Systemic Human Neutrophil Lipocalin Associates with Severe Acute Kidney Injury in SARS-CoV-2 Pneumonia

Abstract

Neutrophils have been suggested mediators of organ dysfunction in COVID-19. The current study investigated if systemic neutrophil activity, estimated by human neutrophil lipocalin (HNL) concentration in peripheral blood, is associated with acute kidney injury (AKI) development. A total of 103 adult patients admitted to intensive care, with PCR-confirmed SARS -CoV-2 infection, were prospectively included (Clinical Trials ID: NCT04316884). HNL was analyzed in plasma (P-HNL Dimer) and in whole blood (B-HNL). The latter after ex vivo activation with N-formyl-methionine-leucine-phenylalanine. All patients developed respiratory dysfunction and 62 (60%) were treated with invasive ventilation. Sixty-seven patients (65%) developed AKI, 18 (17%) progressed to AKI stage 3, and 14 (14%) were treated with continuous renal replacement therapy (CRRT). P-HNL Dimer was higher in patients with invasive ventilation, vasopressors, AKI, AKI stage 3, dialysis, and 30-day mortality (p < 0.001–0.046). B-HNL performed similarly with the exception of mild AKI and mortality (p < 0.001–0.004). The cohort was dichotomized by ROC estimated cutoff concentrations of 13.2 µg/L and 190 µg/L for P-HNL Dimer and B-HNL respectively. Increased cumulative risks for AKI, AKI stage 3, and death were observed if above the P-HNL cutoff and for AKI stage 3 if above the B-HNL cutoff. The relative risk of developing AKI stage 3 was nine and 39 times greater if above the cutoffs in plasma and whole blood, respectively, for CRRT eight times greater for both. In conclusion, systemically elevated neutrophil lipocalin, interpreted as increased neutrophil activity, was shown to be associated with an increased risk of severe AKI, renal replacement therapy, and mortality in COVID-19 patients with respiratory failure.

Impaired Antibody Response Is Associated with Histone-Release, Organ Dysfunction and Mortality in Critically Ill COVID-19 Patients

“…However, it is possible that the increased levels of histones are a marker of unspecific cell damage and are not linked to NET formation. Previous research shows that the number of neutrophils and markers of NETosis are elevated in severe COVID-19 patients [ 22 ], and a link has been suggested between NETosis and poor outcome [ 23 ], indicating a crucial contribution of NETs to the severity of the COVID-19 disease [ 24 , 25 ]. An association has also been described between anti-SARS-CoV-2 IgA2, NET formation and poor outcome [ 46 ].…”

“…We hypothesised that a delayed or absent adaptive immune response in critically ill patients with COVID-19 would cause higher mortality and organ failure. Several groups have also reported that SARS-CoV-2 can induce neutrophil extracellular trap (NET) formation in neutrophiles and that NET-formation could be part of the immunopathology in severe COVID-19 [ 19 , 20 , 21 , 22 , 23 , 24 , 25 ].…”

The Human Phospholipase B-II Precursor (HPLBII-P) in Urine as a Novel Biomarker of Glomerular Activity in COVID-19 and Diabetes Mellitus

“…One hundred and thirty two patients were admitted to the ICU (Intensive Care Unit) of Uppsala University Hospital with SARS-CoV-2 infections as diagnosed with PCR and signs of organ failure. Detailed information of the patient demographics was given previously [4,5].…”

The Human Phospholipase B-II Precursor (HPLBII-P) in Urine as a Novel Biomarker of Glomerular Activity in COVID-19 and Diabetes Mellitus

“…One hundred and thirty-two patients were admitted to the ICU (intensive care unit) of Uppsala University Hospital with SARS-CoV-2 infections as diagnosed with PCR and signs of organ failure. Detailed information of the patient demographics was given previously [10,11]. The healthy group consisted of 40 women (median age 32 years, range 22-64 years) and 18 men (median age 26 years, range 22-63 years).…”