Višnja Ležaić

Contribution to the definition of diagnostic criteria for Balkan endemic nephropathy

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. METHODS The study involved 182 patients: 98 patients with BEN, 57 patients with other kidney diseases (20 with glomerulonephritis, 17 with tubulointerstitial diseases and 20 with hypertensive nephrosclerosis) and 27 healthy subjects. The BEN group comprised patients who fulfilled criteria for BEN and suspected BEN, together with patients with proteinuria and at least two tubular abnormalities or one tubular abnormality and a history of urothelial tumour. Demographic, clinical, laboratory and ultrasound variables of examined groups were combined in univariate/multivariate logistic regression analysis. RESULTS Out of 28 analysed variables only urine alpha1-microglobulin (MG) and kidney length were selected as significant predictors in differentiating BEN from other kidney diseases and healthy controls. Using ROC curves the cutoff values of these variables and proteinuria and kidney volume, variables collinear with them, were found. Moderate sensitivity and specificity characterized all these cutoff values except for proteinuria, which provided high sensitivity and specificity in combination of BEN and healthy persons. The predictive value of different combinations of selected variables was not significantly different from the predictive value of each variable individually. CONCLUSIONS Proteinuria, urine alpha1-MG, kidney length and volume were selected as significant predictors of BEN. Variables related to kidney failure as well as several tubular disorders (urine specific gravity, FENa and TRP) had an insignificant predictive value and could not be used for differential diagnosis of BEN.

Screening of a Population at Risk of Chronic Kidney Disease: Analysis of Factors Associated with Low eGFR and Microalbuminuria

Background and objective: Numerous screenings of chronic kidney disease (CKD) have been performed all over the world. This screening study was undertaken with the aim of estimating the prevalence of low glomerular filtration rate (eGFR) and microalbuminuria (MAU) and/or proteinuria in a population at risk for CKD and to detect factors associated with these CKD markers. Materials and methods: This cross-sectional study included 1617 patients without previously known kidney disease who came for regular check-ups to their general practitioners in 13 Belgrade health centers over a 3-month period. Patients selected were as follows: 1316 with hypertension, 208 with type 2 diabetes, and 93 older than 60 years without hypertension or diabetes. Screening included a questionnaire, blood pressure measurement, single MAU dipstick measurement (Micral-test® strip) and proteinuria and GFR estimation by Modification of Diet in Renal Disease. Results: MAU was found in 419 (25.9%) patients, proteinuria in 163 (10.1%), and eGFR < 60 mL/min/1.73 m2 in 370 (22.9%). Multivariate logistic regression analysis revealed that female gender, age, duration of hypertension, and smoking were associated with eGFR. Male gender, hypertension, treatment with angiotensin-converting enzyme inhibitors, proteinuria, and systolic blood pressure were associated with MAU. Conclusions: High prevalence of MAU/proteinuria and reduced eGFR were found in high-risk persons for CKD. Besides nonmodifiable, significant modifiable factors for MAU were use of angiotensin-converting enzyme inhibitors and strict regulation of hypertension and the factor for reduced eGFR was smoking.

Epidemiology of end‐stage renal disease and hemodialysis treatment in Serbia at the turn of the millennium

The study presents the epidemiological features of patients treated with renal replacement therapy (RRT) in Serbia from 1997 to 2009 and compares the results of hemodialysis treatment in 1999 and 2009. Epidemiological data were obtained from the National Registry of RRT patients and data on hemodialysis treatment from special surveys conducted in 1999 and 2009. Within the period 1997–2009 the incidence of patients on RRT increased from 108 to 179 per million population (pmp), prevalence rose from 435 to 699 pmp, while mortality rate fell from 20.7% to 16.7%. The frequency of patients with glomerulonephritis decreased, while that of patients with diabetes and hypertensive nephropathy increased. In late 2009 there were 5208 patients receiving RRT in Serbia. Within the examined period new hemodialysis and reverse osmosis equipment were purchased, high‐flux dialyzers with synthetic membranes were increasingly used and the number of patients receiving hemodiafiltration increased to 17.6%. Kt/V greater than 1.2 was recorded in 16% of the patients in 1999 but 52% in 2009. Options for correction of anemia and mineral disorders have also improved. The percentage of patients with HbsAg (13.8% vs. 4.8%) as well as anti‐hepatitis C virus antibodies positive patients (23.2% vs. 12.7%) was significantly lower in 2009 than in 1999. Both the incidence and prevalence of RRT patients in Serbia are rising continuously, while the mortality rate is falling. More favorable conditions for dialysis treatment have brought about significant improvement in the results over the last 10 years.

Transforming Growth Factor-β1 in Balkan Endemic Nephropathy

Background/Aim: The aim of this study was to compare plasma and urine transforming growth factor-β1 (TGF-β1) levels in patients with different stages of Balkan endemic nephropathy (BEN) with those in patients with primary glomerulonephritis (GN) and healthy controls. Methods: The study involved 47 patients with BEN (30 with manifest BEN and 17 in the early stage of BEN), 12 patients with GN and 10 healthy controls. Plasma and urine TGF-β1 was assayed by enzyme-linked immunosorbent assay. Results: The median plasma TGF-β1 levels differed nonsignificantly between the groups (4,908–6,442 pg/ml), but individual plasma TGF-β1 levels in BEN patients exhibited the highest dispersion. Median urinary TGF-β1 excretion (pg/mg creatinine) was significantly higher in patient groups (manifest BEN: 203, early-stage BEN: 341, GN: 775) than in healthy controls (42). No correlation was found between plasma and urine TGF-β1 levels or between plasma TGF-β1 levels and creatinine clearance for any of the examined groups. Conclusion: Plasma TGF-β1 levels in BEN patients extended over the widest range, but no significant differences were found between the median values for the groups. Median urinary TGF-β1 excretion was significantly higher in patients with BEN and GN than in healthy controls.

Beneficial effects of donor-specific transfusion on renal allograft outcome.

Jovičić S, Ležaić V, Simonović R, Djukanović L. Beneficial effects of donor‐specific transfusion on renal allograft outcome. 
Clin Transplant 2011: 25: 317–324.

Factors associated with hyperhomocysteinemia after renal transplantation

Recent studies show that clinically stable renal transplant recipients have an increased prevalence of hyperhomocysteinemia (hyperHcy), but the mechanism of this disorder has not yet been elucidated. The aim of the present study was to evaluate the factors associated with hyperHcy after a successful renal transplantation. In 106 stable renal transplant recipients, total serum Hcy level (tHcy), folate, total protein, serum creatinine concentration, creatinine clearance, lipid status, body weight (BW), body mass index (BMI), and body fat (BF) were determined. The mean doses of cyclosporine, prednisolone, and azathioprine (mg/kg/day) were recorded. The mean serum tHcy level was significantly higher in renal transplant patients than in healthy controls (22.02 ± 8.02 versus 13.0 ± 3.3 μmol/L; p < 0.001), and the incidence of patients with hyperHcy was 82%. Comparison of the group of 20 patients with tHcy level <15 μmol/L and the group of 86 patients with tHcy level >15 μmol/L revealed that the latter was significantly older, heavier, had been longer on dialysis before renal transplantation, and had older donors and poorer renal graft function. Significant correlation was found between tHcy level and recipient age, dialysis duration, BW, creatinine clearance, serum creatinine, and folate concentration. However, multivariate analysis indicated that creatinine clearance (p = 0.025) and BW (p = 0.03) were the only determinants of elevated total Hcy level in renal transplant recipients. HyperHcy persists after successful kidney transplantation in the majority of renal transplant recipients, and its appearance is primarily associated with creatinine clearance and body weight.

High prevalence of kidney disease in two rural communities in Kosovo and Metohia.

A systematic survey was carried out in an enclave in Kosovo and Metohia, with the aim of assessing the prevalence of kidney diseases. The survey involved 423 (180 males) adult inhabitants from two small settlements, Velika Hoča and Orahovac, and included an interview, medical documentation, physical, ultrasound, and laboratory examinations. Persons with any detected disorder indicating kidney disease were invited for additional examination of kidney function. Using urine dipstick test, proteinuria was detected in 19.1% and hemoglobinuria in 4.5% of the examined subjects. Glomerular filtration rate (Modification of Diet in Renal Disease (MDRD) formula) below 60 mL/min/1.73 m2 was found in 5.2% of subjects. Kidney ultrasound examination detected reduced length of right and left kidneys in 38 and 24 persons, respectively. Cysts were also a frequent finding, but polycystic kidney, hydronephrosis, and kidney stones were found in about 2% each. The analysis of data obtained by the present examination and available medical documentation revealed kidney and urinary tract diseases in 98 persons: 52 patients with already known disease and 46 patients detected in the survey. Out of them in 22 patients diagnosis of kidney disease could not be established during the survey but laboratory analyses indicated that they might suffer from tubulointerstitial disease: 14 had tubular dysfunctions, 8 of them low-grade proteinuria, and 12 had a positive family history for kidney disease. In the enclave of Velika Hoča and Orahovac the prevalence of kidney disease was 7.0% indicating that these communities might be placed among those with a high prevalence of kidney disease in Serbia.

Comparison of accepted and unaccepted living kidney donors: one-center experience

Abstract Background: Kidney transplantation from living donors (LD) has stagnated in many countries. This study aimed to check whether correction of LD selection practice could increase the number of kidney transplantations. Methods: From January 2003 to December 2012, 241 potential adult LD were evaluated in our hospital. Outcome (mortality and end-stage renal disease-ESRD) of accepted LD (182) was compared with unaccepted (59) donors. Results: Mortality of LD was comparable with that for the standardized Serbian population (SMR = 1.104; 95% CI (0.730–1.606). Among evaluated potential LD, almost every fourth had been unaccepted, but reasons were modifiable in 42.4% of them. In pre-donation period unaccepted donors were significantly older, measured glomerular filtration rate was lower, with higher 15-year and lifelong projected ESRD risks than accepted donors. Despite this, ten years outcome of both groups LD was similar: none of LD developed ESRD, 9.8% of accepted and 11.8% of unaccepted LD died (p = .803). Conclusions: During an average of 101 months of follow-up mortality of accepted LD did not differ significantly as compared to the age standardized Serbian population and none of them developed ESRD. In examination of potential LD, the use of accurate and precise methods for kidney function estimation and the evaluation of risk for ESRD and mortality as well as treatment of modifiable contraindications for kidney donation are necessary.

Dual Roles of the Mineral Metabolism Disorders Biomarkers in Prevalent Hemodilysis Patients: In Renal Bone Disease and in Vascular Calcification

Summary Background Vascular calcification (VC) is highly prevalent in dialysis (HD) patients, and its mechanism is multifactorial. Most likely that systemic or local inhibitory factor is overwhelmed by promoters of VC in these patients. VC increased arterial stiffness, and left ventricular hypertrophy. Thus, the present study aimed to investigate the association of VC and myocardial remodeling and to analyze their relationship with VC promoters (fibroblast growth factor 23-FGF23, Klotho, intact parathormon-iPTH, vitamin D) in 56 prevalent HD patients (median values: age 54 yrs, HD vintage 82 months). Methods Besides routine laboratory analyzes, serum levels of FGF 23, soluble Klotho, iPTH, 1,25-dihydroxyvitamin D3; pulse wave velocity (PWV); left ventricular (LV) mass by ultrasound; and VCs score by Adragao method were measured. Results VC was found in 60% and LV concentric or eccentric hypertrophy in 50% patients. Dialysis vintage (OR 1.025, 95%CI 1.007–1.044, p=0.006) FGF23 (OR 1.006, 95% CI 0.992–1.012, p=0.029) and serum magnesium (OR 0.000, 95%CI 0.000–0.214, p=0.04) were associated with VC. Changes in myocardial geometry was associated with male sex (beta=-0.273, 95% CI -23.967 1.513, p=0.027), iPTH (beta 0.029, 95%CI -0.059–0.001, p=0.027) and vitamin D treatment (beta 25.49, 95%CI 11.325–39.667, p=0.001). Also, patients with the more widespread VC had the highest LV remodeling categories. PWV was associated patient’s age, cholesterol, diastolic blood pressure, LV mass (positively) and serum calcium (negatively), indicating potential link with atherosclerotic risk. Conclusions Despite to different risk factors for VC and myocardial remodeling, obtained results could indicate that risk factors intertwine in long-term treatment of HD patients and therefore careful and continuous correction of mineral metabolism disorders is undoubtedly of the utmost importance.

Classification of patients at risk for chronic kidney disease by use of eGFR and albuminuria

Introduction. Screening for chronic kidney disease (CKD) has been advised in high-risk populations. However, data on the prevalence of early asymptomatic stages vary and depend on the definition of CKD. In the present study subjects at risk for CKD (patients with diabetes mellitus type 2-DM2, with hypertension and older than 60 years without diabetes and hypertension) were classified in categories defined by eGFR and albuminuria staging system. Methods. After regular check-up in primary health center, 285 consecutive patients at risk for CKD, were selected: 75 patients with well-controlled DM2 without hypertension, 130 with hypertension and 80 subjects older than 60 years without diabetes or hypertension. Screening included a questionnaire, blood pressure measurement, single albuminuria determined by immunonephelometry, and eGFR estimation using MDRD. Results. Six DM2 patients, 15 withe hyprtension and 12 elderly had eGFR 30mg/g. Using the classification of CKD based on eGFR and albuminuria,