Balkan Endemic Nephropathy and the Causative Role of Aristolochic Acid.

Balkan endemic nephropathy is a chronic tubulointerstitial disease with insidious onset, slowly progressing to end-stage renal disease and frequently associated with urothelial carcinoma of the upper urinary tract (UTUC). It was described in South-East Europe at the Balkan peninsula in rural areas around tributaries of the Danube River. After decades of intensive investigation, the causative factor was identified as the environmental phytotoxin aristolochic acid (AA) contained in Aristolochia clematitis, a common plant growing in wheat fields that was ingested through home-baked bread. AA initially was involved in the outbreak of cases of rapidly progressive renal fibrosis reported in Belgium after intake of root extracts of Aristolochia fangchi imported from China. A high prevalence of UTUC was found in these patients. The common molecular link between Balkan and Belgian nephropathy cases was the detection of aristolactam-DNA adducts in renal tissue and UTUC. These adducts are not only biomarkers of prior exposure to AA, but they also trigger urothelial malignancy by inducing specific mutations (A:T to T:A transversion) in critical genes of carcinogenesis, including the tumor-suppressor TP53. Such mutational signatures are found in other cases worldwide, particularly in Taiwan, highlighting the general public health issue of AA exposure by traditional phytotherapies.

Differences in Risk Factors and Prevalence of Vascular Calcification between Pre-Dialysis and Hemodialysis Balkan Nephropathy Patients.

Aims: The aim of this study was to compare the risk factors and prevalence of vascular calcification (VC) in pre-dialysis and hemodialysis (HD) patients with Balkan endemic nephropathy (BEN) or other kidney diseases (non-BEN). Materials and Methods: The study involved 115 patients, 32 pre-dialysis and 83 HD patients, separated into groups of BEN and non-BEN patients. In addition to interviews, objective examinations and laboratory analyses, VC was assessed using Adragao score. Results: Patients with BEN were significantly older in both groups, while pre-dialysis BEN patients had significantly lower systolic blood pressure, serum cholesterol and phosphorus levels, but higher urinary excretion of phosphorus than non-BEN patients. These differences were lost in HD groups. In pre-dialysis patients, prevalence of VC was lower in BEN than in non-BEN group and mean VC score differed significantly between them (2.8 (1.7) vs. 4.6 (1.8); p = 0.009). No significant difference in VC score was found between BEN and non-BEN patients on HD. Multivariate analysis showed that in pre-dialysis patients VC score >4 was associated with lower iPTH and higher serum cholesterol level, but in the HD group with higher serum triglyceride level and longer HD vintage. Conclusions: Lower prevalence of risk factors for VC in the BEN than non-BEN patients was found in pre-dialysis but not in HD group and this was reflected in the prevalence and severity of VC in the groups. Prevalence of VC and mean VC score were significantly lower in pre-dialysis BEN than in non-BEN patients but not for those on HD.

Biomarkers of oxidative damage and antioxidant enzyme activities in pre-dialysis Balkan endemic nephropathy patients.

AIM: To obtain more insight into molecular mechanisms underlying oxidative stress in Balkan endemic nephropathy (BEN), biomarkers of oxidative stress and antioxidant enzyme activities were studied in 38 pre-dialysis BEN patients, 21 healthy BEN family members and 36 healthy subjects from non-endemic areas. METHODS: Protein thiol groups (P-SH), antioxidant enzyme activities [superoxide dismutase (SOD) and glutathione peroxidase (GPX)], were determined in plasma spectrophotometrically, while malondialdehyde adducts (MDA) by enzyme immunoassay. RESULTS: BEN patients had significantly lower plasma GPX activity in comparison with values for both control groups (p = 0.016), gradually decreasing with kidney function impairment estimated by glomerular filtration rate (r = 0.53, p = 0.002). GPX activity was inversely correlated with serum urea (r = -0.627, p < 0.001), creatinine (r = -0.53, p < 0.05), urinary excretion of protein and α1-microglobulin (r = -0.44, p = 0.012; r = -0.50, p < 0.007). Significant upregulation of SOD activity was observed in healthy BEN family members (p < 0.05). While the concentration of MDA adducts was similar in all three groups, BEN patients and healthy BEN family members exhibited increased protein damage, based on fewer P-SH groups in comparison with subjects from non-BEN areas (p = 0.085; p = 0.014, respectively). CONCLUSIONS: Based on our results on increased oxidative protein damage in both pre-dialysis BEN patients and healthy BEN family members, it can be speculated that individuals from BEN areas, in general, are chronically exposed to some prooxidant environmental compounds. Moreover, decrease in plasma GPX activity, as a consequence of impaired kidney function, could further affect oxidative status in BEN patients.

Surprising good antioxidant status in patients with Balkan Endemic Nephropathy on hemodialysis undergoing vitamin C therapy. A pilot study.

AIMS: End Stage Renal Disease (ESRD) represents a microinflammatory state accompanied by oxidative stress and an imbalance between pro- and antioxidants. Vitamin C is a highly effective antioxidant, acting to lessen oxidative stress. The aim of our study was to assess the Antioxidant Capacity of Water soluble substances (ACW) and the Antioxidant Capacity of Liposoluble substances (ACL) in patients with Balkan Endemic Nephropathy (BEN) on hemodialysis undergoing Vitamin C therapy as compared to healthy controls. METHODS: Twenty-one patients with BEN on hemodialysis (HD), mean age: 63.33 +/- 5.42 years, 6 M and 15 F, were enrolled into the study. All patients received 10 vials of Vitamin C 750 mg/5 ml every 2 months. Eleven apparently healthy subjects, mean age: 63.73 +/- 5.21 years, 6 M and 5 F, served as controls. The photochemiluminescence assay was used to measure the antioxidant activity of plasma samples. The results are presented in equivalent concentration units of Vitamin C for water soluble antioxidants and in equivalent concentration units of Trolox (synthetic Vitamin E) for lipid soluble antioxidants. Both concentrations are expressed in micromols/L. Statistical analysis (non-parametric Wilcoxon test) was performed using NCSS. RESULTS: Mean duration since BEN diagnosis was: 8.24 +/- 3.5 years. Mean duration since HD initiation was: 4.92 +/- 3.4 years. Smoking status was negative in all patients. Hypertension was present in 15 patients (71.42%), cardiovascular disease in 10 (47.61%), HCV infection in 13 (61.9%), 1 patient had HBV + HCV infection, 1 had renal tuberculosis, 1 had upper urinary tract cancer, 1 genital cancer, and I autoimmune thyroid disease. The Antioxidant Capacity of Water soluble substances (ACW) in patients with BEN was 477.6 +/- 177.63 micromols/L, significantly higher as compared to controls: 198.05 +/- 196.63 micromols/L; p = 0.01, whereas the Antioxidant Capacity of Liposoluble substances (ACL) in patients with BEN was 33.9 +/- 22.99 micromols/L, non-significantly different as compared to controls: 27.38 +/- 4.21 micromols/L; p = 0.22. CONCLUSIONS: We conclude that Vitamin C therapy in patients with BEN on HD significantly increases the Antioxidant Capacity of Water soluble substances (ACW) as compared to controls and could be used to counter oxidative stress in patients with ESRD.

The assessment of arterial stiffness in endemic (Balkan) nephropathy patients undergoing haemodialysis.

Cardiovascular (CV) complications are the most important cause of morbidity and mortality in patients with advanced chronic kidney disease (CKD). Arterial stiffness (AS) has been recognized as a strong and independent predictor for CV events in CKD. Our aim was to assess indices of AS in a group of Endemic (Balkan) Nephropathy (EN) patients undergoing haemodialysis (HD). Hypertenison was not considered an importnat feauture in earlier stages of the disease, and therefore we presumed that those patients would have lower AS. Interestingly, we found AS to be even higher in this group of EN patients. This result should be confirmed in a larger cohort of EN patients.

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.

The pharmacokinetics of recombinant human erythropoietin in Balkan endemic nephropathy patients.

BACKGROUND: Balkan endemic nephropathy (BEN) hemodialysis patients require a higher dose of recombinant human erythropoietin for maintaining target hemoglobin level than patients with other kidney diseases. OBJECTIVES: Comparison of the pharmacokinetics of beta-erythropoietin given subcutaneously to hemodialysis patients with BEN or other kidney diseases (non-BEN). METHODS: Recombinant human erythropoietin (75 U/kg) was administered subcutaneously to 10 BEN and 14 non-BEN hemodialysis patients. The predose plasma level of erythropoietin (Epo) was subtracted from all postdose levels. The relevant pharmacokinetic parameters were calculated after noncompartmental pharmacokinetic analysis using Kinetica software (Thermo Scientific, ver.5.0). RESULTS: Although basal plasma Epo concentration was similar in BEN (20.1 ± 10.3 U/L) and non-BEN (15.1 ± 8.1 U/L; p=.1964) patients, there were significant differences between the groups for elimination rate constant (0.016 ± 0.006 vs 0.026 ± 0.011 hr⁻¹; p=.020) and elimination half-life (50.24 ± 19.12 vs 33.79 ± 18.91 hr, p=.048). These differences remained significant after adjustment for patient characteristics (age, sex, hemodialysis duration, ferritin, PTH and ACEI use). No significant differences between groups were found in maximal Epo concentration, time to maximum Epo concentration, area under the curve from time of dosing extrapolated to infinity, clearance, mean residence time of Epo between groups both before and after adjustment. CONCLUSION: Pharmacokinetic analysis of beta-erythropoietin detected a significantly longer elimination half-life in BEN than in non BEN patients. This finding needs to be confirmed in a well-controlled study with a larger sample size.

The epidemiology, diagnosis, and management of aristolochic acid nephropathy: a narrative review.

It has been 20 years since the first description of a rapidly progressive renal disease that is associated with the consumption of Chinese herbs containing aristolochic acid (AA) and is now termed aristolochic acid nephropathy (AAN). Recent data have shown that AA is also the primary causative agent in Balkan endemic nephropathy and associated urothelial cancer. Aristolochic acid nephropathy is associated with a high long-term risk for renal failure and urothelial cancer, and the potential worldwide population exposure is enormous. This evidence-based review of the diagnostic approach to and management of AAN draws on the authors' experience with the largest and longest-studied combined cohort of patients with this condition. It is hoped that a better understanding of the importance of this underrecognized and severe condition will improve epidemiologic, preventive, and therapeutic strategies to reduce the global burden of this disease.

[Higher dose of erythropoietin for anemia correction in balkan endemic nephropathy patients].

INTRODUCTION: Balkan endemic nephropathy (BEN) patients maintained with hemodialysis have more severe anemia than patients with other kidney diseases. OBJECTIVE: The aim of the study was to compare the improvement of anemia in BEN patients and those with other kidney diseases during treatment with human recombinant erythropoietin (rHuEpo). METHODS: The study involved 240 patients on regular hemodialysis for more than one year. Out of them 146 had BEN and 94 other kidney diseases (21 glomerulonephritis, 20 hypertension, 18 diabetes, 10 policystic kidney disease, 5 obstructive nephropathy, 18 other diseases). Treatment with rHuEpo was carried out according to European guidelines for the management of anemia. RESULTS: Patients with BEN were older and were less frequently treated with ACEi than patients with other kidney diseases. At the onset of the study mean hemoglobin level (109.6 +/- 22.3 vs. 112.7 +/- 11.3 g/l) was significantly lower, but serum ferritin level and rHuEpo dose (65.4 +/- 22.3 vs. 57.5 +/- 22.5 U/kg/week) were significantly higher in BEN patients than in others. In prospective four months study these differences in hemoglobin levels and rHuEpo doses maintained.The rate of anemia improvement was examined in 15 BEN patients and 10 patients with other kidney diseases at the beginning of rHuEpo treatment. No difference in the rate of anemia improvement was found between the two groups but higher rHuEpo doses were used in BEN patients. CONCLUSION: Patients with BEN on regular hemodialysis had more severe anemia and required higher rHuEpo doses for maintaining target hemoglobin level.

Epidemiological data regarding Balkan endemic nephropathy in relationship with the Pliocene coal etiological hypothesis.

Balkan Endemic nephropathy (BEN) is a tubulointerstitial disease of unknown etiology signaled in a limited geographical area. In the neighbourhood of endemic villages are coal deposits from the Pliocene, that contain toxic substances that by mobilizing groundwater can leach in water sources used by the inhabitants. In the present paper the possible impact of the coal from Pliocene on people that worked many years in mines in the endemic County Mehedinti, Romania, and who lived in this area are analysed. The risk of toxicity of coal was theoretically increased in miners because they consumed frequently water from mine springs that came from coal layers, while at home water from wells could have been contaminated by toxic substances from coal. It has been found that only 5 of the 96 patients with BEN were under dialysis program in 2008. Also out of 34 former miners only 3 had GFR < 60 ml/min/1.73 sqm, and only one with creatinine of 3 mg/dl had GFR < 30 ml/min/1.73 sqm. The mean GFR in the 34 miners was: 94.13 +/- 26.58 ml/min/1.73 sqm. We analysed GFR and proteinuria in persons from the endemic zone from 2 types of villages: some with mining activity presently (Husnicioara) others where presently there are no mining activities (Hinova, Bistrita, Livezile). We also analysed comparatively 2 non-endemic localities near the endemic focus: Drobeta Turnu Severin (without mining activity) and Motru with mining activity where different coal deposits are (non-Pliocene). Data were provided from the family doctors databases. The GFR was lower in the inhabitants from the endemic villages Bistrita and Hinova than in the investigated inhabitants from the non-endemic town Drobeta Turnu Severin (p = 0.008 and p = 0.0004 respectively). Inhabitants from the endemic village Husnicioara (Pliocene coal mine still functioning) had a higher GFR than inhabitants from Drobeta Turnu Severin and higher than inhabitants from the endemic village Livezile (mine closed 10 years ago): p = 0.0055 and p = 0.001 respectively, but a lower than the investigated inhabitants from the non-endemic town Motru (where a non-Pliocene coal mine is functioning): p < 0.001. Proteinuria was present in 8.03% of the inhabitants from the endemic village Bistrita and in 7.4% of the inhabitants from the endemic village Hinova. In the non-endemic town Drobeta Turnu Severin, proteinuria was present in 7.08% of the investigated inhabitants. Proteinuria was present in 0.78% of the investigated inhabitants of the non-endemic town Motru (where a non-Pliocene coal mine is functioning) and 2.5% of the inhabitants of the endemic village Husnicioara (Pliocene coal mine still functioning). Our paper does not show any relationship between exposure to Pliocene coal and the etiology of BEN.

Fifty years of Balkan endemic nephropathy in Romania: some aspects of the endemic focus in the Mehedinti county.

Balkan endemic nephropathy (BEN) is a chronic tubulointerstitial nephritis seen primarily in countries in the Balkan Peninsula. The disease, which was first described in Romania 50 years ago, often manifests as a form of chronic nephritis that is also associated with upper urothelial cancers (UUC). This review summarizes the observations and studies performed in Romania regarding this disease during the last 50 years with particular emphasis on Mehedinti county. The paper analyzes current data on the epidemiology of the disease in this area, specifically in relation to the observations made in dialysis centers in the same area. It also discusses the diagnostic criteria of patients with BEN stemming from collaborations between specialists working in other countries affected by the disease. Moreover, the paper analyzes the main etiological factors suspected to play a role in BEN: aristolochic acid (the disease has many similarities to aristolochic nephropathy caused by Chinese herbs), mycotoxins, toxic substances from pliocene lignite, genetic factors, and viruses. Studies performed by Romanian authors are presented briefly in comparison to studies performed by other authors. Finally, given that BEN is an important health problem in the region, the relationship between BEN and UUC is further analyzed.

[Investigation of Balkan endemic nephropathy in Serbia: how to proceed?].

Balkan endemic nephropathy (BEN) presents an unsolved puzzle despite fifty years of its investigation. Academy of Medical Sciences of the Serbian Medical Society organized a round table discussion on current unsolved problems related to BEN. The present paper summarizes presentations, discussion and conclusions of this meeting. During the last fifty years, the course of BEN prolonged and it shifted towards the older age in all endemic foci. Data on the incidence of BEN have been controversial and frequently based on the data on the number of BEN patients starting haemodialysis treatment. In Serbia, BEN patients present 6.5% of haemodialysis population and this percentage differs among different centres ranging from 5% (Leskovac) to 46% (Lazarevac). Maintenance of high prevalence of BEN patients on regular haemodialysis indicates that BEN is not an expiring disease. In addition, recent data have shown more frequent microalbuminuria and low-molecular weight proteinuria in children from endemic than from nonendemic families. Aetiology of BEN is still unknown despite numerous investigations of environmental and genetic factors. Today, there is a very current hypothesis on the aetiological role of aristolochic acid but the role of viruses, geochemical factors and genetic factors must not be neglected. Morphological features of BEN are nonspecific and characterized by acellular interstitial fibrosis, tubular atrophy and changes on pre- and postglomerular vessels. New immunohistochemical and molecular biology methods offer a new approach to BEN investigation. Association of BEN with high incidence of upper-urothelial tumours is well-known. Recent studies have shown significant changes of demographic characteristics of patients suffering upper-urothelial tumours, their prevalence in different endemic foci and characteristics of tumours. Further studies of BEN should be directed to determination of incidence and prevalence of disease in different endemic foci, investigations of different insufficiently examined aetiological factors as well as pathomorphological features of the disease by the use of modern methods.

[Testament's ability in Balkan endemic nephropathy].

INTRODUCTION: Testament is a solemn, authentic instrument in writing, by which a person declares his or her will as to disposal of his or her estate, and it has a psychopathological, lawful and ethical importance to a person, family and society. The aim of the study was to assess if the ability to make a testament was more damaged in patients with Balkan Endemic Nephropathy (BEN) than in patients with other diseases that resulted in Chronic Renal Failure in Bosnia and Herzegovina in the period from the 1st January 2001 to 31st December 2006. MATERIAL AND METHODS: The 753 respondents were divided into two groups in the study: BEN group (n=150) and control group made of patients with other diseases resulting in CRF (n=150). In a multicentric longitudinal study we used: adapted questionnaire from the Renal Register of Bosnia and Herzegovina, Hamilton Depression Rating Scale, and Mini-Mental State Examination. Descriptive analysis, discriminative function and regression model have been done statistically. RESULTS: In BEN group, heirs are mostly mentioned - 84.0% (t=14.391; P=0.001), and in control group: heirs - 66.6%, relatives - 43.3% (t=7.751; P=0.003), carers - 44.0% (t= 6.678 P=0.032), and institutions 10.0% (t=5.147, P=0.061). The discriminative function shows differences between BEN and control group: canonical correlation (rc) =0.827, Wilkinson lambda (lambda nj) =0.871, Chi-square test =141.575 and significance (P=0.001). The regression course of the analysis can be used for prediction of the ability to make testament for the patients on dialysis. [y=-0.95x + 15.715, and OR = 0.785, (95%) for CI = -0.997 - -0.375); Can Fanc r2=0.861: Significance is P=0.002]. CONCLUSION: The ability to make a testament is more damaged in patients from the nephropathy group than in the patients from the control group who are on dialysis in Bosnia and Herzegovina. This has been confirmed by socio-demographic and psychological parameters, and it is very important for preservation of the ethic norms of the patients on dialysis, responsibility of the expert teams and persons who are benefitiaries of the testament.

Today Balkan endemic nephropathy is a disease of the elderly with a good prognosis.

BACKGROUND: The outcome for Balkan endemic nephropathy (BEN) patients diagnosed in 1992 was analyzed in 2006 with the aim of detecting factors associated with disease progression and patient outcome. METHODS: In 1992 BEN was detected in 119 patients (53 males, 56.9 +/- 13.8 years) from the village of Sopic. Changes in creatinine clearance as well as outcome (death or onset of regular hemodialysis) were analyzed retrospectively in 2006. RESULTS: During the 14-year period 47 patients deceased (5 on hemodialysis) at the mean age of 72.2 +/- 8.2 years, while no data were available for 13 cases. Out of 59 remaining patients 3 were on hemodialysis in 2006 and 56 participated in the control examination. Of these 12 had creatinine clearance at least 50% lower than in 1992 and 44 had unchanged creatinine clearance. Logistic regression revealed age and proteinuria, but linear regression only age as significant prognostic factors for changes in creatinine clearance. The all-cause mortality rate varied between 1.1 and 5.3% per year and was similar to the mortality rate of the general population. The main cause of death was cardiovascular disease (40.5%) followed by malignant diseases (17%), most frequently (11%) due to upper urothelial tumors. Urine protein and age were found to be a significant independent predictor of all-cause mortality. CONCLUSION: In the village of Sopic BEN was commonly detected in patients in their fifties, progressed slowly, but most patients died from other causes at old age before end-stage renal disease occurred. Kidney function remained stable over the decade in three quarters of the surviving patients. Age and proteinuria were found to be prognostic factors for both disease progression and patient mortality.

Anthropological aspect of death in dialyzed patients.

The aim of this article is to compare the incidence of thanatophobia in dialysed patients having Balkan endemic nephropathy (BEN) with a control group (N18) members where some of them have chronic renal failure (CRF), but not (BEN). We examined thanatophobia on a sample of 753 dialysed patients with chronic renal failure (CRF) in Bosnia and Herzegovina (B&H) during the period from 1st January 2000 to 31st December 2006. The first group is a cohort consisted of 348 patients with Balkan endemic nephropathy (BEN), and the control group consisted of 405 randomly selected patients with different diagnoses of CRF (N18). The measurement instruments used were: General data list, Eysenck's Personality Questionnaire (EPQ), Beck's Anxiety Inventory (BAI), Hamilton's Depression Rating Scale (HDRS), and Mini-Mental State Examination (MMSE). Univariante and multivariante statistical analyses were carried out. From the multivariante analysis, the highest correlations with thanatophobia were found in these variables: avoidance of dialysis in BEN group: R=0.985, OR=0.358, CI=0.483-0.728 (95%), and in control group: R=0.550, OR=0.935, CI=0.615-0.830 (95%), age, years on dialysis, education, pervasive fear with statistical significance P=0.001. BEN group differentiates from control group: BAI-total (R=1.110, OR=0.578 (95%), CI=0.770-0.890, P=0.001), HDRS-total (R=0.995, OR=1.290 (95%), CI=1.180-1.920 P=0.001. BEN group have lower scores than the control group in MMSE-total: (R=0.430, OR=0.023 (95%), CI=0.034-2.850, P=0.001) which represents the organic part of anxiety. Thanatophobia is present in both groups, but it is more frequent in the BEN (11.70%) than in control group (7.50%). We found that thanatophobia occurs before dialysis, and that it is structured as a pervasive fear of death and is associated with endemia, years spent on dialysis, and avoidance of dialysis.

Balkan endemic nephropathy and associated urothelial cancer.

Balkan endemic nephropathy (BEN) is a chronic tubulointerstitial disease described only in some rural parts of southeastern Europe. One of its most peculiar characteristics is a strong association with upper urothelial cancer (UUC). BEN-related UUC has the same histological features as other forms of UUC in general, but is more frequently bilateral, less frequently affects the bladder and has a sex ratio close to 1. BEN and BEN-associated UUC share the same etiology. Over time, incidence of these conditions has been declining. Since BEN was first described, around half a century ago, socioeconomic changes (in housing, farming, living standards, etc.) have been profound and have obscured the factors responsible for the observed reduction in incidence. Whatever the causes of BEN, the disease might not be restricted only to southeastern Europe. Rather, the intensity of exposure to risk factors for BEN and, consequently, clustering of cases has more likely determined our knowledge of topographical distribution of an etiological entity that is much more widespread, or that might even be ubiquitous in its sporadic form.

Hemodialysis treatment in patients with Balkan endemic nephropathy: an epidemiological study.

AIM: To analyze hemodialysis (HD) treatment of patients with Balkan endemic nephropathy (BEN) from five endemic villages in the South Morava Region of Serbia. Analyses of patterns of incidence may generate hypotheses about the underlying causes of BEN, and prevalence data provide information on the current and likely future burden on health services for managing BEN. METHODS: A total of 143 end-stage kidney disease patients (ESKD) with BEN were admitted to the renal replacement program from 1974 to 2004: 121 to HD, 15 peritoneal dialysis, and 7 kidney transplantation. As a control group, 117 patients with other kidney disease (chronic pyelonephritis, glomerulonephritis, and ischemic nephropathy) admitted to HD at the time of BEN patients and matched by age and gender were studied. RESULTS: Most of the BEN patients (93.4%) treated by HD were born from 1917 to 1941. The majority of patients (79.3%) started HD from 1977 to 1991 (period of 15 years). The mean age of BEN patients starting HD treatment was 49.1 years in the period from 1974 to 1978, and increased steadily in the following years, being 72.5 years in the last period of study (2004-2006) The mean survival time of BEN males was 4.70 (95% CI 3.66-5.75) and for females was 5.02 (95% CI 1.47-4.53). Difference between males and females was not statistically significant (log rank 0.14, p = 0.7, P > 0.5). Mean survival times of 4.84 (95% CI 3.97-5.70) in BEN patients and 3.1 (95% CI 2.78-3.84) in other kidney disease patients were found. Difference between BEN patients and controls was statistically significant (log rank 8.38, p = 0.0038, P < 0.01). CONCLUSION: The population of endemic villages around the South Morava River admitted to HD treatment after 1974 was exposed to environmental toxicant(s) from 1917 to 1941. The most intense effect of environmental exposure was in that period, with ESKD in patients in their forties. The exposure to environmental toxicants has diminished, so ESKD of BEN has become less frequent and manifested in the older age, mean 72.5 in the period from 2004 to 2006. Different type of exposure was registered in some other endemic regions in Serbia and abroad.

Depersonalization in Balkan endemic nephropathy.

UNLABELLED: Aim of the study was to confirm depersonalization/derealization in patients with Balkan endemic nephropathy in comparison with other patients on dialysis in Bosnia and Herzegovina within the period 01.01.2000 -31-12-2006. years. METHOD: Examined were 753 out of 2770 dialyzed patients and they were divided into two groups: those with Balkan endemic nephropathy--BEN group (N+348) and the control group of other diseases N18. Patients were followed-up form 01.01.2000 to 31.12. 2006. when the study was made. It is comparative, cross-sectional study and Questionnaire from the renal Registry of B&H adapted to the mental health and psychological tests--Eizenck's personality characteristics test, Hamilton Depression Rating scale (HDRS) and Mini Mental State evaluation were used. RESULTS: Depersonalization was in BEN group present in 3.50% of cases (chi2 = 70.880, df = 2 p < 0.001), a derealization in 3.75% (chi2 = 117.678, df = 2, p < 0.002) and depersonalization/ derealization in 1.19% of them (chi2 = 218.457, df = 2, p < 0.002). Regression analysis was: y = -0.93x + 14.818, a CI = 95% for Fisher's (Z = -0.995462 to -0.26481). CanFanc r2 = 0.86, P = 0.002 za 87.5% for depersonalization prediction in HRF. CONCLUSION: In patients on dialyzed treatment in BaH depersonalization sui generis was found in group BEN 3.50% of cases, derealization in 3.57% of them and in group N18 depersonalization in 3.32% of them and possibility to predict depersonalization is 87.50%.

[Anxiety disorders in dialysis patients].

INTRODUCTION: Anxiety, as a primary symptom, includes all conditions of indefinite fear and psychic disorders dominated by fear. All dialysis patients suffer from anxiety as an independent phenomenon, or as part of another disease. MATERIAL AND METHODS: This study included 753 patients on chronic hemodialysis in Bosnia and Herzegovina (B&H) in the period 1999-2004. The patients were divided into two groups: the first group included 348 patients with Balkan Endemic Nephropathy (BEN), and the control group included 405 patients with other diagnoses causing renal insufficiency (N18). The study was designed as a comparative cross sectional study, and patients were tested using questionnaires assessing anxiety, depression and general mental health status. Statistical analysis was done using standard descriptive and analytical methods. RESULTS: Socio-demographic data showed highly significant differences between BEN and N18 in relation to place of residence (urban/rural) (chi2 = 23.970) p < 0.01: in the incidence of renal comorbidity (chi2 = 23.970) p < 0.01, familial renal comorbidity (chi2 = 23.970) p < 0.01 and mnigrations (chi2 = 4.874) p < 0.01. Beck Anxiety Inventory Scores were highly significantly different between the two groups p < 0.001, in regard to the incidence and variables. Hamilton Depression Rating Scale demonstrated a group significance p < 0.001, and variables pointed to somatization, general anxiety and depression. This was confirmed by mini-mental state examnination pointing to general mental weakness. CONCLUSION: Anxiety appeared in all tested dialysis patients. It may be independent, somatized as part of another mental disorder or reinforced by a cognitive damage. Structured anxiety and depression result in pre-suicidal risk.

[Balkan endemic nephropathy in Bosnia and Herzegovina--renal registry report]. / Balkanska endemska nefropatija u Bosni i Hercegovini--izvjestaj renalnog registra.

INTRODUCTION: Balkan Endemic Nephropathy (BEN) is still dominant cause of the end stage renal disease (ESRD) in North-Eastern Bosnia. The aim of this paper was to analyze the patients with BEN diagnosis on chronic dialysis treatment in Bosnia and Herzegovina. METHODS: In this study we used data from individual questionnaires which we collected for Renal Registry. Individual questionnaires include: sex, age, place of birth and address, primary renal disease, data of the first dialysis treatment, type of dialysis, kidney transplantation, co-morbid diseases, erythropoietin therapy and outcome. For patients with BEN diagnosis we gathered additional data: history of urothelial tumor and family history of similar kidney diseases and renal replacement therapy. We compared these data with data about others dialysis patients in Bosnia and Herzegovina. STATISTICAL ANALYSIS: descriptive statistical analysis. RESULTS: Prevalence of the chronic dialysis patients in Bosnia and Herzegovina in 2003 was 474 pmp, 70 pmp for patients with BEN and 54 pmp for patients with diabetic nephropathy. In North-Eastern Bosnia prevalence of chronic dialysis patients was 844 and of patients with BEN 520 pmp. Incidence of the new chronic dialysis patients in Bosnia and Herzegovina in 2003 was 113 pmp, 11 pmp for BEN, and 19 pmp for diabetic nephropathy. Mortality of the chronic dialysis patients in Bosnia and Herzegovina in 2003 was 11.24 %, and mortality of the BEN patients 10.75 %. CONCLUSION: From the total number of the chronic dialysis patients in Bosnia and Herzegovina 14.7 % are BEN patients and 11.3 % are patients with diabetes. BEN is still big medical and social problem in Bosnia and Herzegovina, especially in the North-Eastern Bosnia. There are certain indicators that the incidence of the BEN patients is in decrease such as decreased difference between the prevalence of the patients with BEN and diabetic nephropathy; as well as increase of average age of patients with BEN.