Could NGAL be a biomarker to help identify kidney tubular injury earlier?

Imagine you’re digging through your toolbox, looking for the right wrench and screwdriver for a time sensitive repair to a leaky pipe. If a key tool is missing, you can rely on what’s available, potentially adding extra time and effort and meaning more damage may occur. But when the right tools are within reach, the work becomes more efficient, and the repairment is smoother. Diagnostics often relies on multiple tools or sources of information, and emerging biomarkers may provide additional context when evaluating alongside established clinical and laboratory findings.

Current markers most commonly used for the diagnosis of AKI include serum creatinine and urine output, which are measures of kidney function. While monitoring kidney function is important, damage to the kidneys can occur which may not be reflected immediately, or even not at all by functional markers. This article serves to provide an overview of the evidence for the NGAL biomarker for identifying kidney damage.  

The expression of Neutrophil gelatinase-associated lipocalin (NGAL) provides an opportunity to help identify damage to the kidneys earlier than utilizing functional criteria for acute kidney injury which may not change until further damage occurs. NGAL is a protein that is secreted by activated neutrophils and expressed in epithelial cells of organs exposed to the external environment. Published studies report that this includes kidney tubular cells where NGAL is rapidly over-expressed and may be detected in the urine and plasma as early as two hours following kidney tubule injury.¹ NGAL has therefore been evaluated in published studies involving both pediatric and adult patient populations with various disease states as an indicator of tubular injury.^2,3 This is displayed by the results of a meta-analysis in which urine NGAL (uNGAL) demonstrated excellent potential to diagnose AKI. uNGAL displayed an AUC of 0.94 for diagnosing AKI in nearly 1300 pediatric patients across nine studies.2 Meanwhile in another meta-analysis of adult patients, uNGAL was found to have the highest discriminative accuracy to diagnose AKI out of multiple studied biomarkers with an HSROC of 85.2% derived from the combination of 35 studies.³

In pediatric patients, uNGAL can help identify tubular injury and patients at risk of developing stage 2 or 3 AKI defined by serum creatinine (SCr). Two multicenter, prospective studies investigated uNGAL’s ability to predict (SCr)-based stage 2 or 3 AKI at 48-72 hours when measured within 24 hours of ICU admission. uNGAL at the cut-off of 125 ng/mL showed a good performance, with a specificity of 88.6% and negative predictive value of 98.1% when admission SCr was not indicative of AKI. The high NPV helps to show that the identification of patients with no active tubular injury and low uNGAL are at a much lower risk of developing AKI as opposed to those pediatric ICU patients with elevated uNGAL.⁴  

uNGAL could also be a beneficial clinical decision support (CDS) tool for fluid overload management and optimization of continuous kidney replacement therapy (CKRT) usage. In one published pediatric study, the CDS tool with uNGAL was associated with reduced fluid accumulation, time to CKRT initiation, ICU length of stay, and higher survival rates post CKRT.⁵

uNGAL has also been studied as a marker of subclinical AKI, where tubular injury is present but not yet reflected in functional markers such as SCr. Both pediatric and adult patients with subclinical AKI had a greater need for kidney replacement therapy, longer hospital stays, and more in-hospital mortality compared to patients with no subclinical AKI.^6,7 Pediatric patients with subclinical AKI were also more likely to develop SCr-defined AKI by day 3 than those without AKI.⁶  

NGAL has also shown potential value in the differential diagnosis of kidney injury in adult patients with cirrhosis by helping distinguish acute tubular injury (ATI) from hepatorenal syndrome (HRS), with higher levels observed in ATI.⁸ It has also shown promise for early identification of drug-induced AKI and for monitoring both pediatric and adult patients receiving nephrotoxic medications, based on published studies of kidney damage biomarkers.⁹

Overall, published clinical studies indicate that NGAL may be a valuable biomarker for identifying patients with tubular injury who are at risk of AKI or have already developed it. Because urine and plasma NGAL may rise earlier than functional markers, NGAL may help identify kidney injury before changes in markers such as SCr become apparent. This earlier identification, together with its potential ability to help distinguish kidney injury from other causes, may help to support more timely assessment and management of AKI. Currently, ProNephro AKI™, on the Roche cobas c 501 is the only FDA-approved NGAL diagnostic test and is indicated for patients aged 3 months to 21 years who are at risk of developing, or have persistent, moderate-to-severe AKI within 48 to 72 hours after ICU admission. The test is not currently approved for patients over 21 years of age. A uNGAL cut-off study in adults has recently been completed, and preliminary results are being further evaluated in an ongoing validation study. 

Disclaimer: This Scientific Short discusses published scientific literature on NGAL and is intended for educational and scientific discussion only. It is not intended to promote any unapproved use of any medical device. In the United States, ProNephro AKI™ is FDA-approved only for its indicated use in patients aged 3 months to 21 years who are at risk of developing, or have persistent, moderate-to-severe AKI within 48 to 72 hours after ICU admission and is not currently FDA-approved for use in adults.

References

1. Devarajan P. Neutrophil gelatinase-associated lipocalin: a promising biomarker for human acute kidney injury. Biomark Med. 2010;4(2):265-80.
2. Filho LT, Grande AJ, Colonetti T, et al. Accuracy of neutrophil gelatinase-associated lipocalin for acute kidney injury diagnosis in children: systematic review and meta-analysis. Pediatr Nephrol. 2017;32:1979-1988.
3. Pan H-C, Yang S-Y, Ting-Yu Chiou T, et al. Comparative accuracy of biomarkers for the prediction of hospital-acquired acute kidney injury: a systematic review and meta-analysis. Crit Care. 2022;26:349.  
4. Goldstein SL, Akcan-Arikan A, Afonso N, et al. Derivation and Validation of an Optimal Neutrophil Gelatinase-Associated Lipocalin Cutoff to Predict Stage 2/3 Acute Kidney Injury (AKI) in Critically Ill Children. Kidney Int Rep. 2024;9(8):2443-2452.  
5. Goldstein SL, Krallman KA, Roy J-P, et al. Real-Time Acute Kidney Injury Risk Stratification-Biomarker Directed Fluid Management Improves Outcomes in Critically Ill Children and Young Adults. Kidney Int Rep. 2023;8(12):2690-2700.  
6. Stanski N, Menon S, Goldstein SL, et al. Integration of urinary neutrophil gelatinase-associated lipocalin with serum creatinine delineates acute kidney injury phenotypes in critically ill children. J Crit Care. 2019:53;1-7.  
7. Haase M, Devarajan P, Haase-Fielitz A, et al. The Outcome of Neutrophil Gelatinase-Associated Lipocalin (NGAL)-positive Subclinical Acute Kidney Injury: A Multicenter Pooled Analysis of Prospective Studies. J AM Coll Cardiol. 2011;57(17):1752-1761.  
8. Puthamana J, Lugon NC, Xu Y, et al. Systematic Review and Meta-Analysis of Urine Neutrophil Gelatinase-Associated Lipocalin for Acute Kidney Injury in Cirrhosis. Kidney Int Rep. 2024;9(7):2278-2281.  
9. Desai RJ, Kazarov CL, Wong A, et al. Kidney Damage and Stress Biomarkers for Early Identification of Drug-Induced Kidney Injury: A Systematic Review. Drug Saf. 2022;45(8):839-852.