Introduction: Previous studies from our group have shown that activity of the biomarker enzyme IDO elevates prior to acute rejection in kidney transplant recipients, as commonly inferred by ratio of enzyme product kynurenines (kyn) to enzyme substrate tryptophan (trp). Acute rejection episodes increase the risk for chronic rejection, a leading cause of allograft loss. The relationship between serum IDO activity and chronic rejection has not been previously studied. We investigated the possible association of kyn/trp ratio elevation to biopsy-proven transplant glomerulopathy (TG), a phenotype of chronic rejection and to presence of serum antibodies to the kidney-associated self-antigens fibronectin (FN) and collagen IV (Col IV), shown by some in our group to be strongly associated with TG.

Methods: Kyn and trp were quantitated using mass spectrometry m/z transitions of 209>94 and 205>146, respectively, using D5-tryptophan and D6-kynurenine as internal standards, from serum samples extracted from our Kidney Translational Research Core. Samples were chosen which had been obtained within 2 weeks of a biopsy which showed chronic rejection. Antibodies to FN and Col IV were measured by ELISA developed by our group using techniques previously described.

Results: In 56 patients with predominantly chronic rejection on allograft kidney biopsy, the kyn/trp ratio (median 6.9, IQR 5.32, 10.3) was not significantly higher compared to the level in 46 with other features but no chronic rejection (median 6.65, IQR 4.67, 9.62, p = 0.37 by non-parametric two-tailed Mann-Whitney test). Similarly, the kyn/trp ratio in TG patients (n=38) was not significantly higher compared to non-TG (n=64; median 6.95, IQR 5.23, 10.43 in TG versus median 6.65, IQR 5.12, 9.67 in non-TG, p = 0.55).The kyn/trp ratios did not show a significant correlation with either FN (two-tailed Spearman r = 0.10, p = 0.29) or Col IV (Spearman r = 0.14, p = 0.15).

Conclusions: In this cross-sectional analysis, serum kyn/trp ratio was not elevated at time of biopsy-proven chronic rejection, nor did it associate with high levels of antibodies to kidney-specific self-antigens. Further studies should assess the longitudinal associations of these serum biomarkers prior to, rather than concomitant to, the development of established chronic rejection.

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