Proposed mechanistic involvement of the novel biomarkers in AKI: initial tubular cells sustain injury by various insults. In response to DNA and possibly other forms of damage, IGFBP7 and TIMP-2 are expressed in the tubular cells. IGFBP7 directly increases the expression of p53 and p21 and TIMP-2 stimulates p27 expression. These effects are conducted in an autocrine and paracrine manner via IGFBP7 and TIMP-2 receptors. The p proteins in turn, block the effect of the cyclin-dependent protein kinase complexes (CyclD-CDK4 and CyclE-CDK2) on the cell cycle promotion, thereby resulting in G1 cell cycle arrest for short periods of time presumably to avoid cells with possible damage from dividing. AKI, acute kidney injury; IGFBP7, insulin-like growth factor-binding protein 7; TIMP-2, tissue inhibitor of metalloproteinases-2.