Host Response Protein Biomarkers Indicative of Persistent Acute Kidney Injury in Critically Ill COVID-19 Patients

Abstract

Importance: Sepsis-related host-response anomalies contribute to acute kidney injury (AKI) duration. Data on the host-response specific to COVID-19-associated AKI (COVID-AKI) in critically ill patients is limited.

Objectives: We postulated that persistent COVID-AKI (> 48 hr) differs in host response from transient (< 48 hr) or no COVID-AKI.

Design, setting, and participants: This prospective biomarker study observed patients with severe acute respiratory syndrome coronavirus 2 infection, without chronic kidney disease, in three ICUs from March 2020 to July 2020. AKI was assessed by hourly urine output and daily plasma creatinine.

Main outcomes and measures: Luminex and enzyme-linked immunosorbent assay were used to analyze 48 plasma protein biomarkers across six pathophysiological domains, which were tested with mixed-effects models.

Results: Of 177 included patients, 106 (59.9%) had AKI within the first 48 hours of admission, of whom 76 (71.7%) had persistent AKI and 30 (28.3%) transient AKI. Those with persistent AKI often had obesity, hypertension, and a higher Sequential Organ Failure Assessment score due to the renal component. Longitudinal analyses revealed that seven proteins were elevated in persistent AKI compared with no AKI. These were related to inflammation (triggering receptor expressed on myeloid cells 1, p < 0.001; tumor necrosis factor receptor 1, p < 0.001; procalcitonin, p = 0.001), complement activation (mannan-binding lectin serine protease-2, p = 0.001), kidney dysfunction (cystatin C, p < 0.001; neutrophil gelatinase-associated lipocalin, p < 0.001), and lung dysfunction (Clara cell secretory protein 16, p < 0.001). AKI (duration) was not associated with differences in the cytokine signaling, endothelial cell activation, or coagulation domains.

Conclusions and relevance: In contrast with sepsis-associated AKI, primarily inflammation-related biomarker levels correlated with COVID-AKI persistence. This study offers insights into COVID-AKI and may guide approaches to mitigate its persistence.

Figure 1.

Relative acute kidney injury (AKI) presence during stay in the ICU, according to stage of AKI. A, Whole cohort (n = 177). B, Biomarker cohort (n = 112).

Figure 2.

Volcano plots of the differentially expressed biomarkers across groups. Measured on the first day of ICU admission, comparing: 1) patients without acute kidney injury (AKI) to AKI (at least Kidney Disease: Improving Global Outcomes stage 1; A), 2) patients without AKI and transient AKI (B), and 3) patients without AKI and persistent AKI (C). Only significant Benjamini-Hochberg (BH) adjusted biomarkers are highlighted, denoted in red (upregulated) or blue (downregulated). Gray dots represent nonsignificantly different expressed biomarkers. Each comparison was tested for statistical significance with the BH multiple testing correction. CC16 = Clara cell secretory protein 16, NGAL = neutrophil gelatinase-associated lipocalin, TNF.RI = tumor necrosis factor receptor 1, TREM.1 = triggering receptor expressed on myeloid cells 1.

Figure 3.

Seven biomarkers measured in the first 5 d after ICU admission, stratified into patients without acute kidney injury (AKI; in the first 48 hr), transient AKI, and persistent AKI. Day 1 represents ICU admission day. Overall, p values were derived from the linear mixed model, in which the group or the interaction of time × group (i.e., the trajectory) were defined as fixed effects and patient-specific intercept and slopes were defined as random effects. All 48 biomarker results were multiple testing adjusted with the Benjamini-Hochberg procedure. Line plots of observed biomarker values are shown with 95% CIs. CC16 = Clara cell secretory protein 16, NGAL = neutrophil gelatinase-associated lipocalin.

Figure 4.

Mixed model analyses of sequential plasma concentrations of biomarkers in patients who did not have acute kidney injury (AKI) in the first 48 hr and were at risk of developing AKI after 48 hr. In this analysis, patients who developed ICU-acquired AKI (n = 19) were compared with patients who did not acquire AKI (n = 12). A, Baseline differences between patients who develop ICU-acquired AKI vs. who did not, while at this stage both groups had no sign of AKI. B, Interaction analyses between the two groups and time showing biomarkers increased relatively over time in patients who developed ICU-acquired AKI compared with patients who did not acquire AKI. Mixed model included time (per day), group, and their interaction (group × time) as fixed effects, and patients specific intercept and linear slope of time as random effects. Models were not adjusted for other variables due to low sample size. Only significant estimates of biomarkers, either at baseline or interaction, are shown with p < 0.05. ADAMTS13 = a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13, CC16 = Clara cell secretory protein 16, IL = interleukin, MASP-2 = mannose-binding protein-associated serine protease 2, NGAL = neutrophil gelatinase-associated lipocalin, RAGE = receptor for advanced glycation endproducts, TFPI = tissue factor pathway inhibitor, TNF.R1 = tumor necrosis factor receptor 1, TREM.1 = triggering receptor expressed on myeloid cells 1, uPA = urokinase-type plasminogen activator, uPAR = urokinase-type plasminogen activator receptor, VWF.A2 = von Willebrand factor A2 domain.