Clinical Implementation of Urinary Neutrophil Gelatinase-Associated Lipocalin

Neutrophil gelatinase-associated lipocalin (NGAL), initially discovered in secondary granules of human neutrophils, plays important roles in iron transport to inhibit bacterial proliferation, reduce extracellular iron-induced injury, and promote proliferation and differentiation of human cells.1 NGAL is synthesized in the bone marrow, colon, trachea, lung, and kidney epithelium. In rat kidneys, NGAL promotes iron-dependent differentiation of mesenchymal progenitors, exemplifying a role for tissue repair after AKI.2 Intravenously administered NGAL increased tubular cell proliferation and reduced tubular cell death in animal models of ischemia reperfusion-induced AKI. Early evidence demonstrating that NGAL was one of the most rapidly upregulated genes during AKI and that urinary NGAL (uNGAL) concentration increased several fold within hours of ischemic insult led to uNGAL's initial claim to fame as an early marker of AKI (up to 48 hours before AKI detectable by creatinine).1 This led to the initial application of uNGAL as an early diagnostic biomarker for AKI and prognostic biomarker for severe AKI. Results from clinical validation studies have been disappointing, likely owing to concurrent rise in uNGAL because of nonkidney inflammation such as peritonitis, bacterial infections, cystitis, inflammatory bowel disease, infective exacerbations of chronic obstructive pulmonary disease, and some tumors.1,3 In acute pediatric illnesses, uNGAL seems to be more robust as a marker of AKI likelihood and severity across a number of settings,4 potentially more accurate because of the absence of chronic comorbidities. More recently, uNGAL has been used to differentiate intrinsic from functional/extrinsic causes of AKI with better success.5,6 In this issue of Kidney360, Strader et al. investigated the role of uNGAL for differentiating mild/functional AKI from more established severe AKIs with acute tubular necrosis (ATN) in a cohort of 292 patients in a single tertiary center, where uNGAL testing had been implemented into usual clinical practice.6 The major strength of the study by Strader et al. is the evaluation of uNGAL in all-comers with AKI in real-world clinical scenarios. Although the biomarker discovery phase typically involves controlled clinical studies where study participants with multifactorial AKI or potential confounding factors are screened out, implementation studies such as this reveal how biomarkers are likely to perform in people with multiple acute health issues and comorbidities. The respective sensitivity and specificity of 87% and 42% of uNGAL >150 ng/ml in this study was similar to values reported in other studies (Table 1).5,7 Other uNGAL formats such as ng/ml had a lower sensitivity of 62% but higher specificity of 71%, whereas uNGAL:creatinine had a similar sensitivity of 67% and specificity of 71%.6 The Youden threshold calculated to optimize sensitivity/specificity for uNGAL was 690 ng/ml and uNGAL:creatinine was 750 ng/mg.6 This was significantly higher than the threshold calculated in a Canadian study of 250 consecutive patients with AKI conducted by Côté et al. (139 ng/ml for uNGAL and 288 ng/mg for uNGAL:creatinine).5 This may be because there was a higher number of stage 3 AKIs in the Strader et al. cohort (55% compared with 37% overall), and stage 3 AKIs made up 41% of the prerenal cases. It is possible that the absolute uNGAL values of these patients were higher; despite not behaving like ATN clinically, patients with stage 3 AKIs had more extensive tubular injury than those with grade 1–2 AKI. Table 1 - Examples of studies evaluating use of urinary NGAL to differentiate between intrinsic and extrinsic AKI Study Cohort Size+Type uNGAL Format Sensitivity Specificity Cutoff Value (ng/ml) Strader 20256 292, consecutive AKI uNGAL 87% 42% 150 uNGAL 62% 71% 690 uNGAL:Cr 67% 71% 750 Côté 20225 250, consecutive AKI uNGAL 84% 73% 139 uNGAL:Cr 75% 80% 288 Puthumana 20248 1219, hospitalized patients with AKI+liver cirrhosis; 11 studies meta-analysis uNGAL 81% 82% uNGAL 220auNGAL:Cr 220a Cr, creatinine; NGAL, neutrophil gelatinase-associated lipocalin; uNGAL, urinary NGAL.aMedian values across 11 studies. A meta-analysis of 11 studies found that uNGAL had a sensitivity of 81% and specificity of 82% for differentiating ATN from hepatorenal syndrome in hospitalized people with cirrhosis.8 The median threshold values were 220 ng/ml for uNGAL and 220 ng/mg for uNGAL:creatinine.8 These results highlight the need for further studies to determine the optimal uNGAL threshold, although the optimal uNGAL threshold may be site-specific and vary depending on the intended test population (e.g., liver cirrhosis versus all-comers). Although uNGAL had marginally greater specificity for intrinsic AKI in people without urinary tract infections compared with all-comers, the differences were not clinically significant. The authors proposed the use of uNGAL as a rule out test, whereby a uNGAL level of <150 ng/ml excludes intrinsic AKI with a negative predictive value of 82%. This was similar to the study by Côté et al., where uNGAL reportedly aided with 95% of diagnoses.5 The question remains: What is the value-add of uNGAL? In this study, Strader et al. used clinical judgment by experienced kidney specialists as the gold standard; however, adjudicators often did not have the full set of information (e.g., biopsy results) available at the time of adjudication. Clinical case adjudication was the gold standard and standard of care (as medical teams are led by experienced clinicians). Future studies could address this by having clinicians record the suspected AKI etiology at the time of uNGAL testing, with retrospective complete case adjudication as the gold standard. In a perfect world, biomarkers would outperform the current diagnostic gold standard. The reality of medicine is that nothing is ever perfect and lines blur as the number of variables increases. This study demonstrated that uNGAL is in many respects comparable with an experienced kidney specialist (who may have the benefit of hindsight) at differentiating intrinsic from extrinsic AKI, with the most uncertainty in the 150–500 ng/ml range. The case could still be made that uNGAL has utility for nonspecialist clinicians to trigger investigations for intrinsic AKI, referral to kidney specialists for intrinsic AKI management, and assist nephrologists to triage consults that they do receive. This is particularly relevant as AKI complicates 21% hospital admissions where the primary medical issue driving admission may not be kidney-related and so, the treating clinician may not be a kidney specialist (the gold standard applied in this study).9 Furthermore, uNGAL may be useful in low resource or remote environments where kidney specialists are not readily available to aide in both diagnosis and triage for patients who may need to transfer to a larger center. Other applications include the assessment of recurrent AKIs over a long admission where the etiology could change over time and uNGAL could be used to pinpoint when ATN becomes apparent after a period of functional AKI. In this study, Strader et al. noted the weakness that timing of uNGAL testing was not standardized.6 This aspect may end up being an unexpected strength of this study as the association between elevated uNGAL and intrinsic AKI persisted despite variability in uNGAL testing relative to AKI course, demonstrating the robustness of uNGAL as a biomarker of AKI etiology. The cost effectiveness and utility of uNGAL as an adjunct to identify AKI cause is center-specific, depending on access to kidney specialists, case complexity, and frequency of uNGAL testing. In tertiary centers where kidney specialist advice is readily accessible, uNGAL may be less useful. However, at a remote center, uNGAL may be helpful to inform the decision to transfer a patient for specialist review. If a kidney specialist unit handles relatively few complex AKI cases where uNGAL would be useful, the cost-benefit ratio of maintaining the uNGAL test (e.g., maintenance of in-date stock, staff training on assay, regular equipment calibration) may be unacceptably high. Although, maintenance costs may be lower with the availability of a point-of-care dipstick uNGAL test.10 uNGAL lives to fight another day although, as a biomarker of AKI etiology instead of AKI risk/prognosis. Clinical implementation of uNGAL will likely be nuanced and dependent on center-specific characteristics.

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