Renal lesions are important extracolonic findings on computed tomographic colonography (CTC). They are difficult to detect on non-contrast CTC images due to low image contrast with surrounding objects. In this paper, we developed a novel computer-aided diagnosis system to detect a subset of renal lesions, exophytic lesions, by (1) exploiting efficient belief propagation to segment kidneys, (2) establishing an intrinsic manifold diffusion on kidney surface, (3) searching for potential lesion-caused protrusions with local maximum diffusion response, and (4) exploring novel shape descriptors, including multi-scale diffusion response, with machine learning to classify exophytic renal lesions. Experimental results on the validation dataset with 167 patients revealed that manifold diffusion significantly outperformed conventional shape features (Symbol) and resulted in 95% sensitivity with 15 false positives per patient for detecting exophytic renal lesions. Fivefold cross-validation also demonstrated that our method could stably detect exophytic renal lesions. These encouraging results demonstrated that manifold diffusion is a key means to enable accurate computer-aided diagnosis of renal lesions.