Renal Allograft Histopathology in Dog Leukocyte Antigen (DLA) Mismatched Dogs Following Renal Transplantation

Abstract

Chronic renal failure (CRF) is the most common disease of the kidney in dogs.1 It can result from congenital abnormalities, toxic and infectious insults, metabolic alterations, and age related pathology. Replacement of damaged nephrons by fibrotic tissue leads to destruction of neighboring interdependent nephrons, ultimately affecting the entire organ. The exact cause of the initial insult may be difficult to define; however, once seventy-five percent of the total mass of nephrons are irreversibly damaged, end-stage renal disease (ESRD) ultimately develops. 1 Once renal pathology is deemed progressive and irreversible, supportive medical care becomes costly and unrewarding. The ideal solution for ESRD is renal transplantation. Feline renal transplantation has become a feasible therapeutic option; however, canine renal transplantation has had only limited clinical success. Improvements in immunosuppressive drugs have helped canine renal transplantation become a short-term clinical option, but the side effects associated with long-term immunosuppression are significant. The development of life-threatening opportunistic infections, an increased risk of developing tumors, the high cost of immunosuppressive drugs, drug-related toxicities, and eventual chronic rejection of the kidney have all limited routine application of renal transplantation in the dog. An additional challenge of renal transplantation is accurate post-transplantation monitoring of potential renal allograft pathology. Hematological analysis of blood urea nitrogen (BUN) and creatinine (Cr) may underestimate the extent of renal allograft disease.2 Protocol biopsies, which are taken according to a preplanned time schedule, are an acceptable approach for diagnosing subclinical rejections in human patients.2-5 In humans, identification and prompt treatment of subclinical rejection results in increased renal allograft survival compared to patients who are treated solely on clinical evidence of rejection.4 Recently, it has been shown that a novel nonmyeloablative bone marrow transplantation protocol which induces stable mixed hematopoietic chimerism in DLA-matched dogs can be used to induce donor specific tolerance to skin and renal allografts. 6;7 The current study uses the same immunosuppressive induction protocol which includes 200cGy total body irradiation (TBI), +/- bone marrow transplantation (BMT), and short-term immunosuppression with cyclosporine (CSA), mycophenolate mofetil (MMF) and intermittent prednisone. The purpose of this study was to evaluate the progression of allograft histopathology in relation to renal biochemical parameters (BUN and Cr), and clinical status of DLA-mismatched dogs undergoing renal transplantation.