Microemulsified cyclosporine-based immunosuppression for the prevention of acute renal allograft rejection in unrelated dogs: preliminary experimental study.
OBJECTIVE
To determine whether the microemulsified formulation of cyclosporine (MCsA; Neoral; Novartis A.G.), combined with azathioprine (Imuran; Glaxo Wellcome), and prednisolone (Delta-Cortef; Upjohn), would be effective in preventing acute renal allograft rejection in unrelated mongrel dogs. To document any toxic effects associated with this drug combination.


METHODS
rospective, pilot study.


METHODS
Four healthy, adult, mongrel, canine renal allograft recipients.


METHODS
Heterotopic renal transplantation, with bilateral nephrectomy, was performed in 4 dogs. Allografts were harvested from 2 unrelated dogs that were to be euthanatized for reasons unrelated to this study. The dogs were treated for 100 days or until signs of illness or allograft rejection required euthanasia. Microemulsified cyclosporine (20 mg/kg/day), azathioprine (5 mg/kg every other day), and prednisolone (1 mg/kg/day) were administered for the prevention of acute rejection. Body weight, serum biochemistry profiles, complete blood counts, and trough whole-blood cyclosporine concentrations were measured throughout the study. Cyclosporine dose was adjusted to maintain a trough concentration of 400-500 ng/mL. Azathioprine dose was decreased if evidence of hepatotoxicity developed or if the total blood white cell count was <4,000 cells/micro L. The prednisolone was tapered by 0.25 mg/kg increments every 3 weeks and discontinued 14 days before the end of the study in the surviving dogs. Complications were recorded. A complete necropsy and histopathologic examination were performed in each recipient.


RESULTS
Two of the 4 dogs survived the 100-day period. One dog was euthanatized at 8 days because of an intestinal intussusception. One dog was euthanatized at 64 days because of a severe upper respiratory infection. At the time of death, these 2 dogs had plasma creatinine concentrations of 1.5 and 2.6 mg/dL, respectively, with no histopathologic evidence of allograft rejection. All dogs had transient weight loss (range, 4.6%-17.7% of preoperative body weight) between days 7 and 14. Two dogs had evidence of hepatotoxicity. The 2 dogs surviving to 100 days had normal serum creatinine concentrations and no clinical signs of rejection. One of these dogs had evidence of a grade IIa acute/active rejection based on the modified BANFF 97 histopathologic classification. The second dog had no evidence of rejection or inflammation within the allograft.


CONCLUSIONS
This preliminary experimental study shows that immunosuppression using MCsA, combined with azathioprine and prednisolone, may be effective in preventing acute renal allograft rejection in unrelated mongrel dogs for 100 days. Complications included ileocolic intussusception, upper respiratory infection, weight loss, and transient hepatotoxicity.


CONCLUSIONS
Immunosuppression using MCsA, azathioprine, and prednisolone may be effective in preventing acute renal allograft rejection in unrelated, mongrel dogs. This triple drug protocol is cost-effective and was easy to administer. Further investigation is warranted to minimize toxic effects and to determine the efficacy of prophylactic renal biopsies to detect and treat subclinical acute/active rejection.
Bernsteen
Lynda
L
Comparative Transplantation Laboratory, Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616, USA.
Gregory
Clare R
CR
Kyles
Andrew E
AE
Griffey
Stephen M
SM
Patz
John
J
D000284:Administration, Oral; D000818:Animals; D001379:Azathioprine / Q000008:administration & dosage / Q000627:therapeutic use; D003404:Creatinine / Q000097:blood; D016572:Cyclosporine / Q000008:administration & dosage / Q000627:therapeutic use*; D004285:Dogs / Q000601:surgery*; D004359:Drug Therapy, Combination; D004655:Emulsions; D005260:Female; D006084:Graft Rejection / Q000517:prevention & control / Q000662:veterinary*; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D016030:Kidney Transplantation / Q000662:veterinary*; D009392:Nephrectomy / Q000662:veterinary; D010865:Pilot Projects; D011239:Prednisolone / Q000008:administration & dosage / Q000627:therapeutic use; D011446:Prospective Studies; D012016:Reference Values; D016896:Treatment Outcome
D004655:Emulsions; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D011239:Prednisolone; D003404:Creatinine; D001379:Azathioprine