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 Table of Contents  
REVIEW ARTICLE
Year : 2017  |  Volume : 4  |  Issue : 4  |  Page : 115-120

Uromodulin and YKL-40 as biomarkers in pediatric acute kidney injury: A review of current evidence


Department of Paediatrics, College of Medicine, University of Nigeria/University of Nigeria Teaching Hospital, Ituku-ozalla, Enugu, Nigeria

Date of Web Publication29-Dec-2017

Correspondence Address:
Dr. Samuel Nkachukwu Uwaezuoke
Department of Paediatrics, University of Nigeria Teaching Hospital, Ituku-Ozalla, Enugu 400001
Nigeria
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jina.jina_19_17

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  Abstract 


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 Sep 22];4:115-20. Available from: http://www.journal-ina.com/text.asp?2017/4/4/115/222064




  Introduction Top


Biomarkers are increasingly being used in the diagnostic and prognostic evaluation of common childhood renal diseases such as idiopathic nephrotic syndrome,[1],[2] urinary tract infection (UTI),[3] chronic kidney disease (CKD),[4],[5] and acute kidney injury (AKI).[6],[7] 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.[8]

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.[9],[10] 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.[11] 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.[12] 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),[13],[14] kidney injury molecule-1 (KIM-1),[15] interleukin-18 (IL-18),[16] and cystatin C.[17],[18] Others include hepatocyte growth factor, N-acetyl-b-D-glucosaminidase (NAG), and vascular endothelial growth factor.[7]

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.[12] 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.[19] 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.[6]

Recently, uromodulin (UMOD) and YKL-40 have elicited scientific interest as potential biomarkers in AKI, as well as in CKD progression.[20],[21],[22],[23],[24],[25] 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.[26] 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 Top


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 [26] and is the most abundant protein excreted in the urine under physiologic conditions.[17],[28] 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.[27] 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.[29]

Furthermore, there has been a renewed interest in the role of UMOD in kidney injury [26] 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.[27] 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.[27] 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.[28]

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.[26] 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.[26]

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.[28],[29] 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.[30] 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.[22] 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.[22]

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.[31] 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].
Table 1: Uromodulin versus other novel retention biomarkers

Click here to view



  Predictive and Diagnostic Roles in Acute Kidney Injury Top


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,[20] 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.[22] Better still, the recent discovery of its protective role in AKI rather than as an instigator,[26] 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.[32] 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.[33] 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.[20],[22],[26] 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.[34] 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.[35] 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 Top


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.[36] 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.[21] 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 Top


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,[37] severe lung disease in cystic fibrosis,[38],[39],[40] acute exacerbations of chronic obstructive pulmonary disease,[41] severe bronchial asthma,[42] malignant diseases,[43],[44] community-acquired pneumonia,[45] and cardiovascular diseases related to diabetic microvascular complications.[46],[47] In addition, urine YKL-40 is reportedly associated with progression of AKI and mortality in hospitalized patients.[24] 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 Top


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.[24] 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.[48] 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.[49] 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 Top


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.[50] 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.[25] 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.[51]


  Conclusions Top


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

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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