NephroCheck at 10: addressing unmet needs in AKI diagnosis and risk stratification

Abstract

Despite its name, the current diagnosis of acute kidney injury (AKI) still depends on markers of decreased kidney function and not on markers of injury. This results in a delayed diagnosis: AKI is diagnosed based on serum creatinine criteria only when the severity of injury is enough to decrease glomerular filtration rate. Moreover, by the time AKI is diagnosed, the insult may have already ceased, and even appropriate therapy targeted at the specific insult and its associated pathogenic pathways may no longer be effective. Biomarkers of injury are needed that allow the diagnosis of AKI based on injury criteria. At least three commercially available immunoassays assessing urinary or plasma neutrophil gelatinase-associated lipocalin and urinary tissue inhibitor of metalloproteinases-2 × insulin-like growth factor-binding protein-7 ([TIMP2]*[IGFBP7]) (NephroCheck^®) have generated promising data regarding prediction and early diagnosis of AKI, although their relative performance may depend on clinical context. Recently, a urinary peptidomics classifier (PeptAKI) was reported to predict AKI better than current biomarkers. Focusing on [TIMP2]*[IGFBP7], the cellular origin of urinary TIMP2 and IGFBP7 remains unclear, especially under the most common predisposing condition for AKI, i.e. chronic kidney disease. We now discuss novel data on the kidney cell expression of TIMP2 and IGFBP7 and its clinical implications.

Keywords: IGFBP7; NGAL; NephroCheck; TIMP2; acute kidney injury; biomarkers; chronic kidney disease; urinary proteomics.

Figure 1:

Decrease in eGFR associated with an increase in serum creatinine of 0.3 mg/dL or more in individuals with different levels on baseline serum creatinine. Baseline eGFR and eGFR after serum creatinine increase by 0.3 mg/dL was estimated in females aged 20 years using the 2009 CKD Epidemiology Collaboration equation without using race correction. For the calculations, it was assumed that following the increase in serum creatinine that allowed the diagnosis of AKI, serum creatinine remained stable thereafter for at least a week.

Figure 2:

Number of publications in PubMed retrieved by the query “(nephrocheck OR TIMP2 OR IGFBP7) AND acute kidney injury” on 15 February 2023.

Figure 3:

Potential sources of urinary TIMP2 and IGFBP7. Urinary [TIMP2]*[IGFBP7] values may be the end-result of multiple simultaneous or sequential processes. (1) Both molecules may be released from injured organs outside the kidneys. For example, this has been shown for the injured heart. (2) Circulating TIMP2 and IGFBP7 of non-renal origin may be filtered by normal glomeruli, given that they are small proteins. Increased non-renal production with subsequent increased glomerular filtration may contribute to higher urinary [TIMP2]*[IGFBP7] levels and to their association with adverse outcomes if urinary [TIMP2]*[IGFBP7] represents more severe non-renal injury. (3) As for other small proteins, proximal tubular cells could reabsorb both TIMP2 and IGFBP7. Injured proximal tubular cells may fail to reabsorb TIMP2 and IGFBP7 and this may also contribute to higher urinary [TIMP2]*[IGFBP7] levels and to their association with adverse outcomes. (4) Additionally, both TIMP2 and IGFBP7 can directly injure proximal tubular cells. The fact that both molecules may cause tubular cell injury may also contribute to explain the association between higher urinary [TIMP2]*[IGFBP7] levels and adverse outcome. (5) Immunostaining of human kidney tissue has localized IGFBP7 to tubular cells, mainly proximal tubular cells. Gene expression data and the fact that IGFBP7 immunostaining is not limited to proximal tubular cells support that proximal tubular cells are indeed a source of IGFBP7 beyond any immunostaining resulting from reabsorbed proteins. Increased IGFBP7 release from injured proximal tubular cells may contribute to higher urinary [TIMP2]*[IGFBP7] levels and to their association with adverse outcome. (6) Finally, immunostaining of human kidney tissue has localized TIMP2 to distal tubular cells, suggesting that they may be a source of urinary TIMP2. TIMP2 release from injured distal tubular cells may contribute to higher urinary [TIMP2]*[IGFBP7] levels and to their association with adverse outcomes. (7) Overall, urinary [TIMP2]*[IGFBP7] may be the end result of multiple processes, each of which may be independently associated with more severe kidney injury.