Balkan nephropathy

Ochratoxin, citrinin Contaminant (mycotoxin) Produced by Penicillium strains nephropathy (endemic Balkan nephropathy)... 

Ochratoxin A. ochraceus P niger A. alliaceus A. terreus P viridicatum apoptosis nephrotoxin teratogen Balkan nephropathy, renal tumors... 

Another important and widespread fungal toxin is ochratoxin, which is also found in cereals and, to a lesser extent, in coffee and cocoa beans. The toxin Ochratoxin A is the most commonly found and is produced by the Aspergillus t5rpe of fungus. Exposure occurs in many countries in Europe and affects farm animals as well as humans. The major toxic effect in both humans and animals is kidney damage and cancer of the kidney. The available epidemiological evidence indicates that the disease called Balkan nephropathy is associated with consumption of food contaminated with ochratoxin, and the toxin has been detected in the blood of people living... 

Stefanovic V, Polenakovic MH. Balkan nephropathy. Kidney disease beyond the Balkans Am J Nephrol 1991 11 1-11 Mengs U. Acute toxicity of aristolochic acid in rodents. Arch Toxicol 1987 59 328-331... 

During initial Balkan nephropathy research, patients were frequently in their thirties [14], and it was widely accepted that azotemia usually affects the age group 30-50 [3]. Later an apparent shift towards the older ages occurred, with most identified patients being above the age of 60 [9]. The diagnosis of clinical forms before the age of 20 was rare and never independently confirmed. Despite occasional statements on laboratory and bioptic abnormahties in the first decade of life among clinically healthy children from endemic areas, no follow up study ever showed that these children developed subsequently kidney disorder. 

The initial description of Balkan nephropathy emanated from Bulgaria [15,16] and Serbia [17-19]. By 1957, the disease was recognized in Bosnia and Croatia and by 1958 in Romania [20]. 

Between 1/3 and 1/2 of patients with Balkan nephropathy develop urothelial tumors [21]. An exceptionally high frequency of these tumors was also observed in the general population of endemic regions [22]. When initially studied, the attributive risk of developing upper urothehal fumors in inhabitants of endemic foci amounted to several dozen or even to as much as 100-200. 

The most elaborate and, seemingly consistent, hypotheses regarding etiology initially came from proponents of heredify as an explanation of fhe disease occurrence. These authors assumed that the risk of developing the disease was restricted only to specific, ethnically distinct, population groups, irrespectively of their place of birth and residence history. Wider acceptance of these hypotheses was hampered by the different perception of descriptive epidemiology of Balkan nephropathy by a majority of researchers on the topic. 

There is no evidence supporting an immunological mechanism in Balkan nephropathy. 

Bacteria received particular attention in initial stages of the Balkan nephropathy research but their possible etiological importance has been unanimously considered as ruled out [2]. Protozoa have never attracted any attention. 

Association of ochratoxin A with chronic interstitial nephropathy in Tunisia [41] and its relation to renal tumors [42] provides additional support for the idea of the etiological role of this mycotoxin. Other fungal toxins, as zerealenone, citrinin [43] and aflatoxin were also isolated in endemic foci. Experimental models suggested that a combination of mycotoxins, rather than a single one, might be involved in the etiology of Balkan nephropathy [44]. 

Aristolochic acid and its salts, originated from a weed, Aristolochia clematitis, have toxic and carcinogenic effects to the kidneys and urothelium [45], respectively. Ivic [46] postulated that this plant may be a cause of Balkan nephropathy, but failed to provide convincing evidence from field surveys. Evidence that A. clematitis played a central role in the etiology of Chinese herb nephropathy [47-49], a condition similar to Balkan nephropathy, initiated a second look at this previously abandoned hypothesis and it gained a lot of weight by recent data on the association between DNA adduct formation derived from AA, mutation pattern and tumour development in BEN [50] (see also chapter 33). 

Effects of non-occupational exposure to cadmium [51], itai-itai disease in particular [52, 53], were occasionally compared with kidney damage seen in Balkan nephropathy patients. In spite of some resembhng features, the idea of a common etiology between cadmium nephropathy (including itai-itai disease) and Balkan nephropathy was refuted [52, 54]. 

As for non-metals, there were attempts to relate Balkan nephropathy to silicon [59-62]. However, when affected and non-affected households were compared, there was even an inverse relationship between the silica content and endemicity. On one occasion, small differences in silica content happened to reach the level of statistical significance but the association was explained as a result of confounding variables [63]. 

Based on chronological data, it is clear that no pesticides, fertilizers or chemicals introduced during the last few decades may be blamed for the occurrence of Balkan nephropathy. Except for exposure to agricultural activities, no occupation, habit (e.g., smoking, alcohol consumption), or hobby (e.g., hunting, fishing) might have been shown to precede the disease onset. 

Genetic factors may play a role in different individual risk of developing Balkan nephropathy, upper urothelial tumors, both diseases or none of them [68]. However, epidemiological data indicate that one or more external, environmental factors are crucial for the occurrence of both Balkan nephropathy and excessive frequency of these tumors in endemic areas. 

As for inanimate environment, there is no chemical element that has been consistently detected in higher concentrations in biological material of Balkan nephropathy patients and/or their environment, as compared to the controls. However, though unlikely, insufficiency of an essential element has not been completely ruled out. Speculations on a combination of vaguely defined environmental factors have never been substantiated by facts. 

Balkan nephropathy is non-destructive and noninflammatory tubulointerstitial renal disease [69]. The changes are non-specific and in the chronic, sclerotic phase they may be quite similar to changes observed in other chronic interstitial diseases such as analgesic nephropathy [70], vascular nephrosclerosis [69] cyclosporine-induced nephropathy [71], radiation nephritis [72,73] and aging [72], intoxication with silicate, cadmium, lead, uranium [74], mycotoxin ochratoxin... 

Before introduction of hemodialysis in the treatment of chronic renal patients, the kidneys of patients who died of Balkan nephropathy used to be the smallest seen at post mortem examinations, weighing 14.8-80 g each (Figure 2A) the difference between the left and right kidneys being small (5-20 g) [74, 76-78]. Surface of the kidneys is smooth, occasionally wavy but never granulated or roughly nodular. The section shows markedly narrowed cortex, pyramid and Bertin s columns are fairly well preserved, and corticomedular border is well differentiated. Papillary necrosis of the pyramids has not been found. 

The striking atrophic process observed in Balkan nephropathy suggests that apoptosis may play a role in this disease. In this context it is of interest that Savin et al. observed an increased apoptosis to proliferahon ratio at the level of the tubuli [80]. 

Despite these findings, some authors described Balkan nephropathy as a form of glomerulonephritis [81, 86]. However, the lack of rehable evidence supporting glomerulonephritis has lead to it being discarded [73, 77] and abandoned even by its advocates [87]. 

Optic microscopic, immunofiuorescent and electron microscopic studies of renal biopsies in children aged 5-15 from affected families in endemic regions failed to detect any Balkan nephropathy related changes [79]. 

It is generally agreed that the morphological changes of Balkan nephropathy are not specific and correspond to non-destructive, non-inflammatory kidney disease accompanied by marked changes on the blood vessels in both early and late stages of the disease, interstitial, multifocal fibrous expansion and severe tubular atrophy mainly in the upper cortex [69, 72, 73, 79, 81]. 

Balkan nephropathy is a chronic tuhulointerstitial disease with occult, insidious onset, usually progressing slowly with no apparent signs of symptoms. After a long asymptomatic period, the disease is manifested as chronic renal failure. Less commonly hlunt lumbar pain or renal colic may develop or, occasionally, dysuric symptoms induced by urinary tract infechon. If hematuria exists, urothelial tumor should be suspected. In an advanced case polyuria and nocturia are present due to impaired concentrating ability of the kidneys. The disease is tolerated well and the patients preserve their working ability until advanced stages of renal failure [18, 76, 88, 89]. 

Objective examination reveals characteristic skin tan of Balkan nephropathy patients a pale yellow with copperish glow on the cheeks has been recognized since the augural reports on the disease [18, 88]. Besides, xantochromia of the palms and soles is also frequently observed. In the advanced phase of the disease physical examination detects signs of chronic renal failure [19]. 

Patients with Balkan nephropathy do not suffer from edema, and their blood pressure is usually described as normal [18,88-90]. Recently, several studies reported a higher prevalence of hypertension even in offspring of Balkan nephropathy famihes [91, 92, 93]. 

As Balkan nephropathy is characterized with slow asymptomatic course, most authors identify two main stages of the disease the first, asymptomatic (latent, subclinical) and second, manifest (symptomatic). The latter is usually subdivided into the stage without renal failure (early, compensated Balkan nephropathy, with no azotemia) and chronic renal failure (decompensated Balkan nephropathy, uremia) [19,88, 89]. 

An important feature of Balkan nephropathy is its association with a high incidence of tumors of the renal pelvis and ureters, but not urinary bladder tumors [22, 94,95]. However, the difference between the incidence of upper urothelial tumors in endemic and non-endemic regions diminished in the last decades. In the sixties and seventies the incidence of these tumors was reported to be several dozen times higher in endemic than in non-endemic regions, while in the last decades this difference almost disappeared [21, 22, 94, 96, 97]. 

Upper urothelial tumors of patients originating from the region with Balkan nephropathy differ from tumors identified in patients from other regions in their similar incidence in both sexes, bilateral occurrence, and more common association with chronic renal failure [95]. 

Appearance and urine color are unchanged in most patients with Balkan nephropathy. Urine sediment is usually scarce, while microhematuria or leukocyturia are usually associated with the occurrence of tumors or urinary tract infection [88, 89]. 

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