Novel Biomarkers of AKI in Cirrhosis

Adrià Juanola; Ann T. Ma; Elisa Pose; Pere Ginès

doi:10.1055/a-1954-4136

Seminars in Liver Disease, Table of Contents

Semin Liver Dis 2022; 42(04): 489-500
DOI: 10.1055/a-1954-4136

Review Article

Novel Biomarkers of AKI in Cirrhosis

Adrià Juanola^*

¹Liver Unit, Hospital Clínic de Barcelona, University of Barcelona, Barcelona, Catalonia, Spain

²Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain

³Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD), Barcelona, Catalonia, Spain

,

Ann T. Ma^*

²Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain

³Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD), Barcelona, Catalonia, Spain

,

Elisa Pose^#

¹Liver Unit, Hospital Clínic de Barcelona, University of Barcelona, Barcelona, Catalonia, Spain

²Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain

³Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD), Barcelona, Catalonia, Spain

,

Pere Ginès^#

¹Liver Unit, Hospital Clínic de Barcelona, University of Barcelona, Barcelona, Catalonia, Spain

²Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain

³Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD), Barcelona, Catalonia, Spain

⁴Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Catalonia, Spain

› Author Affiliations

Abstract

Acute kidney injury (AKI) is a frequent complication in patients with cirrhosis that is associated with poor outcomes and decreased survival. The definition of AKI in cirrhosis is currently based on changes of serum creatinine levels with respect to baseline values. Differential diagnosis of the causes of AKI is of major relevance, considering that some causes of AKI, such as hepatorenal syndrome, have specific treatment options and different prognosis. Prediction of kidney function recovery and patients' survival is also crucial in this patient population to guide clinical decisions. AKI biomarkers in cirrhosis have emerged as a promising tool for differential diagnosis and prognosis in this situation. There are consistent data showing that some urine biomarkers, particularly neutrophil gelatinase-associated lipocalin, may be useful in daily clinical practice for the differential diagnosis of the cause of AKI in cirrhosis. AKI biomarkers may constitute a useful tool for use in differential diagnosis, prognosis of renal function, and survival in patients with cirrhosis. This review focuses on the current state of knowledge and future perspective of novel biomarkers of AKI in cirrhosis.

Keywords

AKI - cirrhosis - HRS - biomarkers - novel - NGAL - IL-18 - cystatin C - KIM-1

Full Text

References

References
1 Ginès P, Solà E, Angeli P, Wong F, Nadim MK, Kamath PS. Hepatorenal syndrome. Nat Rev Dis Primers 2018; 4 (01) 23
2 Huelin P, Piano S, Solà E. et al. Validation of a staging system for acute kidney injury in patients with cirrhosis and association with acute-on-chronic liver failure. Clin Gastroenterol Hepatol 2017; 15 (03) 438-445.e5
3 Maiwall R, Kumar S, Chandel SS. et al. AKI in patients with acute on chronic liver failure is different from acute decompensation of cirrhosis. Hepatol Int 2015; 9 (04) 627-639
4 Allegretti AS, Parada XV, Endres P. et al; HRS-HARMONY Study Investigators. Urinary NGAL as a diagnostic and prognostic marker for acute kidney injury in cirrhosis: a prospective study. Clin Transl Gastroenterol 2021; 12 (05) e00359
5 Desai AP, Knapp SM, Orman ES. et al. Changing epidemiology and outcomes of acute kidney injury in hospitalized patients with cirrhosis - a US population-based study. J Hepatol 2020; 73 (05) 1092-1099
6 Bassegoda O, Huelin P, Ariza X. et al. Development of chronic kidney disease after acute kidney injury in patients with cirrhosis is common and impairs clinical outcomes. J Hepatol 2020; 72 (06) 1132-1139
7 Maiwall R, Pasupuleti SSR, Bihari C. et al. Incidence, risk factors, and outcomes of transition of acute kidney injury to chronic kidney disease in cirrhosis: a prospective cohort study. Hepatology 2020; 71 (03) 1009-1022
8 Durand F, Francoz C, Asrani SK. et al. Acute kidney injury after liver transplantation. Transplantation 2018; 102 (10) 1636-1649
9 Arroyo V, Ginès P, Gerbes AL. et al. Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. International Ascites Club. Hepatology 1996; 23 (01) 164-176
10 Angeli P, Ginès P, Wong F. et al. Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites. J Hepatol 2015; 62 (04) 968-974
11 Piano S, Rosi S, Maresio G. et al. Evaluation of the Acute Kidney Injury Network criteria in hospitalized patients with cirrhosis and ascites. J Hepatol 2013; 59 (03) 482-489
12 Martín-Llahí M, Guevara M, Torre A. et al. Prognostic importance of the cause of renal failure in patients with cirrhosis. Gastroenterology 2011; 140 (02) 488-496.e4
13 Fagundes C, Barreto R, Guevara M. et al. A modified acute kidney injury classification for diagnosis and risk stratification of impairment of kidney function in cirrhosis. J Hepatol 2013; 59 (03) 474-481
14 Angeli P, Bernardi M, Villanueva C. et al; European Association for the Study of the Liver. Electronic address: easloffice@easloffice.eu, European Association for the Study of the Liver. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol 2018; 69 (02) 406-460
15 FDA-NIH Biomarker Working Group. BEST (Biomarkers, EndpointS, and other Tools) Resource. Silver Spring, MD: Food and Drug Administration (US); Bethesda (MD): National Institutes of Health (US); 2006
16 Khwaja A. KDIGO clinical practice guidelines for acute kidney injury. Nephron Clin Pract 2012; 120 (04) c179-c184
17 Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. Modification of Diet in Renal Disease Study Group. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Ann Intern Med 1999; 130 (06) 461-470
18 Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron J 1976; 16 (01) 31-41
19 Campion D, Rizzi F, Bonetto S. et al. Assessment of glomerular filtration rate in patients with cirrhosis: available tools and perspectives. Liver Int 2022; 42 (11) 2360-2376
20 Moreau R, Jalan R, Gines P. et al; CANONIC Study Investigators of the EASL–CLIF Consortium. Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis. Gastroenterology 2013; 144 (07) 1426-1437 , 1437.e1–1437.e9
21 Stevens LA, Coresh J, Greene T, Levey AS. Assessing kidney function–measured and estimated glomerular filtration rate. N Engl J Med 2006; 354 (23) 2473-2483
22 Waikar SS, Bonventre JV. Creatinine kinetics and the definition of acute kidney injury. J Am Soc Nephrol 2009; 20 (03) 672-679
23 Francoz C, Glotz D, Moreau R, Durand F. The evaluation of renal function and disease in patients with cirrhosis. J Hepatol 2010; 52 (04) 605-613
24 Singapura P, Ma TW, Sarmast N. et al. Estimating glomerular filtration rate in cirrhosis using creatinine-based and cystatin C-based equations: systematic review and meta-analysis. Liver Transpl 2021; 27 (11) 1538-1552
25 Francoz C, Sola E. Assessment of renal function in cirrhosis: sarcopenia, gender and ethnicity matter. J Hepatol 2019; 70 (05) 828-830
26 Waikar SS, Betensky RA, Emerson SC, Bonventre JV. Imperfect gold standards for kidney injury biomarker evaluation. J Am Soc Nephrol 2012; 23 (01) 13-21
27 Herget-Rosenthal S, Trabold S, Pietruck F, Holtmann M, Philipp T, Kribben A. Cystatin C: efficacy as screening test for reduced glomerular filtration rate. Am J Nephrol 2000; 20 (02) 97-102
28 Mishra J, Ma Q, Prada A. et al. Identification of neutrophil gelatinase-associated lipocalin as a novel early urinary biomarker for ischemic renal injury. J Am Soc Nephrol 2003; 14 (10) 2534-2543
29 Mishra J, Dent C, Tarabishi R. et al. Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery. Lancet 2005; 365 (9466): 1231-1238
30 Gerbes AL, Benesic A, Vogeser M, Krag A, Bendtsen F, Møller S. Serum neutrophil gelatinase-associated lipocalin - a sensitive novel marker of renal impairment in liver cirrhosis?. Digestion 2011; 84 (01) 82-83
31 Fagundes C, Pépin MN, Guevara M. et al. Urinary neutrophil gelatinase-associated lipocalin as biomarker in the differential diagnosis of impairment of kidney function in cirrhosis. J Hepatol 2012; 57 (02) 267-273
32 Parikh CR, Jani A, Melnikov VY, Faubel S, Edelstein CL. Urinary interleukin-18 is a marker of human acute tubular necrosis. Am J Kidney Dis 2004; 43 (03) 405-414
33 Barreto R, Elia C, Solà E. et al. Urinary neutrophil gelatinase-associated lipocalin predicts kidney outcome and death in patients with cirrhosis and bacterial infections. J Hepatol 2014; 61 (01) 35-42
34 Qasem AA, Farag SE, Hamed E, Emara M, Bihery A, Pasha H. Urinary biomarkers of acute kidney injury in patients with liver cirrhosis. ISRN Nephrol 2014; 2014: 376795
35 Belcher JM, Garcia-Tsao G, Sanyal AJ. et al; TRIBE-AKI Consortium. Urinary biomarkers and progression of AKI in patients with cirrhosis. Clin J Am Soc Nephrol 2014; 9 (11) 1857-1867
36 Ariza X, Solà E, Elia C. et al. Analysis of a urinary biomarker panel for clinical outcomes assessment in cirrhosis. PLoS One 2015; 10 (06) e0128145
37 Sirimongkolkasem J, Teerasarntipan T, Wongkarnjana A. et al. Clinical outcome and prognosis of acute-on-chronic liver failure: experience from a tertiary care center. J Med Assoc Thai 2019; (102) 66
38 Tsai MH, Chen YC, Yang CW. et al. Acute renal failure in cirrhotic patients with severe sepsis: value of urinary interleukin-18. J Gastroenterol Hepatol 2013; 28 (01) 135-141
39 Gungor G, Ataseven H, Demir A. et al. Neutrophil gelatinase-associated lipocalin in prediction of mortality in patients with hepatorenal syndrome: a prospective observational study. Liver Int 2014; 34 (01) 49-57
40 Han WK, Bailly V, Abichandani R, Thadhani R, Bonventre JV. Kidney injury molecule-1 (KIM-1): a novel biomarker for human renal proximal tubule injury. Kidney Int 2002; 62 (01) 237-244
41 Moresco RN, Bochi GV, Stein CS, De Carvalho JAM, Cembranel BM, Bollick YS. Urinary kidney injury molecule-1 in renal disease. Clin Chim Acta 2018; 487: 15-21
42 Hotamisligil GS, Bernlohr DA. Metabolic functions of FABPs – mechanisms and therapeutic implications. Nat Rev Endocrinol 2015; 11 (10) 592-605
43 Yamamoto T, Noiri E, Ono Y. et al. Renal L-type fatty acid–binding protein in acute ischemic injury. J Am Soc Nephrol 2007; 18 (11) 2894-2902
44 Jo SK, Yang J, Hwang SM, Lee MS, Park SH. Role of biomarkers as predictors of acute kidney injury and mortality in decompensated cirrhosis. Sci Rep 2019; 9 (01) 14508
45 Maiwall R, Kumar G, Bharadwaj A. et al. AKI persistence at 48 h predicts mortality in patients with acute on chronic liver failure. Hepatol Int 2017; 11 (06) 529-539
46 Kim TH, Seo YS, Kang SH. et al; Korean Study Group of Portal Hypertension. Prognosis predictability of serum and urine renal markers in patients with decompensated cirrhosis: a multicentre prospective study. Liver Int 2020; 40 (12) 3083-3092
47 Markwardt D, Holdt L, Steib C. et al. Plasma cystatin C is a predictor of renal dysfunction, acute-on-chronic liver failure, and mortality in patients with acutely decompensated liver cirrhosis. Hepatology 2017; 66 (04) 1232-1241
48 Slack AJ, McPhail MJW, Ostermann M. et al. Predicting the development of acute kidney injury in liver cirrhosis – an analysis of glomerular filtration rate, proteinuria and kidney injury biomarkers. Aliment Pharmacol Ther 2013; 37 (10) 989-997
49 Treeprasertsuk S, Wongkarnjana A, Jaruvongvanich V. et al. Urine neutrophil gelatinase-associated lipocalin: a diagnostic and prognostic marker for acute kidney injury (AKI) in hospitalized cirrhotic patients with AKI-prone conditions. BMC Gastroenterol 2015; 15 (01) 140
50 Yap DYH, Seto WK, Fung J. et al. Serum and urinary biomarkers that predict hepatorenal syndrome in patients with advanced cirrhosis. Dig Liver Dis 2017; 49 (02) 202-206
51 Pietrukaniec M, Migacz M, Żak-Gołąb A. et al. Could KIM-1 and NGAL levels predict acute kidney injury after paracentesis? - preliminary study. Ren Fail 2020; 42 (01) 853-859
52 Sun T, Qu S, Huang T. et al. Rapid and sensitive detection of L-FABP for prediction and diagnosis of acute kidney injury in critically ill patients by chemiluminescent immunoassay. J Clin Lab Anal 2021; 35 (11) e24051
53 Torregrosa I, Montoliu C, Urios A. et al. Urinary KIM-1, NGAL and L-FABP for the diagnosis of AKI in patients with acute coronary syndrome or heart failure undergoing coronary angiography. Heart Vessels 2015; 30 (06) 703-711
54 Jaques DA, Spahr L, Berra G. et al. Biomarkers for acute kidney injury in decompensated cirrhosis: a prospective study. Nephrology (Carlton) 2019; 24 (02) 170-180
55 Kim TH, Lee HA, Seo YS. et al; Korean Study Group of Portal Hypertension. Assessment and prediction of acute kidney injury in patients with decompensated cirrhosis with serum cystatin C and urine N-acetyl-β-D-glucosaminidase. J Gastroenterol Hepatol 2019; 34 (01) 234-240
56 Belcher JM, Sanyal AJ, Peixoto AJ. et al; TRIBE-AKI Consortium. Kidney biomarkers and differential diagnosis of patients with cirrhosis and acute kidney injury. Hepatology 2014; 60 (02) 622-632
57 Puthumana J, Ariza X, Belcher JM, Graupera I, Ginès P, Parikh CR. Urine interleukin 18 and lipocalin 2 are biomarkers of acute tubular necrosis in patients with cirrhosis: a systematic review and meta-analysis. Clin Gastroenterol Hepatol 2017; 15 (07) 1003-1013.e3
58 Huelin P, Solà E, Elia C. et al. Neutrophil gelatinase-associated lipocalin for assessment of acute kidney injury in cirrhosis: a prospective study. Hepatology 2019; 70 (01) 319-333
59 Solé C, Ma AT, Solà E. et al. Sequential changes in urinary biomarker levels in patients with cirrhosis and severe hepatorenal syndrome. Liver Int 2021; 41 (11) 2729-2732
60 Juanola A, Graupera I, Elia C. et al. Urinary L-FABP is a promising prognostic biomarker of ACLF and mortality in patients with decompensated cirrhosis. J Hepatol 2022; 76 (01) 107-114
61 Belcher JM, Sanyal AJ, Garcia-Tsao G. et al. Early trends in cystatin C and outcomes in patients with cirrhosis and acute kidney injury. Int J Nephrol 2014; 2014: 708585
62 Maiwall R, Kumar A, Bhardwaj A, Kumar G, Bhadoria AS, Sarin SK. Cystatin C predicts acute kidney injury and mortality in cirrhotics: a prospective cohort study. Liver Int 2018; 38 (04) 654-664
63 Ariza X, Graupera I, Coll M. et al; CANONIC Investigators, EASL CLIF Consortium. Neutrophil gelatinase-associated lipocalin is a biomarker of acute-on-chronic liver failure and prognosis in cirrhosis. J Hepatol 2016; 65 (01) 57-65
64 Forster CS, Jackson E, Ma Q, Bennett M, Shah SS, Goldstein SL. Predictive ability of NGAL in identifying urinary tract infection in children with neurogenic bladders. Pediatr Nephrol 2018; 33 (08) 1365-1374
65 Decavele ASC, Dhondt L, De Buyzere ML, Delanghe JR. Increased urinary neutrophil gelatinase associated lipocalin in urinary tract infections and leukocyturia. Clin Chem Lab Med 2011; 49 (06) 999-1003
66 Piano S, Singh V, Caraceni P. et al; International Club of Ascites Global Study Group. Epidemiology and effects of bacterial infections in patients with cirrhosis worldwide. Gastroenterology 2019; 156 (05) 1368-1380.e10
67 Levitsky J, Baker TB, Jie C. et al. Plasma protein biomarkers enhance the clinical prediction of kidney injury recovery in patients undergoing liver transplantation. Hepatology 2014; 60 (06) 2017-2026
68 Graupera I, Solà E, Fabrellas N. et al. Urine monocyte chemoattractant protein-1 is an independent predictive factor of hospital readmission and survival in cirrhosis. PLoS One 2016; 11 (06) e0157371
69 Solà E, Kerbert AJC, Verspaget HW. et al. Plasma copeptin as biomarker of disease progression and prognosis in cirrhosis. J Hepatol 2016; 65 (05) 914-920
70 Deshmane SL, Kremlev S, Amini S, Sawaya BE. Monocyte chemoattractant protein-1 (MCP-1): an overview. J Interferon Cytokine Res 2009; 29 (06) 313-326
71 Asrani SK, Shankar N, da Graca B, Nadim MK, Cardenas A. Role of novel kidney biomarkers in patients with cirrhosis and after liver transplantation. Liver Transpl 2022; 28 (03) 466-482
72 Zhai JL, Ge N, Zhen Y, Zhao Q, Liu C. Corticosteroids significantly increase serum cystatin C concentration without affecting renal function in symptomatic heart failure. Clin Lab 2016; 62 (1-2): 203-207
73 Bökenkamp A, van Wijk JAE, Lentze MJ, Stoffel-Wagner B. Effect of corticosteroid therapy on serum cystatin C and β2-microglobulin concentrations. Clin Chem 2002; 48 (07) 1123-1126
74 Delgado C, Baweja M, Crews DC. et al. A unifying approach for GFR estimation: recommendations of the NKF-ASN task force on reassessing the inclusion of race in diagnosing kidney disease. Am J Kidney Dis 2022; 79 (02) 268-288.e1
75 Lei L, Li LP, Zeng Z, Mu JX, Yang X, Zhou C, Wang ZL, Zhang H. Value of urinary KIM-1 and NGAL combined with serum Cys C for predicting acute kidney injury secondary to decompensated cirrhosis. Sci Rep 2018; 8 (01) 7962
76 Verna EC, Brown RS, Farrand E, Pichardo EM, Forster CS, Sola-Del Valle DA, Adkins SH, Sise ME, Oliver JA, Radhakrishnan J, Barasch JM, Nickolas TL. Urinary neutrophil gelatinase-associated lipocalin predicts mortality and identifies acute kidney injury in cirrhosis. Dig Dis Sci 2012; 57 (09) 2362-2370 . Epub May 6, 2021
77 Waikar SS, Bonventre J v. Creatinine kinetics and the definition of acute kidney injury. J Am Soc Nephrol 2009; 20: 672-679
78 Spahillari A, Parikh CR, Sint K. et al. Serum Cystatin C– versus creatinine-based definitions of acute kidney injury following cardiac surgery: a prospective cohort study. Am J Kidney Dis 2012; 60: 922-929
79 Soto K, Coelho S, Rodrigues B. et al. Cystatin C as a marker of acute kidney injury in the emergency department. Clin J Am Soc Nephrol 2010; 5: 1745-1754
80 Au V, Feit J, Barasch J, Sladen RN, Wagener G. Urinary neutrophil gelatinase-associated lipocalin (NGAL) distinguishes sustained from transient acute kidney injury after general surgery. Kidney Int Rep 2016; 1: 3-9
81 Washburn KK, Zappitelli M, Arikan AA. et al. Urinary interleukin-18 is an acute kidney injury biomarker in critically ill children. Nephrol Dial Transplant 2008; 23: 566-572
82 Liang XL, Liu SX, Chen YH. et al. Combination of urinary kidney injury molecule-1 and interleukin-18 as early biomarker for the diagnosis and progressive assessment of acute kidney injury following cardiopulmonary bypass surgery: a prospective nested case–control study. Biomarkers 2010; 15: 332-339
83 Liangos O, Tighiouart H, Perianayagam MC. et al. Comparative analysis of urinary biomarkers for early detection of acute kidney injury following cardiopulmonary bypass. Biomarkers 2009; 14: 423-431
84 Portilla D, Dent C, Sugaya T. et al. Liver fatty acid-binding protein as a biomarker of acute kidney injury after cardiac surgery. Kidney Int 2008; 73: 465-472
85 Hamdy HS, El-Ray A, Salaheldin M, Lasheen M, Aboul-Ezz M, Abdel-Moaty AS, Abdel-Rahim A. Urinary neutrophil gelatinase-associated lipocalin in cirrhotic patients with acute kidney injury. Ann Hepatol 2018; 17 (04) 624-630 . PMID: 29893703