Validity of Klotho, CYR61 and YKL-40 as ideal predictive biomarkers for acute kidney injury: review study

Mosa, Osama; Skitek, Milan; Jerin, Ales

doi:10.1590/1516-3180.2016.0099220516

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Sao Paulo Medical Journal

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REVIEW ARTICLE • Sao Paulo Med. J. 135 (01) • Jan-Feb 2017 • https://doi.org/10.1590/1516-3180.2016.0099220516 copy

Validity of Klotho, CYR61 and YKL-40 as ideal predictive biomarkers for acute kidney injury: review study

Validade de Klotho, CYR61 e YKL-40 como biomarcadores preditivos ideais para lesão renal aguda: estudo de revisão

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

CONTEXT AND OBJECTIVE:

Acute kidney injury (AKI) is still a headache for clinicians and scientists as a possible reason for increased death among intensive care unit (ICU) patients after invasive cardiac surgery. Furthermore, the diagnostic process for AKI using conventional biomarkers is not sufficient to ensure early warning of this condition because of the morbid influence of non-renal factors that definitively delay the time for the prognosis. These imposed limitations have led to significant amounts of research targeted towards identifying novel biomarkers for AKI with a sustained degree of sensitivity and specificity. Here, we reviewed previous studies conducted on the Klotho, CYR61 and YKL-40 biomarkers in relation to AKI.

DESIGN AND SETTING:

Review of the literature conducted in the Institute of Clinical Chemistry & Biochemistry, Ljubljana University Medical Center, Slovenia.

METHODS:

The literature was searched in PubMed and the Cochrane Library. From the database of this specialty, we selected 17 references that matched our context for detailed analysis and further investigation.

RESULTS:

The studies reviewed showed notable differences in their results relating to the diagnostic impact of Klotho, CYR61 and YKL-40 on early prediction of AKI.

CONCLUSIONS:

The results regarding the Klotho, CYR61 and YKL-40 biomarkers showed markedly equivocal performance in the previous studies and did not fulfill the expectations that these factors would form valid possible biomarkers for AKI.

KEY WORDS:
Acute kidney injury; Thoracic surgery; Proteins; Biomarkers; Review

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[1] Address for correspondence: Osama Mosa. Umm Al Qura University. Health Science College at Al-Leith. P.O. Box 127, Ekremaa St. Al-Leith, Saudi Arabia. Tel. +966541485058. E-mail: Drosama2030@gmail.com

Serials	Author/year	Study design	Purpose of the study	Results and recommendations
1	De Loor et al.³⁷37. De Loor J, Decruyenaere J, Demeyere K, et al. Urinary chitinase 3-like protein 1 for early diagnosis of acute kidney injury: a prospective cohort study in adult critically ill patients. Crit Care. 2016; 20(1):38.	Pilot study	To evaluate whether urinary Chitinase 3-like protein 1 (YKL-40) can predict AKI stage ≥ 2 in ICU patients compared with NGAL.	The concentration of UCHI3L1 within 12 hours of AKI stage ≥ 2 was increased with good performance on AUC-ROC curve (0.792, 95% CI), similar to UNGAL AUC-ROC (0.748, 95% CI), and after 24 h, UCHI3L1 showed AUC-ROC twice as high (95% CI: 1.3-3.1) as controls.
2	Huen et al.³⁸38. Huen SC, Parikh CR. Molecular phenotyping of clinical AKI with novel urinary biomarkers. Am J Physiol Renal Physiol. 2015; 309(5):F406-13.	Review	Focus on future phenotyping of AKI regarding NGAL and YKL-40.	NGAL and YKL-40 are important novel biomarkers involved in moderate renal tubular protection after AKI.
3	Schmidt et al.³⁹39. Schmidt IM, Hall IE, Kale S, et al. Chitinase-like protein Brp-39/YKL-40 modulates the renal response to ischemic injury and predicts delayed allograft function. J Am Soc Nephrol. 2013; 24(2):309-19.	Cohort (comparative) study	To evaluate the role of urinary and blood levels of YKL-40 in allografts after renal transplantation.	Urinary YKL-40 increased early on, within 18 h after surgery (131.3 ± 155.2), with AUC 0.86 ± 0.07; blood YKL-40 retarded to 1 day after surgery (623 ± 285.9), with AUC 0.59 ± 0.08
4	Hall et al.⁴⁰40. Hall IE, Stern EP, Cantley LG, Elias JA, Parikh CR. Urine YKL-40 is associated with progressive acute kidney injury or death in hospitalized patients. BMC Nephrol. 2014; 15:133.	Observational cohort study	To measure YKL-40 levels in the urine of clinically hospitalized AKI patients.	Urinary YKL-40 levels were detectable (≥ 5 ng/ml) within 1 h and gave better prognostic value (P = 0.04) with NGAL.
5	Tatar et al.⁴¹41. Tatar E, Gungor O, Celtik A, et al. Correlation between serum YKL-40 (chitinase-3-like protein) level and proteinuria in renal transplant recipients. Ann Transplant. 2013; 18:95-100.	Cohort study	To define relationship between YKL-40 and proteinuria in renal transplant recipients.	Mean serum YKL-40 and proteinuria levels were 66 ± 46 ng/ml and 0.77 ± 1.15 g/day respectively without any apparent correlation.
6	Maddens et al.³⁶36. Maddens B, Ghesquière B, Vanholder R, et al. Chitinase-like proteins are candidate biomarkers for sepsis-induced acute kidney injury. Mol Cell Proteomics. 2012; 11(6):M111.013094.	Clinical and experimental study	Measurement of urinary and plasma levels of Chitinase 3-like protein 1 and -3 in mice and patients with and without septic AKI.	Urinary CHI3L1 higher in septic-AKI patients than in non-AKI (P < 0.05), but in septic-AKI mice models, CHI3L1 and -3 were found to be high.
7	Malyszko et al.⁴²42. Malyszko J, Lukaszyk E, Glowinska I, Durlik M. Biomarkers of delayed graft function as a form of acute kidney injury in kidney transplantation. Sci Rep. 2015;5:11684.	Review article	Illustration of candidate biomarkers in cases of delayed graft function as a form of acute kidney injury.	Elevated YKL-40 in both urine and serum levels of patients with DGF, 2 days after transplantation.
8	Muramatsu et al.³²32. Muramatsu Y, Tsujie M, Kohda Y, et al. Early detection of cysteine rich protein 61 (CYR61, CCN1) in urine following renal ischemic reperfusion injury. Kidney Int. 2002; 62(5):1601-10.	Experimental study	To test CYR61 in the urinary levels of mice and rats after immediate renal ischemic reperfusion injury.	CYR61 protein increased first within 1 h and appeared in urine 3-6 h after ischemic renal injury.
9	Lai et al.⁴³43. Lai CF, Lin SL, Chiang WC, et al. Blockade of cysteine-rich protein 61 attenuates renal inflammation and fibrosis after ischemic kidney injury. Am J Physiol Renal Physiol. 2014; 307(5):F581-92.	Experimental study	To investigate the role of CYR61 after unilateral IRI in mice.	CYR61 was significantly induced at renal and urinary levels after IRI.
10	Xu et al.⁴⁴44. Xu Y, Shen X, Ma R, Jiang W, Zhang W. Protection of renal tubular epithelial cells from apoptosis by Cyr61 expression under hypoxia. Cell Biology International Reports. 2014; 21(2):47-52. Available from: http://onlinelibrary.wiley.com/doi/10.1002/cbi3.10016/full. Accessed in 2016 (Jun 7). http://onlinelibrary.wiley.com/doi/10.10...	Experimental study	To indicate CYR61 expression in renal cell lines under hypoxia	Enhanced expression of renal CYR61 in response to hypoxic ischemic injury.
11	Kim et al.⁴⁵45. Kim AJ, Ro H, Kim H, et al. Klotho and S100A8/A9 as Discriminative Markers between Pre-Renal and Intrinsic Acute Kidney Injury. PLoS One. 2016; 11(1):e0147255.	Cohort study	To determine possible influence of AKI on serum and urinary levels of Klotho, S100A8/A9 and NGAL	Urinary Klotho levels were 13.21 ± 17.32 versus 72.97 ± 17.96 pg/ml (P = 0.002) in pre-renal and intrinsic AKI respectively.
12	Torregrosa et al.⁴⁶46. Torregrosa I, Montoliu C, Urios A, et al. Urinary Klotho measured by ELISA as an early biomarker of acute kidney injury in patients after cardiac surgery or coronary angiography. Nefrología. 2015; 35(2):172-8.	Cohort study	Assessment of urinary Klotho levels in patients after cardiac surgery or coronary angiography.	Klotho levels did not behave as a good early biomarker of AKI.
13	Castellano et al.⁴⁷47. Castellano G, Intini A, Stasi A, et al. Complement Modulation of Anti-Aging Factor Klotho in Ischemia/Reperfusion Injury and Delayed Graft Function. Am J Transplant. 2016; 16(1):325-33.	Experimental study	To investigate whether or not complement components affect Klotho levels after IRI.	Complement activation result in remarkable decline in renal Klotho levels, 24 h after IRI.
14	Liu et al.⁴⁸48. Liu YJ, Sun HD, Chen J, et al. Klotho: a novel and early biomarker of acute kidney injury after cardiac valve replacement surgery in adults. Int J Clin Exp Med. 2015; 8(5):7351-8.	Case-control study	To evaluate serum Klotho levels at different time intervals after cardiac surgery.	Serum Klotho levels were 101.97 ± 16.93 versus 121.64 ± 19.87 (P < 0.01) in AKI and non-AKI group respectively at 0 h and continued until 4 h. After 3 days, serum Klotho values were 120.50 ± 13.17 versus 128.67 ± 18.84.
15	Seo et al.⁴⁹49. Seo MY, Yang J, Lee JY, et al. Renal Klotho expression in patients with acute kidney injury is associated with the severity of the injury. Korean J Intern Med. 2015;30(4):489-95.	Retrospective cohort study	Assessment of renal Klotho levels in human samples instead of animal models.	Renal Klotho levels were significant reduced with AKI severity.
16	Hu et al.²⁹29. u MC, Shi M, Zhang J, et al. Klotho deficiency is an early biomarker of renal ischemia-reperfusion injury and its replacement is protective. Kidney Int. 2010; 78(12):1240-51.	Experimental and case-control study	To estimate Klotho at urinary and plasma levels, investigating probable protective ability.	Urinary Klotho values (pmoles/l) were 2.52 ± 0.76 in AKI versus 20.66 ± 1.81 in non-AKI, with P < 0.01.
17	Sugiura et al.³⁰30. ugiura H, Yoshida T, Tsuchiya K, et al. Klotho reduces apoptosis in experimental ischaemic acute renal failure. Nephrol Dial Transplant. 2005; 20(12):2636-45.	Experimental study	To explain the physiological relevance of renal Klotho after IRI in rats.	Renal Klotho levels were significantly reduced in IRI rats, 24 h after ischemia.