Treatment of Biopsy-Proven Acute Antibody-Mediated Rejection Using Thymoglobulin (ATG) Monotherapy and a Combination of Rituximab, Intravenous Immunoglobulin, and Plasmapheresis: Lesson Learned from Primary Experience.
BACKGROUND
Three strategies have been previously proposed to treat or prevent antibody-mediated rejection (AMR): (1) inhibition/depletion of antibody producing cells; (2) removal/blockage of antibodies; and, (3) inhibition of antibody-mediated tissue injury. Here we test the efficacy of lymphocyte-depleting agent antithymocyte globulin (ATG) and triple therapy of rituximab, intravenous immunoglobulin (IVIG), and plasmapheresis in treating AMR.


METHODS
Five biopsy-proven AMR patients were enrolled in this acute AMR treatment study. All patients received renal transplants from HLA highly mismatched donation after cardiac death (DCD) donors. Four patients received thymoglobulin (ATG) monotherapy at a dose of 75 mg/day for 5-8 days. One patient received a combination of rituximab (375 mg/m2), IVIG (50 g/day x2 days), and double filtration plasmapheresis (4x). Donor specific HLA antibodies (DSA), serum creatinine, and clinical signs and symptoms were used to determine the efficacy of anti-AMR treatment.


RESULTS
All 5 patients developed AMR within 2 weeks after transplant. Two patients had class I DSA and 2 patients had class II DSA. One patient had both class I & II DSA. DSA in four patients (#1, 2, 4, 5) were pre-existing and the levels of these DSA surged significantly within a week following transplant. The only patient (#3) without pre-existing DSA developed de novo DSA within 2 weeks post-transplant that rose rapidly regardless of anti-rejection treatment. All patients had positive C4d staining in peritubular capillaries. The proportion of B cells in all patients increased significantly above baseline level when patients experienced AMR. Even though both ATG and rituximab therapies successfully reduced the B cell proportion one week post anti-AMR treatment, their effects on DSA were not ideal. Patient #1 with mild AMR responded well to ATG monotherapy and DSA level steadily decreased from 2 weeks post-ATG treatment and became negative in the last follow-up test. The DSA levels in patient #2 with moderate AMR (ATG), #4 with mild AMR (ATG), and #5 with severe AMR (rituximab+IVIG+plasmapheresis) were reduced post treatment but remained at a level of 4,000-7,000 mean fluorescence intensity. Patients #2 and #4 had impaired renal graft function and severe AMR case #5 lost graft function and was back on dialysis from post-transplant day 12. Patient #3 with mild AMR (ATG) suffered from severe pneumonia 4 days after ATG treatment, which rapidly resulted in heart failure and the patient died on post-transplant day 36.


CONCLUSIONS
All 5 AMR cases occurred in patients who received renal transplants from HLA highly mismatched DCD donors. Both ATG and rituximab had a significant depleting effect on B cells, but their effects on DSA were not ideal. Mild or moderate acute AMR was ameliorated but not cured by ATG monotherapy. For AMR patient with severe biopsy-proven graft injuries, B cell- and antibody-targeted therapies were not successful since they do not have immediate inhibitory or blocking effects on antibody-caused tissue injury. Therefore, anti-inflammatory, anti-coagulation and complement blockage agents should also be considered as part of an AMR treatment regimen in addition to strategies to remove or block DSA and to inhibit antibody production.
Jin
J
Zheng
Wujun
W
Xue
Xin
X
Qing
Xin
X
Jing
Jun
J
Hou
Xiaohui
X
Tian
Qi
Q
Guo
Xiaoli
X
He
Junchao
J
Cai
D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D058846:Antibodies, Monoclonal, Murine-Derived / Q000627:therapeutic use*; D000961:Antilymphocyte Serum / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D001706:Biopsy; D003404:Creatinine / Q000097:blood; D004359:Drug Therapy, Combination; D005260:Female; D006084:Graft Rejection / Q000097:blood / Q000175:diagnosis / Q000276:immunology / Q000628:therapy*; D006085:Graft Survival / Q000187:drug effects; D006680:HLA Antigens / Q000276:immunology*; D006648:Histocompatibility; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000627:therapeutic use*; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007518:Isoantibodies / Q000097:blood*; D016030:Kidney Transplantation / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D015166:Monitoring, Immunologic; D010956:Plasmapheresis; D011237:Predictive Value of Tests; D000069283:Rituximab; D013997:Time Factors; D016896:Treatment Outcome
D058846:Antibodies, Monoclonal, Murine-Derived; D000961:Antilymphocyte Serum; D015415:Biomarkers; D006680:HLA Antigens; D016756:Immunoglobulins, Intravenous; D007166:Immunosuppressive Agents; D007518:Isoantibodies; D000069283:Rituximab; D003404:Creatinine; C512542:thymoglobulin