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| A case of the alternative immunosuppression to control the de novo TMA in allograft patient |
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| Department of Pathology, Yeungnam University College of Medicine, Daegu, Korea |
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| Division of Nephrology, Department of Internal Medicine, Bong Seng Hospital, Busan |
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Yong-Hun Sin, Jin Ho Lee, Seong Min Kim, Joong Kyung Kim |
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The incidence of de novo thrombotic microangiopathy (TMA) ) in renal transplantation is reportedly 0.8% to 3.3% [1, 2]. It generally appears within the first weeks after transplantation [1] and may be drug-induced when calcineurin inhibitors (CNIs) or proliferation signal inhibitors (PSIs) are used [2-5]. Typical strategies for treatment include reduction or withdrawal of CNI, switching from CNIs to PSIs, such as sirolimus or evelorimus [5]. Other suggested therapies include plasmapheresis and the use of intravenous immunoglobulin in combination with steroids, rituximab, or eculizumab [3, 6, 7]. Belatacept is an immunosuppressive drug that blocks the CD28 costimulation pathway, inhibiting T-lymphocyte activation [8, 9]. Here, we report a one renal transplant patient with de novo drug-induced TMA who are managed with belatacept as an alternative immunosuppressive agent.
A 49-year-old female, with unknown primary renal disease, who had been on hemodialysis for 1 months, underwent a transplant with her son as the donor. Induction therapy consisted of basiliximab on day 0. Because on POD 2, her serum creatinine increased to 2.7mg/dl (POD 1 serum creatinine was 2.2mg/dl) and urine volume was decreased to 1445ml/day, antithymocyte globulin at 1mg/kg daily was administered for 5 days with rituximab 200mg/body and MMF 1500mg/day and steroids. Maintenance therapy consisted of tacrolimus, MMF, and prednisone; ganciclovir was used for CMV prophylaxis. On POD 9, her platelet count abruptly decreased to 44 x 109/L, with lactate dehydrogenase (LDH) rising from normal to 1523 IU/L. Haptoglobins were undetectable. She was not febrile and did not have confusion or any neurological signs. Under the presumptive diagnosis of post-transplant drug-induced TMA, tacrolimus immediately withdrawn and one time of plasma exchange was done. With Mycophenolate mofetil and prednisolone as an immune suppression, we added an additional dose of 0.5 mg/kg/d of thymoglobulin IV for 7 days. After that, maintenance therapy consisted of alkyloxan 50mg/day, MMF, and prednisone.
On POD 25, her creatinine increased again to 1.8 mg/dl. The graft biopsy (1st) showed recovery phase of tubular damage without significant inflammatory cell infiltration. But microthrombi are in glomeruli and the positivity of CD31 was lost in glomerular capillary partially (fig 1, 2). C4d was positive along the peritubular capillaries. The serum creatinine was decreased to 0.8 mg/dl on POD 29 without any specific treatement. and platelet count normalized by day 19 after withdrawn of tacrolimus (POD 29).
On day POD 48, leukopenia (ANC〈300 x 109/L) and anemia was developed. Alkyloxan treatment was discontinued and dose of MMF was reduced. And we added belatacept with patient’ s consent.
The first dose of belatacept (5mg/kg) was given on POD 59 and repeated at 4 week or 8 week interval after the initial dose. Additionally, the patient continued to receive MPA and prednisone.
On POD 100, the 2nd biopsy showed mild peritubular capillary inflammation (ptc1), glomerulitis (g2) (fig 3). C4d was negative. However, her creatinine level is 0.8mg/dl and her platelet count is 123 x 109/L and she did not develop any serious adverse event for 5 month-follow up period.
Although we cannot generalize our result, we think that belatacept was an effective and safe alternative immunosuppressive agent for the management of renal transplant patients with de novo drug-induced TMA.
REFERENCES
[1] M. Noris and G. Remuzzi, “Thrombotic microangiopathy after kidney transplantation,” American Journal of Transplantation , vol. 10, no. 7, pp. 1517-1523, 2010.
[3] T. Barbour, S. Johnson, S. Cohney, and P. Hughes, “Thrombotic microangiopathy and associated renal disorders,” Nephrology Dialysis Transplantation , vol. 27, no. 7, pp. 2673-2685, 2012.
[2] A. A. Satoskar, R.Pelletier, P.Adams et al., “Denovo thrombotic microangiopathy in renal allograft biopsies: role of antibodymediated rejection,”A merican Journal of Transplantation , vol. 10, no. 8, pp. 1804-1811, 2010.
[4] O. Øyen, E. H. Strøm, K. Midtvedt et al., “Calcineurin inhibitor-free immunosuppression in renal allograft recipients with thrombotic microangiopathy/hemolytic uremic syndrome,”A merican Journal of Transplantation , vol. 6, no. 2, pp. 412-418, 2006.
[5] V. Karthikeyan, R. Parasuraman, V. Shah, E. Vera, and K. K. Venkat, “Outcome of plasma exchange therapy in thrombotic microangiopathy after renal transplantation,” American Journal of Transplantation , vol. 3, no. 10, pp. 1289-1294, 2003.
[6] K. Hadaya, S. Ferrari-Lacraz, D. Fumeaux et al., “Eculizumab in acute recurrence of thrombotic microangiopathy after renal transplantation,” American Journal of Transplantation , vol. 11, no. 11, pp. 2523-2527, 2011.
[7] W. F. Clark, “Thrombotic microangiopathy: current knowledge and outcomes with plasma exchange,” Seminars in Dialysis , vol. 25, no. 2, pp. 214-219, 2012.
[8] J. M. Griny´o, K. Budde, F. Citterio, and B. Charpentier, “Belatacept utilization recommendations: an expert position,” Expert Opinion on Drug Safety , vol. 12, no. 1, pp. 111-122, 2013.
[9] B. Charpentier, “Belatacept: a novel immunosuppressive agent for kidney transplant recipients,” Expert Review of Clinical Immunology , vol. 8, no. 8, pp. 719-728, 2012. |
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