Fibrinoid necrosis in a Rhesus macaque

1. Fibrinoid necrosis in a Rhesus macaque Karen Strait, Dan Anderson, and Elizabeth Strobert Yerkes National Primate Research Center Emory University Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

2. History • Signalment: ~5 year old, male, rhesus macaque • Assigned to renal transplant study • Left nephrectomy followed by right nephrectomy and allogeneic renal transplant 5 months later • Received sirolimus and Cremophor EL vehicle beginning the day of transplantation • Control Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

3. History • Clinical findings following renal transplant • Right kidney prominent and firm • Scrotal edema/perineal edema, absent by post-op day 14 • Intermittent diarrheal episodes, treated with appropriate antibiotics • Occasional periorbital edema • Thrombocytopenia at day 38 post-op • Poor appetite/weight loss at 40 days post-op • Animal euthanized due to a deteriorating clinical condition Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

4. Gross Findings Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

5. Gross findings Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

6. Histopathology Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

7. Histopathology Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

8. Histopathology Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

9. Histopathology Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

10. Histopathology Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

11. Histopathology Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

12. Diagnosis • Morphologic diagnosis: multifocal severe fibrinoid necrosis of submucosal arteries with edema and thickening of associated tissues Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

13. Discussion • Cause is undetermined • Possible association with drug regimen in this animal model Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

14. Discussion • Sirolimus • Immunosuppressive/ anti-rejection drug • Non-nephrotoxic • Fibrinoid necrosis in GI previously reported in rhesus macaques receiving sirolimus, tacrolimus, and daclizumab to prevent renal allograft rejection – attributed to sirolimus toxicity • Link between sirolimus and fibrinoid necrosis shown in some species, absent in others • Not seen in other transplant studies at Yerkes Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

15. Discussion • Cremophor EL • Vehicle for hydrophobic drugs • Not inert • May change pharmacological profile of drugs administered with it • Unknown interaction between Cremophor EL and sirolimus • Fibrinoid necrosis not reported with this drug • Combination of animal model, sirolimus and Cremophor EL?? Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

16. Acknowledgements • Eileen Breding • Evan Dessasau Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

17. References 1. Gelderblom, H., J. Verweij, K. Nooter, A. Sparreboom. 2001. Cremophor EL: the drawbacks and advantages of vehicle selection for drug formulation. Eur J Cancer. 37(13):1590-8. 2. Montgomery, S.P., S.R. Mog, H. Xu, D.K. Tadaki, B. Hirshberg, J.D. Berning, J. Leconte, D.M. Harlan, D. Hale, A.D. Kirk. 2002. Efficacy and toxicity of a protocol using sirolimus, tacrolimus, and daclizumab in a nonhuman primate renal allotransplant model. Am J Transplant. 2(4):381-5. Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

18. Questions? Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only