Editor's note: This article is based on Haase M, Devarajan P, Haase-Fielitz A et al. The outcome of neutrophil gelatinase-associated lipocalin–positive subclinical acute kidney injury: a multicenter pooled analysis of prospective studies. J Am Coll Cardiol. 2011;57:1752-61.

Neutrophil gelatinase-associated lipocalin (NGAL), a protein that scavanges iron, is rapidly induced and released from the injured distal nephron in animal and human studies.^(1-3) Urine and plasma concentrations increase proportionally to severity and duration of renal injury^{(2, 4, 5)} and its concentration rapidly decreases with attenuation of renal injury.⁽⁶⁾ Importantly, it is readily and easily measured in plasma⁽⁴⁾ and urine.⁽⁵⁾ In this study,⁽⁷⁾ the authors assessed whether NGAL levels could identify patients with subclinical acute kidney injury (AKI) and before changes in creatinine are detected.

To do so, they pooled data from 10 prospective observational studies of NGAL that included primarily critically ill patients with predominantly cardiorenal syndrome. Patients were classified as NGAL(−) or NGAL(+) according to study-specific NGAL cutoffs. AKI was defined using the RIFLE classification⁽⁸⁾ as an increase in serum creatinine ≥50% from baseline to peak value within 7 days of ICU admission. Patients were also classified as Cr(−) or Cr(+) according to the presence of AKI as defined by RIFLE criteria. Clinical end points included need for renal replacement therapy (primary endpoint), hospital mortality, their combination, and duration of stay in the ICU and hospital.

Of the 2,322 patients included, the incidence of AKI varied from 15% to 49%. Overall, 25% of the patients developing AKI, 3% requiring renal replacement therapy, and 8% who died. Using the prespecified marker classification scheme, 56% were NGAL(−)/Cr(−), 19% were NGAL(+)/Cr(−), 4.6% were NGAL(−)/Cr(+), and 20% were NGAL(+)/Cr(+).

There was a statistically significant stepwise increase in all endpoints with increasing biomarker positivity, including subsequent renal replacement therapy initiation: NGAL(−)/Cr(−): 0.0015% compared to NGAL(+)/Cr(+): 8.0%, hospital mortality (4.8% vs 15%) and their combination (4-group comparisons: all p < 0.001) (Figure 1). There was a similar statistically significant progressive increase in median number of intensive care and in-hospital days with increasing biomarker positivity: NGAL(−)/Cr(−): 4.2 and 8.8 days; NGAL(+)/Cr(−): 7.1 and 17.0 days; NGAL(−)/Cr(+): 6.5 and 18 days; NGAL(+)/Cr(+): 9 and 22 days (4-group comparisons: p = 0.003 and p = 0.040, respectively). Patients who were NGAL(+)/Cr(-) tended to have outcomes more similar to NGAL (+)/Cr (+) than the NGAL(-)/Cr(+) patients. Urine and plasma NGAL had similar outcomes.

The authors concluded that even in the absence of diagnostic increases in creatinine, NGAL detected patients with likely subclinical AKI who had an increased risk of adverse outcomes.

Commentary

Acute kidney injury (AKI) is a complication not infrequently seen after cardiac procedures and in critically ill patients. When it occurs, it significantly increases the risk of adverse events, including mortality, with associated increased costs.^(9,10) Therefore, a marker that could accurately identify patients early could potentially allow intervention that could ameliorate or even event prevent significant damage.⁽¹¹⁾

Currently serum Cr has been the only marker available marker for detecting AKI. Unfortunately, Cr levels are affected by body muscle mass and excreted through the kidneys; therefore levels will differ with body size and renal function. Another limitation is that the assays used to measure Cr have not been standardized, which results in some variation from hospital to hospital, which will be exacerbated in multi-center studies.

A number of markers have been investigated for diagnosing AKI (recently reviewed on Hot Topics), of which NGAL appears the most promising. It acts as a scavenger of cellular and pericellular iron, an important component to free radial generation, a process that has been implicated in various types of organ injury, including myocardial infarction, sepsis, and pertinent to the current study, AKI.

In this study, the authors were able to combine data on clinical outcomes of AKI patients according to NGAL and Cr status in 2,322 patients. When patients who were NGAL(-)/Cr(-) were compared to those who had elevations in both, there was a 2-fold longer stay in the ICU and in the hospital, more dialysis initiation, and a three fold increase in mortality.

An additional important and interesting finding was that patients who were NGAL(+)/Cr(-), patients in whom the NGAL might be considered as a falsely elevated NGAL, had adverse events at a rate similar to the NGAL(+)/Cr(+) patients (Figure 1). This group is one who do not fulfill current Cr-based consensus criteria for AKI; however, they had a prolonged ICU and hospital stay and higher mortality rate.

Only a small minority, 4.6% of patients, were NGAL(-)/Cr(+). It was hypothesized that these patients might have pre-renal azotemia as a mechanism of renal failure, as opposed to those who have started to secrete increased quantities of NGAL. Conversely, identification of the NGAL(+)/Cr(−) patient is a critical step forward, because the production of NGAL signals a response to oxidative stress before organ dysfunction is apparent. Because NGAL is typically detected AKI 36 to 48 hours earlier than Cr, it could potentially lead to therapeutic interventions for AKI. In addition, it could lead to clinical trials of various treatments, initiated at a much earlier time point, in which interventions would be more likely to succeed.

There were a number of strengths to the study. Patients who were included had a wide spectrum of disease, including post-cardiac surgery patients, pediatric and adult population with a variety of illnesses. All studies originally were designed to examine the diagnostic accuracy of NGAL level, prospectively enrolled consecutive patients, and had clearly defined enrollment and exclusion criteria, and laboratory/research personnel and clinicians were blinded. All studies enrolled representative patient cohorts in whom there is an increased risk for AKI, in whom NGAL testing would be clinically relevant.

There are some limitations to the current study. Combining patients with multiple different reasons for AKI is both a strength and limitation. Patient level data was not available. More detail on patients reasons for increased mortality and length of stay in the NGAL(+)/Cr(-) patients would be helpful.

These results suggest adding NGAL measurement to the routine Cr that is often performed, one a measure of oxidative stress and the other a marker of renal filtration function (Cr) provide complementary information in the diagnosis and prognosis of AKI across a variety of hospitalized populations. Further investigations could lead to improved treatment of patients with AKI, a high risk population.

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References

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7. M. Haase, P. Devarajan and A. Haase-Fielitz et al., The outcome of neutrophil gelatinase-associated lipocalin–positive subclinical acute kidney injury: a multicenter pooled analysis of prospective studies. J Am Coll Cardiol. 2011;57:1752–61.
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Keywords: Acute Kidney Injury, Azotemia, Biomarkers, Body Size, Cardio-Renal Syndrome, Creatinine, Critical Illness, Hospital Mortality, Intensive Care, Intensive Care Units, Iron, Kidney, Nephrons, Oxidative Stress, Prospective Studies, Renal Dialysis, Renal Insufficiency, Renal Replacement Therapy

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