C4d staining in post-reperfusion renal biopsy is not useful for the early detection of antibody-mediated rejection when CDC crossmatching is negative (original) (raw)
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Kidney International, 2013
In order to define the intensity of immunosuppression, we examined risk factors for acute rejection in desensitization protocols that use baseline donor-specific antibody levels measured as mean fluorescence intensity (MFI max). The study included 146 patients transplanted with a negative flow crossmatch and a mean follow-up of 18 months with the majority (83%) followed for at least 1 year. At the time of transplant, mean-calculated panel-reactive antibody and MFI max ranged from 10.3-57.2% and 262-1691, respectively, between low-and high-risk protocols. Mean MFI max increased significantly from transplant to 1 week and 1 year. The incidence of acute rejection (mean 1.65 months) as a combination of clinical and subclinical rejection was 32%, including 14% cellular, 12% antibody-mediated, and 6% mixed rejection. In regression analyses, only C4d staining in post-reperfusion biopsies (hazard ratio 3.3, confidence interval 1.71-6.45) and increased specific antibodies at 1-week post transplant were significant predictors of rejection. A rise in MFI max by 500 was associated with a 2.8-fold risk of rejection. Thus, C4d staining in postreperfusion biopsies and an early rise in donor specific antibodies after transplantation are risk factors for rejection in moderately sensitized patients.
Journal of the American Society of Nephrology : JASN, 1999
The distinction between acute humoral rejection (AHR) and acute cellular rejection (ACR) in renal allografts is therapeutically important, but pathologically difficult. Since AHR is probably mediated by antibodies to the donor endothelium that activate the classical complement pathway, it was hypothesized that peritubular capillary C4d deposition might distinguish this group. Renal biopsies (n = 16) from 10 patients with AHR who had acute graft dysfunction, neutrophils in peritubular capillaries, and a concurrent positive cross-match were stained for C4d by immunofluorescence. Control biopsies for comparison showed ACR (n = 14), cyclosporin A toxicity (n = 6), or no abnormality (n = 4). Peribiopsy sera were tested for anti-donor HLA antibody. C4d deposited prominently and diffusely in the peritubular capillaries in all AHR biopsies (16 of 16). IgM and/or C3 were also present in 19 and 44%, respectively. With two-color immunofluorescence, C4d was localized in basement membranes (type...
C4d staining in renal allograft biopsies with early acute rejection and subsequent clinical outcome
Clinical Journal of the American Society of Nephrology
Diffuse C4d staining in peritubular capillaries (PTCs) during an acute rejection episode (ARE) is the footprint of antibody-mediated rejection. In current clinical practice, diffuse C4d+ staining during acute rejection is regarded as an inferior prognostic sign. This case-control study investigated the prognostic role of mere C4d staining for graft outcome during an ARE in a well defined cohort of similarly ARE-treated patients. All kidney transplant recipients in the authors' center from January 1, 1995 to December 31, 2005 were reviewed. From these patients, 151 had a clinical ARE. Paraffin and/or frozen material was available for 128 patients showing a histologically proven ARE within the first 6 months after transplantation. All ARE patients were treated similarly with high-dose pulse steroids and in the case of steroid unresponsiveness with anti-thymocyte globulin. Biopsies were scored according to Banff criteria. Frozen and paraffin sections were stained by immunofluoresce...
Presentation and Outcomes of C4d-Negative Antibody-Mediated Rejection After Kidney Transplantation
American Journal of Transplantation, 2015
The updated Banff classification allows for the diagnosis of antibody-mediated rejection (AMR) in the absence of peritubular capillary C4d staining. Our objective was to quantify allograft loss risk in patients with consistently C4d-negative AMR (n ¼ 51) compared with C4d-positive AMR patients (n ¼ 156) and matched control subjects without AMR. All first-year posttransplant biopsy results from January 2004 through June 2014 were reviewed and correlated with the presence of donor-specific antibody (DSA). C4d-negative AMR patients were not different from C4d-positive AMR patients on any baseline characteristics, including immunologic risk factors (panel reactive antibody, prior transplant, HLA mismatch, donor type, DSA class, and anti-HLA/ ABO-incompatibility). C4d-positive AMR patients were significantly more likely to have a clinical presentation (85.3% vs. 54.9%, p < 0.001), and those patients presented substantially earlier posttransplantation (median 14 [interquartile range 8-32] days vs. 46 [interquartile range 20-191], p < 0.001) and were three times more common (7.8% vs 2.5%). One-and 2-year post-AMR-defining biopsy graft survival in C4d-negative AMR patients was 93.4% and 90.2% versus 86.8% and 82.6% in C4d-positive AMR patients, respectively (p ¼ 0.4). C4d-negative AMR was associated with a 2.56-fold (95% confidence interval, 1.08-6.05, p ¼ 0.033) increased risk of graft loss compared with AMR-free matched controls. No clinical characteristics were identified that reliably distinguished C4d-negative from C4d-positive AMR. However, both phenotypes are associated with increased graft loss and thus warrant consideration for intervention.
Advanced Biomedical Research, 2012
Background: C4d as a part of complement activation process is a marker for detecting antibody-mediated rejection (ABMR) and its positivity accompanied by positive donor specific antibody (DSA), and morphologic view of humoral rejection has been suggested to detect ABMR since 2003. Materials and Methods: 41 specimens of transplanted kidney biopsies gathered from 2006 to 2008 were evaluated for morphological changes on light microscopy, and nephro-pathologist made distinct diagnosis for all of specimens then c4d staining was done for all of them. The association between primary diagnosis without c4d staining and c4d scoring on peritubular capillaries and glomerular capillaries were evaluated to determine whether morphological changes were enough for distinct diagnosis or not. Results: Acute tubular necrosis (ATN) 27%, interstitial fibrosis and tubular atrophy (IF&TA) 17%, and T cell mediated rejection (TCMR) 22% were the commonest diagnosis on light microscopy, and 17% of all biopsies had diffuse positive c4d staining. There was not any report of ABMR in morphological evaluation while c4d positive staining was seen in some specimens (17%). It may result from masking of ABMR by other morphological changes such as TCMR and no specific histologic changes for ABMR on light microscopy. Conclusion: We would like to emphasize that c4d staining should be done for all of renal allograft biopsies, and pathologists all over the world should consider the probability of ABMR masked by other morphological changes on light microscopic evaluation.
Clinical Biochemistry, 2016
Objective: Antibody-mediated rejection (ABMR) is an important cause of kidney allograft injury. In the last two decades, detection of complement split product C4d along transplant capillaries, a footprint of antibodymediated classical complement activation, has evolved as a useful diagnostic marker of ABMR. While it was recognized that ABMR may occur also in the absence of C4d, numerous studies have shown that C4d deposition may indicate a more severe rejection phenotype associated with poor graft survival. Such studies suggest a possible diagnostic benefit of ex vivo monitoring the complement-activating capability of circulating alloantibodies. Design and methods: We reviewed the literature between 1993 and 2015, focusing on in vivo (biopsy workup) and in vitro detection (modified bead array technology) of HLA antibody-triggered classical complement activation in kidney transplantation. Results: Precise HLA antibody detection methods, in particular Luminex-based single antigen bead (SAB) assays, have provided a valuable basis for the design of techniques for in vitro detection of HLA antibodytriggered complement activation reflected by C1q, C4 or C3 split product deposition to the bead surface. Establishing such assays it was recognized that deposition of complement products to SAB, which critically depends on antibody binding strength, may be a cardinal trigger of the prozone effect, a troublesome in vitro artifact caused by a steric interference with IgG detection reagents. False-low IgG results, especially on SAB with extensive antibody binding, have to be considered when interpreting studies analyzing the diagnostic value of complement in relation to standard IgG detection. Levels of complement-fixing donor-specific antibodies (DSA) were shown to correlate with the results of standard crossmatch tests, suggesting potential application for crossmatch prediction. Moreover, while the utility of pre-transplant complement detection, at least in crossmatch-negative transplant recipients, is controversially discussed, a series of studies have shown that the appearance of posttransplant complement-fixing DSA may be associated with C4d deposition in transplant capillaries and a particular risk of graft failure. Conclusions: The independent value of modified single antigen bead assays, as compared to a careful analysis of standard IgG detection, which may be affected considerably by complement dependent artifacts, needs to be clarified. Whether they have the potential to improve the predictive accuracy of our current diagnostic repertoire warrants further study.
Clinical Nephrology, 2011
The use of C4d staining as a tissue marker for humoral immunity has served an important role in allowing pathologists to more accurately diagnose acute antibody-mediated rejection (AMR) in renal and other allograft biopsies, and also to recognize the contribution of humoral immunity to lesions of chronic renal allograft rejection, including transplant glomerulopathy. However, while C4d remains a specifi c marker of a humoral response, recent evidence indicates that a considerable fraction of renal allograft biopsies showing antibody-mediated injury are C4d-negative, even by immunofl uorescence. This review summarizes the current evidence supporting the existence of C4d-negative AMR, as well as evidence that this entity may, if untreated, lead to the development of scarring within the graft, transplant glomerulopathy and even graft loss.
Transplantation Proceedings, 2016
Background. Kidney transplant recipients who have pretransplant donor-specific human leukocyte antigen (HLA) antibodies have greater risk for developing allograft rejection and allograft loss. However, there is a varied effect of graft injury among patients with pretransplantation donor-specific antibodies (DSA). The difference of complement activating ability may be the reason why some DSA are detrimental to kidney allograft. This study aimed to investigate the association between pretransplantation C1q-binding DSA and clinical outcomes. Methods. This retrospective study included 48 pretransplant sera from kidney transplant recipients who had pretransplant DSA with negative complement-dependent cytotoxic (CDC) crossmatches. The IgG DSA testing and C1q testing were performed on a Luminex platform with single antigen bead assay. The clinical outcomes between C1qpositive and C1q-negative groups were compared. Results. C1q-positive DSA were detected in 12 out of 48 patients (25%). The incidences of antibody-mediated rejection (AMR) were higher among patients with C1q-positive DSA than patients with C1q-negative DSA (66.7% vs 41.7%). Nevertheless, there were no statistically significant associations between C1q-DSA and AMR (odds ratio 2.8, 95% CI 0.68e11.6, P ¼ .13) and between C1q-DSA and graft loss (odds ratio 0.52, 95% CI 0.09e2.89, P ¼ .44). The C1q-positive DSA group had significantly higher IgG DSA MFI than the C1q-negative DSA group (P < .001). Conclusion. C1q-binding ability of DSA in pretransplant sera of kidney recipients was not associated with antibody-mediated rejection and graft loss post-transplantation. In contrast with the clinical relevance of C1q testing in the post-transplantation setting, C1q testing in pretransplant sera has limited use for immunological risk assessment. S INCE the introduction of single antigen bead (SAB) combined with Luminex multiplex technology, the identification of antibody specificity has advanced tremendously. The use of SAB together with Luminex technology not only allows antibody identification with high precision, but also with high sensitivity [1]. However, due to the high sensitivity of the new technology, the clinical impact of donor-specific antibodies (DSA) detected only by solid phase assay is still controversial. Various studies have indicated the increased risk of antibody-mediated rejection and inferior outcomes when the transplantation is performed in the presence of DSA detected by SAB assay, but negative crossmatch [2e4]. However, many kidney transplant recipients with pretransplantation DSA detected only by Luminex assay did
Journal of clinical and diagnostic research : JCDR, 2016
Biopsy remains gold standard for diagnosis of Graft Dysfunction (GD). It guides clinical management, provides valuable insights into pathogenesis of early and late allograft injury and is indispensable for distinguishing rejection from non- rejection causes of GD. The primary aim of the study was to evaluate the diverse histomorphological lesions in renal allograft biopsy (RAB). Further, we determined the frequency of peritubular capillary (PTC) C4d positivity and its correlation with microvascular inflammation in Antibody Mediated Rejection (AMR). This was a prospective study on RAB over a period of 2 months. Histopathological evaluation was undertaken as per revised Banff'13 schema. Immunohistochemistry was performed to detect PTC C4d deposition. Sixty five diagnostic biopsies were evaluated. Mean patient age was 34 years and males were predominant. The time interval between graft biopsy and transplantation ranged from 5 days to 8 years, with 52.3% biopsies belonging to period...
Complement Activation in Acute Humoral Renal Allograft Rejection
Journal of the American Society of Nephrology, 1999
The distinction between acute humoral rejection (AHR) and acute cellular rejection (ACR) in renal allografts is therapeutically important, but pathologically difficult. Since AHR is probably mediated by antibodies to the donor endothelium that activate the classical complement pathway, it was hypothesized that peritubular capillary C4d deposition might distinguish this group. Renal biopsies (n ϭ 16) from 10 patients with AHR who had acute graft dysfunction, neutrophils in peritubular capillaries, and a concurrent positive crossmatch were stained for C4d by immunofluorescence. Control biopsies for comparison showed ACR (n ϭ 14), cyclosporin A toxicity (n ϭ 6), or no abnormality (n ϭ 4). Peribiopsy sera were tested for anti-donor HLA antibody. C4d deposited prominently and diffusely in the peritubular capillaries in all AHR