Levels of circulating kidney injury markers and IL-10 identify non-critically ill patients with COVID-19 at risk of death

Abstract

BACKGROUNDAfter identifying 2 immunomarkers of acute injury, KIM-1 and LCN2, in all kidney biopsies from 31 patients with COVID-19 pneumonia and de novo kidney dysfunction, we investigated whether circulating markers of kidney epithelial injury are common in patients with laboratory-confirmed COVID-19 who require oxygen support but do not have critical illness.METHODSWe studied 196 patients admitted to 15 hospitals with moderate to severe pneumonia who were enrolled in 2 independent randomized clinical trials. We measured 41 immune mediators and markers of kidney and endothelial injury in peripheral blood in these patients within 24 hours of randomization.RESULTSWe constructed a generalized linear CORIMUNO model combining serum levels of KIM-1, LCN2, IL-10, and age at hospital admission that showed high discrimination for mortality (derivation cohort: AUC = 0.82, 95% CI: 0.73-0.92; validation cohort: AUC = 0.83, 95% CI: 0.74-0.92). An early rise in circulating kidney injury markers, in the absence of acute kidney injury criteria, was markedly associated with the risk of developing a severe form of COVID-19 and death within 3 months.CONCLUSIONThe CORIMUNO score may be a helpful tool for risk stratification, and for the first time to our knowledge, it identifies the overlooked impact of subclinical kidney injury on pneumonia outcomes.TRIAL REGISTRATIONClinicalTrials.gov NCT04324047, NCT04324073, and NCT04331808.FUNDINGThis research was funded by the French Ministry of Health, Programme Hospitalier de Recherche Clinique (PHRC COVID-19-20-0151, PHRC COVID-19-20-0029), Fondation de l'Assistance Publique Hôpitaux de Paris (Alliance Tous Unis Contre le Virus), Assistance Publique Hôpitaux de Paris, and grants from the Fondation pour la Recherche Médicale (FRM) (REA202010012514) and Agence Nationale de Recherches sur le Sida and emerging infectious diseases (ANRS) (ANRS0147) from the VINTED sponsorship.

Keywords: COVID-19; Clinical trials; Infectious disease; Nephrology; Outcomes research; Pulmonology.

Figure 1. KIM-1 expression in kidneys of patients with COVID-19.

(A) Representative photomicrographs of KIM-1 (red) and ACE2 (yellow) immunostaining of 3 cases of COVID-19–related acute kidney injury and 2 optically normal kidney sections. (B) Comparison of KIM-1–associated immunoreactive signal in whole slide images of kidney biopsies of 31 patients with COVID-19 and 8 controls. **P < 0.01 versus controls. Scale bars: 100 μm.

Figure 2. LCN2 expression in kidneys of patients with COVID-19.

(A) Representative photomicrographs of LCN2 (green) and KIM-1 (red) immunostaining of 1 case of COVID-19–related acute kidney injury and 3 nephropathies as controls. Membranous nephropathy (MN) and crescentic glomerulonephritis (crescentic GN) anti-neutrophil cytoplasm antibody–associated (ANCA-associated) were used as positive controls for LCN2 staining. (B) Comparison of LCN2-associated immunoreactive signal in whole slide images of kidney biopsies of 17 patients with COVID-19 and 5 controls. *P < 0.05 versus controls. Scale bars: 100 μm.

Figure 3. Comparison of KIM-1, LCN2/NGAL, and ACE2 mRNA abundance in autopsy kidneys and liver from COVID-19 critical cases and controls.

The data are expressed as DESeq2-normalized counts.

Figure 4. Feature selection using the LASSO binary logistic regression model and multivariable analysis in the training cohort.

A logistic regression was performed using the selected variables (see Table 5). Lambda = 0.10.

Figure 5. Performance of the scoring system to predict mortality of patients with COVID-19.

(A) ROC curve and AUC to assess the prediction accuracy in the training cohort. Youden index: 18.6. A threshold of 16.9 corresponded to a 98% negative predictive value, and a threshold of 20.9 corresponded to an 87% positive predictive value. (B) Kaplan-Meier survival curves with 95% CIs for high- and low-risk groups in the training cohort. sp, specificity; se, sensitivity.

Figure 6

Kaplan-Meier survival curves with 95% CIs for high- and low-risk groups in the validation cohort.

Figure 7

Kaplan-Meier survival curves of patients with COVID-19 stratified into low- and high-risk groups in the anti–IL-6R Ab treatment arms (Trt) and the usual care arms.