The diverse biomarker
3 Apr 2012 by Evoluted New Media
A biomarker for early, real-time assessment of Acute Kidney Injury is now also proving valuable in the prediction of patient outcomes in a number of disease areas
Acute Kidney Injury (AKI) is a common complication within the hospital environment and is often associated with poor prognosis and escalating costs, since about 5% of all hospitalised patients and as many as 30 to 50% of adults in the ICU develop AKI.1 In critically ill patients, AKI is independently associated with increased costs of medical care, as well as increased risk of morbidity and mortality.2 This is highlighted by the fact that AKI requiring costly renal replacement therapy (RRT), such as dialysis, affects approximately 6% of critically ill patients and results in hospital mortality of 45 to 60%.3
Early diagnosis of AKI as it is occurring might significantly improve patient outcomes by allowing earlier interventions and timely treatment decisions to minimise further harm to kidneys.4 However, this has been difficult in the absence of true biomarkers of new renal injury, as AKI has often only been diagnosed following the observation of a later decline in renal function, often several days delayed. Due to these issues, NGAL has recently come to the fore as a better tool for the earlier detection and assessment of AKI.
Neutrophil Gelatinase-Associated Lipocalin, or NGAL, is a 25 kDa iron-transporting protein. Under normal conditions, NGAL is detected at very low levels in the kidneys. However, NGAL levels increase significantly after AKI and can be detected in blood or plasma. NGAL concentrations increase 10-100 fold during the two hours that follow tubular injury, whereas creatinine, often used in AKI assessment, does not rise until 24 to 72 hours after the initial renal insult and can be elevated due to causes other than AKI.2 A biomarker such as plasma NGAL (pNGAL) that rises early to indicate real-time renal injury may, therefore, be beneficial for early diagnosis and enable more timely, actionable healthcare decisions.
“AKI diagnosis using Cr elevation alone is challenging because many patients arrive at the ICU without a known steady-state Cr baseline, thus requiring multiple Cr readings over time”In addition to providing a means of early detection, assessment and treatment of AKI, a number of recent studies have demonstrated areas of potential expanded utility for plasma NGAL. These include its use for prediction of renal function recovery in patients suffering from AKI, as well as identification of heart failure patients at risk of readmission or death.
[caption id="attachment_27246" align="alignleft" width="200" caption="Figure 1. Receiver operator characteristic (ROC) curve for pNGAL at admission to predict the development of AKI within the first week"]
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When added to serum creatinine (Cr), pNGAL may offer the possibility of earlier intervention and timely treatment decisions for patients with AKI. Early recognition of renal injury is critical and may help prevent further renal damage and functional impairment.2 AKI diagnosis using Cr elevation alone is challenging because many patients arrive at the ICU without a known steady-state Cr baseline, thus requiring multiple Cr readings over time. Additionally, Cr elevations are not specific to AKI and could be indicative of Chronic Kidney Disease (CKD), Pre-Renal Azotemia (PRA), or other causes.5 Finally, AKI can occur long before a loss in renal function is observed by Cr elevations.
The clinical utility for early AKI detection using a pNGAL test – Alere Triage NGAL –measured at the time of ICU admission has recently been demonstrated with consistent results in three published studies of critically ill patients.
In an 88 patient study, pNGAL measured upon ICU admission was used to accurately predict AKI and assess the level of disease severity.6 Figure 1 demonstrates excellent discrimination between patients with AKI and those without (AUC = 0.927). A cut-off of 155 ng/mL resulted in a sensitivity of 83% and a specificity of 97%.
A further 301 patient study7, where pNGAL was again measured upon ICU admission, also accurately predicted and staged the severity of AKI. pNGAL was significantly elevated 48 hrs prior to clinical diagnosis and demonstrated good performance for the diagnosis of AKI (AUC = 0.78). A cut-off of 150 ng/mL, showed a sensitivity and a specificity of 73% and 81% respectively for the pNGAL test (Figure 2).
In the third study of 632 patients2, pNGAL test results were able to identify patients at risk of AKI, correlated with AKI severity, and were also shown to be additive to the information provided by clinical variables and Cr. AKI occurred in 171 patients, 95% of whom developed AKI within the first 72 hours of ICU admission. For predicting AKI RIFLE-I and above, the pNGAL test exhibited an AUC = 0.80. (Figure 3).
[caption id="attachment_27247" align="alignright" width="200" caption="Figure 2. ROC curve for pNGAL. The area under the ROC is 0.78 (95% CI 0.65-0.90), demonstrating a good performance for AKI within the next 48 hours"]
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Notably, approximately 80% of the patient population presented to the ICU with uninformative, normal Cr values at admission. In these patients, an elevated pNGAL was additive to Cr in the prediction of AKI, and outperformed Cr and estimated glomerular filtration rate (eGFR) alone. The study found that multivariate logistic regression improved the prediction of severe AKI when pNGAL values were incorporated into the model.
In addition to aiding the early detection of AKI and assessment of its severity, a recent study has shown that pNGAL may also be useful in predicting the recovery of renal function in AKI patients.8 As previously discussed, severe kidney injury often leads to the need for renal replacement therapy (RRT), which in addition to being costly, can create serious complications, and is associated with increased mortality. For these reasons, clinicians are reluctant to initiate RRT in patients who may recover renal function without such therapy. However, this presents a conundrum as patients who ultimately need RRT have been shown to experience better outcomes the earlier therapy begins.4
Patients hospitalised for community-acquired pneumonia frequently develop complications that lead to AKI, and a number of these patients develop severe AKI that leaves them dependent upon dialysis or RRT. Consequently, the study sought to establish whether pNGAL levels could predict recovered renal function in patients with community-acquired pneumonia and severe AKI in order to target those at risk with therapy as early as possible.
Within the study, 1,839 patients were identified with community-acquired pneumonia, and 631 developed AKI. Of the patients who developed AKI, 181 met the criteria for severe AKI (defined as RIFLE-F Failure criteria), and, of those, 93 recovered renal function (51.4%). Patients were considered to have recovered renal function if they remained alive without persistent, severe injury or did not require RRT at the time of hospital discharge.
[caption id="attachment_27248" align="alignleft" width="200" caption="Figure 3. ROC curve analysis for the ability of admission pNGAL to predict AKI, stratification by RIFLE classification. AUC values +_ 2SE are presented parenthetically after RIFLE classification"]
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pNGAL concentrations were measured using the Alere Triage NGAL point-of-care test in patient samples that were collected at the time of severe AKI diagnosis. Patients who did not recover renal function had significantly higher median concentrations of pNGAL (371ng/mL; IQR 201-519) than patients who met the criteria for recovery (165ng/mL; IQR 113-266). Based on these results, the researchers concluded that pNGAL measurements in patients with severe AKI can effectively predict which patients will recover renal function.
A further area of expanded utility for pNGAL has recently been established by a study to identify the risk of readmission or death in patients admitted to hospital with acutely decompensated heart failure.9 Heart failure is often associated with dysfunction of both the heart and kidneys. Consequently, the study investigated if plasma NGAL could aid in the identification of patients at risk of experiencing further adverse, heart failure related events after discharge. This might allow for clinical management decisions targeting such patients for more intensive follow-up treatment in the clinic — a protocol that could reduce their likelihood of readmission with the associated healthcare costs.
The multi-centre study involved five medical centres in the US and Europe where pNGAL was measured in 194 patients using a simple, point-of-care blood test at the time of discharge. BNP, a widely recognised marker for adverse heart failure related outcomes, was also measured, along with other markers of kidney function. Patients were then followed for 30 days in order to record heart failure related readmissions and deaths.
The results of this study showed that pNGAL was the only renal marker to significantly predict 30-day heart failure related outcomes. Furthermore, pNGAL was found to be substantially superior to conventional measures of renal function, such as serum creatinine and eGFR. Elevation in both pNGAL and BNP portended the highest risk of poor outcomes (Figure 4).
While it is important to bring down BNP levels in patients with acute heart failure, doing so puts a significant proportion of patients at risk of developing renal dysfunction. Plasma NGAL allows early detection and possibly prevention of such problems in these patients.
[caption id="attachment_27249" align="alignright" width="200" caption="Figure 4. Kaplan-Meir plots of heart failure re-hospitalisation free survival based on cut-offs of 100 ng/mL for pNGAL and 330 pg/mL for B-type natriuretic peptide (BNP). Log rank test p<0.001"]
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A number of recent studies have consistently found plasma NGAL to be a critical biomarker aiding in the early identification of AKI, the assessment of disease, as well as the improvement upon the diagnostic accuracy of other clinical parameters. In addition, pNGAL has now been found to help clinicians rapidly risk stratify AKI patients on the basis of their likelihood for renal recovery, which could assist in the more timely and effective management of these patients.
A further expansion of utility for pNGAL has also recently been established for the identification of heart failure patients at risk of readmission or death at the time discharge. These, and other recent studies, all serve to demonstrate the value of plasma pNGAL as an important new biomarker enabling the enhancement of patient outcomes through earlier interventions, with associated cost savings, in a variety of disease areas. Indeed, further applications are still coming to the fore in on-going studies. For example, future interests and possible utility for pNGAL has been seen within pilot trials in contrast induced nephropathy, prediction of delayed graft function in kidney transplant, as well as for use in predicting chronic kidney disease progression.
References
1. Mishra et al. Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery. Lancet 2005; 365: 1231–38.
2. De Geus et al. Neutrophil gelatinase associated lipocalin at ICU admission predicts for acute kidney injury in adult patients. AJRCCM Articles in Press. October 8, 2010 as doi:10.1164/rccm.200908-1214OC
3. Kumpers et al. Serum neutrophil gelatinase associated lipocalin at inception of renal replacement therapy predicts survival in critically ill patients with acute kidney injury. Critical Care 2010; 14:R9
4. Bagshaw et al. Timing of renal replacement therapy and clinical outcomes in critically ill patients with severe acute kidney injury. Journal of Critical Care. Volume 24, Issue 1, Pages 129-140, March 2009.
5. Nickolas et al. Sensitivity and Specificity of a Single Emergency Department Measurement of Urinary NGAL for Diagnosing AKI. Ann Intern Med. 2008;148:810-819.
6. Constantin et al. Plasma NGAL is an early marker of acute kidney injury (AKI) in adult critically ill patients: A prospective study. Journal of Critical Care doi:10.1016/j.jcrc.2009.05.010
7. Cruz et al. Plasma neutrophil gelatinase-associated lipocalin is an early biomarker for acute kidney injury in an adult ICU population. Intensive Care Med doi: 10.1007/s00134-009-1711-1
8. Srisawat et al. Plasma neutrophil gelatinase-associated lipocalin predicts recovery from acute kidney injury following community-acquired pneumonia. Kidney International advance online publication, 15 June 2011; doi:10.1038/ki.2011.160.
9. Maisel et al. Prognostic utility of plasma neutrophil gelatinase-associated lipocalin in patients with acute heart failure: The NGAL Evaluation Along with B-type NaTriuretic Peptide in acutely decompensated heart failure (GALLANT) trial. European Journal of Heart Failure, Volume 13, pages 846-851, August 2011
