Prevalence, Cardiometabolic Comorbidities and Reporting of Chronic Kidney Disease; A Hungarian Cohort Analysis

Objectives: Chronic kidney disease (CKD) implies increased comorbidity burden, disability, and mortality, becoming a significant public health problem worldwide, however, prevalence data are lacking in Hungary.Methods: We determined CKD prevalence, stage distribution, comorbidities using estimated glomerular filtration rate (eGFR), albuminuria, and international disease codes in a cohort of healthcare utilizing residents within the catchment area of the University of Pécs, in the County Baranya, Hungary, between 2011 and 2019 by database analysis. The number of laboratory-confirmed and diagnosis-coded CKD patients were compared.Results: Of the total 296,781 subjects of the region, 31.3% had eGFR tests and 6.4% had albuminuria measurements, of whom we identified 13,596 CKD patients (14.0%) based on laboratory thresholds. Distribution by eGFR was presented (G3a: 70%, G3b: 22%, G4: 6%, G5: 2%). Amongst all CKD patients 70.2% had hypertension, 41.5% diabetes, 20.5% heart failure, 9.4% myocardial infarction, 10.5% stroke. Only 28.6% of laboratory-confirmed cases were diagnosis-coded for CKD in 2011–2019.Conclusion: CKD prevalence was 14.0% in a Hungarian subpopulation of healthcare-utilizing subjects in 2011–2019, and substantial under-reporting of CKD was also found

Elevated Vascular Level of ortho-Tyrosine Contributes to the Impairment of Insulin-Induced Arterial Relaxation.

Previous studies have shown that in diabetes mellitus, insulin-induced relaxation of arteries is impaired and the level of ortho-tyrosine (o-Tyr), an oxidized amino acid is increased. Thus, we hypothesized that elevated vascular level of o-Tyr contributes to the impairment of insulin-induced vascular relaxation. Rats were fed with o-Tyr for 4 weeks. Insulin-induced vasomotor responses of isolated femoral artery were studied using wire myography. Vascular o-Tyr content was measured by HPLC, whereas immunoblot analyses were preformed to detect eNOS phosphorylation. Sustained oral supplementation of rats with o-Tyr increased the content of o-Tyr in the arterial wall and significantly reduced the relaxations to insulin. Sustained supplementation of cultured endothelial cells with o-Tyr increased the incorporation of o-Tyr and mitigated eNOS Ser (1 177) phosphorylation to insulin. Increasing arterial wall o-Tyr level attenuates insulin-induced relaxation - at least in part - by decreasing eNOS activation. Elevated level of o-Tyr could be an underlying mechanism for vasomotor dysfunction in diabetes mellitus

Acute Regulation of Cardiac Metabolism by the Hexosamine Biosynthesis Pathway and Protein O-GlcNAcylation

OBJECTIVE: The hexosamine biosynthesis pathway (HBP) flux and protein O-linked N-acetyl-glucosamine (O-GlcNAc) levels have been implicated in mediating the adverse effects of diabetes in the cardiovascular system. Activation of these pathways with glucosamine has been shown to mimic some of the diabetes-induced functional and structural changes in the heart; however, the effect on cardiac metabolism is not known. Therefore, the primary goal of this study was to determine the effects of glucosamine on cardiac substrate utilization. METHODS: Isolated rat hearts were perfused with glucosamine (0-10 mM) to increase HBP flux under normoxic conditions. Metabolic fluxes were determined by (13)C-NMR isotopomer analysis; UDP-GlcNAc a precursor of O-GlcNAc synthesis was assessed by HPLC and immunoblot analysis was used to determine O-GlcNAc levels, phospho- and total levels of AMPK and ACC, and membrane levels of FAT/CD36. RESULTS: Glucosamine caused a dose dependent increase in both UDP-GlcNAc and O-GlcNAc levels, which was associated with a significant increase in palmitate oxidation with a concomitant decrease in lactate and pyruvate oxidation. There was no effect of glucosamine on AMPK or ACC phosphorylation; however, membrane levels of the fatty acid transport protein FAT/CD36 were increased and preliminary studies suggest that FAT/CD36 is a potential target for O-GlcNAcylation. CONCLUSION/INTERPRETATION: These data demonstrate that acute modulation of HBP and protein O-GlcNAcylation in the heart stimulates fatty acid oxidation, possibly by increasing plasma membrane levels of FAT/CD36, raising the intriguing possibility that the HBP and O-GlcNAc turnover represent a novel, glucose dependent mechanism for regulating cardiac metabolism

Incorporation of Ortho- and Meta-Tyrosine Into Cellular Proteins Leads to Erythropoietin-Resistance in an Erythroid Cell Line

Background/Aims: Erythropoietin-resistance is an unsolved concern in the treatment of renal anaemia. We aimed to investigate the possible role of ortho- and meta-tyrosine - the hydroxyl free radical products of L-phenylalanine - in the development of erythropoietin-resistance. Methods: TF-1 erythroblast cell line was used. Cell concentration was determined on day 1; 2 and 3 by two independent observers simultaneously in Bürker cell counting chambers. Protein concentration was determined with colorimetric method. Para-, ortho- and meta-tyrosine levels were measured using reverse phase-HPLC with fluorescence detection. Using Western blot method activating phosphorylation of STAT5 and ERK1/2 were investigated. Results: We found a time- and concentration-dependent decrease of erythropoietin-induced proliferative activity in case of ortho- and meta-tyrosine treated TF-1 erythroblasts, compared to the para-tyrosine cultured cells. Decreased erythropoietin-response could be regained with a competitive dose of para-tyrosine. Proteins of erythroblasts treated by ortho- or meta-tyrosine had lower para-tyrosine and higher ortho- or meta-tyrosine content. Activating phosphorylation of ERK and STAT5 due to erythropoietin was practically prevented by ortho- or meta-tyrosine treatment. Conclusion: According to this study elevated ortho- and meta-tyrosine content of erythroblasts may lead to the dysfunction of intracellular signaling, resulting in erythropoietin-hyporesponsiveness

Effect of glucosamine on A) glucose; B) pyruvate; C) lactate and D) palmitate oxidation.

<p>^* P<0.05 vs. 0 mM glucosamine, one-way ANOVA with Dunnett's posthoc test. 0 mM (n = 6), 0.05 mM (n = 4), 0.1 mM (n = 5), 5 mM (n = 5), 10 mM (n = 4).</p

A hereditaer haemochromatosis jelentősége a diabeteses betegek gondozásában = Importance of hereditary haemochromatosis in the care of diabetes mellitus

Szerzők a vas- és a szénhidrátanyagcsere kapcsolatait vizsgálták saját és irodalmi eredmények tükrében. Különös hangsúlyt fektettek a szabad gyökös folyamatok ismertetésére, mivel a hereditaer haemochromatosis és a diabetes mellitus is, mint a vas- és a szénhidrátanyagcsere-zavarok leggyakoribbjai oxidatív stressz keltése révén vezetnek szövődményekhez. A nagy vér és szöveti glükózkoncentráció elektronfelesleget eredményez. Ez redukálhatja a redox ciklusban részt vevő, transzport- vagy raktárfehérjéhez nem kötött vasat, és ez vezet az oxidatív stresszhez. A hereditaer haemochromatosis mind a válogatás nélküli, mind pedig a diabeteses populációban a szöveti redox-aktív vas szintjének emelkedését okozhatja. A hereditaer haemochromatosis leggyakoribb mutációit hordozók aránya hazánkban, szelekció nélküli népességben 30,4%-ot és diabetesben 35,8%-ot tesz ki. Az irodalom adatai szerint feltételezhető, hogy már a hereditaer haemochromatosis leggyakoribb mutációi (HFE-C282Y és HFE-H63D) szempontjából heterozigotákban is megemelkedik a szöveti vasszint, bár a fenotípusban a hereditaer haemochromatosis ilyenkor általában nem jelenik meg, mivel penetranciája alacsony. Mégis, ez a megemelkedett vas-ellátottság a már más okból – például diabetes mellitus miatt – károsodott szövetek betegségének progresszóját okozhatja. Másrészt a hereditaer haemochromatosis olyan endothelkárosodáshoz vezethet, ami miatt – a diabetes mellitus manifesztálódását megelőzően – hypertonia alakulhat ki. Feltételezhető, hogy a vérnyomásemelkedés a hereditaer haemochromatosis egyik legkorábbi klinikai jele. Nehezen beállítható hypertonia és szénhidrátanyagcsere-zavar esetén érdemes gondolni a hereditaer haemochromatosis lehetőségére. Interactions of iron and carbohydrate metabolism were examined using results of the literature. Special attention was paid to the description of processes involving free radical production because both hereditary haemochromatosis and diabetes mellitus lead to complications by inducing oxidative stress. High levels of blood and tissue glucose produce an excess of electrons. This overload of tissues by electrons may reduce redox-active, non-haeme ferric iron to ferrous one evolving oxidative stress. Hereditary haemochromatosis may cause an elevation in the concentration of the intracellular redox-active iron in both the general and in the diabetic populations. The ratio of carriers (hetero- + homozygotes) of mutations for hereditary haemochromatosis may be as high as 30.4% in the general and 35.8% in the diabetic Hungarian populations. Some data support the possibility that these common forms of hereditary haemochromatosis mutation (HFE-C282Y and HFE-H63D) – even in the heterozygote form – elevate the tissue level of iron without manifesting the phenotype of classical hereditary haemochromatosis. Elevated tissue iron – in patients with already damaged organs due to other diseases e.g. diabetes mellitus – may cause a progression of the complications. On the other hand, hereditary haemochromatosis may lead to endothelial damage and this way hypertension may precede the manifestation of diabetes mellitus. On the basis of these, it may be supposed that elevation of blood pressure should be taken into consideration as one of the earliest clinical symptoms of hereditary haemochromatosis. A therapy-resistant state caused by the hereditary haemochromatosis may be found in diabetes mellitus and hypertension

Exenatide induces aortic vasodilation increasing hydrogen sulphide, carbon monoxide and nitric oxide production

BACKGROUND: It has been reported that GLP-1 agonist exenatide (exendin-4) decreases blood pressure. The dose-dependent vasodilator effect of exendin-4 has previously been demonstrated, although the precise mechanism is not thoroughly described. Here we have aimed to provide in vitro evidence for the hypothesis that exenatide may decrease central (aortic) blood pressure involving three gasotransmitters, namely nitric oxide (NO) carbon monoxide (CO), and hydrogen sulphide (H2S). METHODS: We determined the vasoactive effect of exenatide on isolated thoracic aortic rings of adult rats. Two millimetre-long vessel segments were placed in a wire myograph and preincubated with inhibitors of the enzymes producing the three gasotransmitters, with inhibitors of reactive oxygen species formation, prostaglandin synthesis, inhibitors of protein kinases, potassium channels or with an inhibitor of the Na+/Ca2+-exchanger. RESULTS: Exenatide caused dose-dependent relaxation of rat thoracic aorta, which was evoked via the GLP-1 receptor and was mediated mainly by H2S but also by NO and CO. Prostaglandins and superoxide free radical also play a part in the relaxation. Inhibition of soluble guanylyl cyclase significantly diminished vasorelaxation. We found that ATP-sensitive-, voltage-gated- and calcium-activated large-conductance potassium channels are also involved in the vasodilation, but that seemingly the inhibition of the KCNQ-type voltage-gated potassium channels resulted in the most remarkable decrease in the rate of vasorelaxation. Inhibition of the Na+/Ca2+-exchanger abolished most of the vasodilation. CONCLUSIONS: Exenatide induces vasodilation in rat thoracic aorta with the contribution of all three gasotransmitters. We provide in vitro evidence for the potential ability of exenatide to lower central (aortic) blood pressure, which could have relevant clinical importance

Effect of glucosamine on A, B) Overall cardiac O-GlcNAc levels; C) UDP-HexNAc concentrations and D) ATP concentrations.

<p>^* P<0.05 vs. 0 mM, one-way ANOVA with Dunnett's posthoc test. Western blots: 0 mM (n = 8), 0.05 mM (n = 5), 0.1 mM (n = 9), 1 mM (n = 4), 5 mM (n = 8), 10 mM (n = 7). HPLC: 0 mM (n = 4), 0.05 mM (n = 5), 0.1 mM (n = 5), 1 mM (n = 4), 5 mM (n = 3), 10 mM (n = 3). Note that equal protein loading for the O-GlcNAc immunoblots was assessed by Sypro staining and overall O-GlcNAc levels were normalized to untreated control group.</p