Role of Urinary Kidney Stress Biomarkers for Early Recognition of Subclinical Acute Kidney Injury in Critically Ill COVID-19 Patients

Abstract

A high proportion of critically ill patients with COVID-19 develop acute kidney injury (AKI) and die. The early recognition of subclinical AKI could contribute to AKI prevention. Therefore, this study was aimed at exploring the role of the urinary biomarkers NGAL and [TIMP-2] × [IGFBP7] for the early detection of AKI in this population. This prospective, longitudinal cohort study included critically ill COVID-19 patients without AKI at study entry. Urine samples were collected on admission to critical care areas for determination of NGAL and [TIMP-2] × [IGFBP7] concentrations. The demographic information, comorbidities, clinical, and laboratory data were recorded. The study outcomes were the development of AKI and mortality during hospitalization. Of the 51 individuals that were studied, 25 developed AKI during hospitalization (49%). Of those, 12 had persistent AKI (23.5%). The risk factors for AKI were male gender (HR = 7.57, 95% CI: 1.28–44.8; p = 0.026) and [TIMP-2] × [IGFBP7] ≥ 0.2 (ng/mL)2/1000 (HR = 7.23, 95% CI: 0.99–52.4; p = 0.050). Mortality during hospitalization was significantly higher in the group with AKI than in the group without AKI (p = 0.004). Persistent AKI was a risk factor for mortality (HR = 7.42, 95% CI: 1.04–53.04; p = 0.046). AKI was frequent in critically ill COVID-19 patients. The combination of [TIMP-2] × [IGFBP7] together with clinical information, were useful for the identification of subclinical AKI in critically ill COVID-19 patients. The role of additional biomarkers and their possible combinations for detection of AKI in ritically ill COVID-19 patients remains to be explored in large clinical trials.

Advances in the study of subclinical AKI biomarkers

“…According to new research, elevated NGAL in urine can detect AKI as early as 2 h ( Karademir et al, 2016 ). Haase et al discovered that high NGAL levels were related with poor results even in the lack of diagnostic SCr elevations in a pooled data analysis of 10 studies of patients hospitalized to ICU ( Casas-Aparicio et al, 2022 ). Urine NGAL was shown to detect NSAID-mediated renal tubular injury in the initial phase of renal injury in a cohort study of children with congenital heart disease who underwent cardiopulmonary bypass (CPB), and urine NGAL had good diagnostic accuracy in identifying children receiving NSAIDs, with an AUC of 0.95–0.96 at 24–48 h after administration of NSAIDs.…”

“…NGAL was also discovered to be an independent risk factor for COVID-19 patients ( He et al, 2021 ). In another cohort study, those with NGAL ≥45 ng/ml had a substantially shorter time to AKI than those with <45 ng/ml, but NGAL was not a risk factor for AKI during admission, and NGAL performed considerably better on day 7 than throughout hospitalization, implying that NGAL has a limited time window for predicting AKI and that higher NGAL thresholds appear to help predict the progression of AKI rather than the onset of AKI ( Casas-Aparicio et al, 2022 ). Because NGAL threshold value is still controversial, including NGAL in clinical prediction models to improve disease identification requires additional research.…”

“…This study discovered that urinary TIMP-2-IGFBP7 ≥0.2 (ng/ml) 2/1000 was a risk factor for AKI, and individuals with higher TIMP-2-IGFBP7 had a significantly shorter time to AKI. TIMP-2-IGFBP7, when combined with clinical information, was an excellent predictor of subclinical AKI in crucially ill COVID-19 patients (AUC: 0.682) ( Casas-Aparicio et al 2022 ). Meersch et al measured TIMP2-IGFBP7 concentrations in serial urine samples from 50 patients undergoing cardiac surgery; changes in creatinine and urine volume did not occur until 1–3 days postoperatively, whereas TIMP2-IGFBP7 concentrations began to rise as early as 4 h postoperatively in patients who had AKI, and the 4-h postoperative cutoff value demonstrated positive sensitivity and specificity, with an area under the ROC curve of 0.81 (CI: 0.68–0.93).…”

The role of kidney injury biomarkers in COVID-19

“…[ 85 ] demonstrated that the NGAL level was an independent predictor in predicting AKI. Recently, a series of studies have shown that NGAL displayed acceptable performance for predicting AKI, the need for RRT, and death [ 14 , 46 , 86 , 87 ]. In addition, one clinical trial was established to study the role of NGAL and CysC in the prediction of AKI in COVID-19 infection ( NCT04603664 ) .…”

“…Gustavo et al. [ 86 ] demonstrated that elevated values of urinary [TIMP-2] • [IGFBP7] were risk factors for AKI. A clinical trial has been established to study whether TIMP-2 and IGFBP7 could identify patients with COVID-19 at risk of developing AKI early (NCT04393428), and the findings of this investigation will be made public in the future.…”