*5.4. Comparison of Biomarkers*

Several studies have compared the utility of NAGL, KIM-1, and/or L-FABP levels as biomarkers of childhood UUTO. In studies, urine and/or serum NAGL levels outperformed urine KIM-1 or L-FABP levels [48,49]. In one study, striking increases in serum and urine NGAL levels were evident in patients with obstructive nephropathy, whereas urine KIM-1 levels did not differ significantly between patients and controls, which suggests that KIM-1 is not sensitive in this setting [50]. In another study, urine NGAL levels were significantly higher in patients with both hydronephrosis and obstruction than in those with hydronephrosis but no obstruction or normal controls. Urine KIM-1 and L-FABP levels did not differ significantly among the groups [48]. Patients with renal colic who also exhibited hydronephrosis had significantly higher urine NAG and NGAL, but not KIM-1, levels than did patients without hydronephrosis [114]. In a mouse model of ischemia/reperfusion kidney injury, serum and urine KIM-1 levels increased during the acute phase and declined gradually in the chronic phase, while serum and urine NGAL levels increased continuously during the transition from AKI to chronic kidney disease, which suggests that NGAL is a valuable biomarker in this setting [41]. This may explain why NGAL is a better biomarker of UUTO than KIM-1. However, one predictive model of worsening kidney function after surgery found that urine KIM-1 and L-FABP levels more reliably predicted kidney deterioration after surgical removal of ureteral stones than did urine NGAL levels [83].

MCP-1 is one of the best biomarkers of childhood UUTO. In one study, urine MCP-1 levels were significantly higher in a pyeloplasty group than a non-obstruction group, while urine NGAL and KIM-1 levels did not differ significantly between the groups [36]. In another study, urine MCP-1 levels were significantly higher in patients with hydronephrosis who required surgery than in those who did not; urine NAG levels did not differ significantly between the groups [68]. In one study, the AUC-ROC values of bladder urine MCP-1 and NGAL in children with UPJO were 0.89 and 0.90, respectively, higher than those of bladder urine interleukin-6 (0.78) or TGF-β1 (0.67) [46].

#### *5.5. Panel Assessment of Biomarkers*

No single biomarker is specific for UUTO, and given the multifactorial nature of obstruction, not all obstructions can be identified using a single biomarker [24]. In children with UPJO, combined NGAL/MCP-1 assessment improved diagnostic performance compared to assessment of either biomarker alone [46]. In another study on such children, the AUC-ROC values were 0.63 for SCr, 0.72 for serum cystatin C, 0.80 for urinary NGAL, 0.70 for urinary KIM-1, and 0.70 for urinary cystatin C. The AUC-ROCs of combinations of these biomarkers were higher than those of the single biomarkers, being highest (0.88) for urinary NGAL + urinary cystatin C + serum cystatin C [34]. In critically ill patients with AKI, a combination of urine NGAL and L-FABP levels, sepsis status, blood lactate level, and stratification using the Acute Physiology and Chronic Health Evaluation score improved AKI predictive performance (AUC-ROC 0.94) compared to NGAL alone (AUC-ROC 0.86) or

L-FABP alone (AUC-ROC 0.84) [43]. In a model predicting worsening kidney function after surgery in UUTO patients, the AUC-ROC of the preoperative combination of urinary biomarkers L-FABP, KIM-1, and NGAL was 0.97, higher than the highest AUC of a single biomarker (0.91 for L-FABP) [83].
