Tracking Microchimeric DNA in Plasma to Diagnose and Manage Organ Transplant Rejection (Editorials‪)‬

One of the most promising areas of transplantation research is the recent discovery of biomarkers for rejection that are detectable in blood and urine. Biopsy-confirmed rejection, the current gold standard for diagnosis of allograft rejection, is invasive and subject to sampling errors. For example, diagnosis of episodes of rejection of pancreas allografts, which are frequent and can destroy the allograft, depends on conventional percutaneous biopsies that have a diagnostic sensitivity of only 79%-88% (1, 2) and are associated with a 2%-7% risk of serious complications (3). Development of noninvasive assays that detect molecular biomarkers for rejection could revolutionize management of transplant recipients by (a) detecting a prerejection profile that will allow therapeutic interventions before rejection causes graft dysfunction; (b) improving the sensitivity and specificity of rejection diagnosis; (c) developing new classification systems for rejection that will improve prognosis; and (d) providing information for designing individualized immunosuppressive regimens that could prevent rejection while minimizing drug toxicity. There have been several exciting reports of potential biomarkers for allograft rejection, with the most significant progress occurring in the area of renal transplantation. This work began by studying concentrations of particular mRNAs or proteins that were associated with immune activation or tissue stress (4). These studies have revealed several gene products that have altered expression in blood, urine, and/or biopsy tissue during rejection episodes. In the most recent contribution in this rapidly evolving field, Muthukumar et al. (5) demonstrated that urine concentrations of FOXP3 mRNA, a member of the forkhead family of cell differentiation genes and a lineage-specific transcript for graft-protecting regulatory T cells, can predict reversal of acute renal allograft rejection with 90% sensitivity and 73% specificity. Although measurement of the products of individual genes such as FOXP3 will probably not supplant conventional biopsies for diagnosis of rejection, development of panels of informative gene products in blood and urine, in concert with renal function and immune response markers, ultimately should achieve the sensitivities and specificities required for diagnosis and clinical management of kidney rejection (6).