**8. Management of antibody mediated rejection**

and that ENDAT changes in renal transplants occur in rejection and in other forms of re‐ nal injury, and their impact on transplant glomerulopathy and graft loss is principally in patients with circulating HLA antibodies. The elevation of the ENDATs is of value in de‐ termining which biopsies for cause in patients with antibody may have antibody-mediat‐ ed injury, even when they are C4d negative. Based on their study, the combined burden of C4d+ and C4d negative AMR accounts for the majority of graft losses in kidney trans‐ plants biopsied for clinical indications (17 of 26, 65%). ENDAT expression in biopsy pro‐ vides a new tool for understanding the pathogenesis of late kidney graft loss and AMR, and for predicting graft outcomes and defining AMR even in C4d negative biopsies in

The discovery of novel and less invasive surrogate biomarkers of acute cellular rejection, for which urine levels of Granzyme B and FOXP3 transcripts have been shown to have diagnostic and prognostic value (Muthukumar et al., 2005; Veale et al., 2006), has proved successful. Such an approach in the case of the different causes of late graft failure would facilitate the introduction of more targeted immunosuppression and thereby im‐ prove long-term outcome. Ashton-Chess and colleagues (Ashton-Chess et al., 2008) set out to discover novel minimally invasive biomarkers of more precise histologic diagno‐ ses of late graft scarring. Using a literature gene-set comparison approach for late graft injury, they identified TRIB1, a human homolog of Drosophila tribbles, (Grosshans & Wieschaus, 2000) as a potentially informative biomarker. TRIB1 is a scarcely character‐ ized member of the tribbles family that has been shown to be a potent regulator of cell signaling18 in various cells lines. It was determined that TRIB1 is expressed primarily by antigen-presenting cells (APC) and activated endothelial cells (EC). TRIB1 differs from the other minimally invasive biomarkers of transplant rejection described to date that are of T/NK cell origin, (Muthukumar et al., 2005; Seiler et al., 2007; Veale et al., 2006) in

They explored the potential of TRIB1 as a tissue, peripheral blood, and urine biomarker by measuring its mRNA profiles in graft biopsies, blood, and urine from healthy volunteers and kidney transplant recipients with different histologic and/or clinical diagnoses. For testing this, mRNA expression in 76 graft biopsies, 71 blood samples, and 11 urine samples were profiled from independent cohorts of renal transplant patients with different histologic diagnoses recruited at two European centers. TRIB1 but not TRIB2 or TRIB3 was found to be a potential blood and tissue (but not urine) biomarker of chronic antibody-mediated rejection. Moreover, TRIB1 mRNA in the blood was more specific and sensitive for diagnosing chronic AMR than

TRIB1 mRNA levels in peripheral blood mononuclear cells discriminated patients with chronic antibody-mediated rejection from those with other types of late allograft injury with high sensitivity and specificity, suggests TRIB1 to be a marker of an active immune response. Overall, these data support the potential use of TRIB1 as a biomarker of chronic antibody-

patients with antibodies (Sis et al., 2009).

428 Current Issues and Future Direction in Kidney Transplantation

*7.3.2. TRIB1as a new non-invasive marker for CAMR*

that it is expressed primarily by APC as well as EC.

TRIB1 mRNA in biopsies.

mediated allograft failure.

Unfortunately, no immunosuppressive standard for the prevention or therapy of alloantibody production has been established yet. Although based on very limited evidence, acute humoral rejections are frequently treated with a switch to tacrolimus, plasmapheresis or immunoad‐ sorption, as well as T- and B-cell-depleting antibodies. However, the best therapeutic approach for C4d-positive, chronic humoral kidney rejection associated with an unfavourable prognosis remains completely unclear. Neither the dose nor the best drug combination for the therapy of an established humoral rejection is based on solid evidence. Although various immuno‐ suppressive drugs can reduce the number of acute rejection ns via inhibition of the T-cell response, only very few data are available regarding immunosuppressive drugs affecting the humoral alloresponse after organ transplantation.
