June 1, 2009 (Milan, Italy) — Neutrophil gelatinase-associated lipocalin (NGAL) is emerging as a useful early marker of worsening renal function and acute kidney injury (AKI) in a range of clinical situations and patients, according to a number of studies presented here at the World Congress of Nephrology.

Tobias Breidthardt, MD, from the University Hospital, Basel, Switzerland, who presented some of the research on the fluorescence assay, told Medscape Nephrology, "NGAL is all the rage now. It's allowing us to make the diagnosis up to 48 hours before we get serum creatinine results, our traditional method of diagnosis."

NGAL is a small robust protein produced by activated neutrophils in the renal proximal tubules. It is highly inducible during kidney ischemia and appears in urine just 2 to 4 hours after AKI. The current standard test for AKI, serum creatinine (sCr), is not specific for kidney injury and does not accurately detect impaired kidney function until 2 to 3 days after injury. The NGAL assays, which are expected to facilitate diagnosis, are now in the final stages of clinical development.

Useful in Suspected Sepsis

In a large study of 661 patients seen in the emergency department for suspected sepsis, median plasma NGAL concentrations were predictive of renal dysfunction occurring within 72 hours, according to a large multicenter US study reported by Nathan Shapiro, MD, from Beth Israel Deaconess Medical Center in Boston, Massachusetts.

Of the study population, 24 patients (3.6%) developed renal dysfunction (sCr increase > 0.5 mg/dL), and these patients had elevated NGAL concentrations. Median plasma NGAL concentration was 456 ng/mL (interquartile range [IQR], 296 – 727 ng/mL) in patients who developed renal dysfunction compared with 144 ng/mL (IQR, 61 – 302 ng/mL) in those who did not (P < .001).

NGAL was a strong predictor of renal dysfunction, with an area under the curve (AUC) of 0.82 (95% confidence interval [CI], 0.76 – 0.88). By comparison, sCr had an AUC of 0.73 (95% CI, 0.63 – 0.84). Sensitivity for NGAL concentrations higher than 150 ng/mL was 96% (95% CI, 79% – 100%) and specificity was 51% (95% CI, 47% – 55%) for renal dysfunction, Dr. Shapiro reported.

The adjusted odds ratio per quartile for NGAL in a model adjusting for sCr, age, sex, and race was 3.0 (95% CI, 1.6 – 5.8; P < .001), he said.

Predictive After Cardiac Surgery

NGAL's predictive ability was also shown in a prospective international study of 100 patients who underwent cardiac surgery. Investigators evaluated the ability of plasma NGAL, serum cystatin C (another protein that is a measure of kidney function), and a combination of the two to predict the duration and severity of AKI.

NGAL and cystatin C correlated with, and proved to be independent predictors of, the duration and the severity of AKI after surgery, reported Michael Haase, MD, from Charité University Medicine in Berlin, Germany.

Mean AKI duration was 75 ± 42 hours and mean sCr increase was 104 ± 73 µmol/L. On arrival in the intensive care unit (ICU), and 24 hours postoperatively, NGAL and cystatin C each correlated with AKI duration, and the association was stronger when the 2 measures were used together, Dr. Haase said.

"We found that the combination of both renal markers increased their value," Dr. Haase said.

The area under the receiver operating characteristic curve for predicting AKI was 0.85 (95% CI, 0.70 – 0.99) for NGAL combined with cystatin C on arrival in the ICU. Both markers individually and their combination measured on arrival in the ICU also correlated with length of stay in the ICU (P =.037 for NGAL; P = .001 for cystatin C; P < .007 for the combination).

Serial Measures Predictive in Acute Decompensated Heart Failure

In patients with acute decompensated heart failure (ADHF), serial measurements of NGAL were useful in identifying worsening renal function, according to researchers from the University Hospital in Basel, Switzerland.

Their prospective study included 50 consecutive patients presenting to the emergency department with ADHF. Plasma NGAL samples were collected upon admission and at 6 hours. Serum creatinine was evaluated at baseline and daily for 4 days.

"We wanted to see if NGAL, which has performed well in other kidney areas, would be useful in ADHF too, since there is often a lot of 'background' noise in this condition," Dr. Breidthardt said.

Worsening renal function (sCr increase ≥ 0.3 mg/dL compared with baseline) occurred in 13 cases (26%). In these 13 cases, sCr increases were first observed at 24 hours in 3 cases, at 48 hours in 3 cases, and after 96 hours in 7 cases. The median baseline NGAL concentration in the entire population was 95 ng/mL (IQR, 60 – 200 ng/mL) and the median 6-hour NGAL concentration was 81 ng/mL (IQR, 64 – 177 ng/mL), Dr. Breidthardt reported.

The ratio NGAL level (ratio of 6-hour NGAL concentration to baseline) was statistically significant for predicting worsening renal failure (P < .05). The median was 0.88 (IQR, 0.65 – 1.10) in patients without worsening renal function compared with 1.22 (IQR, 0.96 – 1.38) in patients with worsening renal function.

At a cut-off value of 1.20 ng/mL (ie, a 20% increase over baseline), the odds ratio for worsening renal failure was 4.23 (95% CI, 1.10 – 16.2), the study found.

"Taking only one spot measurement on admission was not useful, but 2 serial measurements were predictive," Dr. Breidthardt added. "It's possible the prognostic value can be improved further using additional NGAL monitoring throughout the patient's hospitalization."

Chirag Parikh, MD, PhD, associate professor of medicine at Yale University Medical School in New Haven, Connecticut, in a separate session applauded the development of new methods for assessing renal injury, which will allow for more rapid treatment and thus could help reduce the cost of treating AKI, now estimated to be $10 billion a year. "Serum creatinine testing is greatly responsible for the lack of progress in the field of kidney injury. It is a nonspecific marker that delays the diagnosis of AKI," he commented.

"Earlier diagnosis of evolving AKI could result in quicker changes in patient management to make potentially life-saving therapeutic interventions and also to stop harmful interventions," added Patrick Murray, MD, professor at University College Dublin and Mater Misericordiae University Hospital in Dublin, Ireland. "More accurate differential diagnosis of AKI could direct appropriate therapy, and more accurate, serial staging could help us in making prognostic stratifications and assessing the current and future severity of injury," he explained.

These studies were funded by Biosite Diagnostics, Abbott Diagnostics, and Inverness Medical. Dr. Haase has received travel expenses from Biosite Incorporated and Abbott Diagnostics.

World Congress of Nephrology 2009: A Joint Meeting of the European Renal Association–European Dialysis and Transplant Association (ERA-EDTA) and the International Society of Nephrology (ISN): Abstracts M196, M187, and M180. Presented May 25, 2009.

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