Antibody-mediated rejection (AMR) is the leading cause of kidney allograft failure.1 The Food and Drug Administration (FDA) sponsored a two-day open public workshop on AMR in kidney transplantation in Silver Spring, Maryland, on April 12 and 13, 2017, with the participation of academia, industry, and patient representatives to review the new advances in the field since the 2010 FDA AMR Workshop.2
The main goals of the workshop were to discuss:
- the importance of immunosuppressive medication adherence in the development of de novo donor-specific antibodies (dnDSA) and AMR,
- the impact of new advances including donor/recipient HLA epitope mismatch assessment and routine posttransplant DSA monitoring on patient management,
- the acute-chronic AMR continuum, associations with T cell–mediated rejection (TCMR) and changes in allograft function,
- the unmet medical needs and challenges of clinical trial design.
As a unique aspect of this workshop, patient representatives presented their viewpoint and participated in the public discussions. The following is a summary of the scientific presentations and discussions at the workshop with emphasis on new developments and does not necessarily reflect the FDA's point of view or endorsement of any particular opinion. Please refer to the publicly available transcripts and slides of presentations for a more comprehensive overview.3
DETECTION AND MEASUREMENT OF HLA ANTIBODIES
Complement-dependent cytotoxicity assay has been the gold standard for the pretransplant detection of antidonor HLA antibodies; however, it has limitations such as cell viability issues, suboptimal sensitivity and specificity, and inability to differentiate class I and class II antibodies.4,5 Cell-based flow cytometric and solid phase assays are commercially available only for qualitative use. These assays are currently used both pretransplantation and posttransplantation for measuring antibody levels; notwithstanding, none of these assays are cleared for quantitative use. Mean fluorescence intensity (MFI) values are used to predict crossmatch results, assess response to desensitization and treatment of AMR, and to predict long-term outcomes. Although semiquantitative use of MFI values may be acceptable with some caveats, several limitations to full quantitative use stem from reagents, manufacturing, assay-specific, and serum-specific issues, such as inhibition, oversaturation, and the shared epitope phenomenon.4,6 Correlation between the antibody level and the MFI may be lost above a certain MFI. Antibody titration methods can provide a more accurate measure of antibody strength and better estimate of responsiveness to treatment compared with MFI values or complement binding (C1q) assays.7-9 Interlaboratory standardization of the assays for quantitative use is needed.
ANTIBODIES IN THE PRETRANSPLANT PERIOD
Sensitized Transplant Candidate
The number of highly sensitized kidney transplant candidates (Panel Reactive Antibodies [PRA], 80-100%) on the waitlist is about 14 000 in the United States, and continues to increase. Very highly sensitized candidates (PRA > 98%) have benefited from the new Kidney Allocation System implemented in 2014 by increased transplantation rates, whereas those with relatively lower PRAs (80-98%) were disadvantaged by decreased transplantation rates. As observed in the overall kidney transplant patient population, transplantation after desensitization is the preferred choice compared with remaining on hemodialysis in the highly sensitized candidates, doubling patient survival at 8 years.10 Patients with pretransplant DSA greater than 500 MFI have a higher risk of developing AMR posttransplantation even if the complement-dependent cytotoxicity crossmatch is negative.11
Alloreactive memory can arise not only from previous HLA sensitization but also from previous pathogen exposures.12 The level of sensitization is generally assessed by PRA; however, risk assessment by serum antibody screening alone may be incomplete or misleading, and zero PRA may not always denote a nonsensitized state.13 Antibodies are surrogates for sensitization; yet, donor-reactive memory T cells and memory B cells are also barriers to success.14 New assays are being developed for the quantification of donor-specific memory B cells in the peripheral blood of HLA-immunized individuals.15
Prevention of Sensitization
In first-time transplant recipients, primary sources of sensitization are pregnancies, blood transfusions, and potentially pathogen exposures; however, in repeat transplant recipients, the importance of previous graft exposures exceeds other potential sources of sensitization and DSAs resulting from previous graft exposure are more likely.16 Class II antibodies are also more likely to persist compared with class I. In retransplantation, class II repeat mismatches seem to increase the risk of graft loss, particularly in patients with detectable PRA before the second transplant.17 Therefore, prevention of dnDSA formation is beneficial to the current graft, increases chances of matching subsequent grafts, and positively impacts their survival. Whether the failed graft should be explanted, and whether immunosuppression should be continued after graft loss to prevent sensitization are remaining questions. Whether or not the failed graft is removed, continuing immunosuppression could be beneficial if the patient is a retransplantation candidate.
HLA Epitope-Based Donor/Recipient Mismatch Assessment
HLA antibodies recognize critical, polymorphic, short fragments of the HLA antigen, called epitopes, rather than the complete antigen as one unit.18 These epitopes can be unique to one HLA antigen or shared by several antigens that have different serologic specificities. The annotation “eplet” refers to a patch of amino acids within a 3 Å radius of polymorphic residues on the molecular surface. New scientific advances permit assessment of donor-recipient HLA mismatch at the epitope/eplet level. New published data suggest that such donor-recipient HLA epitope/eplet mismatches serve as potential targets for dnDSA development.19 It is possible to determine the alloreactive eplets with software (HLAMatchmaker), developed by René Duquesnoy, publicly available at http://www.epitopes.net/, which requires high resolution HLA typing of the donor and the recipient. Among potential benefits of epitope/eplet-based mismatch assessment are identification of acceptable mismatches for sensitized patients, increasing their chances of finding a compatible match, minimization of allosensitization risk through better matching and personalized immunosuppression based on the extent of the mismatch between the donor and the recipient. Published data suggest that epitope/eplet mismatch load at the HLA class II loci in kidney transplantation can predict the development of dnDSA posttransplantation.20,21
New Developments in Desensitization Protocols
Currently, there are no FDA-approved treatments for desensitization, and very few randomized controlled trials have been conducted in this area to date. Standard of care (SOC) desensitization treatments are generally based on off-label use of either plasmapheresis ± low-dose IVIg or high-dose IVIg. Newer agents, such as anti-CD20 antibody (rituximab), proteasome inhibitors, and complement inhibitors, are generally used in combination with SOC treatments. These treatment modalities are generally combined in one regimen without a concurrent control arm, making it difficult to assess the contribution of each component to the overall results. Most treatments used for desensitization are also used to treat AMR (Table 1).
Class I antibodies are eliminated at a much higher rate compared with class II antibodies, especially with plasmapheresis-based therapies, which may explain the poor outcome observed in patients with class II antibodies. Mean fluorescence intensity values are commonly used to guide treatment, with the caveat that no reduction in MFI values may be observed until a substantial reduction in antibody titer is achieved in patients with very high antibody titers. Because of this initial discordance between antibody titer and MFI values in patients with very high antibody titers, experts caution against mistakenly concluding that the antibody removal treatment has been ineffective based on serial MFI values alone.
An investigational agent developed for desensitization, called IgG-degrading enzyme of Streptococcus pyogenes (IdeS)34,35 was discussed. IdeS is a cysteine proteinase secreted by the S. pyogenes, and it interferes with the phagocytic killing of streptococci by specifically cleaving the heavy chain of the host IgG. Unlike plasmapheresis, which only removes antibodies from the intravascular space with subsequent equilibration from the extravascular space, IdeS is purported to cleave human IgG in the intravascular and extravascular spaces. Potential concerns include rebound DSA by day 14, limitation of treatment to 2 doses because of anti-IdeS antibody formation, and the theoretical adverse impact from massive proteinuria consisting of IgG fragments on the newly transplanted kidney.22,33
Regarding rituximab, panel members suggested that although rituximab does not seem to be effective in treating AMR26 it may be effective at preventing an anamnestic type of response, when used in combination with high-dose IVIg for desensitization.36
Proximal and distal complement inhibitors may have potential roles as part of the desensitization regimens; however, panel members suggested that a multipronged approach consisting of agents with different mechanisms of action would be more effective than relying on a single agent.
ANTIBODIES IN THE POSTTRANSPLANT PERIOD
Different Phenotypes of AMR (Type 1 and Type 2)
Acute AMR occurs in 2 different phenotypes primarily based on whether it is due to preexisting DSA (type 1) or dnDSA (type 2).37 Type 1 AMR (early AMR) may be caused by class I or class II antibodies (or both) in sensitized patients within the first few months after transplantation and generally has a good response to treatment. Type 2 AMR (late AMR) generally occurs beyond the first year after transplantation, mainly due to class II antibodies, frequently with a TCMR component and commonly with a history of medication nonadherence. Type 2 is more treatment resistant compared with type 1 AMR. One of the main reasons for the higher success rate in the treatment of type 1 AMR could be due to its early occurrence posttransplantation, at a time when occurrence is anticipated and level of immunosuppression is maximal. In contrast, relatively lower success rates in treating type 2 AMR were partially attributed to late and generally unanticipated occurrence posttransplantation, at a time when immunosuppression is more likely to be suboptimal.
Definition of dnDSA
There are considerable differences across centers regarding the cutoff MFI value used to define a positive test with single-antigen bead assays. A high cutoff MFI value may falsely result in labeling of a resurgent DSA posttransplantation as “dnDSA.” Presence of the same (common) antibody epitope on multiple single-antigen beads dilute the individual bead MFI and can result in a low MFI value, falsely interpreted as absence of DSA at the time of transplantation. In such a case, as memory B cells become activated posttransplant, resurgent DSA may mistakenly be interpreted as dnDSA.
Prevalence, Etiology, and Correlates of dnDSA
DnDSA, a major risk factor for type 2 AMR and allograft loss, develops in 15% to 25% of renal transplant recipients within 5 years after transplantation38 with an incidence of 2% per year in adherent patients.39 Some centers report dnDSA up to an incidence of 20% within the first year, depending on their methodology of ruling out preexisting DSA at the time of transplantation. Immunosuppressive medication nonadherence has emerged as the primary cause of dnDSA formation, with a prevalence of 90% among recipients with clinical dnDSA compared with 24% in recipients with subclinical dnDSA and only 5% in recipients without dnDSA and without allograft dysfunction.39 dnDSA may well be a consequence of insufficient immunosuppression, either patient initiated (medication nonadherence) or physician initiated (minimization protocols). However, for lack of tools to tailor immunosuppression to individualized risk assessment, it is possible that dnDSA appears in patients who are not on a minimization protocol, albeit adherent to their prescribed regimen suboptimal for their immunologic risk profile.
DSA is generally the product of T cell–dependent immune responses. At least in calcineurin inhibitor-based regimens early TCMR episodes correlate with subsequent dnDSA and AMR.40 Medication nonadherence, eplet mismatch and young age are among the risk factors for dnDSA formation, mainly for class II.38 Although there are cases with class I antibodies, class II antibodies appear as the dominant dnDSA in the majority of cases. Compared with preexisting DSA, at the molecular level, more TCMR-related transcripts are observed in dnDSA cases, supporting the observation that the preexisting DSA seems to occur predominantly as an antibody phenotype whereas the dnDSA commonly has a mixed phenotype with T-cell transcripts, natural killer (NK) cell, and interferon gamma transcripts.41
In one study, 76% of the patients with dnDSA met the Banff criteria for acute AMR in kidney allograft biopsies at the time of dnDSA detection.39 In another recent study, at the time of dnDSA detection, 20% of the biopsies met Banff criteria for acute TCMR; 25% of the biopsies met criteria for acute, active AMR; and 7.5% of the biopsies showed chronic AMR (with concomitant acute, active AMR). The prevalence of acute, active AMR and chronic AMR increased to 52.9%, and 38.2% respectively, by 1 year after dnDSA detection, whereas the prevalence of acute TCMR was unchanged.42
Time to graft loss from dnDSA onset appears to be accelerated in patients with clinical dnDSA compared with patients with subclinical dnDSA. Subclinical dnDSA was defined as 25% or less rise in serum creatinine and proteinuria less than 500 mg/d within 2 months of dnDSA detection.39 Kidney recipients with subclinical dnDSA experience estimated glomerular filtration rate (eGFR) decline and progress to graft loss with 50% of the grafts lost in 8.3 years, compared with a much faster decline in recipients who initially present with clinical dnDSA among whom 50% of the grafts were lost in 3.3 years.39
Prevention of dnDSA
Multicomponent interventions tailored to individual patient's needs appear to be most effective in minimizing nonadherence, the major cause of dnDSA; whether such interventions affect the long-term outcomes remains unclear. Regarding physician-initiated minimization of immunosuppression, the transplant community has increased awareness of the potential long-term negative consequences of minimization practices, after the increased adoption of routine posttransplant DSA monitoring. Minimization or avoidance of the most immunogenic donor/recipient eplet mismatches may be another potential mitigation strategy to prevent dnDSA. Knowledge of the eplet mismatch load, especially class II, may help guide personalized immunosuppression based on the anticipated risk for each patient.19
Monitoring for dnDSA and Treatment Considerations
There are differences of opinion regarding the clinical utility of routine posttransplant DSA monitoring and management of patients with dnDSA, especially in the absence of graft dysfunction, although most centers would perform a biopsy on discovering dnDSA. Routine posttransplant DSA monitoring is not yet widely adopted. The natural course of dnDSA and its correlation with graft function and histopathology have not been fully elucidated in large clinical studies. In one study, the rate of eGFR decline in recipients with dnDSA was significantly increased even before the detection of dnDSA, compared to recipients who did not later develop dnDSA, and further accelerated after the appearance of dnDSA.39 If there is no concomitant rejection on biopsy at the onset of dnDSA, it appears that most centers would increase the level of immunosuppression, only if it were below the institution-specific target levels, although some centers appear to increase it above prior target levels.
Diagnosis of AMR
Diagnosis of type 1 AMR is relatively easy because of its early occurrence after transplantation and anticipation based on the preexisting DSA; however, it is unlikely that a type 2 AMR will be recognized at its onset, in the absence of allograft dysfunction, without routine (or risk-based) DSA monitoring or protocol biopsies.
Regarding the Banff classification of AMR, it was suggested that a third category “smoldering AMR” should be added in addition to the current binary classification of acute/active and chronic active categories. This new category would be representative of the cases without transplant glomerulopathy (TG) but would not fall into the category of “acute AMR.” Per this concept, true acute cases are usually a memory response and rebound of preexisting DSA occurring very early on posttransplant, generally observed in highly sensitized patients (type 1 AMR). Smoldering cases are the ones that have not reached the stage of chronic active, but may have more in common with chronic active than acute AMR. The chronic AMR category would include cases with TG that are truly chronic. Molecular diagnostics, including endothelial cell activation and NK cell transcripts could be helpful in classifying AMR cases as “active”. (Authors’ note: As noted in the ‘The Banff 2017 Kidney Meeting Report’ 43 which was published after the FDA AMR Workshop, the word “acute” in the term “acute/active ABMR” in the classification of AMR is removed. Therefore, the revised Banff 2017 classification of AMR defines 2 categories of AMR (active and chronic). However, as previously noted in the 2013 44 and the 2015 45 Banff Meeting Reports the concept that active AMR may be clinically acute, smoldering, or subclinical is still valid and maintained).
Microvascular Inflammation Without DSA
The presence of microvascular inflammation in the biopsy, suggestive of AMR but without DSA in serum, is a challenge to patient management. This is a condition where molecular diagnostics could be helpful. Treatment of such lesions could be recommended if the molecular score were higher than a prespecified cutoff value.46 An alternative explanation for such cases is the possible occurrence of non-HLA antibody-induced microvascular inflammation.
Role of Complement in AMR
Tissue damage caused by DSA is not limited to complement-mediated mechanisms. Demonstration of C4d deposition is no longer an absolute requirement for the diagnosis of AMR. Complement inhibition alone may not be sufficient to prevent or treat DSA-induced damage, especially in the continued presence of DSA. C1q binding is a reflection of MFI levels; higher MFI values are associated with C1q positivity, low values with being C1q negative. In most circumstances, the C1q-positive samples become C1q-negative upon dilution, which must be considered when interpreting C1q assay results.47
New Advances in the Treatment of AMR
Currently, there are no FDA-approved treatments for acute or chronic AMR. Similar to desensitization protocols, plasmapheresis or high-dose IVIg constitute SOC with different add-on treatments per center preference (Table 1).48 Newer investigational treatments can be grouped into 4 categories: distal and proximal complement inhibitors, plasma cell targeting agents, and agents directly acting on immunoglobulins. Complement inhibitors have recently been the center of attention; however, panel members emphasized that not all antibody-mediated injury occurs through complement activation and Fc receptor-mediated injury also plays an important role in AMR. Plasma cell targeting therapies consist mainly of proteasome inhibitors, which appear to have class-specific limitations such as development of resistance, and humoral compensation induced by plasma cell depletion.49 IdeS, currently investigated for desensitization, is an example of an agent that may act directly on immunoglobulins.
ANIMAL MODELS OF AMR
Rodent and nonhuman primate transplant models of acute AMR have been developed utilizing recipient sensitization with donor cells, such as splenocytes, or tissues, such as skin grafts. Nonhuman primate transplant models are particularly helpful because of the genetic similarity with humans and the development of TG50; however, these models are expensive and much more resource intensive compared to rodent models. In the nonclinical models, similar to the clinic, AMR can be targeted in 3 different phases; prevention of antibody production, stopping or reducing antibody production, or limiting antibody-mediated damage. The importance of crosstalk between B cells and T cells is increasingly recognized in the activation of the B cell and development of the antibody response in transplantation.51 In rodent and primate models of AMR, costimulation blockade has emerged with potential to inhibit the allospecific germinal center B-cell response and prevent or reverse alloantibody production, especially if used in combination with other treatments, such as proteasome inhibition and anti-CD40.29,52 Such models could allow in-depth mechanistic studies and provide stronger rationales for testing novel agents for AMR in kidney transplantation.
UNMET MEDICAL NEEDS AND CLINICAL TRIAL DESIGN
Desensitization of the highly sensitized transplant candidates, prevention of dnDSA formation, and treatment of acute and chronic AMR, constitute important unmet medical needs. Because there are no FDA-approved treatments, it appears that clinical trials for these conditions will be designed as superiority trials with a clinical endpoint, such as graft loss, or a surrogate endpoint (SEP), such as decline in GFR or DSA (Table 2).
Clinical trials in AMR have specific challenges due to the nature of the disease and the patient populations. Trial designs should be discussed in advance with the FDA. Distinction between type 1 and type 2 AMR is needed in selection (or stratification) of patient populations, because disease mechanisms and response to treatment are different. Careful assessment of adherence is needed in patient selection and monitoring of clinical trials, because 50% to 90% of dnDSA cases are associated with nonadherence.39 Incidence of dnDSA development is around 2% per year, with higher rates in subpopulations at risk, including recipients with early TCMR or high loads of donor/recipient eplet mismatch, criteria for potential enrichment strategies.
Enrichment strategies, such as focusing on patients at high risk for AMR, may be used to decrease variability and maximize power, therefore, increasing the chances of success often with a smaller sample size. However, recruitment time may be considerably prolonged if the enrichment criteria are too narrowly defined. DSA-relative intensity scale was given as a potential example of prognostic enrichment tool. For example, in a study enrolling patients with dnDSA, with a mean expected graft survival rate of 60% at 5 years, detection of a reduction of graft loss by 25% at 5 years would require a sample size more than 600 patients. With a 2% incidence of dnDSA per year, timely and complete recruitment could prove difficult. Limiting enrollment to patients with clinical dnDSA, associated with reported 5-year graft survival of 28% (enrichment), could reduce the sample size to less than 250 patients; however, a 90% nonadherence rate in such patients would remain a challenge.
Three kidney transplant recipients (2 with retransplants) were invited and presented their perspective, perceptions, and viewpoints/opinions (Table 3).
KEY MESSAGES, CONCLUSIONS, AND FUTURE DIRECTIONS
Important messages from the workshop are summarized in Table 4.
It appears that formation of dnDSA is an important intermediate event in an already ongoing alloimmune process, rather than its origin, as supported by its associations with early TCMR episodes, accelerated GFR decline even before its detection, as suggested by one published study,39 and by the well-known dependence of B cells on T cells for alloantibody production.
Desensitization of the highly sensitized transplant candidates, prevention of dnDSA formation, and treatment of acute and chronic AMR constitute important unmet medical needs. Clinical trials in these patient populations pose specific challenges, partly due to the high prevalence of nonadherence in patients at risk and the indolent nature of disease progression, especially in the “smoldering” and chronic types of AMR. Various strategies may be considered to address these challenges. For example, adaptive trial design, enrichment strategies, and consideration of SEPs, might allow smaller sample size and shorter study duration. In the future, standardization and more widespread adoption of routine posttransplant DSA monitoring may permit timely diagnosis and improve our understanding of the natural course of type 2 and chronic AMR. Given the low frequency of these conditions, collaborative multicenter trials will be needed. Identifying and qualifying a biomarker (eg, DSA, DSA titer, select DSA) from prospective or retrospective studies, showing correlation with long-term outcome would provide a potential future endpoint(s) to evaluate in these studies. With the passage of FDA’s Food and Drugs Administration Reauthorization Act of 2017 (FDARA)53 and the 21st Century Cures Act,54 the continued attention to drug development in areas of unmet medical need, qualification of drug development tools, as well as continued patient focused drug development and better understanding of the potential role of real-world evidence will be important to consider by stakeholders in the transplant community. FDA's performance goals for the next 5 years are publicly available online and include relevant discussions under the section, Enhancing Regulatory Science and Expediting Drug Development.55 The presentations at this workshop and information gained in this area will inform a future guidance document on drug development in antibody-mediated rejection.
List of workshop participants
- (1) Rita Alloway, PharmD, University of Cincinnati, Ohio
- (2) Lakhmir S. Chawla, MD, Veterans Affairs Medical Center, Washington DC
- (3) Anita S. Chong, PhD, University of Chicago, Illinois
- (4) Robert Colvin, MD, Massachusetts General Hospital, Massachusetts
- (5) Arjang Djamali, MD, MS, University of Wisconsin School of Medicine and Public Health, Wisconsin
- (6) Robert Gaston, MD, University of Alabama at Birmingham, Alabama
- (7) Howard Gebel, PhD, D(ABHI), Emory University Hospital, Georgia
- (8) Mark Haas, MD, PhD, Cedars-Sinai in Los Angeles, California
- (9) William Irish, PhD, CTI Clinical Trial and Consulting, North Carolina
- (10) Roslyn Mannon, MD, University of Alabama at Birmingham, Alabama
- (11) Arthur Matas, MD, University of Minnesota, Minnesota
- (12) Robert A. Montgomery, MD, DPhil, NYU Langone Transplant Institute, New York
- (13) Peter Nickerson, MD, University of Manitoba, Canada
- (14) Stuart J. Knechtle, MD, Duke Transplant Center, North Carolina
- (15) Gregory Knoll, MD, University of Ottawa, Canada
- (16) Anat Roitberg-Tambur, DMD, PhD, D(ABHI), Northwestern University, Illinois
- (17) Milagros Samaniego-Picota, MD, University of Michigan, Michigan
- (18) Mark Stegall, MD, Mayo Clinic, Rochester, Minnesota
- (19) Chris Wiebe, MD, University of Manitoba, Canada
- (20) Steve E. Woodle, MD, University of Cincinnati, Ohio
- (21) Dawn P. Edwards, New York, NY
- (22) Michael Lennon, MBA, Cincinnati, OH
- (23) Michael Mittelman, Philadelphia, PA
Food and Drug Administration participants
- (24) Renata Albrecht, MD, Center for Drug Evaluation and Research, Maryland
- (25) Shukal Bala, PhD, Center for Drug Evaluation and Research, Maryland
- (26) Ozlem Belen, MD, MPH, Center for Drug Evaluation and Research, Maryland
- (27) Marc W. Cavaillé-Coll, MD, PhD, Center for Drug Evaluation and Research, Maryland
- (28) Ergun Velidedeoglu, MD, Center for Drug Evaluation and Research, Maryland
- (29) Yan Wang, PhD, Center for Drug Evaluation and Research, Maryland
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