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Biomarkers of Acute Kidney Injury

Prasad Devarajan, MD

The Urgent Need for Improved Biomarkers of Acute Kidney Injury

The incidence of acute kidney injury (AKI) is increasing globally, and so are the associated morbidity and mortality rates. The prevalence of severe AKI requiring renal replacement therapy (RRT) in critically ill patients is about 6%, with a mortality rate of 60%.¹ Acute kidney injury is largely asymptomatic, and the diagnosis currently depends on serial measurements of functional biomarkers such as serum creatinine measurements. Unfortunately, serum creatinine measurements are fraught with inaccuracies.² First, serum creatinine reference ranges are confounded by several nonrenal factors such as age, gender, diet, muscle mass, muscle metabolism, medications, hydration status, nutrition status, and tubular secretion. Second, serum creatinine levels are dramatically influenced by dialytic therapies, rendering this marker of limited use in critically ill subjects receiving RRT. Third, it is estimated that greater than 50% of kidney function must be lost before serum creatinine increases, due to the concept of renal reserve. Fourth, serum creatinine concentrations do not reflect the true decrease in glomerular filtration rate in the acute setting, since several hours to days must elapse before a new equilibrium between the presumably steady state of creatinine production and the decreased excretion of creatinine is established. Fifth, serum creatinine production is diminished in critical illnesses such as sepsis, and measured serum creatinine is often falsely reduced by hemodilution resulting from aggressive fluid therapies. However, animal studies have shown that several interventions can prevent and/or treat AKI if instituted early, before the injury is established and the serum creatinine increases.³ The lack of early biomarkers has hampered our ability to translate these promising therapies to human AKI. Also lacking are early predictive biomarkers of drug toxicity and reliable methods to assess efficacy of preventive or therapeutic interventions.

Qualities of Ideal AKI Biomarkers

First, with respect to assay characteristics, AKI biomarkers should be noninvasive and easy to measure using easily accessible samples such as blood or urine, with rapid results. Urinary diagnostics have advantages, including the noninvasive nature of sample collection, the reduced number of interfering proteins, and hence the greater specificity for kidney injury. However, disadvantages also exist, including the lack of urine in patients with severe AKI and changes in urinary biomarker concentration induced by hydration status and diuretic therapy. Plasma-based diagnostics have the advantage of easy sample availability. However, plasma biomarkers may be confounded by extrarenal sources as well as by systemic accumulation due to decreased renal function. Thus, in the case of AKI, it is ideal to develop both urinary and plasma biomarkers. Second, with respect to diagnostic properties, AKI biomarkers should be sensitive, entailing a wide dynamic range to facilitate early detection, and specific enough to enable the identification of AKI subtypes and differentiation of AKI from chronic kidney disease (CKD). Third, with respect to prognostic abilities, AKI biomarkers should allow the clinician to stratify risk (duration and severity of AKI), predict hard clinical outcomes (need for RRT, length of hospital stay, mortality), and monitor the response to AKI interventions. Biomarkers associated with clear biologic plausibility and known pathophysiological mechanisms in AKI are most likely to satisfy the desired diagnostic and prognostic characteristics.

The quest for improved AKI biomarkers is of intense contemporary interest. During the past decade, an improved understanding of the early pathophysiological response of the kidney to stress has uncovered a number of genes and proteins that are rapidly induced in the kidney and dramatically modulate the pathways of AKI.³ Serendipitously, some of these kidney injury proteins are also detected in the urine and/or plasma and are emerging as early noninvasive biomarkers of AKI and its clinical outcomes. Table 10-1 lists the qualities of ideal AKI biomarkers in general and illustrates the status of the 4 most promising novel AKI biomarkers discussed in this chapter. Table 10-2 summarizes the biological characteristics of these emerging AKI biomarkers. In this rapidly evolving area of study, ongoing functional genomics and proteomic analyses may reveal additional biomarkers that further advance this field in the near future.

Neutrophil Gelatinase-Associated Lipocalin as a Biomarker for Acute Kidney Injury

Human neutrophil gelatinase-associated lipocalin (NGAL) was identified as a 25-kDa protein bound to neutrophil gelatinase in human neutrophils. However, mature peripheral neutrophils lack NGAL messenger RNA (mRNA) and contain only remnant NGAL protein synthesized at the early myelocyte stage of granulopoiesis. NGAL mRNA is also normally expressed in a variety of human tissues, including salivary gland, stomach, colon, liver, trachea, lung, and kidney.³ Several of these tissues are prone to exposure to microorganisms and constitutively express NGAL protein at low levels. The promoter region of the NGAL gene contains binding sites for nuclear factor-κB, which explains the constitutive as well as inducible expression of NGAL in several tissues. NGAL binds siderophores, which are small iron-chelating molecules. Siderophores are synthesized by bacteria to scavenge iron from the surroundings. Hence, the siderophore-binding property of NGAL renders it as a bacteriostatic agent. Teleologically, NGAL comprises a critical component of innate immunity to bacterial infection. The need for siderophore and iron binding also provides a clear explanation for the massive up-regulation of NGAL in the distal nephron in AKI. Soon after an episode of AKI, surviving cells from the thick ascending Henle’s limb and collecting duct secrete NGAL into the urine and plasma, whereupon NGAL prevents invasion of the damaged kidney by bacteria. In addition, the biological activity of NGAL in early AKI is one of marked preservation of function, attenuation of apoptosis, and an enhanced proliferative response.^4,5 This growth modulatory effect is mediated by the chelation of toxic iron from extracellular environments and the recycling of iron from the endocytosed NGAL–siderophore-iron complex.

Unbiased transcriptome profiling studies identified Ngal (also known as lcn2) to be one of the most up-regulated genes in the kidney very early after acute injury in animal models.⁶ NGAL is also one of the most highly induced proteins in the kidney after experimental AKI.^7-9 Experimental whole-organ studies, including the reciprocal cross-transplantation of NGAL knock-out and wild-type mouse kidneys, have now unequivocally demonstrated that both urine NGAL and plasma NGAL derive largely from the injured kidney.⁹ Acute kidney injury results in a rapid and massive up-regulation of NGAL mRNA in the distal nephron segments. The NGAL response is specific to intrinsic AKI—prerenal azotemia induced only a 2-fold change in NGAL gene expression, whereas true intrinsic ischemic injury resulted in a 200-fold induction in NGAL message.⁹ The resultant synthesis of NGAL protein in the distal nephron and secretion into the urine comprise the major fraction of urinary NGAL. Although plasma NGAL is freely filtered by the glomerulus, it is largely reabsorbed in the proximal tubules.⁵ Thus, any urinary excretion of NGAL is likely only when a kidney disease precludes proximal tubular NGAL reabsorption and/or induces distal tubular NGAL secretion. Although plasma NGAL also derives largely from the injured kidney itself, NGAL protein released into the circulation from distant organs such as the liver and lung due to organ cross-talk in AKI also contributes to the systemic pool. Additional sources may include activated neutrophils, macrophages, and other immune cells.

The consistent finding that NGAL protein was easily detected in the urine and plasma early in experimental AKI has now been successfully translated to the human condition. NGAL has now emerged as an excellent biomarker in the urine and plasma for early diagnosis, risk stratification, severity prediction, differential diagnosis, and outcomes prediction in several common clinical AKI scenarios. The availability of standardized clinical platforms for the rapid quantitation of NGAL in urine and plasma has further facilitated the validation of NGAL as an AKI biomarker. Pertinent human studies are summarized next.

The value of NGAL for AKI prediction has been most extensively studied in cardiac surgery–associated AKI, where the timing and mechanisms of kidney injury are well known. In this setting, even a minor degree of postoperative AKI as manifest by only a 0.2- to 0.3-mg/dL increase in serum creatinine from baseline (which occurs in up to 30% of cardiac surgeries) is associated with a significant increase in mortality and other adverse outcomes. In single-center prospective studies of children who underwent cardiac surgery, AKI (defined as a 50% increase in serum creatinine) typically occurred 1 to 3 days after surgery.^10-16 In contrast, NGAL measurements revealed a 10-fold or more increase in the urine and plasma within 2 to 6 hours of surgery in those who subsequently developed AKI. Both urine and plasma NGAL were excellent independent predictors of AKI, with an area under the receiver operating characteristic curve (AUC) of greater than 0.9 for the 2- to 6-hour urine and plasma NGAL measurements. A recent prospective multicenter study of children undergoing cardiac surgery has confirmed the early peak (within 6 hours of initiating cardiopulmonary bypass [CPB]) of urine and plasma NGAL associated with higher odds of developing AKI, but the AUC was lower at 0.71.¹⁷ These findings have been confirmed in several prospective studies of adults who developed AKI after cardiac surgery, in whom urinary and/or plasma NGAL was significantly elevated by 1 to 6 hours after the operation.^18-33 The AUCs for the prediction of AKI have ranged widely from 0.61 to 0.96. The somewhat inferior performance in adult populations may reflect confounding variables such as older age groups, preexisting kidney disease, prolonged bypass times, chronic illness, and diabetes. The predictive performance of NGAL also depends on the AKI definition, severity, and the baseline kidney function.³⁴ Despite these potential variables, a 2009 meta-analysis of published studies in all patients after cardiac surgery revealed an overall AUC of 0.78 for prediction of AKI when NGAL was measured within 6 hours of initiation of CPB.³⁵ A more current analysis of 25 published studies^10-34 further supports the use of NGAL for AKI prediction after cardiac surgery, with an overall sensitivity of 71% and specificity of 78% and an average AUC of 0.80.

Acute kidney injury is a frequent complication in critically ill patients.^10-34 Mortality is high in this subpopulation, ranging from 40% to 60% in some series. This patient population is heterogeneous, and the origin and timing of AKI are often unclear. Even in such mixed settings, urine and plasma NGAL measurements represent robust early biomarkers of AKI. Initial studies in the pediatric intensive care setting demonstrated that NGAL predicted AKI about 2 days prior to the increase in serum creatinine, with high sensitivity and AUCs of 0.68 to 0.78.^36,37 Several studies have examined plasma and urine NGAL levels in critically ill adult populations.^38-48 The performance of urine NGAL for AKI prediction on ICU admission was good (AUCs of 0.71-0.89) and that of plasma NGAL even better (AUCs of 0.79-0.92). In the setting of the emergency department, where again the causes of AKI are myriad and the timing of the initial community-acquired insult is uncertain, a single measurement of urine NGAL at the time of initial presentation predicted AKI with an outstanding AUC of 0.95 in a single-center study of adult patients.⁴⁹ This has now been confirmed in children⁵⁰ as well as in a large multicenter prospective study of adults presenting to the emergency department,⁵¹ in which urine NGAL was predictive of subsequent AKI with an excellent AUC of 0.81. A 2009 meta-analysis revealed an overall AUC of 0.73 for prediction of AKI when NGAL was measured within 6 hours of clinical contact in critically ill subjects.³⁵ A more current analysis, which examined 17 published studies,^36-52 further supports the use of NGAL for AKI prediction in the critically ill population, with an overall sensitivity of 77% and specificity of 81% and an average AUC of 0.83.

Acute kidney injury due to ischemia–reperfusion occurs to some extent almost invariably in deceased donor renal allografts. Acute kidney injury leading to delayed graft function (DGF) complicates 5% to 50% of deceased donor kidney transplants. Delayed graft function 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. NGAL has been evaluated as a promising biomarker of AKI and DGF (defined as dialysis requirement within the first postoperative week) in patients undergoing kidney transplantation. Protocol biopsies of kidneys obtained 1 hour after vascular anastomosis revealed a significant correlation between NGAL staining intensity in the allograft and the subsequent development of DGF.⁵³ 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 of 0.9.⁵⁴ This has now been confirmed in a larger multicenter cohort, in which urine NGAL measured within 6 hours of kidney transplantation predicted subsequent DGF with an AUC of 0.81.⁵⁵ In the largest study reported to date, in 176 recipients of deceased donor grafts, 70 developed DGF. Urinary NGAL levels obtained on the first day after kidney transplant predicted prolonged DGF with an AUC of 0.75.⁵⁶

Several investigators have examined the role of NGAL as a predictive biomarker of AKI following contrast administration.^57-60 In a prospective study of children undergoing elective cardiac catheterization with contrast administration, both urine and plasma NGAL predicted contrast-induced nephropathy (defined as a 50% increase in serum creatinine from baseline) within 2 hours after contrast administration, with an AUC of 0.91 to 0.92.⁵⁷ In several studies of adults administered contrast, an early increase in both urine (4 hours) and plasma (2 hours) NGAL was documented, in comparison with a much later increase in plasma cystatin C levels (8-24 hours after contrast administration), providing further support for NGAL as an early biomarker of contrast nephropathy.^58-60 A meta-analysis revealed an overall AUC of 0.894 for prediction of AKI when NGAL was measured within 6 hours after contrast.³⁵

In the setting of acute illness, up to 60% of patients may have already sustained AKI on presentation, and up to 30% already display an increase in serum creatinine concentrations on initial presentation.¹ Differentiating between volume-responsive prerenal azotemia, intrinsic AKI, and CKD is critical for appropriate triaging and medical management. Recent evidence suggests that NGAL measurements can serve this purpose. In 3 published studies of NGAL measurements done at the time of presentation to the emergency department,^44,49,51 NGAL levels were only mildly elevated in patients with prerenal azotemia or CKD but were markedly elevated in those subsequently adjudicated to have intrinsic AKI, with an excellent overall AUC for intrinsic AKI prediction of 0.86. In this respect, NGAL differs from other recently proposed biomarkers that demonstrate a less robust dose response to injury and less discriminatory power between transient and sustained AKI.⁵¹

Many reports have demonstrated that early NGAL measurements are predictive of AKI severity, as classified by the standardized RIFLE criteria.⁶¹ The average concentrations of early urine and plasma NGAL measurements correlate with increasing RIFLE stage.^{2,13-16,48-51} These findings derived from several AKI settings support the use of early NGAL measurements for AKI risk prediction and stratification. A number of studies have also demonstrated the utility of early NGAL measurements for predicting adverse clinical outcomes of AKI. In children undergoing cardiac surgery, early postoperative plasma and urine NGAL levels correlated with duration and severity of AKI, length of hospital stay, and mortality.^13,14 In a multicenter study of children with diarrhea-associated hemolytic uremic syndrome, urine NGAL obtained early during the hospitalization predicted the severity of AKI and dialysis requirement with high sensitivity.⁶² Early urine NGAL levels were also predictive of duration of AKI (AUC 0.79) in a heterogeneous cohort of critically ill pediatric subjects.³⁶ In adults undergoing CPB, those who subsequently required renal replacement therapy were found to have the highest urine NGAL values soon after surgery.^18-29 Similar results were documented in the adult critical care setting.^39-43 Collectively, a meta-analysis of the published studies revealed an overall AUC of 0.78 for prediction of subsequent dialysis requirement when NGAL was measured within 6 hours of clinical contact.³⁵ 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, with an overall AUC of 0.71 in these heterogeneous populations.³⁵ There is now evidence for the utility of subsequent NGAL measurements in critically ill adults with established AKI. Serum NGAL measured at the inception of renal replacement therapy was shown to be an independent predictor of 28-day mortality, with an AUC of 0.74.⁶³

The status of NGAL with respect to desirable characteristics of AKI biomarkers is shown in Table 10-2. However, NGAL does have limitations. NGAL appears to be most sensitive and specific in homogeneous patient populations with temporally predictable forms of AKI. Meta-analyses have also identified age as a potential modifier of NGAL’s performance as an AKI biomarker,³⁵ showing that it had better overall predictive ability in children (overall AUC 0.93) than in adults (AUC 0.78). Plasma NGAL measurements may be influenced by a number of coexisting variables such as CKD, chronic hypertension, systemic infections, inflammatory conditions, anemia, hypoxia, and malignancies.² In the CKD population, both plasma and urine NGAL levels are elevated and correlate with the severity and progression of renal impairment. However, the increase in NGAL in these situations is generally much less than those typically encountered in AKI. Urine NGAL has been shown to represent an early biomarker for the degree of chronic injury in patients with immunoglobulin A nephropathy and lupus nephritis may be increased in urinary tract infections.² However, the levels of urine NGAL in these situations are significantly blunted compared with the levels typically measured in AKI. Another limitation of NGAL is the lack of uniformly defined cutoff values among various patient populations. A meta-analysis of published studies suggested a cutoff of 190 ng/mL across various AKI settings.³⁵ However, cutoff values differed significantly depending on the assay used and on the specific clinical setting, with cutoffs being highest in the critically ill patients and lower in the subjects exposed to contrast agents or in community-acquired AKI.³⁵

Given the potential limitations of NGAL, recent studies have explored biomarker combinations. A large prospective multicenter study, involving 971 emergency department patients with suspected sepsis, examined a panel of 9 biomarkers to predict clinical outcomes; plasma NGAL emerged as the strongest predictor of shock and death.⁶² In a secondary analysis of this cohort, an elevated plasma NGAL level at the time of presentation to the emergency department predicted severe AKI with an AUC of 0.82.⁴⁸ In a study examining biomarkers for the prediction of AKI following elective cardiac surgery, urinary NGAL concentrations measured at the time of admission to the ICU predicted the subsequent development of AKI with an AUC of 0.77 and outperformed other biomarkers.³⁰ In a similar analysis of multiple urinary biomarkers following adult cardiac surgery, the 6-hour postoperative NGAL best predicted severe AKI with an AUC of 0.88.²⁹ Serial measurements of multiple urinary biomarkers after pediatric cardiac surgery have revealed a sequential pattern for the appearance of AKI biomarkers,¹⁶ with NGAL and liver-type fatty acid binding protein (L-FABP) being the earliest responders (with 2-4 hours after initiation of CPB), inter-leukin (IL)-18 representing the intermediate responders (increased 6 hours after surgery), and kidney injury molecule (KIM)-1 being a delayed responder (12 hours after surgery). Measurement of biomarkers on the day of AKI diagnosis in adults undergoing cardiac surgery showed that higher values for NGAL, KIM-1, and IL-18 conferred a 3-fold greater risk for adverse outcomes, namely worsening of AKI or in-hospital death.⁶⁴ In critically ill patients, multiple biomarker measurements revealed that urinary concentrations of KIM-1 and IL-18 were significantly increased in prerenal azotemia compared with no AKI, whereas NGAL increases were not significant, suggesting an enhanced specificity of NGAL for intrinsic AKI.⁶⁵ Current multicenter studies of multiple biomarkers will help determine which combinations best predict AKI and its outcomes in a context-specific manner.

Additional limitations in the published AKI literature must be acknowledged with respect to all biomarker studies. First, the majority of studies reported were from single centers. Validation in some large multicenter studies has yielded less robust results in the cardiac surgery population,^17,33 although the performance of AKI biomarkers in the emergency department setting remains excellent.⁵¹ Second, only a few studies have investigated biomarkers for the prediction of AKI severity and adverse clinical outcomes. Third, only a few studies have demonstrated the added value of biomarkers over clinical scores. Fourth, and perhaps most important, the definitions of AKI in the published studies have been highly variable but are based largely on elevations in serum creatinine, which raises the conundrum of using a flawed outcome variable to analyze biomarker performance. Creatinine-based definitions of AKI set up the biomarker assay for lack of accuracy due to either false positives (true structural injury but no significant change in serum creatinine) or false negatives (absence of true structural injury but elevations in serum creatinine due to prerenal or nonrenal causes). It will be crucial in future studies to understand the outcomes of subjects who are clinically at risk for AKI and are “biomarker-positive” but “creatinine-negative.” Indeed, a recent multicenter pooled analysis of published data on 2,322 critically ill subjects revealed the surprising finding that approximately 20% of patients display early elevations in NGAL concentrations but never develop increases in serum creatinine.⁶⁶ Importantly, this subgroup of NGAL-positive, creatinine-negative subjects encountered a substantial increase in adverse clinical outcomes, including mortality, dialysis requirement, ICU stay, and overall hospital stay. Thus, early NGAL measurements can identify patients with subclinical AKI who have an increased risk of adverse outcomes, even in the absence of diagnostic increases in serum creatinine.

Kidney Injury Molecule-1 as a Biomarker for Acute Kidney Injury

Preclinical subtractive hybridization screens identified kidney injury molecule 1 (Kim-1) as a gene that is markedly up-regulated in ischemic rat kidneys.⁶⁷ Downstream proteomic studies have also shown KIM-1 to be one of the most highly induced proteins in the kidney after AKI in animal models.^68,69 KIM-1 is a transmembrane protein that is not expressed in normal kidney but is specifically up-regulated in dedifferentiated proximal tubule cells after ischemic or nephrotoxic AKI. It has been identified as a phosphatidylserine receptor that transforms epithelial cells into phagocytes by recognizing cell surface–specific epitopes expressed by apoptotic tubular epithelia.⁷⁰ A proteolytically processed extracellular domain of KIM-1 is detectable in the urine soon after AKI. KIM-1 represents a promising biomarker for the early diagnosis of AKI and its clinical outcomes.^67,68 The recent availability of a rapid urine dipstick test for KIM-1 will facilitate its further evaluation in preclinical and clinical studies.⁷¹

In critically ill adults with established AKI, KIM-1 levels were markedly elevated compared with healthy controls, yielding an AUC of 0.95.³⁸ Age-adjusted levels of urinary KIM-1 were significantly higher in patients who died or required dialysis.³⁸ In another study of hospitalized patients with established AKI, urinary KIM-1 levels predicted dialysis requirement and mortality.⁷² In children undergoing CPB who developed AKI 1 to 3 days post surgery, urine KIM-1 concentrations were significantly increased within 12 hours.^16,26 The AUC for AKI prediction at 2 and 6 hours was nondiagnostic, and at 12 hours it was 0.70. By comparison, the AUC for NGAL at each of those time points was in the 0.87 to 0.91 range.¹⁶ In critically ill patients, urinary concentrations of KIM-1 were significantly increased in prerenal azotemia compared with no AKI, suggesting a diminished specificity for intrinsic AKI.⁶⁵ In a multicenter study of emergency room patients, KIM-1 measurements in urine obtained at the time of initial presentation were moderately predictive of intrinsic AKI, with an overall AUC of 0.71, in comparison with an AUC of 0.81 for NGAL.⁵¹ In preclinical studies, KIM-1 is an excellent marker of nephrotoxicity, including contrast agents.^73,74 Several additional prospective studies examining KIM-1 as a biomarker of AKI in various clinical settings are underway. The status of KIM-1 as an AKI biomarker is illustrated in Tables 10-3 and 10-4. A recent systematic review concluded that KIM-1 was potentially useful for the prediction of AKI but that it showed only weak association with RRT requirement and mortality in AKI patients.⁷⁵ Urinary KIM-1 is also increased in a number of chronic kidney diseases and is an independent predictor of chronic graft loss in renal transplant recipients.⁷⁶

Liver-Type Fatty Acid Binding Protein as a Biomarker for Acute Kidney Injury

Liver-type fatty acid binding protein (L-FABP) is a protein expressed in the proximal tubule of the kidney. Increased expression and urinary excretion have been described in animal models of AKI.^77-79 Although its precise function is unknown, L-FABP in the kidney has been postulated to represent an endogenous antioxidant capable of suppressing tubulointerstitial damage.

In children undergoing CPB who subsequently developed AKI, urine L-FABP concentrations were significantly increased within 4 to 6 hours of the surgery.^12,16 The AUC for AKI prediction at 2 hours was nondiagnostic, and at 6 and 12 hours it was 0.73 and 0.78, respectively.¹⁶ The early urinary L-FABP level was an independent risk factor for the development of AKI, with an AUC of 0.81. In the emergency department setting, L-FABP measurements in urine obtained at the time of initial presentation were moderately predictive of intrinsic AKI, with an overall AUC of 0.70, in comparison with an AUC of 0.81 for NGAL.⁵¹ In hospitalized patients with established AKI, the AUC of urinary L-FABP for prediction of AKI was 0.93.⁸⁰ Urinary L-FABP levels in this cohort were significantly higher in patients with poor outcome, defined as the requirement for RRT or the composite end point of death or renal replacement therapy. In patients with septic shock and AKI, urinary L-FABP measured at admission was significantly higher in the nonsurvivors than in the survivors, with an AUC for mortality prediction of 0.99.⁸¹ In a recent prospective pilot study of adults with CKD who received contrast, L-FABP levels measured on the following day were associated with contrast-induced AKI, with an AUC of 0.70.⁸² However, serum creatinine was also significantly increased on the following day, and earlier measurements of L-FABP were not available to assess its ability to predict contrastinduced AKI. Thus, emerging data point to L-FABP as a promising urinary biomarker of AKI and its outcomes (Tables 10-3 and 10-4). However, the urinary excretion of L-FABP is also increased in the setting of prerenal azotemia⁸³ and CKD.⁸⁴ Standardized clinical platforms for the measurement of urinary L-FABP are not available.

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