*2.4. Pre-Injury Phase Biomarkers IGFBP-7*/*TIMP-2*

Insulin-like growth factor binding protein 7 (IGFBP-7) is a 29 kDa protein, a member of IGFBPs. It is a kind of glycoprotein with a molecular weight of 30 kDa. IGFBP-7 is known to bind and inhibit signaling through IGF-1 receptors [8]. Urinary IGFBP-7 is increased in kidney damage caused by sepsis or ischemia [8,9].

TIMP-2 is a 21 kDa protein, a member of the TIMP family. TIMP2 is a member of the tissue inhibitor of matrix metalloproteinase family. TIMP2 is an endogenous inhibitor of metalloproteinase activities and participates in the regulation of cell growth and apoptosis [8,9].

Combined urinary IGFBP-7 and TIMP-2 predict the occurrence of AKI better than other markers (NGAL KIM, IL19) [8,9]. NephroCheck, which combines TIMP-2 and IGFBP-7, is the only FDA-approved AKI biomarker test for use in the USA and is also used in some European countries [10].

Surprisingly, IGFBP-7 and TIMP-2 were studied only in one study after exercise. Chapman et al. studied thirteen healthy adults exercising in heat (the study is described above) and found elevated levels of uIGFBP-7 and uTIMP-2. There was a greater increase in the urinary biomarkers of AKI in the *Control* group. The differential findings between IGFBP7 (preferentially secreted in the proximal tubules) and TIMP-2 (secreted in the distal tubules) suggested that the proximal tubules are the location of potential renal injury [43].
