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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2013  |  Volume : 24  |  Issue : 6  |  Page : 1111-1124
Novel troponin-like biomarkers of acute kidney injury

1 Department of Nephrology, Theodor Bilharz Research Institute, Cairo, Egypt
2 Nephrology Unit, Al-Adan Hospital, Kuwait

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Date of Web Publication13-Nov-2013


Acute kidney injury (AKI) is a common and serious condition in both the inpatient and outpatient settings, and its diagnosis depends on serum creatinine measurements. Unfortunately, creatinine is a delayed and unreliable indicator of AKI. The lack of early biomarkers has limited our ability to translate promising experimental therapies to human AKI. Fortunately, understanding the early stress response of the kidney to acute injuries has realized a number of potential biomarkers. For example, neutrophil gelatinase-associated lipocalin is emerging as an excellent stand alone troponin-like biomarker in the plasma and urine for predicting and monitoring clinical trials and in the prognosis of AKI. In recent years, a number of new biomarkers of AKI with more favorable test characteristics than creatinine have been identified and studied in a variety of experimental and clinical settings. This review will consider the most well-established biomarkers of AKI.

How to cite this article:
Abdallah E, Waked E, Al-Helal B, Asad R, Nabil M, Harba T. Novel troponin-like biomarkers of acute kidney injury. Saudi J Kidney Dis Transpl 2013;24:1111-24

How to cite this URL:
Abdallah E, Waked E, Al-Helal B, Asad R, Nabil M, Harba T. Novel troponin-like biomarkers of acute kidney injury. Saudi J Kidney Dis Transpl [serial online] 2013 [cited 2021 Feb 25];24:1111-24. Available from: https://www.sjkdt.org/text.asp?2013/24/6/1111/121267

   Introduction Top

Acute kidney injury (AKI) refers to a common syndrome that results from multiple causative factors and occurs in a variety of clinical settings, with varied clinical manifestations, ranging from minimal elevation in serum creatinine to anuric renal failure. AKI is characterized functionally by a rapid decline in the glomerular filtration rate (GFR) and biochemically by the resultant accumulation of blood-urea nitrogen and creatinine. [1] The term AKI has largely replaced acute renal failure as the latter designation overemphasizes the failure of kidney function and fails to account for the diverse molecular, biochemical and structural processes that characterize the AKI syndrome. [2]

When a subject presents with symptoms of chest pain, the objective measurement of structural biomarkers that are released from the damaged myocytes, such as troponin, can rapidly identify acute myocardial injury. This has allowed for timely therapeutic interventions and a dramatic decrease in mortality over the past few decades. By striking contrast, AKI is largely asymptomatic and establishing the diagnosis in this increasingly common disorder currently hinges on functional biomarkers such as serial serum creatinine measurements.

Unfortunately, serum creatinine is a delayed and unreliable indicator of AKI for a variety of reasons. [1],[2],[3],[4] First, even normal serum creatinine is influenced by several non-renal factors such as age, gender, muscle mass, muscle metabolism, medications, hydration status, nutrition status and tubular secretion. Second, a number of acute and chronic kidney conditions can exist with no increase in serum creatinine owing to the concept of renal reserve - it is estimated that over 50% of the kidney function must be lost before serum creatinine rises. Third, serum creatinine concentrations do not reflect the true decrease in GFR in the acute setting as several hours or days must elapse before a new equilibrium between the steady-state production and the decreased excretion of creatinine is established. Fourth, an increase in serum creatinine represents a late indication of a functional change in GFR that lags behind important structural changes that occur in the kidney during the early-damage stage of AKI [Figure 1] and [Figure 2]. Indeed, animal studies have identified several interventions that can prevent and/or treat AKI if applied early in the course of disease, before the serum creatinine even begins to rise. [2] The lack of early biomarkers has hampered our ability to translate these promising therapies to human AKI. Also lacking are reliable methods to assess the efficacy of protective or therapeutic interventions and early predictive biomarkers of drug toxicity.
Figure 1: Plasma NGAL levels measured by the Triage® NGAL device at various time points after cardiopulmonary bypass in subjects with no AKI (N) or in those with AKI.

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Figure 2. Urine NGAL levels measured by the ARCHITECT® analyzer at various time points after cardiopulmonary bypass in subjects with no AKI (N) or in those with AKI (R, I or F), stratified by RIFLE.

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A troponin-like biomarker of AKI that is easily measured, unaffected by other biological variables and capable of both early detection and risk stratification, would represent a tremendous advance in the care of hospitalized patients as the incidence of AKI in this population is estimated as 5-7%. [2],[3],[4],[5],[6] The incidence of AKI in an intensive care unit (ICU) is even higher - approximately 25% - and carries an overall mortality rate of 50- 80%. The treatment of AKI represents an enormous financial burden to the society, with annual AKI-associated medical expenses conservatively estimated at US $8 billion. [2] Fortunately, the application of innovative technologies such as functional genomics and proteomics to human and animal models of AKI has uncovered several novel genes and gene products that are emerging as biomarkers. The most promising of these are listed in [Table 1] and detailed in this article.
Table 1: The most promising biomarkers of AKI

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   Characteristics of an Ideal AKI Biomarker Top

  • They should be non-invasive and easy to perform at the bedside, using easily accessible samples such as blood or urine.
  • They should be rapidly and reliably measurable using standardized clinical assay platforms.
  • They should be sensitive to facilitate early detection with a wide dynamic range and cut-off values that allow for risk stratification.
  • They should exhibit strong biomarker performance on statistical analysis, including accuracy testing by receiver - operating curve (ROC).
  • They should identify the primary location of injury (proximal tubule, distal tubule, interstitium or vasculature).
  • They should pinpoint the duration of kidney failure (AKI, chronic kidney disease [CKD] or "acute-on-chronic" kidney injury).
  • They should identify the AKI etiologies (ischemia, toxins, sepsis or a combination).
  • They should help risk stratification and prognostication (duration and severity of AKI, need for renal replacement therapy [RRT], length of hospital stay and mortality).
  • They should be able to monitor the response to AKI interventions.

   Overview of the Most Promising Biomarkers of AKI Top

Neutrophil gelatinase-associated lipocalin (NGAL)

Expression and structure of NGAL

Human NGAL was originally identified as a novel protein isolated from the secondary granules of human neutrophils, [7] and was subsequently demonstrated to be a 25-kDa protein covalently bound to neutrophil gelatinase. [8] Mature peripheral neutrophils lack NGAL messenger ribonucleic acid (mRNA) expression, and NGAL protein is synthesized at the early-myelocyte stage of granulopoiesis during the formation of secondary granules. NGAL mRNA is normally expressed in a variety of adult human tissues, including the bone marrow, uterus, prostate, salivary gland, stomach, colon, trachea, lung, liver and kidney. [9]

NGAL for the prediction of AKI

Pre-clinical transcriptome profiling studies identified NGAL (also known as lipocalin 2) to be one of the most upregulated genes in the kidney very early after acute injury in animal models. [10] Downstream proteomic analyses also revealed NGAL to be one of the most highly induced proteins in the kidney after ischemic or nephrotoxic AKI in animal models. [11] The finding that NGAL protein was easily detected in the urine soon after AKI in animal studies has initiated a number of translational studies to evaluate NGAL as a non-invasive biomarker in human AKI. In a cross-sectional study of adults with established AKI (doubling of serum creatinine) from varying etiologies, a marked increase in urine and serum NGAL was documented by Western blotting when compared with normal controls. [12] Urine and serum NGAL levels correlated with serum creatinine and kidney biopsies in subjects with AKI who demonstrated intense accumulation of immunoreactive NGAL in cortical tubules, confirming NGAL as a sensitive index of established AKI in humans. A number of subsequent studies have now implicated NGAL as an early diagnostic biomarker for AKI in common clinical situations, as demonstrated in [Table 2] and [Table 3].
Table 2: Urinary NGAL for the early prediction of AKI

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Table 3: Plasma NGAL for the early prediction of AKI

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NGAL in cardiac surgery-associated AKI

Operations involving cardiopulmonary bypass (CPB) comprise the most frequent major surgical procedure performed in hospitals worldwide. AKI requiring dialysis represents the strongest independent risk factor for death in these patients. [13] Even a minor degree of post-operative AKI, as manifest by only a 0.2- 0.3 mg/dL rise in serum creatinine from baseline, is associated with a significant increase in mortality after cardiac surgery. [14] In addition, AKI after cardiac surgery is associated with adverse outcomes, such as prolonged intensive care and hospital stay, dialysis dependency and increased long-term mortality. [15] The pathogenesis of cardiac surgery-associated AKI is complex and multifactorial. [2] Mechanisms include ischemia - reperfusion injury (caused by low mean arterial pressures and loss of pulsatile renal blood flow), exogenous toxins (caused by contrast media, non-steroidal anti-inflammatory drugs and aprotinin), endogenous toxins (caused by iron released from hemolysis) and inflammation and oxidative stress (from contact with bypass circuit, surgical trauma and intrarenal inflammatory responses). These mechanisms of injury are likely to be active at different times with different intensities, and may act synergistically. There is a dearth of randomized controlled trials for the prevention or treatment of cardiac surgery-associated AKI caused, at least in part, by the paucity of early predictive biomarkers. In several prospective studies in children who underwent elective cardiac surgery, AKI (defined as a 50% increase in serum creatinine) occurred 1 - 3 days after surgery. [16],[17],[18] In contrast, NGAL measurements by enzyme-linked immunoassay (ELISA) revealed a ten-fold or higher increase of their levels in the urine and plasma within 2-6 h of the surgery in those who subsequently developed AKI. Both urine and plasma NGAL were excellent independent predictors of AKI, with an area under curve -receiver operating curve (AUC - ROC) of over 0.9 for the 2-6 h urine and plasma NGAL measurements. These findings have now been confirmed in prospective studies of adults who developed AKI after cardiac surgery and in whom urinary and/or plasma NGAL was significantly elevated by 1-3 h after the operation, with an AUC - ROC ranging widely from 0.61 to 0.96. [19],[20],[21],[22],[23],[24],[25],[26] The somewhat inferior performance in adult populations may be reflective of confounding variables such as older age, pre-existing kidney disease, prolonged bypass times, chronic illness and diabetes. [27] The predictive performance of NGAL also depends on the definition of AKI employed as well as on the severity of AKI. [26] Despite these numerous potential variables, a recent meta-analysis of published studies in all patients after cardiac surgery revealed an overall AUC - ROC of 0.78 for the prediction of AKI when NGAL was measured within 6 h of the initiation of CPB and AKI was defined as a greater than 50% increase in serum creatinine. [28]

NGAL in AKI after kidney transplantation

AKI due to ischemia - reperfusion occurs, to some extent, almost invariably in deceased donor renal allografts and even in some live donor transplants, often resulting in varying degrees of early renal dysfunction. [29] AKI leading to delayed graft function (DGF) complicates 4-10% of live donor and 5-50% of deceased donor kidney transplants. DGF predisposes the graft to both acute and chronic rejection, is an independent risk factor for suboptimal graft function at 1 year post-transplant and increases the risk of chronic allograft nephropathy and graft loss. [30]

NGAL has been evaluated as a biomarker of AKI and DGF (defined as dialysis requirement within the first post-operative week) in patients undergoing kidney transplantation. Protocol biopsies of kidneys obtained 1 h after vascular anastomosis revealed a significant correlation between NGAL staining intensity in the allograft and the subsequent development of DGF. [31] In a prospective, multicenter study of children and adults, urine NGAL levels in samples collected on the day of transplant identified those who subsequently developed DGF (which typically occurred 2-4 days later), with an AUC - ROC of 0.9. [32] This has now been confirmed in a larger multicenter cohort, in which urine NGAL measured within 6 h of kidney transplantation predicted subsequent DGF with an AUC - ROC of 0.81. [33] Plasma NGAL measurements have also been correlated with DGF following kidney transplantation from donors after cardiac death. [34]

NGAL in contrast-induced AKI

Studies of large adult cohorts have revealed that contrast-induced AKI is the third most common cause of hospital-acquired AKI, accounting for approximately 11% of the cases. [35] Approximately half of these cases are in subjects undergoing cardiac catheterization and angiography, and approximately one-third results from computed tomography. [36] Several investigators have examined the role of NGAL as a predictive biomarker of AKI following contrast administration. [37],[38],[39],[40] In a prospective study of children undergoing elective cardiac catheterization with contrast administration, both urine and plasma NGAL predicted contrast-induced nephropathy (CIN) (defined as a 50% increase in serum creatinine from baseline) within 2 h after contrast, with an AUC - ROC of 0.91-0.92. [40] In several studies of adults who received contrast, an early rise in both urine (4 h) and plasma (2 h) NGAL were documented, in comparison with a much later increase in plasma cystatin C levels (8-24 h after contrast), providing further support for NGAL as an early biomarker of contrast nephropathy. [37],[38],[39] A recent meta-analysis revealed an overall AUC - ROC of 0.894 for the prediction of AKI when NGAL was measured within 6 h after contrast and AKI was defined as an increase in the serum creatinine levels of over 25%. [28]

NGAL in AKI in the critical care setting

AKI is a frequent complication in critically ill patients and results in a hospital mortality of 45-60%. [41] Up to 60% of the patients may have already sustained AKI on admission to the ICU. [42] Sepsis accounts for 30-50% of all AKI in the critically ill patients, and generally portends a poorer prognosis with lower survival. [43] Other etiologies for AKI in this setting include exposure to nephrotoxins, hypotension, kidney ischemia, mechanical ventilation and multiorgan disease. Each of these etiologies is associated with distinct mechanisms of injury that are likely to be active at different times with different intensities, and may act synergistically.

Urine and plasma NGAL measurements have been demonstrated to represent early biomarkers of AKI in the pediatric intensive care setting, being able to predict this complication approximately 2 days prior to the rise in serum creatinine, with a high sensitivity and AUC -ROCs of 0.68-0.78. [44],[45] Several studies have also examined plasma and urine NGAL levels in the critically ill adult population. [46],[47],[48],[49],[50],[51] Urine NGAL, obtained on admission, predicted subsequent AKI in multi-trauma patients with an AUC - ROC of 0.98. [46] For patients admitted to the ICU, NGAL can be a powerful predictor of AKI severity, as recently demonstrated in a study of 632 consecutive patients admitted to the ICU and in whom both plasma and urine NGAL levels measured at admission were associated with AKI severity. [47] In studies of adult intensive care patients, plasma NGAL on admission constituted a very good biomarker for the development of AKI within the next 2 days, with an AUC - ROC of 0.78-0.92. [48],[49],[50] In subjects undergoing liver transplantation, a single plasma NGAL level obtained within 2 h of reperfusion was highly predictive of subsequent AKI, with an AUC - ROC of 0.87. [51] Finally, in a study of adults in the emergency department setting, a single measurement of urine NGAL at the time of initial presentation predicted AKI with an outstanding AUC - ROC of 0.95, and reliably distinguished pre-renal azotemia from intrinsic AKI and from CKD. [52] However, it should be noted that patients with septic AKI display the highest concentrations of both plasma and urine NGAL when compared with those with non-septic AKI. [47] A recent meta-analysis revealed an overall AUC - ROC of 0.73 for the prediction of AKI when NGAL was measured within 6 h of clinical contact with critically ill subjects and AKI was defined as a >50% increase in serum creatinine. [28] There is some evidence that urinary NGAL can be a useful tool in discerning the cause of AKI as well. In a recent study, 145 hospitalized patients with AKI were classified into different categories based on the clinical cause of their AKI and urinary NGAL levels were measured. The latter was able to discriminate between intrinsic and pre-renal causes, with an AUC - ROC of 0.87. In addition, urinary NGAL levels above 104 μg/L indicated intrinsic AKI (likelihood ratio 5.97), while NGAL levels below 47 μg/L made intrinsic AKI unlikely (likelihood ratio 0.2). Using biomarkers to distinguish the etiology of AKI may be of particular importance in hospitalized patients with multiple potential causes of AKI (e.g., septic patients on potentially nephrotoxic antibiotics). [53]

NGAL for the prognosis of AKI

A number of studies have demonstrated the utility of early NGAL measurements for predicting the severity and clinical outcomes of AKI. In children undergoing cardiac surgery, early post-operative plasma and urinary NGAL levels strongly correlated with the duration and severity of AKI, length of hospital stay, dialysis and mortality. [54],[55] In a multicenter study of children with diarrhea-associated hemolytic uremic syndrome, urine NGAL obtained early during hospitalization predicted the severity of AKI and dialysis requirement with a high sensitivity. [56] Early urine NGAL levels were also predictive of duration of AKI (AUC -ROC 0.79) in a heterogeneous cohort of critically ill pediatric subjects. [44]

In adults undergoing CPB, those who subsequently required RRT were found to have the highest urine NGAL values soon after surgery. [19],[20],[21],[22],[23],[24],[25],[26] Similar results were documented in the adult critical care setting. [46],[47],[48],[49],[50],[51],[52] Collectively, the published studies revealed an overall AUC - ROC of 0.78 for the prediction of subsequent dialysis requirements when NGAL was measured within 6 h of clinical contact. [28] Furthermore, a number of studies conducted in the cardiac surgery and critical care populations have identified early NGAL measurements as a very good mortality marker. [19],[20],[21],[47],[48],[52],[57] Finally, in kidney transplant patients undergoing either protocol biopsies or clinically indicated biopsies, urine NGAL measurements were found to be predictive of tubulitis or other tubular pathologies, [58] raising the possibility that NGAL represents a non-invasive screening tool for the detection of tubule - interstitial disease in the early months following kidney transplantation.

Clinical platforms for NGAL measurement

The majority of NGAL results described in the literature have been obtained using research-based ELISA assays that are currently available from commercial sources such as Bioporto (Gentofte, Denmark) and R&D Systems (Boston Biochem, MN, USA). These assays are accurate but are not practical in the clinical setting. In this regard, a major advance has been achieved in the development of a point-of-care kit for the clinical measurement of plasma NGAL (Triage® NGAL device; Biosite Inc., San Diego, CA, USA), [Figure 1]. The assay is simple, with quantitative results available in 15 min and requiring only microliter quantities of whole blood or plasma, and is currently being tested in multicenter trials for further validation. [54] In addition, a urine NGAL immunoassay has been developed for a clinical platform (ARCHITECT® analyzer; Abbott Diagnostics, Abbott Park, IL, USA) [Figure 2]. This assay is also easy to perform as it has no manual pre-treatment steps, requires only 150 μL of urine and results are available within 35 min. [55] This assay is also currently undergoing multicenter validation in several patient populations.

Interleukin-18 (IL-18)

Like NGAL, IL-18 plays a role in the immune system. IL-18 is a widely expressed pro-inflammatory cytokine weighing 18kDa. In addition to its involvement in the immune response, this cytokine has been identified as a mediator of ischemic injury in the heart, brain and kidney. Animal studies explored the role of IL-18 in ischemic AKI. First, inhibiting IL-18 in mice has been shown to decrease the severity of ischemic AKI. [59] Further animal studies demonstrated significant increases in IL-18 in whole kidneys after experimentally induced AKI, and a series of additional studies using transgenic models or IL-18-neutralizing antiserum have confirmed IL-18's key role in ischemic AKI. [60] Studies of isolated mouse proximal tubules have demonstrated increased IL-18 levels in the setting of hypoxia and mice with ischemic AKI were found to have elevated urinary levels of IL-18. [61]

IL18 in AKI after kidney transplantation

The findings in animal models have resulted in extensive research on IL-18 as a biomarker of AKI in humans. IL-18 levels are typically measured with ELISA and a specific assay was developed for their detection (Architect assay, Abbott Laboratories). A 2004 study first examined this possibility by measuring urinary IL-18 levels in 72 patients, 22 with AKI including 14 with acute tubular necrosis (ATN), eight with pre-renal azotemia, five with urinary tract infection, eight with CKD, four with nephrotic syndrome, 22 with renal transplant and 11 healthy controls. [62] Among the non-transplant patients, those with ATN had significantly higher IL-18 levels than all others. In addition, transplant recipients who developed DGF had significantly higher urine IL-18 levels than those with prompt graft function.

IL 18 in AKI in critically ill patients

The predictive value of elevated IL-18 levels in critically ill patients was assessed in a nested case - control study within the Acute Respiratory Distress Syndrome Network trial (median urine IL-18 was 104pg/mL at 24 h in the AKI group vs 0 pg/mL in the group without AKI). [63] Banked urine samples were assayed for IL-18 levels in 52 patients with AKI and 86 patients with no AKI. IL-18 was found to be significantly elevated up to 48 h before the creatinine-defined occurrence of AKI. In addition, elevated IL-18 levels were found to be an independent predictor of death. A more recent study in the critical care setting has involved 451 patients, 86 of whom developed AKI. Urinary IL-18 was used to construct an ROC curve and it was found that elevated urinary IL-18 was independently predictive of a composite outcome of death or acute dialysis within 28 days (with an odds ratio of 1.86).

The predictive ability of urinary IL-18 has also been demonstrated in critically ill children in 103 pediatric patients with renal impairment and 34 controls with normal renal function; the renal failure patients manifested a greater than three-fold increase in the urinary IL-18 levels. [65] As in the adult population, urinary IL-18 levels rose prior to the rise in creatinine in patients with AKI, and elevated IL-18 levels were independently associated with mortality. Furthermore, the degree of urinary IL-18 elevation predicted the severity of AKI.

IL-18 in cardiac surgery-associated AKI

AKI is also common after CPB, both in children and in adults. Comparing 20 children who developed AKI after CPB with 35 controls whose renal function remained normal, it was found that elevated IL-18 was an early predictor of AKI in this setting (with a >15-fold increase at 4 h in AKI patients vs non-AKI patients). [66] In adults undergoing CPB, the early data on urinary IL-18 are less clear; one study has demonstrated a good predictive value for urinary IL-18, while a larger study did not. [67]

The most recent data on AKI following cardiac surgery comes from the Translational Research Investigating Biomarker Endpoints for AKI (TRIBE-AKI) study. The pediatric part of this study measured pre-operative and post-operative urine IL-18 and NGAL as well as plasma NGAL in 311 children undergoing surgery for congenital heart disease; 17% of the patients reached the primary outcome of severe AKI. The highest quintiles of urine IL-18 and urine NGAL were strongly associated with AKI risk (adjusted odds ratios of 6.9 and 4.1). Elevated urinary biomarkers were associated with longer ICU stay, longer hospitalization and longer mechanical ventilation. The AUCs for the urine IL-18 and NGAL ROC curves were 0.72 and 0.71, respectively. [68]

The TRIBE-AKI study group also examined these biomarkers in 1219 adult patients following cardiac surgery. They had urine IL-18 and NGAL as well as plasma NGAL measured prior to surgery and for five post-operative days. Multivariate analysis revealed that the highest quintiles of urine IL-18 and plasma NGAL at 6 h were strongly associated with a risk of AKI (adjusted odds ratios of 6.8 and 5, respectively). Higher biomarker levels were also associated with longer hospitalization, longer length of ICU stay, higher risk of dialysis and death. [69]

IL18 in contrast-induced AKI

A nested case - control study of 157 patients undergoing elective percutaneous coronary intervention (PCI) did not identify significant differences between urine IL-18 levels in the 9.5% of patients who developed AKI and those who did not. [70] Conflicting results were reported in another study that included NGAL in its biomarker analysis. This study of adults undergoing PCI compared 13 patients who developed CIN with 27 controls. ROC curves were created for urinary IL-18 and NGAL measured at 24 h and the AUCs were found to be 74.9% and 73.4%, respectively. [71] Additionally, an increase of 25% from baseline in the biomarker level at 24 h had an odds ratio for CIN of 10.7 for IL-18 and 5.0 for NGAL. Urinary IL-18 was an earlier predictor of CIN than serum creatinine and, unlike creatinine, urinary IL-18 was found to be an independent predictor of later major cardiac events.

Kidney Injury Molecule-1 (KIM-1)

KIM-1, a type 1 transmembrane protein with an immunoglobulin and mucin domain, was first described in 1998. [72] In normal kidney tissue, it is expressed at a low level, but, following ischemic injury, it is dramatically upregulated in regenerating proximal tubules. Animal studies have shown that the levels of urinary KIM-1 increase in models of ischemic AKI, sometimes without concomitant blood-urea nitrogen or creatinine elevation. [73] KIM-1 levels are measured using ELISA.

The use of KIM-1 as a biomarker of AKI in humans was suggested in a 2002 study that described urinary KIM-1 levels in patients with AKI. In seven patients with ischemic ATN, the mean KIM-1 levels were significantly higher than in 16 patients with other forms of AKI (2.92 ng/mL vs 0.63 ng/mL). [74] This study also described the immunohistochemical evaluation of six patients with proven ATN; all tissue samples showed extensive KIM-1 expression in the proximal tubule cells.

KIM-1 in cardiac surgery-associated AKI

A 2009 report described biomarker measurements from 90 adult cardiac surgery patients; 36 of them developed AKI. [75] An ROC curve for urinary KIM-1 drawn immediately after surgery had an AUC of 0.68, which was better than the value for NGAL. This study also demonstrated that combining multiple AKI biomarkers improved the overall predictive value. A more recent study of 123 adults undergoing cardiac surgery illustrated that pre-operative KIM-1 levels were able to predict the development of AKI. [76]

KIM-1 in AKI in critically ill patients

Another study published in 2007 described 201 hospitalized patients with AKI and demonstrated a correlation between urinary KIM-1 levels and Acute Physiologic and Chronic Health Evaluation (APACHE) II scores. In addition, KIM-1 quartiles were shown to correlate with dialysis requirement and hospital mortality. [77] A more recent report in the pedia-tric literature described a 252-patient cohort of whom 7.1% had AKI. Their KIM-1 levels measured in the emergency department showed an AUC - ROC to predict AKI (pRIFLE criteria I) of 0.73. [78]

KIM-1 in AKI after kidney transplantation

A recent study has explored urinary bio-markers in renal transplant recipients with worsening kidney function. In this study of 63 transplant recipients biopsied for worsening of kidney function, the authors reported that the rate of decline of renal function over an average of 39.7 months significantly correlated with urinary KIM-1 expression (but not with NGAL or IL-18). In addition, stratifying the patients into low and high KIM-1 groups demonstrated a significantly worse graft survival in the group with high KIM-1 expression. [79]

Cystatin C

Cystatin C, a 13-kD protein of the cystatin family of protease inhibitors, is produced by all nucleated cells. [80] Serum levels of cystatin C are established as a reliable correlate of GFR, superior to serum creatinine as cystatin C production is not influenced by muscle mass, its serum level is not affected by age, race or gender and its urinary clearance does not involve tubular secretion. In addition, serum cystatin C appears to rise 1 - 2 days earlier than serum creatinine in the setting of AKI. [81] However, while serum cystatin C levels can be used as a surrogate marker of GFR, it is not a true biomarker of AKI as its levels are not a direct marker of renal injury.

Elevation of urinary cystatin C, on the other hand, is closer to a true biomarker of AKI. Cystatin C is freely filtered at the glomerulus and then nearly completely reabsorbed by the proximal tubules. Thus, any process that damages the renal tubules can impair cystatin C reabsorption, and AKI can manifest with elevated urinary cystatin C levels. [82] Specifically, it appears that elevated urinary cystatin C reflects renal tubular dysfunction, as opposed to glomerular injury. [83]

Cystatin C in cardiac surgery-associated AKI

Recent human studies showed a promising role of urinary cystatin C measurement with ELISA as a biomarker of AKI. In the setting of adult cardiac surgery, a study of 72 patients (34 with AKI) was used to construct ROC curves for urinary cystatin C that had AUCs of 0.705 for the immediate post-operative time point and 0.704 for the 6-h post-operative timepoint. [84] Within 3 days of surgery, the ratio of urinary cystatin C to urine creatinine ratios increased >20-fold in patients with AKI compared with a five-fold increase in non-AKI patients. In a study of 444 ICU patients (198 with AKI), urinary cystatin C showed an AUC of 0.70 for the diagnosis of AKI and was associated with sepsis, AKI and death. [85]

Cystatin C in AKI after kidney transplantation A study of 91 patients who received deceased-donor kidney transplants showed that urinary cystatin C could predict DGF (AUC of 0.74 for the 6-h urine cystatin C/creatinine ratio). In addition, the urine cystatin C/creatinine ratio on the first post-operative day correlated significantly with the 3-month graft function. [86]

Liver fatty acid-binding protein (L-FABP)

Fatty acid-binding proteins are small (15 kDa) cytoplasmic proteins abundantly expressed in tissues with active fatty acid metabolism. Their primary function is facilitation of long-chain fatty acid transport, regulation of gene expression and reduction of oxidative stress. Urinary L-FABP is undetectable in healthy control urine, which is explained by efficient proximal tubular interna-lization via megalin-mediated endocytosis. [87],[88] Under ischemic conditions, tubular L-FABP gene expression and proximal tubular reabsorption of L-FABP are reduced. [88] To date, there is one small study reported on the early diagnostic performance of L-FABP in adult ICU patients. The reported AUC - ROC value was 0.95. However, several uncertainties remain after disclosure of the study's methodology. Firstly, patient selection (n = 25 with 14 AKI and 11 non-AKI) seems to have been a result of convenient sampling. Secondly, the "true early diagnosis" remains very doubtful as peak serum creatnine and L-FABP values were reported as having the same median value; no further clear information concerning timing was provided. [89]

   Summary and Future Perspective Top

As an AKI biomarker, NGAL has successfully passed through the pre-clinical assay development and initial clinical testing stages of the biomarker development process. It has now entered the prospective screening stage facilitated by the development of commercial tools for the measurement of NGAL in large populations and across different laboratories, but will any single biomarker suffice in AKI? In addition to early diagnosis and prediction, it would be desirable to identify biomarkers capable of discerning AKI subtypes, identifying etiologies, predicting clinical outcomes, allowing for risk stratification and monitoring the response to interventions. In order to obtain all the desired information, a panel of validated biomarkers may be needed. Currently, the role of NGAL as an AKI biomarker for these indications has been achieved. Other AKI biomarker candidates may include IL-18, kIM-1, cystatin C and L-FBP, to name a few. The availability of a panel of AKI biomarkers could further revolutionize renal and critical care. However, such idealistic thinking must be tempered with the enormous technical and fiscal issues surrounding the identification, validation, commercial development and acceptance of multi-marker panels.

   References Top

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Correspondence Address:
Emad Abdallah
Assistant Professor of Nephrology, Department of Nephrology, Theodor Bilharz Research Institute, Cairo
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DOI: 10.4103/1319-2442.121267

PMID: 24231472

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