Taizo Hibi¹, Seigo Nishida¹, Jennifer Garcia², Panagiotis Tryphonopoulos¹, Akin Tekin¹, Gennaro Selvaggi¹, Jang Moon¹, David Levi¹, Debbie Weppler¹, Phillip Ruiz³, Andreas Tzakis¹

¹Department of Surgery, Division of Transplantation, University of Miami Miller School of Medicine/Jackson Memorial Hospital, Miami, FL, United States; ²Department of Pediatrics, University of Miami Miller School of Medicine/Jackson Memorial Hospital, Miami, FL, United States; ³Department of Pathology, University of Miami Miller School of Medicine/Jackson Memorial Hospital, Miami, FL, United States

Background: Serum citrulline has been advocated as a marker for acute cellular rejection in intestinal transplantation; however, its significance in long-term follow-up among the pediatric population has yet to be defined. This study aimed to investigate the association between citrulline levels and the grade of rejection and to establish cutoff levels after transplant that accurately predicts moderate or severe rejection.

Methods: During a 10-year period (2002-2011), 954 serum citrulline samples from 44 pediatric intestinal and multivisceral transplant recipients beyond 3 months posttransplant were obtained concurrently with intestinal biopsies (during rejection episodes and for surveillance). We evaluated the correlation of serum citrulline and biopsy-based grade of rejection and analyzed the best citrulline value for its use in clinical practice.

Results: Median age at transplant was 1.6 years (6 months-16 years), 15 patients received an isolated intestinal or combined liver-intestinal transplant and 29 patients underwent a multivisceral or modified multivisceral transplant. During a median follow-up period of 8.5 years (range 5 months-16 years), median number of rejection episodes were 2 (range 0-9). The average serum citrulline levels inversely correlated with the degree of rejection as follows: no rejection, 19.09 μmol/L; indeterminate, 15.85 μmol/L; mild rejection, 10.27 μmol/L; moderate rejection, 6.70 μmol/L; severe rejection, 6.21 μmol/L. Calculation using a cutoff point of 9.2 μmol/L showed the sensitivity for detecting moderate or severe rejection of 83.7% with the negative predictive value of 97.6%. Specificity was 75.1%.

Conclusions: Serum citrulline level is a potent surrogate indicator which significantly correlates with the rejection status of the intestinal graft in the long term. Citrulline levels < 9.2 μmol/L during serial follow-up should alert the transplant team that a serious rejection could be emerging. Timing of this warning and search for other possible biomarkers to be combined with citrulline for improved sensitivity and specificity are currently under investigation.