Antibodies in Kidney Transplantation

Antibodies in Kidney Transplantation

Stephen H. Gray, MD, MSPH

University of Alabama at Birmingham, Birmingham, Alabama

A significant and constant obstacle to the long-term survival of renal allografts is antibody-mediated rejection. During the 2012 American Transplant Congress held in Boston, Massachusetts, this past June, experts in organ transplantation discussed the mechanism of this phenomenon, the identification of its markers, the development of diagnostics to detect rejection early in the process, and the evaluation of drugs to prevent antibody-mediated rejection and improve the long-term survival of renal allografts.

Dr. GrayAntibody-mediated rejection (AMR) is a serious problem that bedevils the transplant community. In recent years, laboratory researchers and clinical investigators have collaborated to develop strategies to detect organ rejection; they also have begun reporting successful prophylactic and therapeutic protocols for managing AMR. These efforts have resulted in excellent outcomes, even in individuals who were highly sensitized to foreign substances before an organ transplant took place.

During the 2012 American Transplant Congress, experts in organ transplantation explored novel methods of diagnosing AMR, strategies for monitoring antibody levels in sensitized and unsensitized recipients of organ grafts, and new directions for managing patients at risk of transplant rejection. The symposium was moderated by Howard Gebel, PhD, Professor of Pathology and Laboratory Medicine, Emory University Hospital, Atlanta, Georgia, and Milagros D. Samaniego-Picota, MD, FACP, FASN, Associate Professor of Internal Medicine, Division of Nephrology, University of Michigan Medical School, Ann Arbor, Michigan.

NOVEL METHODS TO DIAGNOSE AMR
Based on a presentation by Lorraine Claire Racusen, MD, Professor of Pathology, Johns Hopkins Hospital, Baltimore, Maryland

The current diagnosis of AMR is based on the Banff criteria, which require morphologic findings of tissue injury, immunohistologic evidence of complement in tissue, and the presence of donor-specific antibodies (DSA) in the circulation.

C4d Deposition
Endothelial deposition of the complement split product C4d is an established marker of acute AMR in renal allografts. In biopsy-proven acute rejection episodes, the presence of anti–class I antibodies correlates with severe vascular lesions, glomerulitis, and infarction, whereas rejection episodes in the absence of antibodies are associated with more predominant severe tubulitis.1 Detection of DSA has been associated with greater graft loss.

Regele and colleagues2 described a link between immunohistochemically detected endothelial C4d deposition in peritubular capillaries (PTCs) and morphologic features of chronic renal allograft injury. Endothelial C4d deposition was associated with chronic transplant glomerulopathy; it also was linked to basement membrane multilayering and accumulation of mononuclear inflammatory cells in PTCs. Likewise, complement activation in the renal microvasculature, which indicates humoral alloreactivity, contributed to chronic rejection, characterized by chronic transplant glomerulopathy and basement membrane multilayering in PTCs (Figure 1).2

FIGURE 1 Immunohistochemical detection of endothelial C4d deposits in peritubular capillaries (PTC) on paraffin sections of renal allograft biopsies. (A) Linear C4d deposits along the walls of PTC. (B) C4d-positive PTC congested with mononuclear inflammatory cells (triangles; detail from A). (E) Yellow staining along the inner aspect of PTC indicating perfect co-localization of green staining for C4d (C) and red staining for CD31 (labeling endothelial cells) (D). (H) PTC showing only focal overlap (yellow staining) but no widespread co-localization of green staining signals for C4d (F) and red staining for collagen type IV (G). Both tubular and capillary (triangles) basement membranes are labeled by an anti-collagen type IV antibody (F, G). (A, B) Indirect immunoperoxidase staining with C4dpAb on paraffin sections. (C–G) Indirect immunofluorescent double-staining of paraffin sections with C4dpAb, monoclonal anti-CD31, and monoclonal anti-collagen type IV; C = peritubular capillary; T = tubule. Magnification: (A) 275×; (B) 550×; (C, D, F, G) 230×; (E, H) 460×. Reproduced, with permission, from Regele et al.2

The distinction between AMR and acute cellular rejection (ACR) in renal allografts is therapeutically important but pathologically difficult. Histologically, AMR is characterized by glomerular thrombi, mesangiolysis, PTC neutrophil infiltration, interstitial hemorrhage, necrosis, and C4d deposition. Immunohistochemically detected C4d in PTC walls distinguishes AMR from ACR; C4d is more specific and sensitive than traditional criteria and represents a potentially valuable adjunct to diagnosing graft dysfunction.3 Additionally, glomerular thrombi appear early in AMR; their appearance prior to graft dysfunction may allow therapeutic intervention.4

In renal allograft biopsies, C4d deposition within PTC is a specific marker of the antibody-graft interaction that is extremely useful for diagnosing AMR. The presence of PTC C4d itself is not diagnostic of AMR, but this finding usually is accompanied by histologic features of acute and/or chronic AMR. 5 In the setting of chronic rejection, a substantial fraction is mediated by antibodies. Detection of C4d can be used to separate this group of patients with chronic rejection from the nonspecific category of individuals experiencing chronic allograft nephropathy and may guide successful treatment. 6

De Novo DSA Production
Acute rejection associated with de novo production of DSA is a clinicopathologic entity that carries a poor prognosis. In most cases, the presence of DSA at the time of rejection is linked to widespread C4d deposits in PTCs, suggesting a pathogenic role of the circulating alloantibody. Combined DSA testing and C4d staining provides a useful approach for the early diagnosis of AMR, a condition that often necessitates use of a more intensive therapeutic rescue regimen.7

Test availability and sensitivity. Various assays are available to detect antibodies. The cytotoxicity assays that became available first are inexpensive, and they supply rapid results; because of their low specificity, they currently are used for screening. Flow cytometry, the current standard used, offers better sensitivity. Solid-phase assays (eg, enzyme-linked immunosorbent assay [ELISA], B-phase) are more sensitive and specific.

Contemporary technology clearly is advancing the detection of various antibodies that can contribute to AMR. Still, continued work is needed to elucidate the relevance of very low levels of human leukocyte antigen (HLA)-specific antibody and the importance of antibodies to other alloantigens and autoantigens.8

Issues with the Banff Criteria
Histopathologic changes such as glomerulitis, capillaritis, and microangiopathic changes are nonspecific. According to the current classification, AMR also can be identified by severe arteritis involving the muscle layers.9

Significance of histologic lesions. The Banff classification empirically established scoring of histologic lesions, but the relationships of lesions to each other and to underlying biologic processes remain unclear. Using cluster analysis, Sis et al10 found that intimal arteritis clustered with DSA, C4d deposition, and microcirculation inflammation, but it also correlated with tubulitis. This observation suggested that pathologic lesions found on biopsy represented distinct pathogenic forces: microcirculatory changes, reflecting the stress of DSA; scarring, hyalinosis, and arterial fibrosis, evidencing the cumulative burden of injury over time; and tubulointerstitial inflammation. Other recent studies demonstrated that milder lesions may represent AMR.11

A number of studies have identified morphologic lesions of AMR in protocol biopsies of normally functioning renal allografts, and particularly in sensitized recipients, which correlate with later chronic changes in the graft, such as transplant glomerulopathy.12,13 These same studies and molecular research involving biopsies of conventional renal allografts have noted evidence of microvascular injury, which, in the presence of DSA but the absence of C4d deposition in PTCs, is associated with development of transplant glomerulopathy and graft loss. Finally, intimal arteritis, which was believed to represent a lesion of cell-mediated rejection (CMR), and bland arterial intimal fibrosis resembling arteriosclerosis may be manifestations of DSA-induced graft injury.14

The role of C4d. Recently, there has been an immunohistologic emphasis on improving the interpretation, detection, and quantification of C4d. Over the past 10 years, the recognition of alloantibody responses in organ transplantation has grown, although AMR-specific responses, unfortunately, remain incompletely defined. For example, Loupy and others12 reported that the C4d Banff scores (1, 2, 3) in protocol biopsies of kidney transplant patients with preformed DSA were associated with significant increments of microcirculation inflammation at 3 months and 1 year post transplant, worse transplant glomerulopathy, and higher class II DSA mean fluorescence intensity. However, C4d staining was not a sensitive indicator of parenchymal disease. Upon further analysis, the presence of microcirculation inflammation and class II DSA at 3 months was associated with a fourfold increased risk of progression to chronic AMR, which was independent of C4d status. Additionally, there was significant fluctuation in C4d deposition over time.

Sis and Halloran15 described C4d-negative AMR using biopsy evidence of active antibody-mediated damage. C4d-negative AMR is characterized by high within-graft endothelial gene expression, the presence of alloantibodies, histology reflecting chronic AMR (and, less frequently, acute AMR), and poor outcomes. Thus, the endothelial molecular phenotype in biopsies with circulating antibody detects the degree of active graft injury, and many of these transcripts reflect endothelial activation. C4d-negative AMR is noted twice as often as C4d-positive AMR. Recognition of this new phenotype reveals C4d-positive or C4d-negative AMR to be the most common cause of late kidney transplant loss. However, although C4d staining is useful, it is not sensitive enough to detect AMR. Measuring endothelial gene expression in biopsies from kidneys with alloantibodies is a sensitive, specific method for diagnosing AMR and predicting graft outcomes.

Challenges to analysis. Obtaining information about antigens can be challenging, since their concentrations and conditions may vary. Further, both internal and external factors can interfere with the analysis of antigens, and different laboratories use various detection hardware. The detection of nontraditional antibodies also is problematic—most assays focus on HLA-A, HLA-B, and HLA-DR. Standardization of positive results is likewise problematic, because each laboratory establishes its own positive and negative cutoffs. Finally, establishing the sensitivity threshold between detectable and pathogenic levels is difficult.

In summary, researchers must decide on whether to focus upon important physiologic and pathologic findings; for example, a single target for an antibody is an artificial laboratory construct that is not physiologic.

Future Directions
Histopathology in this field remains focused on microcellular circulation, inflammation, and injury. State-of-the art screening for glomerulitis and PTCs currently is available. The transplant community as a whole is working on evaluating and improving semiquantitative grading based on outcome studies.

Additional effort has been directed at improving interobserver agreement. Strategies include using additional immunohistochemical stains to define the severity and extent of AMR, which has led to the development of a new algorithm for predicting the presence of DSA. Sis et al16 studied the significance of microcirculation inflammation in 329 indication biopsies from 251 renal allograft recipients who were mostly non-presensitized (crossmatch-negative). The decision tree revealed that the sum of the glomerulitis score and the PTC score (g + PTC) was the best predictor of DSA, followed by time elapsed post transplant and then C4d deposition, which had a small role. Late biopsies having a g + PTC > 0 showed a higher frequency of DSA than did early biopsies having a g + PTC > 0 (79% vs 27%). The decision tree predicted the presence of DSA with a higher sensitivity and accuracy than did C4d staining (Figure 2).16 Finally, any degree of microcirculation inflammation in late kidney transplant biopsies strongly indicated the presence of DSA and predicted progression to graft failure.

FIGURE 2  New diagnostic algorithm for antibody-mediated microcirculation inflammation in kidney transplants. DSA = donor-specific antibodies. Adapted, with permission, from Sis et al.16

Efforts have also been directed at improving the grading of immunohistology of C4d staining. Additional studies have begun looking at the membrane attack complex and complement regulatory molecules. Further studies with CD34 may help to define capillaritis and assess capillary injury. A C4d/CD34 double-immunofluorescence staining protocol for renal allograft frozen sections allows rapid and sensitive detection of C4d positivity and more accurate estimation of the C4d-positive fraction of PTCs.17

Improvements in antibody detection have been used to identify HLAs corresponding to the major histocompatibility complex (eg, HLA-CW, HLA-DQ, and HLA-DP). Non-HLA and complement assays have been developed to assess antibody function; because all antibodies do not produce rejection, function is important. Antiendothelial antibodies have been associated with hyperacute AMR, poor outcomes, increased CMR, and elevated creatinine levels.18

Antibody detection also is improved by automation of the process with decreased run-to-run variation. The standard method of detecting pretransplant antibodies has been the complement-dependent cytotoxicity test of donor leukocytes. Solid-phase assays to detect HLA antibodies in pretransplant serum have revealed a greater number of sensitized patients, but the clinical impact of this finding is less certain. Smith et al19 described a method of detecting C4d-fixing HLA antibodies on Luminex beads in heart transplant recipients; detection of Luminex-positive DSA in pretransplant serum provides a powerful negative predictor of graft survival, especially if it binds C4d.

Identification and staining of natural killer (NK) cells may lead to an additional unique marker for AMR. NK-cell transcripts are increased in biopsies with AMR, whereas T-cell transcripts are increased in T-cell–mediated rejection. However, NK and T cells share many features, creating potential ambiguity. Research supports the distinct role of NK cells in late AMR, but it also indicates a role for NK transcript-expressing cells (NK or T cells with NK features) in both T-cell–mediated rejection and inflammation associated with injury and atrophy scarring.20

ANTIBODY MONITORING IN TRANSPLANT RECIPIENTS
Based on a presentation by David N. Rush, MD, Professor and Head, Section of Nephrology, Department of Internal Medicine, University of Manitoba Health Sciences Center, Winnipeg, Manitoba, Canada

Monitoring DSA in Sensitized Renal Transplant Recipients
Renal transplant candidates with evidence of DSA have an increased risk of AMR. The baseline DSA level correlates with risk of early and late antibody-mediated graft injury. Patients having a very high DSA level also have high rates of AMR and poor long-term allograft survival, which highlights the need for improved therapy.21

Low-level DSA that is detectable using single-antigen flow beads (SAFBs) but not detectable using complement-dependent cytotoxicity crossmatching represents a risk factor for early graft rejection.22 AMR is associated with the development of high DSA levels post transplant, and protocols aimed at maintaining DSA at lower levels may decrease the incidence of AMR.23

The monitoring of alloantibody levels following transplantation might facilitate the early diagnosis of chronic rejection. In a recent study by Kimball et al24 in patients who exhibited positive flow cytometric crossmatch (FCXM) at the time of transplant, distinct posttransplant profiles emerged that were associated with different clinical outcomes. Two thirds of patients showing complete elimination of FCXM and solid-phase assay reactions within 1 year had few adverse events and 95% 3-year graft survival. In contrast, the remaining third failed to eliminate FCXM or solid-phase reactions directed against HLA class I or II antibodies. The inferior graft survival (67%) with loss in this latter group was primarily due to chronic rejection. The systematic assessment of longitudinal changes in alloantibody levels, by either FCXM or solid-phase assay, can help in the identification of patients at increased risk of developing chronic rejection.

Biopsies are useful in detecting AMR among patients with DSA. Surveillance biopsies obtained during the first year post transplant in patients with positive crossmatches have been shown to be useful by uncovering clinically occult processes and phenotypes, which, without intervention, could diminish allograft survival and function.25 Screening biopsies also may be useful in identifying patients who are more likely to develop subclinical AMR. 26

The baseline DSA level correlates with the risk of early and late alloantibody-mediated allograft injury.21 The risk of both AMR and graft loss directly correlates with peak HLA-DSA strength. Quantification of HLA antibodies allows stratification of immunologic risk.27 Defining the clinical relevance of DSA detected by SAFBs is important, because these assays are increasingly used for pretransplant risk assessment and organ allocation. Research supports the use of SAFBs for risk assessment and organ allocation; findings suggest that improvement of the positive predictive value of HLA-DSA defined by SAFBs will require an enhanced definition of pathogenic factors of HLA-DSA.28

The persistence of elevated DSA levels after treatment is more frequent in patients who experience graft loss than in those with preserved renal function. DSA post rejection can be quantified using solid-phase assays; 3 months after AMR, DSA titers are elevated in patients with graft loss.29

Monitoring for De Novo DSA
The production of panel-reactive lymphocytotoxic antibodies (PRA) in recipients of renal transplants is associated with antidonor reactivity and poor graft outcome.30 The presence of HLA antibodies post transplantation is predictive of subsequent graft failure, and the predictive value is increased among patients with elevated serum creatinine levels.31

The development of de novo DSA (dnDSA) at the time of late biopsy is primarily directed against class II antibodies and is associated with microcirculatory changes and subsequent graft failure.32 Pathology consistent with AMR can occur and progress in patients with dnDSA in the absence of graft dysfunction.33 The presence of HLA antibodies significantly correlates with lower graft survival, poor transplant function, and proteinuria. Screening for HLA antibodies post transplantation could be a good tool to follow patients who receive a renal transplant and would allow for timely modification of a patient’s immunosuppressive regimen.34,35

Multiple studies have shown that dnDSA develops prior to graft failure and before the onset of proteinuria or elevated serum creatinine levels. 33 Serial DSA measurement during treatment of AMR revealed that patients who had a > 50% reduction in solid-phase mean fluorescence intensity within 14 days of starting treatment experienced improved transplant survival at 21 months.35

Early studies of de novo HLA antibody titers used cytotoxicity assays that were less sensitive and accurate than those now available or used ELISA assays, which did not determine donor specificity. Most early studies only analyzed antibodies at one point in time, early post transplant, whereas DSA often first appears late post transplant.35,36 A recent study found that dnDSA developed in 15% of low-risk renal transplant recipients more than 5 years post transplant; it was associated with a 40% decrease in 10-year graft survival.

Independent risk factors for dnDSA development are HLA-DRβ1 mismatch, nonadherence, and a strong trend toward clinical rejections before dnDSA onset. 33 The dominant strategy for detecting AMR in patients with pretransplant DSA should be surveillance biopsy. Serial DSA monitoring should supplement biopsy data. Screening for dnDSA in unsensitized patients should be based on serial HLA antibody screening, starting 6 months post transplant.

TREATMENT OF DETECTED ANTIBODY AND AMR: WHAT’S NEW?
Based on a presentation by Mark D. Stegall, MD, Professor of Surgery, Mayo Clinic, Rochester, Minnesota

Increases in DSA levels post transplant are associated with AMR, but this increase may be transient. Burns et al23 made several important points regarding AMR in crossmatch-positive kidney transplant recipients. First, AMR occurs across a wide spectrum of baseline DSA levels, as determined by T-cell and B-cell flow crossmatch (BFXM) levels, including those associated with a negative T-cell antihuman­­-globulin crossmatch. Second, the risk of AMR generally increases with increasing baseline DSA levels, but the occurrence is still unpredictable. Third, prior kidney transplant does not increase the incidence or severity of AMR when compared with other methods of sensitization. Fourth, anti-class II DSA alone or with anti-class I alloantibodies plays an important role in AMR and may be the sole cause of AMR. Therefore, post-transplant monitoring with BFXM or SAFBs coupled with early intervention to prevent or ameliorate the impact of AMR has been recommended.

Different strategies appear to improve the success of AMR management, but no best method has yet emerged. Recent data from a study of AMR treatment by Lefaucheur and colleagues29 showed that administration of high doses of intravenous immune globulin (IVIG) alone is inferior to combined use of plasmapheresis, IVIG, and treatment with anti-CD20 monoclonal antibody to treat AMR. In addition, DSA post rejection could be quantified using solid-phase assays; 3 months after AMR, DSA titers are elevated in patients with graft loss.

Sensitized renal transplant recipients with high DSA titers commonly develop AMR, which may cause acute graft loss or shorten allograft survival. Stegall et al37 reported that inhibition of terminal complement activation with eculizumab decreases the incidence of early AMR in sensitized renal transplant recipients.

Current antihumoral therapies used in transplantation and the treatment of autoimmune disease do not target the mature antibody-producing plasma cell. Bortezomib is a first-in-class proteosomal inhibitor that was approved by the US Food and Drug Administration for the treatment of plasma cell–derived tumors. Bortezomib therapy provides effective treatment of AMR and ACR with minimal toxicity and results in sustained reduction in immunodominant­ and non-immunodominant DSA levels.38

CONCLUSION
Current research has led to better understanding of both acute and chronic AMR. The results of ongoing prospective, randomized, long-term studies should lead to further understanding of the intricate pathways of organ rejection. Pretransplant protocols that desensitize patients by depleting antibody-secreting plasma cells are needed. Post-transplant protocols that prevent or treat transplant glomerulopathy are a focus for future research. Developing and defining the role of prolonged eculizumab therapy are needed.

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Dr. Gray is Assistant Professor of Surgery, Division of Transplant Surgery, University of Alabama at Birmingham, Birmingham, Alabama.

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