Ochratoxin A: 50 Years of Research.

Since ochratoxin A (OTA) was discovered, it has been ubiquitous as a natural contaminant of moldy food and feed. The multiple toxic effects of OTA are a real threat for human beings and animal health. For example, OTA can cause porcine nephropathy but can also damage poultries. Humans exposed to OTA can develop (notably by inhalation in the development of acute renal failure within 24 h) a range of chronic disorders such as upper urothelial carcinoma. OTA plays the main role in the pathogenesis of some renal diseases including Balkan endemic nephropathy, kidney tumors occurring in certain endemic regions of the Balkan Peninsula, and chronic interstitial nephropathy occurring in Northern African countries and likely in other parts of the world. OTA leads to DNA adduct formation, which is known for its genotoxicity and carcinogenicity. The present article discusses how renal carcinogenicity and nephrotoxicity cause both oxidative stress and direct genotoxicity. Careful analyses of the data show that OTA carcinogenic effects are due to combined direct and indirect mechanisms (e.g., genotoxicity, oxidative stress, epigenetic factors). Altogether this provides strong evidence that OTA carcinogenicity can also occur in humans.

A historical overview of Balkan Endemic Nephropathy (BEN) in relation to published hypotheses.

Balkan Endemic Nephropathy occurs with a high rate of prevalence in Serbia, Bulgaria, Romania, Bosnia and Herzegovina, and Croatia. The first cases described in Bulgaria, Serbia and Romania date to the late 1950s and early 1960s. BEN has been characterized to date as a chronic, slowly progressive familial tubular interstitial renal disease of unknown aetiology. The disease is characterized by its endemic nature, long incubation period, the familial clustering of the disease, and a exceptionally high incidence of upper urothelial tumour associated with BEN. To date several hypotheses have presented some findings that could be relevant to the etiology of BEN, but only one of them, chronic poisoning with Aristolochic acids, has provided convincing evidence related to BEN etiology and its clinical characteristics.

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.

The first clinical description of Balkan endemic nephropathy (1956) and its validity 35 years later.

A high prevalence of renal disease in Vratza, a district in north-west Bulgaria, was studied in 1950-54 by Tanchev at the district hospital. A particular unknown renal condition was described at local meetings in 1953 and was referred to as 'endemic Vratza nephritis' in 1955. The first clinical description of this new nosological entity, published by Tanchev and colleagues in 1956, was based on 664 patients hospitalized for renal disease. Of 296 with chronic nephritis, 17 died in hospital and 103 died a few days later at home, all with uraemia, to give a total of 40.5%. Peasants formed the majority of the patients (85.7%), and 4-43 came from only 16 villages and 1-3 from 36 villages; none came from the remaining 21 villages in the district. Clusters of patients were thus noted in villages, families and even houses. The patients had the following common characteristics: from endemic areas; other renal ailments in the family; copper-yellow skin and orange palms and soles; normochromic anaemia; absence of acute onset, considerable albuminuria, hypertension and oedema; no compensatory polyuria; azotaemia progressing insidiously to fatal uraemia; 83.5% died within one year of the appearance of symptoms. After similar ailments were described in Yugoslavia in 1957 and Romania in 1961, the condition became known as Balkan endemic nephropathy. The etiology of this disease remains unknown, and no treatment is available, although haemodialysis and kidney transplants have prolonged patients' survival.

[Additional information on the history of Balkan endemic nephropathy]. / Dopulnitelni svedeniia za istoriia na balkanskta endemichna nefropatiia.

The paper presents additional information to the bibliographic check up in the two papers of Asst. Prof. Dimitrov, published in the periodical "Vutreshni bolesti" in 1982 as regards the history of Balkan endemic nephropathy, being of importance for the early history of the disease. Some of the data not accurately cited in the two papers of Asst. Prof. Dimitrov are corrected. Critical notes are also presented about the erroneous interpretation of some of the early written scientific facts.