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Istraživanje „Endemska nefropatija u Hrvatskoj – epidemiologija, etiologija i patofiziologija” provodila se u okolici Slavonskoga Broda tijekom 7 godina. Ispitanici su bili praćeni 5 ili 7 godina, ovisno o godini kada su uključeni u istraživanje. U ovo istraživanje uključene su osobe iz endemskih sela bez endemske nefropatije te stanovnici neendemskih sela. Ukupno 880 ispitanika (57,8 % žena i 42,2 % muškaraca) podijeljeno je prema arterijskomu tlaku (AT) u tri skupine. 295 ispitanika (33,5 %) klasificirano je u skupinu s optimalnim arterijskim tlakom (OAT), 317 ispitanika (36 %) kao predhipertoničari (PHT), a 268 ispitanika (30,5 %) kao neliječeni hipertoničari (HT). Učinjen je fizikalni pregled, uzeta opsežna anamneza te prikupljeni uzorci krvi i urina za laboratorijske pretrage. Arterijski tlak i srčana frekvencija mjereni su šest puta tlakomjerom OMRON. Ispitanici s OAT-om su najmlađi, PHT su značajno stariji, dok su najstariji HT. PHT ispitanici također imaju veću tjelesnu masu, opseg struka, indeks tjelesne mase (BMI), serumsku glukozu, ukupni kolesterol i razinu triglicerida u usporedbi s OAT-om. U skupini PHT uočeno je značajno više osoba s metaboličkim sindromom u odnosu na OAT. Nije nađena statistički značajna razlika u serumskoj koncentraciji čimbenika rasta hepatocita (HGF) među skupinama, iako postoji trend porasta koncentracije HGF-a s rastom AT-a. Nađena je značajna pozitivna korelacija između vrijednosti sistoličkoga i dijastoličkoga AT-a s koncentracijom HGF-a za sve ispitanike te u skupini predhipertoničara. Postoji značajna pozitivna korelacija između vrijednosti HGF-a i TGF-a bete za sve ispitanike te značajna korelacija za HGF i albuminuriju za sve ispitanike. Nije nađena značajna razlika za koncentraciju HGF-a u odnosu na prisutnost metaboličkoga sindroma. U multivarijantnoj linearnoj regresijskoj analizi su sistolički tlak i koncentracija HGF-a bili nezavisni prediktori albuminurije, a dob i TGF-beta nezavisni prediktori porasta koncentracije HGF-a. Na kraju praćenja značajno je više ispitanika razvilo arterijsku hipertenziju u skupini PHT u odnosu na OAT., The study "Endemic Nephropathy in Croatia - Epidemiology, Etiology and Pathophysiology" was conducted in the villages near Slavonski Brod throughout a period of seven years. Subjects were divided into three groups according to the value of their blood pressure (BP): 295 subjects (33.5 %) were classified into the group with optimal blood pressure (OAT), 317 subjects (36 %) were classified as prehypertensive (PHT), and 268 subjects (30.5 %) as untreated hypertensives (HT). All subjects underwent a physical examination, and provided blood and urine samples for laboratory tests. Blood pressure and heart rate were measured six times with an OMRON device using appropriate cuff size. Mean values were used for analysis. Subjects with the OAT were the youngest, the PHTs are significantly older, and the HTs were the oldest. Subjects with the PHT also had significantly higher body weight, waist circumference, BMI, fasting serum glucose, total cholesterol, and triglyceride levels compared to the OATs. There was significantly higher number of subjects with the metabolic syndrome in the PHT group than in the OAT group. There were no significant differences between the concentration of the HGFin the PHT and HT groups compared to the OAT group. A significantly positive correlation was found between systolic and diastolic blood pressure values and HGF concentration for all subjects. The correlation was higher for diastolic AT. There was a significantly positive correlation between HGF and TGF beta values for all subjects, while there was no significant difference between the HGF concentration and blood leukocyte count or CRP. There was also a significant correlation between HGF and albuminuria for all subjects. No significant difference was found in HGF concentration in relation to the presence of metabolic syndrome in all subjects Multivariant linear regression showed that systolic BP and HGF concentration are independent predictors of albuminuria elevation, whereas age and TGF beta are independent predictors of HGF concentration elevation. At the end of the seven- or five-year follow-up, significantly higher number of subjects developed arterial hypertension in the PHT group compared to the OAT group.

Aristolochic acid includes a group of naturally occurring nitro phenanthrene carboxylic acids, but usually this refers to aristolochic acid I (AA I) and aristolochic acid II (AA II). It could be found in the stem and seeds of plants from the genus Aristolochia spp., which are widespread all over the world. It is believed that aristolochic acid is responsible for the development of endemic nephropathy (EN). This is a chronic tubulointerstitial nephropathy in humans, which is clinically manifested by terminal renal failure after an asymptomatic period of several years. Aristolochic acid is proven to be nephrotoxic, mutagenic and carcinogenic. Characteristically it affects two target tissues: cells of the proximal renal tubule and urothelial cells. In 2012. The International Agency for Research on Cancer (IARC) classified aristolochic acid in group 1, i.e. as a human carcinogen, because there were sufficient evidence that it causes cancer of the renal tubule and ureter. On the territory of the Republic of Croatia, more precisely in west Brod of Posavina, a focus of endemic nephropathy was found. Since there is a lack of data on the exposure of the population of the Republic of Croatia to aristolochic acid, especially the population in the endemic area, the Scientific Panel on Chemical Hazards of the Croatian Food Agency (now the Croatian Agency for Agriculture and Food) proposed a three-year research study entitled "Citrinine and aristolochic acid as cereal contaminants and potential agent of endemic nephropathy" in cereals (wheat, barley, corn) in four Croatian counties (Brod-Posavina, Osijek-Baranja, Koprivnica-Križevci and Međimurje). The results of the research were used for preparation of this scientific report. The research results show a very high percentage of samples with the concentration of AA I below the limit of quantification (LOQ), and only 4,17% of the samples were above the LOQ in concentration ranging from 1.36 mg/kg to 93 mg/kg. Also, in this research a sample contaminated with AA II with a concentration higher than the LOQ (1 mg/kg) was not found. By comparing the results of the concentration of aristolochic acid in samples collected in 2017, 2018 and 2019, no statistically significant difference in the concentration of aristolochic acid I (p=0.25) was found. Furthermore, the statistical analysis found that there is no statistically significant difference between the contamination of different types of cereals (p=0.4953), as well as that there is no statistically significant difference in the distribution of positive samples by county (p=0.65). Statistical data analysis was performed using Statistics 13.3. software package. Therefore, the results of this research indicate that the occurrence of aristolochic acid I (AA I) cannot be associated with endemic nephropathy in the Republic of Croatia and the contamination of cereals with aristolochic acid I and II does not pose a health risk for humans.

Endemska nefropatija kronična je tubulointersticijska bolest s latentnim početkom i sporim napredovanjem do završnog stadija bubrežne bolesti. Pogađa podjednako muškarce i žene koji žive u određenim endemskim ruralnim mjestima smještenih oko pritoka Dunava u Rumunjskoj, Bugarskoj, Hrvatskoj, Bosni i Hercegovini, Kosovu i Srbiji. Procjenjuje se da je gotovo sto tisuća ljudi u opasnosti za razvoj bolesti dok trenutno ima više od dvadeset pet tisuća oboljelih, a prevalencija iznosi oko 2 – 5 %. Prirodni tijek bolesti karakteriziraju dugo razdoblje inkubacije, nespecifični i teško prepoznatljivi klinički znakovi i simptomi te visoka incidencija za razvoj zloćudnog tumora prijelaznog epitela gornjeg dijela mokraćnog sustava s učestalosti čak do 50 %. Naglašeno obilježje obuhvaća obiteljski obrazac u združenim kućanstvima u kojim nekoliko članova istog domaćinstva, koji nisu nužno u krvnom srodstvu, mogu razviti bolest. Tijekom godina predložen je veliki broj potencijalnih etioloških čimbenika od kojih je većina bila opovrgnuta. Glavni okolišni uzročnik nefropatije i urotelijalnog karcinoma je kronično trovanje aristolohičnom kiselinom koja se nalazi u sjemenkama biljke vučje stope (Aristolochia clematitis L.). Specifični biomarkeri koji služe za procjenu izloženosti kancerogenoj i nefrotoksičnoj aristoholičnoj kiselini su aristolaktamski DNA adukti detektirani u bubrežnom tkivu i karcinomima urinarnog trakta. Također induciraju specifične mutacije u tumor supresorkom genu p53 koji će dalje utjecati na faze kancerogeneze. Genetska predispozicija ugroženih pojedinaca ima sekundarnu ulogu kao endogeni etiološki čimbenik. Danas postoje jednostavne mjere za kontroliranje i smanjenje rasta vučje stope s ciljem sprječavanja ili eliminiranja kontaminacije aristolohične kiseline., Endemic nephropathy is a chronic tubulointerstitial disease with a latent onset and slow progression to end-stage renal disease. It affects both men and women living in certain endemic rural areas located around the tributaries of the Danube in Romania, Bulgaria, Croatia, Bosnia and Herzegovina, Kosovo and Serbia. It is estimated that almost one hundred thousand people are at risk of developing the disease, while there are currently more than twenty-five thousand patients, and the prevalence is about 2-5 %. The natural course of the disease is characterized by a long incubation period, nonspecific and difficult to recognize clinical signs and symptoms, and a high incidence of the development of a malignant tumor of the transitional epithelium of the upper part of the urinary tract with a frequency of up to 50 %. The highlighted feature includes a family pattern in conjointed households in which several members of the same household who are not necessarily related by blood can develop the disease. Over the years, a large number of potential etiological factors have been proposed, most of which have been disproved. The main environmental cause of nephropathy and urothelial carcinoma is chronic poisoning with aristolochic acid, which is found in the seeds of the birthwort plant (Aristolochia clematitis L.). Specific biomarkers used to assess exposure to carcinogenic and nephrotoxic aristocholic acid are aristolactam DNA adducts detected in kidney tissue and urinary tract cancers. They also induce specific mutations in the p53 tumor suppressor gene that will further affect the stages of carcinogenesis. The genetic predisposition of vulnerable individuals has a secondary role as an endogenous etiological factor. Today, there are simple measures to control and reduce the growth of birthwort with the aim of preventing or eliminating aristolochic acid contamination.

Cilj: Endemska nefropatija (EN) je kronična bubrežna bolest koja nastaje zbog dugotrajnog izlaganja aristolohičnoj kiselini. EN je povezan s razvojem terminalnog stadija bubrežne insuficijencije, ali i s razvojem karcinoma urotela, poglavito gornjeg dijela mokraćnoga sustava. U radu ćemo prikazati pacijenticu s endemskom nefropatijom, u koje se nakon presađivanja bubrega razvio panurotelijalni karcinom. Prikaz slučaja: U 76-godišnje pacijentice s EN-om je 2013. godine učinjena uspješna kadaverična transplantacija bubrega. Nakon transplantacije otkriven joj je površinski karcinom mokraćnoga mjehura koji je više puta liječen transuretralnim putem. Zbog pojave karcinoma u gornjem dijelu mokraćnoga sustava učinjena joj je i obostrana nefroureterektomija. Unatoč promjeni imunosupresivne terapije i kirurškom liječenju razvila se metastatska bolest uz letalni ishod tri godine po transplantaciji uz funkcionirajući presadak. Zaključak: U pacijenata s EN-om može doći do razvoja panurotelijalne bolesti, a posebno su ugroženi pacijenti u kojih je učinjena transplantacija bubrega. U ove skupine pacijenata vrlo je važna prijetransplantacijska obrada, kao i praćenje nakon transplantacije bubrega., Aim: Endemic nephropathy (EN) is a chronic kidney disease caused by long-lasting exposure to aristolochic acid. EN is linked to the development of end-stage renal disease but also with the development of urothelial carcinoma, especially upper urinary tract carcinoma. We present a rare case of patient with EN who developed panurothelial cancer after kidney transplantation. Case report: In a 76-year-old woman with EN, a successful kidney transplantation was performed in 2013. After the transplantation, superficial bladder cancer was diagnosed and therefore treated with transurethral resection a few times. Later on, carcinoma of the upper urinary tract was also diagnosed so the bilateral nephroureterectomy was performed. Despite modified immunosuppression and surgical treatment, the metastatic disease was developed and the patient died three years after the transplantation, with the graft still being functional. Conclusion: Patients with EN have a higher risk of developing panurothelial carcinoma. Special attention must be given to EN patients who had kidney transplantation. In this group of patients, special considerat i on must be emphasized on pretransplant evaluation and follow-up after kidney transplantation.

In 2002, a report from El Salvador described a high incidence of chronic kidney disease (CKD) of unknown cause, mostly in young males from specific coastal areas. Similar situations were observed along the Pacific Ocean coastline of other Central American countries and southern Mexico (Mesoamerica). This new form of CKD has been denominated Mesoamerican endemic nephropathy (MeN). The typical presentation of MeN is a young male from an endemic area with a family history of CKD, low eGFR, high serum creatinine, low level of albuminuria, hypokalemia, hyperuricemia, and urine urate crystals. Kidney biopsy demonstrating tubulointerstitial nephritis remains the gold standard for diagnosis but is available only for a minority. Commonly proposed causes include thermal stress/dehydration and/or exposure to environmental pollutants. However, likely, a third factor, which could be genetic or epigenetic, could contribute to the cause and development of the disease, along with social determinants. Currently, preventive measures focus on minimizing workers exposure to thermal stress/dehydration. There are many research opportunities and priorities should include clinical trials to evaluate the efficacy and safety of the current treatment protocols, along with etiological and genetic studies, and the development of kidney disease data systems. Although there is scant and controversial literature with regard s to the etiology, diagnosis and management of the disease, our aim is to provide the reader a vision of the disease based on our experience.

Mesoamerican nephropathy (MeN) is an endemic form of chronic kidney disease (CKD) that is not related to risk factors for CKD, such as diabetes and hypertension. It primarily affects men, rural and agricultural laborers, who work in an extremely hot and dry environment. The greatest increase in the prevalence of CKD, particularly since the late 1990s, has been reported in Central America and Southern Mexico, where the prevalence is almost 9 times higher than in the USA. The highest mortality associated with CKD is reported in El Salvador where a 10-fold increase was recorded in 1984-2005. In histological examination, MeN patients manifest tubulointerstitial lesions and, in some cases, also lesions in the glomeruli. The cause of MeN remains unclear. Repeated episodes of occupational heat stress, and sweating accompanied by water loss, have a significant impact on the disease development. The disease is a significant social and economic problem, and a challenge in the field of diagnostics, therapy and prevention for physicians of many specialties, especially for occupational physicians. Med Pr. 2020;71(3):353-61.Nefropatia mezoamerykańska (imesoamerican nephropathy/i– MeN) to endemiczna forma przewlekłej choroby nerek (PChN), która nie ma związku z czynnikami ryzyka rozwoju PChN, takimi jak cukrzyca i nadciśnienie tętnicze. Występuje przede wszystkim u mężczyzn zatrudnionych w rolnictwie, wykonujących ciężką pracę fizyczną w gorącym i suchym klimacie. Od końca lat 90. XX w. zanotowano znaczący wzrost liczby zachorowań na PChN w Ameryce Środkowej i południowym Meksyku, a częstość jej występowania w tym regionie jest prawie 9-krotnie wyższa niż w Stanach Zjednoczonych. Najwyższa na świecie śmiertelność z powodu PChN jest w Salwadorze: w latach 1984–2005 wzrosła 10-krotnie. Patofizjologia MeN pozostaje niewyjaśniona. W materiale histopatologicznym obecne są przewlekłe zmiany cewkowo-śródmiąższowe, którym mogą towarzyszyć zmiany w kłębuszkach nerkowych. Na rozwój choroby mają istotny wpływ powtarzany cyklicznie stres cieplny, związane z nim nadmierne pocenie się oraz odwodnienie. Choroba stanowi ważny problem społeczny i ekonomiczny oraz wyzwanie w zakresie diagnostyki, terapii i profilaktyki dla lekarzy wielu specjalności, szczególnie dla lekarzy medycyny pracy. Med. Pr. 2020;71(3):353–361.

Endemska nefropatija (EN) je kronična tubulointersticijska bolest bubrega kod koje se često javlja karcinom urotela gornjega urotrakta (UUC). Imunološki odgovor, u kojem ključnu ulogu imaju geni HLA, povezan je s nastankom brojnih bolesti. Cilj ovog rada bio je istražiti polimorfizam gena, alela i haplotipova lokusa HLA-A, -B i - DRB1 u skupini nesrodnih EN bolesnika (N=111; 52 bolesnika s UUC i 59 bolesnika bez UUC) u svrhu otkrivanja njihove moguće povezanosti s EN. Ispitana su i 52 zdrava srodnika i 190 zdravih nesrodnih osoba. Za određivanje polimorfizma HLA koristila se metoda lančane reakcije polimerazom u kombinaciji s oligunukleotidima specifičnih sekvenci (PCR-SSO) ili početnicama specifičnih sekvenci (PCR-SSP). Otkrivene su značajne razlike u zastupljenosti pojedinih alela HLA između skupine EN bolesnika i zdrave kontrole. U skupini EN bolesnika aleli HLA-A*01:01, B*57:01 i B*27:05 su bili značajno manje zastupljeni, dok je alel HLA-DRB1*04:02 bio značajno češće prisutan. Pozitivna povezanost s pojavom EN i UUC utvrđena je za haplotipove: HLA-B*18~DRB1*11 i HLA-B*44~DRB1*16 kao i produženi haplotip HLA-A*26:01~B*38:01~DRB1*04:02. Otkrivene su razlike u raspodjeli alela i haplotipova HLA s obzirom na dob pojave bolesti, kao i na preživljenje. Dobiveni rezultati ukazuju da su pojedini aleli i haplotipovi HLA potencijalno podložni, odnosno zaštitni genetski čimbenici za razvoj bolesti., Endemic nephropathy (EN) is a chronic tubulointerstitial kidney disease in which upper urothelial carcinoma (UUC) often occurs. The immune response and HLA genes have been linked with a number of diseases. Aim of this study was to analyze genes, alleles and haplotypes of HLA-A, -B and -DRB1 loci among EN patients (N=111; 52 patients with UUC and 59 patients without UUC) in order to investigate their possible role in EN etiology. In addition, analysis included 52 healthy relatives and 190 healthy unrelated individuals. HLA gene polymorphisms were determined by polymerase chain reaction methods in combination with oligonucleotides specific for HLA gene groups (PCR-SSO) or primers of specific sequences (PCR-SSP). Significant differences in distribution of several HLA alleles between EN patients and healthy controls were detected. The HLA-A*01:01, B*57:01 and B*27:05 alleles were significantly less present, while HLADRB1* 04:02 allele appeared significantly more frequently among EN patients. Positive corelation with the onset of EN and UUC was determined for HLAB* 18~DRB1*11 and HLA-B*44~DRB1*16 haplotypes, and HLAA* 26:01~B*38:01~DRB1*04:02 extended haplotype. Differences in distribution of alleles and haplotypes were also detected in correlation to age of disease onset and survival. Obtained data demonstrate that investigated HLA loci could be potential susceptibility/protection genetic markers for disesase development.

Background Upper tract urothelial carcinoma (UTUC) is a rare urological cancer that is still an important public health concern in many areas around the world. Although UTUC has been linked to a number of risk factors, to our knowledge no systematic review has been published on the overall incidence and prevalence of de-novo UTUC. This review aimed to examine the global epidemiology of UTUC to provide clinicians and public health specialists a better understanding of UTUC. Methods A systematic search was conducted on MEDLINE, Embase, and the Web of Science using a detailed search strategy. Observational epidemiological studies describing the incidence and prevalence of de-novo UTUC in adults were included, and the Joanna Briggs Institute checklist was used for critical appraisal and data extraction of the studies selected. Results The systematic search identified 3506 papers, of which 59 papers were included for qualitative synthesis. The studies selected included data ranging from the years 1943 to 2018. A comprehensive qualitative synthesis of the data was performed. UTUC incidence generally varied according to age (higher with increasing age), sex (unclear), race (unclear), calendar time (increased, stable, or decreased according to region), geographical region (higher in Asian countries), occupation (higher in seamen and printers), and other population characteristics. Prevalence was only reported by one study, which showed UTUC to have the highest incidence of the rare urogenital cancers in Europe. Conclusion This systematic review highlights an increased incidence of UTUC in certain groups, including increasing age and certain occupations such as seamen. The incidence of UTUC also varies between certain geographical regions. The trend of UTUC incidence for sex, race, and calendar time is less clear due to a wide variety of metrics used by the studies identified. More studies are also required on the prevalence of UTUC to understand its disease burden. Trial registration This review was registered on PROSPERO (registration number CRD42019134255).

Hantavirus infection belongs to a group of zoonoses rare in the Balkan Peninsula, causing two major syndromes, depending on the viral serotype involved: Hemorrhagic fever with renal syndrome (HFRS) also known as endemic nephropathy and cardiopulmonary syndrome (CPS). Because there is no specific treatment or vaccine for this condition approved in the USA or Europe, the key to minimizing the risk of adverse progression to chronic kidney disease, secondary hypertension or even death is primarily the recognition and early diagnosis of this condition with prompt therapeutic intervention. The aim of this study was to review the literature data on the epidemiology, pathogenesis and management of this disease and to identify several aspects related to the difficulties encountered in diagnosing this pathology, taking into consideration that the disease is not endemic in this geographical area.

Background and Aims Balkan endemic nephropathy (BEN) is a chronic tubulointestitial kidney disease prevalent in Serbia, Bosnia, Croatia, Bulgaria and Romania. One of its most peculiar characteristics is a strong association with upper tract urothelial carcinoma (UTUC). The aim of the paper is to assess the basic epidemiological characteristics of UTUC, such as the incidence, sex, age geographic distribution of the diseased from Jablanica region in the 40-year period, as well as determining the linear trend of UTUC frequency in regions with BEN compared to non-endemic regions, bearing in mind those recent studies that have shown a significant decrease in the incidence of the diseased from BEN. Method The research period lasted from 1978 to 2017. In the analysis of the frequency of UTUC, we used the operative material of Urology Department, Health Care Center, Leskovac, and Urology Clinic, Clinical Center, Nis. The patients were divided according to the place of residence-certain areas of Jablanica region. The data from the Institutes of Nephrology and Hemodialysis were used for the classification of the area(A-endemic settlements for BEN; B-hypo-endemic; C-non-endemic urban type; and D-non-endemic rural type. The average annual incidence rate (AAIR) was calculated per 100 000 people. Finally, e jointly observed groups C and D(non-endemic areas) for UTUC. For practical reasons, this period was divided into the first(1978-1997) and the second one(1998-2017). Results The highest AAIR of UTUC was registered in endemic settlements(11.82) and the lowest one in non-endemic urban settlements(0.83). Association of UTUC and other tumours were observed in 39.13% in endemic regions compared to 22.53% in non-endemic regions. In endemic settlements in the first observed period, the frequency of UTUC was registered five times higher than in the second. The linear trend of UTUC in the 40-year-period shows a slow decrease(y=-0.0797x+4.2846; r2=0.2028). In addition, there was strong positive linear trend toward urinary bladder cancer occurence(y=1.6415 + 3.45; r2=0.85). However, trend of occurence of bladder cancer in endemic regions were positive, but without significance(y=0.023x+57; r2=0.0004). The results show that UTUC in endemic settlements are 2.63 times more frequent than in hypo-endemic ones; 14.24 times more frequent than in non-endemic settlements. Our research in Jablanica region also demonstrated unexpectedly high frequency of on UTUC not only in certain endemic settlements with BEN but also in the non-endemic area-Brejanovac village-1 tumour per 99.63 people and AAIR of 40.50, Rudare village-1 tumour per 139.50 people and AAIR 28.67. This occurrence of UTUC frequency in some non-endemic settlements refers to the first observed period until no occurrence was recorded in the second observed period. Conclusion The high frequency of UTUC in the regions with BEN in Jablanica region possibly point to the common nephropathogenic and carcinogenic etiologic factor and confirms the existence of a positive correlation between BEN and UTUC. It is necessary that additional investigations be carried out in certain non-endemic settlements in which the frequency of UTUC and hemodialyzed patients in still high.

This review aims to highlight the effects of ochratoxin A (OTA) in the feed of meat-producing animals. The accumulation of OTA in feed and its distribution in various farm animals were compared and evaluated. Primarily, the oral administration of OTA-contaminated feed and the predisposition in an animal's vital organ were critically examined in this work. The collated reports show that OTA directly associated with endemic nephropathy and its high concentration leads to degeneration of liver cells, and necrosis of intestinal and lymphoid tissues. At present, limited reports are available in the recent literature on the problems and consequences of OTA in feed. Therefore, this review focused on the OTA carryover from feed to farm animals and the interaction of its secondary metabolites on their biochemical parameters. Hence, this report provides greater insights into animal health related to OTA residues in meat and meat products. This article also explores mitigation strategies that can be used to prevent the carryover effects of OTA in livestock feeds and the effects in the food chain.

Although collecting duct carcinoma is a subtype of renal cell carcinoma, several studies implicate association with urothelial carcinoma. The coexistence of collecting duct carcinoma and another renal neoplasm is rare. Endemic nephropathy is a renal disease causing chronic renal failure. It is highly associated with urothelial neoplasm and occurs in endemic villages in Bosnia, Croatia, Bulgaria, Romania and Serbia. Recent studies have confirmed the important role of exposure to aristolochic acid as an etiologic factor. We present three cases of collecting duct carcinoma with literature overview. In one case, we describe collecting duct carcinoma with metachronous urothelial carcinoma of the pyelon and urinary bladder in an endemic nephropathy patient. To our knowledge, this is the first case report describing this coexistence. Certain similarities between collecting duct carcinoma and urothelial carcinoma were found, e.g., higher incidence in female compared to male, higher mean age, and multifocal and multicentric occurrence of the tumor. Our observations support the hypothesis that collecting duct carcinoma and urothelial carcinoma could be connected., Iako je karcinom sabirnih kanalića podvrsta karcinoma bubrežnih stanica, određena istraživanja ukazuju na povezanost ovog entiteta s karcinomom prijelaznog epitela. Istodobna pojava karcinoma sabirnih kanalića i drugih bubrežnih neoplazma je rijetka. Endemska nefropatija je bubrežna bolest koja dovodi do kroničnog bubrežnog zatajenja. Vrlo je povezana s urotelnim tumorima i javlja se u endemskim selima u Bosni, Hrvatskoj, Bugarskoj, Rumunjskoj i Srbiji. Nedavna istraživanja potvrdila su značajnu ulogu izloženosti aristolohičnoj kiselini kao etiološkom čimbeniku. Predstavljamo tri slučaja karcinoma sabirnih kanalića s pregledom literature. U jednom slučaju opisujemo karcinom sabirnih kanalića s metakronom pojavom urotelnog karcinoma pijelona te mokraćnog mjehura u bolesnika s potvrđenom endemskom nefropatijom. Prema našim saznanjima ovo je prvi slučaj koji opisuje ovakvu koegzistenciju. Pronađene su određene sličnosti između karcinoma sabirnih kanalića i karcinoma prijelaznog epitela, a to su veća učestalost u ženskoj populaciji, viša prosječna dob, multifokalna i multicentrična pojava tumora. Naša zapažanja podupiru hipotezu o mogućoj povezanosti karcinoma sabirnih kanalića i karcinoma prijelaznog epitela.

Endemska nefropatija je sporo progresivna, kronična tubulointersticijska bolest bubrega. Bolest se pojavljuje sa visokom prevalencijom kod stanovnika endemskih ruralnih područja u Hrvatskoj, Srbiji, Bosni i Hercegovini, Bugarskoj. Kronična izloženost aristolohičnoj kiselini identificirana je kao glavni čimbenik rizika za EN te ima i ulogu u razvoju karcinoma urotrakta. Bolest nema specifičnih kliničkih simptoma te zbog toga ostaje neprepoznata dugi niz godina te u konačnici uzrokuje terminalni stadij bubrežne bolesti. Cilj ovog istraživanja bio je prikazati pacijente kojima su zbog EN transplantirani bubrezi. Retrospektivno smo analizirali bolesnike s endemskom nefropatijom u kojih je učinjena transplantacija bubrega u Kliničkom bolničkom centru Rijeka. Tijekom 12 godina na Klinici za urologiju KBC Rijeka transplantirana su 4 pacijenta s endemskom nefropatijom. Jedna pacijentica prezentirala se akutnom tubularnom nekrozom u ranom postoperativnom razdoblju sa sumnjom na odbacivanje grafta. U druge pacijentice došlo je do razvoja karcinoma mokraćnoga mjehura te je višestruko operirana. U niti jednog pacijenta nije došlo do značajnijeg pogoršanja bubrežne funkcije transplantata. Do sada su umrla 3 bolesnika od čega jedna bolesnica zbog metastatskog panurotelijalnog karcinoma. Najbolja terapijska metoda liječenja bolesnika s EN u terminalnom stadiju kronične bubrežne insuficijencije je transplantacija bubrega. Zbog povećane incidencije pojave karcinoma gornjeg dijela urotrakta preporuča se učiniti preventivnu bilateralnu nefroureterektomiju kao pripremu za transplantaciju bubrega., Endemic nephropathy is a slowly progressive, chronic tubulointerstitial renal disease. The occurrence has been recorded with high prevalence in residents of endemic rural regions in Croatia, Serbia, Bosnia and Herzegovina, Bulgaria. A chronic exposure to aristolochic acid has been identified as a major risk factor for EN and has a role in the development of urotract cancer. The clinical symptoms of EN are not specific and remain unrecognized for several years and disease finally can cause terminal stage of renal disease. The aim of this study was to present patients with transplanted kidneys who had an EN. The study was set up as a retrospective study of patients with endemic nephropathy in which kidney transplantation was performed at Clinical Hospital Center Rijeka. During the 12 years at the Clinic for Urology of KBC Rijeka, 4 patients with endemic nephropathy were transplanted. One patient presented with acute tubular necrosis with suspected graft rejection in the early postoperative period. The other patient develops urinary bladder cancer, which is why the multiple operations was done. There was no significant increase in renal function of the transplant in any patient. Up to now, 3 patients died of which one patient is due to metastatic panurothelial carcinoma. The best therapeutic treatment method of EN in the terminal stage of chronic renal insufficiency is kidney transplantation. The increased incidence of upper urothelial cancer in patients with EN has been reported and because of that a preventive bilateral nephroureterectomy is recommended.

Aim: Endemic nephropathy (EN) is classified as a tubulointerstitial progressive chronic disease that affects kidneys with a slow clinical course. Disease occurs in rural communities along the river flows of the Danube river basin in Croatia, Bosnia and Herzegovina, Serbia, Bulgaria and Romania. In Croatia, the endemic focal point includes fourteen villages and affects population of about 10 000 people located in the BrodskoPosavska County on the Sava River bank, west of Slavonski Brod. Over the past period, the influence of hereditary and environmental factors on the appearance of EN (heavy metals, microelements, various viruses and bacteria, soil, drinking water, polycyclic hydrocarbons aromatic compounds) were investigated. Recently, next generation sequencing nominated three genes tightly connected to process of angiogenesis as candidate genes for predisposition to Balkan endemic nephropathy, one of them (KCNK5) being located on chromosome 6p21.2, in close proximity to the HLA region. Methods: Prompted by this finding, we investigated HLA-A, -B, and -DRB1 alleles and haplotypes in the population of patients with EN (N=103) and matched healthy controls (N=190). All individuals were tested by PCR-SSO for low resolution typing and PCR-SSP to obtain a high-resolution typing. Results: The results showed higher presence of HLA-DRB1*04:02 allele in EN (P=0.013, OR=3.006, 95% CI=1.28- 7.07), in contrast to the lower frequency of HLA- A*01:01, B*57:01 and B*27:05 alleles (P=0.002, OR=0.373, 95% CI=0.19-0.72 ; P=0.032, OR=0.339, 95% CI=0.13-0.90 and P=0.006, OR=0.098, 95% CI=0.01-0.74, respectively). Moreover, when EN patient’s HLA haplotypes were compared to controls, two haplotypes were present with higher frequency within EN patients group, HLA- A*02:01~B*27:02~DRB1*16:01 and HLA- A*26:01~B*38:01~DRB1*04:02 (P=0.002, OR=0 and P=0.054, OR=4.702, 95% CI=0.90- 24.45, respectively) while HLA-A*02:01~B*57:01~DRB1*16:01 (P=0.031, OR=0) haplotype showed a significantly lower frequency. Two other haplotypes, HLA- A*02:01~B*27:05~DRB1*01:01 and HLAA*01:01~B*57:01~DRB1*07:01, were also less frequent among EN patients, but this difference did not reach statistical significance. Conclusion: The results point toward genetic susceptibility to EN indicating the necessity of further studies.

Introductions: Endemic nephropathy (EN) is a chronic tubulointerstitial renal disease associated with the development of cancer of the upper urinary tract (UUC). The Human Leukocyte Antigen (HLA) plays role in immune response and its genes are involved in aetiology of autoimmune diseases as well as in carcinomas. The aim of this study was to investigate the differences between EN patients with and without UUC and HLA-DRB1 genes. Materials and methods: The study included 85 patients aged 58-88 years, with EN, treated at the Urology Department and Dialysis Department, General Hospital “Dr.Josip Benčević” Slavonski Brod, in the period from 2005 to 2018, and 150 healthy matched controls. Peripheral blood of all patients and controls was collected for HLA typing. All individuals were tested for HLA-DRB1 genes using Polymerase Chain Reaction – Sequence Specific Oligos (Luminex technology). Results: Thirteen different HLA-DRB1 genes were observed among EN patients as well as among controls. The most frequent HLA-DRB1 gene in patient’s group was HLA-DRB1*11 (20.7%), while among controls two HLA- DRB1* genes (DRB1*11 and DRB1*16 were observed with the same frequency (15.9%, each). Comparison between tested groups revealed significant P value for DRB1*16 which was significantly more present among patients in comparison to controls (15.9% vs. 8.3% ; P=0.0144). Conclusion: Our preliminary data demonstrated existence of positive association between DRB1*16 gene and EN in our population. The obtained data needs to be confirmed in future studies which should also investigate the distribution of HLA-DRB1 genes among patients with and without UUC, and include other HLA genes.

Otkrivanje kronične bubrežne bolesti (KBB) u ranoj fazi može spriječiti ili usporiti napredovanje bolesti i smanjiti rizik komplikacija. Stadiji KBB se prema klasifikaciji National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF K/DOQI) određuju na temelju procjene brzine glomerularne filtracije (engl. Glomerular Filtration Rate, GFR) koja se izračunava pomoću prediktivnih jednadžbi baziranim na vrijednosti kreatinina u serumu i drugih varijabli kao što su dob, spol, rasa i tjelesna masa. U ovom radu ispitana je pouzdanost prediktivnih jednadžbi (CG-Cockcroft - Gault, MDRD2-Modification of Diet in Renal Disease Study, MCQE-Mayo clinic quadratic equation i CKD-EPI-Chronic Kidney Disease Epidemiology Collaboration) za procjenu učestalosti pojedinih stadija KBB u područjima s endemskom nefropatijom (EN). Također, ispitano je koreliraju li vrijednosti transformirajućeg čimbenika rasta β (engl. Transforming Growth Factor-β, TGFβ) u uzorcima mokraće ispitanika s KBB, tj GFR određenoj različitim jednadžbama što predstavlja novi doprinos spoznavanju patofiziologije endemske nefropatije. Dobiveni rezultati pokazuju vrlo visoku prevalenciju KBB u ruralnom hrvatskom području te razliku u svrstavanju ispitanika u stadije bubrežnog oštećenja 3-5 ovisno o primjenjenoj jednadžbi. Najlošiju podudarnost s ostale tri jednadžbe imala je CG jednadžba, dok su najbolju usporedbu pokazale jednadžbe MDRD2 i CKD-EPI. Zbog dokazane značajne povezanosti procijenjene GFR i dijagnoze EN, dobiveni rezulatati upućuju na mogućnost jasnog razlikovanja pojednih podskupina ispitanika u EN selima pa procjena GFR prediktivnim jednadžbama treba biti i dalje uključena u kriterije za EN. TGFß kao biljeg uznapredovale fibroze, nije se pokazao kao pouzdan biljeg u razlikovanju podskupina bolesnih i ostalih ispitanika. Detection of the Chronic kidney disease (CKD) disease in an early stage can help prevent or slow the progression of CKD and reduce the risk of complications. CKD stages, according to the classification NKFK /DOQI, are classified based on the estimated glomerular filtration rate (GFR) calculated using predictive equations. This study analyze how different predictive equations (CG – Cockcroft -Gault, MDRD2 - Modification of DietinRenal DiseaseStudy, MCQE - Mayo Clinic Quadratic equation and CKD-EPI - Chronic Kidney Disease Epidemiology Collaboration) have an influence on assessing CKD in Croatia endemic nephropathy (EN) region. A total of 1573 inhabitants of the Croatian Posavina rural area from 6 endemic and 3 non-endemic villages were enrolled. Participants were classified according to the modified criteria of the World Health Organization for EN. The aim was to examine the effect of different GFR equations on GFR and to determine prevalence of CKD stages 3-5 in Croatian endemic region. Also, it was analyzed are the TGFß values in patients urine samples correlated with estimated GFR calculated using different predictive equations. The results show a very high CKD prevalence and differences in the classification of patients in stages 3-5. The CG equation demonstrated worst concordance with other studied equations, while MDRD2 and CKD-EPI showed the best compatibility. TGFß has not proved to be a reliable marker in distinguishing between a subset of the sick and other of subjects. Estimated GFR correlated significantly with the diagnosis of EN. Kidney function assessment using predictive equations proved to be a good marker in differentiating the study subgroups remined as one of the diagnostic criteria for EN.

Introduction: Chronic kidney disease (CKD) is a significant public health problem and it is not possible to precisely predict its progression to terminal renal failure. According to current guidelines, CKD stages are classified based on the estimated glomerular filtration rate (eGFR) and albuminuria. Aims of this study were to determine the reliability of predictive equation in estimation of CKD prevalence in Croatian areas with endemic nephropathy (EN), compare the results with non-endemic areas, and to determine if the prevalence of CKD stages 3-5 was increased in subjects with EN. Materials and methods: A total of 1573 inhabitants of the Croatian Posavina rural area from 6 endemic and 3 non-endemic villages were enrolled. Participants were classified according to the modified criteria of the World Health Organization for EN. Estimated GFR was calculated using Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI). Results: The results showed a very high CKD prevalence in the Croatian rural area (19%). CKD prevalence was significantly higher in EN then in non EN villages with the lowest eGFR value in diseased subgroup. Conclusions: eGFR correlated significantly with the diagnosis of EN. Kidney function assessment using CKD-EPI predictive equation proved to be a good marker in differentiating the study subgroups, remained as one of the diagnostic criteria for EN.

Cilj: Kliničko i imunološko praćenje bolesnika s presađenim bubregom u KBC-u Rijeka te procjena imunosne reaktivnosti primatelja bubrežnog presatka, koji primaju anti-CD25 monoklonsko protutijelo daklizumab u sklopu standardnog imunosupresivnog protokola. Bolesnici i metode: Retrospektivna analiza obuhvaća kliničke podatke o 588 bolesnika, kojima je presađen bubreg u KBC-u Rijeka u proteklom gotovo 25-godišnjem razdoblju. Prospektivno randomizirano istraživanje obuhvaća primatelje bubrežnog presatka od 2006. do 2008. g. Iz ispitivanja su isključeni bolesnici s pozitivnim biljezima na hepatitis B ili C. Imunosna reaktivnost bolesnika određivana je analizom staničnog ciklusa limfocita periferne krvi, metodom protočne citometrije. Kontrolne skupine činili su zdravi darivatelji krvi i bolesnici na liječenju redovitom dijalizom. Rezultati: Kumulativno preživljavanje bolesnika i bubrežnih presadaka od 2001. do 2007. g. postalo je značajno bolje u odnosu na primatelje u razdoblju od 1985. do 1995. g. Tijekom 25-godišnjeg razdoblja, najčešći uzroci smrti bili su srčanožilne bolesti, infekcije i zloćudni tumori. Među zloćudnim tumorima najčešće se javljao karcinom kože, a potom karcinom bubrega i uretera. U bolesnika s endemskom nefropatijom nađena je visoka učestalost karcinoma prijelaznog epitela s lošom prognozom. Tijekom razdoblja praćenja zabilježen je porast prosječne starosne dobi bolesnika, značajan porast udjela muških primatelja bubrežnog presatka te značajno smanjenje učestalosti kroničnog glomerulonefritisa kao uzroka završnog bubrežnog zatajenja. Bolje preživljavanje presatka uočeno je u primatelja koji su bolovali od policistične bolesti bubrega, dok je značajno lošije bilo u slučaju primatelja ili darivatelja starijih od 50 g., te u muških primatelja nakon presađivanja bubrega od ženskih darivatelja. U prospektivnom dijelu ispitivanja, analizom staničnog ciklusa, uočeno je da tijekom prvih šest tjedana nakon presađivanja bubrega dolazi do postupnog pada proliferativnog odgovora limfocita T u odnosu na kontrolne skupine. Daklizumab je, ovisno o dozi, blokirao anti-CD3 potaknutu proliferaciju limfocita T te je doveo do naglog pada zastupljenosti IL-2 receptora na njihovoj membrani, dok je izražaj IL-2 receptora na stanicama NK varirao na niskoj razini. Uočen je i pad zastupljenosti ukupnih limfocita T, pomoćničkih i citotoksičnih stanica te limfocita B. U kasnijoj fazi, od 2.-6. tj. nakon presađivanja, zastupljenost ovih stanica se normalizirala. NK stanice su neposredno nakon presađivanja pokazale porast postotnog udjela, koji se u kasnijoj fazi ponovno normalizirao. Zaključak: Ovi rezultati predstavljaju značajan doprinos kliničkom praćenju bolesnika s bubrežnim presatkom i optimizaciji imunosupresivnog liječenja, s ciljem da se smanje neželjeni učinci prekomjerne imunosupresije i da se poboljša preživljavanje bolesnika i presatka., Aim: Clinical and immunological follow-up of renal allograft recipients in UHC Rijeka and estimation of the immune reactivity of patients receiving the anti-CD25 monoclonal antibody daclizumab, in combination with the standard immunosuppressive protocol. Patients and methods: Retrospectively, clinical data on 588 patients who received a renal allograft in UHC Rijeka over an almost 25 year period, were analyzed. The prospective randomized trial included recipients of renal allografts from 2006 until 2008. Excluded were patients with positive hepatitis B or C markers. The patients' immune reactivity was determined by analyzing the cell cycle of peripheral blood lymphocytes with flow-cytometry. Control groups were healthy blood donors and patients undergoing regular dialysis treatment. Results: Cummulative patient and graft survival of transplants performed during the period from 2001 until 2007 became significantly better than for kidney recipients in the period from 1985 until 1995. Over the 25 year period, most common causes of death were cardiovascular disease, infections and malignant tumors. The most common malignant tumor was skin cancer, followed by kidney and uretheral cancer. In patients with endemic nephropathy, a high incidence of urothelial cancer was observerd with a poor prognosis. During the follow-up period an increase in the patients' age average, a significant increase in the proportion of male renal allograft recipients and a significant decrease in the incidence of chronic glomerulonephritis as primary renal disease were observed. Recipients with polycystic kidney disease had better graft survival while the survival was significantly worse in case of recipients or donors age over 50 and in male recipients of kidneys from female donors. In the prospective part of the trial, cell cycle analysis showed a step-wise decrease of the proliferative response of T lymphocytes in comparison to the control groups during the first six weeks after renal transplantation. Daclizumab inhibited, dose-dependently, the anti-CD3 stimulated proliferation of lymphocytes T and lead to a sudden drop in the proportion of IL-2 receptors on their membrane, while the expression of IL-2 receptors on NK cells varied at a low level. A drop of the proportion of all T lymphocytes, both helper and cytotoxic cells as well as of B lymphocytes was observed. Over a period of two to six weeks after transplantation, the proportion of these cells normalized. NK cells showed a rise of their proportion immediately after engraftment, which normalized again in the latter phase. Conclusion: These results represent a valuable contribution for the clinical follow-up of renal transplant recipients and the optimization of immunosuppressive treatment, in order to minimize side effects of overimmunosuppression and to improve patients and graft survival.

Background: Citrinin is a mycotoxin produced by several species of the genera Aspergillus, Penicillium and Monascus and it occurs mainly in stored grain. Citrinin is generally formed after harvest and occurs mainly in stored grains, it also occurs in other plant products. Often, the co-occurrence with other mycotoxins is observed, especially ochratoxin A, which is usually associated with endemic nephropathy. At the European Union level, systematic monitoring of Citrinin in grains began with the aim of determining its highest permissible amount in food. Thus, far the systematic monitoring of the above mentioned mycotoxin in Croatia is yet to begin.Materials and Methods: The main goal of this study was to determine the presence of Citrinin in grains sampled in the area of Međimurje, Osijek-Baranja, Vukovar-Srijem and Brod-Posavina County. For the purpose of identification and quantification of citrinin, high performance liquid chromatograph (HPLC) with fluorescence was used (Calibration curve k ≥ 0.999; Intra assay CV = 2.1%; Inter assay CV = 4.3%; LOQ < 1 μg/kg).Results: From the area of Međimurje County, 10 samples of corn and 10 samples of wheat were analyzed. None of the samples contained Citrinin (

Background/Aims: An epidemiological survey of endemic nephropathy (EN) was performed in endemic Croatian areas and the current prevalence was compared to that reported for the same villages several decades ago. Methods: A total of 2,487 adult farmers from 6 endemic villages and 3 non-endemic villages were enrolled. An extensive epidemiological questionnaire, clinical examination and laboratory analyses of blood and urine were performed. According to the modified WHO criteria, participants were classified into diseased, suspected of having EN, and those at risk of developing EN. Results: The overall prevalence of EN in the Croatian areas was 1.0%, ranging between 0.3 and 2.3% in different villages. Those suspected of having EN amounted to 3.9%. In the endemic villages a decreasing trend in the prevalence of EN was observed comparable to the results obtained in previous surveys. It is interesting to note that no EN patients were recorded in the endemic village of Dubočac. Conclusion: The prevalence of EN in the endemic Croatian areas appears to be decreasing. For the first time, we failed to detect any EN patients in a village that was previously considered endemic, which might indicate that EN is diminishing.

The authors are second-year medical students who spent the previous summer at a nongovernmental organization in Nicaragua. As interns on the public health team, they evaluated barriers to peritoneal dialysis in an agricultural community experiencing an epidemic of chronic kidney disease and end-stage renal disease.

Introduction & Objectives: Endemic nephropathy (EN) is a chronic tubule interstitial renal disease. Studies made over the years have shown that EN is associated with the development of cancer of the upper urinary tract (UUC). The aim of the study was to investigate the differences in HLA-A, -B, and -DRB1 genes between EN patients both with and without the UUC and the controls and to answer the question whether the HLA genes play susceptible or protective role for the development of EN. Materials & Methods: The study included 89 patients aged 58-88 years divided into 2 subgroups (39 with UUC and 50 patients without UUC) and 150 healthy unrelated individuals from the same region as controls. All subjects were tested for HLA genes by Polymerase Chain Reaction - Sequence Specific Oligos (PCR-SSO) method. HLA frequencies were determined by direct counting. Statistical significance of difference in gene frequencies was calculated using Fisher’s exact test with P value of 0.05 being considered significant. Results: The frequency of HLA genes at tested loci in the present study was similar to that observed for the control group. On the HLA-A locus, only HLA-A*26 specificity was significantly increased among the whole group of patients with EN when compared with controls (P=0.0407), but significance was lost when compared with two subgroups. For the HLA-B locus, there was a decrease in frequency of HLA- B*51 in the EN group (P=0.0399). HLA-B*27 was the only specificity that differed significantly between the patients without UCC and the controls (P=0.0094) and also between the two subgroups with and without UCC (P=0.0027). On the HLA-DRB1 locus, the difference was seen for the HLA-DRB1*16 gene which was significantly increased in the entire EN group when compared with controls (P=0.0230) and also in the subgroup without UUC when compared with controls (P=0.0360). Conclusions: The study of genetic aetiology of endemic nephropathy and urothelial cancer of the upper urinary tract will contribute to better understanding of the mechanisms of these diseases. In the future this should enhance a new way of prevention and therapy. The presence of susceptible HLA genes like HLA-A*26 and -DRB1*16 among family members will point out the healthy subjects with increased risk to developed disease and to include them in the program of preventive examinations while HLA- B*51 may serve as a marker with a protective role.

Introduction. Balkan endemic nephropathy (BEN) is a familial chronic progressive tubulointerstitial disease of unknown aetiology that occurs with high prevalence in endemic rural environments of Serbia, Bosnia and Herzegovina, Croatia, Bulgaria and Romania. It has been documented only in adults. Objective. The aim of this study was to examine clinical markers of BEN in children and adolescent offspring of BEN patients. Methods. Prospective clinical trial involved two groups of children and adolescents: I consisted of 30 offspring of BEN patients and II of 29 offspring of non-BEN dialysis patients, both of them living in the same South Morava region of Serbia. All of them were healthy at the time of the investigation, not receiving any drugs. The study included personal and family history, physical examination, comprehensive laboratory analyses and renal ultrasound. Blood pressure (BP) was determined by using casual BP and 24 h ABPM in subjects older than 5 years. Urinary proteins were investigated by analysing microalbumin, alfa 1 microglobulin, beta 2 microglobulin and SDS-PAGE electrophoresis. GFR was measured by estimated creatinine clearance and by serum Cystatin C concentrations. Results. There were no statistically significant differences in age, gender, history of urinary tract infections or functional voiding disorders between these two groups. All of the studied subjects had normal BP and GFR. Renal ultrasound was abnormal only in BEN offspring (6.66%) as well as increased urine concentrations of microalbumin (3.3%), alpha 1 microglobulin (10%) and beta 2 microglobulin (13.3%) while low molecular protein (

Balkan endemic nephropathy (BEN) is a familial chronic tubulointerstitial disease with insidious onset and slow progression to terminal renal failure. Diagnostic criteria for BEN have been described more than 40 years ago. Research groups on BEN use one of at least three described lists of criteria. Comparison of studies using such criteria is difficult, and a recent meeting of investigators (Zagreb, October 2006) has suggested that unified criteria have to be elaborated. In this paper, an International Panel of BEN Investigators agreed on criteria appropriate to epidemiologic studies and clinical investigations of BEN. A screening procedure of BEN in endemic settlements is proposed.

U ovome radu modeliramo pojavnost endemske nefropatije logističkom regresijom. Promatramo modele nastale "FORWARD", "BACKWARD" i "STEPWISE" metodom selekcije, te zadani model i njegove varijacije. Statistička obrada podataka rađena je u statističkom paketu SAS Studio. U svakom modelu dobivenom SAS-ovim metodama selekcije kao rizični faktori za razvijanje endemske nefropatije pojavljuju se duljina života u endemskom selu, razina \(\alpha\)1 mikroglobulina te pozitivna obiteljska anamneza na endemsku nefropatiju. In this thesis, we are modelling prevalence of endemic nephropathy with logistic regression. We are observing models which are created with "FORWARD", "BACKWARD" and "STEPWISE" selection methods, and also demanded model and its variations. Statistical analysis was done in statistical software SAS Studio. In each model created with SAS selection methods, living duration in endemic village, level of $\alpha$1 microglobulin and positive family history on endemic nephropathy are appearing as risk factors for developing an endemic nephropathy.

During the twenty- five-year period the incidence of urothelial tumors was followed in the endemic village Brestovac. Thirty patients (3 of which with confirmed endemic nephropathy and 15 persons with suspected nephropathy) were investigated. Our retrograde study showed that there is a relationship between endemic nephropathy and urothelial cancer, and this association persisted with marked tendency to rise. Tumors were more common among males, aged from 50 to 70 years, with upper urinary tract urothelial cancer, papillary or trancellular forms, predominantly. Clinical feature showed classic triad of hematuria, flank pain and, rarely, flank mass, accompanied with non-specific symptomatology. Normal renal function was observed in 25 patients, but chronic renal failure was proven in five. Ten patients were treated by surgery, while 20 patients were treated by conservative therapy. There are no marked risk factors.