Comparative ultrastructural studies on endemic (Balkan) nephropathy and chicken embryo nephritis caused by infectious bronchitis virus. I. Endemic (Balkan) nephropathy.
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Cryptic serpentine divergence and substrate adaptation of Cardamine glauca in the Balkan Peninsula.
BACKGROUND AND AIMS: Serpentine soils represent one of the most challenging substrates for plant life due to skewed ratios of essential nutrients and toxic concentrations of metals. Plant adaptation to such conditions may lead to locally adapted edaphic ecotypes or, when reproductive barriers evolve, to distinct serpentine endemics. However, a third scenario may occur: cryptic edaphic divergence, where phenotypically similar lineages adapted to contrasting substrates exhibit deep genetic divergence. Here, we tested whether substrate-associated divergence reflects repeated serpentine adaptation or cryptic edaphic lineage divergence in Cardamine glauca (Brassicaceae) in Balkan peninsula - a hotspot of serpentine endemism in Europe. METHODS: We sampled and sequenced genomes of 43 individuals of C. glauca together with four individuals representing closely related taxa, C. plumieri and C. pancicii, from variable substrates across the Balkans. We combined phylogenomics, population genomic analyses of selection and a reciprocal transplant experiment to infer the most likely evolutionary scenario. KEY RESULTS: Phylogenomic analysis of 941 loci confirmed monophyly of C. glauca, including the local endemic C. pancicii, but revealed deep splits (∼2.2-3.2 Mya) between co-occurring serpentine and non-serpentine lineages. Population genomic analyses of replicated geographically proximate serpentine-non-serpentine population pairs demonstrated strong genome-wide differentiation and limited gene flow between edaphic types. Window-based analyses of local genomic divergence and tests for positive selection revealed candidate genes involved in ion transport, membrane transporter activity and metal homeostasis, consistent with the hypothesis of substrate-driven ecological adaptation. This was further supported by a significant substrate-of-origin fitness advantage in a reciprocal transplant experiment. CONCLUSIONS: Altogether, our results demonstrate that edaphic preferences may correspond with deep genetic divergence between similar-looking yet differently adapted lineages. The presence of cryptic edaphic lineages suggests that plant diversity may still be underestimated in genomically underexplored but edaphically diverse hotspots such as the Balkans.
Cardamine glauca↗
Balkan (endemic) nephropathy and a toxin-producing strain of Penicillium verrucosum var cyclopium: An experimental model in rats.
Cultures of an isolate of Penicillium verrucosum var. cyclopium, obtained from stored maize in an area of Balkan (endemic) nephropathy--Vratza, Bulgaria--has consistently induced renal tubular lesions when force-fed to rats for 20 days. The lesions, confined to the lower reaches of the proximal convoluted tublues (pars recta and junctional zone), closely resemble the tubular changes in patients with Balkan nephropathy. Preliminary evidence suggests that this nephrotoxin-producing strain of P. verrucosum var. cyclopium may be implicated in the aetiology of Balkan nephropathy.
Animals↗
Balkan (endemic) nephropathy and foodborn ochratoxin A: preliminary results of a survey of foodstuffs.
Ochratoxin A is a nephrotoxic fungal metabolite (mycotoxin) occurring in foodstuffs. The compound is causally associated with mycotoxic porcine nephropathy, a disease comparable with a human kidney disease, Balkan endemic nephropathy. A preliminary survey of home-produced foodstuffs in areas of Yugoslavia revealed that contamination with ochratoxin A is more frequent in an area where Balkan endemic nephropathy is prevalent (endemic area) than in area where this disease is absent. This indicates higher exposure to foodborn ochratoxin A in the endemic area. Thus further evidence is provided supporting the hypothesis that ochratoxin A is a disease determinant of Balkan endemic nephropathyk0
Food Analysis↗
Ochratoxin A contamination of foodstuffs in an area with Balkan (endemic) nephropathy.
Ochratoxin A is a nephrotoxic fungal metabolite (mycotoxin) occurring in foodstuffs. The compound is causally associated with mycotoxic porcine nephropathy, a disease comparable with a human kidney disease, Balkan (endemic) nephropathy. A survey of 768 samples of foodstuffs (cereals and bread), locally produced in an area of Yugoslavia where Balkan (endemic) nephropathy is prevalent, has revealed that ochratoxin A is constantly present in parts of foodstuffs. The mean frequency of ochratoxin A contamination of cereals in the study period was 8.7 per cent, but a pronounced annual variation was encountered, with frequencies of contamination up to 43 per cent. These contamination frequencies are higher than those reported elsewhere for foodstuffs for human consumption. Thus further evidence is provided to support the hypothesis that ochratoxin A might by a disease determinant of Balkan (endemic) nephropathy.
Adult↗
[Amino acid pattern in endemic (Balkan-)nephropathy (author's transl)].
Free amino acids were determined quantitatively in serum from the fasting blood of healthy children from families with patients with endemic (Balkan) nephropathy. A group of healthy children of the same age served as controls. Compared with the boys from healthy families the healthy boys from families with patients of endemic (Balkan) nephropathy had statistically significantly higher concentrations of the following amino acids: alanin, citrulline, isoleucine, leucine, ornithine, phenylalanine, proline and serine. The healthy girls from families with patients with endemic (Balkan) nephropathy had statistically significantly higher concentrations of citrulline, cystine, glycine, isoleucine, methionine, ornithine, phenylalanine, proline and serine than girls in the control group.
Adolescent↗
[Medical geographical map of Balkan endemic nephropathy in Vratsa District].
The author has studied the spread of the Balkan endemic nephropathy (BEN) according to the dispensary, clinical and post mortem data in the district of Vartza and established that the disease is met in 41 settlements of the district with a total population of 47,589. The average morbidity rate in the endemic villages is 35.9% of the population. In three villages it is over 200% in five--over 100--200% and four from 50--100%, in 25--from 2--50% and only in four villages under 2%. The author has elaborated a medico-geographical map on the base of the number of the settlements where patients with BEN are to be found. As seen from the map, the disease is met in settlements situated at the foot of the Balkan and its foothills: Vratza region of the Balkan and Veslez. It is interesting to be pointed out that certain settlements free of the disease are to be found among the endemic villages. The disease affects the village population. In the towns of Vratza and Mesdra, though situated in the center of the endemic region, no BEN patients have been found among the local population.
Adolescent↗
Evidence of a viral aetiology in endemic (Balkan) nephropathy.
Segemental and focal pathological changes were found in the glomeruli and tubules of postoperative renal-biopsy specimens from seven cases of clinically confirmed endemic (Balkan) nephropathy. In the glomeruli, there was mesangial reaction and segmental thickening of the basement membrane with subendothelial and membranous depositions. In the tubules there was spongiform degeneration and fusion of cells. In all the cells of the nephron numerous cytoplasmic vesicles containing free and budding particles (80-200 nm) were found. These particles had the characteristics of a coronarivus. Balkan nephropathy occurs almost exclusively in people who have been in close contact with pigs. Coronaviruses have been isolated from pigs, and it is suggested that a slow coronavirus infection causes endemic nephropathy in man.
Animals↗
Relation between endemic (Balkan) nephropathy and urinary-tract tumours.
Serum and urine beta 2-microglobulin concentrations were determined in 38-6% of the 869 inhabitants of a village in which both Balkan endemic nephropathy and papillary tumours of the urinary-tract epithelium are common. Over 23% of the "healthy" population had raised serum and/or urine beta 2-microglobulin. 5 of 6 patients with papillary tumours of the renal pelvis, without evidence of renal parenchymal involvement, and 13-4% of the "healthy" population had raised serum-beta 2-microglobulin. It is suggested that overproduction of beta 2-microglobulin, a light-chain-like immune globulin, by the tumour cells may result in a light-chain-like nephropathy--i.e., endemic Balkan nephropathy.
Adenocarcinoma↗
Urinary excretion of albumin and beta 2-microglobulin in a population from an area where Balkan nephropathy is endemic.
The urinary excretion of albumin and beta 2-microglobulin in a population of 294 persons, living in an area where Balkan nephropathy is endemic, has been studied. In fifty-six (about 19%) of the subjects the beta 2-microglobulin concentration was above the +2 SD level for a reference group of healthy individuals from non-endemic areas. Albumin elevation was found in forty-four (about 15%) of the cases. In twenty-one of the subjects the urinary concentration of both beta 2-microglobulin and albumin were increased, in sixteen of these cases the relationship between the two proteins was consistent with tubular proteinuria. An increased beta 2-microglobulin excretion is considered to be a sign of Balkan nephropathy. Radioimmunoassay of the protein is sensitive enough to detect tubular proteinuria at an early stage and is suggested as a suitable screening test for the disease.
Adolescent↗
[Balkan-nephropathy, a particular form of interstitial nephritis (author's transl)].
Because of epidemiological, clinical, pathomorphological, and etiological criteria the Balkan-nephropathy is suggested to be a particular form of chronic interstitial nephritis with super-imposed pyelonephritis in about 30 p.c. of the patients. A basic scheme illustrates the origin and the development of the endemia as well as etiology and clinical course of the disease. Another scheme shows pathogenesis and pathomorphogenesis of the nephritis. This analysis about the characteristics of the endemic Balkan-nephropathy allows for the clarification of the triad: endemic occurrance, familial susceptibility, and mosaik like morbidity. The following important aspects of the disease are given: rarely occuring hypertension, facultative leukuria, and bacteriuria, smooth nephrocirrhosis. Prophylactic and therapeutic prospects are given.
Adult↗
HLA system and Balkan endemic nephropathy (a collective study with the collaboration of all participants in the HLA workshop--Sofia 1976).
Balkan endemic nephropathy, a fatal family disease with unknown aetiology and pathogenesis is typical for three neighbouring regions in Bulgaria, Yugoslavia and Rumania. HLA typing of 180 patients from the endemic area in Bulgaria was done and the antigen frequencies were compared with 1264 healthy controls. An increased frequency (P less than 0.001) of the antigen HLA-B18 in the patients was demonstrated.
Bulgaria↗
Balkan (endemic) nephropathy.
The clinical and pathological features of Balkan (endemic) nephropathy are discussed and correlations of incidence with excess late summer and autumn rainfall outlined. Cultures of a strain of Penicillium verrucosum var. cyclopium isolated from maize collected in an endemic area were fed to rats and lesions were produced in the straight third segment of the proximal kidney tubules. Extensive degeneration and nuclear changes were seen and on prolonged feeding further nuclear enlargement (to greater than 6n) and the formation of multinucleate cells occurred. The relevance of these findings to the clinical disease in man, especially the occurrence of urinary tract tumours, and the evidence supporting mycotoxin involvement, are discussed.
Animals↗
Balkan nephritis. A synthetic view on 50 studied cases.
Epidemiological, clinical pathological investigations concerning Balkan nephritis (BN) have revealed some particular aspects which define this condition as a distinct nosologic entity. Its endemic familial character and its occurrence restricted to some limited geographic areas in Bulgaria, Yugoslavia and Romania, are highly unusual. BN leads to chronic impairment of the renal function which is, however, not constantly associated with edema and hypertension. The duration of the disease is prolonged; death takes place from uremia within five to ten years. Gross pathologic changes are consisting of severe bilateral atrophy of the kidneys, with structural changes suggesting a 'renal cirrhosis'. The etiology of the disease is obscure. Investigations carried out by means of electron microscopy and immunofluorescence tests are suggesting that the pathogenesis is rather complex. The role of a persistent tolerated or slow, latent virus infection in certain families, that of some toxic factors, and the implication of autoimmune mechanisms are to be considered.
Bulgaria↗
The Balkan endemic nephropathy and urinary tract tumors.
Topographical distribution of the Balkan endemic nephropathy and tumors of urinary organs was investigated in the most affected region -- Central Serbia (Yugoslavia). The data expose that there is an association of endemic nephropathy and tumors of the pelvis and ureters, but not of the bladder. Disagreement related to the kind and degree of correlation of endemic nephropathy and tumors of the urinary organs is explained by insufficient knowledge of the problem rather than by influence of different ecological factors.
Disease Reservoirs↗
[Case of an immigrant with Balkan endemic nefropathy].
The author describes a female patient with Balkan endemic nephropathy (BEN) born in a non-endemic village of Sofia district, who at the age of 23, after her marriage, emigrated to an endemic village of Vratza district and after living 38 years in that village, got sick and died. The case was confirmed pathohisto-morphologically. The case is a contribution to the clinical development of BEN and solves definitely the problem that emigrants suffer that disease after a long period living in an endemic settlement.
Bulgaria↗
Beta2-microglobulin excretion and autoimmune phenomena in endemic Balkan nephropathy.
Quantitative determinations of beta2-microglobulins were carried out in 335 urinary samples collected from 335 subjects living in villages with a high rate of morbidity and mortality from endemic Balkan nephropathy. Three months after the first determination of beta2-microglobulin excretion, blood and urine samples were obtained from 19 patients with high values and from 19 with normal values of beta2-microglobulins. The results of the biochemical and immunological investigations performed on these samples suggest that the tubular alteration is the first lesion. The autoimmune phenomena elicited by the tubular alteration may contribute, by an antigen-antibody complex disease mechanism, to the appearance of glomerular secondary lesions.
Antigen-Antibody Complex↗
beta2-Microglobulin in Balkan endemic nephropathy.
The results of low molecular weight (LMW) proteinuria test in urines of patients and suspect subjects in an endemic area of Balkan endemic nephropathy (BEN) in Yugoslavia are reported. An accordance between the positive LMW test and the clinical diagnosis of BEN has been found in more than 70%. The authors claim that LMW immunodiffusion test is a very useful procedure for detecting BEN and a great aid in the epidemiological work in the endemic field. The results of determining beta2-microglobuline (beta2m) in serums and urines by radioimmunoassay technique as well as counting of clearances of endogenous creatinine in healthy persons, "endangered" subjects in endemic area, and BEN patients without azotemia, with azotemia and uremia are reported. The group of 17 patients suffering of BEN without azotemia having slightly or more markedly lowered creatinine clearances showed higher serum and much higher urinary concentration of beta2m which are not in proportion with creatinine clearance. The results are interpreted so far as a consequence of the predominant tubular lesion in BEN. In groups of patients with azotemia and uremia no differences in beta2m handling have been found. The report has a preliminary character and requires further study.
Beta-Globulins↗