Soluble Serum alpha Klotho Is a Potential Predictive Marker of Disease Progression in Clear Cell Renal Cell Carcinoma

Renal cell carcinoma (RCC) accounts for approximately 3% of adult malignancies, and clear cell RCC (ccRCC), that has a high metastatic index and high relapse rate, is the most common histological subtype. The identification of new biomarkers in ccRCC is fundamental for stratifying patients into prognostic risk groups and to guide therapy. The renoprotective antiaging gene, Klotho, has recently been found to work as a tumor suppressor in different human cancers. Here, we evaluated Klotho expression in tissue and serum of ccRCC patients and correlated it with disease progression. Tissue Klotho expression was studied by quantitative RT-PCR and immunohistochemistry. In addition, soluble serum Klotho levels were preoperatively measured in 160 patients who underwent nephrectomy for RCC with ELISA. Estimates of cancer-specific (CSS) and progression-free survival (PFS) were calculated according to the Kaplan-Meier method. Multivariate analysis was performed to identify the most significant variables for predicting CSS and PFS. Klotho protein levels were significantly decreased in RCC tissues compared with normal tissues (P<0.01) and the more advanced the disease, the more evident the down-regulation. This trend was also observed in serum samples. Statistically significant differences resulted between serum Klotho levels and tumor size (P = 0.003), Fuhrman grade (P = 0.007), and clinical stage (P = 0.0004). CSS and PFS were significantly shorter in patients with lower levels of Klotho (P<0.0001 and P = 0.0004, respectively). At multivariate analysis low serum levels of Klotho were independent adverse prognostic factors for CSS (HR = 2.11; P = 0.03) and PFS (HR = 2.18; P = 0.03).These results indicate that a decreased Klotho expression is correlated with RCC progression, and suggest a key role of declining Klotho in the onset of cancer metastasis.