Serum and Urinary NGAL and Cystatin C Levels as Diagnostic Tools for Acute Kidney Injury and Chronic Kidney Disease: A Histobiochemical Comparative Study

Author(s): Mustafa M. Sinna, Faris M.N. Altaf, Osama F. Mosa*

Journal Name: Current Pharmaceutical Design

Volume 25 , Issue 10 , 2019


Become EABM
Become Reviewer
Call for Editor

Abstract:

Background: High global incidence of acute kidney injury (AKI) is an observable complication in critically ill patients. Long-term disease and medication complexity contribute to devastating chronic kidney disease (CKD), diminishing quality of life.

Objectives: To establish new biomarkers to guide patient care and facilitate novel therapeutics development.

Methods: Serum and urinary levels of creatinine, CysC, and NGAL were estimated in 86 renal patients and compared with healthy controls for AKI and CKD categorization. Creatinine and CysC measurements were used to estimate GFR. Kidney biopsies were prepared for light microscopy for further characterization. Patients’ demographic data were used in group association studies.

Results: Thirty-six patients met the criteria for AKI and 50 for CKD. Both mean serum and urine creatinine levels were significantly elevated by 2.8 and 2.6, respectively, from baseline in 48 h in the AKI group but not CKD group. Mean serum Cystatin C (CysC) values were higher than controls but similar in both disease states, while urine levels were slightly higher in CKD patients, and remained steady by the end of the follow-up (EF-Up). Further, a significant 2.9-fold and 5.5-fold (p=0.001) increase in serum NGAL in AKI and CKD, respectively, and a dramatic 7.1-factor reduction in AKI group, but no appreciable change in the CKD group from admission to EF-Up were observed. Similarly, urine NGAL level for AKI and CKD increased 3.2-fold and 6-fold respectively, on admission, which decreased moderately with the AKI group (2.5-fold) but increased by a factor of 1-8 (10.7- fold; p=0.001) at EF-Up. ROC assessment curve revealed relatively higher NGAL performance at good predictive values than CysC (p < 0.009).

Conclusion: Our data demonstrated creatinine elevation by a factor > 2 in 48 h in AKI group but not CKD group, which returned close to normal levels by the EF-Up, an indication of abrupt renal injury in AKI, compared with a persistent effect in the CKD group. Both serum and urine NGAL sensitivity and specificity provided powerful discriminative tool between AKI and CKD by reduction in the AKI group and an increase in the CKD group by the EF-UP, thus, contributing in establishing the basis for AKI and CKD classification. CysC, however, displayed less sensitivity than NGAL, indicating effects by enigmatic non-specific factors.

Keywords: Acute kidney injury (AKI), chronic kidney disease (CKD), biomarkers, cystatin C (CysC), NGAL, estimated glomerular filtration rate (eGFR).

[1]
Hsu RK, Hsu CY. The Role of Acute Kidney Injury in Chronic Kidney Disease. Semin Nephrol 2016; 36(4): 283-92.
[http://dx.doi.org/10.1016/j.semnephrol.2016.05.005] [PMID: 27475659]
[2]
Lysak N, Bihorac A, Hobson C. Mortality and cost of acute and chronic kidney disease after cardiac surgery. Curr Opin Anaesthesiol 2017; 30(1): 113-7.
[PMID: 27841788]
[3]
Bellomo R, Ronco C, Mehta RL, et al. Acute kidney injury in the ICU: from injury to recovery: reports from the 5th Paris International Conference. Ann Intensive Care 2017; 7(1): 49.
[http://dx.doi.org/10.1186/s13613-017-0260-y] [PMID: 28474317]
[4]
Bihorac A, Brennan M, Ozrazgat-Baslanti T, et al. National surgical quality improvement program underestimates the risk associated with mild and moderate postoperative acute kidney injury. Crit Care Med 2013; 41(11): 2570-83.
[http://dx.doi.org/10.1097/CCM.0b013e31829860fc] [PMID: 23928835]
[5]
Uchino S, Kellum JA, Bellomo R, et al. Acute renal failure in critically ill patients: a multinational, multicenter study. JAMA 2005; 294(7): 813-8.
[http://dx.doi.org/10.1001/jama.294.7.813] [PMID: 16106006]
[6]
Chawla LS, Kimmel PL. Acute kidney injury and chronic kidney disease: an integrated clinical syndrome. Kidney Int 2012; 82(5): 516-24.
[http://dx.doi.org/10.1038/ki.2012.208] [PMID: 22673882]
[7]
Luyckx VA, Tonelli M, Stanifer JW. The global burden of kidney disease and the sustainable development goals. Bull World Health Organ 2018; 96(6): 414-422D.
[http://dx.doi.org/10.2471/BLT.17.206441] [PMID: 29904224]
[8]
Jha V, Garcia-Garcia G, Iseki K, et al. Chronic kidney disease: global dimension and perspectives. Lancet 2013; 382(9888): 260-72.
[http://dx.doi.org/10.1016/S0140-6736(13)60687-X] [PMID: 23727169]
[9]
Inker LA, Astor BC, Fox CH, et al. KDOQI US commentary on the 2012 KDIGO clinical practice guideline for the evaluation and management of CKD. Am J Kidney Dis 2014; 63(5): 713-35.
[http://dx.doi.org/10.1053/j.ajkd.2014.01.416] [PMID: 24647050]
[10]
Ostermann M, Philips BJ, Forni LG. Clinical review: Biomarkers of acute kidney injury: where are we now? Crit Care 2012; 16(5): 233.
[http://dx.doi.org/10.1186/cc11380] [PMID: 23014769]
[11]
Salvadori M, Rosso G, Bertoni E. Update on ischemia-reperfusion injury in kidney transplantation: Pathogenesis and treatment. World J Transplant 2015; 5(2): 52-67.
[http://dx.doi.org/10.5500/wjt.v5.i2.52] [PMID: 26131407]
[12]
Peake M, Whiting M. Measurement of serum creatinine--current status and future goals. Clin Biochem Rev 2006; 27(4): 173-84.
[PMID: 17581641]
[13]
Mishra J, Mori K, Ma Q, et al. Amelioration of ischemic acute renal injury by neutrophil gelatinase-associated lipocalin. J Am Soc Nephrol 2004; 15(12): 3073-82.
[http://dx.doi.org/10.1097/01.ASN.0000145013.44578.45] [PMID: 15579510]
[14]
Ostermann M, Joannidis M. Acute kidney injury 2016: diagnosis and diagnostic workup. Crit Care 2016; 20(1): 299.
[http://dx.doi.org/10.1186/s13054-016-1478-z] [PMID: 27670788]
[15]
Finney H, Newman DJ, Price CP. Adult reference ranges for serum cystatin C, creatinine and predicted creatinine clearance. Ann Clin Biochem 2000; 37(Pt 1): 49-59.
[http://dx.doi.org/10.1258/0004563001901524] [PMID: 10672373]
[16]
El-Farghali OG, El-Raggal NM, Mahmoud NH, Zaina GA. Serum neutrophil gelatinase-associated lipocalin as a predictor of acute kidney injury in critically-ill neonates. Pak J Biol Sci 2012; 15(5): 231-7.
[http://dx.doi.org/10.3923/pjbs.2012.231.237] [PMID: 24199457]
[17]
Stevens LA, Schmid CH, Greene T, et al. Factors other than glomerular filtration rate affect serum cystatin C levels. Kidney Int 2009; 75(6): 652-60.
[http://dx.doi.org/10.1038/ki.2008.638] [PMID: 19119287]
[18]
World Medical Association Declaration of Helsinki. ethical principles for medical research involving human subjects. JAMA 2013; 310(20): 2191-4.
[http://dx.doi.org/10.1001/jama.2013.281053] [PMID: 24141714]
[19]
Toora BD, Rajagopal G. Measurement of creatinine by Jaffe’s reaction--determination of concentration of sodium hydroxide required for maximum color development in standard, urine and protein free filtrate of serum. Indian J Exp Biol 2002; 40(3): 352-4.
[PMID: 12635710]
[20]
Nezami BG, Farris AB. Assessing fibrosis in kidney biopsiesBiomarkers in kidney disease Biomarkers in disease: Methods, discoveries and applications. Dordrecht: Springer 2016; pp. 933-53.
[http://dx.doi.org/10.1007/978-94-007-7699-9_51]
[21]
Iseki K, Iseki C, Ikemiya Y, Fukiyama K. Risk of developing end-stage renal disease in a cohort of mass screening. Kidney Int 1996; 49(3): 800-5.
[http://dx.doi.org/10.1038/ki.1996.111] [PMID: 8648923]
[22]
Iseki K. Gender differences in chronic kidney disease. Kidney Int 2008; 74(4): 415-7.
[http://dx.doi.org/10.1038/ki.2008.261] [PMID: 18670407]
[23]
Gelber RP, Kurth T, Kausz AT, et al. Association between body mass index and CKD in apparently healthy men. Am J Kidney Dis 2005; 46(5): 871-80.
[http://dx.doi.org/10.1053/j.ajkd.2005.08.015] [PMID: 16253727]
[24]
Lu JL, Molnar MZ, Naseer A, Mikkelsen MK, Kalantar-Zadeh K, Kovesdy CP. Association of age and BMI with kidney function and mortality: a cohort study. Lancet Diabetes Endocrinol 2015; 3(9): 704-14.
[http://dx.doi.org/10.1016/S2213-8587(15)00128-X] [PMID: 26235959]
[25]
Chronic Kidney Disease (Partial Update) Early Identification and Management of Chronic Kidney Disease in Adults in Primary and Secondary Care NICE Clinical Guidelines. 2014.https://www.ncbi.nlm.nih.gov/books/NBK248058/
[26]
Inker LA, Schmid CH, Tighiouart H, et al. Estimating glomerular filtration rate from serum creatinine and cystatin C. N Engl J Med 2012; 367(1): 20-9.
[http://dx.doi.org/10.1056/NEJMoa1114248] [PMID: 22762315]
[27]
Croda-Todd MT, Soto-Montano XJ, Hernández-Cancino PA, Juárez-Aguilar E. Adult cystatin C reference intervals determined by nephelometric immunoassay. Clin Biochem 2007; 40(13-14): 1084-7.
[http://dx.doi.org/10.1016/j.clinbiochem.2007.05.011] [PMID: 17624320]
[28]
Conti M, Moutereau S, Zater M, et al. Urinary cystatin C as a specific marker of tubular dysfunction. Clin Chem Lab Med 2006; 44(3): 288-91.
[http://dx.doi.org/10.1515/CCLM.2006.050] [PMID: 16519600]
[29]
Tian S, Kusano E, Ohara T, et al. Cystatin C measurement and its practical use in patients with various renal diseases. Clin Nephrol 1997; 48(2): 104-8.
[PMID: 9285147]
[30]
Cullen MR, Murray PT, Fitzgibbon MC. Establishment of a reference interval for urinary neutrophil gelatinase-associated lipocalin. Ann Clin Biochem 2012; 49(Pt 2): 190-3.
[http://dx.doi.org/10.1258/acb.2011.011105] [PMID: 22323662]
[31]
Halbesma N, Brantsma AH, Bakker SJ, et al. Gender differences in predictors of the decline of renal function in the general population. Kidney Int 2008; 74(4): 505-12.
[http://dx.doi.org/10.1038/ki.2008.200] [PMID: 18496511]
[32]
Rubinstein S, Wang C, Qu W. Occupational risk and chronic kidney disease: a population-based study in the United States adult population. Int J Nephrol Renovasc Dis 2013; 6: 53-9.
[http://dx.doi.org/10.2147/IJNRD.S39522] [PMID: 23662070]
[33]
Bello AK, Peters J, Rigby J, Rahman AA, El Nahas M. Socioeconomic status and chronic kidney disease at presentation to a renal service in the United Kingdom. Clin J Am Soc Nephrol 2008; 3(5): 1316-23.
[http://dx.doi.org/10.2215/CJN.00680208] [PMID: 18579673]
[34]
Garcia-Garcia G, Jha V. Chronic kidney disease in disadvantaged populations. Indian J Nephrol 2015; 25(2): 65-9.
[http://dx.doi.org/10.4103/0971-4065.150078] [PMID: 25838641]
[35]
Merkin SS, Coresh J, Diez Roux AV, Taylor HA, Powe NR. Area socioeconomic status and progressive CKD: the Atherosclerosis Risk in Communities (ARIC) Study. Am J Kidney Dis 2005; 46(2): 203-13.
[http://dx.doi.org/10.1053/j.ajkd.2005.04.033] [PMID: 16112038]
[36]
Foster MC, Hwang SJ, Larson MG, et al. Overweight, obesity, and the development of stage 3 CKD: the Framingham Heart Study. Am J Kidney Dis 2008; 52(1): 39-48.
[http://dx.doi.org/10.1053/j.ajkd.2008.03.003] [PMID: 18440684]
[37]
Kramer H, Gutiérrez OM, Judd SE, et al. Waist circumference, body mass index, and ESRD in the REGARDS (Reasons for Geographic and Racial Differences in Stroke) study. Am J Kidney Dis 2016; 67(1): 62-9.
[http://dx.doi.org/10.1053/j.ajkd.2015.05.023] [PMID: 26187471]
[38]
Mahmoodnia L, Tamadon MR. On the occasion of world kidney day 2017; obesity and its relationship with chronic kidney disease. J Nephropathol 2017; 6(3): 105-9.
[http://dx.doi.org/10.15171/jnp.2017.18] [PMID: 28975087]
[39]
Chang A, Finelli A, Berns JS, Rosner M. Chronic kidney disease in patients with renal cell carcinoma. Adv Chronic Kidney Dis 2014; 21(1): 91-5.
[http://dx.doi.org/10.1053/j.ackd.2013.09.003] [PMID: 24359991]
[40]
Doğaner YC, Aydoğan Ü, Rohrer JE, et al. Comparison of estimated GFR equations based on serum cystatin C alone and in combination with serum creatinine in patients with coronary artery disease. Anatol J Cardiol 2015; 15(7): 571-6.
[http://dx.doi.org/10.5152/akd.2014.5535] [PMID: 25537999]
[41]
Filler G, Bökenkamp A, Hofmann W, Le Bricon T, Martínez-Brú C, Grubb A. Cystatin C as a marker of GFR--history, indications, and future research. Clin Biochem 2005; 38(1): 1-8.
[http://dx.doi.org/10.1016/j.clinbiochem.2004.09.025] [PMID: 15607309]
[42]
Owen LJ, Keevil BG. Does bilirubin cause interference in Roche creatinine methods? Clin Chem 2007; 53(2): 370-1.
[http://dx.doi.org/10.1373/clinchem.2006.075846] [PMID: 17259257]
[43]
Nigam PK, Chandra A. Positive and negative false estimates of serum creatinine. Interv Cardiol (Lond) 2017; 9(4): 163-7.
[http://dx.doi.org/10.4172/Interventional-Cardiology.1000572]
[44]
Lieberman J. Elevation of serum angiotensin-converting-enzyme (ACE) level in sarcoidosis. Am J Med 1975; 59(3): 365-72.
[http://dx.doi.org/10.1016/0002-9343(75)90395-2] [PMID: 169692]
[45]
Kostadinova ES, Miteva LD, Stanilova SA. ACE serum level and I/D gene polymorphism in children with obstructive uropathies and other congenital anomalies of the kidney and urinary tract. Nephrology (Carlton) 2017; 22(8): 609-16.
[http://dx.doi.org/10.1111/nep.12824] [PMID: 27206329]
[46]
Schmidt-Ott KM, Mori K, Kalandadze A, et al. Neutrophil gelatinase-associated lipocalin-mediated iron traffic in kidney epithelia. Curr Opin Nephrol Hypertens 2006; 15(4): 442-9.
[http://dx.doi.org/10.1097/01.mnh.0000232886.81142.58] [PMID: 16775460]
[47]
Bolignano D, Lacquaniti A, Coppolino G, Campo S, Arena A, Buemi M. Neutrophil gelatinase-associated lipocalin reflects the severity of renal impairment in subjects affected by chronic kidney disease. Kidney Blood Press Res 2008; 31(4): 255-8.
[http://dx.doi.org/10.1159/000143726] [PMID: 18600028]
[48]
Mori K, Nakao K. Neutrophil gelatinase-associated lipocalin as the real-time indicator of active kidney damage. Kidney Int 2007; 71(10): 967-70.
[http://dx.doi.org/10.1038/sj.ki.5002165] [PMID: 17342180]


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 25
ISSUE: 10
Year: 2019
Published on: 04 August, 2019
Page: [1122 - 1133]
Pages: 12
DOI: 10.2174/1381612825666190516080920
Price: $65

Article Metrics

PDF: 39
HTML: 8