Fibrinoid necrosis Fibrinoid necrosis in a Rhesus in a Rhesus

macaquemacaque

Karen Strait, Dan Anderson, and Karen Strait, Dan Anderson, and Elizabeth StrobertElizabeth Strobert

Yerkes National Primate Research Yerkes National Primate Research CenterCenter

Emory UniversityEmory University

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HistoryHistory

Signalment: ~5 year old, male, rhesus Signalment: ~5 year old, male, rhesus macaquemacaque

Assigned to renal transplant study Assigned to renal transplant study Left nephrectomy followed by right Left nephrectomy followed by right

nephrectomy and allogeneic renal nephrectomy and allogeneic renal transplant 5 months latertransplant 5 months later

Received sirolimus and Cremophor EL Received sirolimus and Cremophor EL vehicle beginning the day of vehicle beginning the day of transplantationtransplantation

ControlControlPresented at SEVPAC 2008 –

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HistoryHistory

Clinical findings following renal transplantClinical findings following renal transplant Right kidney prominent and firmRight kidney prominent and firm Scrotal edema/perineal edema, absent by post-op Scrotal edema/perineal edema, absent by post-op

day 14day 14 Intermittent diarrheal episodes, treated with Intermittent diarrheal episodes, treated with

appropriate antibioticsappropriate antibiotics Occasional periorbital edemaOccasional periorbital edema Thrombocytopenia at day 38 post-opThrombocytopenia at day 38 post-op Poor appetite/weight loss at 40 days post-opPoor appetite/weight loss at 40 days post-op

Animal euthanized due to a deteriorating Animal euthanized due to a deteriorating clinical conditionclinical condition

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Gross FindingsGross Findings

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Gross findingsGross findings

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HistopathologyHistopathology

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HistopathologyHistopathology

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HistopathologyHistopathology

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HistopathologyHistopathology

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HistopathologyHistopathology

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HistopathologyHistopathology

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DiagnosisDiagnosis

Morphologic diagnosisMorphologic diagnosis: multifocal : multifocal severe fibrinoid necrosis of severe fibrinoid necrosis of submucosal arteries with edema and submucosal arteries with edema and thickening of associated tissues thickening of associated tissues

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DiscussionDiscussion

Cause is undeterminedCause is undetermined Possible association with drug Possible association with drug

regimen in this animal modelregimen in this animal model

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DiscussionDiscussion SirolimusSirolimus

Immunosuppressive/ anti-rejection drugImmunosuppressive/ anti-rejection drug Non-nephrotoxicNon-nephrotoxic Fibrinoid necrosis in GI previously reported Fibrinoid necrosis in GI previously reported

in rhesus macaques receiving sirolimus, in rhesus macaques receiving sirolimus, tacrolimus, and daclizumab to prevent renal tacrolimus, and daclizumab to prevent renal allograft rejection – attributed to sirolimus allograft rejection – attributed to sirolimus toxicitytoxicity

Link between sirolimus and fibrinoid necrosis Link between sirolimus and fibrinoid necrosis shown in some species, absent in othersshown in some species, absent in others

Not seen in other transplant studies at Not seen in other transplant studies at YerkesYerkes

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DiscussionDiscussion

Cremophor ELCremophor EL Vehicle for hydrophobic drugsVehicle for hydrophobic drugs Not inertNot inert May change pharmacological profile of May change pharmacological profile of

drugs administered with itdrugs administered with it Unknown interaction between Unknown interaction between

Cremophor EL and sirolimus Cremophor EL and sirolimus Fibrinoid necrosis not reported with this Fibrinoid necrosis not reported with this

drugdrug Combination of animal model, Combination of animal model,

sirolimus and Cremophor EL??sirolimus and Cremophor EL??Presented at SEVPAC 2008 – Permission granted for use on SEVPAC

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AcknowledgementsAcknowledgements

Eileen BredingEileen Breding Evan DessasauEvan Dessasau

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ReferencesReferences

1. Gelderblom, H., J. Verweij, K. Nooter, A. 1. Gelderblom, H., J. Verweij, K. Nooter, A. Sparreboom. 2001. Cremophor EL: the Sparreboom. 2001. Cremophor EL: the drawbacks and advantages of vehicle drawbacks and advantages of vehicle selection for drug formulation. selection for drug formulation. Eur J CancerEur J Cancer. . 37(13):1590-8.37(13):1590-8.

2. Montgomery, S.P., S.R. Mog, H. Xu, D.K. 2. Montgomery, S.P., S.R. Mog, H. Xu, D.K. Tadaki, B. Hirshberg, J.D. Berning, J. Leconte, Tadaki, B. Hirshberg, J.D. Berning, J. Leconte, D.M. Harlan, D. Hale, A.D. Kirk. 2002. D.M. Harlan, D. Hale, A.D. Kirk. 2002. Efficacy and toxicity of a protocol using Efficacy and toxicity of a protocol using sirolimus, tacrolimus, and daclizumab in a sirolimus, tacrolimus, and daclizumab in a nonhuman primate renal allotransplant model. nonhuman primate renal allotransplant model. Am J TransplantAm J Transplant. 2(4):381-5.. 2(4):381-5.Presented at SEVPAC 2008 –

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Questions?Questions?

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