Up Front MattersThrough a Glass Darkly Seeking Clarity in Preventing Late Kidney Transplant FailureStegall, Mark D.*; Gaston, Robert S.†; Cosio, Fernando G.‡; Matas, Arthur§ Author Information *Division of Transplant Surgery, Departments of Surgery and Immunology, von Liebig Transplant Center, Mayo Clinic, Rochester, Minnesota; †Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; ‡Division of Nephrology and Hypertension, Department of Medicine, von Liebig Transplant Center, Mayo Clinic, Rochester, Minnesota; and §Department of Surgery, University of Minnesota, Minneapolis, Minnesota Correspondence: Dr. Mark D. Stegall, Mayo Clinic, 200 SW First Street, Rochester, MN 55905. E-mail: [email protected] Journal of the American Society of Nephrology 26(1):p 20-29, January 2015. | DOI: 10.1681/ASN.2014040378 Buy Metrics Abstract A common lament is that long-term kidney transplant outcomes remain the same despite improvements in early graft survival. To be fair, progress has been made—in both our understanding of chronic injury and modestly, graft survival. However, we are still a long way from actually solving this important and difficult problem. In this review, we outline recent data supporting the existence of several causes of renal allograft loss, the incidences of which peak at different time points after transplantation. On the basis of this broadened concept of chronic renal allograft injury, we examine the challenges of clinical trial design in long-term studies, including the use of surrogate end points and biomarkers. Finally, we suggest a path forward that, ultimately, may improve long-term renal allograft survival. Copyright © 2015 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.