=35; P<0.01). Plasma free thiols were decreased in hypertensive children independent of their BMI. An increased lipid peroxidation and higher blood and plasma viscosity were found only in obese patients with hypertension. Multivariate analysis revealed significant interactions in the effects of obesity and hypertension on platelet aggregation and thiol oxidation. Conclusion: in obese children an increased platelet aggregation and oxidative insult contribute to the development of hypertension and to the promotion of vascular damage.

Roles of Paraoxonase and Oxidative Stress in Adolescents with Uraemic, Essential or Obesity-Induced Hypertension

Background/Aims: Paraoxonase 1 (PON1) is associated with high-density lipoproteins in the plasma, and is capable of hydrolysing oxidized lipids and preventing the oxidation of low-density lipoproteins. Oxidative stress and the PON1 (activity and Q192R polymorphism) were analysed in adolescent patients with essential (n = 49) or obesity-induced hypertension (n = 79), uraemic patients (n = 20), and also in obese normotensive patients (n = 60) and age-matched controls (n = 57). Methods: The PON1 activity was measured via paraoxon hydrolysis. The PON1 genotype was determined by real-time PCR. The levels of oxidized and reduced glutathione, the end-products of nitric oxide, cysteine, homocysteine and lipid peroxidation in the plasma were measured and related to the PON1 status. Results: There were no significant differences between the patient groups and the control group in the genotype distributions and the allele frequencies of the Q192R polymorphism. The PON activity was significantly lower (p < 0.001) in the uraemic hypertensive group than in the controls. The MDA concentration was significantly higher in the uraemic hypertensive (p < 0.001) and obese hypertensive (p < 0.05) patients. The plasma NOx concentrations were significantly lower (p < 0.001) and the ratio MDA/NOx were significantly higher in all four patient groups. The GSH levels were significantly lower in the patients with hypertension (p < 0.001) and obesity-induced hypertension (p < 0.05) than in the controls, while the GSSG level (p < 0.01) and the ratio GSSG/GSH (p < 0.05) was significantly higher in the uraemic hypertensive group. The plasma homocysteine level was significantly higher (p < 0.001) in the uraemic hypertensive patients as compared with the controls. Conclusions: We found no significant correlation between the biochemical parameters and neither genotypes nor enzyme activities. The PON1 status and the levels of certain biochemical parameters are independently associated with the hypertension in hypertensive and obese hypertensive patients, and the elevated levels of lipid peroxides and plasma homocysteine may contribute to the increased risk of cardiovascular complications in patients on haemodialysis.

Different pathomechanisms of essential and obesity-associated hypertension in adolescents

Obesity-induced hypertension and essential hypertension in lean patients are two different forms of hypertension. The main goal of this study was to test whether there are differences in biochemical parameters between subjects with obesity-associated hypertension and those with essential hypertension. We examined whether the biochemical responses to angiotensin-converting enzyme inhibitor (ACEI) ramipril therapy reveal properties of these two conditions that might explain the differences in clinical outcome. Before ramipril therapy, the hypertensive group exhibited increases in ACE activity (p<0.05), plasma malondialdehyde (MDA) concentration and the malondialdehyde/nitric oxide end-product ratio (MDA/NOx) (p<0.05), and decreases in xanthine oxidase (XO) activity (p<0.05) and plasma nitric oxide end-product (NOx) level (p<0.01). Before medication, plasma endothelin-1 (ET-1), plasma leptin, and leptin receptor levels were normal. Following ramipril treatment, ACE activity normalized. Before ACE inhibitor treatment, the obese-hypertensive group exhibited elevated levels of plasma ET-1 (p<0.05), plasma leptin (p<0.01), XO activity (p<0.05), plasma MDA and MDA/NOx (p<0.05), and reduced levels of plasma NOx(p<0.01) and leptin receptors (p<0.001). Following medication, the plasma NOx level, MDA/NOx, and XO activity returned to normal while ACE activity decreased (p<0.001). In patients with essential hypertension, NO availability and ACE activity, and in those with obesity-associated hypertension, hyperleptinemic effects, NO level, endothelin-1 concentration and XO activity, may be important factors in the pathology.

Erythropoiesis-stimulating agent withdrawal and oxidative stress in hemodialysis.

AIMS Variation of the action of erythropoiesis-stimulating agent (ESA) may modify oxidative stress in hemodialyzed (HD) patients. Our aim was to follow changes of oxidative stress during withdrawal and subsequent resumption of ESA therapy. PATIENTS AND METHODS After a 14-day suspension of epoietin-beta treatment, 11 HD patients received epoietin-beta and 10 patients darbepoietin-alpha. The whole blood oxidized and reduced glutathione (GSSG, GSH) and erythrocyte malondialdehyde (E-MDA) concentrations and the erythrocyte superoxide dismutase (E-SOD) and catalase (E-CAT) activities were determined before the ESA-free interval (baseline) and at Weeks 2, 6, 10 and 14. RESULTS In both groups, the ratios GSSG/ GSH were increased at Weeks 2 and 6 (p < 0.001). The E-MDA levels were elevated (p < 0.01) and the E-SOD activities were decreased (p < 0.001) at Week 6. By Week 14, these markers had returned to the baseline, whereas the GSH (p < 0.001) and E-CAT activity levels (p < 0.001) had increased. CONCLUSIONS An increase in oxidative stress was revealed by the ratio GSSG/GSH directly after the short-term withdrawal of epoietin-b therapy in HD. This new finding may have implications in conditions involving transiently depressed ESA action. For both ESAs, the early phase of readministration was associated with similarly increased oxidative stress, with a subsequent return to the baseline level.

Efficient Targeted Next Generation Sequencing-Based Workflow for Differential Diagnosis of Alport-Related Disorders

Alport syndrome (AS) is an inherited type IV collagen nephropathies characterized by microscopic hematuria during early childhood, the development of proteinuria and progression to end-stage renal disease. Since choosing the right therapy, even before the onset of proteinuria, can delay the onset of end-stage renal failure and improve life expectancy, the earliest possible differential diagnosis is desired. Practically, this means the identification of mutation(s) in COL4A3-A4-A5 genes. We used an efficient, next generation sequencing based workflow for simultaneous analysis of all three COL4A genes in three individuals and fourteen families involved by AS or showing different level of Alport-related symptoms. We successfully identified mutations in all investigated cases, including 14 unpublished mutations in our Hungarian cohort. We present an easy to use unified clinical/diagnostic terminology and workflow not only for X-linked but for autosomal AS, but also for Alport-related diseases. In families where a diagnosis has been established by molecular genetic analysis, the renal biopsy may be rendered unnecessary.