Biomarkers in acute kidney injury - pathophysiological basis and clinical performance

Abstract

Various biomarkers of acute kidney injury (AKI) have been discovered and characterized in the recent past. These molecules can be detected in urine or blood and signify structural damage to the kidney. Clinically, they are proposed as adjunct diagnostics to serum creatinine and urinary output to improve the early detection, differential diagnosis and prognostic assessment of AKI. The most obvious requirements for a biomarker include its reflection of the underlying pathophysiology of the disease. Hence, a biomarker of AKI should derive from the injured kidney and reflect a molecular process intimately connected with tissue injury. Here, we provide an overview of the basic pathophysiology, the cellular sources and the clinical performance of the most important currently proposed biomarkers of AKI: neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), liver-type fatty acid-binding protein (L-FABP), interleukin-18 (IL-18), insulin-like growth factor-binding protein 7 (IGFBP7), tissue inhibitor of metalloproteinase 2 (TIMP-2) and calprotectin (S100A8/9). We also acknowledge each biomarker's advantages and disadvantages as well as important knowledge gaps and perspectives for future studies.

Keywords: acute kidney injury; biomarkers; calprotectin; kidney injury molecule 1 (KIM-1); neutrophil gelatinase-associated lipocalin (NGAL); tissue inhibitor of metalloproteinase-2 (TIMP-2) and IGF-binding protein 7 (IGFBP7).

Figure 1

Sites of origin of biomarkers of acute kidney injury.

Figure 2

Schematic model of the functions of neutrophil gelatinase-associated lipocalin (NGAL) (a) Siderophore–iron associated NGAL delivers iron into the cell in a megalin-dependent manner. After the uptake, NGAL traffics into the endosome from where iron is released. This results in a regulation of iron-responsive genes. (b) Siderophore-free NGAL captures siderophore-bound iron and transports it into the extracellular space.

Figure 3

Schematic model of the functions kidney injury molecule-1 (KIM-1). KIM-1 acts as a phosphatidylserine receptor and binds apoptotic cell bodies. KIM-1 binds to the alpha subunit of heterotrimeric G12 protein (Gα12), thereby mediating phagocytosis of apoptotic cell bodies. The extracellular domain of KIM-1 is shed from the cell surface by a metalloproteinase (MMP)-dependent process.

Figure 4

Schematic model of the functions of liver-type fatty acid-binding protein (L-FABP). L-FABP transports albumin bound free fatty acids (FFA) to mitochondria and peroxisomes to be metabolized. L-FABP is excreted into the tubular lumen together with bound toxic peroxisomal products, which accumulate otherwise.

Figure 5

Schematic model of the functions of interleukin-18 (IL-18). IL-18 is synthesized as an inactive precursor without a signal peptide. It is cleaved by caspase-1, which is a part of the inflammasome. Toll-like receptors (TLRs), retinoic acid-induced gene-like receptors (RIG), nucleotide-binding domain-leucine-rich repeat (NLR), scavenger receptors (SR) and C-type lectins (CLR) can activate the inflammasome. Cleaved IL-18 exerts a proinflammatory effect by activating T cells and innate lymphoid cells.

Figure 6

Schematic model of the functions of calprotectin. The two monomers S100A8 and S100A9 form calprotectin. Intracellular calprotectin’s main function is to interact with the cytoskeleton. When calprotectin is secreted by activated immune cells, it acts as a danger-associated molecular pattern protein. S100A8 and S100A9 are endogenous activators of toll-like receptor 4 (TLR4). This promotes the differentiation of monocytes to macrophages.