Consensus statement on screening, diagnosis, classification and treatment of endemic (Balkan) nephropathy.

Currently used diagnostic criteria in different endemic (Balkan) nephropathy (EN) centers involve different combinations of parameters, various cut-off values and many of them are not in agreement with proposed international guidelines. Leaders of EN centers began to address these problems at scientific meetings, and this paper is the outgrowth of those discussions. The main aim is to provide recommendations for clinical work on current knowledge and expertise. This document is developed for use by general physicians, nephrologists, urologist, public health experts and epidemiologist, and it is hoped that it will be adopted by responsible institutions in countries harboring EN. National medical providers should cover costs of screening and diagnostic procedures and treatment of EN patients with or without upper urothelial cancers.

Comparative Analysis of Vascular Calcification Risk Factors in Pre-Hemodialysis and Prevalent Hemodialysis Adult Patients: Insights into Calcification Biomarker Associations and Implications for Intervention Strategies in Chronic Kidney Disease.

This retrospective study aimed to compare risk factors for vascular calcification (VC) between pre-hemodialysis (HD) and prevalent HD adult patients while investigating associations with calcification biomarkers. Baseline data from 30 pre-HD and 85 HD patients were analyzed, including iPTH, vitamin D, FGF 23, fetuin-A, sclerostin, and VC scores (Adragao method). Prevalence of VC was similar in both groups, but HD patients had more frequent VC scores ≥ 6. Pre-HD patients were older, with higher prevalence of hypertension and less frequent use of calcium phosphate binders. Both groups showed similar patterns of hyperphosphatemia, low vitamin D, and iPTH. Fetuin-A and sclerostin levels were higher in pre-HD, while FGF 23 was elevated in HD patients. Higher VC risk in pre-HD patients was associated with male gender, older age, lower fetuin-A and higher sclerostin, lower ferritin, and no vitamin D treatment, while in HD patients with higher sclerostin, FGF 23 and urea, and lower iPTH. Conclusion: Biomarkers could be measurable indicators of biological processes underlying VC in CKD patients that may serve as a potential guide for considering personalized therapeutic approaches. Further studies are needed to elucidate the underlying pathways.

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 m(2) 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.

Transforming growth factor-beta 1 in Balkan endemic nephropathy.

BACKGROUND/AIM: The aim of this study was to compare plasma and urine transforming growth factor-beta1 (TGF-beta1) 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-beta1 was assayed by enzyme-linked immunosorbent assay. RESULTS: The median plasma TGF-beta1 levels differed nonsignificantly between the groups (4,908-6,442 pg/ml), but individual plasma TGF-beta1 levels in BEN patients exhibited the highest dispersion. Median urinary TGF-beta1 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-beta1 levels or between plasma TGF-beta1 levels and creatinine clearance for any of the examined groups. CONCLUSION: Plasma TGF-beta1 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-beta1 excretion was significantly higher in patients with BEN and GN than in healthy controls.

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

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.

How common is Balkan endemic nephropathy among immigrants in endemic regions?

PURPOSE: In the early 1970s, a number of authors described the development of Balkan endemic nephropathy (BEN) in immigrants in endemic regions. The aim of this study was to examine whether immigrants in endemic regions are suffering from BEN today. METHODS: The study involved 193 residents of two endemic regions divided into three groups: two groups of native residents-(1) members of BEN families, (2) members of non-BEN families, and (3) immigrants, who had moved from non-affected settlements to the endemic regions of Kolubara (38 years ago) or Semberia (20 years ago). All persons were subjected to an interview, objective examination, kidney ultrasound, and laboratory analysis to detect the presence of BEN consensus diagnostic criteria. RESULTS: The number of immigrants with BEN biomarkers outside cutoff values was significantly lower than for BEN family members. Five BEN family members met diagnostic criteria for BEN and four for suspected BEN. Although five non-BEN family members had different combinations of BEN biomarkers, all of them had diseases other than BEN in which these biomarkers also occurred. None of the immigrants met the criteria for BEN. Nevertheless, one descendant of an immigrant, a 78-year-old male, whose mother was from a non-BEN family in the Kolubara district, exhibited all the criteria for BEN: alpha1-microglobulinuria, chronic renal failure, and anemia. CONCLUSION: While 30 years ago, BEN was reported equally among immigrants and natives, currently it is diagnosed in some BEN family members in the eighth decade of life, but extremely rarely in immigrants also in old age.

[Different response to human recombinant erythropoietin in patients undergoing hemodialysis treatment].

INTRODUCTION: Treatment with recombinant human erythropoietin enabled the correction of anemia in the patients on regular hemodialysis but large individual differences in the dose required to achieve the target hemoglobin level were observed. In this study the erythropoietin resistance index was calculated in patients on hemodialysis in order to examine variations in the response to erythropoietin and factors that influence it. MATERIAL AND METHODS: The study included 48 patients (25 males) of mean age 67.5 years, who had been on regular hemodialysis in Samac for 43.9 months on average. All were treated with erythropoietin from the beginning of hemodialysis treatment. Their response to erythropoietin therapy was estimated by the erythropoietin resistance index. RESULTS: The use of erythropoietin enabled the correction of anemia but different doses were needed to achieve and maintain the target hemoglobin level. The individual weekly dose of erythropoietin ranged from 15 U/kg/week to 244 U/kg/week and the erythropoietin resistance index ranged from 0.13 U/kg/week/g/l to 2.46 U/kg/week/g/l. A satisfactory erythropoietin response with erythropoietin resistance index below 0.5 U/kg/week/g/l was found in 14 (30%) patients, while 19 (40%) patients had this index above 0.7 U/kg/week/g/l and 10 (21%) above 0.9 U/kg/week/g/l. Multivariate linear regression analysis detected C-reactive protein as a significant predictor of erythropoietin resistance index. CONCLUSION: Target hemoglobin levels were achieved and maintained by different doses of erythropoietin in individual patients, which resulted in great individual differences in response as estimated by the erythropoietin resistance index. Multivariate analysis indicated C-reactive protein as a variable significantly associated with this index.

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 micromol/ L; p < 0.001), and the incidence of patients with hyperHcy was 82%. Comparison of the group of 20 patients with tHcy level <15 micromol/L and the group of 86 patients with tHcy level >15 micromol/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.

Serum cystatin C and beta2-microglobulin as markers of glomerular filtration rate.

Continuous efforts have been made to find out precise and simple method for determination of glomerular filtration rate (GFR). Cystatin C (cysteine proteinase inhibitor = CyC) is a low molecular weight (LMW) protein which is produced constantly by all nucleated cells independently of different pathological conditions and eliminated from the blood exclusively by glomeruli. So, CyC closely reflects the GFR. In the present study 75 patients aged between 18 and 74 (44.3 +/- 12.2) years were analyzed, with the aim to compare the reciprocal values of serum level of LMW proteins CyC and beta2-microglobulin (beta2-MG) with creatinine clearance (Ccr) as a measure of GFR. Patients were divided into groups according to sex, age (<60; >60 years) and renal diseases: patients with glomerulonephritis (GN) with and without nephrotic proteinuria, pyelonephritis (PyN), and renal transplant (Tx). High correlation between Ccr and 1/CyC (r = 0.81; p < 0.01) and Ccr and 1/beta2-MG (r = 0.80; p < 0.01) in all examined patients was found. There was significant correlation between Ccr and 1/CyC (0.82 vs. 0.79) and Ccr and 1/beta2-MG (0.85 vs. 0.76) in men as well in women, and also in two groups of patients formed according to the age (0.82 vs. 0.77; p < 0.01; 0.80 vs. 0.81; p < 0.01), without any statistical significant difference between the groups. In studied groups with different renal diseases, there were no differences in correlation coefficients between Ccr and 1/CyC and Ccr and 1/beta2-MG (p1 = 0.29; p2 = 0.21; p3 = 0.79; p4 = 0.43), without statistical differences between the groups, except significant difference in correlation coefficients for Ccr and 1/beta2-MG between patients with GN with and without nephrotic proteinuria (p < 0.032). LMW proteins, serum CyC and beta2-MG, are as good markers of GFR as Ccr, regardless sex and age. Both of these LMW proteins are good markers of GFR in patients with GN without nephrotic proteinuria, PyN and Tx patients. In patients with GN and nephrotic proteinuria serum CyC is a better marker of GFR than beta2-MG.

Lupus nephritis: histopathologic features, classification and histologic scoring in renal biopsy.

Lupus nephritis (LN) is one of the most significant manifestations in systemic lupus erythematosus (SLE), although in some cases there is no direct correlation among clinical, serologic and histologic findings. Therefore, renal biopsy and histopathologic classification by the activity and chronicity assessment of LN are considered necessary before the initiation of the treatment. In this paper 311 renal biopsies in patients with LN were analyzed and classified according to the WHO Classification published in 1974. Renal biopsy specimens were routinely processed for standard analysis by light microscopy (LM), immunofluorescent (IF), and electron microscopy (EM). Biopsy findings were compared with the common clinical symptoms. It is important to recognize that histopathologic lesions in the analyzed tissue might precede the symptoms and clinical manifestations, and therefore are an important factor in the appropriate therapeutic approach. Histopathological assessment of the class of LN represents an important predictor in most patients because the lesions of LN class I and class II most often have no progression and consequently do not require an aggressive treatment. Diffuse proliferative glomerulonephritis (class IV) as a severe form of renal lesion requires the application of high doses of corticosteroids and cytotoxic medicaments. The established quantitive indexes have significant predictive value. Activity index (AI) evaluates the presence of fresh inflammatory and potentially reversible lesions and chronicity index (CI) evaluate the presence of irreversible glomerular lesions such as sclerosis, tubular atrophy, interstitial fibrosis, etc. High AI and low CI, particularly in the class IV of LN, suggest the necessity of an aggressive treatment of the inflammatory process aiming to preserve the renal function. High CI and low AI characterize irreversible sclerosing lesions, where an aggressive treatment is considered unnecessary. Our experience suggests the necessity of introducing the new morphologic elements into the activity and chronicity scoring system which would correlate better the clinical symptoms. This should provide higher reliability of scoring, since it evaluates important elements in clinical-morphologic diagnosis of LN.