Velibor Čabarkapa

Changes of serum VEGF concentration after intravitreal injection of Avastin in treatment of diabetic retinopathy

Purpose Avastin (bevacizumab) intravitreal injections are widely used for treatment of diabetic retinopathy. The aim of our study was to analyze effect of 1.25 mg of intravitreal Avastin on serum concentration of vascular endothelial growth factor (VEGF) in diabetic patients. Methods Participants were 10 diabetic patients on insulin therapy, without any other eye or systemic disease, and no kidney disfunction. Both eyes of diabetic patients were injected simultaneously with 1.25 mg of intravitreal Avastin, as a first step in treatment of nonproliferative diabetic retinopathy with clinically significant macular edema (4 patients), and of proliferative diabetic retinopathy (6 patients). Fluorescein angiography was performed prior to and laser therapy followed 1 month after Avastin treatment. VEGF concentration in patients serum was measured by ELISA technique: on the day of the Avastin administration, and 1, 7, and 28 days after intravitreal injection. Results In all analyzed participants, 24 hours after Avastin treatment, serum levels of VEGF were lower then basal (preinjection value). Maximal reduction of serum VEGF was noted on the 7th postoperative day. Twenty-eight days after, VEGF level in serum was raised, without completely reaching basal preoperative concentrations in most patients. Conclusions Intravitreal injections of anti-VEGF drugs have an effect on decreasing systemic VEGF values. Rhythm of changes in serum VEGF concentrations and lowest detected concentration on the seventh postinjection day are according to pharmacokinetics of Avastin in serum and vitreous, reported by similar studies. The small number of patients involved in this pilot study implicates the need for further studies.

Cystatin C in pre-eclampsia.

Objective: To evaluate diagnostic value of cystatin C serum levels as alternative marker of renal function in pre-eclamsia (PE) and compare it with the traditional markers of renal function, creatinine and uric acid. In order to investigate the possible influence of inflammation on biochemical markers of renal function, serum levels of high sensitive CRP were measured (hsCRP). Methods: In this prospective study markers of kidney function were investigated in two groups of pregnant women: one with PE (n = 32) and the other of healthy pregnant women (n = 60). Serum cystatin C levels were measured as well as levels of traditional renal markers creatinin and uric acid and levels of high sensitive C-reactive protein. Results: Serum levels of cystatin C, creatinine and uric acid were significantly higher in the PE group than in the control group. Serum levels of hsCRP were higher in approximately the same number of patients with PE (50%) as in normal pregnancies (40%), without significant differences in CRP values between the two groups of patients. Conclusions: Cystatin C serum level may have significant role as a marker of pre-eclampsia specially when used in combination with uric acid levels.

Plasma endothelin-1 level, measured glomerular filtration rate and effective renal plasma flow in diabetic nephropathy.

Abstract Background: Endothelin-1 (ET-1) is potent vasoconstrictor peptide which is able to contribute to the functional and structural renal changes. The aim of this study was to investigate the relationship between plasma concentration of ET-1 and indices of renal function in patients with diabetic nephropathy. Methods: We measured plasma ET-1 levels in 99 patients with type 2 diabetes, divided into two groups according to the values of their glomerular filtration rate (GFR): group I (GFR ≥ 60 mL/min/1.73 m2; n = 50), group II (GFR ≥ 60 mL/min/1.73 m2, n = 49), and the control group (n = 30) with clinically healthy subjects who were matched by age and sex. GFR and effective renal plasma flow (ERPF) were measured by the radioisotopic clearance. Other renal function parameters, such as serum concentrations of cystatin C, urea, creatinine, uric acid, 24-h albuminuria and proteinuria were additionally measured. Results: There were significant differences in plasma concentration of ET-1 among groups I, II and the control group (1.45 vs. 2.40 vs. 0.80 pg/mL, p < 0.001). The correlation between ET-1 and mGFR (r = −0.52, p < 0.001), ERPF (r = −0.42, p < 0.001), albuminuria and proteinuria (r = 0.36, p < 0.001; r = 0.48, p < 0.001) and cystatin C (r = 0.42, p < 0.001) was significant. In multiple regression analyses, only plasma concentration of ET-1 (p < 0.001) and duration of hypertension (p < 0.05) were independently and significantly associated with mGFR. Conclusion: A higher plasma concentration of ET-1 is independently associated with a decreased value of GFR in patients with diabetic nephropathy.

Cardiovascular Biomarkers in Chronic Kidney Disease

Cardiovascular Biomarkers in Chronic Kidney Disease Cardiovascular morbidity and mortality are markedly increased in chronic renal failure patients. Although it cannot be regarded as a cardiovascular disease risk equivalent, kidney dysfunction is considered an independent predictor of increased cardiovascular risk that increases with deteriorating kidney function. The association is a very complex one, and the term cardiorenal syndrome is now widely used. Cardiovascular disease in chronic kidney disease patients usually manifests as ischemic heart disease (in the form of angina, acute coronary syndrome or sudden cardiac death), cerebrovascular disease, peripheral vascular disease, and congestive heart failure. Vascular disease includes atherosclerosis and vascular calcifications, and cardiomyopathy comprises left ventricular hypertrophy, cardiac fibrosis and left ventricular systolic and diastolic dysfunction. In addition to the well-established traditional risk factors such as hypertension, hyperlipidemia, insulin resistance and diabetes mellitus, the association is supported by synergistic action of non-traditional risk factors such as excessive calcium-phosphorus load, hyperparathyroidism, anemia, hemodynamic overload, malnutrition, inflammation, hyperhomocysteinemia, altered nitric oxide synthase and increased oxidative stress. This paper summarizes the current understanding of the significance of specific uremic retention solutes, natriuretic peptides, biochemical markers of disorders in calcium-phosphorus homeostasis, systemic inflammation, oxidative stress, and dyslipidemia. Biohemijski Markeri Kardiovaskularnih Bolesti U Hroničnoj Bolesti Bubrega Kod pacijenata sa hroničnim oboljenjem bubrega, kardiovaskularni morbiditet i mortalitet su značajno povišeni. Iako se ne može smatrati ekvivalentom rizika za kardiovaskularne bolesti, veruje se da je bubrežna insuficijencija nezavisni prediktor povećanog kardiovaskularnog rizika i da se taj rizik povećava sa slabljenjem bubrežne funkcije. Ova udruženost je veoma kompleksna i danas se široko koristi termin kardiorenalni sindrom. Kardiovaskularna bolest u hroničnoj bolesti bubrega obično se ispoljava kao ishemijska bolest srca (u obliku angine, akutnog koronarnog sindroma ili nagle srčane smrti), cerebrovaskularna bolest, periferna vaskularna bolest i kongestivna bolest srca. Vaskularna bolest obuhvata aterosklerozu i vaskularne kalcifikacije, dok kardiomiopatija obuhvata hipertrofiju leve komore, kardijalnu fibrozu i sistolnu i dijastolnu disfunkciju leve komore. Pored dobro poznatih tradicionalnih faktora rizika kao što su hipertenzija, dislipidemija, insulinska rezistencija i diabetes mellitus, u osnovi ove udruženosti je i sinergističko delovanje netradicionalnih faktora rizika kao što su povećanje odnosa kalcijum-fosfor, hiperparatireoidizam, anemija, hemodinamsko opterećenje, pothranjenost, zapaljenje, hiperhomocisteinemija, izmenjena sinteza azot-monoksida i povećan oksidativni stres. U radu se razmatraju dosadašnja saznanja o značaju pojedinih uremijskih toksina, natriuretičkih peptida, biohemijskih markera poremećaja u homeostazi kalcijuma i fosfora, sistemske inflamacije, oksidativnog stresa i dislipidemije.

Determining the Relationship Between Homocysteinemia and Biomarkers of Inflammation, Oxidative Stress and Functional Kidney Status in Patients with Diabetic Nephropathy

Summary Background: One of the leading causes of terminal renal failure is diabetic nephropathy. The aim of this study was to determine the relationship between homocysteine levels and the biomarkers of renal function, inflammation and oxidative stress, as well as the incidence of macrovascular complications in patients with diabetic nephropathy. Methods: Sixty-four patients with diabetic nephropathy were included in this study. They were divided according to their homocysteine levels into two groups: hyperhomocysteinemic (HHcy, n=47) and normohomocysteinemic patients (NHCy, n=17). The re sults were compared to a control group (n=20) with normal renal function and without diabetes. Besides homocysteine, cystatine C, creatinine, urea, albuminuria, creatinine clearance, lipid status parameters, apolipoprotein A-I and B, lipo protein (a), CRP, fibrinogen, oxidative LDL were determined using appropriate methods. The incidence of macro vascular diabetic complications was also determined. Results: The results indicate that the level of renal dysfunction is greater in HHcy than in NHcy patients (p<0.05). In HHcy patients levels of oxLDL were also higher compared to NHcy patients (119.3±140.4 vs. 71.4±50.8 ng/mL, disp< 0.05) as well as fibrinogen levels (4.3±1.3 vs. 3.7±0.8 g/L, p<0.05). The in cidence of macrovascular complications is more frequent in HHcy than in NHcy patients (55.3. vs. 35.3 %, p>0.05), and in patients with macroalbuminuria compared to patients with microalbuminuria (65% vs. 39%, p<0.05). Conclusions: It can be concluded that HHcy is significantly present in patients with diabetic nephropathy, especially if there is greater reduction of renal function. Besides that, significantly higher concentrations of inflammatory (fibrinogen) and oxidative stress (oxLDL) markers were present in HHcy patients with diabetic nephropathy compared to NHcy patients.Therefore in diabetic nephropathy patients it is useful to regularly monitor the levels of homocysteine, as well as inflammatory and markers of oxidative stress. Kratak sadržaj Uvod: Dijabetesna nefropatija jedan je od vodećih uzroka terminalne bubrežne insuficijencije. Cilj ove studije bio je ispitivanje odnosa homocisteinemije i biomarkera bu bre`ne funkcije, inflamacije i oksidativnog stresa, kao i u~e stalosti makrovaskularnih komplikacija kod bolesnika sa dijabetesnom nefropatijom. Metode: U studiju je uklju~eno 64 ispitanika sa dijabetesnom nefropatijom koji su podeljeni u dve grupe u odnosu na homocisteinemiju: hi per homociste i nemi~ni (HHcy, n=47) i normohomo cistei ne mi~ni (NHcy, n=17). Odgovaraju}im metodama su pored nivoa homocisteina u krvi odre|ivani i nivoi cistatina C, kreatinina, uree, albuminurije, klirensa kreatinina, parametara lipidskog statusa, apolipoproteina A i B, lipoproteina(a), CRP, fibrinogena, oksidisanog LDL, kao i u~estalost makrovaskularnih komplikacija dijabetesne bo - lesti. Rezultati: Dobijeni rezultati upore|ivani su sa rezultatima kontrolne grupe ispitanika (n=20) sa urednom bubre`nom funkcijom, bez prisutne dijabetesne bolesti. Rezultati ukazuju da je stepen bubre`ne disfunkcije ve}i kod HHcy nego kod NHcy pacijenata (p<0,05). Tako|e, kod HHcy pacijenata nivo oxLDL je zna~ajno vi{i u odnosu na NHcy pacijente (119,3±140,4 vs. 71,4±50,8 ng/mL, p<0,05), kao i nivofibrinogena (4,3±1,3 vs. 3,7±0,8 g/L, p<0,05). Pojava makrovaskularnih komplikacija je u~estalija kod HHcy nego NHcy pacijenata (55,3% vs. 35,3%, p> 0,05), kao i kod pacijenata sa makroalbuminurijom u od nosu na pacijente sa mikroalbuminurijom (65% vs. 39%, p<0,05). Zakljućak: Na osnovu dobijenih rezultata mo`e se zaklju~iti da je HHcy u zna~ajnom stepenu prisutna kod bolesnika sa dijabetesnom nefropatijom, naro~ito ukoliko postoji izra `enija redukcija funk cio nalne rezerve bubrega. Osim toga, u odnosu na NHcy bo lesnike, kod HHcy bolesnika sa dijabetesnom nefropatijom zna~ajno su vi{e koncentracije inflamatornih (fibrinogena) i markera oksidativnog stresa u krvi (oxLDL). Stoga je kod bolesnika sa dijabetesnom nefropatijom po`eljno redovno pra}enje homocisteina u krvi, ali i inflamatornih markera, kao i markera oksidativnog stresa.

Ceruloplasmin and antioxidative enzymes in pre-eclampsia

Abstract Objective: To evaluate diagnostic value of ceruloplasmin together with other enzymatic and nonenzymatic antioxidants (superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and uric acid) and to evaluate the level of oxidative stress in patients with pre-eclampsia (PE) and compare it with normal pregnancy. Methods: In this prospective study, antioxidative markers were investigated in two groups of pregnant women: patients with pre-eclampsia (n = 32) and the healthy pregnant women (n = 60). The following antioxidative markers and enzymes were evaluated: serum ceruloplasmin levels, uric acid, superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). Results: Serum levels of ceruloplasmin, uric acid and SOD were significantly higher in the PE group compared to the control group. Serum levels of GSH-Px were not significantly higher in the PE group compared to the control group. Serum ceruloplasmin and serum uric acid have the best diagnostic accuracy for oxidative stress in PE and are more accurate compared to antioxidative enzymes -SOD and specially more accurate than GSH-Px. Conclusions: Serum ceruloplasmin level may have significant role as the markers of oxidative stress in pre-eclampsia especially when used in combination with uric acid levels.

The Incidence of Anemia in the Adult Working Population of Vojvodina

Abstract Background: Anemia is a global public health problem of endemic proportions, especially in women, and with serious health consequences. Anemia was defined according to the World Health Organization criteria as hemoglobin concentration <130 g/L for men and <120 g/L for women. The incidence of anemia varies between regions, so the aim of the study was to determine the incidence of anemia in a randomly selected sample of adult working individuals of both sexes, in Vojvodina. Methods: The study included a total of 6087 subjects (4658 men and 1429 non-pregnant women) aged 18-65 years who presented for a regular checkup at the Public Health Institute of Vojvodina. Blood specimen collection was performed by antecubital venipuncture in all subjects. Results: The results showed that the incidence of anemia in adults in Vojvodina was 7.7%, and it was more frequent in women (20%) than in men (3.86%). The most frequent was normocytic anemia, whereas microcytic anemia was less prevalent. Macrocytic anemia was found in only 3.3% of subjects, exclusively in women. The greatest proportion of anemic subjects, regardless of sex, had hemoglobin levels that indicated mild anemia (Hb 100-119 g/L for women, and 100-129 g/L for men). Only 4% of men and 12% of women had Hb levels that indicated the presence of moderate or severe anemia (≤100 g/L). Conclusions: Considering the medical, social and economic consequences anemia may produce, identification of risk factors and application of adequate preventive measures should be a public health priority. Kratak sadržaj Uvod: Anemija je globalan, problem u oblasti javnog zdrav- stva, endemskih razmera, naročito među ženskom popu- lacijom, sa ozbiljnim posledicama po zdravije. Prema kriteriju- mima Svetské zdravstvene organizacije, anemija je definisana kao koncentracija hemoglobina <130 g/L za muškarce i <120 g/L za žene. Njena incidenca varira od regiona do regiona, te je cilj rada bio da se utvrdi učestalost anemije u slučajnom uzorku odraslih zaposlenih osoba oba pola u Vojvodini. Metode: Istraživanje je sprovedeno u 6087 ispitanika (4658 muškaraca i 1429 žena koje nisu trudne) starosti 18-65 go- dina koji su se javili na periodični sistematski pregled u Insti- tutu za javno zdravlje Vojvodine. Svim ispitanicima je ante- kubitalnom venepunkcijom uzet uzorak krvi za određivanje krvne slike. Rezultati: Utvrđeno je da na teritoriji Vojvodine incidenca anemije kod odraslih iznosi 7,7%, pri čemu je ona učestalija među ženskom populacijom (20%) u odnosu na mušku po- pulaciju (3,86%). Među anemičnom odraslom populacijom najveća je bila zastupljenost normocitne anemije, a daleko manja mikrocitne anemije. Makrocitna anemija je bila zastu- pljena kod svega 3,3% ispitanika i to isključivo ženskog pola. U najvećem procentu anemičnih ispitanika u ovoj studiji, bez obzira na pol, vrednosti hemoglobina ukazuju na blaži stepen anemije (Hb 100-119 g/L za žene, odnosno 100-129 g/L za muškarce). Samo 4% muškaraca i 12% žena je imalo vred- nosti Hb koje ukazuju na prisustvo umereno teške ili teške anemije (i 100 g/L). Zaključak: S obzirom na zdravstvene, socijalne i ekonomske posledice do kojih malokrvnost može dovesti, identifikacija faktora rizika za pojavu anemije i primena odgovarajućih pre- ventivnih mera bi trebalo da budu u javnom zdravstvu.

Clinical significance of determining plasma homocysteine: case-control study on arterial and venous thrombotic patients.

Aim To determine the differences in plasma homocysteine levels between three MTHFR 677 genotype subgroups in patients with thrombosis and in controls, as well as between patients with thrombosis and controls with the same MTHFR 677 genotype. Methods This case-control study was conducted in Clinical Center of Vojvodina, Novi Sad, from June to December 2011. We included 65 patients with either arterial or venous thrombosis (mean age, 40.97 ± 11.38 years) and 65 controls with no history or clinical evidence of any thrombotic event (mean age, 41.23 ± 11.12 years). Patients and controls were age- and sex-matched. Results In comparison with controls, thrombotic patients had significantly higher homocysteine levels (12.81 ± 4.94 µmol/L vs 9.82 ± 3.68 µmol/L; P < 0.001) and significantly higher incidence of hyperhomocysteinemia (55% vs 22%; P < 0.001; odds ratio [OR] = 4.521). There were no significant differences in homocysteine levels between homozygous carriers, heterozygous carriers, and non-carriers of the MTHFR 677 mutation in either thrombotic patients (12.97 ± 5.40 µmol/L vs 12.55 ± 5.71 µmol/L vs 13.27 ± 1.71 µmol/L; P = 0.100) or controls (10.07 ± 2.50 µmol/L vs 10.25 ± 4.84 µmol/L vs 9.20 ± 2.44 µmol/L; P = 0.651). However, in comparison with controls, homozygous carriers in thrombotic patient group did not have significantly higher levels of homocysteine (12.97 ± 5.40 µmol/L vs 10.07 ± 2.50 µmol/L; P = 0.072), but heterozygous carriers (12.55 ± 5.71 µmol/L vs 10.25 ± 4.84 µmol/L; P = 0.020) and non-carriers (13.27 ± 1.71 µmol/L vs 9.20 ± 2.44 µmol/L; P < 0.001) did. There was no significant difference in homocysteine levels between patients with arterial and venous thrombosis (12.76 ± 3.60 µmol/L vs 12.86 ± 5.51 µmol/L; P = 0.990) and between patients with one thrombotic event and those with recurrent thrombotic events (12.14 ± 3.20 µmol/L vs 15.25 ± 8.51 µmol/L; P = 0.254). Conclusion Plasma homocysteine levels have a greater clinical significance in the prevention of thrombosis and managing its complications than MTHFR 677 genotyping.

Biochemical Markers of Atherosclerosis

Biochemical Markers of Atherosclerosis This paper is a brief review of some lipid parameters and serum markers of inflammation in a view of their predictive relevance for the atherosclerotic disease. A discourse on the importance of measuring different lipids and lipoproteins, concentration of LDL particles and apolipoprotein levels is still underway. Also, the recommendations for apolipoprotein (a), phenotypization and other lipid markers have not yet been established. In recent years the recommendations imply simultaneous measuring of multiple markers and calculating the lipid index values such as lipid tetrad index (LTI), lipid pentad index (LPI) and atherogenic index of plasma (AIP). Several circulating markers of inflammation such as C-reactive protein, serum fibrinogen and elevated leukocyte number, are consistently associated with atherosclerosis. In spite of a lack of evidence on measuring the C-reactive protein in a wide population, the guidelines for its application in diagnostics and therapy of coronary heart disease were developed. Some proinflammatory cytokines, adhesion molecules and markers of leukocyte activation are promising markers, requiring, however, more detailed prospective evaluation. The question to be elucidated is if these inflammatory markers are directly involved in the pathogenic process. Biohemijski Markeri Ateroskleroze U ovom radu razmatrani su samo neki lipidni parametri i serumski markeri inflamacije u pogledu njihove prediktivne povezanosti s aterosklerotskom bolešću. Nastavlja se debata o značaju merenja različitih lipida i lipoproteina, uključujući koncentraciju LDL čestica i nivoe apolipoproteina. Takođe, nisu uspostavljene preporuke za apolipoprotein (a) fenotipizaciju i druge lipidne markere. Poslednjih godina preporučuje se simultano merenje nekoliko markera i izračunavanje lipidnih indeksa kao što su lipid tetrada index (LTI), lipid pentada index (LPI) i aterogeni indeks plazme (AIP). Nekoliko cirkulišućih markera inflamacije, npr. C-reaktivni protein, serumski fibrinogen i povišenje broja leukocita, dosledno su udruženi s aterosklerozom. Iako nema dokaza za korisnost merenja Creaktivnog proteina u široj zajednici, formirane su preporuke za njegovu upotrebu u dijagnostici i lečenju koronarne bolesti srca. Neki proinflamatorni citokini, adhezioni molekuli i markeri leukocitne aktivacije su obećavajući markeri, ali zaslužuju dalja prospektivna ispitivanja. Pitanje koje zahteva odgovor je i da li su ti inflamatorni markeri direktno uključeni u patogeni proces.

Serum Cystatin C in Estimating Glomerular Filtration Rate

Serum Cystatin C in Estimating Glomerular Filtration Rate Using serum cystatin C in estimating glomerular filtration rate (GFR) has in recent times been recommended. A number of simple formulas for calculating GFR have been derived specifically from serum cystatin C concentrations. The purpose of this study was to assess the significance of cystatin C and of the two most frequently applied of these formulas in estimating glomerular filtration rate compared to serum creatinine and its derived formulas for estimating glomerular filtration rate from creatinine concentrations. The study included 74 patients: 59 were in various stages of chronic renal insufficiency (divided into two subgroups: I with GFR ≥ 60 mL/min/1.73m2 and II with GFR<60 mL/min/1.73m2) and 15 on hemodialysis. A control group of 30 healthy participants was also included in the study. Serum values of cystatin C ranged from: 0.86 ± 0.16 mg/L in subgroup I, and 1.77 ± 0.79 mg/L in subgroup II, to 6.9 ± 1.83 mg/L in patients on hemodialysis. The correlation between the two formulas derived from cystatin C and the clearance of creatinine, as well as the Cockcroft and Gaults formula, was significant, while one of the formulas derived from cystatin C did not show a significant correlation with MDRD. It was concluded that serum cystatin C is a significant marker in estimating glomerular filtration rate, especially in the advanced stages of chronic renal insufficiency. Serumski Cistatin C U Proceni Jačine Glomerulske Filtracije U novije vreme preporučena je upotreba serumskog cistatina C u proceni jačine glomerulske filtracije (GFR). Upravo iz serumske koncentracije cistatina C je izvedeno nekoliko jednostavnih formula za izračunavanje GFR. Cilj ove studije je bio da proceni značaj cistatina C i dve najčešće primenjivane od tih formula u proceni jačine glomerulske filtracije u poređenju sa serumskim kreatininom i izvedenim formulama za procenu jačine glomerulske filtracije iz koncentracija kreatinina. U studiju je uključeno 74 ispitanika: 59 u različitim stadijumima hronične bubrežne insuficijencije (podeljenih u dve podgrupe: I sa GFR ≥ 60 mL/min/1,73m2 i II sa GFR< 60 mL/min/1,73m2) i 15 na hemodijalizi. U studiju je bila uključena i kontrolna grupa od 30 zdravih ispitanika. Serumske vrednosti cistatina C su se kretale: u podgrupi I 0,86 ± 0,16 mg/L, u podgrupi II 1,77 ± 0,79 mg/L i kod ispitanika na hemodijalizi 6,9 ± 1,83 mg/L. Korelacija između obe formule izvedene iz cistatina C i klirensa kreatinina kao i Kokroft-Gaultove formule bila je značajna, dok jedna od ovih formuli izvedenih iz cistatina C nije pokazala značajnu korelaciju sa MDRD. Može se zaključiti da je serumski cistatin C značajan parametar u proceni jačine glomerulske filtracije, naročito u odmaklim stadijumima hronične bubrežne insuficijencije.