An Analysis of the Association between Serum Citrulline and Acute Rejection among 26 Recipients of Intestinal Transplant

Abstract

Small preliminary studies suggest that serum citrulline levels may act as a marker for acute cellular rejection in small intestinal transplant recipients. The results comparing serum citrulline concentrations with biopsy-based grades of rejection are summarized here for an expanded group of 26 isolated intestinal and multivisceral transplant recipients. Other factors considered included patient and donor age and sex, ischemia time, serum creatinine, and type of transplant. Straight-line fits reasonably described how each patient's citrulline levels changed over time. Among 21 patients who demonstrated increasing citrulline levels over time, the estimated median timeto-achieve normal citrulline (≥30 lmol/L) was 79 days post-transplant. Using stepwise linear regression, two characteristics were associated with a significantly higher maximum grade of rejection after 14 d post-transplant: longer time-to-achieve normal citrulline (using ranks, p < 0.00001) and the patient not receiving a multivisceral transplant (p = = 0.0005). Only the latter characteristic was significantly associated with maximum grade of rejection during the first 14 d post-transplant (p = = 0.01). Clearly, time-to-normalization of citrulline was delayed by the incidence of rejection, and in some cases with moderate-to-severe rejection, normalization of citrulline levels never occurred. We plan to further examine the use of citrulline as a marker for rejection in larger prospective studies.

Biomarkers for radiation-induced small bowel epithelial damage: An emerging role for plasma Citrulline

“…The role of the small intestine as the major source for circulating citrulline is demonstrated by experiments in which the plasma citrulline concentration is reduced by means of small bowel targeted interventions such as specific inhibitors of OAT [116] or OCT [132] , yielding a similar decrease of plasma citrulline concentration as observed after small bowel resection [83,86,113,114] . Furthermore, strong lines of evidence have been obtained since then through clinical observations which are in agreement with this concept [66,69,71,73,87,90,133,134] . Experimental and clinical data suggest a non-homogenous distribution of citrulline production.…”

“…Finally, the assay is simple to apply and relatively cheap. Like surgery [65][66][67][68] , celiac and non-celiac disease [69] and acute cellular rejection following small bowel transplantation [70][71][72][73]75,152] , ionizing irradiation has been demonstrated to be an additional event associated with reduced small bowel epithelial cell mass that can be monitored by plasma citrulline [30,[76][77][78][79] . …”

“…A major determinant, however, under steady state conditions for the rate of citrulline released into the portal and subsequently the systemic circulation is the actual number of functional enterocytes [65][66][67][68][69]83,86,87,90,113,114,134,151] . This was further demonstrated by clinical data on small bowel transplantation [70][71][72][73][74][75]152] . In addition to a variation in citrulline synthesis, alterations in citrulline utilization will have an influence on the plasma citrulline concentration [80,119,127] .…”

“…small intestinal enterocytes. Thus under steady state conditions, citrulline can be considered a marker for the functional epithelial cell mass of the small bowel, a concept amply demonstrated in experimental and clinical studies [65][66][67][68][69][70][71][72][73][74][75]80,83,[86][87][88]90,104,111,[113][114][115][116][132][133][134]152] . Of notice, the lower plasma citrulline level observed in short bowel patients was sustained up to one year after treatment [66] emphasizing its strict dependence on the epithelial cell mass.…”

“…Plasma citrulline has been identified as a biomarker for functional small bowel enterocyte mass under various clinical and experimental conditions. In addition to surgery [65][66][67][68] , celiac and non-celiac diseases [69] , viral enteritis [70] and acute cellular rejection following small bowel transplantation [70][71][72][73][74][75] , cytotoxic treatments was identified as another event associated with decreased plasma citrulline level due to epithelial cell loss [30,[76][77][78][79] . As a whole, plasma citrulline seems to be a quantitative parameter independent of the underlying cause for epithelial cell loss.…”