Early Biomarkers of Renal Injury


  • Dinna N. Cruz MD, MPH,

    1. From the Department of Nephrology, San Bortolo Hospital ; 1 and International Renal Research Institute Vicenza, Vicenza, Italy ; 2Department of Nephrology, Selayang Hospital, Selangor, Malaysia ; 3 and Department of Nephrology and Intensive Care, Charité– University Medicine Berlin, Berlin, Germany4
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  • 1,2 Ching Yan Goh MD,

    1. From the Department of Nephrology, San Bortolo Hospital ; 1 and International Renal Research Institute Vicenza, Vicenza, Italy ; 2Department of Nephrology, Selayang Hospital, Selangor, Malaysia ; 3 and Department of Nephrology and Intensive Care, Charité– University Medicine Berlin, Berlin, Germany4
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  • 1,3 Anja Haase-Fielitz PharmD,

    1. From the Department of Nephrology, San Bortolo Hospital ; 1 and International Renal Research Institute Vicenza, Vicenza, Italy ; 2Department of Nephrology, Selayang Hospital, Selangor, Malaysia ; 3 and Department of Nephrology and Intensive Care, Charité– University Medicine Berlin, Berlin, Germany4
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  • 4 Claudio Ronco MD,

    1. From the Department of Nephrology, San Bortolo Hospital ; 1 and International Renal Research Institute Vicenza, Vicenza, Italy ; 2Department of Nephrology, Selayang Hospital, Selangor, Malaysia ; 3 and Department of Nephrology and Intensive Care, Charité– University Medicine Berlin, Berlin, Germany4
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  • and 1,2 Michael Haase MD 4

    1. From the Department of Nephrology, San Bortolo Hospital ; 1 and International Renal Research Institute Vicenza, Vicenza, Italy ; 2Department of Nephrology, Selayang Hospital, Selangor, Malaysia ; 3 and Department of Nephrology and Intensive Care, Charité– University Medicine Berlin, Berlin, Germany4
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Dinna N. Cruz, MD, MPH, Department of Nephrology, San Bortolo Hospital, Viale Rodolfi 37, 36100 Vicenza, Italy
E-mail: dinnacruzmd@yahoo.com


Congest Heart Fail. 2010;16(4)(suppl 1):S25–S31. ©2010 Wiley Periodicals, Inc.

Cardiorenal syndrome (CRS) refers to pathophysiologic interaction of the heart and kidney and is associated with acute kidney injury (AKI) and high mortality. Cardiac surgery or acute decompensated heart failure and radiocontrast-induced nephropathy are common clinical scenarios of CRS. Unfortunately, established functional biomarkers of glomerular filtration rate such as serum creatinine, urea, and diuresis delay AKI diagnosis by 24 to 48 hours. Novel renal biomarkers indicating tubular injury are emerging and may have wide implications. This review focuses on several novel renal biomarkers with the most promising biologic characteristics and clinical evidence for their AKI predictive ability: neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, interleukin 18, and fatty acid–binding proteins. The value of each biomarker is reviewed on currently available clinical data in typical settings of CRS. These markers might extend the therapeutic window during which timely and individualized patient management might be possible.

Acute kidney injury (AKI) is a major health issue with increasing incidence worldwide and is frequently seen among patients with cardiovascular conditions.1 The term cardiorenal syndrome (CRS) is used to describe the complex pathophysiology of concomitant heart and kidney failure. CRS is classified into 5 subtypes that represent common clinical scenarios in which both the heart and the kidney are involved in a bidirectional interaction leading to dysfunction of both organs (Table I).2 Common to each subtype are multiple complex pathogenic factors, a precipitous decline in function, and a progressive course. AKI is an integral part of CRS types 1 and 3. Common clinical scenarios in these 2 CRS subtypes include cardiac surgery, acute decompensated heart failure (ADHF), acute coronary syndrome (ACS), and radiocontrast-induced nephropathy (CIN) occurring after diagnostic and/or therapeutic cardiac procedures.3 AKI may also be seen in CRS type 5, which is characterized by acute or chronic systemic illnesses that concurrently induce both cardiac and kidney dysfunction.

Table I.   Classification of Cardiorenal Syndrome
  1. Adapted from reference 2.

IAcute cardiorenal syndromeAbrupt worsening of cardiac function leading to acute kidney injury (AKI)Hemodynamically mediated AKI secondary to acute heart failure or acute coronary syndrome
IIChronic cardiorenal syndromeChronic abnormalities of cardiac function leading to chronic kidney disease (CKD)CKD in patients with chronic heart failure
IIIAcute renocardiac syndromeAbrupt worsening of kidney function leading to acute cardiac dysfunctionArrhythmias or acute pulmonary edema in patients with AKI
IVChronic renocardiac syndromeCKD leading to chronic cardiac dysfunctionCardiac hypertrophy and adverse cardiovascular events in patients with CKD
VSecondary cardiorenal syndromeSystemic disorders causing both cardiac and renal dysfunctionSepsis, leukemia, amyloidosis, etc

The early diagnosis of AKI, although urgently needed, remains a challenge. Although serum creatinine (sCr) is typically used for diagnosis of AKI, it is an insensitive and unreliable biomarker during acute changes in kidney function.4 It is a marker of function rather than injury, and its concentration does not increase until about half of the kidney function is lost. Since creatinine formation is proportional to muscle mass, sCr may remain within the normal range in patients who are elderly, malnourished, or chronically ill, even as AKI is developing. An acute excess of extracellular body water, such as that occurring with ADHF or after cardiopulmonary bypass (CPB), may contribute to an artifactually low sCr value, compromising further its value as an AKI biomarker. As a result, the clinical diagnosis of AKI is delayed by 24 to 48 hours, a time window that is untenable for renoprotective measures (Figure). Early predictive biomarkers indicating renal structural damage at an earlier stage may potentially allow timely intervention in high-risk patients at a point when damage is still reversible; this has been identified as a top research priority.5

Figure Figure.

 Early diagnosis of cardiac disease–related acute kidney injury by novel renal biomarkers. Bidirectional interaction of heart and kidney results in tubular injury with loss of tubular cell polarity (damage to brush border) and cell death before renal function loss occurs. Novel renal biomarkers indicate tubular injury in advance to functional renal markers such as serum creatinine and urea. ADHF indicates acute decompensated heart failure; GFR, glomerular filtration rate.

An ideal biomarker should fulfill several criteria (Table II). Recently, newer biomarkers for AKI have been the focus of several studies conducted in various clinical settings. In terms of CRS, such biomarker studies were most often conducted for diagnosis of cardiac surgery–associated AKI (CSA-AKI) and CIN. Other studies have also examined these novel biomarkers for prognostication in ACS and both acute and chronic heart failure (HF). In this article, we briefly review some key biomarker studies in the context of CRS.

Table II.   Criteria for an Ideal Biomarker
CriteriaAn Ideal Biomarker
1Must be generated from the damaged cells and exhibit the organ specificity
2Its concentration in the body fluid must be proportional to the damaging event
3Should be expressed early after the occurrence of the organ damage, when such damage is still potentially reversible
4Its concentration should drop quickly following the end of the acute injury episode to enable it as a therapeutic monitoring tool
5Should be rapidly and reliably measurable

Neutrophil Gelatinase-Associated Lipocalin

Human neutrophil gelatinase-associated lipocalin (NGAL) is a 25 kDa protease-resistant polypeptide that was initially identified bound to gelatinase in specific granules of the neutrophil.6 NGAL is a siderophore-binding lipocalin involved in ischemic renal injury and repair processes.7,8 It has transporter function of lipophilic substances (eg, vitamin E and arachidonic acid), regulates intrarenal iron trafficking, and is involved in differentiation of renal tubular epithelial cells and nephrons.9 In animal studies of renal ischemia reperfusion injury, NGAL was one of the 7 genes that were highly up-regulated, and the protein was detectable in the urine within 2 hours following the ischemic insult.10


In a pilot study with 71 children following cardiac surgery for congenital heart disease, NGAL showed excellent predictive value for AKI as early as 2 hours after the surgery, with an area under the curve (AUC) of the receiver operating characteristic (ROC) of 0.99 (urine NGAL) and 0.90 (serum NGAL) for AKI.11 The clinical diagnosis of AKI using sCr was not established until 24 to 48 hours later. In typical cardiac surgery patient cohorts for coronary revascularization and heart valve surgery reasonable predictive values for urinary and serum NGAL were found in the prediction of postoperative AKI with an AUC of 0.7412 and 0.80, respectively.13 Possible reasons for lower AUC values of NGAL in adults could include comorbidities, different measurement times of NGAL, and different specimen preparation or measuring techniques. In these cardiac surgery studies, NGAL concentration was proportional to the degree of severity and duration of AKI, and in multivariate regression analyses it was the strongest independent risk factor for AKI.14,15 In addition, NGAL proved to be of good prognostic value in the prediction of renal replacement therapy (RRT) or a prolonged stay in the intensive care unit (ICU) or in the hospital.13 In a recent meta-analysis of NGAL involving 1204 cardiac surgery patients, its predictive value for AKI was with an AUC of 0.78 and for subsequent initiation of RRT with AUC 0.78 in all patients. The sensitivity and specificity of NGAL were both 75%.16


In a study of 91 children undergoing coronary angiography, both the urine and plasma NGAL levels were found to be significantly increased in the CIN group, but not in the control group, within 2 hours of contrast administration.17 However, AKI detection using increase in sCr was only possible 6 to 24 hours after contrast. Using a cutoff of 100 ng/mL, prediction of CIN was excellent for the 2-hour urine NGAL (AUC, 0.92) as well as the 2-hour plasma NGAL (AUC, 0.91). NGAL had also been evaluated together with other biomarkers like interleukin 18 (IL-18), liver fatty acid–binding protein (L-FABP), and kidney injury molecule 1 (KIM-1) in adult patients with CIN and will be discussed below.18–20

NGAL in ACS and Congestive HF

The development of worsening renal function (WRF) occurs frequently in the setting of ADHF and chronic HF, which strongly predicts adverse clinical outcomes. Therefore, an early diagnosis of WRF in these patients is of importance.21,22 In a study of 91 ADHF patients who were admitted into hospital, patients with an elevated admission serum NGAL level had a higher risk of subsequent development of WRF (odds ratio, 1.92; 95% confidence interval [CI], 1.23–3.12; P=.004). In particular, admission NGAL ≥140 ng/mL was associated with a 7.4-fold increase in risk of WRF, with a sensitivity and specificity of 86% and 54%, respectively.22

Poniatowski and colleagues23 found serum and urine NGAL as sensitive early markers of renal dysfunction in chronic HF patients with normal sCr but reduced estimated glomerular filtration rate (eGFR). Urinary NGAL has also been found to correlate directly with urine albumin excretion and inversely with eGFR in chronic HF patients.21 In a small study of 46 elderly congestive HF patients, higher levels of plasma NGAL were found in parallel with the clinical severity of congestive HF, the highest levels being reached in New York Heart Association class IV patients and associated with higher mortality.24

Growing evidence suggests that NGAL may also be involved in cell survival, inflammation, and matrix degradation by modulating the activity of matrix metalloproteinase 9, an important mediator of vascular remodeling and plaque instability in atherosclerosis. This has been validated in in vitro animal studies.25,26 NGAL and its mouse homologue, 24p3, are increased in atherosclerotic plaques, leading to weakening of plaque structure and plaque rupture with eventual development of myocardial infarction (MI).25 In another rat model HF after MI, NGAL gene expression was increased in the nonischemic part of the left ventricle primarily located to cardiomyocytes, leading to failing myocardium.26 A clinical study from the same author in 236 patients with acute post-MI HF and 150 patients with chronic HF demonstrated that elevated serum levels of NGAL significantly correlated with clinical and neurohormonal deterioration. In patients with HF following acute MI, elevated baseline NGAL levels were associated with adverse cardiac outcomes (median of 27 months’ follow-up). Moreover, strong NGAL immunostaining was found in cardiomyocytes within the failing myocardium in clinical HF patients.26

Cystatin C

Cystatin C (CysC) is a 13-kDa endogenous cysteine proteinase inhibitor that is produced by nucleated cells at a constant rate. It is filtered through the glomerulus, reabsorbed, and completely catabolized by intact renal tubules. Its levels are unaffected by age, sex, race, muscle mass, steroid therapy, infection, liver disease, or inflammation.27 CysC may have value both for detection of early changes in glomerular filtration rate and as a marker of acute injury to the kidney. Compared to sCr, changes in glomerular filtration rate could more accurately and rapidly be detected with serum/plasma CysC.


Che and associates28 found serum CysC to be of value for AKI diagnosis, however, at a time point 10 hours later than NGAL predicted AKI. In a study with 100 cardiac surgery patients, plasma CysC appeared to be a marker of chronic renal impairment rather than of acute WRF.15 Of note, dilutional effects during CPB might contribute to different concentrations and varying predictive value of serum/plasma CysC at postoperative ICU admission compared to concentrations at baseline, with some studies reporting decreased serum CysC29 and others increased concentrations.13 Urine CysC was of similar value in the prediction of CSA-AKI as was NGAL.29

CysC in CIN

CysC was found to be capable of rapidly detecting a decrease in glomerular filtration rate in the early period after contrast administration, compared to sCr in adult patients who underwent coronary angiography.30 In a prospective study of 87 patients who underwent elective catheterization, CIN occurred in 18 patients and ROC analysis showed a higher AUC for CysC compared with sCr (0.933 vs 0.832; P=.012). At a cutoff of >1.2 mg/L, CysC before catheterization exhibited 94.7% (95% CI, 0.851–1.015) sensitivity and 84.8% specificity for detecting CIN. CysC levels were higher in CIN patients than in those without CIN, even before catheterization (CysC, 1.08 ±0.22 vs 1.36±0.28 mg/L; P=.007).31 This also supports the notion that patients with underlying chronic kidney disease are more susceptible to the development of CIN.

CysC in ACS and Congestive HF

CysC has also been recently investigated in several studies as a diagnostic and prognostic marker in several fields of cardiovascular diseases.32–35 Higher levels of CysC were associated with increased left ventricular (LV) mass and a concentric LV hypertrophy phenotype.32

CysC appears to be a marker of cardiovascular (CV) risk at intermediate-term follow-up. Increased levels of CysC were found to be an independent predictor of CV events (cardiac death, nonfatal MI or unstable angina) at 6-month to 1-year follow-up of patients with non-ST elevation ACS compared to high-sensitivity C-reactive protein (CRP), B-type natriuretic peptide (BNP), and sCr.36,37 CysC was also found to be the most valuable parameter compared to CRP, N-terminal proBNP, and troponin I in prediction of LV dysfunction progression in patients with a first STEMI.38

Moreover, in a group of 240 patients admitted to the hospital with acute exacerbation of HF, CysC level was significantly associated with risk of death or rehospitalization during 1-year follow-up. It remained significant after adjusting for age, race, sex, comorbidities, and sCr.39 In patients with stable chronic HF, CysC was associated with more advanced LV diastolic dysfunction and right ventricular systolic dysfunction and remains an independent predictor of long-term prognosis after adjusting for myocardiac factors.40 Other studies have likewise found CysC to be a good predictor of adverse cardiac events beyond classical risk factors.41–44 Of importance, CysC offered complementary prognostic information to other cardiac biomarkers like troponin T (cTnT), high-sensitivity CRP, and N-terminal proBNP, helping clinicians perform more accurate risk stratification of patients with acute HF or ACS.45–47


KIM-1 is a transmembrane glycoprotein belonging to the immunoglobulin gene superfamily; it is involved in the differentiation of T helper cells and expressed on the proximal tubule apical membrane ciliae with injury but not in the normal kidney.


The diagnostic utility of urinary KIM-1 was evaluated for the early detection of postoperative AKI in prospective studies in adults undergoing cardiac surgery. The AUCs for KIM-1 to predict AKI at the time of ICU admission ranged between 0.57 and 0.78.48–50 The predictive value of KIM-1 increased and reached an AUC of 0.83 at 12 hours postoperatively, a time point at which organ injury might be advanced and irreversible.50

KIM-1 in CIN

Some studies have shown that levels of different novel biomarkers rise and peak at varying time points after the renal insult by contrast administration, with KIM-1 rising after NGAL and IL-18.18–20 In the study of a group of patients with normal sCr undergoing cardiac catheterization, Malyszko and associates18 found that there was a significant rise in serum NGAL after 2, 4, and 8 hours and in urinary NGAL and IL-18 4, 8, and 24 hours after cardiac catheterization. Serum CysC increased significantly after 8 hours, peaked at 24 hours, and then decreased 48 hours post-procedure, whereas urinary KIM-1 and L-FABP increased significantly 24 and 48 hours after cardiac catheterization. Because of the paucity of published data for KIM-1 in CIN, its potential utility in this setting is unknown and needs further evaluation.

At present, there are no studies evaluating KIM-1 in the setting of ACS and congestive HF.


IL-18 is a proinflammatory cytokine with a molecular weight of 18 kDa and is produced by renal tubular cells and by macrophages. IL-18 has an active role in a variety of renal diseases processes, including apoptosis, ischemia/reperfusion, allograft rejection, infection, autoimmune conditions, and malignancy.

IL-18 in CSA-AKI

In 3 studies48,51,52 enrolling 258 patients undergoing cardiac surgery, urinary IL-18 showed a moderate predictive performance for AKI with an AUC ranging from 0.53 to 0.66 at postoperative ICU admission. Parikh and associates51 concluded that the combination of urinary IL-18 with urinary NGAL may allow for the reliable early diagnosis and prognosis of AKI after CPB, much earlier than the rise in sCr. In the study by Haase and colleagues,52 urinary IL-18 correlated with the duration of CPB; the changes in IL-18 levels may represent a nonspecific marker of CPB-associated systemic inflammation rather than tubular damage.

IL-18 in CIN

In a study by Ling19 in patients who underwent coronary angiography, urinary IL-18 and NGAL levels were significantly increased in the CIN group 24 hours after the procedure, but not in the control group (P<.05). ROC curve analysis showed that both IL-18 and NGAL showed a better performance in early diagnosis of CIN as compared with sCr (P<.05). Of importance, elevated urinary IL-18 levels 24 hours post–contrast administration have also been found to be an independent predictive marker for later major cardiac events (relative risk, 2.09; P<.01).

IL-18 in ACS and Congestive HF

IL-18 has been associated with atherogenesis, coronary artery diseases, plaque rupture leading to ACS,53,54 and myocardial ischemia-reperfusion injury.55 The immunoinflammatory IL-18 signaling pathway has also been suggested to play a role in the pathophysiology of cardiomyocyte hypertrophy and HF.56 Elevated plasma IL-18 levels were seen in patients with HF, and higher levels were associated with higher mortality on follow-up.55 In post-ACS patients, elevated plasma IL-18 was found to be an independent predictor of short- and long-term CV events (CV death, advanced congestive HF, new episode of ACS, and need for unplanned revascularization).53,54,57 Apart from being a prognostic marker, IL-18 can potentially be used to diagnose unstable angina and MI in patients presenting with chest pain. In a study by Kawasaki and associates58 in 27 ACS patients who had normal admission creatine kinase-MB (CK-MB), admission plasma IL-18 elevation preceded CK-MB elevation, as its concentration elevated quickly after severe myocardial ischemic event regardless of evolving myocardial necrosis. Thus, plasma IL-18 concentration could be a good and early marker to identify whether the symptom was due to myocardial ischemia and, therefore, may be used in deciding the therapeutic strategy in individual patients with possible ACS.58 In an observational study, plasma IL-18 concentrations were significantly increased in patients with ACS and correlated with the severity of myocardial dysfunction.59

Fatty Acid–Binding Proteins

The fatty acid–binding proteins (FABPs) are small cytoplasmic proteins of 14 kDa abundantly expressed in tissues with an active fatty acid–binding metabolism. Two types of FABPs have been isolated from the human kidney. Liver-type FABP (L-FABP) is reabsorbed by the proximal tubule via megalin-dependent endocytosis and is localized in the cytoplasm of proximal renal tubular cells, in the liver, and the small intestine. In L-FABP transgenic mice, urinary L-FABP levels allowed the accurate and earlier detection of both histologic and functional insults in ischemia-induced AKI.60 In contrast, heart-type FABP (H-FABP) is localized in the distal tubules, heart, small intestine, and skeletal muscles.


Portilla and colleagues61 demonstrated that L-FABP predicts the development of AKI in children undergoing cardiac surgery. They found that increases in urinary L-FABP within 4 hours after cardiac surgery predicted the subsequent development of AKI with an AUC of 0.81.61 Taken together, data are not yet sufficient for reasonable evaluation of FABP for AKI after cardiac surgery.


Urinary L-FABP level has been shown clinically to be an early marker20,62 and predictive marker63 for CIN. In the study of adult patients with normal sCr undergoing percutaneous coronary intervention,20 serum NGAL rose at 2 and 4 hours, whereas urinary NGAL and urinary L-FABP increased significantly after 4 hours and remained elevated up to 48 hours post–cardiac catheterization. By comparison, sCr did not change significantly during this period. However, this study did not specifically address the predictive performance of L-FABP for CIN.

FABP in ACS and Congestive HF

Recent studies have suggested that both the serum H-FABP and urinary L-FABP may detect ongoing myocardial damage involved in the progression of ACS and may be potentially useful in diagnosis and prognostication in patients with ACS.64,65 The combination of H-FABP and ischemia-modified albumin measurement on admission has been shown to be highly sensitive and specific in risk stratifying ACS patients with normal cTnT levels.64 In patients with ACS, serum H-FABP is an independent predictor of cardiac events (cardiac death or nonfatal MI) on intermediate follow-up (12 months) and has a greater predictive capacity for cardiac events than cTnT.66,67 H-FABP may also be used as a reliable marker for the evaluation of the severity of congestive HF.68 Its levels have been positively correlated with BNP levels in patients with ADHF before and after treatment.

Potential Management Strategies for Acute Heart-Kidney Injury

In response to a positive test result for a renal biomarker, earlier nephrology consultation might contribute to timely identification and reversal of causes of renal injury. In different settings of CRS, interventions to be initiated may comprise a lower threshold for prolonged periprocedural hemodynamic monitoring (either invasive or noninvasive) with optimized targets such as increased systemic blood pressure and cardiac output. The avoidance or the delay of nephrotoxic agents including nonsteroidal inflammatory drugs or antibiotics such as aminoglycosides and contrast media should be considered. For some high-risk patients, biomarker positivity may also assist with the decision of whether to proceed with surgery or to use more conservative medical management for their cardiovascular disease. In this regard, off-pump cardiac surgery may be an option. On the other hand, biomarker negativity may also be implemented in clinical decision making toward earlier discharge from the hospital or transfer out of the ICU, thereby optimizing the use of hospital resources.


AKI in relation to cardiovascular conditions is common and associated with a poor prognosis. The pathophysiology of the bidirectional interaction of heart and kidney injury is complex. Cardiac surgery or ADHF with AKI and CIN are common clinical scenarios of CRS. However, current biomarkers of renal function delay AKI diagnosis by 24 to 48 hours. Novel renal tubular injury biomarkers facilitating the earlier diagnosis of cardiac disease–related AKI are urgently needed and therefore have been proposed a research priority in this field. Such biomarkers are in development and include urine and plasma NGAL, urine KIM-1, urine IL-18, and L-FABP/H-FABP. These markers might extend the therapeutic window during which timely and individualized patient management decisions with the earlier administration of putative therapeutic agents and specific preventative strategies are possible. Prior to the routine implementation of novel renal biomarkers in clinical practice, randomized controlled trials investigating whether biomarker-guided management strategies provide clinical benefit are warranted.

Disclosures:  M Haase is a fellow of the Alexander von Humboldt-Foundation, Bonn, Germany, and A Haase-Fielitz is a fellow of the Jackstädt-Foundation, Essen, Germany.

DC has previously received lecture honoraries from Biosite/Inverness Medical. CR and MH have previously received lecture honoraries from Abbott Diagnostics and Biosite/Inverness Medical. Both companies are involved in the development of NGAL as diagnostic test for renal injury but were not involved in drafting or revision of this manuscript. CYG and AHF have no conflicts of interest to declare.

DC received an honorarium, funded by Abbott Laboratories and Otsuka America Pharmaceuticals for time and expertise spent in preparation of this article.