Fifty Years of Balkan Endemic Nephropathy: Challenges of Study Using Epidemiological Method

Balkan endemic nephropathy (BEN) is a chronic tubulointerstitial disease associated with urothelial cancer, which affects people living in the alluvial plains along the tributaries of the Danube River. Challenges of studying BEN using the epidemiological method are multiple. The natural history from exposure to occurrence of the disease may take many years. The early stages of BEN are not easily detectable clinically, as the disease is asymptomatic until a significant decline in function occurs, and even then symptoms are usually non-specific. The natural history of BEN is complex, possibly with multiple risk factors operating both at the stage of initiation of renal damage and in its progression. In BEN, genetic susceptibility is due to multiple genes of small effects, gene-gene interactions, and gene-environment interactions of complex nature that are difficult to assess with current study designs. BEN is now kidney disease of the old people, and many risk factors for disease such as smoking, alcohol consumption, obesity, and diabetes could contribute to the kidney damage. Evidence is presented that environmental rather than genetic factors play a decisive role in the etiopathogenesis of BEN. Aristolochic acid, described as a culprit of BEN in 1959, is confirmed in 2007 by the molecular biology methods. Mycotoxins and polycyclic aromatic hydrocarbons, leached from lignites and found in the vicinity of endemic settlements, deserve further investigation. Despite advances in understanding the epidemiology of BEN, more research is needed on the patterns of BEN over time and between places, and on identifying the contributions of modifiable risk factors in initiating and hastening progression of BEN in order to improve the scope for preventing BEN. Primary prevention is still at the beginning. Knowledge accumulated in the fifty years of BEN research and new data about prevention and treatment of chronic kidney disease reveal several effective methods in secondary and tertiary prevention of BEN. Genetic epidemiology could establish the relative size of the genetic effect in relation to other sources of variation in disease risk (i.e., environmental effects such as intrauterine environment, physical and chemical effects, as well as behavioral and social aspects). Public health authorities in the several countries having aristolochic acid nephropathy should take immediate measures for reducing dietary exposure of residents to Aristolochia.     

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.     

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.     

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.     

Balkan endemic nephropathy and genetic variants of glutathione S-transferases

BACKGROUND: Balkan endemic nephropathy (BEN) is a non-inflammatory, chronic, slow progressing kidney disease, frequently associated with urinary tract tumors. BEN displays familial clustering without an apparent Mendelian inheritance pattern. It has been suggested that environmental toxicants damage urothelial cells in genetically susceptible individuals, which could be the cause of BEN. The metabolism of some substrates that are mediated by glutathione S-transferases (GST), which are polymorphic enzymes, results in nephrotoxic products. To evaluate whether GST genetic heterogeneity could be involved in BEN, we launched a case-control study concerning the association of the most common polymorphic GST variants with BEN. METHODS: DNA was extracted from venous blood samples from 54 unrelated BEN patients and 104 controls inhabiting the same endemic region. GSTM1 and GSTT1 null deletions were identified simultaneously by a triplex polymerase chain reaction (PCR) procedure, and GSTP1 polymorphism was analyzed by PCR-restriction fragment length polymorphism (PCR-RFLP) using Alw261. RESULTS: Carriers of at least one GSTM1 wild type allele (wt-allele) were more prevalent among BEN patients compared to controls (chi2=7.92, p=0.005). The GSTT1 and GSTP1 genotype distributions did not demonstrate statistically significant differences between the groups. The carriers of at least one GSTM1 wt-allele among BEN patients were more prevalent in comparison with controls when the GSTM1 genotypes were combined in pairs with all GSTT1 (chi2=9.52, p=0.023) and GSTP1 (chi2=11.92, p=0.036) genotypes. The combined genotype distributions of the three GST genes studied among BEN patients and controls showed that the frequency of carriers of at least one GSTM1 wt-allele among BEN patients was higher or at least equal to the corresponding frequency among controls in all triple combinations. However, this difference did not reach statistical significance (chi2=14.06, p=0.170). CONCLUSIONS: GSTM1 wt-allele associates with BEN. The significantly lower prevalence of the GSTM1 deletion homozygotes among BEN patients suggests that individuals bearing the GSTM1 null genotype could be better protected.     

Diagnostic criteria for Balkan endemic nephropathy: proposal by an international panel

Balkan endemic nephropathy (BEN) is a familial chronic tubulointerstitial disease with insidious onset and slow progression to terminal renal failure. Diagnostic criteria for BEN have been described more than 40 years ago. Research groups on BEN use one of at least three described lists of criteria. Comparison of studies using such criteria is difficult, and a recent meeting of investigators (Zagreb, October 2006) has suggested that unified criteria have to be elaborated. In this paper, an International Panel of BEN Investigators agreed on criteria appropriate to epidemiologic studies and clinical investigations of BEN. A screening procedure of BEN in endemic settlements is proposed.     

Diagnostic Criteria for Balkan Endemic Nephropathy: Proposal by an International Panel

Balkan endemic nephropathy (BEN) is a familial chronic tubulointerstitial disease with insidious onset and slow progression to terminal renal failure. Diagnostic criteria for BEN have been described more than 40 years ago. Research groups on BEN use one of at least three described lists of criteria. Comparison of studies using such criteria is difficult, and a recent meeting of investigators (Zagreb, October 2006) has suggested that unified criteria have to be elaborated. In this paper, an International Panel of BEN Investigators agreed on criteria appropriate to epidemiologic studies and clinical investigations of BEN. A screening procedure of BEN in endemic settlements is proposed.     

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.     

Chinese herbs nephropathy and Balkan endemic nephropathy: toward a single entity, aristolochic acid nephropathy

Chinese herbs nephropathy (CHN) and Balkan endemic nephropathy (BEN) are chronic tubulointerstitial renal diseases associated with urothelial carcinoma. The clinical expression and pathological lesions observed at different stages of CHN and BEN are strikingly similar. Both have been linked to exposure to aristolochic acid (AA), a powerful nephrotoxin and human carcinogen. Jelakovi? et al. present molecular epidemiological evidence relating urothelial carcinoma in patients with BEN to dietary exposure to AA. It is time to abandon the terms 'CHN' and 'BEN' and introduce 'aristolochic acid nephropathy' to cover both clinical conditions.     

Balkan endemic nephropathy: a still unsolved puzzle

Balkan endemic nephropathy (BEN) is a chronic tubulointerstitial renal disease, occurring in certain regions in 5 countries of the Balkan peninsula. Its etiology is largely unknown, though several hypotheses have been formulated and are discussed in this review. In several cases, etiological hypotheses (e.g., viral, ochratoxin or trace element involvement) are verified only in local endemic areas and can not be confirmed when tested elsewhere. Only certain families in the endemic areas are affected. An exposure of at least 20 years to the unknown factors in the endemic areas seems to be mandatory for the development of the disease, but a genetic predisposition to this disease also seems to be mandatory. Prominent clinical features are severely shrunken kidneys, a more severe anemia relative to the level of renal function, and a slow progression to end-stage renal failure. An international approach to solving the etiological and pathogenetic enigma of BEN is needed in the coming years. It is also time to reevaluate other chronic, slowly progressive tubulointerstitial nephropathies diagnosed elsewhere in the world and to search for possible etiological similarities with BEN.     

Balkan nephropathy: a disorder of renal embryogenesis?

There is evidence to suggest that a renal embryogenesis disorder, with an associated deficit of nephrons, may be the cause of nephropathy later in the lives of patients with Balkan endemic nephropathy (BEN). This evidence includes the renal dysplasia or hypoplasia observed in BEN patients, the high incidence of renal pelvic and renal artery aberrations, primitive glomeruli and obstructed tubules on kidney biopsy, and an adult Fanconi-type syndrome of generalized proximal tubular dysfunction with hyperchloremic acidosis, potassium wasting, preserved urinary acidification, tubular proteinuria, aminoaciduria, uricosuria, hypomagnesemia, sodium wasting and normotension, as well as evidence from epidemiological data. The disease has affected no more than 2 generations, most of whom were in their 50s during 1965-1970, when maximal numbers of patients were seen. We are now observing a decreasing prevalence of BEN in Bulgaria and, even though this may have resulted from some prophylactic measures, the disease disappears much as it had appeared, as an epidemic. We speculate that some environmental factor may have had an impact on embryogenesis and resulted in nephropathy in patients with BEN. This could have been famine during the devastating Balkan wars in the beginning of 20th century, but may also have been an infectious or environmental factor, limited to the affected areas around the Danube river, which acted only during a limited period of time.     

Upper urothelial tumors in emigrants from Balkan endemic nephropathy areas in Serbia

AIM: The aim of the study was to investigate upper urothelial tumors (UUT) in emigrants from Balkan endemic nephropathy (BEN) areas in Serbia and compare them with UUT from both endemic and nonendemic areas. MATERIALS AND METHODS: A total of 1,121 patients from the state cancer database, between 1960 and 1998, were investigated. Sixty of them were emigrants from BEN areas. RESULTS: UUT in emigrants from BEN areas occurred after 21.7+/-9.9 years (median 20) spent in a rural environment. The time spent outside of the BEN regions was 33.2+/-12.8 years (median 31, range 10-72). Age at surgery was 55 years (range 31-89). In emigrants from BEN areas, there was a significant association of other diseases with UUT: renal failure in 63%, bladder tumors in 23.3% and bilateralism in 6.7% of the patients. Bilateralism was statistically more frequent in emigrants from BEN areas (p=0.04), as were low-grade tumors (p=0.03). There was no statistical difference in tumor stage between patients from BEN areas and from outside of them. Relatives of the emigrants from BEN areas were also affected by BEN, UUT and both of them (33%). CONCLUSIONS: It is concluded that hereditary as well as environmental factors are important for the expression and evolution of the disease. An early period of life spent in the endemic region seems important for the later development of UUT in emigrants from BEN regions. Different time spans spent in the endemic region have no effect on the age of appearance of UUT.     

An etiological approach to Balkan endemic nephropathy based on the investigation of two genetically different populations

The direct inheritance as a possible etiologic factor of Balkan endemic nephropathy (BEN) has been studied in an endemic area in the district of Slavonski Brod (Croatia-Yugoslavia). The basis for the investigation was given by a natural experiment induced by immigration of people from Ukraina to the endemic and nonendemic areas near Slavonski Brod. 1,536 persons in endemic villages and 733 inhabitants from the villages, where BEN has not been found, were studied with the aim of establishing diagnosis or excluding BEN. The generally adopted criteria enabling to classify the examined persons into the following 3 groups have been used: (a) diseased of BEN; (b) suspect to be diseased of BEN, and (c) individuals without signs of a renal disease. In the endemic villages among the population of Croatian aborigines, 12,1% diseased and suspects have been revealed. Among the Ukrainian immigrants and their offsprings, 10.5% diseased and suspects have been found. The difference is not significant (t = 0.7, p greater than 0.05). On the other hand, in nonendemic villages there were no diseased nor suspect BEN patients among the indigenous people as well as among the Ukrainians. The inference is suggested that the factors of the direct inheritance do not play a decisive role in the etiopathogenesis of BEN.     

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.     

Renal transplantation in patients with Balkan endemic nephropathy

BACKGROUND: Balkan endemic nephropathy (BEN) is a chronic tubulointerstitial disease prevalent in Croatia, Romania, Bulgaria, Bosnia and Herzegovina, and Serbia. In addition to renal disease, an increased incidence of upper urothelial carcinomas (UUCs) has been observed in the foci of BEN. Carcinoma may occur alone or in combination with BEN. Immunosuppression is associated with an increased risk for development of different malignancies. There are no data in the literature about the outcome of patients with BEN after transplantation. METHODS: We performed a retrospective evaluation of the database and review of the charts and pathology reports of 601 renal transplant recipients treated at our institution. RESULTS: From January 1995 to December 2004, kidney transplantations were performed in nine patients with BEN. One-year graft survival was 100%. A man, who was transplanted in 1997 died 2 years after transplantation with a functioning graft due to disseminated cancer from the pelvis of his own kidney. A female patient developed UCC 2 years after transplantation. They were both treated with a bolus of methylprednisolone before transplantation, because of four HLA-mismatches. A male patient developed UCC in the native and transplanted kidneys. He underwent a native nephroureterectomy with partial nephroureterectomy of transplanted kidney. His graft function was preserved with decreased immunosuppression. Three years later a urinary bladder carcinoma was discovered on a regularly performed multislice computed tomography. One patient developed a skin malignancy. Other patients have had uneventful posttransplantation courses with excellent graft function. Thus, 33.3% of patients with BEN developed UUC, compared with a 0.67% prevalence of urinary tract tumors among transplanted patients with other causes of end-stage renal disease. CONCLUSION: Patients with BEN are at increased risk for the development of UCC after transplantation. Regular screening for early detection of malignancy is mandatory. Longer follow-up and results from other transplant centers are needed to further investigate the relationship between BEN and UCC after renal transplantation.     

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.

     

Identification of NQO1 and GSTs genotype frequencies in Bulgarian patients with Balkan endemic nephropathy

BACKGROUND: Polymorphisms in NAD[P]H:quinone oxidoreductase (NQO1) and glutathione S-transferases (GSTs) have been reported to be associated with an increased risk for environmentally and/or occupationally induced renal and bladder cancers. Genetic factors related to chronic nephropathy and to urinary bladder or renal cancer development in Balkan endemic nephropathy (BEN) is unknown. In order to evaluate their possible role in BEN susceptibility, we determined the frequencies of NQO1 alleles *1, *2 and *3, as well as the GSTT1 and GSTM1 null genotypes in BEN patients and healthy subjects from a non-endemic region of Bulgaria. METHODS: The respective genotypes of 95 unrelated Bulgarian BEN patients and of 112 healthy individuals (control group) were determined by rapid cycle polymerase chain reaction (PCR) and detected with either SYBR green I fluorescent dye or melting curve analysis using allele specific probes. RESULTS: NQO1 genotyping showed a higher NQO1*2 allele frequency (23.68%) in BEN patients compared to controls (18.75%; p=0.219), while NQO1*3 allele frequencies were similar in both groups (2.63% in BEN patients vs. 2.23% in controls; p=0.791). The GSTT1 deficiencywas observed in 20% of BEN patients vs. 16.1% of controls (p=0.613). The GSTM1 null genotype was found in 45.3% of BEN patients vs. 51.8% of controls (p=0.674). There was no influence of NQO1 and GSTs genotypes found on BEN risk. CONCLUSIONS: Our results established that alleles NQO1*2 and NQO1*3, as well as lack of GSTT1 and GSTM1 did not influence the BEN risk. These findings provide novel information on the genetic heterogeneity in the healthy Bulgarian population.     

Acute effects of acetaminophen on renal function and urinary excretion of some proteins and enzymes in patients with kidney disease.

The acute effects of acetaminophen, a commonly used as analgesic drug, upon the urinary excretion of some proteins and enzymes as markers of kidney damage, was investigated. Patients with chronic glomerulonephritis (GN) and Balkan endemic nephropathy (BEN), having kidney vulnerable to toxic drugs, were enrolled in the study. Timed urine specimens were collected: before drug administration, and in 3-hour periods for 24 hours after an oral dose of 2 g of acetaminophen. Urinary excretion of albumin before acetaminophen treatment was significantly higher in patients with GN and BEN than in healthy adults, however, beta 2-microglobulin excretion was increased in BEN patients only. Urinary excretion of creatinine markedly increased immediately after acetaminophen ingestion. Urinary excretion of total protein and albumin was not changed after acetaminophen administration. However, acetaminophen treatment produced a significant increase in beta 2-microglobulin excretion in patient with BEN and GN, and in clinically healthy members of nephropathic families. Excretion of aminopeptidase N (APN) activity before acetaminophen treatment was significantly higher in patients with GN, however, NAGA excretion was higher in both GN and BEN patients than in healthy controls. After acetaminophen administration urinary excretion of APN, dipeptidylpeptidase IV (DPP IV), gamma-glutamyltranspeptidase (GGT) and N-acetyl-beta-D-glucosaminidase (NAGA) did not increase significantly in any group studied. This study has shown that urinary excretion of APN, DPP IV, NAGA and GGT, as markers of kidney brush border and lysosomal damage, did not change after 2 g of acetaminophen taken orally. beta 2-microglobulin was a marker of acute acetaminophen nephrotoxicity in kidney disease patients and in clinically healthy adults from nephropathic families.     

Global and specific histone acetylation pattern in patients with Balkan endemic nephropathy,a worldwide disease

Background: Balkan endemic nephropathy (BEN) is a chronic tubulointerstitial nephropathy present in the Danube river regions in several Balkan countries. There appears to be a polygenic susceptibility to the disease in interaction with multiple environmental factors (aristolochic acid, ochratoxin A). In a previous study SEC61G, IL17RA, HDAC11 proved to be differently methylated throughout all patient-control pairs of BEN patients from Serbia and Bulgaria. Emerging connections between DNA methylation and histone acetylation prompted the present study on histone acetylation in patients with BEN. Methods: The study involved 39 patients with BEN, and 39 controls collected from non-endemic regions in Serbia. The EpiSeeker Histone H3 and H4 Total Acetylation Detection colorimetric Kits and specific acetylated at lysine 18 H3K18 and H3K36 acetylated at lysine 36 detection kits were used. Results: It was documented that total H4 histone acetylation level was increased significantly, while total H3 histone acetylation did not differ significantly. Specific histone structure and functional properties may be affected by the observed derangement of H3 histone acetylation pattern, since H3K36 site was significantly more acetylated, while H3K18 tended to be less acetylated than in control subjects. Multiple regression analysis revealed a statistically significant relationship between H4, H3T and H3K36 in BEN patients. Conclusion: This preliminary study suggests that the acetylation of histone lysine residues was detectable and found increased at specific sites of H3 and total H4 histones isolated from urothelial cells of patients with BEN. Having in mind a possible mechanism and biological role of epigenetic chromatin modification in urothelial tumor development they obtained results may open opportunity for selective therapeutic interventions in patients with BEN.     

Prevalence of Balkan endemic nephropathy has not changed since 1971 in the Kolubara region in Serbia

BACKGROUND/AIMS: Thirty-one years after the first cross-sectional study, the population of Vreoci, a Balkan endemic nephropathy (BEN) village, was reinvestigated in order to determine the current prevalence of BEN and the clinical and laboratory characteristics of BEN family members with detected signs of kidney disease. METHODS: A total of 2,009 inhabitants (82% of the adult population) of the village were examined. Danilovic's criteria were used for diagnosis and classification of BEN. RESULTS: The prevalence of BEN (1.70%) was similar to that in 1971 (1.67%). Diagnosis of BEN was established in 19 BEN family members, suspected BEN in 23, proteinuria in 29, while 16 healthy members were examined as controls. Urine protein, alpha1-microglobulin levels and frequency of glucosuria were significantly higher and kidney length significantly smaller in the three patient groups than in healthy persons. Serum urea and creatinine levels were significantly higher, but creatinine clearance was lower in BEN and BEN suspected patients than in the other two groups. CONCLUSION: The prevalence of BEN remains stable over time in Vreoci village. Manifested disease was found in both BEN and BEN suspected patients. In persons with proteinuria but not enough criteria for BEN, tubular disorders and hypertension were frequently found.