Tissue inhibitor of metalloproteinase 2 and insulin-like growth factor binding protein 7 are cell cycle arrest biomarkers that have demonstrated, in recent clinical trials, to have good sensitivity and specificity for early detection of AKI.
In 2014, the US Food and Drug Administration permitted marketing of NephroCheck® (Astute Medical) (measuring urinary [TIMP-2]·[IGFBP7]) to determine if certain critically-ill patients are at risk of developing moderate to severe AKI.
Urinary [TIMP-2] × [IGFBP-7] was not predictive for AKI at the end of OLT (AUC: 0.54, CI [0.32-0.75], P = 0.72), at day 1 (AUC: 0.60, CI [0.41-0.79], P = 0.31), or day 2 after OLT (AUC: 0.63, CI [0.46-0.8], P = 0.18).
The aim of this analysis was to evaluate the utility of [TIMP-2] × [IGFBP7] measured serially to anticipate the occurrence of AKI over the first 7 days of critical illness.
Comparison of urinary TIMP-2 and IGFBP7 cut-offs to predict acute kidney injury in critically ill patients: A PRISMA-compliant systematic review and meta-analysis.
The product of urinary tissue inhibitor of metalloproteinase-2 and insulin-like growth factor-binding protein 7 ([TIMP-2]•[IGFBP7]) was significantly elevated in the AKI subgroup at 12 h (P < 0.05), hence 24 h earlier than the increase in SCr.
The maximum [TIMP-2]·[IGFBP7] between these 2 timepoints provided an area under the receiver operating characteristic curve of 0.82 (95% confidence interval [CI], 0.73-0.90), 100% sensitivity, and 100% negative predictive value using the >0.3 cutoff to predict stage 2 or 3 AKI.
In this prospective randomized controlled intervention trial, patients at high risk for AKI were screened with urinary [TIMP-2]·[IGFBP7] in the ED of Robert-Bosch-Hospital (Stuttgart, Germany).
The median [IQR] baseline [TIMP-2]*[IGFBP7] level was higher in patients who developed severe AKI (1.57 [0.80-6.62] (ng/ml)<sup>2</sup>/1000) than in those who did not (0.17 [0.05-0.59] (ng/ml)<sup>2</sup>/1000; p < 0.001).
Other biomarkers of drug-induced kidney toxicity that have been detected in the urine of rodents or patients include IL-18, neutrophil gelatinase-associated lipocalin, netrin-1, liver-type fatty acid-binding protein (L-FABP), urinary exosomes, and TIMP2 (insulin-like growth factor-binding protein 7)/IGFBP7 (insulin-like growth factor-binding protein 7), also known as NephroCheck, the first Food and Drug Administration-approved biomarker testing platform to detect acute kidney injury in patients.
Secondary analysis examined the relationship between tissue inhibitor of metalloproteinases-2 ([TIMP-2]) and insulin growth factor binding protein 7 ([IGFBP7]) and 9-month death or dialysis conditioned on progression to stage 2-3 acute kidney injury within 1 week.
Four hundred and thirty patients will be randomized to the intervention (withholding ACEIs/ARBs) or control (continue/start ACEIs/ARBs) arms for 72 h. Primary outcomes include rates of acute kidney injury (AKI), patient global assessment, and change in kinetic eGFR over 72 h, while secondary outcomes include change in weight, fluid balance, change in signs and symptoms of congestion, change in renal function, change in urinary biomarkers (tissue inhibitor of metalloproteinases 2 [TIMP-2] × insulin-like growth factor-binding protein 7 [IGFBP7]), patients experiencing treatment failure, hospital length of stay (LOS), cost analysis, mortality within 30 days, and hospital readmissions over 30 days and 1 year.
[TIMP-2]∙[IGFBP7] at ICU admission had a lower performance in predicting AKI at any stage within 48 hours and 7 days after measurement (area under the receiver operating characteristic curve (AUC) equal to 0.70 (95%CI 0.65-0.76), AUC 0.68 (95%CI 0.63-0.73)).
Cell cycle arrest urinary biomarkers insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP2) provide early detection of kidney stress and possibly AKI.
To evaluate this, we conducted a cohort study, measuring [TIMP2]•[IGFBP7] levels in critically ill patients admitted to the ICU and classified the patients as NephroCheck (NC) (+) or NC (-) according to [TIMP-2]•[IGFBP7] values and AKI (+) or AKI (-) according to Kidney Disease: Improving Global Outcomes (KDIGO) criteria.
Further prospective studies are needed to confirm these findings in a real-world setting.Key points for decision makersAn economic model was constructed to determine the budget impact of adding a diagnostic test ([TIMP-2]·[IGFBP7]), which identifies patients at risk of moderate-to-severe acute kidney injury, to the current standard of care (SOC) in a hospital setting.According to the present model, the use of [TIMP-2]·[IGFBP7] to identify acute kidney injury risk may reduce costs for hospitals by ∼$1,578 per patient tested.
Urinary tissue inhibitor of metalloproteinases-2 (TIMP-2) and insulin-like growth factor binding protein-7 (IGFBP7) have been validated as biomarkers for acute kidney injury.
Urinary [TIMP-2]·[IGFBP7] is an effective predictive test for cardiac surgery associated acute kidney injury with good diagnostic accuracy within 24 h. Studies examining use of biomarker-guided care bundles are indicated.
A combination of urinary cell cycle arrest markers, tissue inhibitor of metalloproteinase-2 (TIMP-2) and insulin-like growth factor binding protein7 (IGFBP7), is validated for the early prediction of acute kidney injury in non-obstetric patients.
Both tissue inhibitor metalloproteinase type 2 and insulin-like growth factor-binding protein type 7 (TIMP-2*IGFBP-7) ≥0.78 at 12 hours (OR 2.72; 95% CI, 1.01-7.38; P = 0.04) and kidney injury molecule 1 (KIM-1) ≥529.57 at 24 hours (OR 2.76; 95% CI, 1.06-7.17; P = 0.04) predicted excessive milrinone activity before a diagnosis of AKI.