Urinary CXCL9 and CXCL10 Levels Correlate with the Extent of Subclinical Tubulitis

Subclinical tubulitis has been associated with the later development of interstitial fibrosis and tubular atrophy (IF/TA), leading to diminished allograft survival. The aim of this study was to investigate how concentrations of urinary CXC-receptor 3 (CXCR3) chemokines (i.e. CXCL4/9/10/11) and CCL2 relate to the extent of subclinical tubulitis. Using ELISA, urinary CXCR3 chemokines, CCL2 and tubular injury markers (i.e. urinary NGAL and alpha 1-microglobulin [alpha 1 m]) were measured in patients with stable estimated GFR >= 40 mL/min exhibiting normal tubular histology (n = 24), subclinical borderline tubulitis (n = 18) or subclinical tubulitis Ia/Ib (n = 22), as well as in patients with clinical tubulitis Ia/Ib (n = 17) or IF/TA (n = 10). CXCL9 and CXCL10 were significantly higher in subclinical tubulitis Ia/Ib than in subclinical borderline tubulitis (p <= 0.03) and normal tubular histology (p <= 0.0002). By contrast, NGAL, alpha 1-m, CXCL4, CXCL11 and CCL2 were not or only marginally distinctive across these patient groups. All urinary chemokines and tubular injury markers were higher in clinical tubulitis Ia/Ib than in normal tubular histology (p <= 0.002), but only tubular injury markers were elevated in IF/TA. These results demonstrate a correlation of urinary CXCL9 and CXCL10 levels with the extent of subclinical tubulitis suggesting potential as noninvasive screening biomarkers.