Soluble urokinase plasminogen activator receptor is associated with short-term mortality and enhanced reactive oxygen species production in acute-on-chronic liver failure

Yunyun Wang, Fengtian Wu, Chao Chen, Lichen Xu, Wei Lin, Chunhong Huang, Ying Yang, Shanshan Wu, Jinjin Qi, Hanqin Cao, Guojun Li, Meng Hong, Haihong Zhu, Yunyun Wang, Fengtian Wu, Chao Chen, Lichen Xu, Wei Lin, Chunhong Huang, Ying Yang, Shanshan Wu, Jinjin Qi, Hanqin Cao, Guojun Li, Meng Hong, Haihong Zhu

Abstract

Background: Acute-on-chronic liver failure (ACLF) is a comprehensive syndrome characterized by an acute deterioration of liver function and high short-term mortality rates in patients with chronic liver disease. Whether plasma soluble urokinase plasminogen activator receptor (suPAR) is a suitable biomarker for the prognosis of patients with ACLF remains unknown.

Method: A prospective cohort of 282 patients with ACLF from three hospitals in China was included. 88.4% of the group was hepatitis B virus-related ACLF (HBV-related ACLF). Cox regression was used to assess the impact of plasma suPAR and other factors on 30- and 90-day mortality. Reactive oxygen species (ROS) production were detected to explore the role of suPAR in regulating neutrophil function in HBV-related ACLF.

Result: There was no difference in plasma suPAR levels between HBV-related and non-HBV-related ACLF. Patients with clinical complications had higher suPAR levels than those without these complications. A significant correlation was also found between suPAR and prognostic scores, infection indicators and inflammatory cytokines. Cox's regression multivariate analysis identified suPAR ≥ 14.7 ng/mL as a predictor for both day 30 and 90 mortality (Area under the ROC curve: 0.751 and 0.742 respectively), independent of the MELD and SOFA scores in patients with ACLF. Moreover, we firstly discovered suPAR enhanced neutrophil ROS production under E.coli stimulation in patients with HBV-related ACLF.

Conclusions: suPAR was a useful independent biomarker of short-term outcomes in patients with ACLF and might play a key role in the pathogenesis. Trial registration CNT, NCT02965560.

Keywords: ACLF; HBV; Mortality; ROS; suPAR.

Conflict of interest statement

The authors declare that they have no competing interests.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Flow diagram of patient selection. ACLF-MOF indicated the patients with ACLF developed MOF during 90-day follow-up
Fig. 2
Fig. 2
Comparison of plasma suPAR levels in different disease groups. a Distribution of plasma suPAR concentrations among HC (n = 14), CHB (n = 14) and ACLF (n = 42). b The comparison of suPAR levels between ACLF patients with and without clinical complications. Horizontal lines represent median values. ns not statistically significant; *p < 0.05; **p < 0.01, ***p < 0.001, ****p < 0.0001
Fig. 3
Fig. 3
Comparison of K–M survival curves between ACLF patients with or without cirrhosis and with or without HE. The cumulative 90-day survival between groups was compared using the log-rank test
Fig. 4
Fig. 4
suPAR enhanced ROS production in neutrophils in HBV-related ACLF under E.coli stimulation. Whole blood from eight patients with HBV-related ACLF was stimulated with E. coli in the presence of suPAR (50 ng/ml) or PBS for 30 min in vitro. Gating Strategies for ROS detection of neutrophils was shown in (a). The impact of suPAR on neutrophil ROS production was determined in (b). Statistical analyses were performed using the Wilcoxon signed-rank test. *p < 0.05; **p < 0.01

References

    1. Bernal W, Jalan R, Quaglia A, Simpson K, Wendon J, Burroughs A. Acute-on-chronic liver failure. The Lancet. 2015;386(10003):1576–1587. doi: 10.1016/S0140-6736(15)00309-8.
    1. Hernaez R, Sola E, Moreau R, Gines P. Acute-on-chronic liver failure: an update. Gut. 2017;66(3):541–553. doi: 10.1136/gutjnl-2016-312670.
    1. Li C, Zhu B, Lv S, You S, Xin S. Prediction model of the progression of patients with acute deterioration of hepatitis B virus-related chronic liver disease to acute-on-chronic liver failure. Medicine (Baltimore) 2018;97(34):e11915. doi: 10.1097/MD.0000000000011915.
    1. Zhang GL, Zhang T, Zhao QY, Lin CS, Gao ZL. Th17 cells over 5.9% at admission indicate poor prognosis in patients with HBV-related acute-on-chronic liver failure. Medicine (Baltimore) 2018;97(40):e12656. doi: 10.1097/MD.0000000000012656.
    1. Cai J, Wang K, Han T, Jiang H. Evaluation of prognostic values of inflammation-based makers in patients with HBV-related acute-on-chronic liver failure. Medicine (Baltimore) 2018;97(46):e13324. doi: 10.1097/MD.0000000000013324.
    1. Kobayashi N, Ueno T, Ohashi K, Yamashita H, Takahashi Y, Sakamoto K, Manabe S, Hara S, Takashima Y, Dan T, Pastan I, Miyata T, Kurihara H, Matsusaka T, Reiser J, Nagata M. Podocyte injury-driven intracapillary plasminogen activator inhibitor type 1 accelerates podocyte loss via uPAR-mediated beta1-integrin endocytosis. Am J Physiol Renal Physiol. 2015;308(6):F614–626. doi: 10.1152/ajprenal.00616.2014.
    1. Genua M, D'Alessio S, Cibella J, Gandelli A, Sala E, Correale C, Spinelli A, Arena V, Malesci A, Rutella S, Ploplis VA, Vetrano S, Danese S. The urokinase plasminogen activator receptor (uPAR) controls macrophage phagocytosis in intestinal inflammation. Gut. 2015;64(4):589–600. doi: 10.1136/gutjnl-2013-305933.
    1. Manetti M, Rosa I, Milia AF, Guiducci S, Carmeliet P, Ibba-Manneschi L, Matucci-Cerinic M. Inactivation of urokinase-type plasminogen activator receptor (uPAR) gene induces dermal and pulmonary fibrosis and peripheral microvasculopathy in mice: a new model of experimental scleroderma? Ann Rheum Dis. 2014;73(9):1700–1709. doi: 10.1136/annrheumdis-2013-203706.
    1. Mazzieri R, Pietrogrande G, Gerasi L, Gandelli A, Colombo P, Moi D, Brombin C, Ambrosi A, Danese S, Mignatti P, Blasi F, D'Alessio S. Urokinase receptor promotes skin tumor formation by preventing epithelial cell activation of notch1. Cancer Res. 2015;75(22):4895–4909. doi: 10.1158/0008-5472.CAN-15-0378.
    1. Thuno M, Macho B, Eugen-Olsen J. suPAR: the molecular crystal ball. Dis Mark. 2009;27(3):157–172. doi: 10.1155/2009/504294.
    1. Sidenius N, Sier CF, Blasi F. Shedding and cleavage of the urokinase receptor (uPAR): identification and characterisation of uPAR fragments in vitro and in vivo. FEBS Lett. 2000;475(1):52–56. doi: 10.1016/S0014-5793(00)01624-0.
    1. Dande RR, Peev V, Altintas MM, Reiser J. Soluble urokinase receptor and the kidney response in diabetes mellitus. J Diabetes Res. 2017;2017:3232848. doi: 10.1155/2017/3232848.
    1. Blasi F, Carmeliet P. uPAR: a versatile signalling orchestrator. Nat Rev Mol Cell Biol. 2002;3(12):932–943. doi: 10.1038/nrm977.
    1. Smith HW, Marshall CJ. Regulation of cell signalling by uPAR. Nat Rev Mol Cell Biol. 2010;11(1):23–36. doi: 10.1038/nrm2821.
    1. Huai Q, Mazar AP, Kuo A, Parry GC, Shaw DE, Callahan J, Li Y, Yuan C, Bian C, Chen L, Furie B, Furie BC, Cines DB, Huang M. Structure of human urokinase plasminogen activator in complex with its receptor. Science. 2006;311(5761):656–659. doi: 10.1126/science.1121143.
    1. Wei C, El Hindi S, Li J, Fornoni A, Goes N, Sageshima J, Maiguel D, Karumanchi SA, Yap HK, Saleem M, Zhang Q, Nikolic B, Chaudhuri A, Daftarian P, Salido E, Torres A, Salifu M, Sarwal MM, Schaefer F, Morath C, Schwenger V, Zeier M, Gupta V, Roth D, Rastaldi MP, Burke G, Ruiz P, Reiser J. Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis. Nat Med. 2011;17(8):952–960. doi: 10.1038/nm.2411.
    1. Abraham E, Gyetko MR, Kuhn K, Arcaroli J, Strassheim D, Park JS, Shetty S, Idell S. Urokinase-type plasminogen activator potentiates lipopolysaccharide-induced neutrophil activation. J Immunol. 2003;170(11):5644–5651. doi: 10.4049/jimmunol.170.11.5644.
    1. Jaeschke H. Reactive oxygen and mechanisms of inflammatory liver injury: present concepts. J Gastroenterol Hepatol. 2011;26(Suppl 1):173–179. doi: 10.1111/j.1440-1746.2010.06592.x.
    1. Reyes-Gordillo K, Shah R, Muriel P. Oxidative stress and inflammation in hepatic diseases: current and future therapy. Oxid Med Cell Longev. 2017;2017:3140673. doi: 10.1155/2017/3140673.
    1. Donadello K, Scolletta S, Covajes C, Vincent JL. suPAR as a prognostic biomarker in sepsis. BMC Med. 2012;10:2. doi: 10.1186/1741-7015-10-2.
    1. Sarin SK, Kedarisetty CK, Abbas Z, Amarapurkar D, Bihari C, Chan AC, Chawla YK, Dokmeci AK, Garg H, Ghazinyan H, Hamid S, Kim DJ, Komolmit P, Lata S, Lee GH, Lesmana LA, Mahtab M, Maiwall R, Moreau R, Ning Q, Pamecha V, Payawal DA, Rastogi A, Rahman S, Rela M, Saraya A, Samuel D, Saraswat V, Shah S, Shiha G, Sharma BC, Sharma MK, Sharma K, Butt AS, Tan SS, Vashishtha C, Wani ZA, Yuen MF, Yokosuka O. Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific Association for the Study of the Liver (APASL) 2014. Hepatol Int. 2014;8(4):453–471. doi: 10.1007/s12072-014-9580-2.
    1. Angeli P, Gines P, Wong F, Bernardi M, Boyer TD, Gerbes A, Moreau R, Jalan R, Sarin SK, Piano S, Moore K, Lee SS, Durand F, Salerno F, Caraceni P, Kim WR, Arroyo V, Garcia-Tsao G. Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites. Gut. 2015;64(4):531–537. doi: 10.1136/gutjnl-2014-308874.
    1. Runyon BA. Management of adult patients with ascites due to cirrhosis. Hepatology. 2004;39(3):841–856. doi: 10.1002/hep.20066.
    1. Maras JS, Maiwall R, Harsha HC, Das S, Hussain MS, Kumar C, Bihari C, Rastogi A, Kumar M, Trehanpati N, Sharma S, Pandey A, Sarin SK. Dysregulated iron homeostasis is strongly associated with multiorgan failure and early mortality in acute-on-chronic liver failure. Hepatology. 2015;61(4):1306–1320. doi: 10.1002/hep.27636.
    1. Wang Y, Chen C, Qi J, Wu F, Guan J, Chen Z, Zhu H. Altered PGE2-EP2 is associated with an excessive immune response in HBV-related acute-on-chronic liver failure. J Transl Med. 2019;17(1):93. doi: 10.1186/s12967-019-1844-0.
    1. Shi Y, Yang Y, Hu Y, Wu W, Yang Q, Zheng M, Zhang S, Xu Z, Wu Y, Yan H, Chen Z. Acute-on-chronic liver failure precipitated by hepatic injury is distinct from that precipitated by extrahepatic insults. Hepatology. 2015;62(1):232–242. doi: 10.1002/hep.27795.
    1. Zimmermann HW, Reuken PA, Koch A, Bartneck M, Adams DH, Trautwein C, Stallmach A, Tacke F, Bruns T. Soluble urokinase plasminogen activator receptor is compartmentally regulated in decompensated cirrhosis and indicates immune activation and short-term mortality. J Intern Med. 2013;274(1):86–100. doi: 10.1111/joim.12054.
    1. Koch A, Zimmermann HW, Gassler N, Jochum C, Weiskirchen R, Bruensing J, Buendgens L, Duckers H, Bruns T, Gerken G, Neumann UP, Adams DH, Trautwein C, Canbay A, Tacke F. Clinical relevance and cellular source of elevated soluble urokinase plasminogen activator receptor (suPAR) in acute liver failure. Liver Int. 2014;34(9):1330–1339. doi: 10.1111/liv.12512.
    1. May AE, Kanse SM, Lund LR, Gisler RH, Imhof BA, Preissner KT. Urokinase receptor (CD87) regulates leukocyte recruitment via beta 2 integrins in vivo. J Exp Med. 1998;188(6):1029–1037. doi: 10.1084/jem.188.6.1029.
    1. Claria J, Arroyo V, Moreau R. The acute-on-chronic liver failure syndrome, or when the innate immune system goes astray. J Immunol. 2016;197(10):3755–3761. doi: 10.4049/jimmunol.1600818.
    1. Hayek SS, Sever S, Ko YA, Trachtman H, Awad M, Wadhwani S, Altintas MM, Wei C, Hotton AL, French AL, Sperling LS, Lerakis S, Quyyumi AA, Reiser J. Soluble urokinase receptor and chronic kidney disease. N Engl J Med. 2015;373(20):1916–1925. doi: 10.1056/NEJMoa1506362.
    1. Wei C, Moller CC, Altintas MM, Li J, Schwarz K, Zacchigna S, Xie L, Henger A, Schmid H, Rastaldi MP, Cowan P, Kretzler M, Parrilla R, Bendayan M, Gupta V, Nikolic B, Kalluri R, Carmeliet P, Mundel P, Reiser J. Modification of kidney barrier function by the urokinase receptor. Nat Med. 2008;14(1):55–63. doi: 10.1038/nm1696.
    1. Hahm E, Wei C, Fernandez I, Li J, Tardi NJ, Tracy M, Wadhwani S, Cao Y, Peev V, Zloza A, Lusciks J, Hayek SS, O'Connor C, Bitzer M, Gupta V, Sever S, Sykes DB, Scadden DT, Reiser J. Bone marrow-derived immature myeloid cells are a main source of circulating suPAR contributing to proteinuric kidney disease. Nat Med. 2017;23(1):100–106. doi: 10.1038/nm.4242.
    1. Hayek SS, Koh KH, Grams ME, Wei C, Ko YA, Li J, Samelko B, Lee H, Dande RR, Lee HW, Hahm E, Peev V, Tracy M, Tardi NJ, Gupta V, Altintas MM, Garborcauskas G, Stojanovic N, Winkler CA, Lipkowitz MS, Tin A, Inker LA, Levey AS, Zeier M, Freedman BI, Kopp JB, Skorecki K, Coresh J, Quyyumi AA, Sever S, Reiser J. A tripartite complex of suPAR, APOL1 risk variants and alphavbeta3 integrin on podocytes mediates chronic kidney disease. Nat Med. 2017;23(8):945–953. doi: 10.1038/nm.4362.
    1. Sevgi DY, Bayraktar B, Gunduz A, Ozguven BY, Togay A, Bulut E, Uzun N, Dokmetas I. Serum soluble urokinase-type plasminogen activator receptor and interferon-gamma-induced protein 10 levels correlate with significant fibrosis in chronic hepatitis B. Wien Klin Wochenschr. 2016;128(1–2):28–33. doi: 10.1007/s00508-015-0886-4.
    1. Sjowall C, Martinsson K, Cardell K, Ekstedt M, Kechagias S. Soluble urokinase plasminogen activator receptor levels are associated with severity of fibrosis in nonalcoholic fatty liver disease. Transl Res. 2015;165(6):658–666. doi: 10.1016/j.trsl.2014.09.007.
    1. Kim EY, Hassanzadeh Khayyat N, Dryer SE. Mechanisms underlying modulation of podocyte TRPC6 channels by suPAR: Role of NADPH oxidases and Src family tyrosine kinases. Biochim Biophys Acta. 2018;1864(10):3527–3536. doi: 10.1016/j.bbadis.2018.08.007.
    1. Taylor NJ, Manakkat Vijay GK, Abeles RD, Auzinger G, Bernal W, Ma Y, Wendon JA, Shawcross DL. The severity of circulating neutrophil dysfunction in patients with cirrhosis is associated with 90-day and 1-year mortality. Aliment Pharmacol Ther. 2014;40(6):705–715. doi: 10.1111/apt.12886.

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