Advances in diagnosing and managing antibody-mediated rejection

Abstract

Antibody-mediated rejection (AMR) is a unique, significant, and often severe form of allograft rejection that is not amenable to treatment with standard immunosuppressive medications. Significant advances have occurred in our ability to predict patients at risk for, and to diagnose, AMR. These advances include the development of newer anti-human leukocyte antigen (HLA)-antibody detection techniques and assays for non-HLA antibodies associated with AMR. The pathophysiology of AMR suggests a prime role for antibodies, B cells and plasma cells, but other effector molecules, especially the complement system, point to potential targets that could modify the AMR process. An emerging and potentially larger problem is the development of chronic AMR (CAMR) resulting from de novo donor-specific anti-HLA antibodies (DSA) that emerge more than 100 days posttransplantation. Therapeutic options include: (1) High-dose intravenously administered immunoglobulin (IVIG), which has many potential benefits. (2) The use of IVIG+rituximab (anti-CD20, anti-B cell). (3) The combination of plasmapheresis (PP)+low-dose IVIG with or without rituximab. Data support the efficacy of all of the above approaches. Newer approaches to treating AMR include using the proteosome inhibitor (bortezomib), which induces apoptosis in plasma cells, and eculizumab (anti-C5, anticomplement monoclonal antibody).

Fig. 1

a Donor-specific antibody (DSA) pattern for a highly human leukocyte antigen (HLA)-sensitized patient who had awaited deceased-donor (DD) transplantation for >10 years. The patient was treated with intravenously administered immunoglobulin (IVIG) + rituximab as per protocol and received a DD transplantation shortly after completing desensitization. DSA levels rapidly decreased from >200,000 standard fluorescent intensity (SFI) units to unmeasurable. At the time of writing this article, the patient was >1 year posttransplant without antibody-mediated rejection (AMR), with a serum creatinine (Cr) 0.8 mg/dl. b DSA pattern from a patient who received a living-donor (LD) kidney transplant approximately 2 years ago. The patient exhibited DSAs to A2, DR53, and DQ6. After desensitization, good responses were seen, which allowed transplantation. Approximately 3 months posttransplant, the patient experienced AMR, with an increase in DSAs. These responded somewhat to IVIG + rituximab treatment. Serum Cr was stable at 1.4 mg/dl for 2 years, and no proteinuria has been observed

Fig. 2

Relationship among donor-specific antibody (DSA), flow cytometry cross match (FCMX) results and risk for antibody-mediated rejection (AMR) in patients desensitized with intravenously administered immunoglobulin (IVIG) + rituximab. We show that reduction, but not elimination, of DSA to levels of ~100,000 standard fluorescent intensity (SFI) correlates with a FCMX of ~200–225 mean channel shifts (MCS). This usually allows transplantation of highly human leukocyte antigen (HLA)-sensitized patients with a low risk of AMR. However, patients who demonstrate DSA 100,000–200,000 SFI and FCMX >250 channel shifts (CS) are more likely to experience AMR. Patients who demonstrate complement-dependent cytotoxicity (CDC+) cross matches have FCMXs >300 MCS and DSA levels >200,000. These patients are at an extremely high risk for AMR if transplanted. The line shows the hypothetical relationship between DSA and FCMX results. A normal FCMX is defined as 50 CS or less and an SFI DSA level of 10,000 or less

Fig. 3

Outcomes of cardiac transplant recipients followed for >2 years. Patients were divided into those who had persistent demonstration of antiendothelial cell antibody (AECA+) posttransplant vs patients who never demonstrated positivity (AECA−) posttransplant. The importance of non-human leukocyte antigen (non-HLA) antibodies directed at endothelial cell targets not present on lymphocytes can cause antibody-mediated rejection (AMR) and graft loss [25]

Fig. 4

Cedars-Sinai Medical Center protocol for treating antibody-mediated rejection (AMR) that is C4d+. After AMR diagnosis by biopsy, patients are treated with pulse Solumedrol (SM) (10 mg/kg) daily × 3 on day 1 and intravenously administered immunoglobulin (IVIG) 2 g/kg (maximum dose 140 g), followed on day 2 by rituximab 375 mg/m² . A repeat IVIG dose is usually given at 30–60 days after AMR diagnosis

Fig. 5

Cedars-Sinai Medical Center protocol for treating more severe antibody-mediated rejection (AMR) associated with glomerular thrombi and graft dysfunction [thrombotic microangiopathy (TMA)]. Here, early plasmapheresis (PP) is essential to remove antibody and other inflammatory mediators before treatment with intravenously administered immunoglobulin (IVIG) and rituximab. In our protocol, we do not use low-dose IVIG after each plasmapheresis but replace it with albumin and fresh-frozen plasma. IVIG 2g/kg (maximum dose 140 g) is given at the completion of plasmapheresis treatment, followed by rituximab 375 mg/m². Renal function and donor-specific antibodies (DSA) are monitored posttreatment

Fig. 6

Outcomes of two patients who developed class II donor-specific antibodies (DSA) 3–4 years posttransplant associated with the onset of proteinuria with minimal changes in allograft function. The biopsy for one patient is shown, but both patients had similar findings of transplant glomerulopathy. Both patients showed a significant reduction in class II DSAs, with stabilization of renal function and some reduction in proteinuria after treatment with intravenously administered immunoglobulin (IVIG) + rituximab