There are unexplained geographical variations in the incidence of kidney cancer with the high rates reported in Baltic countries, as well as eastern and central Europe. Having access to a large and well-annotated collection of "tumor/non-tumor" pairs of kidney cancer patients from the Czech Republic, Romania, Serbia, UK, and Russia, we aimed to analyze the morphology of non-neoplastic renal tissue in nephrectomy specimens. By applying digital pathology, we performed a microscopic examination of 1012 frozen non-neoplastic kidney tissues from patients with renal cell carcinoma. Four components of renal parenchyma were evaluated and scored for the intensity of interstitial inflammation and fibrosis, tubular atrophy, glomerulosclerosis, and arterial wall thickening, globally called chronic renal parenchymal changes. Moderate or severe changes were observed in 54 (5.3%) of patients with predominance of occurrence in Romania (OR = 2.67, CI 1.07-6.67) and Serbia (OR = 4.37, CI 1.20-15.96) in reference to those from Russia. Further adjustment for comorbidities, tumor characteristics, and stage did not change risk estimates. In multinomial regression model, relative probability of non-glomerular changes was 5.22 times higher for Romania and Serbia compared to Russia. Our findings show that the frequency of chronic renal parenchymal changes, with the predominance of chronic interstitial nephritis pattern, in kidney cancer patients varies by country, significantly more frequent in countries located in central and southeastern Europe where the incidence of kidney cancer has been reported to be moderate to high. The observed association between these pathological features and living in certain geographic areas requires a larger population-based study to confirm this association on a large scale.

1st Faculty of Medicine Charles University Prague Prague Czech Republic

Cambridge University Hospitals NHS Foundation Trust Cambridge Biomedical Campus Cambridge UK

Carol Davila University of Medicine and Pharmacy Bucharest Romania

Centre of Science and Research Faculty of Health Sciences Palacky University Olomouc Czech Republic

Department of Cancer Epidemiology and Genetics Masaryk Memorial Cancer Institute Brno Czech Republic

Department of Oncology Pathology Karolinska Institutet Stockholm Sweden

Digestive Oncology Research Center Digestive Diseases Research Institute Tehran University of Medical Sciences Tehran Iran

Institute of Mathematics and Computer Science University of Latvia Riga Latvia

Institute of Pathology 1st Faculty of Medicine Charles University and General University Hospital Prague Czech Republic

International Agency for Research on Cancer World Health Organization 150 Cours Albert Thomas 69372 Lyon Cedex 8 France

International Organization for Cancer Prevention and Research Belgrade Serbia

Leeds Institute of Medical Research St James's University of Leeds Leeds UK

McGill University and Génome Québec Innovation Centre Department of Human Genetics McGill University Montreal Quebec Canada

National Institute of Public Health Bucharest Romania

Pathology Department Professor Dr Th Burghele Clinical Hospital Bucharest Romania

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