Immune biomarker panel monitoring utilizing IDO enzyme activity and CD4 ATP levels: prediction of acute rejection vs. viral replication events

Abstract

Infections have become as important an event as acute rejection posttransplant for long-term allograft survival. Less invasive biomarkers tested so far predict risk for one event or the other, not both. We prospectively tested blood and urine monthly for 12 months posttransplant from children receiving a kidney transplant. The IDO enzyme pathway was assessed by MS assays using the ratio of product l-kyn to substrate trp. Kyn/trp ratios and blood CD4 T-cell ATP levels were correlated with acute rejection or major infection events or stable group (no events) in the next 30 days. The 25 subjects experienced six discrete episodes of acute rejection in five subjects and 16 discrete events of major infection in 14 subjects (seven BK viruria, six cytomegaloviremia, one EB and cytomegaloviremia, and two transplant pyelonephritis). Mean serum kyn/trp ratios were significantly elevated in the group that experienced acute rejection (p = 0.02). Within-subject analyses revealed that over time, urine kyn/trp ratios showed an increase (p = 0.01) and blood CD4-ATP levels showed a decrease (p = 0.007) prior to a major infection event. These pilot results suggest that a panel of biomarkers together can predict over- or under-immunosuppression, but need independent validation.

Figure 1

A. Serum kyn/trp ratios across the three groups. (81 stable group, 9 rejection group, 16 infection group). p value = 0.02 by ANOVA across all three groups, significant difference is between stable vs rejection group by Bonferroni post-test B. Urine kyn/trp ratios across the three groups (56 stable, 6 rejection, 8 infection group). p value = 0.27 by ANOVA across all three groups (NS) C. Blood CD4 ATP levels (Immuknow assay) across the three groups (86 stable group, 4 rejection group, 18 infection group). P value = 0.27 by ANOVA across all three groups (NS) D. Blood trough tacrolimus levels across the three groups. (104 stable, 7 rejection group, 23 infection group). P value = 0.78 by ANOVA across all three groups (NS).