Autotaxin Inhibitor Protects from Chronic Allograft Injury in Rat Kidney Allotransplantation

BACKGROUND: Tissue fibrosis is the final common phase of chronic allograft injury, the leading cause of late graft loss in kidney transplantation. Preclinical evidence points to the involvement of lysophosphatidic acid (LPA), a bioactive phospholipid, in the development of renal fibrosis. OBJECTIVES: We assessed whether treatment with an orally available inhibitor of autotaxin (ATXi), the main LPA-producing enzyme, could slow the progression of chronic allograft injury in a fully major histocompatibility complex-mismatched rat kidney transplant model and compared its effects with those of the angiotensin-converting enzyme inhibitor lisinopril. METHODS: Kidney allograft recipients were given ciclosporin for the first 15 postoperative days to prevent early acute rejection. Thereafter, they received either no treatment or ATXi or lisinopril and were followed for 180 days after transplantation. RESULTS: Renal LPA levels were increased in allograft rats, providing the rationale for using ATXi in this model. Chronic treatment with ATXi or lisinopril limited progressive proteinuria and ameliorated tubulointerstitial fibrosis compared with allograft rats, although the effects were more robust under ATX inhibition. The administration of ATXi, but not lisinopril, attenuated systemic hypertension, reduced intragraft T cell infiltration, and eventually improved renal graft survival. CONCLUSIONS: In summary, ATXi had protective effects on indices of chronic allograft injury and could be of therapeutic add-on value in the kidney transplant setting. Notably, an ATX inhibitor is currently being investigated in 2 large phase 3 studies in idiopathic pulmonary fibrosis, underscoring the clinical relevance of our findings.