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      Isolation of a Coronavirus from Urinary Tract Tumours of Endemic Balkan Nephropathy Patients

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          Abstract

          Dear Sir, Endemic Balkan nephropathy (EBN) is a mysterious disease prevalent in recognised areas of three countries: former Yugoslavia, Rumania and Bulgaria. The endemic localities are found along the valleys of the rivers Danube, Sava and their tributaries. The patients are mainly rural people over 40 years old. The cardinal symptoms are progressive loss of kidney function without raised blood pressure leading to end-stage kidney failure. In up to 50% of EBN patients, tumours of the urinary tract appear [1]. It has been estimated that there have been more than 15,000 cases of EBN in the 3 countries. At present there are over 700 EBN patients on dialysis in Serbia alone. Toxins, including heavy metals and mycotoxins have been suggested as a cause. Evidence for the involvement of coronaviruses based on histological and ultrastructural studies has been published [2, 3]. However, it is only recently that a coronavirus was isolated from kidney biopsies [4]. The isolation of the virus (EBNV) and serological investigations suggest its involvement in the aetiology of EBN. This is further supported by the isolation of an identical coronavirus from urinary tract tumours and a metastatic lymph node. Tumour, kidney tissue and a metastatic lymph node were obtained at operations on 5 EBN patients from the endemic region of Doboj, Bosnia. A coronavirus was isolated from the kidneys as described previously [4]. The tumour tissue and the lymph node were stored at −20 °C. After thawing and the establishment of viable cell cultures they were co-cultivated with Vero cells. An agent was isolated from all five tumour specimens and significantly also from a patient's metastatic lymph node. Neutralisation and immunofluorescence tests indicated that the agent is a coronavirus identical to EBNV isolated from the kidneys of the same patients [4]. The virus could also be isolated in Vero cells from the supernatant of the tumour cell cultures as well as from the lymph node suspension cultures. In order to exclude cross-contamination, in a separate experiment EBNV hyperimmune serum was added to a primary tumour cell culture and incubated for several days. On removal of the medium, washing and re-incubation, the virus was repeatedly isolated in Vero cells. Some of the serological investigations are summarised in table 1 updating the one previously published [4]. It is seen that in neutralisation tests 87.7% of the EBN patients on dialysis were positive, while all 13 EBN patients with tumours of the urinary tract were positive. In the single positive case of a tumour without EBN, the patient has lived in an endemic locality. We have also confirmed that the tumours in situ and in culture were positive by immunofluorescence of the hyperimmune serum raised with EBNV [4]. The isolation of a coronavirus from a tumour is surprising. Coronaviruses have not been shown to be associated with tumours. The results presented here and those from a previous report reinforce the notion of a causal relationship between EBN and EBNV.

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          EVIDENCE OF A VIRAL ÆTIOLOGY IN ENDEMIC (BALKAN) NEPHROPATHY

          Segmental 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 coronavirus. 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.
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            Isolation of a Coronavirus from Kidney Biopsies of Endemic Balkan Nephropathy Patients

            Endemic Balkan nephropathy (EBN) is a kidney disease of unknown etiology limited to Bulgaria, Rumania and former Yugoslavia. Primary kidney tissue cultures were established as explants from tissue obtained at operations from 5 EBN patients with urinary tract tumors. Four out of the five biopsy specimens on extended culture incubation at 33°C yielded a coronavirus virus (EBNV) which was cytopathogenic for human fibroblast and Vero cells. In cells inoculated with EBNV, cytoplasmic immunofluorescence was found using antisera for human coronaviruses OC43 and 229E as well as the porcine transmissible gastroenteric virus and avian (chicken) bronchitis virus. In neutralization tests, EBNV failed to react with antisera to these viruses. Using hyperimmune serum raised with EBNV, positive cytoplasmic immunofluorescence was seen with cells infected with OC43, 229E, TGV and significantly with the kidney tissue of the biopsy specimens from the EBN patients. A screen for neutralizing antibody using the EBN virus revealed that 87.2% of EBN patients on dialysis were positive, also 74% of people from an endemic area were also positive, while only 13.5% from outside were positive. It is suggested that a coronavirus is involved in the etiology of the disease and that humans are an incidental host of a coronavirus zoonosis.
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              Author and article information

              Journal
              Nephron Clin Pract
              Nephron Clin Pract
              NEF
              Nephron. Clinical Practice
              S. Karger AG (Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.com )
              1660-8151
              1660-2110
              September 2000
              30 August 2000
              : 86
              : 1
              : 93-94
              Affiliations
              [1 ] aInstitute of Immunobiology and Virology 'Torlak', Belgrade, Yugoslavia
              [2 ] bDepartment of Urology, Doboj District Hospital, Doboj, Bosnia
              [3 ] cDepartment of Nephrology, Clinical Hospital Centre 'Zvezdara', Belgrade, Yugoslavia
              [4 ] dInstitute of Urology and Nephrology, Clinical Centre of Serbia, Belgrade, Yugoslavia
              [5 ] eBiology Section, Macedonian Academy of Arts and Science, Skopje, Macedonia
              Author notes
              * Dr. Brana Uzelac-Keserović, Institute of Immunobiology and Virology 'Torlak', Vojvode Stepe 458, 11221 Belgrade (Yugoslavia), Tel. +381 11 464 908, Fax +381 11 186 391, E-Mail abn@ 123456eunet.yu
              Article
              nef-0086-0093
              10.1159/000045720
              7179529
              10971161
              Copyright © 2000 by S. Karger AG, Basel

              This article is made available via the PMC Open Access Subset for unrestricted re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the COVID-19 pandemic or until permissions are revoked in writing. Upon expiration of these permissions, PMC is granted a perpetual license to make this article available via PMC and Europe PMC, consistent with existing copyright protections.

              Page count
              Tables: 1, Pages: 2
              Categories
              Letter to the Editor

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