Neutrophil gelatinase-associated lipocalin: utility in urologic conditions

There is a well-known association between UTI and the presence of VUR in children [11]. However, there is disagreement regarding the management of patients with UTI in regards to screening for VUR. Much of this debate began with the publication of the American Academy of Pediatrics Guideline in 2011 [12, 13]. The controversy is mainly centered around the recommendation that voiding cysto-urethrograms (VCUGs) should not be routinely performed in children between 2 and 24 months of age with first time febrile UTIs [12]. Advocates of this approach are concerned about the invasive nature of VCUGs and the lack of an effective treatment for lower grades of VUR. However, proponents of the routine use of VCUGs cite the outcomes of reflux nephropathy and renal scarring, which have potential to cause significant morbidity, as well as the potential for delay of surgical intervention for patients with high grade VUR [14]. Given the invasiveness of VCUGs, and the potential for morbidity with untreated VUR, a non-invasive marker of VUR would have significant utility in the management of patients with first time UTIs.

It is difficult to comment upon the utility of NGAL in VUR without considering the presence of scarring given the degree of interrelatedness between them. Accordingly, much of the work done on NGAL and VUR also bears on renal scarring. NGAL is a potential candidate marker for VUR, and subsequent scarring, due to its specificity for renal tubular damage. However, the presupposition of this theory is that the damage associated with renal scarring is ongoing, and prior work has shown that uNGAL is not elevated in quiescent forms of chronic kidney disease [15]. Rat models of pyelonephritis show that the upregulation of NGAL gene expression peaks at 2 weeks following pyelonephritis, after which it decreases at both 4 and 6 weeks, but does not return to baseline levels [16]. Immunostaining of rat kidneys suggests that the NGAL upregulation seen at 2 weeks is an inflammatory response to the presence of the bacteria, but that the NGAL upregulation at 6 weeks, which is localized to the renal tubule, is in response to tubular injury rather than infection. Urine NGAL levels correspond to these transcriptome profiling results: uNGAL levels peak at 2 weeks and then decrease by week 6, although not to baseline levels [17]. The differences in these uNGAL values, while of mechanistic interest, likely have little utility in clinical practice when examined at a single point in time. The clinical data in the literature agrees with this notion. While the difference between uNGAL levels in patients with scarring and those without is statistically significant, the values presented to date are all within the normal range of NGAL for age [18, 19]. Further, in a separate cross-sectional analysis of children with pyelonephritis, while there was a statistical difference in uNGAL levels between children who developed renal scarring and those that did not, the mean uNGAL values of patients who developed scarring (9.8 ± 4.5 ng/ml) and those who did not (7.2 ± 3.8 ng/ml) are still within the normal range of uNGAL for age [19, 20]. These results are again interesting from a mechanistic standpoint, but the value of using a single NGAL as a prognostic marker for the development of scarring is limited.

Despite the lack of utility of a single uNGAL value in this setting, following longitudinal uNGAL levels in children with known recurrent UTIs may provide a non-invasive method to monitor for progression of renal scars. As the data support the notion that uNGAL does not return to normal levels following the development of scarring as a result of pyelonephritis, then trending these values over time may have increased value compared to a single uNGAL measurement in the setting of an acute infection in determining the risk of scarring.