Predictive Markers for Malignant Urothelial Transformation in Balkan Endemic Nephropathy: A Case–Control Study

SIMPLE SUMMARY: Balkan endemic nephropathy (BEN) is chronic kidney disease caused by intoxication with Aristolochia plant. Apart from subtle decline of renal function that eventually results in kidney failure, the patients are at increased risk for urothelial carcinoma (UC) development. Based on the observed UC markers, the aim of this study was to examine urinary and plasma levels of some these markers in BEN patients without carcinoma, in order to potentially identify those with predictive value. Our study revealed either plasma or urinary survivin levels as a potential predictors of future malignant transformation of urothelium. ABSTRACT: Balkan endemic nephropathy (BEN) is a chronic tubulointerstitial disease frequently accompanied by urothelial carcinoma (UC). In light of the increased UC incidence and the markers observed in BEN patients with developed UC, the aim of the current case–control study is to assess survivin, p53 protein, growth factors and receptors (VEGF, VEGFR1, IGF I, IGF-1R and IGFBP5), tumor marker (TF)/CD142, circulating soluble Fas receptor and neopterin, as potentially predictive markers for UC in patients with BEN (52 patients), compared to healthy, age-matched subjects (40). A threefold increase was registered in both circulating and urinary survivin level in BEN patients. Especially noticeable was the ratio of U survivin/U Cr level five times the ratio of BEN patients associated with standard renal markers in multivariate regression models. The concentrations of VEGF, VEGFR1, (TF)/CD142, (sFas) were not significantly different in BEN patients, while urinary/plasma level demonstrated a significant decrease for VEGF. The levels of IGF I, IGFBP5 and IGF-1R were significantly reduced in the urine of BEN patients. Plasma concentration of neopterin was significantly higher, while urinary neopterin value was significantly lower in BEN patients compared to healthy controls, which reflected a significantly lower urine/plasma ratio and low local predictive value. As BEN is a slow-progressing chronic kidney disease, early detection of survivin may be proposed as potential predictor for malignant alteration and screening tool in BEN patients without the diagnosis of UC.