Currently, chronic kidney disease (CKD) lacks effective therapies, since it intricately encompasses multiple pathogenic mechanisms manifested by inflammation, fibrosis, oxidative stress and cell death. Here, we show that manifold modulations of cellular metabolism mediated by a circulating protein AIM (also called CD5L) ameliorate CKD. AIM is incorporated into renal epithelial cells and modifies the cellular lipid composition, thereby suppressing inflammation and fibrosis, while also reducing sphingomyelinase activity to suppress the conversion of sphingomyelin to ceramide. Moreover, AIM acts enzymatically to reduce oxidative stress, including lipid peroxidation, and suppresses cell death. Additionally, AIM activates Nrf2 to promote the expression of various antioxidative genes. Through these effects, recombinant AIM treatment prevents the progression of advanced CKD to end-stage uremia and dramatically improves survival in house cats, which are highly susceptible to CKD and exhibit a similar disease course to humans. Our findings suggest a potential therapeutic avenue to treat CKD based on cellular metabolism manipulation.