Validation of Cell-Cycle Arrest Biomarkers for Acute Kidney Injury Using Clinical Adjudication

Abstract

Urinary [TIMP-2]·[IGFBP7] greater than 0.3 (ng/ml)(2)/1,000 identifies patients at risk for imminent AKI. Clinical trial registered with www.clinicaltrials.gov (NCT 01573962).

Inflammation in AKI

“…Therefore, the primary aim of clinical research in AKI should be to determine whether a new intervention actually ameliorates inflammationassociated kidney tissue damage during the patient's clinical stay. For this reason, measurement of markers of renal injury (e.g., urinary excretion of markers of tubular damage or cell arrest 59 and functional assessment, such as endogenous creatinine clearance or iohexol clearance 60 ) may provide more refined evidence of efficacy compared with hard clinical end points, such as patient survival, length of hospital stay, and RRTfree days. Especially for relatively small phase 2 trials with compounds that show promising data in animal studies, a combination of study drug-induced effects on these end points may facilitate the design of larger trials.…”

Tissue Inhibitor Metalloproteinase-2 (TIMP-2)⋅IGF-Binding Protein-7 (IGFBP7) Levels Are Associated with Adverse Long-Term Outcomes in Patients with AKI

“…[1][2][3][4][5][6][7] Over the last decade, there has been intense investigation of biomarkers of kidney injury in an attempt to complement and augment the diagnostic abilities of current measures of kidney function. 8 To date, little is known about the relationship between these novel biomarkers and long-term outcomes, 9,10 with only one largescale multicenter investigation linking some biomarkers collected around the time of AKI with long-term mortality. 1 We have recently published the results of a prospective, observational international investigation (the Sapphire study) of tissue inhibitor metalloprotease-2 (TIMP-2) and IGF-binding protein 7 (IGFBP7; both markers of G1 cell cycle arrest) in the setting of critical illness.…”

Biomarkers for AKI improve clinical practice: no

“…Consequently, research in the last decade has focussed on the discovery and validation of more specific and sensitive markers of tubular damage/functional impairment. The most advanced biomarkers promise to identify patients at risk of AKI, diagnose AKI earlier than conventional tests and prognosticate risk of progression, including need for (RRT) renal replacement therapy [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16]. The hope is that, with such an approach and more timely and relevant interventions, the outcome of patients with AKI can be improved.…”

“…Finally, the performance of most biomarkers for AKI is better in selected patient groups at high risk of AKI. For instance, the recently FDA approved Nephrocheck Ò , which measures two cell cycle arrest markers, insulinlike growth factor binding protein 7 and tissue metalloproteinase-2, was evaluated and validated in critically ill patients in the intensive care unit (ICU) [14,16]. Whether it performs equally well in unselected cohorts like patients in non-ICU wards or the emergency department remains to be seen.…”