Introduction Both acute rejection (AR) and major infection events (MIE) can reduce long-term allograft survival. We assessed the simultaneous efficacy of serum and urine biomarker indoleamine 2,3 dioxygenase (IDO) enzyme activity and peripheral blood CD4-ATP levels for AR and MIE association, respectively. Methods We prospectively tested 217 blood and 167 urine serial samples, collected monthly for twelve months post-transplant from 29 consecutive children receiving a kidney transplant. The IDO activity was assessed by mass spectrometry assays using the ratio of product L-kynurenine (kyn) to substrate tryptophan (trp). Kyn/trp ratios and blood CD4 T-cell ATP levels were correlated with AR or MIE or stable group (no events) in the next 30 days. Results Using absolute cutoffs and allocating to samples to AR, MIE or stable group, mean serum kyn/trp ratios were significantly elevated in the group that experienced AR (p = 0.0007). Similarly, peripheral blood CD4-ATP levels were significantly lower in the group experiencing MIE (p = 0.0351). Urine kyn/trp ratios and blood tacrolimus levels were not different between AR and stable groups. Within-subject analyses, accounting for repeated measures in subjects, also showed that over time, serum kyn/trp ratios were higher prior to acute rejection (p = 0.031) and blood CD4-ATP levels were lower prior to MIE (p = 0.008). Conclusions These results from our pilot discovery group suggest that a panel of biomarkers together can predict over- or under-immunosuppression. Further independent validation in a multi-center cohort is suggested.
Infections have become as important an event as acute rejection post-transplant 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 twelve months post-transplant from children receiving a kidney transplant. The indoleamine 2,3 dioxygenase (IDO) enzyme pathway was assessed by mass spectrometry assays using the ratio of product L-kynurenine (kyn) to substrate tryptophan (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 6 discrete episodes of acute rejection in 5 subjects and 16 discrete events of major infection in 14 subjects (7 BK viruria, 6 cytomegaloviremia, 1 Epstein-Barr and cytomegaloviremia, 2 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 underimmunosuppression, but need independent validation.
Immune cells utilize the indoleamine 2,3 dioxygenase (IDO) enzymatic conversion of tryptophan (trp) to kynurenines (kyn) to determine T cell activation versus anergy/apoptosis. In prior studies, urine IDO levels were higher in rejecting renal allografts than in stable state. However, urine IDO levels in healthy subjects or children are unknown. As a corollary to a larger longitudinal and prospective study of serum and urine IDO levels for transplant immune monitoring, here we analyzed the difference between urine IDO levels in stable post-transplant versus healthy children. IDO levels were measured by tandem mass spectrometry and expressed as kyn/trp ratios. We compared one-time urine samples, from 34 well children at general pediatric clinics, to the first month post-transplant urine samples from 18 children, while in stable state (no acute rejection or major infection event in next 30 days). Urine kyn/trp ratios were significantly higher in stable children in first month post-kidney transplant (median 16.6, range 3.9-44.0) versus healthy children (median 9.2, range 3.51-17.0; p value = 0.0057 by non-parametric Mann-Whitney test). Higher urine IDO levels even with stable transplant suggests a continuous ongoing low-grade allorecognition/inflammatory process. Our data also provide baseline urine IDO levels in healthy subjects for use in future studies. (word count = 200)
Surveillance testing for major viral infections such as CMV, EBV, and BKV early in their natural history course may allow for early intervention and prevention of FBVD, but the testing is expensive and optimal interval/frequency are uncertain. At our center we initiated routine monthly viral surveillance for CMV, EBV, and BKV in July 2008 for the first 12 months post-transplant. Here, we retrospectively analyzed for outcome of the patients who missed three or more surveillance tests in the first 12 months post-transplant vs. those who did not. Of 21 patients, five missed three or more surveillance tests. Two of those five developed FBVD (one BKV nephropathy and one EBV-PTLD). None of the 16 patients with more regular surveillance testing developed FBVD. The incidence of viral replication was similar in both groups. The odds ratio for FBVD if viral surveillance tests were missed was 23.57 (p-value of 0.047). In this small group of contemporaneous patients on identical immunosuppression, those patients who missed regular viral surveillance were more likely to develop FBVD. Prospective randomized trials to confirm the benefit of regular viral testing are recommended.
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