Kidney disease represents a serious global health problem. One of the main concerns is its late diagnosis, only feasible in a progressed disease state. The lack of a clinical manifestation in the early stages and the fact that the commonly measured parameters of renal function are markedly reduced only during advanced stages of the disease are the main cause. Changes at the molecular level of the kidney tissue occur even before nitrogenous substances, such as creatinine and urea, start to accumulate in the blood. Renal proximal tubules contain a large number of mitochondria and are critical for the energy-demanding process of reabsorption of water and solutes. Mitochondria are the largest producers of oxygen radicals, which, in turn, increase the susceptibility of kidneys to oxidative stress-induced damage. Free radicals and prooxidants produced during acute or chronic kidney injury may further aggravate the course of the disease and play a role in the pathogenesis of subsequent complications. Prevention might be the solution in CKD, but patients are often reluctant to undergo preventive examinations. Noninvasive markers and the possibility to obtain samples at home might help to increase compliance. This review will provide an overview of the possible uses of markers of oxidative status in noninvasive biofluids in patients with renal disease.

IntroductionIn adults, microalbuminuria indicates generalized endothelial dysfunction, and is an independent risk factor for cardiovascular and all cause mortality. Slovak adults present one of the highest cardiovascular mortality rates in Europe. Thus Slovak adolescents are on a high-risk to develop cardiovascular afflictions early, and screening for microalbuminuria might be useful in early assessment of their cardiovascular risk. We aimed to study the prevalence of microalbuminuria in Slovak adolescents, and the association of urinary albumin-to-creatinine ratio (ACR) to cardiovascular risk factors.Subjects and methodsAnthropometric data, blood pressure, blood count, glucose homeostasis, lipid profile, renal function, inflammatory status, concentrations of homocysteine and uric acid were determined and associated with ACR in 2 666 adolescents (49.4% boys, 51.6% girls) aged 14-to-20 years. Microalbuminuria was classified as ACR 2.5–25.0 mg/mmol in boys and 3.5–35.0 mg/mmol in girls.ResultsPrevalence of microalbuminuria in both genders reached 3.3%, and did not differ significantly between lean and centrally obese subjects. Girls presented higher ACR than boys (normoalbuminuric: 0.6±0.5 mg/mmol vs. 0.5±0.4 mg/mmol, p>0.001; microalbuminuric: 9.3±7.3 mg/mmol vs. 5.0±3.8 mg/mmol; p>0.001). Microalbuminuric adolescents and those presenting normoalbuminuria within the upper ACR quartile were slimmer than their normoalbuminuric counterparts or adolescents with normoalbuminuria within the lower quartile, respectively. No association between microalbuminuria and cardiovascular risk markers was revealed.ConclusionResults obtained in this study do not support our assumption that ACR associates with cardiometabolic risk factors in apparently healthy adolescents. Follow-up studies until adulthood are needed to estimate the potential cardiometabolic risk of apparently healthy microalbuminuric adolescents.

Maternal exposure to a Western type diet during pregnancy might predispose the offspring to manifestation of metabolic and behavioral disturbances in later life. The Western type diet contains large amounts of advanced glycation end products (AGEs). In humans and experimental rodents, the intake of an AGE-rich diet (AGE-RD) negatively affected glucose homeostasis, and initiated the production of reactive oxygen species. Rats consuming the AGE-RD presented changes in behavior. It remains unclear whether maternal intake of the AGE-RD might affect developmental plasticity in offspring. We examined early somatic (weight, incisor eruption, ear unfolding, and eye opening) and neuromotor development, oxidative status, insulin sensitivity (HOMA index) and locomotor activity assessed in PhenoTyper cages in the offspring of mice fed during pregnancy with either the AGE-RD (25% bread crusts/75% control chow) or control chow. Until weaning, the somatic development of offspring did not differ between the two dietary groups. The AGE-RD offspring manifested physiological reflexes (auditory startle, eye lid, ear twitch and righting reflexes) earlier. As young adults, the male offspring of the AGE-RD dams were heavier and less insulin sensitive compared with their control counterparts. The AGE-RD offspring showed higher locomotor activity during the active phase. Our data indicate that the maternal AGE-RD during pregnancy might accelerate the maturation of reflexes in offspring, predispose the male progeny to weight gain and affect their glucose homeostasis. These effects manifest without the direct consumption of the AGE-RD by offspring. Further work is needed to determine the mechanisms by which the maternal AGE-RD affects neurobehavioral pathways in offspring, as well as sex differences in adverse metabolic responses.

AimTo assess the impact of prenatal exposure to Maillard reaction products (MRPs) -rich diet and postnatal Coca-Cola consumption on metabolic status of female rats. Diet rich in MRPs and consumption of saccharose/fructose sweetened soft drinks is presumed to impose increased risk of development of cardiometabolic afflictions, such as obesity or insulin resistance.MethodsAt the first day of pregnancy, 9 female Wistar rats were randomized into two groups, pair-fed either with standard rat chow (MRP-) or MRPs-rich diet (MRP+). Offspring from each group of mothers was divided into two groups and given either water (Cola-) or Coca-Cola (Cola+) for drinking ad libitum for 18 days. Oral glucose tolerance test was performed, and circulating markers of inflammation, oxidative stress, glucose and lipid metabolism were assessed.ResultsMRP+ groups had higher weight gain, significantly so in the MRP+/Cola- vs MRP-/Cola-. Both prenatal and postnatal intervention increased carboxymethyllysine levels and semicarbazide-sensitive amine oxidase activity, both significantly higher in MRP+/Cola + than in MRP-/Cola-. Total antioxidant capacity was lower in MRP+ groups, with significant decrease in MRP+/Cola + vs MRP-/Cola+. Rats drinking Coca-Cola had higher insulin, homeostatic model assessment of insulin resistance, heart rate, advanced oxidation of protein products, triacylglycerols, and oxidative stress markers measured as thiobarbituric acid reactive substances compared to rats drinking water, with no visible effect of MRPs-rich diet.ConclusionMetabolic status of rats was affected both by prenatal and postnatal dietary intervention. Our results suggest that combined effect of prenatal MRPs load and postnatal Coca-Cola drinking may play a role in development of metabolic disorders in later life.

AimTo determine the levels of circulating soluble receptor for advanced glycation end products (sRAGE), as a biomarker of risk of metabolic syndrome and cardiovascular disease development in centrally obese (CO) women considered metabolically healthy (COH) in comparison with those metabolically unhealthy (COU).Methods47 lean healthy, 17 COH (presenting waist-to-height ratio ≥0.5 but not elevated blood pressure, atherogenic lipid profile, and insulin resistance), and 50 COU (CO presenting ≥2 risk factors) women aged 40-45 years were included. Anthropometric characteristics, blood chemistry and hematology data, adipokines, markers of inflammation, sRAGE, soluble vascular adhesion protein-1 (sVAP-1), and the activity of semicarbazide sensitive amine oxidase (SSAO) were determined.ResultsCentral obesity associated with low sRAGE levels (lean healthy: 1503 ± 633 pg/mL; COH: 1103 ± 339 pg/mL, P < 0.05; COU: 1106 ± 367 ng/mL, P < 0.0.1), hyperleptinemia, and elevated markers of inflammation irrespective of the presence or absence of cardiometabolic risk factors. COU women presented high adiponectin levels. SVAP-1 concentrations and the activity of SSAO were similar in all 3 groups.ConclusionCOH women present abnormalities in non-standard markers of cardiometabolic risk (sRAGE, leptin, high sensitive C-reactive protein), supporting the view that there is no healthy pattern of obesity. The clinical impact of our findings for future prognosis of metabolically healthy obese subjects remains to be elucidated in longitudinal studies.

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In non-diabetics, low levels of soluble receptor for advanced glycations end products (sRAGE) associate with an increased risk of development of diabetes, cardiovascular afflictions, or death. The majority of studies in non-diabetics report an inverse relationship between measures of obesity, cardiometabolic risk factors and sRAGE and/or endogenous secretory RAGE (esRAGE) levels. To elucidate whether this inconsistency is related to the metabolically healthy obese phenotype, or a different impact of the risk factors in presence and absence of obesity, we analyzed data from 2206 apparently healthy adolescents (51 % girls) aged 15-to-19 years. The association of sRAGE levels with soluble vascular adhesion protein-1/semicarbazide sensitive amine oxidase (sVAP-1/SSAO) was also investigated. Centrally obese, including metabolically healthy, adolescents present significantly lower sRAGE and esRAGE, but not sVAP-1, levels in comparison with their lean counterparts. An increasing number of cardiometabolic risk factors did not associate with significant changes in sRAGE, esRAGE or sVAP-1 levels either in lean or in obese subjects. In multivariate analyses, WHtR, hsCRP, markers of glucose homeostasis, renal function, adiponectin, and sVAP-1 associated significantly with sRAGE and esRAGE. SVAP-1 correlated significantly with glycemia, adiponectin, hsCRP, and sRAGE. Thus, in adolescents, a decline in sRAGE and esRAGE precedes the development of metabolic syndrome. When combined, standard and non-standard cardiometabolic risk factors explain only minor proportion in a variability of sRAGE and esRAGE (8 %-11 %); or sVAP-1 (12 %-20 %). Elucidation of pathogenetic mechanisms underlying early decline in sRAGE and esRAGE levels in obese adolescents and their clinical impact with regard to future cardiometabolic health requires further studies.

Obesity is associated with chronic low-grade inflammation that eventually leads to metabolic complications. Extracellular DNA (ecDNA) is a damage-associated molecular pattern. Extracellular mitochondrial DNA can activate innate immunity. We hypothesized that ecDNA, especially of mitochondrial origin could be associated with components of the metabolic syndrome in young healthy probands. In a cross-sectional study healthy adolescents (n=1249) provided blood samples. Anthropometric data, blood pressure and blood counts were assessed. In addition, biochemical analysis of sera or plasma was conducted including the quantification of advanced oxidation protein products (AOPP) as a marker of oxidative stress induced by neutrophil or monocyte activation. Plasma ecDNA was isolated and measured using fluorometry. Nuclear and mitochondrial DNA were quantified using real time PCR. Males had higher total plasma ecDNA (15 (11-21) vs 11 (8-17) ng/ml; median (IQR)), nuclear (1760 (956-3273) vs 1153 (600-2292) GE/ml) and mitochondrial DNA (37181 (14836-90896) vs 30089 (12587-72286) GE/ml). EcDNA correlated positively with the continuous metabolic syndrome score (r= 0.158 for males and r= 0.134 for females). Stronger correlations were found between ecDNA of mitochondrial origin and AOPP (r= 0.202 and 0.186 for males and females respectively). Multivariate regression analysis revealed associations of nuclear DNA with leukocyte and erythrocyte counts. The results of this study on healthy adolescents show that circulating ecDNA is associated with the risk of metabolic syndrome, not with obesity per se. The association between mitochondrial ecDNA and AOPP requires further attention as it supports a potential role of mitochondria-induced sterile inflammation in the pathogenesis of the metabolic syndrome.