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Keywords:

  • Alloantibody;
  • antibody-mediated rejection;
  • desensitization;
  • immune monitoring;
  • kidney paired donation

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Humoral Immunity: Mechanisms of Graft Injury and Relationship to Cellular Immunity
  5. Detection and Identification of Alloantibodies circa 2010: Qualitative or Quantitative
  6. The Two Key Questions for Desensitization: Who and How?
  7. Giving the Incompatible Patient Hope with Kidney Paired Donation
  8. Conclusions
  9. Acknowledgment
  10. Disclosure
  11. References

The presence of preformed, donor-specific alloantibodies inpatients undergoing renal transplantation is associated with a high risk of hyperacute and acute antibody-mediated rejection (ABMR), and often limits potential recipients’ access to organs from living and deceased donors. Over the last decade, understanding of ABMR has improved markedly and given rise to numerous, diverse strategies for the transplantation of allosensitized recipients. Antibody desensitization programs have been developed to allow renal transplant recipients with a willing but antibody-incompatible living donor to undergo successful transplantation, whereas kidney paired exchange schemes circumvent the antibody incompatibility altogether by finding suitable pairs to donors and recipients. Recognizing the complexity of ABMR and the recent developments that have occurred in this important clinical research field, the Roche Organ Transplantation Research Foundation (ROTRF) organized a symposium during the XXIII Congress of The Transplantation Society in Vancouver, Canada, to discuss current understanding in ABMR and ways to prevent it. This Meeting Report summarizes the presentations of the symposium, which addressed key areas that included the interactions between alloantibodies and the complement system in mediating graft injury, technological advancements for assessing antibody-mediated immune responses to HLA antigens, and the potential benefits and challenges of desensitization and kidney paired donation schemes.


Abbreviations: 
ABMR

antibody-mediated rejection

DAF

decay accelerating factor

DSA

donor-specific antibody

IVIg

intravenous immunoglobulin

KPD

kidney paired donation

MBL

mannose-binding lectin

MFI

mean fluorescence intensity

MCP

membrane cofactor protein

PRA

panel reactive antibody

ROTRF

Roche Organ Transplantation Research Foundation

XM

crossmatch

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Humoral Immunity: Mechanisms of Graft Injury and Relationship to Cellular Immunity
  5. Detection and Identification of Alloantibodies circa 2010: Qualitative or Quantitative
  6. The Two Key Questions for Desensitization: Who and How?
  7. Giving the Incompatible Patient Hope with Kidney Paired Donation
  8. Conclusions
  9. Acknowledgment
  10. Disclosure
  11. References

Despite recent advances in the field, antibody-mediated rejection (ABMR) remains an important issue for clinical transplantation. Treatment options are limited and long-term outcomes are impaired. Consequently, the presence of alloantibodies continues to be an important challenge to clinicians for providing sensitized patients or incompatible donor/recipient pairs with a suitable option for transplantation. The ROTRF Sunrise Symposium on August 16, 2010 at the XXIII Congress of The Transplantation Society brought together internationally renowned researchers to provide an update on recent advances in the laboratory science of ABMR, and strategies for ABMR prevention in clinical practice. Four main presentations were given and are briefly summarized here. The first outlined current thinking on how antibody-mediated immunity damages an allograft, focusing on the role of the complement and new insights into how antibody-mediated immunity may influence the development of cellular rejection. The second presentation addressed technical developments in the detection of HLA antibodies and current challenges for the interpretation and clinical applicability of the results. The third and fourth presentations considered the two different but potentially complementary approaches of desensitization and kidney paired donation (KPD) exchange for the transplantation of incompatible or sensitized patients.

Humoral Immunity: Mechanisms of Graft Injury and Relationship to Cellular Immunity

  1. Top of page
  2. Abstract
  3. Introduction
  4. Humoral Immunity: Mechanisms of Graft Injury and Relationship to Cellular Immunity
  5. Detection and Identification of Alloantibodies circa 2010: Qualitative or Quantitative
  6. The Two Key Questions for Desensitization: Who and How?
  7. Giving the Incompatible Patient Hope with Kidney Paired Donation
  8. Conclusions
  9. Acknowledgment
  10. Disclosure
  11. References

Dr. William Baldwin reviewed the role of the complement system in mediating graft injury. The complement system is a complex system of mediators, receptors and regulators. Although the mediators have been biochemically defined for decades, their function has continued to be better understood over time as the number and distribution of the receptors for complement components has become more completely characterized. While complement activation is closely associated with antibody deposition, leukocytes and endothelial cells have receptors for complement split products and respond to complement activation, such that the influence of complement extends beyond the immediate proximity of antibody. Pro- or anti-inflammatory responses are generated contingent on the amounts of complement split products generated and the availability of complement regulatory proteins.

Antibodies can be effective activators of complement through the classical and lectin pathways by binding C1 and mannose-binding lectin (MBL), respectively. Their capacity to activate complement is determined by their concentration, isotype and carbohydrate side chain structure (1,2), and by the location and density of the target antigen. Tissue-bound and circulating regulators of complement can modulate low levels of complement activation. These include decay accelerating factor (DAF; CD55), membrane co-factor protein (MCP; CD46) and factor I, all of which limit C3 activation. Activation of C3 is a critical step because its split product C3b amplifies the complement cascade through the alternative pathway, which serves as a positive feedback loop. High levels of alloantibodies can overwhelm the regulatory molecules and cause lysis of endothelial cells, which manifests as hyperacute rejection. Short of lysis, the biological split products resulting from complement activation orchestrate vasculitis. Soluble split products (e.g. C3a and C5a) chemoattract and activate granulocytes and macrophages, while tissue-bound complement components (C4b and C3b) target the attachment of leukocytes (Figure 1). Consequently, marginated neutrophils and macrophages are typically seen during ABMR.

image

Figure 1. Hepatocytes, epithelial cells and macrophages are major sources of complement.

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C4d has become a widely used surrogate marker of ABMR in renal and heart transplants because immunohistological stains are significantly more sensitive for C4d than for antibodies. This difference in sensitivity relates to quantitative and qualitative attributes: activation of complement by two IgG antibodies can result in deposition of 25 C4b molecules and, unlike antibodies, C4b and its end-product C4d can covalently bind to tissue. Although C4d is useful and has advanced our appreciation for ABMR, it has limitations. C4d is the biologically inactive end-product of factor I, which degrades C4b. As such, it indicates that regulation has occurred; however, as C4 activation precedes C3, it is possible that regulation prevents the generation of the more inflammatory split products of C3 and C5. This may explainC4d deposition in the absence of neutrophil or macrophage infiltrates, as is found in ABO-incompatible renal transplants that have achieved a state of ‘accommodation’ (3,4). In accommodation, C4d deposition correlates with the presence of circulating antibodies to donor blood group antigens, but inflammation is not evident and graft function is not impaired. Consequently, the Banff criteria for the diagnosis of ABMR in renal transplants require the additional histological finding of tissue injury (5). At the other end of the spectrum are biopsies with no C4d deposition, but with evidence of endothelial injury by histology or gene expression profiling (6). There are several possible explanations for these observations. First, antibodies can cause endothelial cell activation by cross-linking HLA class I antigens in the absence of complement activation (7). Second, comparatively small amounts of C4 activation may promote sufficient C3 amplification to cause endothelial injury, e.g. in patients with lower levels of certain regulators of complement, such as factor H. Further, when C4 is cleaved, a significant amount of the C4b can bind to the antibody and those C4b molecules would have the same turnover as the antibody itself. Fourth, data from animal models indicate that C4d is cleared within a few days even when bound to endothelial cells, probably as a result of membrane endocytosis or exocytosis (8). This last mechanism is most likely during chronic rejection, where antibody levels may fluctuate over time (9).

When an antibody binds to the vascular endothelium, the plasma provides abundant complement, which is produced primarily in the liver, but also in the kidney. Additional sources of complement, including leukocytes (especially macrophages) and epithelial cells in the transplant itself, also can modulate allorecognition and rejection. During antigen presentation, C3 and C5 produced by macrophages and dendritic cells can stimulate T cells through C3a and C5a receptors (10,11). T cells in turn normally express DAF, which regulates this source of stimulation (12). Nevertheless, ABMR can influence the vigor of T cell mediated rejection through these integrated pathways.

As a result of their participation in ABMR, complement mediators, receptors and regulators have become therapeutic targets. Monoclonal antibodies to C5 (e.g. eculizumab in humans, BB5.1 in mice) effectively inhibit complement-mediated inflammation because C5 circulates in limited quantities (0.075 mg/mL compared with 1.3 mg/mL for C3) and C5a has multiple pro-inflammatory effects (13,14). For the same reasons, small molecule inhibitors of the C5a receptor and its soluble form have been designed (15–17). While interventions at earlier steps in the complement pathway may be desirable, these may be associated with more significant defects in protective immunity and immune regulation. C1 would seem to be an ideal target because it initiates the cascade by binding to antibodies; however, the same pathway is also responsible for clearing apoptotic cells and C1 deficiencies are linked to severe autoimmunity (18,19). In line with this, C1-deficient mice reject cardiac allografts more rapidly than wild-type mice (20). Soluble receptors for C3 split products have been used to inhibit ABMR of xenografts (21,22). Although this approach may be effective for short-term treatment, phagocytosis of C3b-opsonized bacteria would also be inhibited. In this context it is important to note that some of the current clinical protocols combine plasmapheresis and intravenous immunoglobulin (IVIg) also remove and consume complement.

Detection and Identification of Alloantibodies circa 2010: Qualitative or Quantitative

  1. Top of page
  2. Abstract
  3. Introduction
  4. Humoral Immunity: Mechanisms of Graft Injury and Relationship to Cellular Immunity
  5. Detection and Identification of Alloantibodies circa 2010: Qualitative or Quantitative
  6. The Two Key Questions for Desensitization: Who and How?
  7. Giving the Incompatible Patient Hope with Kidney Paired Donation
  8. Conclusions
  9. Acknowledgment
  10. Disclosure
  11. References

In his presentation, Dr. Howard Gebel recapped the historical underpinnings of the crossmatch (XM) that established the clinical aversion to transplanting patients with pre-existing donor-specific HLA antibodies (DSA), especially complement fixing DSA (23). The high rate of hyperacute rejection associated with a positive XM essentially required kidney transplant programs to predicate transplantation on a prospectively negative XM. The paradigm was straightforward: do not transplant patients with DSA. Assays were soon developed to detect DSA in patients awaiting transplantation. Typically, panels of HLA-typed lymphocytes (usually 30–60 cells) were incubated with patient sera and complement. Cell death was interpreted to mean that the target cell expressed an antigen or antigens to which the patient's antibodies responded. The rationale behind this test was two-fold. Firstly, the test provides information regarding the patient's likelihood to be XM-compatible with a random donor. The percentage of cells reacting with patient serum was a surrogate for the breadth of sensitization. For example, when 20 out of 60 target cells react with a patient's serum, the patient is considered to have panel reactive antibody (PRA) activity of 33% and would likely be XM-compatible with two out of three random donors. Secondly, antibody specificities could be identified by reviewing the HLA types of reactive cells. The application of such information was the first iteration of what is now called a ‘virtual crossmatch’ (24). Virtual crossmatching predicts whether a physical XM will be positive or negative based on the HLA antibodies present in recipient serum and the HLA antigens expressed by potential donors. Donors who express so-called ‘unacceptable’ antigens are immediately identified, preventing a needless XM from being performed and increasing the likelihood that ‘acceptable’ donor-recipient combinations will be compatible.

In its simplest form, virtual crossmatching distinguishes immunologically compatible from incompatible organ donors for highly sensitized patients requiring a kidney, heart, lung or pancreas transplant. While backed by an appealing rationale, there were numerous problems using a cell-based approach to identify HLA antibodies, including relatively poor sensitivity and specificity, arbitrary composition of target cell panels, issues related to cell viability and importantly, restriction of cell-based tests to the detection of class I antibodies only (25). A breakthrough came with the introduction of antibody-detection assays using solid-phase matrices coated with purified HLA class I or class II antigens (26,27). Briefly, HLA class I or class II antigens isolated from transformed or transfected cell lines (as an entire cluster or single allele, respectively) are attached to inert microparticles. Following incubation with patient serum, the HLA antigen-coated microparticles are analyzed using laser-based instrumentation (e.g. flow cytometry, Luminex®[Luminex Corporation, Austin, USA]). Figure 2 illustrates HLA antibody identification and assignment of unacceptable antigens using a so-called solid-phase single antigen approach. Unacceptable HLA antigens are assigned when the fluorescence intensity of the corresponding microparticles exceeds a pre-established threshold. These extremely sensitive and specific assays transformed the concept of the virtual XM from theory to practice (28,29), though the thresholds used in this approach remain an area of intense investigation.

image

Figure 2. Solid-phase antibody detection. The y-axis represents fluorescence intensity. Each point on the x-axis represents a single HLA antigen specificity. Fluorescence units above 2000 are considered positive and the corresponding specificities would be listed as unacceptable antigens. If a donor possessed one or more of those antigens, the patient's serum would be considered to have donor-specific antibodies (DSA). The unacceptable antigens can be entered into a computer program containing more than 12 000 HLA typed donors to determine the calculated panel reactive antibody (cPRA) level.

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The best use of solid-phase assay data for donor organ allocation and paired donor exchange remains a topic of considerable discussion. Currently, there are no standard policies for assigning threshold values for unacceptable antigens. Each transplant center determines its own thresholds, with decisions based on their level of risk aversion and overall philosophy of practice (30). Deciding how to proceed is not a clear-cut process. For example, while recent data suggest that not all donor-directed antibodies detected in solid-phase assays are clinically relevant (31), there is no way to unequivocally distinguish between harmful and benign antibodies or to distinguish patients in whom antibodies will precipitate ABMR. Thus, while the laboratory tools to identify HLA antibodies have improved dramatically over the past decade, many practical questions remain. As recently reiterated at the US Food and Drug Administration (FDA) conference on ABMR, the existing platforms for DSA detection are considered solely qualitative assays (32). Thus, implementation of clinical practice based on quantitative interpretations of DSA assays remains challenging, and difficult to reconcile with the need for FDA regulations for granting approval for any approach for a specific indication.

The Two Key Questions for Desensitization: Who and How?

  1. Top of page
  2. Abstract
  3. Introduction
  4. Humoral Immunity: Mechanisms of Graft Injury and Relationship to Cellular Immunity
  5. Detection and Identification of Alloantibodies circa 2010: Qualitative or Quantitative
  6. The Two Key Questions for Desensitization: Who and How?
  7. Giving the Incompatible Patient Hope with Kidney Paired Donation
  8. Conclusions
  9. Acknowledgment
  10. Disclosure
  11. References

As discussed by Dr. Denis Glotz, desensitization is the practice of eliminating pre-existing alloantibodies to reach a negative crossmatch and thus allow transplantation, as well as avoiding their associated adverse effects. Desensitization protocols are mainly based on the use of IVIg, either high-dose alone or in combination with rituximab, or low-dose in combination with plasma exchange. The mechanism of IVIg remains the subject of continued investigation, but is thought to trigger homeostatic down-regulation of immunoglobulin synthesis, bind and neutralize complement, and occupy antibody receptors on effector cells (33). The mechanism of rituximab remains similarly unresolved, but may relate to its reduction of maturing B cells and a subsequent eventual reduction of plasma cell precursors. High-dose IVIg protocols consist of courses of IVIg (2g/kg) repeated three or four times every 3 weeks (34,35). This protocol has been shortened to two courses with the addition of a single 1g dose of rituximab between the IVIg courses (36). Successful desensitization, i.e. the percentage of patients receiving a transplant, is approximately 80%. Alternatively, repeated sessions of plasma exchange every other day, each followed by 0.1 g/kg body weight of IVIg, have led to similar, if not higher, transplant rates (37,38). The use of other single agents such as rituximab (39) or bortezomib (40) has not given consistently successful results so far. Once transplanted, patient and graft survival rates are acceptable in the short-term, although there is a high rate (30%) of acute ABMR which necessitates more intense immunosuppression and careful immunological monitoring, and may give way to late graft loss or morbidity with longer follow-up.

The choice of desensitization regimen relies essentially on the origin of the donor kidney, i.e. living or deceased donor. In living donor transplantation, where transplantation can be performed as soon as the required reduction in antibody level has been achieved, the combination of plasmapheresis and low-dose IVIg is the treatment of choice. When one has to wait for an unknown period for a suitable donor, the use of high-dose IVIg alone or in combination with rituximab is preferred, as this protocol provides a more sustained decrease in antibody levels.

As desensitization carries with it the potential for immunosuppressive morbidity, and increased risk of ABMR compared to nonsensitized patients, and considerable expense, the question of who should be considered for desensitization is of utmost importance. Most currently published protocols have selected patients on the basis of cellular assays, i.e. positive XM assays (either cytotoxic or flow based) for living donor transplantation, or high cytotoxic PRA for deceased donor transplantation. However, access to a transplant for patients on the deceased donor waiting list is now dependent in many countries, (e.g. United States and France) on virtual PRA, based on the definition of unacceptable HLA antigens by a solid-phase single antigen assay (41). Accordingly, a growing number of patients are categorized as immunized solely by new sensitive techniques without consideration of a cytotoxic PRA. Those patients may have a virtual PRA of 100%, barring them from transplantation, but a low cytotoxic PRA preventing access to a desensitization protocol. Currently, there is no consensus definition of an unacceptable antigen by solid-phase antigen assay, given the wide-ranging thresholds for detection used.

From clinical experience, it is known that the mere presence of a DSA solely detected by solid-phase methods is not an absolute contraindication to transplantation, as excellent graft survival rates have been achieved despite detection of such antibodies (42,43). Thus, while a quantitative approach is mandated, the reality is that each laboratory sets its own threshold of mean fluorescence intensity (MFI) defining an unacceptable antigen, which may vary from 500 to 3000 MFI. In Dr Glotz’s institution, 402 patients who underwent deceased donor transplantation after a negative T cell cytotoxic XM were studied retrospectively (31). In 83 of those patients DSA were detected using a solid-phase single antigen assay. Although the prevalence of ABMR rose significantly with increasing DSA MFI, a threshold MFI value of 3000 was associated with increased graft loss (Figure 3).

image

Figure 3. Graft survival according to pretransplant MFI of DSA. Journal of the American Society of Nephrology by American Society of Nephrology. Copyright 2011. Reproduced with permission of American Society of Nephrology in the format Journal via Copyright Clearance Center.

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Giving the Incompatible Patient Hope with Kidney Paired Donation

  1. Top of page
  2. Abstract
  3. Introduction
  4. Humoral Immunity: Mechanisms of Graft Injury and Relationship to Cellular Immunity
  5. Detection and Identification of Alloantibodies circa 2010: Qualitative or Quantitative
  6. The Two Key Questions for Desensitization: Who and How?
  7. Giving the Incompatible Patient Hope with Kidney Paired Donation
  8. Conclusions
  9. Acknowledgment
  10. Disclosure
  11. References

In his presentation, Dr. Adam Bingaman explained how the approach to transplant patients with incompatible donors has changed significantly over the past 5 years. Advances in HLA antibody detection techniques and computer programs to facilitate kidney paired donation (KPD) have moved the field forward such that the old dogma that these patients should be turned down for living donor transplantation or be referred to a desensitization protocol should be revisited. Sensitized patients need not be exposed to the increased rates of ABMR associated with desensitization, or its associated morbidity and cost as a first option.

KPD has been widely discussed as an option for patients with incompatible donors for more than a decade, with well-established ethical principles to support its broad utilization (44). Nevertheless, KPD continues to be significantly underutilized. National programs have been established in several countries, including the Netherlands, the United Kingdom and Canada, with a pilot program established in the United States. While the formation of these programs is an advance, the success of national programs depends on organizational structure and willingness of transplantation programs to enroll their patients and donors in such a program. These barriers have limited the immediate impact of these programs. Alternatively, some single centers, including Dr. Bingaman's as presented in this meeting, have shown that effective KPD programs can be established, increasing living donor transplantation by 34% without the use of nondirected donors (45). Single-center experiences are most valuable if the principles underlying their success are broadly applicable to the wider community. It is clear that there are several key principles that underlie successful KPD programs that could be standardized and generalized (Figure 4). Dr. Bingaman presented several methods for efficient KPD operation.

image

Figure 4. Kidney paired donation algorithm. Flow diagram of the progress through the phases of an exemplary KPD protocol.

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Firstly, all transplant recipients and potential donors should be educated about paired donation at the time of initial evaluation or screening. Upon consent, all pairs (including multiple donors per recipient, if available) should be entered into a KPD database. It is not surprising that the success of KPD depends largely on the size of the incompatible database. Only through comprehensive enrollment of all consenting pairs do databases reach the critical mass required for the generation of meaningful numbers of transplant pairs.

Secondly, histocompatibility data from recipients and donors must be comprehensively analyzed and entered into a KPD computer system (46). The KPD matching algorithm should allow the maximal opportunity for matching highly sensitized patients but the smallest opportunity for a positive XM. Solid-phase antibody testing for HLA-A, -B, -C, -DR, -DRw and -DP should be done for all recipients along with comprehensive HLA analysis of donors, including C and DP typing. Unacceptable antigens should be assigned based upon MFI correlated to XM sensitivity. Some transplant programs comfortable with desensitization should consider a very aggressive approach in not assigning moderate- and low-level antigens as unacceptable to allow for a weak positive XM that could safely be overcome with desensitization. In addition, the MFI correlation of C locus and DP antibody with XM results and clinical outcome are not as well defined and should be assigned cautiously in highly sensitized patients who may have little hope for finding a donor with otherwise zero unacceptable antigens.

Thirdly, all blood type A donors should be subtyped into A1 and A2, since blood type A2 accounts for approximately 20% of all blood type A individuals. Blood type A2 has fewer A antigens, and the A antigens are expressed at lower density; thus A2 donors are classified O* in the KPD database. This classification allows blood type A2 donors to possibly match with O or B recipients with an acceptably low anti-A titer, such that this blood group disparately could be crossed without the need for desensitization.

Fourthly, all newly entered incompatible pairs should be analyzed regularly by the KPD matching system. Pairs should be analyzed with a two-way matching algorithm for all potential two-way and three-way exchange transplants, as well as a one-way matching algorithm for all nondirected donors for potential chain transplants.

Regular communication between the HLA laboratory and clinical team is necessary to provide real-time exchange of information, regular updating of the database, and review of virtual XM results. Once a potential match is identified by the computer database, flow cytometry or cytotoxicity XM should be performed to confirm compatibility. Antibody specificities and levels can change significantly over time among sensitized recipients and thus timely evaluation and transplantation (goal 6–8 weeks after the computer match) is critical to the success of KPD.

There are many challenges inherent in organizing and directing a successful KPD program that have limited the wider application of paired exchange transplantation worldwide. In the United States, for example, transplant centers may have widely different approaches to these patients, broadly different philosophies with regard to risk of desensitization and incompatible transplantation, and substantially different interpretations of solid-phase single antigen bead testing results. These differences may significantly limit participation and success of such a program. Nevertheless, it should be a goal for every living donor transplant program to incorporate effective policies and procedures to enroll all consenting incompatible pairs into an effective KPD program such that all recipients with incompatible donors have the opportunity to receive a transplant from a compatible donor.

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Humoral Immunity: Mechanisms of Graft Injury and Relationship to Cellular Immunity
  5. Detection and Identification of Alloantibodies circa 2010: Qualitative or Quantitative
  6. The Two Key Questions for Desensitization: Who and How?
  7. Giving the Incompatible Patient Hope with Kidney Paired Donation
  8. Conclusions
  9. Acknowledgment
  10. Disclosure
  11. References

As highlighted in this symposium, alloantibodies represent an important problem for clinical transplantation and negatively influence accessibility to transplants and transplantation outcomes. Knowledge of the mechanisms involved in ABMR has increased greatly in the last decade improving diagnostic capabilities and forming the development of treatment and avoidance strategies. Research has revealed the complex relationships among the key players and pathways involved. In particular, a pivotal role for complement in regulating ABMR and as a link between innate and adaptive immunity is starting to emerge. From a therapeutic point of view, one of the most important challenges will be the identification of suitable targets to modulate the complement response in order to control ABMR without impairing essential immune activities. There is also a need for standardization of HLA thresholds and identification of harmful versus benign antibodies in order to correctly identify patients at increased risk of rejection. While these problems remain to be solved, the current consensus is that ABMR should be prevented rather than cured. Desensitization protocols, while mostly effective, are not without problems. Pair exchange programs may be able to allow ABO-incompatible living donor transplantation with no added immunosuppressive burden to the recipient. However, the success of these schemes is heavily dependent on patient characteristics and the size and composition of the pool of donor-recipient pairs. Implementation of more complex schemes, such as three-way exchange and altruistic domino paired kidney donation chains, can markedly increase the success rate of paired donation schemes, but also pose logistic challenges.

Disclosure

  1. Top of page
  2. Abstract
  3. Introduction
  4. Humoral Immunity: Mechanisms of Graft Injury and Relationship to Cellular Immunity
  5. Detection and Identification of Alloantibodies circa 2010: Qualitative or Quantitative
  6. The Two Key Questions for Desensitization: Who and How?
  7. Giving the Incompatible Patient Hope with Kidney Paired Donation
  8. Conclusions
  9. Acknowledgment
  10. Disclosure
  11. References

The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation. This symposium was organized and supported by the Roche Organ Transplantation Research Foundation (ROTRF, charity number # CH-270.7.002.678–7).

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Humoral Immunity: Mechanisms of Graft Injury and Relationship to Cellular Immunity
  5. Detection and Identification of Alloantibodies circa 2010: Qualitative or Quantitative
  6. The Two Key Questions for Desensitization: Who and How?
  7. Giving the Incompatible Patient Hope with Kidney Paired Donation
  8. Conclusions
  9. Acknowledgment
  10. Disclosure
  11. References