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Objectives This study aimed to determine the diagnostic and prognostic value of urinary biomarkers of intrinsic acute kidney injury (AKI) when patients were triaged in the emergency department. Background Intrinsic AKI is associated with nephron injury and results in poor clinical outcomes. Several urinary biomarkers have been proposed to detect and measure intrinsic AKI. Methods In a multicenter prospective cohort study, 5 urinary biomarkers (urinary neutrophil gelatinase–associated lipocalin, kidney injury molecule-1, urinary liver-type fatty acid binding protein, urinary interleukin-18, and cystatin C) were measured in 1,635 unselected emergency department patients at the time of hospital admission. We determined whether the biomarkers diagnosed intrinsic AKI and predicted adverse outcomes during hospitalization. Results All biomarkers were elevated in intrinsic AKI, but urinary neutrophil gelatinase-associated lipocalin was most useful (81% specificity, 68% sensitivity at a 104-ng/ml cutoff) and predictive of the severity and duration of AKI. Intrinsic AKI was strongly associated with adverse in-hospital outcomes. Urinary neutrophil gelatinase-associated lipocalin and urinary kidney injury molecule 1 predicted a composite outcome of dialysis initiation or death during hospitalization, and both improved the net risk classification compared with conventional assessments. These biomarkers also identified a substantial subpopulation with low serum creatinine at hospital admission, but who were at risk of adverse events. Conclusion Urinary biomarkers of nephron damage enable prospective diagnostic and prognostic stratification in the emergency department.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) constitutes life-threatening autoimmune diseases affecting every organ, including the kidneys, where they cause necrotizing crescentic glomerulonephritis. ANCA activates neutrophils and activated neutrophils damage the endothelium, leading to vascular inflammation and necrosis. Better understanding of neutrophil-mediated AAV disease mechanisms may reveal novel treatment strategies. Here we report that ANCA induces neutrophil extracellular traps (NETs) via receptor-interacting protein kinase (RIPK) 1/3- and mixed-lineage kinase domain-like (MLKL)-dependent necroptosis. NETs from ANCA-stimulated neutrophils caused endothelial cell (EC) damage in vitro. This effect was prevented by () pharmacologic inhibition of RIPK1 or () enzymatic NET degradation. The alternative complement pathway (AP) was recently implicated in AAV, and C5a inhibition is currently being tested in clinical studies. We observed that NETs provided a scaffold for AP activation that in turn contributed to EC damage. We further established the in vivo relevance of NETs and the requirement of RIPK1/3/MLKL-dependent necroptosis, specifically in the bone marrow-derived compartment, for disease induction using murine AAV models and in human kidney biopsies. In summary, we identified a mechanistic link between ANCA-induced neutrophil activation, necroptosis, NETs, the AP, and endothelial damage. RIPK1 inhibitors are currently being evaluated in clinical trials and exhibit a novel therapeutic strategy in AAV.

In established acute kidney injury (AKI), serum creatinine poorly differentiates prerenal and intrinsic AKI. A damage-associated nephron biomarker, neutrophil gelatinase-associated lipocalin (NGAL) could be a better discriminator. We tested the hypothesis that urinary NGAL distinguishes intrinsic and prerenal AKI, and tested its performance in the prediction of a composite outcome that included progression to a higher RIFLE (“risk, injury, failure, loss of function, end stage renal disease”) severity class, dialysis, or death. We measured urinary NGAL in 161 hospitalized patients with established AKI using a standardized clinical platform. We excluded 16 patients with postrenal obstruction or insufficient clinical information. Of the remaining 145 patients, 75 patients had intrinsic AKI, 32 patients had prerenal AKI, and 38 patients could not be classified. We found that urinary NGAL levels effectively discriminated intrinsic AKI from prerenal AKI (ROC 0.87, CI 0.81-0.94). An NGAL level >104 μg/L indicated intrinsic AKI (likelihood ratio 5.97), while an NGAL level <47 μg/L made intrinsic AKI unlikely (likelihood ratio 0.2). Patients experiencing the composite outcome had higher median urinary NGAL levels on inclusion (248.2 vs. 68.3 μg/L, p<0.001). In logistic regression analysis, NGAL independently predicted the composite outcome, when corrected for demographics, co-morbidities, creatinine, and RIFLE class. Hence, urinary NGAL is useful in classifying and stratifying patients with established AKI.