Title: Urinary Neutrophil Gelatinase Associated Lipocalin as a Biomarker for Diagnosis and Prognosis of Acute Kidney Injury (AKI) in Cirrhotic Patients
Authors: Mona H. Elzohri MD, Effat AE.Tony MD, Mohamed H .Mustafa MD, Nabawia M. Tawfik MD, Tarek T. Elmelegy MD, Radwa A. Ellisy MSc
DOI: https://dx.doi.org/10.18535/jmscr/v5i2.118
Abstract
Introduction: Acute kidney injury is associated with increased mortality in hospitalized cirrhotic patients; therefore early and accurate diagnosis is crucial. The prognosis of AKI in cirrhosis depends on its specific aetiology which remains a challenge.
Aim: We aimed to determine the accuracy of urinary Neutrophil Gelatinase-Associated Lipocalin (uNGAL) for diagnosis, differentiation of the various aetiologies of AKI in cirrhotics and to evaluate its value in short term prognosis.
Methods: Eighty-two cirrhotic patients were investigated for uNGAL during hospital admission and AKI types were determined blinded to uNGAL measurements. Patients were followed up till discharge.
Results: Patients with liver cirrhosis and renal impairment (n= 62) had significantly higher levels of uNGAL (102.4 ±100 ng/ml) when compared with patients with cirrhotics with normal kidney function (n= 20) (102.4 ±100 vs 17.4±14.71 ng/ml). Patients with acute tubular necrosis (ATN) had significantly higher uNGAL (189.2±124 ng/ml) compared to other aetiologies, while prerenal azotemia had the lowest value (46.1±39.9 ng/ml). UNGAL levels were significantly higher in the mortality group of patients (p=0.006) and in patients admitted to ICU (p<0.001) than the survivors and patient without ICU admission respectively. The AUC of uNGAL for diagnosis of AKI was 0.892 with a cutoff > 33 ng/ml providing specificity 90% and sensitivity 79%. In multivariate regression analysis, uNGAL was highly significant independent predictor of inpatient cirrhosis relayed mortality.
Conclusion: UNGAL is a promising biomarker for diagnosis of AKI and differentiation between its different aetiologies in cirrhosis including ATN, HRS and pre renal azotemia. UNGAL can independently predict poor short term prognosis.
Keywords: AKI: Acute kidney injury, NGAL : Urinary neutrophil gelatinase associated lipocalin , cirrhosis, ATN: Acute tubular necrosis , HRS: Hepatorenal syndrome.
References
1. 1. Garcia-Tsao G, Parikh CR, Viola A. Acute kidney injury in cirrhosis. Hepatology 2008;48:2064–2077.
2. du Cheyron D, Bouchet B, Parienti JJ, Ramakers M, Charbonneau P. The attributable mortality of acute renal failure in critically ill patients with liver cirrhosis. Intensive Care Med 2005;31:1693–1699.
3. Hampel H, Bynum GD, Zamora E, El-Serag HB. Risk factors for the develop-ment of renal dysfunction in hospitalized patients with cirrhosis. Am J Gastroent-erol. 2001; 96:2206–2210.[PubMed: 11467654]
4. Terra C, Guevara M, Torre A, Gilabert R, Fernandez J, Martin-Llahi M, et al. Renal failure in patients with cirrhosis and sepsis unrelated to spontaneous bacterial perito-nitis: value of MELD score. Gastroente-rology. 2005; 129:1944–1953. [PubMed: 16344063]
5. Wu CC, Yeung LK, Tsai WS, Tseng CF, Chu P, Huang TY, et al. Incidence and factors predictive of acute renal failure in patients with advanced liver cirrhosis. Clin Nephrol. 2006; 65:28–33.[PubMed: 16429839].
6. Martin-Llahi M, Guevara M, Torre A, Fagundes C, Restuccia T, Gilabert R, et al. Prognostic importance of the cause of renal failure in patients with cirrhosis. Gastroenterology 2011;140:488–496.
7. Schrier RW. ARF, AKI, or ATN? Nat Rev Nephrol 2010;6:125.
8. Schrier RW. Diagnostic value of urinary sodium, chloride, urea, and flow. J Am Soc Nephrol 2011;22:1610–1613.
9. Gill N, Nally Jr JV, Fatica RA. Renal failure secondary to acute tubular necrosis: epidemiology, diagnosis, and manage-ment. Chest 2005;128:2847–2863.
10. Sola E, Gines P. Renal and circulatory dysfunction in cirrhosis: current management and future perspectives. J Hepatol 2010;53:1135–1145.
11. Angeli P, Merkel C. Pathogenesis and management of hepatorenal syndrome in patients with cirrhosis. J Hepatol 2008;48:S93–S103.
12. Salerno F, Gerbes A, Gines P, Wong F, Arroyo V. Diagnosis, prevention and treat-ment of the hepatorenal syndrome in cirrhosis. A consensus workshop of the international ascites club. Gut 2007;56: 1310–1318.
13. Caregaro L, Menon F, Angeli P, Amodio P, Merkel C, Bortoluzzi A, et al. Limitations of serum creatinine level and creatinine clearance as filtration markers in cirrhosis. Arch Intern Med. 1994; 154:201–205. [PubMed: 8285815]
14. Papadakis MA, Arieff AI. Unpredictability of clinical evaluation of renal function in cirrhosis. Prospective study. Am J Med. 1987; 82:945–952. [PubMed: 3578363]
15. Cholongitas E, Shusang V, Marelli L, Nair D, Thomas M, Patch D, et al. Review article: renal function assessment in cirrhosis - difficulties and alternative measurements. Aliment Pharmacol Ther. 2007; 26:969–978. [PubMed: 17877504].
16. Thabut D, Massard J, Gangloff A, Carbonell N, Francoz C, Nguyen-Khac E, et al. Model for end-stage liver disease score and systemic inflammatory response are major prognostic factors in patients with cirrhosis and acute functional renal failure. Hepatology 2007;46:1872–1882.
17. Moreau R, Lebrec D. Acute renal failure in patients with cirrhosis: perspectives in the age of MELD. Hepatology 2003; 37:233–243.
18. Gines P, Schrier RW. Renal failure in cirrhosis. N Engl J Med 2009;361:1279–1290.
19. Mehta RL, Bouchard J. Controversies in acute kidney injury: effects of fluid overload on outcome. Contrib Nephrol 2011;174:200–211.
20. Gines P, Angeli P, Lenz K, Moller S, Moore K, Moreau R, et al. EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis. J Hepatol 2010;53:397–417.
21. Siew ED, Ware LB, Ikizler TA. Biological markers of acute kidney injury. J Am Soc Nephrol 2011;22:810–820.
22. Lisowska-Myjak B. Serum and urinary biomarkers of acute kidney injury. Blood Purif 2010;29:357–365.
23. Fagundes C, Pépin M, Guevara M, Barreto R, Casals G, Solà E, Pereira G, Rodriguez E, Garcia E, Prado V, Poch E, Jiménez W, Fernandez J, Arroyo V, Ginès P. Urinary neutrophil gelatinase-associated lipocalin as biomarker in the differential diagnosis of impairment of kidney function in cirrhosis. Journal of Hepatology 2012; 57: 267–73.
24. Ariza X, Graupera I, Coll M, Solà E, Barreto R, García E, Moreira R, Morales-Ruiz M et al. Neutrophil gelatinase-associated lipocalin useful biomarker in ACLF. J Hepatol 2016;65: 57-65.
25. Treeprasertsuk S, Wongkarnjana A, Jaruvongvanich V, Sallapant S Tiranat-hanagul K Komolmit P and Tangkijvanich P. Urine neutrophil gelatinase-associated lipocalin: a diagnostic and prognostic marker for acute kidney injury (AKI) in hospitalized cirrhotic patients with AKI-prone conditions. BMC Gastroenterology (2015) 15:140.
26. Verna E, Farrand E, Pichardo E, Forster C, Adkins S, et al. Urinary neutrophil gelatinase associated lipocalin (UNGAL) distinguishes type of kidney failure and predicts mortality in patients with cirrhosis. Hepatology 2009;50: 311A.
27. Gungor G, Ataseven H, Demir A, Solak Y, Gaipov A, Biyik M, Ozturk B, Polat I, Kiyici A, Cakir OO, Polat H. Neutrophil gelatinase‐associated lipocalin in prediction of mortality in patients with hepatorenal syndrome: a prospective observational study. Liver International. 2015; 34.1: 49-57.
28. Mehta RL, Kellum JA, Shah SV, Molitoris BA, Ronco C, Warnock DG, et al. Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit Care. 2007; 11:R31.
29. Salerno F, Gerbes A, Gines P, Wong F, Arroyo V. Diagnosis, prevention and treat-ment of the hepatorenal syndrome in cirrhosis. A consensus workshop of the international ascites club. Gut 2007; 56:1310–1318.
30. Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for bleeding oesophageal varices. The British journal of surgery.1973; 60 (8): 646–9.
31. Wiesner R, Edwards E, Freeman R, et al. Model for end-stage liver disease (MELD) and allocation of donor livers. Gastroenterology. 2003; 124:91-6.
32. Rahman M, Shad F and Smith M. Acute Kidney Injury: A Guide to Diagnosis and Management. American Family Physician 2012;86(7):631 639.
33. Yehia M. a uniquely Egyptian epidemic. Nature.2011:474:s11-s13.
34. El-Bassat H, Ziada DH, Taha A, Alm-Eldin R. Urinary neutrophil gelatinase-associated lipocalin as a biomarker for the diagnosis of hepatorenal syndrome in cirrhotic patients. Tanta Medical Journal 2013;41(4):346 -52.
35. Angeli P, Merkel C. Pathogenesis and management of hepatorenal syndrome in patients with cirrhosis. J Hepatol. 2008;48 Suppl 1:S93–103.
36. Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P. Acute renal failure - definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care. 2004; 8:R204–212.
37. Wong F, Nadim MK, Kellum JA, Salerno F, Bellomo R, Gerbes A, et al. Working Party proposal for a revised classification system of renal dysfunction in patients with cirrhosis. Gut. 2011.
38. Qasem AA,Farag S E, Hamed E, Emara M, Bihery A, and Pasha H. Urinary Biomarkers of Acute Kidney Injury in Patients with Liver Cirrhosis. SRN Nephrology 2014;7:411-418.
39. Bolignano D, Lacquaniti A, Coppolino G, Donato V, Campo S, Fazio MR, Nicocia G and Buemi M. Neutrophil Gelatinase-Associated Lipocalin (NGAL) and Progre-ssion of Chronic Kidney Disease. Clin J Am Soc Nephrol. 2009; 4(2): 337–44.
40. Lin HY, Hwang DY, Lee SC, Kuo HT, Kuo MC, Chang JM, Tsai JC, Hung CC, Hwang SJ, Chen HC. Urinary neutrophil gelatinase-associated lipocalin and clinical outcomes in chronic kidney disease patients. Clin Chem Lab Med. 2015; 53(1):73-83.
41. Bauer M, Eickhoff JC, Gould MN, Mundhenke C, Maass N, Friedl A: Neutrophil Gelatinase-Associated Lipoc-alin (NGAL) Is a Predictor of Poor Prognosis in Human Primary Breast Cancer. Breast Cancer Res Treat 2008; 108:389-97.
42. Tong Z, Kunnumakkara AB, Wang H, Matsuo Y, Diagaradjane P, Harikumar KB, Ramachandran V, Sung B, Chakraborty A, Bresalier RS, Logsdon C, Aggarwal BB, Krishnan S, Guha S: Neutrophil Gelatinase- Associated Lipocalin: A Novel Suppressor of Invasion and Angiogenesis in Pancreatic Cancer. Cancer Res. 2008;68:6100-6108.
43. Devarajan P: The Promise of Biomarkers for Personalized Renal Cancer Care. Kidney Int 2010;77:755-7.
44. Barreto R, Elia C, Solà E, Moreira R, Ariza X, Rodríguez E, Graupera I, Alfaro I, Morales-Ruiz M, Poch E, Guevara M, Fernández J, Jiménez W, Arroyo V, Ginès P. Urinary neutrophil gelatinase-associated lipocalin predicts kidney outcome and death in patients with cirrhosis and bacterial infections. J Hepatol. 2014;61(1):35-42