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.

Endemic nephropathy (EN) is a renal disease of unknown etiology. In Croatia it occurs in the rural population in 14 villages located in the western part of Brodsko-Posavska county. This region also has an unusually high incidence of otherwise rare upper urothelial cancers. Between 1991 and 2002 the average general mortality for both sexes in the endemic region was 10.3 per thousand and the specific mortality for patients with EN was 0.65 per thousand (M 0.58/10((3)), F 0.72/10(3)). The average age of death of patients with EN was 69.2 years (M 67.7, F 70.3), which is similar to the life expectancy for the rest of the population in the county (67.8, M 64.4, F 71.8). This life expectancy is significantly higher than in the period 1957-1960 when the average age of EN-related death was 45.1 years. Between 1995 and 2002, in contrast to both Croatia as a whole and the respective county, the specific mortality with tumors of the pyelon and ureter in the endemic region was much higher in women than in men (9.020 and 4.697 per 100,000, respectively). The specific mortality of all patients with urothelial tumors was 14 times higher in the endemic region than in Brodsko-Posavska county and 55 times higher than in Croatia overall. The much higher specific urothelial-tumor mortality in women than in men (in contrast to the rest of the country) and the higher specific EN mortality indicate that the causative agent of the two nosological entities is the same.

HFRS is an endemic disease throughout Croatia. The incidence of HFRS varies in a cyclic fashion, with peaks occurring every couple of years, coinciding with peaks in vole populations. PUUV was shown to be dominant pathogen during the last HFRS outbreak in Croatia in 2002. We focused our research on two newly discovered localities (Okucani and Nova Gradiska) with a high number of reported HFRS cases and a significant increase in rodent population. PUUV infection was verified in 84.2% of patients at this region during the 2002 outbreak. Genetic analysis of wild-type (wt) PUUV strains was performed. Fifty seven bank voles Clethrionomys glareolus originating from PUUV-associated HFRS areas were screened for the presence of PUUV N antigen and 15 (26%) were found positive. Total RNA isolated from rodent lung tissues was reverse transcribed followed by PCR amplification with primers specific for PUUV medium (M) or small (S) genome segments. Partial PUUV M segment sequences (approximately 450 bp long) were recovered from five bank voles and partial S segment sequences (app. 250 nt long)-from two bank voles. Genetic analysis of Croatian wt-PUUV strains revealed their close relatedness suggesting that the two localities belong to the same natural focus of infection. On phylogenetic trees Croatian PUUV strains clustered together with the strains from Slovenia and Austria forming distinct Alpe-Adrian genetic lineage.

Endemic nephropathy is a human kidney disease that still escapes scientific explanation. It is accompanied by a high incidence of urothelial tumors in rural populations in endemic areas, which suggests that a natural nephrotoxic and carcinogenic compound may be involved in the etiology. The most imputed causative agent of endemic nephropathy is the mycotoxin ochratoxin A (OTA), because of its confirmed nephrotoxic and carcinogenic action. This paper presents a review of studies of OTA in food collected in the endemic areas and in blood and urine of their residents. Data on the co-occurrence of OTA and other nephrotoxic and carcinogenic mycotoxins such as citrinin and fumonisin B(1) in food are also presented. Unfortunately, there is no study on the co-occurrence of OTA and other mycotoxins in humans and there is only one study on fumonisin B(1) exposure in endemic areas. The paper also presents experimental data on cultured cells and laboratory animals treated with combinations of OTA and other nephrotoxic mycotoxins, because most such combinations show a synergistic effect. The occurrence of OTA- and aristolochic acid-DNA adducts is also presented.

In Europe, Dobrava‐Belgrade (DOBV), Saaremaa (SAAV), and Puumala (PUUV) viruses are known to cause hemorrhagic fever with renal syndrome (HFRS). All three hantaviruses are now found in Croatia. Lung tissue samples of 315 Apodemus mice trapped in 2003–2004 were screened for the presence of hantaviral N‐Ag and 20 mice (6.3%) were found either strongly positive or weak/suspected‐positive. Partial sequences of hantavirus M and S segments were recovered by RT‐PCR from six mice and subjected to (phylo)genetic analysis that revealed the presence of four novel strains of DOBV and one of SAAV. Curiously, one of the newly described DOBV strains was found in Apodemus agrarius mouse, that is, not in the traditional host, A. flavicollis mice, suggesting a spillover event. S segment sequences recovered previously from HFRS cases [Markotić et al., 2002] were confirmed as DOBV sequences; one of which appeared particularly close to the prototype Slovenian DOBV isolate. Taken together with earlier data on PUUV in Croatia, these results show a co‐circulation of three European hantavirus pathogens in this country. So far, not a single SAAV sequence has been recovered from HFRS patients either in Croatia or neighboring Slovenia and Hungary nor in Slovakia suggesting a somewhat lower fequency of acute SAAV infection in humans in this part of Europe than for example in the Baltics. J. Med. Virol. 83:108–114, 2011. © 2010 Wiley‐Liss, Inc.