Potential Utility of Combined Urine Lipocalin‑2 and Copper Test in Diagnosing Acute Pyelonephritis or Cystitis

The noninvasive differentiation of acute pyelonephritis (AP) and complicated urinary tract infections (cUTI), from acute cystitis (AC), represents an important diagnostic challenge in urology and nephrology. In a study of 95 adults, urine from patients with AP (n = 17), cUTI (n = 6), AC (n = 28), and controls (n = 44) was examined using a multidisciplinary approach: enzyme-linked immunosorbent assays for quantitation of acute phase proteins ceruloplasmin (Cp), pentraxin-3 (Ptx3), and lipocalin-2 (Lcn2); inductively coupled plasma mass spectrometry for determination of total copper (Cu), zinc (Zn), and iron (Fe) concentrations; and liquid chromatography coupled to electrospray ionization MS (LC-MS) for identification and quantitation of bacterial metallophores. Markedly elevated levels of human Cp, Ptx3, and Lcn2, all normalized to urine creatinine (Cr), in AC, cUTI, and AP patients compared to controls identified ongoing urinary tract infection without further differentiation between AC and AP. On the contrary, total urine copper normalized to Cr (Cu/Cr index) significantly differentiated AP from AC (p = 0.0209), as well as from the controls. Bacterial metallophores aerobactin and yersiniabactin, but not enterobactin, were indicators of AP, cUTI, and AC caused by Enterobacteriaceae. Importantly, the newly proposed combined test based on the quantitation of Lcn2 normalized to Cr (Lcn2/Cr) and Cu/Cr could noninvasively differentiate AP and cUTIs from AC with a diagnostic accuracy of 78% sensitivity and 65% specificity. The combination of characteristic elemental and molecular biomarkers may represent a future research direction with the potential to improve diagnostics of UTIs.