Plasma Uric Acid Levels Research Articles

NLRP3 Inflammasome is activated in the kidneys of Metabolic Syndrome animals

Inflammasomes are oligomeric protein complexes formed in response to Danger‐associated molecular patterns (DAMPS) such as uric acid crystals and asbestos and have been shown to contribute to the pathogenesis of metabolic syndrome (MetS). Since uric acid is increased in chronic kidney disease, we hypothesized that increase uric acid might induce NLRP3 inflammasomes and exacerbate MetS via disrupting the redox balance and causing structural and functional impairment of the kidneys. Male Lean zucker controls (LZR) and Obese (OZR) underwent acute renal clearance and hemodynamic study. Compared to the OZR rats, the LZR exhibited higher glomerular filtration rate, higher renal blood flow and lower renal vascular resistance. Renal histopathology results revealed glomerulosclerosis, interstitial nephritis and proteinuria, and Real time RT PCR showed an increased gene expression of kidney injury markers and inflammasomes in OZR rats. Free radical production rates measured by electron paramagnetic spectroscopy showed a reduced total reactive oxygen species, superoxide and peroxynitrite levels in LZR animals. The gene and protein expression levels of IL‐1β and IL‐18 were higher in OZR rats. The plasma uric acid levels were higher in OZR rats. Our results indicate that inflammasomes are activated in the kidneys of MetS, thereby contributing to increased oxidative stress and renal damage. Research supported by LSU.

Common genetic variants of the human uromodulin gene regulate transcription and predict plasma uric acid levels

Uromodulin (UMOD) genetic variants cause familial juvenile hyperuricemic nephropathy, characterized by hyperuricemia with decreased renal excretion of UMOD and uric acid, suggesting a role for UMOD in the regulation of plasma uric acid. To determine this, we screened common variants across the UMOD locus in one community-based Chinese population of 1000 individuals and the other population from 642 American twins and siblings of European and Hispanic ancestry. Transcriptional activity of promoter variants was estimated in luciferase reporter plasmids transfected into HEK-293 cells and mIMCD3 cells. In the primary Chinese population, we found that carriers of the GCC haplotype had higher plasma uric acid, and three promoter variants were associated with plasma uric acid. UMOD promoter variants displayed reciprocal effects on urine uric acid excretion and plasma uric acid concentration, suggesting a primary effect on renal tubular handling of urate. These UMOD genetic marker-on-trait associations for uric acid were replicated in the independent American cohort. Site-directed mutagenesis at trait-associated UMOD promoter variants altered promoter activity in transfected luciferase reporter plasmids. Thus, UMOD promoter variants seem to initiate a cascade of transcriptional and biochemical changes influencing UMOD secretion, leading to altered plasma uric acid levels.

Studies on Antioxidant Role of (+)-Catechin Hydrate in High Sucrose High Fat Diet Induced Oxidative Stress

In the present investigation, effect of pure green tea catechin, (+)-catechin hydrate was studied on plasma uric acid, plasma nitrite, cardiac lipid peroxidation, reduced glutathione and cardiac antioxidant enzymes in high sucrose high fat diet fed rats for a period of 12 weeks. Our results indicate that feeding high sucrose high fat diet resulted in the development of oxidative stress in rats and (+)-catchin hydrate has antioxidant effect. High sucrose high fat diet decreased plasma uric acid and increased plasma nitrite levels. Further lipid peroxidation increased and reduced glutathione levels decreased in heart of high sucrose high fat diet fed rats. Activity of antioxidant enzymes (SOD, GST, GR and GPx) was significantly reduced in high sucrose high fat fed rats. Catechin supplementation improved plasma uric acid and nitrite levels and reduced lipid peroxidation. Further there was normalization in reduced Glutathione levels and activities of cardiac antioxidant enzymes upon administration of (+)-catechin hydrate. It can be concluded that high sucrose high fat diet produces oxidative stress in rats and administration of catechin is helpful to combat oxidative stress.

Comparative Evaluation of Single Fixed Dosing and Weight‐Based Dosing of Rasburicase for Tumor Lysis Syndrome

To evaluate single fixed dosing versus weight-based dosing strategies for rasburicase to determine the minimum dose required to mitigate hyperuricemia in the treatment or prevention of tumor lysis syndrome. Retrospective medical record review Academic medical center A total of 373 patients with a diagnosis of a hematologic malignancy or solid tumor and who received at least one dose of rasburicase over a 6-year period between January 1, 2005, and February 18, 2011; 180 patients received single doses of 3mg (38 patients), 6mg (99 patients), or 7.5mg (43 patients), and 193 patients received weight-based dosing. Tumor lysis syndrome laboratory data were recorded at baseline and monitored up to 72hours after initial rasburicase administration. Median baseline plasma uric acid levels were 6.85mg/dl, 8.80mg/dl, 8.00mg/dl, and 9.20mg/dl, respectively, in the 3-mg, 6-mg, 7.5-mg, and weight-based dosing groups. Treatment success was defined as a normalized plasma uric acid level (<7.5 mg/dl) within 24hours after receiving rasburicase. The mean weight-based dose was 0.16mg/kg. Six rasburicase treatment failures occurred; two were in the 3-mg group, one was in the 6-mg group, and three were in the weight-based dosing group. At 24hours after rasburicase administration, no statistically significant differences in treatment success were noted among groups (92.9% vs 97.6% vs 100.0% vs 98.0% in the 3-mg, 6-mg, 7.5-mg, and weight-based dosing groups, respectively, p=0.1238). The efficacy of all single fixed doses and weight-based dosing strategies evaluated in this study appear to be comparable in normalizing plasma uric acid levels within 24hours of rasburicase administration. Although use of a 3-mg rasburicase dose may be the most cost-effective treatment strategy in managing hyperuricemia secondary to tumor lysis syndrome, the 6-mg dose resulted in lower sustained uric acid levels after rasburicase administration. Further analysis of patient specific factors contributing to the need for repeat rasburicase administration should be conducted in larger, prospective clinical trials.

Melatonin May Curtail the Metabolic Syndrome: Studies on Initial and Fully Established Fructose-Induced Metabolic Syndrome in Rats

To examine the effect of melatonin given to rats simultaneously with fructose on initial and fully developed metabolic syndrome, male Wistar rats had free access to chow and 5% or 10% fructose drinking solution for 8 weeks. As compared to controls, systolic blood pressure augmented significantly under both treatments whereas excessive body weight was seen in rats receiving the 10% fructose only. Rats drinking 5% fructose showed a greater tolerance to a glucose load while rats having access to a 10% fructose drinking solution exhibited the expected impaired glucose tolerance found in the metabolic syndrome. Circulating triglyceride and low density lipoproteins-cholesterol (LDL-c) concentration augmented significantly in rats showing a fully developed metabolic syndrome only, while high blood cholesterol levels were found at both stages examined. Melatonin (25 μg/mL drinking solution) counteracted the changes in body weight and systolic blood pressure found in rats administered with fructose. Melatonin decreased the abnormal hyperglycemia seen after a glucose load in 10% fructose-treated rats but it did not modify the greater tolerance to glucose observed in animals drinking 5% fructose. Melatonin also counteracted the changes in plasma LDL-c, triglyceride and cholesterol levels and decreased plasma uric acid levels. The results underline a possible therapeutical role of melatonin in the metabolic syndrome, both at initial and established phases.

A Potential Role for Plasma Uric Acid in the Endothelial Pathology of Plasmodium falciparum malaria

BackgroundInflammatory cytokinemia and systemic activation of the microvascular endothelium are central to the pathogenesis of Plasmodium falciparum malaria. Recently, ‘parasite-derived’ uric acid (UA) was shown to activate human immune cells in vitro, and plasma UA levels were associated with inflammatory cytokine levels and disease severity in Malian children with malaria. Since UA is associated with endothelial inflammation in non-malaria diseases, we hypothesized that elevated UA levels contribute to the endothelial pathology of P. falciparum malaria.Methodology/Principal FindingsWe measured levels of UA and soluble forms of intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), E-selectin (sE-Selectin), thrombomodulin (sTM), tissue factor (sTF) and vascular endothelial growth factor (VEGF) in the plasma of Malian children aged 0.5–17 years with uncomplicated malaria (UM, n = 487) and non-cerebral severe malaria (NCSM, n = 68). In 69 of these children, we measured these same factors once when they experienced a malaria episode and twice when they were healthy (i.e., before and after the malaria transmission season). We found that levels of UA, sICAM-1, sVCAM-1, sE-Selectin and sTM increase during a malaria episode and return to basal levels at the end of the transmission season (p<0.0001). Plasma levels of UA and these four endothelial biomarkers correlate with parasite density and disease severity. In children with UM, UA levels correlate with parasite density (r = 0.092, p = 0.043), sICAM-1 (r = 0.255, p<0.0001) and sTM (r = 0.175, p = 0.0001) levels. After adjusting for parasite density, UA levels predict sTM levels.Conclusions/SignificanceElevated UA levels may contribute to malaria pathogenesis by damaging endothelium and promoting a procoagulant state. The correlation between UA levels and parasite densities suggests that parasitized erythrocytes are one possible source of excess UA. UA-induced shedding of endothelial TM may represent a novel mechanism of malaria pathogenesis, in which activated thrombin induces fibrin deposition and platelet aggregation in microvessels. This protocol is registered at clinicaltrials.gov (NCT00669084).

Mean platelet volume and the extent of coronary atherosclerosis in patients with stable coronary artery disease

The aim of this study was to assess the relationship between mean platelet volume (MPV) and the presence and extent of coronary artery disease (CAD) in patients who underwent coronary angiography for stable chest pain. A total of 540 patients (350 male, 190 female; mean age: 59.6±11.4 years) were consecutively included in the study. The patients were divided into four groups according to the presence and extent of their CAD as follows: Group 1 - patients with no significant CAD, group 2 - one vessel disease, group 3 - two vessel diseases, and group 4 - three vessel disease. Also, the Gensini score of each coronary angiogram was calculated. There were 159 patients in group 1, 169 in group 2, 110 in group 3, and 102 in group 4. As expected, we found significant differences among the groups regarding mean age and other coronary risk factors including gender, hypertension, diabetes mellitus, hyperlipidemia, smoking, and family history of ischemic heart disease. However, there were no significant differences among the groups regarding platelet counts and MPV values (8.5±0.1 fl, 8.5±1.2 fl, 8.6±0.9 fl and 8.6±0.9 fl, MPV values of groups 1-4, respectively). Although the Gensini score was found to be significantly correlated with age, plasma uric acid level, white blood cell count, hemoglobin level, fasting blood glucose, and high density lipoprotein level, no significant association was detected between MPV and Gensini score values. This study is one of the largest studies assessing the relationship between MPV and the extent of coronary atherosclerosis in patients with stable CAD to date. However, we found no association between MPV and the presence and extent of coronary atherosclerosis.

The Impact of Hyperglycemic Emergencies on the Kidney and Liver

Studies on the alterations of liver and kidney function parameters in patients with diabetic ketoacidosis (DKA) and diabetic ketosis (DK) were limited. Participants with DKA, DK, non-DK, and healthy controls were enrolled in the current study. Parameters of liver and kidney function were measured and evaluated. The patients with DKA had higher levels of plasma glucose, hemoglobin A1c (HbA1c), uric acid, and creatinine but lower levels of transferases and protein compared with the other three groups (P < 0.05 for all). The patients with DK had higher levels of plasma glucose and HbA1c but lower levels of glutamyl transpeptidase and protein compared with the non-DK and control groups (P < 0.05). Prealbumin levels were significantly reduced in the severe DKA patients compared with the mild/moderate DKA patients. Serum prealbumin levels were correlated with albumin levels (r = 0.401, P = 0.010), HCO3 (r = 0.350, P = 0.027), and arterial pH (r = 0.597, P < 0.001) in the DKA patients. A diagnostic analysis showed that lower prealbumin levels significantly reflected the presence of hyperglycemic emergencies (P < 0.001). Liver and kidney function parameters deteriorated, especially in DKA. Prealbumin levels can be of value in detecting the presence of hyperglycemic crisis. This clinical trial is registered with ChiCTR-OCH-12003077.

Cardiovascular disease risk factors among HIV-infected Nigerians receiving highly active antiretroviral therapy

Background:Highly active antiretroviral therapy (HAART) has become more accessible to Human immunodeficiency virus infection/Acquired Immunodeficiency Syndrome (HIV/AIDS) patients worldwide. There is growing concern that the metabolic complications associated with HIV and HAART may increase cardiovascular risk and lead to cardiovascular diseases. We, therefore, set out to describe the cardiovascular risk profile of HIV/AIDS patients receiving HAART at a health facility in northern part of Nigeria.Materials and Methods:This cross-sectional study was conducted at the Aminu Kano Teaching Hospital, Kano, Nigeria. Consenting patients, who had been receiving HAART, were compared with age and sex matched HAART-naive subjects. Questionnaire interview, electrocardiography, anthropometric and blood pressure measurements were conducted under standard conditions. Blood samples were obtained for the determination of plasma glucose, uric acid and lipid levels.Results:Two hundred subjects were studied, 100 were on HAART (group 1) and the other 100 (group 2) were HAART-naive. Subjects’ mean age for all the participants was 32.5 (7.6) years. The prevalence of hypertension was 17% in group 1 and 2% in group 2 (P < 0.001). Similarly, 11% and 21% of group 1 subjects were obese or had metabolic syndrome compared with 2% and 9% of group 2 patients (P < 0.05 for both).Conclusion:HAART treatment was associated with significantly higher prevalences of hypertension, obesity and metabolic syndrome.

Urate Transporter 1 Protein Levels and Localization in Type 2 Diabetic and Non-Diabetic Zucker Rat Kidneys

Objective: Persons with type 2 diabetes have increased incidence of hyperuricemia and gout. The hypothesis that Urate transporter 1 (URAT1) levels are increased in type 2 diabetic Zucker rats and this is responsible for elevation of uric acid was tested. Methods: Male 12-week-old obese Zucker rats were compared to non-diabetic lean counterparts. Plasma glucose, uric acid and creatinine were measured. URAT1 protein levels in the renal cortex and medulla were determined by Western blot. Immunohistochemistry was used to determine the location of URAT1 inrenal tubules. Results: Plasma glucose and uric acid levels were higher in the diabetic rats. There was no difference in plasma createnine. URAT1 antibody-positive bands of 27, 31, 50, 62 and 70 kDa were observed in cortex. A similar pattern was observed in medulla with addition of a 44 kDa band. No differences were observed in URAT1 proteins in the cortex between obese and lean rats. In the medulla, expression of the 44 and 50 kDa proteins was higher in lean rats. Expression of 27, 50, 62 kDa URAT1 proteins in the cortex was higher than in the medulla, while expression of the 70 kDa URAT1 was higher in medulla than in cortex. Localization of URAT1 did not differ between groups and included tubules in both cortex and medulla. Conclusions: In male Zucker rats, URAT1 protein expression was observed in both kidney cortex and medulla. Uric acid elevation in the obese group was associated with decreases in the 44 and 50 kDa URAT1 proteins in renal medulla.

Particular characteristics of the metabolic syndrome in patients with morbid obesity

BackgroundCriteria for the diagnosis of the metabolic syndrome are currently being reconsidered, as their usefulness is not the same for all phenotypes in relation to the risk of cardiovascular disease. AimWe analyzed the changes in metabolic parameters after a fat overload in different groups of patients. Materials and methodsThe study included 20 healthy persons, 30 metabolic syndrome patients without morbid obesity, 80 metabolic syndrome patients with morbid obesity and 16 patients with morbid obesity without the metabolic syndrome. All the participants received a fat overload of 60g. Measurements were made before the overload and 3h afterwards of triglycerides, free fatty acids, insulin and uric acid. ResultsMetabolic syndrome patients with morbid obesity had a lower waist-to-hip ratio, and lower plasma free fatty acid and triglycerides levels at baseline and after the overload than patients without morbid obesity. Plasma uric acid levels rose after the fat overload in the metabolic syndrome patients who had morbid obesity but not in the patients without morbid obesity. A positive relation was found between plasma triglycerides and free fatty acid levels in all the patients but not in the controls after the fat overload. A positive relation was also found between uric acid and insulin levels in the metabolic syndrome patients with morbid obesity. ConclusionsMetabolic syndrome patients with and without morbid obesity presented different metabolic characteristics. This suggests that there are 2 different clinical phenotypes, both grouped under the metabolic syndrome umbrella.

The effect of albumen removal before incubation (embryonic protein under-nutrition) on the post-hatch performance, regulators of protein translation activation and proteolysis in neonatal broilers

Albumen was removed from broiler eggs before the start of incubation to induce prenatal protein under-nutrition in chicken embryos. With this method, the direct effect of protein deficiency was investigated, differing from mammalian models manipulating the maternal diet where indirect, hormonal effects can interfere. Based on the estimated albumen/egg weight ratio, 10 % of albumen was removed with an 18G needle, after making a hole at the sharp end of the egg with another 18G needle. Eggs were taped thereafter. The sham group underwent the same procedure, except that no albumen was removed. Control eggs did not receive any treatment. The removal of albumen decreased both embryonic and post-hatch body weight up to day 7 compared with the control group. On embryonic day 18, embryos from the albumen-deprived group had higher plasma uric acid levels compared with the sham (P= 0·016) and control (P= 0·009) groups. Moreover, a lower plasma amino acid concentration was observed at hatch compared with the sham (P= 0·038) and control (P= 0·152) groups. These findings indicate an altered protein metabolism. At hatch, a higher mRNA expression of muscle ring finger-1 (MuRF1), a gene related to proteolysis, was observed in albumen-deprived chicks compared with the control and sham chicks, together with an up-regulated expression of atrogin-1 (another atrogene) at this time point in the male protein-deficient chicks. These findings suggest that muscle proteolysis is transiently increased by the removal of albumen before the start of incubation. No evidence was found for altered protein synthesis capacity and translational efficiency in albumen-deprived chicks.

Uric acid modulates vascular endothelial function through the down regulation of nitric oxide production

Endothelial dysfunction characterized by decreased nitric oxide (NO) bioavailability is the first stage of coronary artery disease. It is known that one of the factors associated with an increased risk of coronary artery disease is a high plasma level of uric acid. However, causative associations between hyperuricaemia and cardiovascular risk have not been definitely proved. In this work, we tested the effect of uric acid on endothelial NO bioavailability. Electrochemical measurement of NO production in acetylcholine-stimulated human umbilical endothelial cells (HUVECs) revealed that uric acid markedly decreases NO release. This finding was confirmed by organ bath experiments on mouse aortic segments. Uric acid dose-dependently reduced endothelium-dependent vasorelaxation. To reveal the mechanism of decreasing NO bioavailability we tested the effect of uric acid on reactive oxygen species production by HUVECs, on arginase activity, and on acetylcholine-induced endothelial NO synthase phosphorylation. It was found that uric acid increases arginase activity and reduces endothelial NO synthase phosphorylation. Interestingly, uric acid significantly increased intracellular superoxide formation. In conclusion, uric acid decreases NO bioavailability by means of multiple mechanisms. This finding supports the idea of a causal association between hyperuricaemia and cardiovascular risk.

Correlation of serum uric acid levels with coronary flow in patients with ST-segment elevation myocardial infarction undergoing primary coronary intervention

To explore the association of the uric acid levels and coronary blood flow in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). A total of 276 STEMI patients undergoing primary PCI were enrolled and divided into 2 groups based upon the Thrombolysis in Myocardial Infarction (TIMI) flow grade. No-reflow was defined as TIMI Grade 0, 1 and 2 flows. The association of uric acid levels on admission with TIMI flow grade after PCI was assessed by multivariate Logistic regression. Major adverse cardiac events (MACE) were defined as death, non-fatal myocardial infarction and need for repeat percutaneous revascularization or coronary artery bypass grafting. The uric acid level was significantly higher in the no-reflow group (n = 57) than that of the normal-flow group (n = 219, 372 ± 111 vs 303 ± 102, P < 0.01). In-hospital MACEs were significantly higher in the patients with no reflow (8.8% vs 1.8%, P = 0.016). A uric acid level ≥ 345 mmol/L measured on admission had a 61.2% sensitivity and 77.5% specificity in predicting no-reflow at ROC curve analysis. At multivariate analyses, high plasma uric acid (OR 1.01, 95%CI 1.01 - 1.01, P < 0.01), neutrophil count (OR 1.02, 95%CI 1.00 - 1.06, P < 0.01), admission plasma glucose (OR 1.14, 95%CI 1.08 - 1.21, P < 0.01), time from pain to PCI (OR 1.67, 95%CI 0.46 - 5.97, P = 0.012), pre PCI thrombus score ≥ 4 (OR 2.67, 95%CI 1.29 - 5.13, P = 0.008), collateral circulation grade ≤ 1 (OR 1.86, 95%CI 1.27 - 2.73, P = 0.008), and Killip classes (OR 2.01, 95%CI 1.01 - 3.94, P = 0.042) were independent predictors of no-reflow post primary PCI. The plasma level of uric acid on admission is a strong and independent predictor of poor coronary blood flow following at post-primary PCI among STEMI patients. Uric acid levels may be a useful biomarker of risk stratification.

Long-term safety of pegloticase in chronic gout refractory to conventional treatment

ObjectiveTo evaluate the long-term safety (up to 3 years) of treatment with pegloticase in patients with refractory chronic gout.MethodsThis open-label extension (OLE) study was conducted at 46 sites in the...

Economic Implications of Rasburicase Treatment in Adult Patients with Tumour Lysis Syndrome

Rasburicase is a recombinant urate-oxidase enzyme used to reduce high levels of plasma uric acid (PUA) resulting from tumour lysis syndrome (TLS). Rasburicase reduces PUA levels within 4 hours of administration, thereby minimizing the risk of serious complications from TLS. Treatment pattern analyses indicate rasburicase is often used in combination with allopurinol; however, no studies have evaluated the clinical and economic consequences of this pattern of care. The purpose of this study was to compare hospitalization costs, overall length of stay (LOS), and critical-care LOS in patients receiving rasburicase with or without allopurinol. Hospital claims data from the Premier Perspective Database™ were used to conduct this retrospective analysis. Patients in the Premier hospital database who were administered rasburicase or combination therapy (rasburicase + allopurinol) within 2 days of hospital admission were eligible for study inclusion. Patients were excluded if they were <18 years of age or received haemodialysis (or any other renal replacement therapy support) on admission. Rasburicase patients were propensity-score-matched to combination therapy patients based on gender, race, hospital type (urban/rural, teaching), provider type, payer type, admission source, use of electrolyte modification therapy, critical-care admission and presence of a cancer diagnosis. Differences in healthcare costs, overall LOS and critical-care LOS were assessed using γ-distributed generalized linear models with a log-link function. The study population comprised 66 patients receiving rasburicase monotherapy matched to 66 patients receiving combination therapy. Mean age was 62.9 years, and 29% were female. Patients initiated on combination therapy had a shorter mean duration of rasburicase administration than patients initiated on monotherapy (2.1 vs 2.7 days) [p = 0.0059]. Additionally, rasburicase monotherapy incurred an average total cost of $US35 843 per hospitalization, compared with $US46 672 for those receiving combination therapy (p = 0.0820). Rasburicase monotherapy patients also had a shorter mean overall LOS (10.0 days vs 15.4 days; p = 0.0067). The mean critical-care LOS was similar in both cohorts (2.4 days rasburicase vs 2.9 days combination therapy; p = 0.3389). Examination of claims data showed that combination therapy (rasburicase + allopurinol) trended toward higher total hospitalization costs than rasburicase monotherapy. In addition, combination therapy was associated with significantly longer overall LOS compared with upfront rasburicase monotherapy in patients at risk for developing TLS.

Hypertension and Childhood Obesity: A Whirling Tango. A Review of the Dance Steps

Despite large sensitization, excess weight, hypertension and cardiovascular risk factors in children and adolescents are extending more and more, as a real new ‘epidemic’. Always more attention has been paid on epidemiology, causes, consequences and factors related to increase blood pressure values among young people. For the first time during 2009, the recommendations of the European Society of Hypertension for the management of high blood pressure in children and adolescents were published, remarking that the most important condition related to paediatric hypertension is the excess weight. The negative metabolic effects of obesity on blood pressure begin early during childhood and track through adolescence into adulthood. Waist circumference and waist-to-height ratio have emerged as better adiposity indicators than body mass index and important predictors of hypertension and cardiovascular risk. Also insulin resistance and high uric acid plasma levels have been advocated as relevant risk factors in children. Moreover a correlation between adipocytokines, in particular leptin and adiponectin, and hypertension and cardiovascular damage in children has been suggested. Obesity-associated hypertension results related to heart damage ( particularly an increase of the left ventricular mass), renal involvement ( presence of microalbuminuria) and autonomic alterations. As first therapy approach in hypertensive children, fundamental is the role of lifestyle measures: reduction of excess weight, increase of physical activity and limitation of sodium in the diet represent the main aspects of this kind of intervention.

Antioxidant response after the operations for congenital heart diseases

Background: In this study, we investigated total antioxidant response and plasma levels of albumin, total bilirubin, uric acid and high sensitive C reactive protein (hsCRP) in patients with congenital heart disease treated with surgery using on-pump and off-pump techniques. Methods: T hirty-five p atients w ith c ongenital h eart diseases undergoing surgical treatment were divided into two groups: 20 patients were operated with using cardiopulmonary bypass (group 1, on-pump) and 15 patients were operated without cardiopulmonary bypass (group 2, off-pump). Blood samples were collected before surgery and at 1, 24 and 72 hours following surgery. Results: Total antioxidant response was prompt and drew a peak within the first hour following surgery in group 1. After 24 hours, it showed a sustained increase (p=0.009). In the group 2, total antioxidant response decreased significantly within the first hour, and then increased to a peak level within the 24 hours (p=0.04). Thereafter, it was gradually reduced. Total antioxidant response, albumin, bilirubin and hsCRP levels remained high in group 1, after 24 hours. Total antioxidant response levels were positively associated with the albumin levels at 24 hours following surgery in group 2 (r=0.669, p=0.01). Conclusion: The plasma levels of albumin may be considered in the assessment of global antioxidant response in patients treated with CPB technique.

Plasma uric acid levels correlate with inflammation and disease severity in Malian children with Plasmodium falciparum malaria.

Background Plasmodium falciparum elicits host inflammatory responses that cause the symptoms and severe manifestations of malaria. One proposed mechanism involves formation of immunostimulatory uric acid (UA) precipitates, which are released from sequestered schizonts into microvessels. Another involves hypoxanthine and xanthine, which accumulate in parasitized red blood cells (RBCs) and may be converted by plasma xanthine oxidase to UA at schizont rupture. These two forms of ‘parasite-derived’ UA stimulate immune cells to produce inflammatory cytokines in vitro.Methods and FindingsWe measured plasma levels of soluble UA and inflammatory cytokines and chemokines (IL-6, IL-10, sTNFRII, MCP-1, IL-8, TNFα, IP-10, IFNγ, GM-CSF, IL-1β) in 470 Malian children presenting with uncomplicated malaria (UM), non-cerebral severe malaria (NCSM) or cerebral malaria (CM). UA levels were elevated in children with NCSM (median 5.74 mg/dl, 1.21-fold increase, 95% CI 1.09–1.35, n = 23, p = 0.0007) and CM (median 5.69 mg/dl, 1.19-fold increase, 95% CI 0.97–1.41, n = 9, p = 0.0890) compared to those with UM (median 4.60 mg/dl, n = 438). In children with UM, parasite density and plasma creatinine levels correlated with UA levels. These UA levels correlated with the levels of seven cytokines [IL-6 (r = 0.259, p<0.00001), IL-10 (r = 0.242, p<0.00001), sTNFRII (r = 0.221, p<0.00001), MCP-1 (r = 0.220, p<0.00001), IL-8 (r = 0.147, p = 0.002), TNFα (r = 0.132, p = 0.006) and IP-10 (r = 0.120, p = 0.012)]. In 39 children, UA levels were 1.49-fold (95% CI 1.34–1.65; p<0.0001) higher during their malaria episode [geometric mean titer (GMT) 4.67 mg/dl] than when they were previously healthy and aparasitemic (GMT 3.14 mg/dl).ConclusionsElevated UA levels may contribute to the pathogenesis of P. falciparum malaria by activating immune cells to produce inflammatory cytokines. While this study cannot identify the cause of elevated UA levels, their association with parasite density and creatinine levels suggest that parasite-derived UA and renal function may be involved. Defining pathogenic roles for parasite-derived UA precipitates, which we have not directly studied here, requires further investigation.Trial RegistrationClinicalTrials.gov NCT00669084

A mouse model of early-onset renal failure due to a xanthine dehydrogenase nonsense mutation.

Chronic kidney disease (CKD) is characterized by renal fibrosis that can lead to end-stage renal failure, and studies have supported a strong genetic influence on the risk of developing CKD. However, investigations of the underlying molecular mechanisms are hampered by the lack of suitable hereditary models in animals. We therefore sought to establish hereditary mouse models for CKD and renal fibrosis by investigating mice treated with the chemical mutagen N-ethyl-N-nitrosourea, and identified a mouse with autosomal recessive renal failure, designated RENF. Three-week old RENF mice were smaller than their littermates, whereas at birth they had been of similar size. RENF mice, at 4-weeks of age, had elevated concentrations of plasma urea and creatinine, indicating renal failure, which was associated with small and irregularly shaped kidneys. Genetic studies using DNA from 10 affected mice and 91 single nucleotide polymorphisms mapped the Renf locus to a 5.8Mbp region on chromosome 17E1.3. DNA sequencing of the xanthine dehydrogenase (Xdh) gene revealed a nonsense mutation at codon 26 that co-segregated with affected RENF mice. The Xdh mutation resulted in loss of hepatic XDH and renal Cyclooxygenase-2 (COX-2) expression. XDH mutations in man cause xanthinuria with undetectable plasma uric acid levels and three RENF mice had plasma uric acid levels below the limit of detection. Histological analysis of RENF kidney sections revealed abnormal arrangement of glomeruli, intratubular casts, cellular infiltration in the interstitial space, and interstitial fibrosis. TUNEL analysis of RENF kidney sections showed extensive apoptosis predominantly affecting the tubules. Thus, we have established a mouse model for autosomal recessive early-onset renal failure due to a nonsense mutation in Xdh that is a model for xanthinuria in man. This mouse model could help to increase our understanding of the molecular mechanisms associated with renal fibrosis and the specific roles of XDH and uric acid.