Incidence and predictive factors of Balkan endemic nephropathy: a longitudinal study.

Balkan endemic nephropathy (BEN) is a chronic kidney disease that progresses slowly. There are no known clinical markers to identify an early disease development. We evaluated the relationship between parental history of BEN and clinical markers as predictors of new occurrences of BEN. A 5-year prospective study in the offsprings of BEN and control patients was conducted in Vratza, Bulgaria, between 2003 and 2009 using markers in years one and three to predict new cases of BEN in the year five. We defined incident cases of BEN based on parental history, reduced kidney size and reduced kidney function, distinguishing probable and definite BEN, both combined as total incidence. The data were analyzed by Cox regression models using age as time scale and controlling for gender. We estimated hazard ratios and their 95% confidence intervals. The incidence of BEN was 17.4%. Paternal history was strongly associated with all three incidence groups (hazards ratio: 27-68, P <0.05). A reduction of kidney size of 1 mm resulted in a 5% increased hazard. However, taking parental history of BEN into account, these associations lost their significance. No kidney function measures were associated with new onset of BEN. A parental history of BEN is more important than clinical markers predicting the incidence of BEN. Without this information, kidney length forecasts probable BEN and the total incidence, while none of any clinical markers was related to definite BEN.

Chronic kidney disease: global dimension and perspectives.

Chronic kidney disease is defined as a reduced glomerular filtration rate, increased urinary albumin excretion, or both, and is an increasing public health issue. Prevalence is estimated to be 8-16% worldwide. Complications include increased all-cause and cardiovascular mortality, kidney-disease progression, acute kidney injury, cognitive decline, anaemia, mineral and bone disorders, and fractures. Worldwide, diabetes mellitus is the most common cause of chronic kidney disease, but in some regions other causes, such as herbal and environmental toxins, are more common. The poorest populations are at the highest risk. Screening and intervention can prevent chronic kidney disease, and where management strategies have been implemented the incidence of end-stage kidney disease has been reduced. Awareness of the disorder, however, remains low in many communities and among many physicians. Strategies to reduce burden and costs related to chronic kidney disease need to be included in national programmes for non-communicable diseases.

Morphology of Balkan endemic nephropathy: current state.

Balkan endemic nephropathy (BEN) is interesting renal disease, because of its unique clinical, epidemiological and morphological characteristics: intensive interstitial fibrosis and tubular atrophy without any inflammation. In the present paper we evaluate the incidence of BEN from the morphological point of view for the last decade. Therefore we analyzed material obtained from autopsies, kidney biopsies and nephrectomy due to upper urothelial cancer (UUC) from the patients which were divided into two groups: those with permanent residence in BEN areas and those from nonendemic areas. At the Institute of Pathology, University of Belgrade for the last 15 years we had only 1 autopsy due to BEN out of 6,825. More than 30 years ago there were over 50 autopsy cases of BEN at the same institute. For the last decade we had only 2 kidney biopsies suspected for BEN out of 2,182, but morphologically not confirmed as BEN. However, previously we had over 40 kidney biopsies diagnosed as early or late stage of BEN. At the Clinical Center of Serbia 180 nephrectomies were performed due to UUC. The incidence of UUC for the last five years in BEN regions has significantly decreased, whereas at the same time in non-BEN regions it has remained on the same level. There was no morphological difference of the renal tissue adjacent to tumor between patients from BEN and non-BEN regions. According to our study based on routine pathological work, we could clearly conclude that BEN today is more clinical and epidemiological than a morphological entity.

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.

Survival of patients with transitional cell carcinoma of the ureter and renal pelvis in Balkan endemic nephropathy and non-endemic areas of Serbia.

OBJECTIVE: To evaluate the characteristics and survival of patients with upper urinary tract (UUT) transitional cell carcinoma (TCC) in Serbia, followed for >/=5 years or until death. PATIENTS AND METHODS: From 1998 to 2005 we analysed 114 cases of pathologically confirmed UUT TCC, divided into two groups according to topographical characteristics, and compared their demographic, clinical and pathological characteristics. The influence of various factors on overall 5-year survival of patients with UUT TCC was also tested. The prognostic value of different variables was assessed by univariate and multivariate Cox proportional-hazard models. RESULTS: The most important change in demographic characteristics of the patients with UUT TCC in Serbia was a similar proportion of patients residing in areas of Balkan endemic nephropathy (BEN) and non-endemic areas. The median (range) follow-up was 67 (46-88) months. The 5-year probability of survival was 51.2 +/- 5.8%. There was a significantly lower probability of 5-year survival for patients with a higher histological grade (P = 0.001), higher T stage (P < 0.001) and tumour size >3 cm (P = 0.001) at diagnosis. In this cohort of patients the independent predictors of a poorer outcome of the disease were being female (hazard ratio, HR, 2.2, P = 0.010), tumour size >3 cm (HR 2.8, P = 0.001) and T3 or T4 stages (HR 3.1, P = 0.001). CONCLUSION: Comparative analysis of the characteristics of UUT TCC between patients from BEN and non-endemic areas of Serbia showed similarities in demographic, clinical and pathological features. Factors that significantly influenced survival of patients with UUT TCC were being female, tumour size and tumour grade and stage.

Recent data on endemic nephropathy and related urothelial tumors in Croatia.

Endemic nephropathy (EN) is a renal disease of unknown etiology. In Croatia it occurs in the rural population in 14 villages located in the western part of Brodsko-Posavska county. This region also has an unusually high incidence of otherwise rare upper urothelial cancers. Between 1991 and 2002 the average general mortality for both sexes in the endemic region was 10.3 per thousand and the specific mortality for patients with EN was 0.65 per thousand (M 0.58/10((3)), F 0.72/10(3)). The average age of death of patients with EN was 69.2 years (M 67.7, F 70.3), which is similar to the life expectancy for the rest of the population in the county (67.8, M 64.4, F 71.8). This life expectancy is significantly higher than in the period 1957-1960 when the average age of EN-related death was 45.1 years. Between 1995 and 2002, in contrast to both Croatia as a whole and the respective county, the specific mortality with tumors of the pyelon and ureter in the endemic region was much higher in women than in men (9.020 and 4.697 per 100,000, respectively). The specific mortality of all patients with urothelial tumors was 14 times higher in the endemic region than in Brodsko-Posavska county and 55 times higher than in Croatia overall. The much higher specific urothelial-tumor mortality in women than in men (in contrast to the rest of the country) and the higher specific EN mortality indicate that the causative agent of the two nosological entities is the same.

Survival of Balkan endemic nephropathy patients.

The retrospective cohort study comprised 97 Balkan endemic nephropathy (BEN) and BEN-suspected patients discovered in 1971 in the field examination in the village of Sopic, one of the regions most frequently affected by the disease. Our aim was to determine the outcome of the disease in patients and to compare the survival of BEN-suspected and BEN-manifested patients and the survival of their kidneys. The mean survival time was 16.4 years for all patients (95% CI 14.51-18.21) and 23.1 years for suspected and 13.3 years for manifested patients (log-rank = 19.46; d.f. = 1; p < 0.001). According to our results, it can be concluded that BEN is characterized by slow course and prolonged evolution and that the prognosis was consistently better for BEN-suspected than for BEN-manifested patients.

Balkan endemic nephropathy: a decreasing incidence of the disease.

Balkan endemic nephropathy (BEN) is a chronic tubulointerstitial kidney disease prevalent in Serbia, Bosnia, Croatia, Bulgaria and Romania. This study investigates the incidence of BEN patients on dialysis with end-stage kidney disease (ESKD), and BEN-associated mortality in endemic areas around the South Morava River in Serbia from 1978 to 1997. In the last 10 years a marked decrease in the incidence of ESRD and BEN-induced mortality has been documented in the region. This study shows a significantly decreased incidence of BEN in endemic areas in South Serbia. Since the effects of etiological agent(s) on renal function in children from families in endemic areas was demonstrated in the early nineties and the disease seems to have an endemic-epidemic profile, the possibility of another epidemic outbreak in the future cannot be excluded.

Epidemiology of Balkan endemic nephropathy.

The first outbreak of Balkan endemic nephropathy (BEN) was reported between 1955 and 1957, initially in Serbia and soon afterwards in Croatia and in Bosnia and Herzegovina. The disease appears to be of a focal nature. In Yugoslavia at least six foci are known, generally along major rivers of the Danubian river basin, in areas that have often been flooded in the past and even today suffer from high ground waters. The prevalence rate of the disease is reported to be between 2 and 10%. In the endemic area of Croatia, a systematic survey of 'in-the-field' cases of the disease since 1975 has shown a prevalence between 0.5 and 4.4%. When suspected cases are also included the prevalence rises to 20% or more. Specific mortality (based on official statistics) during the period 1957-1984 averaged 1.54/1000 per annum, but some studies have shown that mortality is actually more than twice as high as this figure. More women are affected than men; women also more frequently die of BEN than men. Lethality is extremely high. A striking feature of BEN is the familial occurrence of the disease. Incidence does not seem to be connected with ethnic group differences. Immigrants into the endemic area may also contract the disease. An increased incidence of malignant tumours of the urinary tract has been recorded in populations living in endemic areas. Epidemiological characteristics suggest that the disease is contracted in the domestic situation, or possibly from other family members. Factors to be considered are food, water or long close contact. It is also possible that the disease is contracted outside the house, in connection with farming activities, since the affected persons are almost exclusively farmers.

Pathomorphology of Balkan endemic nephropathy.

Within the county of Slavonski Brod, Yugoslavia hyperendemic areas of Balkan endemic nephropathy (BEN) have been recognized for a long time. As the Department of Pathology and Forensic Medicine of the Medical Centre in Slavonski Brod is responsible for all diagnostic post-mortem examinations in the county, and at the same time is engaged in surgical pathological diagnosis, a considerable amount of material relating to BEN and concomitant urinary-tract tumours has been collected during a 16-year period. This material has been classified and used for pathological, anatomical and histological investigations. In this paper the most relevant findings are described and briefly discussed, without the intention to speculate on possible aetiology of BEN. As the origin of BEN and of the high frequency of urinary tumours among the people from the endemic areas are still unexplained, and uniform criteria for the pathomorphological diagnosis of BEN are badly needed, the proposal to set up an archive encompassing cases from all the centres investigating BEN is supported.

Beta 2-microglobulinuria as a predictor of death in a population exposed to Balkan endemic nephropathy.

During the year 1974, urinary beta 2-microglobulin (beta 2mu) was measured at monthly intervals using the first-morning urine sample of randomly selected individuals from the BEN affected village of Petka (416 persons) and from the nearby situated control village of Stubica (216 persons). Initial compliance was complete; over 90% of villagers had at least 10 tests performed. beta 2mu, as assessed by radial immunodiffusion (RID), was repeatedly (at least twice) positive in 12% and 1.4% of the populations of the endemic and control villages, respectively. Over the 15 years of follow-up (1974 to 1988), none from the control village developed BEN, while many medical records of the cohort exposed to BEN contained data suggestive of BEN. Death from/with BEN was used as a measure of outcome. Incidence density of 12 was 3.3 per 1000 person/years of observation (19/5723). A single positive beta 2mu test was a sensitive predictor of BEN death (sensitivity = 89.5%). Selecting two or more positive tests as the cut-off point, the specificity and positive predictive value were considerably increased. Using the sulfosalicylic acid test for detection of significant proteinuria, a similar level of validity indices was reached only by four testings.

Epidemiological characteristics of Balkan endemic nephropathy in eastern regions of Yugoslavia.

Foci of Balkan endemic nephropathy have been found scattered along several rivers in many parts of Serbia, as well as in north-eastern Bosnia. There is no indication that the medical geography of the disease changes over time. As for the intensity of the endemic process, both the poor quality of the routinely collected data and an inconsistent methodological approach obscure the real epidemiological situation. The incidence of deaths, the most reliable measure of outcome, has been stable over the last few decades, slightly exceeding 3 per 1000 person-years of observation in the most heavily affected endemic villages. The point prevalence rate of hyper-beta-2-microglobulinuria, an indicator of tubular damage, also remained unchanged over that period, at a value as high as 20-25%. Over time, however, the course of the disease became more protracted and its onset moved towards older ages. These two facts may indicate a less intense contact with the agent(s) and, consequently, suggest a decreased burden of Balkan endemic nephropathy in the near future. The natural history of Balkan endemic nephropathy is still not well understood, however. The disease seems to have had an endemo-epidemic pattern in the past, and the possibility of another epidemic wave in the future cannot be completely ruled out.

Epidemiological aspects of Balkan endemic nephropathy in a typical focus in Yugoslavia.

Balkan endemic nephropathy is a noninflammatory bilateral kidney lesion that affects rural populations in several circumscribed areas of the Balkans. Its etiology is still not understood, but recently it has been associated with exposure to nephrotoxic mycotoxins. It has been known to be present since the mid-1950s in 14 villages in an endemic area of Croatia, where approximately 10,000 people are at risk. Its prevalence fluctuates between 0.4 and 8.3%, showing a slight decline in recent years, but it has not disappeared from any of the endemic villages. The occurrence of the disease in several ethnic groups contradicts the hypothesis of a primary hereditary basis for Balkan endemic nephropathy. Recently, evidence has been found of an extremely high incidence of urinary tract tumours in the endemic area, and particularly of urothelial tumours of the pelvis and ureter. There may therefore be a common causative agent for these two rare diseases.

Balkan nephropathy and malignant tumors.

The question of whether the cancer death risk is higher in Balkan nephropathy (BN) foci has been approached by a comparison of 25 BN endemic municipalities with the same number of the group matched ones. It came out that the total cancer mortality was considerably higher, and mortality of nonurinary cancer slightly higher in BN endemic municipalities. The absence of a significant difference for the non-urinary cancer sites the authors explain by the fact that in municipalities designated as endemic only a part of the population lived in actual BN foci. They re-evaluated data published for Bulgarian BN endemic foci and concluded that, apart of a higher total cancer mortality, there was a significantly higher (although unrecognized) risk of nonurinary deaths in BN endemic settlements.

[Possibility for studying the life expectancy of patients with Balkan endemic nephropathy by dispensary observation]. / Vuzmozhnost za prouchvane produlzhitelnostta na zhiveene na bolnite ot balkanska endemichna nefropatiia chrez dispanserno nabliudenie.

The follow-up cards of 1100 patients that died of Balkan endemic nephropathy (BEN) within the period 1962-1981 were studied with a view to establishing the incidence of the disease in Vratza district, affection of sex and age and chiefly--the duration of the disease. The authors established that the disease was found in 47 settlements of Vratza district, that the females were more often affected as compared with the males and that the subjects aged from 30 to 70 were most frequently affected. More that the half of the patients with BEN was established by the authors, to die with--in the first 5 years since the onset of the disease, whereas the rest--live longer, in single cases, over 20 years.