Incidence Of Antibody-mediated Rejection Research Articles

Type and Extent of HLA Mismatch and Antibody-Mediated Rejection in Heart Transplantation

Purpose Advances in ex-vivo organ perfusion may soon allow for extension of the time between organ procurement and heart transplant. However, presently the necessity for short allograft ischemic time in heart transplantation makes human leukocyte antigen (HLA) matching between donors and recipients impractical. Our aim was to investigate whether HLA mismatch is correlated with antibody mediated rejection (AMR) in heart transplantation. Methods and Materials The records of patients transplanted at the UTAH Cardiac Transplant Program between 1992 and 2011 were reviewed. HLA-mismatch at major antigen class I loci HLA-A and HLA-B, and class II loci HLA-DR and HLA-DQ, were analyzed using the Cox proportional hazards regression model. AMR was defined with the occurrence of ≥ 3 AMR episodes. Results Four hundred and fifty one patients met our inclusion criteria, 77% were male and the age was 45±19 years. HLA-DR and DQ have significant association with the incidence of AMR within the first year and at any time ( table ). There was no significant difference in the incidence of antibody mediated rejection (AMR) in patients with HLA class I mismatch. Conclusions HLA-DR and HLA-DQ mismatch appear to be associated with increased incidence of AMR after heart transplant. Prospective HLA class II antigens matching may result in reduced incidence of AMR and better outcome in heart transplantation. [ Figure 1 ]

Pre-Transplant Circulating Antibodies Predict Antibody-Mediated Rejection Using the New ISHLT Grading Scale

Purpose The presence of pre-transplant circulating anti-HLA antibodies (PRA) portend worse survival and increase the risk of antibody-mediated rejection (AMR) after transplantation. The diagnosis of AMR is now standardized with the new ISHLT grading scale. The purpose of the current study was to determine whether the presence of pre-transplant PRA is associated with an increased incidence of AMR according to the new ISHLT AMR grading scale. Methods and Materials 106 heart transplant recipients transplanted January 2010 to July 2011 were divided into groups based on the peak pre-transplant PRA: 0%, 1-25%, and 26-100%. 1152 biopsies from the 106 patients were examined. Endpoints were total number of pAMR episodes, highest grade of pAMR on biopsy, and incidence of treated AMR. Results Of the 106 patients, 66 had PRA 0%, 10 had PRA 1-25%, and 30 had PRA 26-100%. Patients with elevated PRA were younger, more often female, and more likely to have a ventricular assist device. Patients with elevated pre-transplant PRA had a higher incidence of pAMR on biopsy, a higher incidence of higher grade pAMR, were more likely to have AMR requiring treatment, and had a higher median number of pAMR episodes ( Table ). Conclusions Pre-transplant circulating anti-HLA antibodies are associated with more frequent pAMR on biopsy, higher grade of pAMR on biopsy, a higher incidence of treated AMR. This suggests that patients with elevated pre-transplant PRA should be considered for augmentation of immuonosuppression. Peak PRA 0% (66 pts; 701 biopsies) Peak PRA 1-25% (10 pts; 113 biopsies) Peak PRA 26-100% (30 pts; 338 biopsies) pAMR0 98% (701) 88% (100/113) 85% (286/338) pAMR1 2% (12/701) 10% (11/113) 11( (37/338) pAMR2 0 2% (2/113) 4% (15/338) pAMR3 0.1% (1/701) 0 0 Total pAMR 2% (13/701) 12% (13/113) 15% (52/338) Treated AMR 0 10% (1/10) 17% (5/30) Median AMR episodes per patient 1 1.5 3

Terminal Complement Inhibition Decreases Antibody-Mediated Rejection in Sensitized Renal Transplant Recipients

Sensitized renal transplant recipients with high levels of donor-specific alloantibody (DSA) commonly develop antibody-mediated rejection (AMR), which may cause acute graft loss or shorten allograft survival. We examined the efficacy of terminal complement inhibition with the humanized anti-C5 antibody, eculizumab, in the prevention AMR in renal transplant recipients with a positive crossmatch against their living donor. The incidence of biopsy-proven AMR in the first 3 months posttransplant in 26 highly sensitized recipients of living donor renal transplants who received eculizumab posttransplant was compared to a historical control group of 51 sensitized patients treated with a similar plasma exchange (PE)-based protocol without eculizumab. The incidence of AMR was 7.7% (2/26) in the eculizumab group compared to 41.2% (21/51) in the control group (p = 0.0031). Eculizumab also decreased AMR in patients who developed high levels of DSA early after transplantation that caused proximal complement activation. With eculizumab, AMR episodes were easily treated with PE reducing the need for splenectomy. On 1-year protocol biopsy, transplant glomerulopathy was found to be present in 6.7% (1/15) eculizumab-treated recipients and in 35.7% (15/42) of control patients (p = 0.044). Inhibition of terminal complement activation with eculizumab decreases the incidence of early AMR in sensitized renal transplant recipients (ClincalTrials.gov number NCT006707).

How the latest evidence from clinical research informs patient care

How the latest evidence from clinical research informs patient care

Luminex-Based Desensitization Protocols: The University of Wisconsin Initial Experience

We have demonstrated that immunodominant donor-specific antibody (DSA) more than 100 mean fluorescence intensity (MFI) at the time of transplant is associated with a significantly higher risk of rejection. We now present short-term outcomes of DSA-based desensitization (DSZ) strategies in patients with a negative complement-dependent cytotoxicity crossmatch. Between January 1, 2009, and January 1, 2010, live-donor kidney transplant recipients were divided into three protocols based on their immunodominant DSA MFI pretransplant (D1: 100-500, D2: 501-1000, and D3: 1001-3000). Deceased donor kidney transplant recipients were stratified into two protocols (D4: 501-1000 and D5: 1001-3000). The intensity of the conditioning treatment increased with DSA levels and included thymoglobulin induction, plasmapheresis, and intravenous immunoglobulin in the highest risk groups. We compared outcomes between desensitized patients (DSZ) and those undergoing no DSZ (or D0) during the same interval. Forty-eight of 249 (23%) kidney transplants underwent DSZ (n=20, 4, 3, 4, and 17 in D1-D5 protocols, respectively). There was more retransplantation (50% vs. 18%, P<0.001) and live donor transplantation (56% vs. 30%, P<0.001) in the DSZ group. In this group, mean peak panel reactive antibody and MFI at transplant were 51% ± 7% and 960 ± 136, respectively. The incidence of antibody-mediated rejection (25% vs. 12.5%, P=0.008) and acute cellular rejection (23% vs. 14%, P=0.02) was greater in the DSZ group. However, mixed rejection (8%), graft loss (0 vs. 6), patient death (0 vs. 3), cytomegalovirus infection (15% vs. 12%), and 1-year serum creatinine (1.4 ± 0.5 and 1.4 ± 0.4 mg/dL) were similar between DSZ and no-DSZ groups. CONCLUSION.: Long-term follow-up is needed to determine the role of Luminex-based strategies in current preconditioning regimens.

Pretransplant IgG Subclasses of Donor-Specific Human Leukocyte Antigen Antibodies and Development of Antibody-Mediated Rejection

The subclass of IgG antibodies contributes to their capability to activate complement. It is currently unknown whether the pretransplant IgG subclass composition allows distinguishing harmful from presumably irrelevant donor-specific human leukocyte antigen (HLA) antibodies (HLA-DSA) detected by single-antigen flow beads (SAFB). Seventy-four patients transplanted in the presence of HLA-DSA were investigated. HLA-DSA characteristics were not different between patients experiencing antibody-mediated rejection (AMR) (n=40) and patients who did not (n=34) experience AMR. Sera were reanalyzed using SAFB with IgG subclass-specific reporter antibodies. The 74 patients had in total 141 HLA-DSA. IgG1 was the predominant subclass (78%), followed by IgG2 (49%), IgG3 (36%), and IgG4 (20%). When grouped according to the complement-activating capability, only 4 of 74 patients (5%) had exclusively weak/no complement-activating HLA-DSA (i.e., IgG2 and IgG4), 21 of 74 patients (28%) had isolated strong complement-activating HLA-DSA (i.e., IgG1 and IgG3), and 46 of 74 patients (62%) had a mixture of both. There was no difference between the strong complement-activating and the mixture group regarding incidence of AMR (57% vs. 54%; P=0.81), phenotypes of AMR (P=0.70), and death-censored allograft survival at 5 years (78% vs. 78%; P=0.74). Interestingly, patients with exclusively weak/no complement-activating HLA-DSA (n=4) had a numerically lower incidence of AMR (25%) and no allograft loss has occurred yet. In 90% of patients, pretransplant HLA-DSA are composed of isolated strong or a mixture of strong and weak/no complement-activating IgG subclasses. Because outcomes in these two groups were similar, pretransplant IgG subclass analysis is likely not providing substantial value beyond the standard IgG SAFB assay for pretransplant risk stratification.

Soluble CD30 and Hepatocyte growth factor as predictive markers of antibody-mediated rejection of the kidney allograft

Our retrospective study was aimed to assess the relevance of pre- and post-transplant measurements of serum concentrations of the soluble CD30 molecule (soluble CD30, sCD30) and the cytokine Hepatocyte growth factor (HGF) for prediction of the risk for development of antibody-mediated rejection (AMR) in kidney transplant patients. Evaluation of sCD30, HGF levels and the presence of HLA-specific antibodies in a cohort of 205 patients was performed before, 2 weeks and 6 months after transplantation. Patients were followed up for kidney graft function and survival for two years. We found a tendency of higher incidence of AMR in retransplanted patients with elevated pre-transplant sCD30 (≥ 100 U/ml) (p = 0.051), however no such correlation was observed in first-transplant patients. Kidney recipients with simultaneously high sCD30 and HLA-specific antibodies (sCD30+/Ab+) before transplantation had significantly lower AMR-free survival compared to the other patient groups (p < 0.001). HGF concentrations were not associated with the incidence of AMR at any time point of measurement, nevertheless, the combined analysis HGF and sCD30 showed increased incidence of AMR in recipients with elevated pretransplant sCD30 and low HGF levels. Conclusion: the predictive value of pretransplant sCD30 for the development of antibody-mediated rejection after transplantation is significantly potentiated by the co-presence of HLA specific antibodies. The role of HGF as a rejection-protective factor in patients with high pretransplant HGF levels would need further investigation.

Therapeutic apheresis before and after kidney transplantation

Kidney transplantation is considered the treatment of choice for most individuals with end-stage kidney disease, as well as the most cost-effective renal replacement therapy for the health care system that serves them. Immunologic sensitization, defined by the presence of antibodies directed against foreign HLA (or so called, donor specific antibodies, or DSA), is a significant barrier to kidney transplantation. Further, the presence of DSA is associated with an increase in the incidence of antibody-mediated rejection and decreased graft survival following transplantation. Therapeutic plasma exchange, an extracorporeal therapy directed at removing plasma proteins, including DSA, has proven to be an important part of a comprehensive strategy to minimize the effect of sensitization before, and following kidney transplantation. As such, it offers the promise of increasing access to transplantation, as well as improving outcomes following transplantation. In this concise narrative review, we describe more specifically the benefits of kidney transplantation, the epidemiology of kidney transplantation in the United States, the clinical significance of anti-HLA antibodies, and the evidence supporting a role for therapeutic plasma exchange before and after kidney transplantation.

Isoagglutinin adsorption in ABO-incompatible transplantation

As the demand for kidney transplantation is constantly growing methods to expand the donor pool have become increasingly important. ABO-incompatibility has hitherto been regarded as an absolute contraindication to living donor donation. However, as ABO-incompatibility has accounted for the majority of living donor exclusions, efforts have been made to overcome this immunologic barrier. Successful desensitization protocols thus far, have combined plasmapheresis for antibody removal with splenectomy to reduce the antibody producing B-cell pool, in addition to quadruple immunosuppression. Although good graft function has been achieved, the high risks involved have been deterrent. We have developed a protocol for ABO-incompatible kidney transplantation based on antigen-specific immunoadsorption and rituximab, in combination with standard maintenance immunosuppression (tacrolimus, mycophenolate mofetil and corticosteroids). We hypothesized that the anti-A/B antibodies could be effectively eliminated and good graft function achieved, without the complications of coagulopathy and transfusion reactions associated with plasmapheresis. Furthermore, we hypothesized that the substitution of splenectomy with a single dose of the anti-CD20 antibody rituximab would further reduce surgical risk as well as the risk of infectious complications. In 2001 the program for ABO-incompatible kidney transplantation was started at our center. To date 50 ABO-incompatible kidney transplantations have been performed according to the protocol based on antigen-specific immunoadsorption and rituximab. Safety and efficacy of the protocol has been evaluated in several studies, all showing that the antigen-specific immunoadsorption is well tolerated and without any serious side effects. Patient and graft survival as well as kidney function have been comparable to that of ABO-compatible living donor kidney transplantation and the incidence of antibody-mediated rejection 0%. We conclude that AB0-incompatible kidney transplantation using a protocol based on antigen-specific immunoadsorption and rituximab, in combination with triple immunosuppressive therapy is safe and effective. ABO-incompatibility following this protocol does not have a negative impact on graft function. ABO-incompatible kidney transplantation is equivalent to standard ABO-compatible living donor kidney transplantation.

Outcomes of Simultaneous Liver/Kidney Transplants Are Equivalent to Kidney Transplant Alone: A Preliminary Report

With adoption of Model for End-Stage Liver Disease, the number of simultaneous liver-kidney transplants (SLK) has greatly increased. A recent registry study questioned the equity of allocating kidney transplants (KTx) simultaneously with liver transplantation due to poor outcomes (Locke et al., Transplantation 2008; 85: 935). To investigate outcome of KTx in SLK, all SLK (n=36) performed at our center from January 2000 to December 2007 were reviewed and KTx outcomes compared with those of kidney transplant alone (KTA) performed during that period (n=1283). We also reviewed whether pretransplant panel reactive antibody and donor-specific antibody affected KTx outcome in SLK. One- and 3-year KTx and patient survival were not different between KTA and SLK regardless of sensitization level. There were 348 (27%) KTx failures in KTA vs. 6 (17%) in SLK (NS). Overall freedom from acute cellular rejection (ACR) and antibody-mediated rejection (AMR) in SLK was 93 and 96% at 3 years, compared with 72 and 78% in KTA (P=0.0105 and P=0.0744, respectively). Sensitized KTx recipients had more ACR and AMR (32 and 38%) at 3 years compared with nonsensitized recipients (28 and 20%) (P=0.23 and 0.0001, respectively). No differences in ACR and AMR were observed when SLK was divided and level of sensitization compared (P=0.17 and 0.65, respectively). SLK is a life-saving procedure with excellent patient and graft survival. AMR incidence in the KTx appears reduced in SLK compared with KTA regardless of level of preoperative panel reactive antibody. A high level of donor-specific antibody should not preclude simultaneous transplantation when clinically indicated.

Prolonged allograft ischemic time is not associated with higher incidence of antibody-mediated rejection

Prolonged allograft ischemic time is not associated with higher incidence of antibody-mediated rejection

ABO Incompatible Renal Transplantation: A Paradigm Ready for Broad Implementation

The requirements for potent immunosuppression coupled with the formidable risk of irreversible antibody-mediated rejection (AMR) have thus far limited the expansion of ABO incompatible (ABOi) kidney transplantation. We present a retrospective review of our single-center experience with 60 consecutive ABOi kidney transplants and describe the evolution of our treatment protocol to one that consists only of a brief escalation in immunosuppression without long-term B-cell suppression from splenectomy or anti-CD20. The 1-, 3-, and 5-year graft survival rates for the cohort were 98.3%, 92.9%, and 88.7%, respectively, which is comparable with United Network for Organ Sharing data for compatible live donor transplants. No instances of hyperacute rejection were observed, and no grafts were lost secondary to AMR. In fact, fewer than 15% of the patients experienced a clinical episode of AMR, and rejections were mild. Elimination of B-cell ablative therapies did not result in an increased incidence of AMR. Excellent graft function persists with a current median creatinine clearance of 60 mL/min. The findings of this study and the relatively simple therapeutic regimen used should facilitate widespread application of ABOi kidney transplantation resulting in one of the most rapid escalations in access to organs in the modern era of kidney transplantation.

Alemtuzumab Induction and Antibody-Mediated Kidney Rejection After Simultaneous Pancreas-Kidney Transplantation

The best induction agent for simultaneous pancreas-kidney transplantation (SPKT) remains the subject of debate. Alemtuzumab is effective in preventing acute cellular rejection (ACR) in SPK recipients and has been used to prevent antibody-mediated rejection (AMR) in sensitized kidney transplant candidates. A retrospective cohort study was performed including 136 SPK recipients receiving maintenance immunosuppression with tacrolimus, mycophenolic acid prodrugs, and prednisone. Two groups were compared: those who received induction with alemtuzumab (n=97) and those induced with basiliximab (n=39). Kidney ACR was more frequent in SPKT induced with basiliximab (2-year 12.8% vs. 3.1%, P=0.04), but the incidence of AMR was similar (2-year 18% with basiliximab vs. 13.8% with alemtuzumab, P=NS). Kidney rejection was associated with clinical pancreas rejection in 70% of cases, without differences between the groups. Postrejection kidney graft survival was similar in both groups (2-year basiliximab/alemtuzumab 94.7%/91.2%), but death-censored kidney graft survival was lower with alemtuzumab (100%/91.2%, P=0.056). In the basiliximab group, the predominant cause of kidney loss was death-with-function, whereas in the alemtuzumab group AMR accounted for all losses. Pancreas graft survival was similar in both groups, yet more pancreas losses due to acute rejection occurred in alemtuzumab-treated patients (4 vs. 1). Kidney AMR is more common than ACR in SPKT recipients treated with alemtuzumab, tacrolimus, mycophenolic acid, and steroids. ACR is better prevented by alemtuzumab than basiliximab, but no relevant difference is found in prevention of AMR. Despite the high incidence of AMR, survival rates are excellent in both groups.

Poor graft outcome in recipients withde novodonor-specific anti-HLA antibodies after living related kidney transplantation

Antibody-mediated rejection (AMR) is now widely recognized as a major problem in organ transplantation. This study was conducted to investigate the relationship between newly developing anti-HLA antibodies post-transplantation (de novo Abs) and the outcome of living related kidney transplantation (LRKT). The subjects included 87 patients who had received living donor kidney allografts at our institution. Panel reactive Ab assay (Flow-PRA) and graft biopsies were performed in all the recipients before and 6 months after the LRKT. The incidence of AMR, the donor specificity and time of appearance of the de novo Abs were retrospectively studied. Among the 87 LRKT recipients, 47 (54%) showed negative/negative (N/N) results, 15 (17%) showed positive/positive (P/P) results, 12 (14%) showed positive/negative results (P/N), and 13 (15%) showed negative/positive (N/P) results (de novo Abs) in the pre-/post-transplant Flow-PRA analysis. Among the 13 cases with de novo Abs, 5 (38%) had donor-specific Abs (DSA) and the remaining 8 (62%) had nondonor-specific Abs, as determined by LAB single antigen analysis. Eighty percent of the recipients with DSA showed evidence of AMR in the graft biopsies. The 5-year graft survival rate of the recipients with de novo Abs (N/P) was 69%, as compared with 96% in the N/N, 88% in the P/N and 93% in the P/P recipient groups (P = 0.009). LRKT recipients developing de novo Abs, especially those with DSA, showed a much higher incidence of AMR and a worse prognosis. Cautious monitoring for the appearance of anti-HLA Abs should be adopted after transplantation, even in patients without anti-HLA Abs prior to the transplantation.

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.

Present status of ABO-incompatible living donor liver transplantation in Japan

ABO-incompatible (ABO-I) living donor liver transplantation (LDLT) has been performed in Japan to overcome the organ shortage. Reported herein are the results of this approach through March 2006 in the National Registry of the Japan Study Group for ABO-incompatible transplantation. The questionnaires consisted of patient characteristics, operative data, and strategies for preventing antibody-mediated rejection (AMR). Data of 291 patients (follow-up period, 8 months-15 years; mean, 35 months) from 28 institutions were collected. Age was younger than 1 year in 68 patients, 1 to 7 years in 60 patients, 8 to15 years in 27 patients, and 16 years or older in 136 patients. The strategy for the blood-type barrier was heterogeneous in terms of recipient age, transplant center, and era. Local infusion and rituximab prophylaxis were applied in 2000 and 2003, respectively. The 5-year patient survival rate was 85% in infants and 52% in adults. The major causes of death were infection and antibody-mediated rejection (AMR). Multivariate analysis showed that age group, preoperative condition, antibody titer, and infection significantly affected survival. Age group, antibody titer, and local infusion treatment significantly affected the incidence of AMR. Patient survival rates were significantly higher and the incidence of AMR was significantly lower in adult patients after 2000 (3 year-survival rate, 29%, 56%, and 61%; incidence of AMR, 47%, 27%, and 16%, through May 2000, from June 2000 through October 2003, and from November 2003, respectively). ABO-incompatible LDLT is a standard practice in children, and local infusion and rituximab prophylaxis are promising in adults.

Effect of Induction Therapy Protocols on Transplant Outcomes in Crossmatch Positive Renal Allograft Recipients Desensitized with IVIG

Here we retrospectively examine the efficacy of two antibody induction regimens using Zenapax or Thymoglobulin in patients with positive complement-dependent cytotoxicity crossmatches (CDC-CMXs) desensitized with IVIG (intravenous immunoglobulin). Between January 1999 and March 2005, 97 patients with (+) CDC-CMXs received kidney transplants (43 deceased donors/54 living donors). All patients received at least 2 g/kg IVIG (maximum four doses) until an acceptable CMX was obtained. Patients were divided into two groups: 1. IVIG + Zenapax (n = 58), 2. IVIG + Thymoglobulin (n = 39). A total of 94% of patients in Group 1 and 84% in G2 have at least 2 years of follow up. Patient and graft survival was 96%/84% in Group 1 and 100%/90% in Group 2, p = NS. The number and severity of AR episodes were similar (36% Group 1 vs. 31% Group 2, p = NS) as was the incidence of C4d (+) antibody-mediated rejection (AMR) (Banff Grade II/III) (22% Group 1 vs. 21% Group 2). Mean serum creatinines (SCrs) at 24 months were similar (Group 1: 1.4 +/- 0.7 vs. G2: 1.5 +/- 0.7 mg/dL). Induction therapy with Zenapax or Thymoglobulin results in excellent patient, graft survival and graft function at 2 years. There was no increased risk of viral infections or malignancies with either agent. Neither agent was effective in reducing the incidence of AMR.