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The term chronic kidney disease of unknown aetiology (CKDu) refers to chronic kidney disease (CKD) in the absence of diabetes, long‐standing hypertension, glomerulonephritis, obstructive uropathy or other apparent causes. An increasing number of CKDu cases have been reported from Latin America, Sri Lanka, India and others over the last two decades. These regional nephropathies share the following common attributes: (a) they affect low‐to‐middle income countries with tropical climates, (b) involve predominantly rural agricultural communities, (c) male predilection, (d) absence of significant proteinuria and hypertension, and (e) chronic tubulointerstitial nephritis on kidney biopsy. The current body of literature suggests that CKDu may be caused by heat stress, agrochemicals, contaminated drinking water or heavy metals; however, considerable regional disparities in CKDu research make it difficult to establish a common causal link. In the absence of a definite aetiology, specific preventive and therapeutic interventions are lacking. Improvement of working conditions of farmers and labourers, provision of safe drinking water and changes in agricultural practices are some of the measures that have been implemented; however, there is lack of data to assess their impact on the incidence and progression of CKDu. There is a need for a concerted global effort to address the current knowledge gaps, and to develop effective and sustainable strategies to tackle this devastating disease. [ABSTRACT FROM AUTHOR]

The village of Dubravica is partially located over the western lignite deposits of the Kostolac basin. The examination of the dry residue obtained from drinking water from two individual wells by X-ray diffraction analysis, based on a typical peak, showed the presence of uranium in drinking water. The indirect method by Rajković and associates showed that, in sample I, the concentration of uranium in drinking water was 85.5 percent higher (3.71 mg/L) and that the concentration of uranium in sample II was only 22 percent lower (1.56 mg/L) than the Maximum Allowable Concentration (MAC) values required by the Regulations (2 mg/L). Analysis of the result of the introduction of uranium in the human body has shown that this way brings 0.84 to 2 mg of uranium in the human organism per annum or 0.09 to 0.22 mg of uranium is deposited annually in the kidney. Assessment of the potential health risk due to the presence of uranium in drinking water indicated that the population using drinking water from wells will be threatened by uranium in a short time interval. Regarding the long-term risk, the calculation has indicated that in the first sample of drinking water, about 25 inhabitants, and in the case of the second sample of drinking water, 10 inhabitants out of 1000 inhabitants are endangered. As the kidney is the organ in which uranium is deposited (accumulated) to the greatest extent, its presence causes weakening and failure of kidney function, which can destroy 75 percent of kidney function until the manifestation of the first clinical symptoms. This phenomenon is observed among the population along the rivers the Kolubara, the Drina, the Sava and the Morava and is called endemic nephropathy. The elements found in trace amounts (Pb, Cd, Si), live agents (bacteria and viruses), fungal plant toxins, genetic factors and immune mechanism can be listed as possible causes. However, uranium in drinking water has not been listed so far. The tests performed in this study clearly show the role of uranium in the epidemic, endemic nephropathy, which is growing and which is not at the acute phase of the disease but has already progressed to renal failure and end-stage kidney disease. Official data on the rise of endemic nephropathy and diabetes and increasing their share in diseases, as well as overall mortality rates, which amount to 18.19%, clearly indicate that the role of uranium in the Braničevo district environment should not be ignored. Since there are settlements on the terrain to be investigated, uranium and its migration through the environment must be monitored as all conditions for its migration are unfortunately favourable.

Vicente Sanchez Polo,1 Ramon Garcia-Trabanino,2,3 Guillermo Rodriguez,4 Magdalena Madero5 1Instituto Guatemalteco de Seguridad Social, Guatemala, Guatemala; 2Centro de Hemodiálisis, San Salvador, El Salvador; 3Fondo Social de Emergencia Para la Salud, Tierra Blanca, El Salvador; 4Service of Nephrology, Hospital Dr. R.A. Calderón Guardia, Caja Costarricense de Seguro Social, San José, Costa Rica; 5Division of Nephrology, Instituto Nacional de Cardiología Ignacio Chávez, México, MéxicoCorrespondence: Magdalena MaderoDivision of Nephrology, Instituto Nacional de Cardiologia Ignacio Chavez, Juan Badiano 1, Col Seccion XVI, México CP 14080, MéxicoEmail madero.magdalena@gmail.comAbstract: In 2002, a report from El Salvador described a high incidence of chronic kidney disease (CKD) of unknown cause, mostly in young males from specific coastal areas. Similar situations were observed along the Pacific Ocean coastline of other Central American countries and southern Mexico (Mesoamerica). This new form of CKD has been denominated Mesoamerican endemic nephropathy (MeN). The typical presentation of MeN is a young male from an endemic area with a family history of CKD, low eGFR, high serum creatinine, low level of albuminuria, hypokalemia, hyperuricemia, and urine urate crystals. Kidney biopsy demonstrating tubulointerstitial nephritis remains the gold standard for diagnosis but is available only for a minority. Commonly proposed causes include thermal stress/dehydration and/or exposure to environmental pollutants. However, likely, a third factor, which could be genetic or epigenetic, could contribute to the cause and development of the disease, along with social determinants. Currently, preventive measures focus on minimizing workers exposure to thermal stress/dehydration. There are many research opportunities and priorities should include clinical trials to evaluate the efficacy and safety of the current treatment protocols, along with etiological and genetic studies, and the development of kidney disease data systems. Although there is scant and controversial literature with regard s to the etiology, diagnosis and management of the disease, our aim is to provide the reader a vision of the disease based on our experience.Keywords: Mesoamerican nephropathy, MeN, heat stress, CKDu, CKDnt, endemic nephropathy, regional nephropathy

Mesoamerican nephropathy (MeN) is an endemic form of chronic kidney disease (CKD) that is not related to risk factors for CKD, such as diabetes and hypertension. It primarily affects men, rural and agricultural laborers, who work in an extremely hot and dry environment. The greatest increase in the prevalence of CKD, particularly since the late 1990s, has been reported in Central America and Southern Mexico, where the prevalence is almost 9 times higher than in the USA. The highest mortality associated with CKD is reported in El Salvador where a 10-fold increase was recorded in 1984–2005. In histological examination, MeN patients manifest tubulointerstitial lesions and, in some cases, also lesions in the glomeruli. The cause of MeN remains unclear. Repeated episodes of occupational heat stress, and sweating accompanied by water loss, have a significant impact on the disease development. The disease is a significant social and economic problem, and a challenge in the field of diagnostics, therapy and prevention for physicians of many specialties, especially for occupational physicians. Med Pr. 2020;71(3):353–61

Although collecting duct carcinoma is a subtype of renal cell carcinoma, several studies implicate association with urothelial carcinoma. The coexistence of collecting duct carcinoma and another renal neoplasm is rare. Endemic nephropathy is a renal disease causing chronic renal failure. It is highly associated with urothelial neoplasm and occurs in endemic villages in Bosnia, Croatia, Bulgaria, Romania and Serbia. Recent studies have confirmed the important role of exposure to aristolochic acid as an etiologic factor. We present three cases of collecting duct carcinoma with literature overview. In one case, we describe collecting duct carcinoma with metachronous urothelial carcinoma of the pyelon and urinary bladder in an endemic nephropathy patient. To our knowledge, this is the first case report describing this coexistence. Certain similarities between collecting duct carcinoma and urothelial carcinoma were found, e.g., higher incidence in female compared to male, higher mean age, and multifocal and multicentric occurrence of the tumor. Our observations support the hypothesis that collecting duct carcinoma and urothelial carcinoma could be connected.

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.

Prof. Dr. Dimitar T. Hrisoho was born on June 11, 1924 in Bitola, R. Macedonia. He died in Struga on September 22, 1986, and was buried in Skopje. He completed primary and secondary education in Bitola. He graduated from the Medical Faculty in Belgrade in 1951 as one of the best students of his generation (average grade of 9.75). In 1953 he was employed at the Internal Clinic of the Medical Faculty in Skopje, where in 1955 he passed the specialist exam in internal medicine. He successfully defended his habilitation "Polyarthritis chronica evolutiva" and his doctoral dissertation "Clinical features of Vitina nephropathy". The doctoral dissertation indicates that Vitina nephropathy is a new site of the Balkan Endemic Nephropathy entity and that more genetic testing of patients were needed. Based on numerous clinical and scientific researches published in over 200 papers, he was elected a Full Professor of internal medicine at the Medical Faculty of the Ss. Cyril and Methodius University in Skopje in 1971. In 1970, he formed the nephrology section of the Macedonian Medical Association (MMA), which grew into the nephrology Association of MMA. Through the Association, the education of the medical staff from the field of nephrology was performed. He also set up a bio-cybernetics association. He achieved his vision and desire to transfer and apply the achievements of modern nephrology in the diagnosis and treatment of kidney patients in Macedonia at the Clinic of Nephrology of the Medical Faculty in Skopje, which was the first specialized institution established for examination and treatment of kidney patients in the former Yugoslavia and the Balkans. The Clinic educated nephrological staff and examined and treated kidney patients with new methods and drugs that positively affected the development of nephrology as a subspecialty of the internal medicine. D. Hrisoho was actively involved in the introduction of new methods for examination of kidney patients, as well as in the treatment of patients with acute and chronic renal insufficiency with dialysis since 1965. He also participated in the first two kidney transplantations from living donors performed in 1977. He wrote a chapter on "kidney examination", printed in the book of Prof. A. J. Ignjatovski "Fundamentals of Internal Propedeutics" Part III, published by "Prosvetno delo", 1963, in Skopje. This is the first text to investigate a patient with kidney disease published in a textbook in R. Macedonia. In 1984 he published the textbook "Clinical Nephrology" printed by the University of the Ss. Cyril and Methodius University in Skopje. Prof. D. Hrisoho organized the First Scientific Meeting of Yugoslav Nephrologists with international participation, from 26 to 28 September 1977, in Struga, R. Macedonia. The meeting was attended by prominent nephrologists from the former Yugoslavia, the Balkans, Europe and the United States, among them: J.S. Cameron from UK, J.L. Funck-Brentano from France, M. Burg and P. Ivanovich from the USA, R. Kluthe from Germany and A. Puchlev from Bulgaria. The scientific meeting was the largest nephrology event until then organized in the former Yugoslavia. The meeting provided an exchange of experiences with world-renowned nephrologists. D. Hrisoho presented the paper Artificial intelligence in nephrology. The author tried to apply bio-cybernetics in nephrology. Prof. D. Hrisoho was Vice Dean of the Medical Faculty in Skopje in the period 1963-1965 and Vice Rector of the University of the Ss. Cyril and Methodius University in Skopje in the period 1974-1975. Prof. Hrisoho was also active in socio-political organizations. For his medical, educational and scientific activities he received several awards and recognitions in the country and abroad. Thus, the work of Prof. D. Hrisoho was permanently embedded in the nephrology of R. Macedonia. [ABSTRACT FROM AUTHOR]

In 2002, a report from El Salvador described a high incidence of chronic kidney disease (CKD) of unknown cause, mostly in young males from specific coastal areas. Similar situations were observed along the Pacific Ocean coastline of other Central American countries and southern Mexico (Mesoamerica). This new form of CKD has been denominated Mesoamerican endemic nephropathy (MeN). The typical presentation of MeN is a young male from an endemic area with a family history of CKD, low eGFR, high serum creatinine, low level of albuminuria, hypokalemia, hyperuricemia, and urine urate crystals. Kidney biopsy demonstrating tubulointerstitial nephritis remains the gold standard for diagnosis but is available only for a minority. Commonly proposed causes include thermal stress/dehydration and/or exposure to environmental pollutants. However, likely, a third factor, which could be genetic or epigenetic, could contribute to the cause and development of the disease, along with social determinants. Currently, preventive measures focus on minimizing workers exposure to thermal stress/dehydration. There are many research opportunities and priorities should include clinical trials to evaluate the efficacy and safety of the current treatment protocols, along with etiological and genetic studies, and the development of kidney disease data systems. Although there is scant and controversial literature with regard  s  to the etiology, diagnosis and management of the disease, our aim is to provide the reader a vision of the disease based on our experience. [ABSTRACT FROM AUTHOR]

There have been several global epidemics of chronic kidney disease of unknown etiology (CKDu). Some, such as Itai-Itai disease in Japan and Balkan endemic nephropathy, have been explained, whereas the etiology of others remains unclear. In countries such as Sri Lanka, El Salvador, Nicaragua, and India, CKDu is a major public health problem and causes significant morbidity and mortality. Despite their geographical separation, however, there are striking similarities between these endemic nephropathies. Young male agricultural workers who perform strenuous labor in extreme conditions are the worst affected. Patients remain asymptomatic until end-stage renal failure. Biomarkers of tubular injury are raised, and kidney biopsy shows chronic interstitial nephritis with associated tubular atrophy. In many of these places access to dialysis and transplantation is limited, leaving few treatment options. In this review we briefly describe the major historic endemic nephropathies. We then summarize the epidemiology, clinical features, histology and clinical course of CKDu in Mesoamerica, Sri Lanka, India, Egypt, and Tunisia. We draw comparisons between the proposed etiologies and supporting research. Recognition of the similarities may reinforce the international drive to establish causality and to effect prevention.

Introduction: Chronic kidney disease (CKD) is a significant public health problem and it is not possible to precisely predict its progression to terminal renal failure. According to current guidelines, CKD stages are classified based on the estimated glomerularfiltration rate (eGFR) and albuminuria. Aims of this study were to determine the reliability of predictive equation in estimation of CKD prevalence in Croatian areas with endemic nephropathy (EN), compare the results with non-endemic areas, and to determine if the prevalence of CKD stages 3-5 was increased in subjects with EN. Materials and methods: A total of 1573 inhabitants of the Croatian Posavina rural area from 6 endemic and 3 non-endemic villages were enrolled. Participants were classified according to the modified criteria of the World Health Organization for EN. Estimated GFR was calculated using Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI). Results: The results showed a very high CKD prevalence in the Croatian rural area (19%). CKD prevalence was significantly higher in EN then in non EN villages with the lowest eGFR value in diseased subgroup. Conclusions: eGFR correlated significantly with the diagnosis of EN. Kidney function assessment using CKD-EPI predictive equation proved to be a good marker in differentiating the study subgroups, remained as one of the diagnostic criteria for EN. [ABSTRACT FROM AUTHOR]

Background: Endemic nephropathy (EN) and associated urothelial cell cancers (UUC) are an environmental form of aristolochic acid nephropathy where the most probable rout of ingestion of aristolochic acid (AA) was made by bread contaminated with AA, leading to chronic dietary intoxication. Clinical courses of three members of the same family, similarly exposed to toxin, who exhibited different clinical courses of the disease are presented. Methods: Questionnaires on AA exposure were taken. Tissue samples were obtained during therapeutic nephrouretectomies. Histopathology, immunohistochemical detection of p53, p53 mutation screening in tumor DNA and analysis on the presence of aristolactam (AL)-DNA adducts were performed. Results: Case 1 had UUC with typical EN histopathological signs, whereas Case 2 had bilateral UUCs with typical EN histopathological signs. In contrast, the patient in Case 3 initially showed renal insufficiency, complicated afterwards by right UUC, and later on by left UUC with histopathological end-stage chronic changes but without typical EN changes. AA-DNA adducts and specific p53 mutational spectra (A:T→ T:A transversion) were found in tissues of cases 1 and 2. Conclusion: Diverse clinical courses seem to be related not to differences in exposure but to differences in metabolic activation or detoxification of AA and/or DNA repair resulting from different genetic polymorphisms.

Ochratoxin A (OTA) is a mycotoxin with nephrotoxic, genotoxic and carcinogenic properties produced by Penicillium and Aspergillus moulds under different climatic conditions. Humans and animals are exposed to this compound mainly via ingestion of contaminated food. In Croatia, research on mycotoxins focused on OTA when the mycotoxin theory of endemic nephropathy (EN) was postulated. Ochratoxin A was more frequent and at higher concentration in foods from EN than those from the control regions. Subsequently, OTA concentrations were determined in some commodities intended for human consumption such as maize, wheat, beans and wine. Samples from all parts of Croatia were analyzed and OTA was found in all types of commodities. It was frequently found together with other mycotoxins (fumonisin B1, fumonisin B2 and zearalenone). In general, OTA concentration in foods from Croatia is low, but the frequency of positive samples shows considerable variations from year to year depending also on sampling location. Although low levels of OTA were found in a large proportion of analyzed food samples, its persistent co-occurrence with other significant mycotoxins should raise serious public health concerns as there interactions may be synergistic or additive in causing toxicity in humans and animals. There is need to establish control measures through which such contaminations in foods can be managed.

Despite many hypotheses that have been challenged, the etiology of endemic nephropathy (EN) is still unknown. At present, the implications of aristolochic acid (AA) and mycotoxins (ochratoxin A—OTA and citrinin—CIT) are under debate. AA-theory is based on renal pathohistological similarities between Chinese herbs nephropathy (CHN) and EN, findings of AA-DNA adducts in EN and in patients with urinary tract tumors (UTT), as well as the domination of A:T→T:A transversions in the p53 mutational spectrum of UTT patients, which corresponds with findings of such mutations in AA-treated rats. However, exposure pathways of EN residents to AA are unclear. Experimental studies attempting to deduce whether nephrotoxins OTA and CIT appear at higher frequencies or levels (or both) in the food and blood or urine of EN residents support the mycotoxin theory. Also, some molecular studies revealed the presence of OTA-DNA adducts in the renal tissue of EN and UTT patients. In this review, data supporting or arguing against AA and mycotoxin theory are presented and discussed.

Introduction. Balkan endemic nephropathy (BEN) is a familial chronic progressive tubulointerstitial disease of unknown aetiology that occurs with high prevalence in endemic rural environments of Serbia, Bosnia and Herzegovina, Croatia, Bulgaria and Romania. It has been documented only in adults. Objective. The aim of this study was to examine clinical markers of BEN in children and adolescent offspring of BEN patients. Methods. Prospective clinical trial involved two groups of children and adolescents: I consisted of 30 offspring of BEN patients and II of 29 offspring of non-BEN dialysis patients, both of them living in the same South Morava region of Serbia. All of them were healthy at the time of the investigation, not receiving any drugs. The study included personal and family history, physical examination, comprehensive laboratory analyses and renal ultrasound. Blood pressure (BP) was determined by using casual BP and 24 h ABPM in subjects older than 5 years. Urinary proteins were investigated by analysing microalbumin, alfa 1 microglobulin, beta 2 microglobulin and SDS-PAGE electrophoresis. GFR was measured by estimated creatinine clearance and by serum Cystatin C concentrations. Results. There were no statistically significant differences in age, gender, history of urinary tract infections or functional voiding disorders between these two groups. All of the studied subjects had normal BP and GFR. Renal ultrasound was abnormal only in BEN offspring (6.66%) as well as increased urine concentrations of microalbumin (3.3%), alpha 1 microglobulin (10%) and beta 2 microglobulin (13.3%) while low molecular protein (

Mutational signatures associated with specific forms of DNA damage have been identified in several forms of human cancer. Such signatures provide information regarding mechanisms of tumor induction which, in turn, can reduce exposure to carcinogens by shaping public health policy. Using a molecular epidemiologic approach that takes advantage of recent advances in genome sequencing while applying sensitive and specific analytical methods to characterize DNA damage, it has become increasingly possible to establish causative linkages between certain environmental mutagens and disease risk. In this perspective, we use aristolochic acid, a human carcinogen and nephrotoxin found in Aristolochia herbs, to illustrate the power and effectiveness of this multidisciplinary approach. The genome-wide mutational signature for this toxin, detected initially in cancers of the upper urinary tract, has subsequently been associated with cancers of the liver and kidney. These findings have significant implications for global public health, especially in China, where millions of individuals have used Aristolochia herbal remedies as part of traditional Chinese medicine and, thus, are at risk of developing aristolochic acid nephropathy and/or upper urinary tract carcinomas. The studies reported here set the stage for research into prevention and early detection, both of which will be required to manage a potentially devastating global disease. [ABSTRACT FROM AUTHOR]

Up to now, detailed investigation of tubular function in patients with endemic nephropathy have been performed in the relatively small number of patients who have already been in chronic renal failure /3,4,5,9,15/. That is why we started this work with the aim to determine renal function of the patients suffering by endemic nephropathy in different stages of the disease, especially in the early stage of the disease. The study included 119 patients with endemic nephropathy who were grouped according to creatinine clearance values into four groups (Table 1). The first group covered the patients with normal crearinine clearance values, and other three covered the patients who were in the different stages of renal failure. The diagnosis of endemic nephropathy was established according to criteria given by Danilovic /7/ and Velimirovic /8/ after ruling out the known renal diseases. The results of clinical and laboratory examinations were processed by appropriate epidemiological and statistical techniques. The results proved that there was no significant difference between sexes of our patients (p>0,05). Objective examination reveals characteristic tan pale yellow with copperish glow on the cheeks, in 15,48% of our patients in the early stage of the disease, which is in accordance with the results of Velimirovic/8/. Among nephropathy patients 13% of them had kidney smaller than normal measured by sonography, and even 51% measured by static scintigraphy, in the early phase of the disease (Table 4, Table 5). The earlier works /11,12/ mainly supported that kidneys get smaller during renal insufficiency, and in the early phase of the disease kidneys have a normal size, whereas the later works indicated that even the patients with normal glomerular filtration have smaller kidneys/13,14,15,16/. The laboratory findings and urine analysis of this disease suggested absens of biochemical indicators of inflammation in endemic nephropathy patients (Table 2, Table 3), which is in accordance with the previous in investigations. We noticed correlation between ceatinine clearance values and values of serum beta 2 microglobulin (r==,56; p==,0002; Figure 1). It has been documented that with decreased of creatinine clearance values serum values of beta 2 microglobulin increased, in chronic renal failure /22/. Quantitative measuring of proteinuria shows values less than 1,0g/l in all examined patients. Proteinuria of tubular type has been described in endemic nephropathy/5,8,13,16/. Beta 2 microglobulinuria have been registered at 10,97% patients with normal creatinine clearance values (Table 7). Increased urinry contrecation of beta 2 microglobulin is generally accepted as an important feature of endemic nephropathy /19,20,21/. Glicosuria increased with the progression of the disease. Urine osmolallity of endemic nephropathy patients decreased with the progression of chronic renal failure (Table 6). 65,46% of the investigated patients of the first group, who were in the clinically early phase of the disease, had decreased urine osmolallity (measuring by coefficient of osmolallity U osm/Posm). The tubular reabsorbtion of the phosphate decreased with the progression of chronic renal failure and that correlation was statistically significant r

Aristolochic acid (AA) is a potent dietary cytotoxin and carcinogen, and an established etiological agent underlying severe human nephropathies and associated upper urinary tract urothelial cancers, collectively designated aristolochic acid nephropathy (AAN). Its genome-wide mutational signature, marked by predominant A:T > T:A transversions occurring in the 5′-CpApG-3′ trinucleotide context and enriched on the nontranscribed gene strand, has been identified in human upper urinary tract urothelial carcinomas from East Asian patients and in experimental systems. Here we report a whole-exome sequencing screen performed on DNA from formalin-fixed, paraffin-embedded renal cell carcinomas (RCC) arising in chronic renal disease patients from a Balkan endemic nephropathy (EN) region. In the EN regions, the disease results from the consumption of bread made from wheat contaminated by seeds of Aristolochia clematitis, an AA-containing plant. In five of eight (62.5%) tested RCC tumor specimens, we observed the characteristic global mutational signature consistent with the mutagenic effects of AA. This signature was absent in the control RCC samples obtained from patients from a nonendemic, metropolitan region. By identifying a new tumor type associated with the AA-driven genome-wide mutagenic process in the context of renal disease, our results suggest new epidemiological and public health implications for the RCC incidence worldwide, particularly for the high-risk regions with unregulated use of AA-containing traditional herbal medicines. [ABSTRACT FROM AUTHOR]

Mesoamerican endemic nephropathy (MeN) is a type of chronic kidney disease (CKD) of uncertain etiology that occurs along the Pacific coast of the southern part of Mexico and Central America. During the past 20 years MeN has become a leading cause of death in the region, clamming close to 50,000 lives, with 40% of these deaths occurring in young people. The cause remains unknown, but most researchers believe in a multifactorial etiology that includes social determinants of poverty. Existing evidence suggests that subclinical kidney injury begins early in life and leads to a higher than expected prevalence of CKD among children in Central America. Access to health services in the region, specifically kidney replacement therapy, remains limited. We proposed a strategy to address the perceived needs and urge coordinated efforts of governments, academic organizations, and international bodies to develop a comprehensive plan of action to mitigate this situation among the vulnerable and economically disadvantaged population. [Display omitted] [ABSTRACT FROM AUTHOR]

Copyright of Collegium Antropologicum is the property of Croatian Anthropological Society and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Diagnosis of endemic nephropathy (EN) is based on the combination of several clinical and laboratory criteria. Despite extensive research no specific diagnostic biomarker for EN has yet been identified. The aim of the study was to evaluate the diagnostic significance of the variables previously proposed as diagnostic criteria, but also new ones. After an extended questionnaire, the clinical and laboratory examination population in EN villages was classified according to the modified WHO criteria. The urinary active form of TGF-β was measured with a bioassay using a cell line which expresses luciferase activity. In the study we used ROC analysis to examine the predictive value of the tested variables. In the study there was no difference in haemoglobin level between the study subgroups. Leucine aminopeptidase (LAP) in urine and active urinary TGF-β levels were increased in the EN diseased group when compared to other subgroups, but they did not fulfil the statistical criteria needed for differentiating a diseased form from other study subgroups. Both kidney length and parenchima thickness, alfa1-microglobulinuria, and kidney function assessed by MDRD formula were the variables that differentiated the study subgroups well. Based on our results the cut-off value of alfa1microglobulin for screening should be 23.5 mg/g creatinine instead of 15 mg/g creatinine in the present criteria, and for making a diagnosis of EN 31,5 mg/g creatinine. Persons with a positive family history for EN had a 5.8 times greater risk of developing EN when compared to a negative one. Taken together, the abovementioned variables should be implemented in new uniform diagnostic criteria for EN. [ABSTRACT FROM AUTHOR]

Endemic nephropathy is a syndrome that comprises two entities: chronic interstitial nephropathy and urothelial cell cancers predominantly of the upper urinary tract. The etiological agent for the disease is aristolochic acid, a compound found in the plants of Aristolochia spp. The development of urothelial cancers is characterized by the formation of aristolactam DNA adducts leading to mutations, predominantly A: T- > T: A transversions. In order to comprehensively understand the gene regulation programs in upper urothelial cancers we performed integrated miRNA and mRNA expression profiling of paired tumours and unaffected urothelium samples. The obtained data will help us to understand the carcinogenesis caused by aristolochic acid and might be the source for the design of a diagnostic biomarker. [ABSTRACT FROM AUTHOR]

Endemic nephropathy (EN) is a chronic tubulointerstitial nephropathy with an early insidious and slow development into terminal renal failure. Proteomics is the systematic study of a proteome, which is the total protein content of a cell, organism or body fluids. Application of proteomic technologies in nephrology has enabled more detailed analyses of protein functions and examined their importance in various physiological and pathological states. Biomarkers with high specificity and sensitivity to early diagnosis are needed for a better understanding of the mechanisms of EN development and its consequences. Urine beta2-microglobulin (B2M) was mainly used as a tubular marker of EN but recently alpha1-microglobulin (AMBP) was proposed for the diagnosis of EN. We studied the urine proteins of 360 patients with EN, diabetic nephropathy (DN) and acute kidney injury (AKI) and the healthy population using proteomic tools. Protein maps from the urine of patients with EN showed significant differences in comparison to the healthy subjects and patients with DN and AKI. Our study highlights six proteins in urine that were differentially excreted in the urine of EN patients compared with the other groups and have potential to be markers for EN prediction. In one of our studies, using routine biomarkers, we investigated the potential of urine B2M, AMBP, albumin and total protein as diagnostic markers for EN, in comparison to glomerulonephritis, nephrosclerosis and a healthy state. Modern proteomic technologies are still robust investigation tools, but can access a vast amount of information from one set of experiments in comparison to a classic diagnostic approach. [ABSTRACT FROM AUTHOR]

Copyright of Wiener Klinische Wochenschrift is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: Endemic nephropathy (EN) and associated urothelial cell cancers (UUC) are an environmental form of aristolochic acid nephropathy where the most probable rout of ingestion of aristolochic acid (AA) was made by bread contaminated with AA, leading to chronic dietary intoxication. Clinical courses of three members of the same family, similarly exposed to toxin, who exhibited different clinical courses of the disease are presented. Methods: Questionnaires on AA exposure were taken. Tissue samples were obtained during therapeutic nephrouretectomies. Histopathology, immunohistochemical detection of p53, p53 mutation screening in tumor DNA and analysis on the presence of aristolactam (AL)-DNA adducts were performed. Results: Case 1 had UUC with typical EN histopathological signs, whereas Case 2 had bilateral UUCs with typical EN histopathological signs. In contrast, the patient in Case 3 initially showed renal insufficiency, complicated afterwards by right UUC, and later on by left UUC with histopathological end-stage chronic changes but without typical EN changes. AA-DNA adducts and specific p53 mutational spectra (A:T→ T:A transversion) were found in tissues of cases 1 and 2. Conclusion: Diverse clinical courses seem to be related not to differences in exposure but to differences in metabolic activation or detoxification of AA and/or DNA repair resulting from different genetic polymorphisms. Copyright © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: Strong indications have been presented that dietary poisoning with aristolochic acids (AA) is responsible for Endemic Nephropathy (EN) and AA associated cancer of the upper urinary tract (UUTC). Our recent investigation showed drastic urinary proteome changes in AA treated mice. This study was designed to identify proteome changes associated with AA nephrotoxicity in experimental animal model. The DBA and C57BL mice, which differ in AA sensitivity, were exposed to AA for 4days. The strategy for urinary, plasma and kidney tissue proteome study of AA exposed and control mice integrated gel-based and in-solution tryptic digestion combined with LC-ESI-MS/MS. To maximize proteome coverage, plasma fractionation scheme was developed and MS compatible sequential tissue extraction procedure was established. Proteomic analyses of urinary, plasma and kidney tissue tryptic digests resulted in identification of several cytoskeletal proteins, as well as proteins involved in kidney development and inflammatory response, that are differentially expressed in both AA exposed and control mice. These proteins are consistent with renal pathogenesis of endotoxicity and cancer. This proteomic strategy could be effectively translated for unbiased discovery of potential biomarkers for EN and associated UUTC in humans. At the same time, these results highlight the significance of AA exposure with EN. This article is part of a Special Issue entitled: Integrated omics. [Copyright &y& Elsevier]

Background: Hypertension is not considered to be a characteristic of endemic nephropathy (EN). Recent observations suggested that it might be more prevalent than it was reported before. Aim: The aim of our study was to analyze prevalence, treatment and control of hypertension in a Croatian endemic area. Methods: In the present cross-sectional study, 1,602 farmers were enrolled, 1,246 from EN and 356 from control villages. Epidemiological and medical histories were taken and clinical and laboratory examinations performed for kidney function. Blood pressure was measured following the ESH/ESC guidelines. Results: The prevalence of hypertension in EN villages was higher than in control (50.8 vs. 46.5%, p = 0.005). There was no difference in overall treatment, control of all and treated hypertensives between the villages. In all villages, women were treated more than men (EN 41.6 vs. 28.4%, p < 0.001; control 46.4 vs. 27.3%, p < 0.001), but better control of treated was achieved in men (EN 24.7 vs. 17.4%, p = 0.002; control 29.6 vs. 15.5%, p = 0.002). Women had lower income and level of education than men (p < 0.01). Conclusion: Hypertension is highly prevalent in endemic villages. In all villages, men had better blood pressure control despite being treated less. This finding could be explained by poorer education and income in women. [ABSTRACT FROM AUTHOR]

Abstract: Endemic nephropathy (EN) is defined as a slow progressive renal tubulointestitial disease that mainly occurs in the restricted areas of the Balkan Peninsula. The complexity of the pathogenesis of EN makes its earlier diagnosis very difficult. Urine samples from healthy volunteers from EN regions, EN patients with proteinuria less than 150mg/L and EN patients with proteinuria more than 150mg/L, patients with acute kidney injury, patients with diabetic nephropathy and healthy volunteers from Germany were collected. The urinary proteome analyses were performed using 2-D DIGE and mass spectrometry. The validation of biomarkers was investigated by two approaches (Western blot (WB) and dot blot) in successively increasing size – and partially overlapping – sample sets. Comparative and statistical analyses of the proteomics data from the different patient groups allowed the identification of six proteins (alpha-1-microglobulin, alpha-2-glycoprotein-1, beta-2-microglobulin, mannose-binding-lectin-2, protection-of-telomeres-protein-1, and superoxide-dismutase [Cu–Zn]), which were able to discriminate EN with low and high proteinuria from the other groups with high significance (p<0.05). The reliability of the identified proteins as EN marker was underlined with high statistical significance using WB analyses (sensitivity 66.7-98% and specificity 70-100%), whereas the dot blot analyses revealed a decrease in the sensitivity and specificity of these biomarkers. [Copyright &y& Elsevier]

Background: Tubular proteinuria and enzymuria are hallmarks of endemic nephropathy (EN). The role of I/D angiotensin convertase (ACE) gene polymorphism has not yet been elucidated in this peculiar chronic tubulointerstitial nephritis, and our aim was to investigate the role of this polymorphism in EN focusing on the urinary N-acetyl-β-D-glucosaminidase (NAG) excretion, a biomarker of proximal tubular damage. Methods:ACE genotype and allele frequencies were determined in 229 farmers (147 women and 82 men) from an endemic Croatian village. The farmers were stratified according to the WHO criteria into the following subgroups: those 'at risk' for EN (n = 37), 'suspected of having EN' (n = 57), and 'others' (n = 135). Results: There were 74 (32.3%) subjects homozygous for the D allele, 99 (43.2%) heterozygous (ID genotype) and 56 (24.4%) homozygous for the I allele. No differences in allele frequency were found between the established WHO subgroups (p > 0.05). In the whole group, DD subjects had significantly higher values of diastolic blood pressure (p = 0.003) and urinary NAG than subjects with ID and II genotype (5.5 ± 1.2 vs. 4.0 ± 3.0 vs. 3.8 ± 4.2, respectively; p = 0.023). The highest values of serum creatinine (p = 0.02), proteinuria (p = 0.03) and urinary NAG (6.0 ± 3.7 vs. 3.7 ± 2.1 vs. 3.0 ± 1.6, respectively; p = 0.008) were observed in those suspected of having EN group with the DD genotype. Conclusion:ACE gene polymorphism is not a risk factor for EN. However, it might influence the clinical course of EN, and increased excretion of NAG might be a prognostic marker of this chronic tubulointerstitial nephritis. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The most plausible theory of the aetiology of endemic nephropathy links it with exposure to nephrotoxic mycotoxin ochratoxin A (OTA). In this study, the concentration of OTA and sphinganine/sphingosine (Sa/So) ratio, the biomarker of another nephrotoxic mycotoxin fumonisin B1 exposure, were analysed in 45 human urine samples collected in the endemic village of Kaniža in Croatia and in 18 samples from control village. Samples were collected twice from the same persons in 2000 and 2005. In both years the frequency of OTA-positive samples was higher in Kaniža (43 % and 18 %, respectively) than in the control village (28 % and 6 %, respectively). OTA concentrations in samples collected in Kaniža were higher in 2000 than in 2005 (p<0.005). Although in both years Sa/So ratio was higher in Kaniža, the difference from the control group was not statistically significant. No control sample contained OTA and had the Sa/So ratio >1 at the same time, while in Kaniža four such samples were collected in 2000 and one in 2005. [ABSTRACT FROM AUTHOR]

The aim of this paper was to assess relationship between possible endemic nephropathy (EN) markers visually by the CoPlot methodology, and to illustrate this promising data analysis approach. From 912 screened persons in 3 Croatian endemic villages, 25 persons were diagnosed as confirmed EN patients, 371 as non-EN, and the remainder were classified as suspected of having EN, or at risk. Data on 25 confirmed EN patients were matched with appropriate non-EN examinees. All records with missing data were excluded, resulting in 35 subjects with complete data on the 13 key EN variables for CoPlot mapping. CoPlot solution met the accepted goodness of fit measure thresholds. Result showed relationship between EN markers, identifying some nearly duplicated variables, and possible outliers needing some subsequent analysis. [ABSTRACT FROM AUTHOR]

Abstract: The activation of protooncogenes and inactivation of tumor suppressor genes are considered to be the main molecular events in the multistep process of carcinogenesis. Mutations of the TP53 tumor suppressor gene have been found in nearly all tumor types and are estimated to contribute to more than 50% of all cancers. Most mutations lead to the synthesis of highly stable, inactive proteins that accumulate in the nucleus of cancer cells. Among the 393 codons of the human p53 gene, 222 are targets of 698 different types of mutations. Alterations of codons 175, 248, 273 and 282 correspond to 19% of all mutations and are considered general hot spot mutations. Dietary exposure to aristolochic acid (AA), an established nephrotoxin and human carcinogen found in all Aristolochia species was shown to be the causative agent of aristolochic acid nephropathy (previously called Chinese herbs nephropathy). This syndrome is characterized by proximal tubular damage, renal interstitial fibrosis, slow progression to the end stage renal disease and a high prevalence of upper urinary tract urothelial carcinoma (otherwise a highly unusual location). AA preferentially binds to purines in DNA and is associated with a high frequency of A→T transversions in the p53 gene. Rats treated with AA develop A:T→T:A mutations in codon 61. The pathological and clinical features of endemic (Balkan) nephropathy closely resemble those associated with aristolochic acid nephropathy except for the slower progression to end stage renal disease and longer cumulative period before the appearance of urothelial cancer. Recently, we reported the presence of AA-DNA adducts in renal cortex and A→T p53 mutations in tumor tissue of patients from Croatia and Bosnia with endemic nephropathy. These data support the hypothesis that dietary exposure to AA is a major risk factor for endemic (Balkan) nephropathy. [Copyright &y& Elsevier]

Abstract: Various reports suggest that chronic dietary exposure to ochratoxin A (OTA), a mycotoxin frequently detected in various food items may be linked to the pathogenesis of endemic nephropathy, a chronic tubulointerstitial kidney disease which occurs in geographically limited areas of the Balkan region. OTA is a potent nephrotoxin and renal carcinogen. However, the pathological lesions observed in kidneys of rats treated with OTA appear be rather different from the clinical and pathological characteristics of endemic nephropathy. Moreover, increasing evidence suggests that OTA does not bind to DNA but induces tumors by an epigenetic, thresholded mechanism. This implies that there is a dose below which no adverse health effects are expected to occur. Based on food consumption data and OTA serum concentrations, it appears that human exposure – even in areas with relatively high dietary exposure to OTA such as endemic villages – is several orders of magnitude below doses known to cause nephrotoxicity and tumor formation in laboratory animals. While it is undoubtedly important to encourage prevention of food contamination by OTA and other mycotoxins, these observations suggest that OTA is not likely to be an etiological factor involved in BEN and indicate a need to search for new clues for the etiology of this endemic kidney disease. [Copyright &y& Elsevier]

Ochratoxin A (OTA) is an ubiquitous nephrotoxic and carcinogenic mycotoxin considered to be involved in the aetiology of Balkan endemic nephropathy (BEN). The occurrence of this human fatal disease that appears in regions of Bosnia and Herzegovina, Bulgaria, Croatia, Rumania, and Serbia and Monte Negro correlates with very high incidence of otherwise rare urothelial tumours of the renal pelvis and ureters. Although OTA was found more frequently and/or in higher concentration in food and blood of inhabitants in regions with BEN than in other regions, the involvement of OTA in the development of BEN is still open. Patients with chronic renal insufficiency treated with dialysis have higher blood OTA concentrations than healthy persons, and OTA concentration does not decrease with such treatment. [ABSTRACT FROM AUTHOR]

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