Antibody-Mediated Rejection
2014; Wolters Kluwer; Volume: 98; Issue: Supplement 3S Linguagem: Inglês
10.1097/tp.0000000000000218
ISSN1534-6080
AutoresManuel Arias, David N. Rush, Chris Wiebe, Ian W. Gibson, Tom Blydt‐Hansen, Peter Nickerson, Jacobo Sellarés, Marcos López‐Hoyos, David San Segundo, María G. Crespo‐Leiro, Raquel Marzoa‐Rivas, Eduardo Barge‐Caballero, María J. Paniagua‐Martín, Antonio Román, Daniel Serón, Georg A. Böhmig, Elisabeth Schwaiger,
Tópico(s)Organ Transplantation Techniques and Outcomes
ResumoSECTIONS Introduction (Manuel Arias) De novo Donor-Specific HLA Antibodies in Renal Transplantation: A Major Cause of Graft Loss (David N. Rush, Chris Wiebe, Ian W. Gibson, Tom D. Blydt-Hansen, and Peter W. Nickerson) Causes of Late Kidney Allograft Loss. What’s New? (Joana Sellarés) Epidemiology of Anti-HLA Antibodies in Solid Organ Transplantation: Impact of New Solid-Phase Tests (Marcos López Hoyos, David San Segundo, and Manuel Arias) The Definition and Diagnosis of Antibody-Mediated Rejection in Heart Transplantation (María G. Crespo-Leiro, Raquel Marzoa-Rivas, Eduardo Barge-Caballero, and María J. Paniagua-Martín) Antibody-Mediated Rejection in Lung Transplant. What Is Changing? (Antonio Román) Inflammation, Fibrosis, and Immunosuppressive Treatment (Daniel Serón) Prevention and Treatment of Alloantibody-Mediated Transplant Rejection: New Approaches (Elisabeth Schwaiger and Georg A. Böhmig) 1. INTRODUCTION Manuel Arias Overall graft survival has increased progressively over the last years. According to national and international registries, such as the Collaborative Transplant Study (CTS), graft loss has followed a downward trend (1, 2) (Fig. 1).FIGURE 1: Evolution of graft survival over the last years according to the CTS (1).The introduction of new immunosuppressive (IS) drugs—together with a better understanding of rejection physiopathology in solid organ transplantation—have globally improved short-term outcomes with reduced rates of acute rejection. However, late graft failure is still an issue (2). The risk of graft failure includes immunological and nonimmunological factors (3) (Table 1). Considering the immune factors, the incidence of antibody-mediated rejection (AMR) has increased over the last years: partly caused by a higher number of retransplantation and transplants with human leukocyte antigens (HLA) and ABO incompatibility, and partly because of a greater recognition of this entity and the availability of improved tests to detect donor-specific antibodies (DSA) (4).TABLE 1: Risk factors and reported causes of graft failureThere is a temporary dynamic in the course of chronic humoral rejection (CHR). Based on histological findings, renal allograft damage starts with tubule-interstitial inflammation followed by a later phase of chronic allograft nephropathy defined by arteriolar hyalinosis and glomerulosclerosis. The presence of interstitial inflammation in early protocol biopsies (performed within 6 months after transplantation) is related to a higher risk of developing de novo DSA (dnDSA) and consequently CHR. Therefore, the benefit of treating subclinical rejection must be considered while taking into account that the IS regimen can influence the outcome. Thus, the renal damage attributed to calcineurin inhibitors (CNI) toxicity, leading to a minimization of these drugs, has resulted in greater increases of chronic pathology. The availability of new solid-phase assays (SPA), allowing the detection of low titers of DSA, has revealed the importance of these antibodies in the development of AMR and the related risk of graft failure, regardless of the solid organ transplanted. New SPA also point out the importance of considering other antibody specificities apart from HLA-A, -B and -DR, such as -Cw, -DQ or -DP, in the management of kidney transplantation. Moreover, DSA monitoring could be a useful tool in specific situations, such as desensitization protocols, patients with pretransplant antibodies, and negative complement-dependent cytotoxicity (CDC), when humoral rejection is suspected or when considering an IS therapy. Considering the role of the IS, whereas some authors demonstrated a clear relationship between treatment compliance and the presence of dnDSA, others took into account the physician’s decisions such as IS change or reduction (5). Together with Class II HLA mismatching and prior cellular rejection, inadequate immunosuppression (particularly minimization and nonadherence to IS medications) is a risk factor for the development of dnDSA, which is considered a major cause of renal graft loss. While waiting for a more satisfactory treatment of chronic antibody-mediated rejection (CAMR), it is important to focus on strategies for preventing or minimizing those risk factors. Taking advantage of the long subclinical process of CAMR, from transplant to graft dysfunction, the screening for DSA in all patients may allow physicians to adopt preventive measures such as optimizing current therapies. Therefore, pretransplantation assessment and early diagnosis of AMR, considering histological and serological findings, are of most importance in the prevention and treatment of this problem. For the former, desensitization protocols and antihumoral therapy (based on removal of harmful antibodies and on modulation of components of the immunity) may be considered; for the latter, peritransplantation cross-match conversion has shown effectiveness in the short term after transplantation, although for the medium and long term, there is still a need of developing effective strategies. Above all, AMR is an issue affecting all solid organ transplantations. Two sections in this supplement will address the specific features affecting the cardiac and lung transplant. This supplement collects the lectures presented in the symposium: Antibody-Mediated Rejection: Analyzing the Risk, Proposing Solutions, held in Madrid (Spain) in February 2013. 2. DE NOVO DONOR-SPECIFIC HLA ANTIBODIES IN RENAL TRANSPLANTATION: A MAJOR CAUSE OF GRAFT LOSS David N. Rush, Chris Wiebe, Ian W. Gibson, Tom D. Blydt-Hansen, and Peter W. Nickerson Abstract: The beneficial effects of HLA matching in renal transplantation have been known for decades, and an allocation system that emphasizes Class II matching has been proposed. Recent data have demonstrated that the development of dnDSA, particularly against Class II HLA antigens, is a major cause of renal transplant loss. The histopathology of chronic antibody-mediated rejection is characterized by immune injury to the endothelium of the glomeruli and peritubular capillaries. The early phases of injury occur subclinically, many months before graft dysfunction, providing the opportunity for the optimization of current therapies and the evaluation of new treatment strategies. Risk factors for dnDSA development include Class II HLA mismatching, patient nonadherence to IS medications, and prior cellular rejection. Because the current treatment of chronic antibody-mediated rejection is largely unsatisfactory, prevention strategies that attempt to minimize the known risk factors should be adopted. The effects of HLA matching on renal allograft outcomes have been reported in Transplant Registries over the last 20 years (6–8). Data from the UCLA Tissue Typing Laboratory demonstrated that an increase in the number of A, B, and DR mismatches in renal transplantation patients was associated with a higher incidence of both acute rejection and graft loss, and with impaired renal function at various time points after surgery (6). Conversely, Opelz reported a beneficial effect of HLA matching on graft survival in the recipients of living unrelated kidney donors (7), and Opelz and Döhler subsequently demonstrated that patient and graft survival were better, and rates of rejection in the first year were lower in proportion to the number of matched A and B, and DR antigens in over 135,000 recipients of deceased donor kidneys studied over two decades (8). A beneficial effect of HLA matching (particularly for HLA Class II) has also been reported recently for the recipients of kidneys from heart beating donors in the United Kingdom (9). The idea of kidney allocation that emphasizes DR compatibility has in fact been previously put forward by Doxiadis et al (10). The use of HLA matching as a means of allocating kidneys and improving renal transplantation outcomes has not always received universal support. For example, Su et al (11) reported on over 33,000 renal transplant recipients from the United States Renal Data System (USRDS) database and concluded that the improvement in graft survival attributable to HLA matching had decreased over time and that allocation algorithms that emphasize HLA matching needed to be reconsidered. Furthermore, Matas et al (12) reported that failure of poorly matched grafts did not result in increased rates of sensitization, which questions once more the need of emphasizing HLA matching before transplantation. However, recent data on the development of de novo antibodies against donor HLA antigens (particularly Class II) as a major cause of renal allograft dysfunction and loss (vide infra) will undoubtedly shift the focus back to better HLA matching of donor and recipient pairs in an attempt to improve long-term graft outcomes. ANTIBODIES AND THE HUMORAL THEORY OF TRANSPLANTATION The significance of DSA, as evidenced by the direct consequences of a positive cytotoxic crossmatch at the time of transplantation, was greatly demonstrated in the seminal paper of Patel and Terasaki in 1969 (13). Furthermore, the deleterious effect of “lymphocytotoxic antibodies” detected in the posttransplantation period was clearly established by Martin et al (14) in 1987. An insightful, early review of humoral hyperacute, acute and chronic antibody-mediated rejection was published by Terasaki in 2003 (15). Notwithstanding the abovementioned reports, the modern era in the study of DSA and their effects on allograft outcome has resulted from the development of sensitive solid-phase assays for antibody detection that have exquisite antigen specificity. Additional key observations to support the injurious role of DSA in transplanted organs have been the discovery of tissue C4d staining as a marker of antibody-mediated injury by Feucht et al (16), and the recognition of the microcirculation (glomeruli and peritubular capillaries in the transplanted kidney) as the target for antibody-mediated inflammation in the Banff schema (17). With the combined use of these diagnostic assays, it has become clear that there are two different case scenarios that relate to antibody-mediated allograft injury. The first relates to acute AMR that occurs in patients who have preformed DSA at the time of transplantation. The second relates to the more insidious process of CAMR that occurs in patients who develop dnDSA sometime after transplantation. PREFORMED DSA In renal transplantation patients, early onset AMR has been reported in studies in which preformed DSA were missed in cases where the initial crossmatch was obtained using cytotoxicity and other methods but were detected retrospectively by retesting the pretransplantation sera with solid-phase assays (18, 19). For example, Lefaucheur et al (18) reported on 2,079 patients with a negative cytotoxicity assay against donor T and B lymphocyte pretransplantation, of whom 15% (305) had an acute rejection episode at a median of 3.1 months posttransplantation. Almost half of these patients (n=147) had AMR, which was caused by anti-Class I DSA in one third of the patients and by anti-Class II DSA in the remaining two thirds, after the sera were retested with single-antigen flow bead assays. The authors observed that patients with AMR who had received therapy directed only to T-cells, that is, steroids plus or minus monoclonal or polyclonal anti-T cell therapy, had worse long-term outcomes than patients who received treatment directed against the antibody, that is, steroids or intravenous immunoglobulin (IVIG) or plasmapheresis (PP) plus rituximab. Similarly, in an earlier study from the Mayo Clinic in Rochester, Gloor et al (19) reported on 189 recipients of living donor kidneys who were either crossmatch negative (n=70) or positive (n=119) against their donor. In the latter patients, the crossmatch was performed either by cytotoxicity or by flow cytometry at two levels of mean channel shift ( 300), before patient desensitization. The sera from these patients were also retrospectively analyzed for DSA by solid-phase assay and were reported as mean fluorescence intensity (MFI) of the sum of the MFI values for Class I and Class II HLA antibody. The patient outcomes reported were early AMR (<90 days), transplantation glomerulopathy, and graft loss. In general, there was a good inverse correlation between the sensitivity of the method for antibody detection and the observed outcomes. In particular, early AMR (<90 days) occurred more commonly with antibodies detected by cytotoxicity, with antibodies causing a greater mean channel shift by flow cytometry, and with antibodies with a higher MFI sum. DE NOVO DSA CAMR of renal allografts caused by dnDSA has also received a great deal of attention in the recent literature, and a selected group of studies of particular interest is discussed below (5, 20–30). In a study of 315 adult and pediatric recipients from our center, historical and current sera were examined for the presence of DSA using the most sensitive solid-phase assays with an MFI cutoff of 300. All these patients were negative for DSA at the time of transplantation and had protocol biopsies 6 months later that showed no evidence of microcirculatory inflammation. We found that dnDSA developed relatively late, with no case detected before 6 months posttransplantation. There was a 2% incidence of dnDSA in the first year, and a median onset at 4.6 years. The overall incidence of dnDSA was 15%. An interesting aspect of our study is that we decided to biopsy patients at the time of dnDSA detection, irrespective of the functional status of the graft. This approach led to the finding that one third of patients with dnDSA had stable graft function despite having an unequivocal evidence of inflammation in the microcirculation (glomerulitis, peritubular capillaritis, and C4d deposition in the peritubular capillaries) on renal biopsy. The subclinical presentation of antibody-mediated rejection occurred in patients who were adherent to their IS regimen; however, these patients eventually developed graft dysfunction with a mean delay of about 20 months. Another third of patients with DSA presented with rapid onset of graft dysfunction and a biopsy that showed a mixed form of rejection with both T cell-mediated rejection (TCMR) and AMR features; these patients were uniformly nonadherent. The development of dnDSA was the strongest predictor of graft loss in a multivariate model (odds ratio [OR] 6.4; P 1 year posttransplantation), nonadherence or intentional reduction of IS treatment caused by malignancies was documented in 83% of the cases (39).FIGURE 2: Attributed causes of graft failures in the biopsy-for-cause population. From Sellarés et al (22).CONCLUSIONS Understanding the phenotype of each individual graft loss is an essential step to improve long-term outcomes in kidney transplantation Most failures can be attributed to specific causes if enough information is available (adequate histology sample, antibody, and relevant clinical data). The main causes of late graft failure are antibody-mediated rejection and glomerulonephritis. Other important causes include polyoma virus nephropathy and failure in the context of an intercurrent illness. Nonadherence is a behavior that often presents as a late rejection and eventually triggers graft failure by means of AMR. Strategies to promote adherence should be implemented at least in those patients at risk. Chronic calcineurin-inhibitor toxicity is not a major cause of graft failure per se. Although it induces fibrosis over time, it is rarely the only explanation for failure. 4. EPIDEMIOLOGY OF ANTI-HLA ANTIBODIES IN SOLID ORGAN TRANSPLANTATION: IMPACT OF NEW SOLID-PHASE TESTS Marcos López Hoyos, David San Segundo, and Manuel AriasAA NEW SOLID-PHASE ASSAY: DETECTION AND MANAGEMENT OF ANTI-HLA ANTIBODIES Although the role of preformed anti-HLA antibodies (Abs) in pretransplantation sensitization has became clear since the end of the last century, the arrival in the last decade of new solid-phase assays (SPA) (ELISA and flow cytometry with its automated version, Luminex) has made relevant the importance of de novo anti-HLA Abs. After two prospective studies reported by Terasaki et al (52), showing an increased risk of graft loss in renal transplant recipients when posttransplantation anti-HLA Abs (tested by ELISA, flow cytometry, and Luminex) were detected, the authors recommend universal testing of kidney transplantation patients for posttransplantation Abs. Among the SPA, Luminex technology has been consolidated as a routine procedure for his tocompatibiity laboratories. It is a flow cytometry-based instrument that uses color-coded microbeads coated with purified HLA antigens. Each bead type is defined by an individual fluorescent color tone; after incubating with the patient sample, the recognition of the anti-HLA Abs by the secondary antibody produces another fluorescent emission in a different channel. The fluorescence signals are detected by the detectors of Luminex. In addition, the intensity of the fluorescence correlates with the amount of bound analyte, allowing anti-HLA Abs quantification. Expressed as MFI (mean fluorescence intensity) or MESF (molecules of equivalent soluble fluorochrome), they could be considered important markers for patient and graft progression. This technology also allows the detection of low titers of donor-specific anti-HLA (DSA) Abs that were undetectable by former assays. Until recently, the role of DSA (only detected by SPA) on renal transplantation outcomes has been unclear. However, Mohan et al (53) have reported the results of a meta-analysis where the presence of DSA-SPA significantly correlated with a higher risk for AMR (P<0.001) and increased the risk for graft failure (P=0.01), even in the presence of a negative flow cytometry cross-match result. More importantly, the authors point for the graft loss risk associated with the development of DSA against HLA-DP and -DQ. Thus, when thinking of the management of kidney transplantation in the future, we should consider not only the presence and concentration of DSA against HLA-A, -B, and -DR but also the detection of antibody specificities such as HLA-Cw, -DR, -DQ, and -DP. Considering the importance of these new technologies and the need of standardizing the results among laboratories using different methodologies, the Spanish Society of Immunology has conducted the Iberian Histocompatibility Workshop in 2012 (54), with the double objective of mapping and identifying HLA alleles and the standardization of results obtained by the Luminex technology. Regarding the second component of the work, the results shows that the two methods used in Spain are equally distributed by the two manufacturers, OneLambda and Gen Probe; the specificity is defined by a cutoff by approximately 50% of labs; laboratories set such a cutoff point at MFI 1,500 (31%) or 2,000 (31%); most laboratories (92%) measure immunoglobulin G; and also the majority detect anti-HLA bu
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