Impacts of donor-specific anti-HLA antibodies and antibody-mediated rejection on outcomes after intestinal transplantation in children.

AMR is a risk factor for graft failure after SBTx. We studied impact of DSAs and AMR in 22 children transplanted between 2008 and 2012 (11 isolated SBTx, 10 liver inclusive Tx, and one modified multivisceral Tx). Three patients never developed DSA, but DSAs were found in seven in the pre-Tx period and de novo post-Tx in 19 children. Pathology revealed cellular rejection (15/19), with vascular changes and C4d+. Patients were treated with IV immunoglobulins, plasmapheresis, and steroids. Rescue therapy included antithymocyte globulins, rituximab, eculizumab, and bortezomib. Pathology and graft function normalized in 13 patients, graft loss occurred in two, and death in seven. At the end of the follow-up, 15 children were alive (68%), 13 with functioning graft (59%). Prognosis factors for poor outcome after Tx were the presence of symptoms at AMR suspicion (P +.033). DSAs were often found following SBTx, mostly de novo. Resistant ACR or severe AMR is still difficult to differentiate, with a high need for immunosuppression in both. DSAs may precede development of severe disease and pathology features on the graft: relationship and correlation need to be better investigated with larger groups before and after Tx.

Antibody-Mediated Rejection in Lung Transplantation: Clinical Outcomes and Donor-Specific Antibody Characteristics.

In the context of lung transplant (LT), because of diagnostic difficulties, antibody-mediated rejection (AMR) remains a matter of debate. We retrospectively analyzed an LT cohort at Foch Hospital to demonstrate the impact of AMR on LT prognosis. AMR diagnosis requires association of clinical symptoms, donor-specific antibodies (DSAs), and C4d(+) staining and/or histological patterns consistent with AMR. Prospective categorization split patients into four groups: (i) DSA positive, AMR positive (DSA(pos) AMR(pos) ); (ii) DSA positive, AMR negative (DSA(pos) AMR(neg) ); (iii) DSA limited, AMR negative (DSA(Lim) ; equal to one specificity, with mean fluorescence intensity of 500-1000 once); and (iv) DSA negative, AMR negative (DSA(neg) ). AMR treatment consisted of a combination of plasmapheresis, intravenous immunoglobulin and rituximab. Among 206 transplanted patients, 10.7% were DSA(pos) AMR(pos) (n = 22), 40.3% were DSA(pos) AMR(neg) (n = 84), 6% were DSA(Lim) (n = 13) and 43% were DSA(neg) (n = 88). Analysis of acute cellular rejection at month 12 showed higher cumulative numbers (mean plus or minus standard deviation) in the DSA(pos) AMR(pos) group (2.1 ± 1.7) compared with DSA(pos) AMR(neg) (1 ± 1.2), DSA(Lim) (0.75 ± 1), and DSA(neg) (0.7 ± 1.23) groups. Multivariate analysis demonstrated AMR as a risk factor for chronic lung allograft dysfunction (hazard ratio [HR] 8.7) and graft loss (HR 7.56) for DSA(pos) AMR(pos) patients. Our results show a negative impact of AMR on LT clinical course and advocate for an early active diagnostic approach and evaluation of therapeutic strategies to improve prognosis.

Bortezomib as the sole post-renal transplantation desensitization agent does not decrease donor-specific anti-HLA antibodies.

Persistence of donor-specific anti-HLA antibodies (DSA) associated with antibody-mediated graft injuries following kidney transplantation predicts evolution toward chronic humoral rejection and reduced graft survival. Targeting plasma cells, the main antibody-producing cells, with the proteasome inhibitor bortezomib may be a promising desensitization strategy. We evaluated the in vivo efficacy of one cycle of bortezomib (1.3 mg/m(2)x 4 doses), used as the sole desensitization therapy, in four renal transplant recipients experiencing subacute antibody-mediated rejection with persisting DSA (>2000 [Mean Fluorescence Intensity] MFI). Bortezomib treatment did not significantly decrease DSA MFI within the 150-day posttreatment period in any patient. In addition, antivirus (HBV, VZV and HSV) antibody levels remained stable following treatment suggesting a lack of efficacy on long-lived plasma cells. In conclusion, one cycle of bortezomib alone does not decrease DSA levels in sensitized kidney transplant recipients in the time period studied. These results underscore the need to evaluate this new desensitization agent properly in prospective, randomized and well-controlled studies.

Outcome of subclinical antibody-mediated rejection in kidney transplant recipients with preformed donor-specific antibodies.

This study describes clinical relevance of subclinical antibody-mediated rejection (SAMR) in a cohort of 54 DSA-positive kidney transplant recipients receiving a deceased donor. In 3 months screening biopsies, 31.1% of patients met the criteria of SAMR. A total of 48.9% had an incomplete form of SAMR (g+/ptc+/C4d-negative) whereas 20% had no humoral lesions. Patients with SAMR at 3 months had at 1 year: a higher C4d score, ptc score, and arteriosclerosis score, higher rate of IFTA (100% vs. 33.3%, p < 0.01) and a higher rate of transplant glomerulopathy (43% vs. 0%, p = 0.02) compared to patients without 3-month SAMR. Patients with SAMR at 3 months exhibited at 1 year a higher class II MFImax-DSA and a lower mGFR compared to patients without SAMR (39.2 +/- 13.9 vs. 61.9 +/- 19.2 mL/min/1.73 m(2) respectively, p < 0.01). The group of patients with C4d-negative SAMR at 3 months developed more ptc and IFTA lesions, and lower GFR at 1 year in comparison to biopsies without humoral lesions. SAMR is a frequent entity in KTR with preexisting DSAs and promotes subsequent GFR impairment and development of chronic AMR. C4d-negative SAMR patients displayed an intermediate course between the no-SAMR group and the C4d+ SAMR group. Screening biopsies may be useful to recognize patients more likely to develop SAMR.

Comparison of combination Plasmapheresis/IVIg/anti-CD20 versus high-dose IVIg in the treatment of antibody-mediated rejection.

Different strategies appear to improve the success in treatment of antibody-mediated rejection (AMR), although no one best method has yet emerged. The objective of this study was to compare the efficacy of the combination of Plasmapheresis/intravenous immunoglobulin (IVIg)/anti-CD20-based regimes versus high-dose IVIg alone in the treatment of AMR. Group A (12 patients) was treated with high-dose IVIg between January 2000 and December 2003; group B (12 patients) was treated by Plasmapheresis/IVIg/anti-CD20 between January 2004 and December 2005. Graft survival at 36 months was 91.7% in group B versus 50% in group A (p = 0.02). Donor-specific human leukocyte antigens (DSA) levels detected by Luminex single antigen (Luminex SA) and ELISA, 3 months postrejection are significantly lower in group B than in group A: DSA ELISA class 2 score 6-8 (p = 0.02), DSA mean intensity of fluorescence (MFI) max (p = 0.009) and DSA mean MFI (p = 0.0004). The persistence of elevated DSA levels posttreatment is more frequent in patients with graft loss as compared to those with preserved renal function: score 6-8 on ELISA (p = 0.04); mean MFI (p = 0.00009) and MFImax (p = 0.018). We conclude that: (1) high dose IVIg alone is inferior to Plasmapheresis/IVIg/anti-CD20 as therapy for AMR and (2)DSA postrejection can be quantified using solid phase assays, showing that 3 months after AMR, DSA levels are higher in patients with graft loss.

Clinical relevance of preformed HLA donor-specific antibodies in kidney transplantation.

Since the pioneering work of Patel and Terazaki, the presence of an anti-donor anti-body of the IgG isotype, as demonstrated by a lymphocytotoxic assay on T cells, has been a contraindication to transplantation, due to the very high rate of graft loss reported (>80% in the first few weeks posttransplant). The advent of more sensible and specific techniques of detection of anti-HLA antibodies (such as ELISA or Luminex techniques) has questioned this dogma, with a number of reports showing that transplantation, despite the presence of an donor-specific antibody (DSA), could be done without excessive graft losses, despite higher rates of rejection. We thus decided to retrospectively screen a cohort of 237 patients consecutively transplanted in our unit. This study analyzes the influence of preformed DSA, identified by HLA-specific ELISA assays, on graft survival and evaluates the incidence of antibody-mediated rejection (AMR). Kidney graft survival at 8 years was significantly worse in patients with DSA. The incidence of AMR in patients with DSA was 9-fold higher than in patients without DSA and led to a significantly worse graft survival. The prevalence for AMR in patients with DSA detected on historic serum was 32.3% and was significantly more elevated in patients with strongly positive DSA (score 6-8) and in patients with his-toric positive crossmatches. Interestingly, those patients with DSA that did not experience AMR had the same graft survival as patients without DSA. Thus, the presence of preformed DSA is strongly associated with increased graft loss in kidney transplants, related to an increased risk of AMR. Our findings demonstrate the importance of detection and charac-terization of DSA before transplantation. Stratification of this immunological risk should be used both to determine kidney allocation and to devise specific strategies for these patients.

Clinical relevance of preformed HLA donor-specific antibodies in kidney transplantation.

This study analyzes the influence of preformed DSA, identified by HLA-specific ELISA assays, on graft survival and evaluates the incidence of antibody-mediated rejection (AMR) in patients with and without pregraft desensitization. Kidney graft survival at 8 years was significantly worse in patients with DSA (n = 43) than in those without DSA (n = 194)(p = 0.03). The incidence of AMR in patients with DSA is 9-fold higher than in patients without DSA (p < 0.001) and their graft survival is significantly worse than in DSA patients without AMR and in non-DSA patients (p = 0.005). The prevalence for AMR in patients with DSA detected on historic serum is 32.3% in nondesensitized patients and 41.7% in desensitized patients. The risk for AMR is significantly more elevated in patients with strongly positive DSA (score 6-8) compared to those with DSA score 4 (p < 0.001), and in patients with historic DSA+/CXM+ compared to those with DSA+/CXM- (p = 0.01). The presence of preformed DSA is strongly associated with graft loss in kidney transplants, related to an increased risk of AMR. Our findings demonstrate the importance of detection and characterization of DSA before transplantation. Stratification of this risk could be used to determine kidney allocation and to devise specific strategies for these patients.

Determinants of poor graft outcome in patients with antibody-mediated acute rejection.

This study analyzes the incidence and course of antibody-mediated rejection (AMR) in a cohort of 237 renal transplant patients followed for 30 +/- 20 months. Among these, 32 patients were considered to be at risk for AMR and received intravenous immunoglobulin (IVIg), either as preconditioning (Group A, n = 18) or at the time of transplant (Group B, n = 14). The prevalence of AMR was 27.8% in Group A, 57.1% in Group B and 3.9% in the remainder of the population. Although graft loss remains greater among AMR than for acute cellular rejection (ACR) or the overall transplant population, we have identified a good outcome group (GFR > 15 mL/min/1.73 m(2)) (n = 13), whose renal function at the end of follow-up was comparable to that of the general transplant population. The factors associated with bad outcome are: (1) immunologic: presence and/or persistence of donor-specific anti-HLA antibodies post-transplantation and (2) histologic: neutrophilic glomerulitis, peritubular capillary dilatation with neutrophil infiltrates and interstitial edema at the time of first biopsy; and at the time of late biopsy (3-6 months): lesions of vascular rejection, and monocyte/macrophage infiltrates in glomeruli and dilated peritubular capillaries. Persistence of C4d does not predict outcome. This study outlines for the first time the immunologic and histologic profiles of AMR patients with poor prognosis.