Introduction: Clear cell renal cell carcinoma (ccRCC) is the most lethal tumor of the urinary tract, with still unclear mechanisms of origin and limited treatment options. Materials and Methods: Paraffin blocks of tumor samples of 20 subjects with SKD, operated on at the Department of Urology, University Hospital Center Split, in the period from 2019 to 2020, were collected from the archives of the Clinical Institute of Pathology, Forensic Medicine and Cytology of the University Hospital Center Split, stained with antibodies Patched (Ptch), anti-Smoothened (Smo), anti-Sonic Hedgehoh (Shh), kallikrein 6 and acetyl-a-tubulin. Results: Strong Shh expression was observed in grade 1 carcinoma cells with a diffuse staining pattern (>50% of neoplastic cells), which was higher than all other grades and controls (p < 0.001–p < 0.0001). A trend of linear decrease in the intensity and extent of Shh expression was observed with increasing tumor grade (p < 0.0001). Ptch expression was significantly lower in grade 1 and 2 tumors compared to controls (p < 0.01) and grade 4 tumors (p < 0.0001). Diffuse extent of Smo expression was found in grade 4 tumors compared to all other grades (p < 0.0001) and controls (p < 0.001). Kallikrein 6 is most strongly expressed in control tissue, and mildest in grade 4 compared to all other grades (p < 0.0001) and the control (p < 0.001) (Figure 11). Acetyl-A-tubulin shows the highest expression in grade G2, however, with no statistically significant difference compared to the control and other grades. Tumor stroma and/or inflammatory infiltrate do not show staining of Shh, Ptch, Smo, kallikrein 6 and acetyl-A-tubulin proteins in grade 1 and 2 tumors, while slight focal staining of Shh, Ptch and Smo proteins (10–50% of neoplastic cells) is observed in grade 3 and 4 tumors. Conclusions: The observed differences in the expression of the analyzed proteins correlate with the grade of the kidney tumor. Different levels of expression of the analyzed proteins could play a role in renal tumorigenesis. Understanding the specific patterns of their occurrence could help search for new targets for potential treatments, as well as a better understanding of the mechanisms that lead to the development of ccRCC.