Systemic Human Neutrophil Lipocalin Associates with Severe Acute Kidney Injury in SARS-CoV-2 Pneumonia
Sara Bülow Anderberg, Miklos Lipcsey, Michael Hultström, Ann-Katrin Eriksson, Per Venge, Robert Frithiof, On Behalf Of The Uppsala Intensive Care Covid-Research Group, Sara Bülow Anderberg, Miklos Lipcsey, Michael Hultström, Ann-Katrin Eriksson, Per Venge, Robert Frithiof, On Behalf Of The Uppsala Intensive Care Covid-Research Group
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.
Keywords: COVID-19; HNL; acute kidney injury; intensive care; neutrophils.
Conflict of interest statement
Per Venge is the inventor and holds patents of measuring neutrophil-specific dimeric HNL by unique antibodies and HNL after activation in whole blood. None of the other authors declare any conflict of interest.
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References
- Tyrrell C.S.B., Mytton O.T., Gentry S.V., Thomas-Meyer M., Allen J.L.Y., Narula A.A., McGrath B., Lupton M., Broadbent J., Ahmed A., et al. Managing intensive care admissions when there are not enough beds during the COVID-19 pandemic: A systematic review. Thorax. 2020;76:302–312. doi: 10.1136/thoraxjnl-2020-215518.
- Armstrong R.A., Kane A.D., Cook T.M. Outcomes from intensive care in patients with COVID-19: A systematic review and meta analysis of observational studies. Anaesthesia. 2020;75:1340–1349. doi: 10.1111/anae.15201.
- Nadim M.K., Forni L.G., Mehta R.L., Connor M.J., Jr., Liu K.D., Ostermann M., Rimmelé T., Zarbock A., Bell S., Bihorac A., et al. COVID-19-associated acute kidney injury: Consensus report of the 25th Acute Disease Quality Initiative (ADQI) Workgroup. Nat. Rev. Nephrol. 2020;16:747–764. doi: 10.1038/s41581-020-00356-5.
- Luther T., Bülow-Anderberg S., Larsson A., Rubertsson S., Lipcsey M., Frithiof R., Hultström M. COVID-19 patients in intensive care develop predominantly oliguric acute kidney injury. Acta Anaesthesiol. Scand. 2021;65:364–372. doi: 10.1111/aas.13746.
- Dexamethasone in Hospitalized Patients with Covid-19—Preliminary Report. N. Engl. J. Med. 2020;384:693–704.
- Horby P.W., Campbell M., Staplin N., Spata E., Emberson J.R., Pessoa-Amorim G., Peto L., Brightling C.E., Sarkar R., Thomas K., et al. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): Preliminary results of a randomised, controlled, open-label, platform trial. medRxiv. 2021 doi: 10.1101/2021.02.11.21249258.
- RECOVERY Collaborative Group Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): A randomised, controlled, open-label, platform trial. Lancet. 2021;397:1637–1645. doi: 10.1016/S0140-6736(21)00676-0.
- Rosales C. Neutrophils at the crossroads of innate and adaptive immunity. J. Leukoc. Biol. 2020;108:377–396. doi: 10.1002/JLB.4MIR0220-574RR.
- Mayadas T.N., Cullere X., Lowell C.A. The multifaceted functions of neutrophils. Annu. Rev. Pathol. 2014;9:181–218. doi: 10.1146/annurev-pathol-020712-164023.
- Grudzinska F.S., Sapey E. Friend or foe? The dual role of neutrophils in lung injury and repair . Thorax. 2018;73:305–307.
- Hellebrekers P., Vrisekoop N., Koenderman L. Neutrophil phenotypes in health and disease. Eur. J. Clin. Investig. 2018;48:e12943. doi: 10.1111/eci.12943.
- Tomar B., Anders H.J., Desai J., Mulay S.R. Neutrophils and Neutrophil Extracellular Traps Drive Necroinflammation in COVID-19. Cells. 2020;9:1383. doi: 10.3390/cells9061383.
- Ponti G., Maccaferri M., Ruini C., Tomasi A., Ozben T. Biomarkers associated with COVID-19 disease progression. Crit. Rev. Clin. Lab Sci. 2020;57:389–399. doi: 10.1080/10408363.2020.1770685.
- Liu J., Liu Y., Xiang P., Pu L., Xiong H., Li C., Zhang M., Tan J., Xu Y., Song R., et al. Neutrophil-to-lymphocyte ratio predicts critical illness patients with 2019 coronavirus disease in the early stage. J. Transl. Med. 2020;18:206. doi: 10.1186/s12967-020-02374-0.
- Veras F.P., Pontelli M.C., Silva C.M., Toller-Kawahisa J.E., de Lima M., Nascimento D.C., Schneider A.H., Caetité D., Tavares L.A., Paiva I.M., et al. SARS-CoV-2-triggered neutrophil extracellular traps mediate COVID-19 pathology. J. Exp. Med. 2020;217:e20201129. doi: 10.1084/jem.20201129.
- Huckriede J., Anderberg S.B., Morales A., de Vries F., Hultström M., Bergqvist A., Ortiz-Pérez J.T., Sels J.W., Wichapong K., Lipcsey M., et al. Evolution of NETosis markers and DAMPs have prognostic value in critically ill COVID-19 patients. Sci. Rep. 2021;11:15701.
- Radermecker C., Detrembleur N., Guiot J., Cavalier E., Henket M., d’Emal C., Vanwinge C., Cataldo D., Oury C., Delvenne P., et al. Neutrophil extracellular traps infiltrate the lung airway, interstitial, and vascular compartments in severe COVID-19. J. Exp. Med. 2020;217 doi: 10.1084/jem.20201012.
- Chakraborty S., Kaur S., Guha S., Batra S.K. The multifaceted roles of neutrophil gelatinase associated lipocalin (NGAL) in inflammation and cancer. Biochim. Biophys. Acta-Rev. Cancer. 2012;1826:129–169. doi: 10.1016/j.bbcan.2012.03.008.
- Vogt K.L., Summers C., Chilvers E.R., Condliffe A.M. Priming and de-priming of neutrophil responses in vitro and in vivo. Eur. J. Clin. Investig. 2018;48:e12967. doi: 10.1111/eci.12967.
- Xu S.Y., Carlson M., Engström A., Garcia R., Peterson C.G., Venge P. Purification and characterization of a human neutrophil lipocalin (HNL) from the secondary granules of human neutrophils. Scand. J. Clin. Lab Investig. 1994;54:365–376. doi: 10.3109/00365519409088436.
- Cai L., Rubin J., Han W., Venge P., Xu S. The origin of multiple molecular forms in urine of HNL/NGAL. Clin. J. Am. Soc. Nephrol. 2010;5:2229–2235. doi: 10.2215/CJN.00980110.
- Awad A.S., Rouse M., Huang L., Vergis A.L., Reutershan J., Cathro H.P., Linden J., Okusa M.D. Compartmentalization of neutrophils in the kidney and lung following acute ischemic kidney injury. Kidney Int. 2009;75:689–698. doi: 10.1038/ki.2008.648.
- Törnblom S., Nisula S., Vaara S.T., Poukkanen M., Andersson S., Pettilä V., Pesonen E. Neutrophil activation in septic acute kidney injury: A post hoc analysis of the FINNAKI study. Acta Anaesthesiol. Scand. 2019;63:1390–1397. doi: 10.1111/aas.13451.
- Moreno R.P., Metnitz P.G., Almeida E., Jordan B., Bauer P., Campos R.A., Iapichino G., Edbrooke D., Capuzzo M., Le Gall J.-R. SAPS 3--From evaluation of the patient to evaluation of the intensive care unit. Part 2: Development of a prognostic model for hospital mortality at ICU admission. Intensive Care Med. 2005;31:1345–1355. doi: 10.1007/s00134-005-2763-5.
- Vincent J.L., Moreno R., Takala J., Willatts S., De Mendonça A., Bruining H., Reinhart C.K., Suter P., Thijs L.G. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med. 1996;22:707–710. doi: 10.1007/BF01709751.
- Khwaja A. KDIGO clinical practice guidelines for acute kidney injury. Nephron. Clin. Pract. 2012;120:c179–c184. doi: 10.1159/000339789.
- Venge P., Håkansson L.D., Garwicz D., Peterson C., Xu S., Pauksen K. Human neutrophil lipocalin in fMLP-activated whole bloodas a diagnostic means to distinguish between acute bacterial and viral infections. J. Immunol. Methods. 2015;424:85–90. doi: 10.1016/j.jim.2015.05.004.
- Yu Z., Jing H., Hongtao P., Furong J., Yuting J., Xu S., Venge P. Distinction between bacterial and viral infections by serum measurementof human neutrophil lipocalin (HNL) and the impact of antibody selection. J. Immunol. Methods. 2016;432:82–86. doi: 10.1016/j.jim.2016.02.014.
- Ronco C., Bellomo R., Kellum J.A. Acute kidney injury. Lancet. 2019;394:1949–1964. doi: 10.1016/S0140-6736(19)32563-2.
- Hultström M., von Seth M., Frithiof R. Hyperreninemia and low total body water may contribute to acute kidney injury inCOVID-19 patients in intensive care. J. Hypertens. 2020;38:1613–1614. doi: 10.1097/HJH.0000000000002531.
- Fisher M., Neugarten J., Bellin E., Yunes M., Stahl L., Johns T.S., Abramowitz M.K., Levy R., Kumar N., Mokrzycki M.H., et al. AKI in Hospitalized Patients with and without COVID-19: A Comparison Study. J. Am. Soc. Nephrol. 2020;31:2145–2157. doi: 10.1681/ASN.2020040509.
- Ikizler T.A., Parikh C.R., Himmelfarb J., Chinchilli V.M., Liu K.D., Coca S.G., Garg A.X., Hsu C.-Y., Siew E.D., Wurfel M.M., et al. A prospective cohort study of acute kidney injury and kidney outcomes, cardiovascular events, and death. Kidney Int. 2021;99:456–465. doi: 10.1016/j.kint.2020.06.032.
- Schurink B., Roos E., Radonic T., Barbe E., Bouman C.S.C., de Boer H.H., de Bree G.J., Bulle E.B., Aronica E.M., Florquin S., et al. Viral presence and immunopathology in patients with lethal COVID-19: A prospective autopsy cohort study. Lancet Microbe. 2020;1:e290–e299. doi: 10.1016/S2666-5247(20)30144-0.
- Bermejo-Martin J.F., González-Rivera M., Almansa R., Micheloud D., Tedim A.P., Domínguez-Gil M., Resino S., Martín-Fernández M., Murua P.R., Pérez-García F., et al. Viral RNA load in plasma is associated with critical illness and a dysregulated host response in COVID-19. Crit. Care. 2020;24:691. doi: 10.1186/s13054-020-03398-0.
- Järhult J.D., Hultström M., Bergqvist A., Frithiof R., Lipcsey M. The impact of viremia on organ failure, biomarkers and mortality in a Swedish cohort of critically ill COVID-19 patients. Sci. Rep. 2021;11:7163. doi: 10.1038/s41598-021-86500-y.
- Frithiof R., Bergqvist A., Järhult J.D., Lipcsey M., Hultström M. Presence of SARS-CoV-2 in urine is rare and not associated with acute kidney injury in critically ill COVID-19 patients. Crit. Care. 2020;24:587. doi: 10.1186/s13054-020-03302-w.
- Grommes J., Soehnlein O. Contribution of neutrophils to acute lung injury. Mol. Med. 2011;17:293–307. doi: 10.2119/molmed.2010.00138.
- Gallo Marin B., Aghagoli G., Lavine K., Yang L., Siff E.J., Chiang S.S., Salazar-Mather T.P., Dumenco L., Savaria M.C., Aung S.N., et al. Predictors of COVID-19 severity: A literature review. Rev. Med. Virol. 2021;31:182–218. doi: 10.1002/rmv.2146.
- Zuo Y., Yalavarthi S., Shi H., Gockman K., Zuo M., Madison J.A., Blair C., Weber A., Barnes B.J., Egeblad M., et al. Neutrophil extracellular traps in COVID-19. JCI Insight. 2020;5:e138999. doi: 10.1172/jci.insight.138999.
- Arcanjo A., Logullo J., Menezes C.C.B., de Souza Carvalho Giangiarulo T.C., dos Reis M.C., de Castro G.M.M., Fontes Y.D.S., Todeschini A.R., Freire-De-Lima L., Decoté-Ricardo D., et al. The emerging role of neutrophil extracellular traps in severe acute respiratory syndrome coronavirus 2 (COVID-19) Sci. Rep. 2020;10:19630. doi: 10.1038/s41598-020-76781-0.
- Dent C.L., Ma Q., Dastrala S., Bennett M., Mitsnefes M.M., Barasch J., Devarajan P. Plasma neutrophil gelatinase-associated lipocalin predicts acute kidney injury, morbidity and mortality after pediatric cardiac surgery: A prospective uncontrolled cohort study. Crit. Care. 2007;11:R127. doi: 10.1186/cc6192.
- Maeda A., Hayase N., Doi K. Acute Kidney Injury Induces Innate Immune Response and Neutrophil Activation in the Lung. Front. Med. 2020;7 doi: 10.3389/fmed.2020.565010.
- Joannidis M., Forni L.G., Klein S.J., Honore P.M., Kashani K., Ostermann M., Prowle J., Bagshaw S.M., Cantaluppi V., Darmon M., et al. Lung-kidney interactions in critically ill patients: Consensus report of the Acute Disease Quality Initiative (ADQI) 21 Workgroup. Intensive Care Med. 2020;46:654–672. doi: 10.1007/s00134-019-05869-7.
- Rewa O., Wald R., Adhikari N.K., Hladunewich M., Lapinsky S., Muscedere J., Bagshaw S.M., Smith O.M., Lebovic G., Kuint R., et al. Whole-blood neutrophil gelatinase-associated lipocalin to predict adverse events in acute kidney injury: A prospective observational cohort study. J. Crit. Care. 2015;30:1359–1364. doi: 10.1016/j.jcrc.2015.08.019.
- Cuartero M., Betbesé A.J., Núñez K., Baldirà J., Ordonez-Llanos J. Does Whole-Blood Neutrophil Gelatinase-Associated Lipocalin Stratify Acute Kidney Injury in Critically Ill Patients? Dis. Markers. 2019;2019:8480925. doi: 10.1155/2019/8480925.
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