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July 23, 2009 — A new laboratory test for urine neutrophil gelatinase–associated lipocalin (NGAL) helps predict whether patients in intensive care will develop acute kidney injury (AKI), according to the results of a study reported online July 23 in the Journal of the American Society of Nephrology.

"As a stand-alone marker, urine NGAL performed moderately well in predicting ongoing and subsequent AKI," senior author T. Alp Ikizler, MD, from Vanderbilt University Medical Center in Nashville, Tennessee, said in a news release.

A second study in the Journal of the American Society of Nephrology showed that urine NGAL may also be a useful diagnostic marker for HIV-associated nephropathy (HIVAN), which occurs primarily in black Americans and black Africans.

"NGAL was very specifically expressed in renal cysts — generating the new idea that NGAL may control the development of cysts in [HIVAN]," wrote senior author Jonathan Barasch, MD, PhD, from Columbia University in New York City. "We and Prasad Devarajan, MD, identified NGAL in the kidney 10 years ago and its translation into a clinical entity in such a short time is quite a story. Almost every paper is positive for the association of NGAL and renal dysfunction/disease."

The Vanderbilt study of intensive care unit (ICU) patients prospectively evaluated a heterogeneous population of 451 critically ill adults, of whom 64 (14%) developed AKI within 24 hours of enrollment and 86 (19%) developed AKI within 48 hours of enrollment.

Compared with those who did not develop AKI within 48 hours, those who did had higher median urine NGAL at enrollment (190 vs 57 ng/mg creatinine; P < .001). For the relationship between urine NGAL level and development of AKI within 24 hours and 48 hours, the areas under the receiver operating characteristic curves were 0.71 (95% confidence interval [CI], 0.63 – 0.78) and 0.64 (95% CI, 0.57 – 0.71), respectively.

The increase in urine NGAL in patients who later developed AKI occurred before any change in serum creatinine level, which is typically used to diagnose AKI.

After adjustment for age, serum creatinine level closest to enrollment, illness severity, sepsis, and ICU location, urine NGAL remained independently associated with the development of AKI. However, adjusted urine NGAL only marginally improved the predictive performance of the clinical model alone. Urine NGAL was an independent predictor of severe AKI during hospitalization, according to the results of a Cox proportional hazards model using time to first dialysis, adjusted for Acute Physiology and Chronic Health Evaluation II score (hazard ratio, 2.60; 95% CI, 1.55 – 4.35).

"Although a single measurement of [urine NGAL] exhibited moderate predictive utility for the development and severity of AKI in a heterogeneous ICU population, its additional contribution to conventional clinical risk predictors appears limited," the study authors write. "The role of [urine NGAL] in predicting more important measures of AKI severity, including dialysis provision or mortality, remains to be fully explored in larger cohorts."

Limitations of this study include a lack of data on incidence of death or need for dialysis, lack of data regarding renal function at baseline, and prediction models based on a single assessment of urine NGAL. In addition, creatinine measurements were made based on clinical decision-making and were not protocol-driven.

NGAL for HIVAN Diagnosis

HIVAN is defined histologically as a collapsing focal segmental glomerulosclerosis with prominent tubular damage and is characterized clinically by nephrosis and a rapid decline in renal function. The goal of the second study was to assess whether NGAL is a useful marker for noninvasive diagnosis of HIVAN.

Compared with HIV-positive and HIV-negative patients who had other forms of chronic kidney disease, expression of urinary NGAL was much higher in patients with biopsy-proven HIVAN. An HIV-transgenic mouse model of HIVAN showed an abundance of NGAL mRNA in dilated, microcystic segments of the nephron, which are characteristic features of HIVAN. In contrast, urinary NGAL was not associated with proteinuria in human or mouse models.

"These data show that marked upregulation of NGAL accompanies HIVAN and support further study of [urine NGAL] levels in large cohorts to aid in the noninvasive diagnosis of HIVAN and screen for HIVAN-related tubular damage," the study authors write.

Limitations of the human component of the study included small sample size.

"If our results are confirmed, measuring urine NGAL might help triage patients into different risk categories," Dr. Barasch concludes.

The Vanderbilt ICU study was supported by the National Heart, Lung and Blood Institute from the National Institute of Diabetes, Digestive and Kidney Diseases, and a Clinical Translational Science Award from the National Center for Research Resources. One of the study authors was partially supported by the National Kidney Foundation Research Fellowship Award and the Vanderbilt Mentored Clinical Research Scholar Program. The HIV study was supported by grants from the Emerald Foundation, the March of Dimes, and the National Institute of Diabetes, Digestive and Kidney Diseases. Columbia University and Cincinnati Children's Hospital Medical Center received licensing fees from Biosite and Abbott Diagnostics. The collection of patient specimens was supported by the National Institutes of Health and by the Clinical Research Center of the Mount Sinai School of Medicine. The study authors have disclosed no relevant financial relationships.

J Am Soc Nephrol. Published online July 23, 2009.