Features Of Antibody-mediated Rejection Research Articles

C3d and C4d Deposition Early After Lung Transplantation

Complement staining as a predictor of antibody-mediated rejection (AMR) after lung transplantation continues to be debated. In a cohort of 33 lung transplant recipients (LTRs) we assessed early post-transplant (<or=3 months) graft deposition of the complement factors C3d and C4d and correlated staining with clinical outcome. A retrospective analysis of allograft C3d and C4d deposition was performed by an experienced histopathologist blinded to clinical outcomes. Biopsies were graded 0 to 3 based on extent of septal capillary complement staining. Significant C3d and C4d staining (i.e., Grade >or=2 on more than one occasion) was observed in 20 and 11 LTRs, respectively. Complement staining was increased in LTRs with severe primary graft dysfunction or airway infection, but was not associated with acute cellular or chronic rejection, or with morphologic features of AMR. In a sub-group analysis we identified 9 LTRs who developed early bronchiolitis obliterans syndrome (BOS) in the absence of acute cellular rejection or cytomegalovirus reactivation, but they had significant lung allograft C3d/C4d deposition along with corroborative light-microscopic features suggestive of AMR. Complement activation, as judged by lung allograft deposition of C3d/C4d, is common early post-lung transplant and may be triggered by primary graft dysfunction and/or airway infection, and may play a role in the development of early BOS.

Renal allograft biopsies in the era of C4d staining: the need for change in the Banff classification system

C4d immunostaining in the peritubular capillaries (PTC) is a marker of antibody-mediated rejection (AMR). We evaluated the histopathologic diagnoses of 388 renal transplant biopsies since the implementation of routine C4d immunostaining at our center. Of these, 155 (40%) biopsies had evidence of acute cellular rejection (ACR), out of which 119 (77%) had pure ACR, 31 (20%) had ACR with concomitant features of AMR, and five (3%) had ACR with focal C4d staining. Sixty-four (16%) biopsies exhibited features of AMR [33 (52%) pure AMR, and 31(48%) concomitant AMR and ACR]. One hundred and fifty-five (40%) biopsies had features of interstitial fibrosis and tubular atrophy (IFTA). Of these, 20 (13%) had concomitant AMR [13 (8.5%) had pure AMR and seven (4.5%) had concomitant ACR and AMR]. Creatinine at the time of biopsy was higher in patients with mixed ACR and AMR and the clinical behavior of mixed lesions is more aggressive over time. Despite having a lower serum creatinine at the time of biopsy, patients with IFTA experienced gradual decline in graft function over time. The pathologic findings in renal allograft biopsies are often mixed and mixed lesions appear to have more aggressive clinical behavior. These findings suggest the need for change in the Banff classification system to better capture the complexity of renal allograft pathologies.

C4D Deposition and Positive Posttransplant Crossmatch Are Not Necessarily Markers of Antibody-Mediated Rejection in Renal Allograft Recipients

The aim of the study was to search for serologic, immunopathologic, and morphologic evidence of antibody-mediated rejection (AMR) among patients with acute renal allograft dysfunction. The study included 19 patients with episodes of acute rejection (ARE) within the first year after transplantation. All patients had negative crossmatch tests before transplantation. Patients underwent biopsy for histologic and C4d examinations. All patients were monitored for donor-specific HLA alloantibodies during the first posttransplant year. Complement-dependent cytotoxic crossmatches were performed with donor lymphocytes. In eight patients, the crossmatch test results changed to positive during ARE. In all biopsies except one with cortical infarction, we observed C4d staining (group 1). The biopsies of four patients showed histologic changes of AMR, and all of their grafts were lost. In one patient, cellular and vascular rejection (Banff II) were present; in two, Banff I; and in one, borderline lesions. These results were compared with 11 patients with ARE but negative posttransplant crossmatches and negative staining for C4d (group 2). The histologic findings in the biopsies of these patients were cellular interstitial and vascular rejection (Banff I and Banff II). With no features suggestive of AMR. During the first year after transplantation, the creatinine levels of group 1 patients, were significantly higher than group 2 patients. One-year graft survival was 50% in group 1 and 91% in group 2. Conclusions C4d and a positive posttransplant crossmatch were not associated with histologic features of AMR in half of the ARE. Nevertheless, C4d deposition and positive posttransplant crossmatches correlated with allograft injury among renal transplant patients.

Characterization of rejection episodes in patients following positive crossmatch and ABO-incompatible live donor renal transplantation

For kidney transplant recipients with donor-specific antibody (DSA) to HLA- (+XM) or ABO-antigens (ABOI), there is a need to improve detection and treatment of antibody-mediated rejection (AMR). The methods included a retrospective review of consecutive patients that received plasmapheresis and immune globulin (PPIVIg) to abrogate +XM or ABOI. Twelve patients were transplanted after PPIVIg (+XM = 9, ABOI = 2, +XM/ABOI = 1). No hyperacute rejections occurred. Rejection occurred in seven patients [four AMR, three acute cellular rejection (ACR)]. In four +XM patients, DSA was detected during graft dysfunction despite lack of histologic and C4d features of AMR. In one patient, DSA preceded the histologic and immunofluorescent features of AMR. In another patient with borderline changes and DSA, graft function improved after PPIVIg, despite lack of histologic or immunofluorescent evidence of AMR. One patient with Banff IIA ACR and DSA treated with antithymocyte antibody but not PPIVIg had recurrent rejections and poor graft function. In +XM and ABOI recipients with graft dysfunction: (i) DSA may represent AMR in the absence of C4d or histologic features of AMR; (ii) DSA can precede C4d or light microscopic features of AMR; (iii) A poor outcome may result if DSA or continued allograft dysfunction is present and not treated despite a negative biopsy.

Post‐transplant therapy with high‐dose intravenous gammaglobulin: Applications to treatment of antibody‐mediated rejection

B-cells and their products (antibodies) are now recognized as important mediators of allograft rejection. This represents a significant departure from previous doctrine where the T-cells were felt to be of paramount importance. Antibody-mediated rejection (AMR) has emerged as a significant and common complication of transplantation. The development of donor-specific (anti-HLA class I and class II) antibodies is known to correlate strongly with the development of AMR. Recognition of the unique features of AMR that were often confused with non-specific acute tubular injury is aided considerably by improvements in monitoring of anti-HLA antibodies and the immunopathologic demonstration of C4d staining in affected capillary beds. Although imperfect, the demonstration of C4d (a complement breakdown product) staining in an allograft, especially accompanied by the presence of anti-HLA antibodies in the recipient sera, strongly suggests a diagnosis of AMR. Thus, AMR is a complement-dependent, antibody-mediated disorder. AMR can occur as a de novo complication of transplantation in individuals not previously recognized to be sensitized to HLA antigens, but more often occurs as a complication of desensitization therapies in highly-HLA sensitized patients. AMR may also constitute a significant portion of what is now referred to as chronic allograft nephropathy (CAN). The prognosis of C4d (+) AMR is poor as current therapies for treatment of AR are directed primarily at the T-cell. Until recently, no therapeutic options existed to address this problem from a primary etiological standpoint. Here we discuss the use of high dose IVIG as an option for treatment of AMR. We have significant experience with this approach which is outlined here. IVIG has many ideal advantages as a therapy for AMR. First, it can down regulate B-cell activation and antibody production, second, it can induce anti-inflammatory cytokines and contains blocking antiidiotyic antibodies to anti-HLA antibodies and third, IVIG has the unique ability to block complement-mediated injury through inhibition of C3 activation. Further clinical trials are necessary to prove efficacy for treatment of AMR.