A report of intravenous immune globulin therapy to decrease angiotensin II type 1 receptor antibodies after pediatric liver transplantation
Amanda Motomochi1,2, Lyndsey Grover1,2, Dev M. Desai1,3.
1Children’s Medical Center, Dallas, TX, United States; 2Anesthesiology & Pain Management, UT Southwestern Medical Center, Dallas, TX, United States; 3Division of Surgical Transplantation, UT Southwestern Medical Center, Dallas, TX, United States
Introduction: Angiotensin II type 1 receptor (AT1R) antibodies are non-HLA IgG antibodies. They have been associated with direct graft injury as well as antibody mediated rejection after solid organ transplantation, including after liver transplantation in the adult1,2 and pediatric3 populations. Studies show that AT1R antibodies may cause severe hypertension, vascular inflammation, and endothelial cell damage leading to allograft injury, vascular thrombosis, and graft failure.4
We present a case of intravenous immune globulin (IVIG) use to decrease AT1R levels after pediatric liver transplantation in attempt to reduce the risk of antibody mediated rejection.
Case Report: A 3-year-old male underwent orthotopic liver transplantation due to a history of citrullinemia type I. His postoperative course was complicated by hepatic artery thrombosis requiring thromboembolectomy on postoperative day (POD) 3. The patient required vasoactive infusions for hemodynamic support postoperatively, but by POD 6, a nicardipine infusion was started due to hypertension. This was eventually transitioned to amlodipine for long term management.
The immediate preoperative AT1R level was elevated at >40 U/mL, but declined to 11 U/mL by POD 4. AT1R levels were obtained retrospectively due to the patient’s clinical course. When found to be elevated, an angiotensin II receptor blocker (losartan) was started to reduce the risk of endothelial damage. By POD 17, the AT1R level was again elevated to >40 U/mL and remained high one week later. Due to this elevation, mycophenolate mofetil was added to the immunosuppression regimen of tacrolimus and prednisolone. It was also decided to administer IVIG (Gamunex-C) 1000 mg/kg once daily for two days. The AT1R level one month following administration of IVIG was reduced to a normal level of 6 U/mL.
Liver enzymes steadily declined and normalized by POD 14. Liver biopsies on POD 3 and 6 were indicative of reactive changes consistent with reperfusion injury (likely in the setting of hepatic artery thrombosis and AT1R mediated graft injury), but did not show signs of acute cellular rejection. The patient was discharged in good condition with plans to repeat the AT1R level at a future outpatient appointment.
Conclusion: IVIG therapy has been used to treat many autoimmune and inflammatory disorders such as immune thrombocytopenia, Kawasaki’s disease, and Guillan-Barre syndrome. It has also successfully been used (in conjunction with plasmapheresis) to treat acute antibody mediated rejection in AT1R antibody positive kidney transplant recipients.5,6
Here we present a case of IVIG use to minimize the risk of antibody mediated rejection. AT1R levels were successfully reduced with no evidence of rejection or graft dysfunction at hospital discharge. Further research will need to be done in order to determine long term outcomes after prophylactic IVIG therapy in the setting of elevated AT1R antibodies, as well as any need for repeat administration.
[1] OʼLeary, J. G., Demetris, A. J., Philippe, A., Freeman, R., Cai, J., Heidecke, H., Smith, C., Hart, B., Jennings, L. W., Catar, R., Everly, M., Klintmalm, G. B. & Dragun, D.. 2017. Non-HLA Antibodies Impact on C4d Staining, Stellate Cell Activation and Fibrosis in Liver Allografts. Transplantation 101: 2399-2409. doi: 10.1097/tp.0000000000001853.
[2] Wozniak, Laura J., Hickey, Michelle J., Chan, Alvin P., Venick, Robert S., Farmer, Douglas G., Busuttil, Ronald W., Reed, Elaine F. & McDiarmid, Sue V.. 2020. Angiotensin II Type-1 Receptor Antibodies Are Associated With Active Allograft Dysfunction Following Pediatric Liver Transplantation. Transplantation 104: 2547-2556. doi: 10.1097/tp.0000000000003206.
[3] Xu, Qingyong, McAlister, Vivian C., Leckie, Steve, House, Andrew A., Skaro, Anton & Marotta, Paul. 2020. Angiotensin II type I receptor agonistic autoantibodies are associated with poor allograft survival in liver retransplantation. American Journal of Transplantation 20: 282-288. doi: https://doi.org/10.1111/ajt.15571.
[4] Pearl, Meghan H. & Reed, Elaine F.. 2019. Angiotensin II type I receptor antibodies in pediatric solid organ transplant. Human Immunology 80: 568-572. doi: https://doi.org/10.1016/j.humimm.2019.03.016.
[5] Kranz, B., Kelsch, R., Kuwertz-Bröking, E., Bröcker, V., Wolters, H. H. & Konrad, M.. 2011. Acute antibody-mediated rejection in paediatric renal transplant recipients. Pediatr Nephrol 26: 1149-56. doi: 10.1007/s00467-011-1864-3.
[6] Dragun, D., Müller, D. N., Bräsen, J. H., Fritsche, L., Nieminen-Kelhä, M., Dechend, R., Kintscher, U., Rudolph, B., Hoebeke, J., Eckert, D., Mazak, I., Plehm, R., Schönemann, C., Unger, T., Budde, K., Neumayer, H. H., Luft, F. C. & Wallukat, G.. 2005. Angiotensin II type 1-receptor activating antibodies in renal-allograft rejection. N Engl J Med 352: 558-69. doi: 10.1056/NEJMoa035717.
