[Significance of the factors of hypoxia and endothelial dysfunction in kidney injury in the presence of obesity].

AIM: To define the clinical significance of asymmetric dimethylarginine (ADMA) and that of methylenetetrahydrofolate reductase (MTHFR) gene polymorphism as factors of endothelial dysfunction (ED) in the development of early kidney injury in obese patients. SUBJECTS AND METHODS: The investigation included 86 patients (64 men and 22 women aged 44 +/- 11 years) with abdominal obesity. Along with physical examination, the authors determined albuminuria, calculated glomerular filtration rate (GFR) using the Modification of Diet in Renal Disease (MDRD) formula, estimated insulin resistance markers (fasting plasma insulin and C-peptide concentrations and homeostatic model assessment (HOMA) index), as well as serum ADMA levels by enzyme immunoassay in all the patients. C677T polymorphism in the MTHFR gene was studied by allele-specific polymerase chain reaction and restriction fragment length polymorphism analysis. Kidney injury (chronic kidney disease (CKD)) was diagnosed using the Kidney Disease Outcomes Quality Initiative (KDOQI) criteria. Early vascular remodeling was determined from the increased intima-media thickness (IMT) of the common carotid artery (CCA). RESULTS: CKD was diagnosed in 27(31%) patients. The latter, unlike the patients with CKD, were observed to have more pronounced obesity (body mass index (BMI) 36.8 +/- 8.0 and 32.0 +/- 4.7 kg/m2, respectively (p < 0.001)), waist circumference (119 +/- 18 and 109 +/- 11 cm (p = 0.002)), higher levels of C-peptide (1348 +/- 363 and 1028 +/- 363 pmol/I; p < 0.001), insulin (16.9 +/- 7.3 and 11.7 +/- 5.5 microU/ ml; p < 0.001), and HOMA index (4.3 +/- 1.7 and 2.9 +/- 1.5; p < 0.001). In the patients with Stage IIIa CKD, ADMA concentrations (0.77 +/- 0.19 micromol/l) was higher than in those with Stages I (0.58 +/- 0.11 micromol/l; p = 0.048) and II (0.61 +/- 0.13 micromol/l; p = 0.071). An association between ADMA concentrations, CCA IMT, and estimated GFR was revealed in the patients with CKD. The predictors of an estimated GFR reduction in obesity were elevated serum concentrations of ADMA, uric acid, insulin, and HOMA index. The combination of obstructive sleep apnea syndrome and metabolic syndrome increased the risk of CKD by 2.1-fold (95% confidence interval, 1.06-3.14). Evaluation of the impact of MTHFR gene polymorphism on kidney injury in obesity disclosed that the patients with homozygous carriage of the abnormal T allele of the MTHFR gene had a higher risk for Stages I-IIIa CKD (2.60 with 95% confidence interval, 1.32-3.88), more marked obesity and hyperinsulinemia, and increased serum ADMA concentrations. CONCLUSION: Insulin resistance and ED hold a central position in the pathogenesis of CKD in obese patients. The mechanisms of the atherosclerotic vascular remodeling associated with elevated serum ADMA concentrations are of paramount importance in the progression of early-stage CKD. The homozygous carriage of the abnormal T allele of the MTHFR gene increases the risk of Stages I-IIIa by more than twice.

[Clinicopathogenetic characteristics of cardiorenal syndrome in non-alcoholic fatty liver disease].

AIM: To study clinicopathogenetic characteristics of cardiorenal syndrome (CRS) in non-alcoholic fatty disease of the liver (nAFDL). MATERIAL AND METHODS: Insulin resistance markers, plasma leptin and serum adiponectin concentrations. albuminuria, intima-media thickness (IMT) of the common carotid artery (CCA) were assessed in 80 patients with metabolic syndrome (60 males and 20 females, mean age 44+-11 years) and NAFDL. RESULTS: With increasing signs of affection of target organs in NAFDL there was a trend to a significant rise in detection of chronic kidney disease (CKD) and carotid artery atherosclerosis, aggravation of albuminuria and CCA IMT, lowering of glomerular filtration rate. Leptinemia was maximal in CKD patients and directly correlated with albuminuria. Patients with CCA atherosclerosis had a significant fall of serum adiponectin which negatively correlated with CCA IMT. The latter positively correlated with insulinemia, a C-peptide plasma level and HOMA index. Serum concentration of adiponectin positively correlated with DeRitis index. CONCLUSION: CRS in NAFDL is characterized with frequent development of CKD and CCA atherosclerosis defined also by unbalance of adiponectin and leptin production.

[Remodeling of the cardiovascular system and development of chronic kidney disease in patients with metabolic syndrome and obesity: role of eNOS, subunit p22-phox of NADPH-oxidase and MTHFR genes].

AIM: To examine contribution of polymorphisms of genes of endothelial NO-synthase (eNOS), NADPH-oxidase and methylenetetrahydrofolate reductase (mTHFR) to development of remodeling of cardiovascular system and chronic disease of the kidneys (CDK) in patients with metabolic syndrome (mS) and obesity. MATERIAL AND METHODS. Standard clinical and device examinations were made and polymorphisms C242T of gene of subunit p22-phox of NADPH-oxidase, G894T of gene of eNOS and C677T of gene of MTHFR were studied in 66 MS patients (49 males and 17 females, age 19-62 years. RESULTS: The presence of even one prognostically poor allele variants of the genes studied was registered in 83 examinees. The genotype 242TTp22-phox of NADPH-oxidase subunit was associated with the highest insulin resistance, allele 894T of gene eNOS- with reduced glomerular filtration rate and progression of left ventricular hypertrophy. CONCLUSION: Polymorphism of the genes the products of which modulate endothelial function can be considered as potential predictors of severity of MS target organs impairment.

[The role of leptin, adiponectin and insulin-resistance markers in development of early stages of chronic kidney disease and atherosclerosis of carotid arteries in obese patients].

AIM: To characterize clinicopathogenetically factors influencing development of early chronic kidney disease (CKD) and impairment of other target organs in obese patients. MATERIAL AND METHODS: The examination of 86 obese patients (64 males and 22 females, mean age 44 +/- 11 years) included standard clinical tests, test for albuminuria, calculation of glomerular filtration rate (GFR) by MDRD formula, ultrasound investigation of the carotid arteries to detect atherosclerotic lesion of the carotid arteries, assessment of insulin resistance - IR (plasma concentration of insulin before meal and blood C-peptide, HOMA-index), test for plasma adipokinins (leptin, adiponectin). RESULTS: Significant direct correlations were found between blood plasma leptin concentration, body mass index (BMI), plasma concentration of insulin and C-peptide, HOMA index, adiponectinemia and albuminuria. CKD patients have significantly higher than patients free of CKD levels of IR markers, waist circumference, BMI, leptinemia (38.2 +/- 28.8 and 21.6 +/- 19.8 ng/ml, respectively; p < 0.01). Obstructive sleep apnea syndrome was associated with higher IR and albuminuria, significantly lower estimated GFR (81 +/- 2 and 95 +/- 2 ml/min/1.73 m2, respectively; p < 0.05). Ultrasound evidence for atherosclerotic lesions of the carotid arteries was associated with a significant increase in blood plasma concentration of C-peptide, reduction of adiponectinemia (14.9 +/- 10.8 and 32.5 +/- 22.5 mcg/ml; p < 0.01), a rise in proportion fasting insulinemia/adiponectinemia (1.6 +/- 1.2 and 0.6 +/- 0.8, respectively; p < 0.05) and reduction of estimated GFR (86 +/- 19 and 102 +/- 25 ml/min/1.73 m2, respectively; p = 0.001). CONCLUSION: In obesity, CKD at early stages develops in parallel with atherosclerotic lesion of the carotid arteries, which correlates with progression of leptinemia, IR and attenuation of organ-protecting properties of adiponectin.

[Association of obstructive sleep apnea syndrome with the signs of nonalcoholic fatty liver disease and calculated glomerular filtration rate in metabolic syndrome].

AIM: to assess a relationship between obstructive sleep apnea syndrome (OSAS) and the signs of nonalcoholic fatty liver disease (NAFLD) in patients with metabolic syndrome (MS). MATERIAL AND METHODS: Serum total cholesterol, triglycerides, high-density lipoprotein cholesterol concentrations, fasting blood glucose, ASAT, ALAT, gamma-glutamyl transpeptidase (gamma-GT), alkaline phosphatase (AP), total bilirubin, uricemia, and creatininemia were determined in 32 patients (mean age 47.6 +/- 9. 7 years) with MS. The authors also measured fasting blood insulin levels with the further calculation of the homeostatic model assessment (HOMA) index, as well as plasma C-peptide concentration. Abdominal ultrasound study and OSAS diagnosis by the routine scheme were made in all the patients. RESULTS: OSAS was associated with the significant increase in the body mass index (40.5 +/- 9.4 and 31.9 +/- 4.6 kg/m2; p = 0.001), waist circumference (130.0 +/- 22.5 and 107.5 +/- 11.0 cm; p = 0.001), and C-peptide levels (1611.0 +/- 614.0 pmol/1; p = 0.019), and the serum activities of gamma-GT (117.0 +/- 57.0 and 42.01 +/- 14.0 IU/ml; p = 0.05) and AP (80.0 +/- 53.0 and 74.0 +/- 48.0 UI/ml; p = 0.05). The patients OSAS had also a significantly lower glomerular filtration rate (GFR) estimated using the modification of diet in renal disease (MDRD) formula (66.0 +/- 19.0 and 82.0 +/- 21.0 ml/min/1.73 m2; p < 0.05). CONCLUSION: The presence of OSAS in patients with MS is associated with the increase in laboratory signs of NAFLD and the decrease in the GFR calculated by the MDRD formula.

[Development of renal affection in obese patients].

AIM: To characterize mechanisms, early markers and clinical signs of renal damage in obesity. MATERIAL AND METHODS: The trial covered 29 males aged under 50 years (mean age 37.7+/-9.3 years) with abdominal obesity having neither carbohydrate metabolism disturbances nor chronic renal disease. All the patients were examined for microalbuminuria (MAU), serum level of leptin. Radionuclide scintigraphy of the kidneys with an acute captopril test, tests for serum concentrations of endothelin-1, homocistein, uric acid, ultrasound dopplerography of the brachial artery for assessment of endothelium-related vasodilation (ERVD) were made in 24 patients. In 9 patients MAU and ERVD were estimated after 3 months of valsartan treatment (80 mg/day). RESULTS: MAU was detected in 62% patients, its rate increasing with elevation of serum leptin and endothelin concentration. Under normal values of creatininemia and GFR, obese patients showed deletion of renal functional reserve (RFR). Patients with low RFR had maximal uricemia and homocysteinemia, serum endothelin-1. Such patients demonstrated also abnormal ERVD. 3-month valsartan intake led to elevation of ERVD and disappearance of MAU. CONCLUSION: Excessive leptin registered in obese patients provoked dysfunction of the endothelium of the intrarenal vessels manifesting with MAU, growth of endothelin-1 serum concentration and disorder of ERVD. This leads to unfavourable changes in filtrating function of the kidneys as seen from gradual deletion of RFR in the absence of hypercreatininemia. Elimination of MAU and ERVD disorders in obesity can be achieved by administration of angiotensin II receptor blockers.

[Endothelial dysfunction and renal lesion in obesity].

The subjects of the study were 29 men (mean age 37.7+/-9.3 years) suffering from abdominal obesity without carbohydrate exchange disturbances or signs of chronic renal diseases. The results of the study show that the surplus of leptin, typical of obese patients, leads to the development of intrarenal vascular endothelial dysfunction, which is manifested by microalbuminuria, the growth of endothelin-1 serum level, and endothelium-dependent vasodilatation impairment, leading to unfavorable changes in renal filtration. Administration of angiotensin II receptor blockers results in the elimination of microalbuminuria and the recovery of endothelium-dependent vasodilatation in obese patients.