Benefits, efficacy, cost-effectiveness and infectious complications in transplant patients desensitized with intravenous immunoglobulin and anti-CD20 therapy

Renal transplantation is the treatment of choice for end-stage renal disease (ESRD), as it offers improved quality of life and survival 1–3. Currently, there are more than 100 000 ESRD patients on the deceased donor (DD) waiting list and almost 30 000 new patients register annually, yet only 16 895 kidney transplants were performed in 2013 [Organ Procurement and Transplantation Network (OPTN) data as of August 2014] 3. Unfortunately, the growing number of patients waiting for kidney transplants exceeds our ability to provide this life-saving treatment. This is particularly true for patients who are difficult to match due to human leukocyte antigen (HLA)-specific alloantibodies (resulting from previous pregnancies, blood or blood transfusions and transplantations). The recognition of the importance of alloantibodies and B cells as mediators of acute and chronic allograft injury is not new, but the magnitude of the problem is now well recognized 4. B cells and alloantibodies were felt to be important (but less important than T cells) as mediators of allograft injury. The deleterious effects of antibodies to HLA antigens that result from exposure to human tissues or blood are well known and prohibitive to transplantation. Patients who receive transplants across these incompatibilities show hyperacute rejection with rapid loss of graft function 4. Therefore, the presence of donor-specific anti-HLA antibodies (DSA) is considered a contraindication to transplantation 4,5. Sensitization to HLA antigens is long-lived and associated with memory B cells and plasma cells. Without modification, the opportunities for transplantation are minimal 6. Because of this, desensitization protocols have emerged using therapies directed at antibodies and B cells 6–13. These therapies have dramatically increased the rates of transplantation for this immunologically disadvantaged population.

Of additional importance is the recognition of distinct and separate pathways that facilitate antibody-mediated rejection (AMR), which is a devastating consequence of DSA production after transplantation, with a more chronic form, transplant glomerulopathy, now recognized as a probable consequence of long-term exposure to DSA 14–17. Thus, alloantibody and allospecific B cells have emerged as major pathogenic factors for prevention of successful transplantation and a major cause for the decreased half-life of kidney transplants 18,19. B cells probably contribute to the pathogenesis of T cell-mediated rejection (CMR) and AMR through multiple pathways. B cells play a key role in presenting antigen to CD4⁺ T cells in collaboration with dendritic cells and other antigen-presenting cells (APC) 20–23. B cells express a number of co-stimulatory molecules (B7, CD40) that aid in co-stimulation of activated T cells and in their progression to full effector and cytotoxic functions. This is, of course, in addition to the role of B cells and plasma cells in producing DSA that has the capacity to activate complement and induce antibody-dependent cellular cytotoxicity (ADCC). B cells also produce a number of cytokines that are proinflammatory and promote cell injury directly or through activation of cytotoxic effector cells. B effector cells produce proinflammatory cytokines such as lymphotoxin-α, interferon (IFN)-γ and interleukin (IL)-6 21–23. IL-6 was identified as a critical B cell cytokine responsible for relapse of multiple sclerosis 24. In this study, patients treated with B cell depletion with rituximab showed elimination of IL-6-producing B cells and developed remission from disease. IFN-γ-producing B cells have been identified in active systemic lupus erythematosus (SLE) and are felt responsible for increased T helper type 1 (Th1) cytokine production with concomitant reductions in regulatory T cells (T_regs). In addition, B regulatory subsets also exist, and have the capacity to modify inflammation and autoimmunity in animal models 20.

In an effort to optimize the availability of compatible donors, several transplant centers have developed desensitization protocols aimed at modification of alloantibodies and B cells to reduce HLA sensitization and AMR. There are two widely accepted desensitization protocols: low-dose intravenous immunoglobulin with plasma exchange (IVIg/PLEX) and high-dose IVIg (HD-IVIg). IVIg/PLEX has been used successfully in ABO-incompatible and in positive cross-match (+CMX) renal transplantation 8,9, while HD-IVIg has been used to desensitize both living-donor +CMX and highly sensitized (HS) DD recipients on the waiting list 6,7,10–13. HD-IVIg (2 g/kg) in multiple-dosing regimens is considered a reasonable approach for desensitization 25. The B cell-depleting agent, rituximab, is used frequently in combination with HD-IVIg and IVIg/PLEX protocols 8–12. Experience with the IVIg/rituximab protocol has shown that rituximab has a critical role in modifying alloreactive B cells and prevention of DSA rebound 26,27. Here, we will discuss data regarding the safety, efficacy and economic aspects of current desensitization protocols.

Desensitization with IVIg and IVIg + rituximab

Desensitization protocols emerged in the late 1990s to deal with the increasing numbers of HS patients who waited years, often in futility, for an opportunity to receive a kidney transplant 6–13. An important concern is the absence of Food and Drug Administration (FDA)-approved drugs for desensitization or treatment of AMR 28. Outcomes of desensitization have, overall, been good 6–11,25, but reports of desensitization failures are noted 29,30. The evolution of desensitization has been inconsistent, related primarily to the complexity of creating a nexus of antibody-reduction therapy, organ donor availability and acceptable cross-match with timing of transplantation to avoid AMR. We recently reported on the efficacy, side effects and outcomes of desensitization with IVIg + rituximab 6. We compared outcomes to a similar group of age-matched and ESRD cause-matched patients with calculated panel-reactive antibody (CPRA) > 80% who remained on dialysis during the study period. This is important, as dialysis is the only option for broadly sensitized patients. The mean waiting time on dialysis for our sensitized patients was 114 ± 56 months before desensitization and to transplant 4·4 ± 4·9 months after desensitization. We were able to transplant 146 of 207 patients treated. Most patients still remained cross-match- and DSA-positive at the time of transplantation. We obtained outcomes similar to those seen with non-sensitized patients at 3 years 31. Another study 9 has demonstrated a significant reduction in risk of mortality for HS patients who underwent desensitization using IVIg/PLEX and transplantation relative to those who remained on dialysis or received dialysis or HLA-compatible transplant. Our analysis also supports this conclusion. When we analyzed sensitized patients (CPRA > 80%) who underwent transplantation without desensitization, the rates of transplantation for this group were approximately 10% per year with a 7% per year probability of death in the matched cohort of HS United Network for Organ Sharing (UNOS) patients still on dialysis 6.

To date, only one randomized placebo-controlled trial of a desensitization therapy versus dialysis has been conducted (1997–2002) 7. This multicenter investigation demonstrated the efficacy of IVIg as a desensitization agent, leading to improved transplantation rates in highly HLA sensitized patients (35% IVIg versus 17% in placebo; P < 0·05). Overall, the DD transplantation rates were 31 versus 12% (P = 0·0137) 6,7.

Recently we performed a study assessing the cost–benefits of desensitization compared with dialysis. During the same period, the costs associated with transplantation after desensitization (all medications, organ acquisition, treatment of rejection and cost of reverting to dialysis) for patients with failed allografts compared favourably with the costs of remaining on dialysis 6. Crucially, at 3 years, the transplanted patients had a 14·7–17·6% greater probability of survival than those who remained on dialysis. Thus, desensitization offers HS patients a significant improvement in transplant rates with improved outcomes in quality and length of life and reduced cost to the health-care system.

Rituximab in desensitization

Rituximab is a monoclonal antibody aimed at CD20, a member of the membrane-spanning 4-domain A family of proteins. CD20 is expressed highly on naive and memory B cells, but expression is lost on plasma cells 22,23.

The efficacy of rituximab as a desensitization agent has been questioned recently. Most concerns regard the relative ineffectiveness of rituximab alone in decreasing DSA levels in HS patients 29,30. In 2005, we undertook a study to assess the efficacy of IVIg + rituximab as desensitization agents. This trial showed an increased ability to transplant HS patients (PRA > 80%) with excellent patient and graft survival 10. These observations have been sustained during the past decade since the studies were initiated 6,11. Fig. 1 shows long-term graft outcomes in patients desensitized with IVIg alone or IVIg + rituximab. The initial data showed a significant benefit in adding rituximab to IVIg in terms of improved long-term graft survival (P = 0·0042). However, to address the concerns regarding ineffectiveness, we undertook a placebo-controlled trial (IVIg + placebo versus IVIg + rituximab) to determine the efficacy of rituximab in desensitization (NCT01178216, FDA IND# 109067) 32.

Figure 1.

Kaplan–Meier curve for long-term graft survival in patients desensitized with intravenous immunoglobulin (IVIg) alone versus IVIg + rituximab.

Briefly, we found that the risk for AMR was significantly greater in the IVIg + placebo group due to rebound DSA responses that occurred after transplantation. No patients in the IVIg + rituximab group experienced AMR and protocol biopsies at 1 year post-transplant showed no evidence of transplant glomerulopathy. Thus, from this study, we concluded that rituximab was an important adjunct for desensitization due to its ability to prevent memory B cell activation and DSA rebound 32.

Alloreactive B cells can emerge rapidly in DSA-negative patients post-transplant 26,27,33. Detecting these cells is an especially difficult problem, as DSA are not always present and assays for alloreactive B cells are emerging. However, rituximab can deplete these memory B cells with consistent prevention of AMR episodes. Rituximab can also alter T cell responses by reducing the APC and cytokine production capabilities of B cells 24,34. This is likely to be more important than the effect on antibody reduction during desensitization.

Disclosures

The authors have received grant support from Genentech-Roche Inc. and CSL Behring Inc.