Background. Diagnostic criteria for Balkan endemic nephropathy (BEN) have not been precisely established. In the present study the predictive value of variables previously proposed as diagnostic criteria for BEN was examined.

Although recent data suggest aristolochic acid as a putative cause of Balkan endemic nephropathy (BEN), evidence also exists in favor of ochratoxin A (OTA) exposure as risk factor for the disease. The potential role of xenobiotic metabolizing enzymes, such as the glutathione transferases (GSTs), in OTA biotransformation is based on OTA glutathione adducts (OTHQ-SG and OTB-SG) in blood and urine of BEN patients. We aimed to analyze the association between common GSTA1, GSTM1, GSTT1, and GSTP1 polymorphisms and BEN susceptibility, and thereafter performed an in silico simulation of particular GST enzymes potentially involved in OTA transformations. GSTA1, GSTM1, GSTT1 and GSTP1 genotypes were determined in 207 BEN patients and 138 non-BEN healthy individuals from endemic regions by polymerase chain reaction (PCR). Molecular modeling in silico was performed for GSTA1 protein. Among the GST polymorphisms tested, only GSTA1 was significantly associated with a higher risk of BEN. Namely, carriers of the GSTA1*B gene variant, associated with lower transcriptional activation, were at a 1.6-fold higher BEN risk than those carrying the homozygous GSTA1*A/*A genotype (OR = 1.6; p = 0.037). In in silico modeling, we found four structures, two OTB-SG and two OTHQ-SG, bound in a GSTA1 monomer. We found that GSTA1 polymorphism was associated with increased risk of BEN, and suggested, according to the in silico simulation, that GSTA1-1 might be involved in catalyzing the formation of OTHQ-SG and OTB-SG conjugates.

In this study, the effects of carvedilol, antihypertensive (alpha-beta blocker) agent with antiproliferative and antioxidative properties, on slowing down of chronic renal failure (CRF) progression in spontaneously hypertensive rats (SHR) with adriamycin (ADR) nephropathy were examined. Eighty adult (24 weeks) SHR were divided into four groups: 20 SHR; ADR group: 20 SHR treated with ADR (2 mg/kg i.v. twice in 20 days); ADR-C group: 20 SHR treated with ADR and with carvedilol (30 mg/kg/day); ADR-CC group: 20 SHR treated with carvedilol and captopril (60 mg/kg/day). Systolic blood pressure was measured every two weeks, renal blood flow (RBF), mean arterial pressure (MAP) and renal vascular resistance (RVR) were determined at Weeks 6 and 12, creatinine clearance and proteinuria at Weeks -3 (see measurements), 6 and 12. The rats were sacrificed at Weeks 6 and 12 after the second ADR injection. Glomerular sclerosis, tubulointerstitial and blood vessel changes were determined by semiquantitative scoring. Carvedilol decreased systolic blood pressure. It decreased RVR and MAP, and increased RBF significantly. Carvedilol also significantly decreased interstitial infiltration in the early phase of the study, slowed down the development of interstitial fibrosis and tubular atrophy and decreased blood vessel changes. The hemodynamic and morphological effects of carvedilol were associated with slowing down the CRF progression as well as a mild decrease in proteinuria. Captopril addition to carvedilol improved its effects especially on prevention of tubulointerstitial changes. Results of this experimental study showed beneficial effect of carvedilol and its combination with captopril on CRF progression, indicating that clinical studies are warranted.

ObjectivesThe aims of the study were to determine the percentage of patients on regular hemodialysis (HD) in Serbia failing to meet KDOQI guidelines targets and find out factors associated with the risk of time to death and the association between guidelines adherence and patient outcome.MethodsA cohort of 2153 patients on regular HD in 24 centers (55.7% of overall HD population) in Serbia were followed from January 2010 to December 2012. The percentage of patients failing to meet KDOQI guidelines targets of dialysis dose (Kt/V>1.2), hemoglobin (>110g/L), serum phosphorus (1.1–1.8mmol/L), calcium (2.1–2.4mmol/L) and iPTH (150–300pg/mL) was determined. Cox proportional hazards analysis was used to select variables significantly associated with the risk of time to death.ResultsThe patients were on regular HD for 5.3±5.3 years, dialyzed 11.8±1.9h/week. Kt/V1.8mmol/L 28.6%, s-calcium 2.4mmol/L 25.3%, iPTH 300pg/mL 39.7% of patients. Using Cox model (adjustment for patient age, gender, duration of HD treatment) age, duration of HD treatment, hemoglobin, iPTH and diabetic nephropathy were selected as significant independent predictors of time to death. When targets of five examined parameters were included in Cox model, target for KtV, hemoglobin and iPTH were found to be significant independent predictors of time to death.ConclusionSubstantial proportion of patients examined failed to meet KDOQI guidelines targets. The relative risk of time to death was associated with being outside the targets for Kt/V, hemoglobin and iPTH

Background and Objectives: Experimental data show that superoxide dismutase 2 (SOD2) is involved in ochratoxin (OTA)-induced nephrotoxicity, whereas clinical data indicate the role of SOD2 rs4880 or glutathione peroxidase 1 (GPX1) rs1050450 polymorphisms in end-stage renal disease and urothelial carcinoma risk, known to be the major complications of Balkan endemic nephropathy (BEN). Therefore, we hypothesized that SOD2 and GPX1 gene polymorphisms would influence the risk of BEN and its associated tumors. Materials and Methods: The study was conducted in 207 BEN patients and 86 controls from endemic areas. Results: Individuals with both copies of variant SOD2 allele, known for lower mitochondrial antioxidant protection, are at a significantly higher BEN risk (OR = 2.6, p = 0.021). No association was observed between GPX1 gene polymorphism and BEN risk. Combining SOD2 and GPX1 genotypes did not alter the risk of BEN development. Regarding the risk of urothelial tumors in BEN patients, none of the polymorphisms studied was significantly associated with the risk of these tumors. Conclusions: Polymorphism in SOD2 rs4880 gene affects the risk of BEN development. Hence, SOD2 genotyping could, together with a panel of other enzymes, be used as a biomarker of susceptibility in BEN areas.