Vikas R Dharnidharka1, Eihab Al Khasawneh, Sushil Gupta, Jonathan J Shuster, Douglas W Theriaque, Amir H Shahlaee, Timothy J Garrett. 1. 1 Divisions of Pediatric Nephrology, University of Florida College of Medicine, Gainesville, FL. 2 Clinical and Translational Science Institute, University of Florida College of Medicine, Gainesville, FL. 3 Department of Health Outcomes and Policy, University of Florida College of Medicine, Gainesville, FL. 4 Hematology-Oncology, Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL. 5 Address correspondence to: Vikas R. Dharnidharka, M.D., M.P.H., Division of Pediatric Nephrology, Washington University in St. Louis School of Medicine & St. Louis Children's Hospital, Northwest Tower Room 10-119, Campus Box 8116, 660 South Euclid Avenue, St. Louis, MO 63110.
Abstract
BACKGROUND: 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 12 months after transplantation from 29 consecutive children receiving a kidney transplant. The indoleamine 2,3-dioxygenase 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, 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 before AR (P=0.031) and blood CD4-ATP levels were lower before MIE (P=0.008). CONCLUSIONS: These results from our pilot discovery group suggest that a panel of biomarkers together can predict overimmunosuppression or underimmunosuppression. Further independent validation in a multicenter cohort is suggested.
BACKGROUND: 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 12 months after transplantation from 29 consecutive children receiving a kidney transplant. The indoleamine 2,3-dioxygenase 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, 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 before AR (P=0.031) and blood CD4-ATP levels were lower before MIE (P=0.008). CONCLUSIONS: These results from our pilot discovery group suggest that a panel of biomarkers together can predict overimmunosuppression or underimmunosuppression. Further independent validation in a multicenter cohort is suggested.
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