|Year : 2017 | Volume
| Issue : 4 | Page : 115-120
Uromodulin and YKL-40 as biomarkers in pediatric acute kidney injury: A review of current evidence
Samuel Nkachukwu Uwaezuoke
Department of Paediatrics, College of Medicine, University of Nigeria/University of Nigeria Teaching Hospital, Ituku-ozalla, Enugu, Nigeria
|Date of Web Publication||29-Dec-2017|
Dr. Samuel Nkachukwu Uwaezuoke
Department of Paediatrics, University of Nigeria Teaching Hospital, Ituku-Ozalla, Enugu 400001
Source of Support: None, Conflict of Interest: None
This review aims to discuss the current evidence about the role of two biomarkers in pediatric acute kidney injury (AKI)-uromodulin (UMOD) and YKL-40 (a glycoprotein whose name is derived from the three N-terminal amino acids present on the secreted form and its molecular size of 40 kDa). Several novel biomarkers have been used in the diagnostic and prognostic evaluation of AKI. UMOD and YKL-40 or chitinase 3-like protein 1 have recently attracted scientific interest as potential biomarkers in the disease. Although UMOD has long been recognized as a marker of tubular health, it was only in the recent past that its functional role in health and disease began to be understood. The finding of low levels of the biomarker in AKI supports the recent discovery that it plays a protective rather than an instigatory role in the disease. Evidence synthesized from the reviewed studies suggests that urine UMOD levels are negatively correlated with AKI risk. Moreover, increased serum UMOD may also be used as a prognostic biomarker for recovery from AKI. On the other hand, YKL-40 (although a multidisease biomarker) has been shown to play a predictive and prognostic role in AKI, its levels being positively correlated with disease risk. Large prospective studies are however required to confirm these results and to assess the clinical utility of estimating UMOD and YKL-40 levels as well as the therapeutic implications of their altered levels.
Keywords: Acute kidney injury, chitinase 3-like protein 1, prediction, prognosis, uromodulin
|How to cite this article:|
Uwaezuoke SN. Uromodulin and YKL-40 as biomarkers in pediatric acute kidney injury: A review of current evidence. J Integr Nephrol Androl 2017;4:115-20
|How to cite this URL:|
Uwaezuoke SN. Uromodulin and YKL-40 as biomarkers in pediatric acute kidney injury: A review of current evidence. J Integr Nephrol Androl [serial online] 2017 [cited 2018 Jan 17];4:115-20. Available from: http://www.journal-ina.com/text.asp?2017/4/4/115/222064
| Introduction|| |
Biomarkers are increasingly being used in the diagnostic and prognostic evaluation of common childhood renal diseases such as idiopathic nephrotic syndrome,, urinary tract infection (UTI), chronic kidney disease (CKD),, and acute kidney injury (AKI)., The utility of an ideal biomarker in diagnostic nephrology is predicated on the following characteristics: its production by injured nephrons and its organ specificity; its commensurate concentration with the degree of nephron injury; its early expression following a potentially reversible organ injury; prompt reduction in concentration after injury to enable its use, a monitoring tool for treatment; and its ability to be estimated quickly and reliably.
Serum creatinine has been considered as the traditional biomarker for AKI, as it is routinely used in clinical practice to measure renal function, thus serving as a marker for the diagnosis and staging of AKI., However, serum creatinine is basically an indicator of renal function rather than renal pathology because a change in its concentration is only evident when about half of renal function is reduced. Other limitations of serum creatinine include the variation in its concentration with respect to size of muscle mass, chronologic age, gender, drugs, and hydration status. Furthermore, the 24–48-h delay in its elevation after an abrupt reduction in renal function and the scant information it provides about the etiology and nature of renal injury have justified the paradigm shift to alternative novel biomarkers. These biomarkers, which have been investigated and found useful in predicting AKI, consist of neutrophil gelatinase-associated lipocalin (NGAL),, kidney injury molecule-1 (KIM-1), interleukin-18 (IL-18), and cystatin C., Others include hepatocyte growth factor, N-acetyl-b-D-glucosaminidase (NAG), and vascular endothelial growth factor.
In the course of AKI, accumulation of biomarkers in plasma and urine reflects the diverse pathophysiological events which occur during the process of renal injury and repair. For instance, biomarkers such as NGAL, IL-18, NAG, and KIM-1 accumulate in urine due to induced tubular epithelial synthesis in different parts of the nephron while urine NGAL and cystatin C may be as a result of reduced reabsorption of the filtered load in the proximal tubule. In addition, urine NGAL and IL-18 may also be accounted for by their production from transmigrated, activated immune cells into the tubular lumen, while their increased production in extrarenal tissues has been demonstrated, thus raising concerns about their sensitivity and specificity for AKI. Given the characteristics of an ideal biomarker, it is indeed difficult to find one marker which can singly fulfill all the criteria. Rather, panels of different biomarkers with specific features are probably required to increase their sensitivity and specificity so that the diagnosis of the disease can be improved.
Recently, uromodulin (UMOD) and YKL-40 have elicited scientific interest as potential biomarkers in AKI, as well as in CKD progression.,,,,, Although much of the existing evidence support the role of UMOD in both AKI and CKD, a recent finding suggests that the biomarker may actually have a protective role in AKI. The present review aims to discuss the current evidence about the role of these two biomarkers in pediatric AKI.
| Uromodulin as a Biomarker in Acute Kidney Injury|| |
UMOD, also known as Tamm–Horsfall protein, is a glycoprotein expressed exclusively by renal tubular cells lining the thick ascending limb of the loop of Henle  and is the most abundant protein excreted in the urine under physiologic conditions., Although its physiologic functions have hitherto remained unclear until recently, substantial progress has been made in highlighting the importance of UMOD in the pathophysiology of medullary cystic kidney disease, UTI, and nephrolithiasis. For instance, UMOD is believed to be renoprotective against UTI and stone formation and has also been linked to fluid and electrolyte homeostasis, as well as to kidney innate immunity.
Furthermore, there has been a renewed interest in the role of UMOD in kidney injury  and in the link of its mutations with the etiology of uromodulin-associated kidney diseases (UAKD): medullary cystic disease type 2, familial juvenile hyperuricemic nephropathy, and glomerulocystic kidney disease. The common features of these diseases are the autosomal dominant inheritance, insignificant urine sediment, and slow progression to end-stage renal disease, while they are also frequently associated with hyperuricemia and gout. Other characteristic features include progressive tubulointerstitial damage, impaired urinary concentrating ability, and renal cysts, with evidence pointing at intracellular accumulation of mutant UMOD (due to delayed intracellular trafficking) as a fundamental primary event in the pathogenesis of UAKD.
Interestingly, the paradigm of UMOD as a trigger in kidney injury has been challenged by new evidence from a murine model showing a protective role for this protein in AKI, possibly through downregulation of interstitial inflammation. Despite its suggested exacerbation of progressive renal injury in CKD, elevation of UMOD has instead been proposed as a reactive event to the injury, reflecting its elevation in the renal parenchyma, where it retards the injury process.
Moreover, genome-wide association studies have recognized UMOD as a risk factor for CKD and hypertension, suggesting that its concentration in the urine could represent a useful biomarker for the development of CKD., The mechanism underlying the association between UMOD risk variants and susceptibility to CKD and hypertension was not fully comprehended until recently, when the link between UMOD and hypertension was discovered to be caused by over activation of sodium-potassium-chloride co-transporter (NKCC2), located at the thick ascending limb of the loop of Henle; it points to UMOD as a therapeutic target for reducing blood pressure and preserving renal function. Indeed, recent findings suggest that higher levels of UMOD are associated with higher estimated glomerular filtration rate (eGFR) and renal size, possibly indicating greater kidney functional reserve. In addition, its greater excretion is associated with markers of volume overload such as fractional excretion of uric acid, sodium, and chloride, suggesting a potential role in salt and water retention, while higher levels of this glycoprotein are linked to lower risk of decline in eGFR, mortality, and perhaps, a lower risk of AKI.
Based on these observations, it therefore appears that body-fluid (serum) UMOD follows a pattern which is in contrast to that of known conventional renal retention biomarkers, by showing lower levels with reduction in renal function. As UMOD is expressed by the cells of the thick ascending limb of the loop of Henle, lower UMOD serum levels may thus reflect a reduction in number or function of these cells in CKD. As a potential biomarker in AKI, UMOD should be able to predict disease risk, play diagnostic and prognostic roles, and serve as an indicator of therapy. Notably, when compared with other novel retention biomarkers, the performance of UMOD in these four areas of AKI evaluation may be relatively weak [Table 1].
| Predictive and Diagnostic Roles in Acute Kidney Injury|| |
These roles of UMOD were reported in a study which aimed to identify urine biomarkers predictive of AKI in infants. In the case–control study, eight urine AKI biomarkers (NGAL, osteopontin, cystatin C, albumin, β-2 microglobulin, epithelial growth factor, UMOD, and KIM-1) were compared in infants with AKI and 24 infants from the cohort without AKI. The authors found that while the levels of urine NGAL, KIM-1, and osteopontin tended to be higher in infants with AKI, lower levels of UMOD and epithelial growth factor were rather observed in these patients. Thus, unlike UMOD, the predictive ability of other biomarkers for AKI risk is measured by their elevation in body fluids. For UMOD, elevated urine levels may mean a less likelihood for AKI risk because higher levels of this glycoprotein are reportedly associated with lower risk of decline in eGFR. Better still, the recent discovery of its protective role in AKI rather than as an instigator, underscores the finding of low levels of this potential biomarker in the disease.
Similarly, in a recent Polish study conducted in patients with acute pancreatitis and AKI (albeit adult individuals), the investigators noted that those with AKI tended to have lower serum UMOD. Although serum UMOD correlated significantly with renal function in the early phase of acute pancreatitis, its measurement did not reliably predict severity of the disease or development of AKI. As a biomarker of tubular health, high urinary levels of UMOD which are associated with less AKI (as reported in animal models) have also been evaluated in human adult patients who had undergone cardiac surgery. From the study findings, the researchers concluded that lower UMOD-to-creatinine ratio was associated with higher odds of AKI and higher peak serum creatinine after cardiac surgery. This study once more confirms the negative correlation between urine UMOD levels and AKI risk, which were noted in previous reports.,, It is thus plausible to infer that low UMOD urine level may be predictive of AKI risk and an indicator of potential therapeutic intervention.
In another study in pediatric individuals conducted in Ireland, the authors evaluated seven urine AKI biomarkers (albumin, β-2 microglobulin, cystatin C, epidermal growth factor, NGAL, osteopontin, and UMOD) in neonates with perinatal asphyxia who developed AKI and in their controls. Remarkably, infants with AKI had significantly higher concentrations of albumin, cystatin C, NGAL and osteopontin, and lower concentrations of epidermal growth factor and UMOD compared to those without AKI. Again, low urine UMOD levels are obviously diagnostic of AKI and should therefore serve as an indicator of therapy.
A related study by a group of investigators assessed the relationship between fourteen different urine biomarkers and AKI in very low-birth weight infants. A summary of the study findings indicates that infants with AKI had higher maximum levels of urine cystatin C, NGAL, osteopontin, clusterin, and α glutathione S-transferase than infants without AKI. Furthermore, infants with AKI had lower minimum levels of epithelial growth factor and UMOD than those without AKI.
| Prognostic Role in Nephrogenesis and Acute Kidney Injury|| |
Interestingly, one recent report suggests that urine UMOD can also be utilized in the assessment of normal kidney development (nephrogenesis) in the absence of renal injury. The authors established that among healthy neonates, levels of urine biomarkers vary with gestational age. For instance, of the seven urine biomarkers evaluated (albumin, β-2 microglobulin, cystatin C, NGAL, osteopontin, epidermal growth factor, and UMOD), epidermal growth factor and UMOD levels were increased while the levels of the rest were decreased with advancing gestational age. By 3 months of age, epidermal growth factor and UMOD levels had increased in preterm infants to levels similar to those of term infants. Thus, epidermal growth factor and UMOD are seen as predominantly developmental biomarkers. Specifically, prenatal UMOD level can serve as a marker to predict good outcome in nephrogenesis. Finally, a recent report suggests that UMOD redistribution in the thick ascending limb after AKI is a protein-specific event; its elevated interstitial presence negatively regulates the evolving inflammatory signaling in neighboring proximal tubules, thereby enhancing renal recovery. The authors thus concluded that increased serum UMOD may be used as a prognostic biomarker for recovery from AKI. In other words, elevated serum UMOD level may suggest a good prognosis in AKI as it points to renal recovery from the acute disease.
| Ykl-40 as a Biomarker in Acute Kidney Injury|| |
YKL-40 (also known as chitinase 3-like protein 1) is a newly identified glycoprotein which is produced by activated macrophages and neutrophils and expressed in a wide range of inflammatory conditions and malignancies. The name, YKL-40, is derived from the three N-terminal amino acids present on the secreted form and its molecular size of 40 kDa. It binds to the ubiquitously expressed chitin but lacks chitinase activity. Its elevated circulating levels have been noted in obesity and insulin resistance among prepubertal children, severe lung disease in cystic fibrosis,,, acute exacerbations of chronic obstructive pulmonary disease, severe bronchial asthma, malignant diseases,, community-acquired pneumonia, and cardiovascular diseases related to diabetic microvascular complications., In addition, urine YKL-40 is reportedly associated with progression of AKI and mortality in hospitalized patients. Unlike UMOD, this potential AKI biomarker is produced in extrarenal sites and expressed in diverse diseases, while its body fluid levels are directly correlated with severity of the disease states. In AKI, elevated urine YKL-40 level may indeed play predictive, diagnostic, and prognostic roles [Table 2]. This is in contrast with UMOD whose reduced levels are predictive and diagnostic of the disease.
|Table 2: Chitinase 3-like protein 1 versus other novel retention biomarkers|
Click here to view
| Predictive and Diagnostic Roles|| |
Its possible role in predicting AKI severity has been highlighted in one study which aimed to determine the relationship between urine YKL-40 alone (or in combination with urine NGAL) and progression to higher AKI stage and/or in-patient mortality. The authors noted that urine YKL-40 was associated with AKI progression and/or mortality in hospitalized patients and concluded that its combination with other AKI biomarkers such as NGAL could also delineate disease progression risk. Nevertheless, more recent studies conducted among critically ill adult individuals suggest that serum and urine YKL-40 levels are elevated in AKI. A group of researchers reported that rising urine YKL-40 levels were associated with progressive increase in AKI severity and thus served as a good biomarker for the prediction of later stages of AKI in adult patients managed in intensive care units. This observation is confirmed corroborated by the findings from another study which noted that serum YKL-40 combined with either urine YKL-40 or urine NGAL was a good predictor of later stages of AKI within 12 h post cardiac surgery. Although the findings of these studies were based on AKI in adult patients, they may are also be applicable in pediatric patients with AKI.
| Prognostic Role|| |
Specifically, YKL-40 has been seen as a repair urine biomarker in AKI as distinct from injury urine biomarkers. In a study of adult individuals after a marathon race, the investigators reported that levelws of six injury urine biomarkers (IL-6, IL-8, IL-18, KIM-1, NGAL, and tumor necrosis factor α) and two repair urine biomarkers (YKL-40 and monocyte chemoattractant protein 1) were all elevated within 48 h. They concluded that elevated injury and repair biomarker levels suggest structural damage to renal tubules which occur postmarathon. Their observations appear to be in tandem with the findings in another study which showed that YKL-40 was produced in response to tubular injury and was independently associated with recovery from AKI and delayed renal graft function. The authors believed that its ultimate validation as a prognostic biomarker would mean its utility in determining the suitability of donor kidneys for transplant. Apart from this prognostic role, a recent review however suggests that its predictive role as a biomarker in AKI remains equivocal.
| Conclusions|| |
Despite the fact that UMOD has long been recognized as a marker of tubular health, it was only in the recent past that medical science has started to appreciate its functional role in health and disease. The finding of low levels of the biomarker in AKI supports the recent discovery that it plays a protective rather than an instigatory role in the disease. Most of the reports indeed suggest that urine UMOD levels are negatively correlated with AKI risk. Moreover, elevated serum UMOD levels may also be used as a prognostic biomarker for recovery from AKI. On the other hand, YKL40 (although a multidisease biomarker) has been shown to play a predictive and prognostic role in AKI, its body fluid levels being positively correlated with disease risk. Large prospective studies are however required to confirm these results (some of which are still preliminary) and to assess the clinical utility of estimating UMOD and YKL-40 levels as well as the therapeutic implications of their altered levels.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Bai Y, Liu W, Guo Q, Zou Y. Screening for urinary biomarkers of steroid-resistant nephrotic syndrome in children. Exp Ther Med 2013;5:860-4.
Uwaezuoke SN. The role of novel biomarkers in childhood idiopathic nephrotic syndrome: A narrative review of published evidence. Int J Nephrol Renovasc Dis 2017;10:123-8.
Yim HE, Yim H, Bae ES, Woo SU, Yoo KH. Predictive value of urinary and serum biomarkers in young children with febrile urinary tract infections. Pediatr Nephrol 2014;29:2181-9.
Lopez-Giacoman S, Madero M. Biomarkers in chronic kidney disease, from kidney function to kidney damage. World J Nephrol 2015;4:57-73.
Fassett RG, Venuthurupalli SK, Gobe GC, Coombes JS, Cooper MA, Hoy WE, et al.
Biomarkers in chronic kidney disease: A review. Kidney Int 2011;80:806-21.
Uwaezuoke SN. Acute kidney injury in children: Enhancing diagnosis with novel biomarkers. J Acute Dis 2016;5:267-70.
Vanmassenhove J, Vanholder R, Nagler E, Van Biesen W. Urinary and serum biomarkers for the diagnosis of acute kidney injury: An in-depth review of the literature. Nephrol Dial Transplant 2013;28:254-73.
Cruz DN, Goh CY, Haase-Fielitz A, Ronco C, Haase M. Early biomarkers of renal injury. Congest Heart Fail 2010;16 Suppl 1:S25-31.
Ricci Z, Cruz DN, Ronco C. Classification and staging of acute kidney injury: Beyond the RIFLE and AKIN criteria. Nat Rev Nephrol 2011;7:201-8.
Bellomo R, Kellum JA, Ronco C. Acute kidney injury. Lancet 2012;380:756-66.
Coca SG, Yalavarthy R, Concato J, Parikh CR. Biomarkers for the diagnosis and risk stratification of acute kidney injury: A systematic review. Kidney Int 2008;73:1008-16.
Mårtensson J, Martling CR, Bell M. Novel biomarkers of acute kidney injury and failure: Clinical applicability. Br J Anaesth 2012;109:843-50.
Schinstock CA, Semret MH, Wagner SJ, Borland TM, Bryant SC, Kashani KB, et al.
Urinalysis is more specific and urinary neutrophil gelatinase-associated lipocalin is more sensitive for early detection of acute kidney injury. Nephrol Dial Transplant 2013;28:1175-85.
Doi K, Urata M, Katagiri D, Inamori M, Murata S, Hisagi M, et al.
Plasma neutrophil gelatinase-associated lipocalin in acute kidney injury superimposed on chronic kidney disease after cardiac surgery: A multicenter prospective study. Crit Care 2013;17:R270.
Shao X, Tian L, Xu W, Zhang Z, Wang C, Qi C, et al.
Diagnostic value of urinary kidney injury molecule 1 for acute kidney injury: A meta-analysis. PLoS One 2014;9:e84131.
Liu Y, Guo W, Zhang J, Xu C, Yu S, Mao Z, et al.
Urinary interleukin 18 for detection of acute kidney injury: A meta-analysis. Am J Kidney Dis 2013;62:1058-67.
Bongiovanni C, Magrini L, Salerno G, Gori CS, Cardelli P, Hur M, et al.
Serum cystatin C for the diagnosis of acute kidney injury in patients admitted in the emergency department. Dis Markers 2015;2015:416059.
Nejat M, Pickering JW, Walker RJ, Westhuyzen J, Shaw GM, Frampton CM, et al.
Urinary cystatin C is diagnostic of acute kidney injury and sepsis, and predicts mortality in the Intensive Care Unit. Crit Care 2010;14:R85.
Mårtensson J, Bellomo R. The rise and fall of NGAL in acute kidney injury. Blood Purif 2014;37:304-10.
Askenazi DJ, Koralkar R, Hundley HE, Montesanti A, Parwar P, Sonjara S, et al.
Urine biomarkers predict acute kidney injury in newborns. J Pediatr 2012;161:270-50.
El-Achkar TM, McCracken R, Liu Y, Heitmeier MR, Bourgeois S, Ryerse J, et al.
Tamm-horsfall protein translocates to the basolateral domain of thick ascending limbs, interstitium, and circulation during recovery from acute kidney injury. Am J Physiol Renal Physiol 2013;304:F1066-75.
Garimella PS, Sarnak MJ. Uromodulin in kidney health and disease. Curr Opin Nephrol Hypertens 2017;26:136-42.
Lhotta K. Uromodulin and chronic kidney disease. Kidney Blood Press Res 2010;33:393-8.
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.
Puthumana J, Hall IE, Reese PP, Schröppel B, Weng FL, Thiessen-Philbrook H, et al.
YKL-40 associates with renal recovery in deceased donor kidney transplantation. J Am Soc Nephrol 2017;28:661-70.
El-Achkar TM, Wu XR. Uromodulin in kidney injury: An instigator, bystander, or protector? Am J Kidney Dis 2012;59:452-61.
Iorember FM, Vehaskari VM. Uromodulin: Old friend with new roles in health and disease. Pediatr Nephrol 2014;29:1151-8.
Fugiel A, Kuzniewski M, Fedak D. Uromodulin – Can it be a new marker of kidney damage? Przegl Lek 2013;70:976-82.
Rampoldi L, Scolari F, Amoroso A, Ghiggeri G, Devuyst O. The rediscovery of uromodulin (Tamm-horsfall protein): From tubulointerstitial nephropathy to chronic kidney disease. Kidney Int 2011;80:338-47.
Scolari F, Izzi C, Ghiggeri GM. Uromodulin: From monogenic to multifactorial diseases. Nephrol Dial Transplant 2015;30:1250-6.
Risch L, Lhotta K, Meier D, Medina-Escobar P, Nydegger UE, Risch M, et al.
The serum uromodulin level is associated with kidney function. Clin Chem Lab Med 2014;52:1755-61.
Kuśnierz-Cabala B, Gala-Błądzińska A, Mazur-Laskowska M, Dumnicka P, Sporek M, Matuszyk A, et al.
Serum uromodulin levels in prediction of acute kidney injury in the early phase of acute pancreatitis. Molecules 2017;22. pii: E988.
Garimella PS, Jaber BL, Tighiouart H, Liangos O, Bennett MR, Devarajan P, et al.
Association of preoperative urinary uromodulin with AKI after cardiac surgery. Clin J Am Soc Nephrol 2017;12:10-8.
Sweetman DU, Onwuneme C, Watson WR, O'Neill A, Murphy JF, Molloy EJ, et al.
Renal function and novel urinary biomarkers in infants with neonatal encephalopathy. Acta Paediatr 2016;105:e513-e519.
Askenazi DJ, Koralkar R, Patil N, Halloran B, Ambalavanan N, Griffin R, et al.
Acute kidney injury urine biomarkers in very low-birth-weight infants. Clin J Am Soc Nephrol 2016;11:1527-35.
DeFreitas MJ, Seeherunvong W, Katsoufis CP, RamachandraRao S, Duara S, Yasin S, et al.
Longitudinal patterns of urine biomarkers in infants across gestational ages. Pediatr Nephrol 2016;31:1179-88.
Kyrgios I, Galli-Tsinopoulou A, Stylianou C, Papakonstantinou E, Arvanitidou M, Haidich AB, et al.
Elevated circulating levels of the serum acute-phase protein YKL-40 (chitinase 3-like protein 1) are a marker of obesity and insulin resistance in prepubertal children. Metabolism 2012;61:562-8.
Leonardi S, Parisi GF, Capizzi A, Manti S, Cuppari C, Scuderi MG, et al.
YKL-40 as marker of severe lung disease in cystic fibrosis patients. J Cyst Fibros 2016;15:583-6.
Fantino E, Gangell CL, Hartl D, Sly PD, AREST CF. Airway, but not serum or urinary, levels of YKL-40 reflect inflammation in early cystic fibrosis lung disease. BMC Pulm Med 2014;14:28.
Hector A, Kormann MS, Mack I, Latzin P, Casaulta C, Kieninger E, et al.
The chitinase-like protein YKL-40 modulates cystic fibrosis lung disease. PLoS One 2011;6:e24399.
Lai T, Wu D, Chen M, Cao C, Jing Z, Huang L, et al.
YKL-40 expression in chronic obstructive pulmonary disease: Relation to acute exacerbations and airway remodeling. Respir Res 2016;17:31.
Duru S, Yüce G, Ulasli SS, Erdem M, Kizilgün M, Kara F, et al.
The relationship between serum YKL-40 levels and severity of asthma. Iran J Allergy Asthma Immunol 2013;12:247-53.
Johansen JS, Jensen BV, Roslind A, Price PA. Is YKL-40 a new therapeutic target in cancer? Expert Opin Ther Targets 2007;11:219-34.
Iwamoto FM, Hormigo A. Unveiling YKL-40, from serum marker to target therapy in glioblastoma. Front Oncol 2014;4:90.
Wang HL, Hsiao PC, Tsai HT, Yeh CB, Yang SF. Usefulness of plasma YKL-40 in management of community-acquired pneumonia severity in patients. Int J Mol Sci 2013;14:22817-25.
Przybyłowski P, Janik L, Wasilewski G, Nowak E, Koźlik P, Małyszko J, et al.
YKL-40, a novel marker of cardiovascular complications, is related to kidney function in heart transplant recipients. Transplant Proc 2014;46:2860-3.
Rathcke CN, Vestergaard H. YKL-40 – An emerging biomarker in cardiovascular disease and diabetes. Cardiovasc Diabetol 2009;8:61.
De Loor J, Decruyenaere J, Demeyere K, Nuytinck L, Hoste EA, Meyer E, 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;20:38.
De Loor J, Herck I, Francois K, Van Wesemael A, Nuytinck L, Meyer E, et al.
Diagnosis of cardiac surgery-associated acute kidney injury: Differential roles of creatinine, chitinase 3-like protein 1 and neutrophil gelatinase-associated lipocalin: A prospective cohort study. Ann Intensive Care 2017;7:24.
Mansour SG, Verma G, Pata RW, Martin TG, Perazella MA, Parikh CR, et al.
Kidney injury and repair biomarkers in marathon runners. Am J Kidney Dis 2017;70:252-61.
Mosa O, Skitek M, Jerin A. Validity of klotho, CYR61 and YKL-40 as ideal predictive biomarkers for acute kidney injury: Review study. Sao Paulo Med J 2017;135:57-65.
[Table 1], [Table 2]