Fig. 2
From: Moving toward a contemporary classification of drug-induced kidney disease
Some novel functional and damage biomarkers of the kidney can help to classify drug-induced kidney disease based on the suggested framework by Ostermann et al. [10]. Damage biomarkers are related to different sites of the kidney and are mostly site-specific. KIM-1 is a cell membrane glycoprotein upregulated in the presence of nephrotoxic/ischemic damage to proximal tubule epithelial cells. NGAL is a glycoprotein expressed in various tissues, including the kidney. Its expression is markedly upregulated after kidney ischemia. IL-18 is a pro-inflammatory cytokine expressed during proximal tubular injury. L-FABP is expressed in the proximal tubule, and its expression is augmented by hypoxic stress. β2M is a low molecular weight polypeptide that presents on the cell surface of all nucleated cells. In the case of tubular dysfunction, its level in urine will increase. TIMP-2 and IGFBP7 are preferentially expressed and secreted from distal and proximal tubules, respectively, in response to stress and damage. All these damage biomarkers have preliminary clinical evidence that is promising. Urinary KIM-1 and NGAL have the most clinical evidence in the setting of drug-induced kidney disease [42]. Besides these two biomarkers, urinary IL-18, L-FABP, and TIMP-2·IGFBP7 can also help diagnose ATI early and differentiate injury from dysfunction. Urinary TIMP-2·IGFBP7 appears to be an appropriate candidate damage biomarker of DIKD, particularly in preoperative and critically ill settings, because of its features discussed elsewhere [43, 44]. Three novel functional biomarkers in serum have been introduced and studied in clinical settings. CysC is a low molecular weight protein produced by all nucleated cells and cleared only by glomerular filtration [41]. PENK is the precursor polypeptide hormone of the enkephalin family freely filtered in the glomerulus [40]. BTP is a small protein primarily produced in the cerebral fluid and eliminated by glomerular filtration [41]. Except for plasma CysC, there are currently no clinical data on other novel functional biomarkers of the kidney associated with medications. Despite promising findings with novel functional and damage biomarkers, they should be interpreted cautiously because AKI, the primary endpoint in these studies, is mostly diagnosed by changes in serum creatinine concentration rather than specific biomarkers. CysC, Cystatin C; PENK, Proenkephalin A; BTP, β-trace protein; KIM-1, Kidney injury molecule-1; NGAL, Neutrophil gelatinase-associated lipocalin; IL-18, Interleukin-18; L-FABP, Liver-type fattyacid-binding protein; β2M, Beta-2 microglobulin; IGFBP7, Insulin-like growth factor binding protein 7; TIMP-2, Tissue inhibitor of metalloproteinases-2