Prognostic Significance of Urinary Biomarkers in Patients Hospitalized With COVID-19

Abstract

Rationale & objective: Acute kidney injury (AKI) is common in patients with coronavirus disease 2019 (COVID-19) and associated with poor outcomes. Urinary biomarkers have been associated with adverse kidney outcomes in other settings and may provide additional prognostic information in patients with COVID-19. We investigated the association between urinary biomarkers and adverse kidney outcomes among patients hospitalized with COVID-19.

Study design: Prospective cohort study.

Setting & participants: Patients hospitalized with COVID-19 (n=153) at 2 academic medical centers between April and June 2020.

Exposure: 19 urinary biomarkers of injury, inflammation, and repair.

Outcome: Composite of KDIGO (Kidney Disease: Improving Global Outcomes) stage 3 AKI, requirement for dialysis, or death within 60 days of hospital admission. We also compared various kidney biomarker levels in the setting of COVID-19 versus other common AKI settings.

Analytical approach: Time-varying Cox proportional hazards regression to associate biomarker level with composite outcome.

Results: Out of 153 patients, 24 (15.7%) experienced the primary outcome. Twofold higher levels of neutrophil gelatinase-associated lipocalin (NGAL) (HR, 1.34 [95% CI, 1.14-1.57]), monocyte chemoattractant protein (MCP-1) (HR, 1.42 [95% CI, 1.09-1.84]), and kidney injury molecule 1 (KIM-1) (HR, 2.03 [95% CI, 1.38-2.99]) were associated with highest risk of sustaining primary composite outcome. Higher epidermal growth factor (EGF) levels were associated with a lower risk of the primary outcome (HR, 0.61 [95% CI, 0.47-0.79]). Individual biomarkers provided moderate discrimination and biomarker combinations improved discrimination for the primary outcome. The degree of kidney injury by biomarker level in COVID-19 was comparable to other settings of clinical AKI. There was evidence of subclinical AKI in COVID-19 patients based on elevated injury biomarker level in patients without clinical AKI defined by serum creatinine.

Limitations: Small sample size with low number of composite outcome events.

Conclusions: Urinary biomarkers are associated with adverse kidney outcomes in patients hospitalized with COVID-19 and may provide valuable information to monitor kidney disease progression and recovery.

Keywords: Acute kidney injury (AKI); COVID-19 prognosis; chronic kidney disease (CKD); coronavirus disease 2019 (COVID-19); death; dialysis; epidermal growth factor (EGF); inflammatory marker; kidney injury molecule 1 (KIM-1); monocyte chemoattractant protein 1 (MCP-1); neutrophil gelatinase-associated lipocalin (NGAL); severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); subclinical AKI; tubular injury; urinalysis; urinary biomarkers; urine microscopy.

Graphical abstract

Figure 1

Risk of stage 3 AKI, new dialysis initiation, or death within 60 days of hospital admission by urinary biomarker level, indexed to urine creatinine and adjusted for World Health Organization disease severity scale. Abbreviations: AKI, acute kidney injury; EGF, epidermal growth factor; IFNγ, interferon γ; IL, interleukin; KIM-1, kidney injury molecule 1; MCP-1, monocyte chemoattractant protein 1; NGAL, neutrophil gelatinase-associated lipocalin; OPN, osteopontin; TFN-α, tumor necrosis factor α; UMOD, uromodulin; WHO, World Health Organization; YKL-40, chitinase-3-like protein 1.

Figure 2

Heat map showing the percentage of patients who have AKI in the setting of COVID-19, patients after cardiac surgery (TRIBE-AKI cohort), patients after brain death (DDS cohort), and patients in the setting of exercise stress (marathon-associated AKI). For exercise stress-associated AKI, blood and urine biomarkers were measured from biosamples obtained within 30 minutes of completing a marathon. The colors denote the percentage of patients by AKI stage who have biomarker levels above the 90th percentile of reference value, based on cardiac surgery preoperative values. Among patients with COVID-19–associated AKI, 40%, 50%, and 60% of patients with stage 1, 2, and 3 AKI, respectively, had KIM-1 levels above the 90th percentile of reference. Similarly, among kidney donors after brain death, 70%, 80%, and 90% of patients with stage 1, 2, and 3 AKI, respectively, had MCP-1 levels above the 90th percentile of reference. Note: Sample sizes by AKI stage: COVID-19: stage 1 (n = 56), stage 2 (n = 31), stage 3 (n = 20); cardiac surgery: stage 1 (n = 456), stage 2 (n = 34), stage 3 (n = 31); brain death: stage 1 (n = 275), stage 2 (n = 93), stage 3 (n = 76); exercise stress: stage 1 (n = 9), stage 2 (n = 2). Abbreviations: AKI, acute kidney injury; COVID-19, coronavirus disease 2019; DDS, Deceased Donor Study; EGF, epidermal growth factor; IL, interleukin; KIM-1, kidney injury molecule 1; MCP1, monocyte chemoattractant protein 1; NGAL, neutrophil gelatinase-associated lipocalin; TRIBE-AKI, Translational Research Investigating Biomarker Endpoints in Acute Kidney Injury; UMOD, uromodulin; YKL-40, chitinase-3-like protein 1.

Figure 3

The percentage of patients with COVID-19 (n = 116) and patients immediately after cardiac surgery (samples taken within 6 hours of end of surgery; n = 1,044) with urinary biomarker levels above the 90th percentile of reference values, defined by preoperative urinary biomarker levels in patients immediately before cardiac surgery. In both clinical settings, approximately 30%-40% of patients had urinary NGAL levels above the 90th percentile of reference values. Approximately 25% of patients with COVID-19 and no AKI had KIM-1 levels above reference, and nearly 60% of patients after cardiac surgery had KIM-1 levels above reference. Abbreviations: AKI, acute kidney injury; COVID-19, coronavirus disease 2019; EGF, epidermal growth factor; IL, interleukin; KIM-1, kidney injury molecule 1; MCP-1, monocyte chemoattractant protein 1; NGAL, neutrophil gelatinase-associated lipocalin; UMOD, uromodulin; YKL-40, chitinase-3-like protein 1.