Risk Of Early Acute Rejection Research Articles

#681 Bw4/6 mismatch or missing donor Bw6 allele is a risk of early acute rejection in panel reactive antibodies negative kidney transplant recipients

Abstract Background and Aims Epitope and antibody diversity allows Bw4+ or Bw6+ patients to produce antibodies to Bw4 or Bw6 epitopes without breaking self-tolerance. This study assessed the prevalence of mismatched Bw4/6 or missing donor Bw6 allele in kidney transplant (KT) recipients with early acute rejection and its relation to patients and graft outcomes. Method A retrospective study included 40 live-related KT recipients divided into 2 equal groups. Group A: 20 KT recipients with early acute rejection in 1st 3 months post-KT and group B: 20 KT recipients with no rejection. Bw4/6 mismatches or missing donor Bw6 were examined in all patients with an assessment of the type of rejection, patients, and graft outcomes. Results The prevalence of Bw4/6 mismatch or missing donor Bw6 allele in patients with early acute rejection was 70% (14 patients). Bw4/6 mismatch represented 25% (5 patients) while missing donor Bw6 allele was 45% (9 patients) while the prevalence of Bw4/6 mismatch or missing donor in patients with no rejection was 10% (2 patients) with significant p-value (0.0001). The analysis of demographic data of Bw4/6 mismatch or missing donor Bw6 allele in patients with rejection (N=14) (Fig. 1); mean age was 27.92 years, 71.4% were males (10 patients), panel reactive antibodies (PRA) was positive in 7.1% (1 patient), Donor specific antibodies (DSA) and complement-dependent cytotoxicity (CDC) cross-match were negative in all patients. The most common type of rejection in these patients was acute antibody-mediated rejection (ABMR) 71.4% (10 patients). Patients and graft outcomes; mean serum creatinine after treatment of rejection was 2.16 mg/dl, mortality was 14.3% (2 patients) with graft loss, and survival with functioning graft was 85.7% (12 patients). Conclusion Bw4/6 mismatch or missing donor Bw6 allele is a risk of early acute rejection in PRA-negative kidney transplant recipients and is linked to negative patients and graft outcomes.

Single-Cell Profiling of Peripheral Blood Mononuclear Cell Identifies Immune Populations Associated with High Risk of Early Acute Rejection

Single-Cell Profiling of Peripheral Blood Mononuclear Cell Identifies Immune Populations Associated with High Risk of Early Acute Rejection

Opportunistic Infections After Induction With Alemtuzumab or Basiliximab: A 3-Year Kidney Transplantation Experience

BackgroundAntibody induction immunosuppression is commonly used in kidney transplantation to decrease the risk of early acute rejection. However, infectious complications may arise in patients treated with higher intensity induction immunosuppression. In this study, we compared the rate of opportunistic infections during the 3 years after kidney transplantation in recipients who received either alemtuzumab or basiliximab for induction therapy. MethodsAll renal transplant recipients from our center who received induction with alemtuzumab between 2011 and 2016 were included and matched 1:2 (by age and date of transplant) to renal transplant recipients who received basiliximab. The primary outcome was the rate of opportunistic infections. ResultsTwenty-seven patients received alemtuzumab (mean age = 50.8 years; SD ±12), and 54 received basiliximab (mean age = 50.8 years; SD ±11.8). Infections within 3 years posttransplant were not different between groups: BK viremia (P = .99), BK nephritis (P = .48), cytomegalovirus infection (P = .13), varicella zoster virus (P = .22), and all infections (P = .87). Time to infection (P = .67), patient survival (P = .21), and time to rejection (P = .098) were similar in both groups. There were also no group differences in delayed graft function (P = .76), graft loss (P = .97), or rejection (P = .2). ConclusionThe rate of infection was not significantly increased in recipients receiving lymphocyte-depleting alemtuzumab compared to recipients receiving basiliximab induction therapy, despite receiving similar maintenance immunosuppression. Although the immunologic risks differed between the 2 groups, there was no observable difference in clinical outcomes.

The Pre-Transplant Drop in Panel-Reactive Antibodies Titer Evaluated Using Complement-Dependent Cytotoxicity (PRA-CDC) and the Risk of Early Acute Rejection in Sensitized Kidney Transplant Recipients.

Background: The panel-reactive antibodies that use the complement-dependent cytotoxicity test (PRA-CDC) are still a standard method for monitoring the degree of immunization in kidney transplant candidates on active waiting lists in some countries, including Poland. The aim of this study was to analyze the relationship between the maximum and the last pre-transplant PRA titer on the percentage of positive cross-matches and rate of early acute rejection episodes. Material and methods: The retrospective analysis included 528 patients from two transplant centers. All patients were divided into three groups, depending on their peak and last pre-transplant PRA titers. There were 437 (82.8%) patients with peak PRA <20% (non-sensitized group, non-ST) and 91 (17.2%) patients with peak PRA >20%. Among the latter group, 38 had maintained PRA level >20% at the time of transplantation (sensitized patients, ST), whereas 53 had pre-transplant PRA ≤20% (previously sensitized patients, prev-ST). Results: The percentages of positive crossmatches were 76.9% in ST and 53.7% in prev-ST groups versus 18.4 in non-ST group (both p < 0.001). The acute rejection rates were 18.9, 17.6 and 6.8%, respectively (p < 0.001 for ST or prev-ST versus non-ST). The pre-transplant PRA titer drop did not decrease the risk of early acute rejection [OR = 1.09 (95% CI: 0.31–3.85)] in a multiple logistic regression analysis. The occurrences of primary graft non-function and delayed graft function were similar in all study groups. Conclusions: Previously immunized kidney transplant candidates even with substantial decrease in pre-transplant PRA-CDC levels are still at high immunological risk when compared with non-immunized patients, and they should receive lymphocyte-depleting induction therapy.

Loss of CD28 on Peripheral T Cells Decreases the Risk for Early Acute Rejection after Kidney Transplantation.

BackgroundEnd-stage renal disease patients have a dysfunctional, prematurely aged peripheral T-cell system. Here we hypothesized that the degree of premature T-cell ageing before kidney transplantation predicts the risk for early acute allograft rejection (EAR).Methods222 living donor kidney transplant recipients were prospectively analyzed. EAR was defined as biopsy proven acute allograft rejection within 3 months after kidney transplantation. The differentiation status of circulating T cells, the relative telomere length and the number of CD31+ naive T cells were determined as T-cell ageing parameters.ResultsOf the 222 patients analyzed, 30 (14%) developed an EAR. The donor age and the historical panel reactive antibody score were significantly higher (p = 0.024 and p = 0.039 respectively) and the number of related donor kidney transplantation was significantly lower (p = 0.018) in the EAR group. EAR-patients showed lower CD4+CD28null T-cell numbers (p<0.01) and the same trend was observed for CD8+CD28null T-cell numbers (p = 0.08). No differences regarding the other ageing parameters were found. A multivariate Cox regression analysis showed that higher CD4+CD28null T-cell numbers was associated with a lower risk for EAR (HR: 0.65, p = 0.028). In vitro, a significant lower percentage of alloreactive T cells was observed within CD28null T cells (p<0.001).ConclusionImmunological ageing-related expansion of highly differentiated CD28null T cells is associated with a lower risk for EAR.

Existence of circulating anti-endothelial cell antibodies after heart transplantation is associated with post-transplant acute allograft rejection.

Anti-endothelial cell antibodies (AECA) may be involved in the development of heart allograft rejection. Its detection might be a cheap and noninvasive method to identify high-risk patients. An indirect immunofluorescence method on human umbilical vein endothelial cells was used to investigate the presence of AECAs in 260 pre- and post-transplant serum samples sequentially collected from 34 patients within the first year after heart transplantation (HTX). The presence of AECAs before (23.5%) and early after HTX (14.7%) was associated with a significantly increased risk of early acute rejection (75 and 60%, respectively) compared to 33% in AECA-negative patients (p=0.049). Moreover, rejections from AECA-positive patients were more severe (p=0.057) with a significantly increased incidence of multiple (p=0.025). The mean number of the sum of rejection episodes was significantly higher in AECA-positive patients (p≤0.05). Patients free of AECAs mainly received mycophenolate mofetil as primary immunosuppression (p=0.067). Nevertheless, the presence of AECAs did not affect long-term outcome and mortality of HTX patients. Despite a low number of patient samples, the detection of AECAs before and early after HTX could be used as a biomarker for an increased risk of early acute rejection in high-risk patients. This easy method might be a valuable tool to support screening procedures to improve individualized immunosuppressive therapy.

Basiliximab Induction in Renal Transplantation: Histopathologic Correlation.

INTRODUCTION: Acute rejection during the first year post-transplant is a key predictor of graft survival after renal transplantation. Use of induction therapy with interleukin-2 receptor (IL-2R) antagonist has been proven to be effective in reducing the rate of acute rejection in the first critical weeks and months post-transplant. PURPOSE: In this study, we retrospectively investigated the role of the anti-IL-2 receptor, basiliximab, as an induction immunosuppression and compared the histopathological patterns of rejection in the immediate post transplantation period between renal transplant recipients with or without IL-2 induction. RESULTS: Total of 92 biopsy proven acute rejection were seen within 3 months of transplantation. Majority of the rejection were acute T-cell mediated rejection, tubulointerstitial and vascular type (82 cases). Of the remaining 10 cases, eight were antibody mediated rejection and two were mixed rejection. IL-2 minus Group was associated with increased risk of early acute rejection (14.3%) as compared to IL-2 plus Group (9%). All T-cell mediated rejection were steroid responsive except for 2 cases of steroid-resistant rejection in IL-2 minus Group. In addition, higher Banff grade of rejection was seen in IL-2 minus Group (46.5%) as compared to IL-2 plus Group (42.5%) CONCLUSION: Induction treatment with IL-2 receptor antagonist was associated with a reduction in acute rejection episodes in the immediate post transplant period and majority of the rejection are of lower histologic grade.

Clinical Relevance of IgG Antibodies Against Human Endothelial Cell Precursors in Recipients of Living Related Kidney Grafts.

There are reports in the literature suggesting that preformed (non-HLA) IgG antibodies (ab) against donor endothelial cells increase the risk of early acute rejection. In the present study we investigated 51 recipients of renal transplants (Tx) for possible clinical relevance of pre-Tx IgG ab against human endothelial cell precursors (ECPs). Using the flow cytometric XM-One crossmatch test kit, angiopoietin receptor positive ECPs were isolated from donor blood and tested with patient serum according to the manufacturer's instructions (Absorber AB, Stockholm, Sweden). Cut-offs for IgG MFI shift: <80 = negative, 80-120 = weakly positive, >120 = positive; corresponding cut-offs IgM MFI shift: <100, 100-120, and >120 channels. The presence of donor-specific HLA ab prior to Tx was excluded using the combination of microlymphocytotoxicity as well as solid phase assay ELISA and Luminex testing. Endothelial cell crossmatch test (ECXM) was performed 49+/-65 days before Tx. Patients were followed for at least 1 month post-Tx. 5 patients developed acute biopsy-proven rejections (Banff Ia: n=3 and Banff Ib: n=2) on days 7, 8, 9, 85 and 130 post-Tx. All 5 patients with acute rejection showed no IgG or IgM ab against ECPs. Conversely, IgG and IgM ab against ECPs were detected in 10 patients without acute rejection (1x both IgG+IgM, 1x IgG and 8x IgM). One patient received a combined pancreas/kidney graft from a deceased donor and lost the graft intraoperatively. Pathology showed histomorphological alterations that could be interpreted as ischemia injury but also shared typical features of hyperacute rejection. ECXM was performed retrospectively with pre-Tx patient serum and donor ECPs enriched from spleen cells. Positive channel shifts were adjusted specifically for spleen cells. The patient showed IgG and IgM ab. Our preliminary data suggest that pre-Tx IgG or IgM ab against ECPs were not associated with early acute rejection (within one month). However, retrospective analysis of a patient with intraoperative graft loss reminiscent of hyperacute rejection using ECPs enriched from spleen cells revealed IgG and IgM ab against ECPs in the pre-Tx serum. This result suggests that ECXM with ECPs enriched from spleen cells is technically possible and may be of clinical relevance.

Challenges in pediatric renal transplantation.

Transplantation in children is the best option to treat renal failure. Over the last 25 years the improvements in therapy have dramatically reduced the risk of early acute rejection and graft loss, however the long term results in terms of graft survival and morbidity still require search for new immunosuppressive regimens. Tolerance of the graft and minimization of side effects are the challenges for improving the outcome of children with a grafted kidney. Notwithstanding the difficulties in settling in children large multicenter trials to derive statistically useful data, many important contributions in the last years brought important modifications in the immunosuppressive therapy, including minimization protocols of steroids and calcineurin inhibitors and new induction drugs. New methods for diagnosis of anti HLA antibodies and some new protocols to improve both chance and outcome of transplantation in immunized subjects represent area of ongoing research of extreme interest for children.

Induction with interleukin-2 antagonist for transplantation of kidneys from older deceased donors: an observational study

BackgroundThe most important limiting factor in kidney transplantation is the scarcity of donor organs. Consequently, there is an increased use worldwide of kidneys from older deceased donors. High donor age is a known risk factor for acute cellular rejection and premature graft failure, and the optimal immunosuppressive regimen in these circumstances remains to be established.MethodsWe investigated whether induction treatment with an interleukin 2 (IL-2) receptor antagonist improves graft survival and reduces rejection episodes in recipients of kidneys from deceased donors aged ≥ 60 years. Data were retrieved for all recipients transplanted at our center from 2004 to 2009 with a kidney from a deceased donor aged > 60 years. The outcome was compared between recipients treated with (IL-2 plus) or without (IL-2 minus) an IL-2 receptor antagonist. All recipients received a calcineurin inhibitor, steroids and mycophenolate.ResultsA total of 232 first-transplant recipients were included (IL-2 plus = 149, IL-2 minus = 83). IL-2 minus was associated with increased risk of early acute rejection (OR 2.42; 95% CI 1.25 to 4.68, P = 0.009) and steroid-resistant rejection (OR 8.04; 2.77 to 23.25, P< 0.001). IL-2 plus patients had superior two-year estimated uncensored (87% versus 70%, P = 0.001) and death-censored (95% versus 79%, P< 0.001) graft survival.ConclusionsInduction treatment with IL-2 receptor antagonist was associated with a reduction in acute rejection episodes and improved two-year graft survival in patients transplanted with kidneys from older deceased donors.

De novo development of circulating anti-endothelial cell antibodies rather than pre-existing antibodies is associated with post-transplant allograft rejection

Anti-endothelial cell antibodies (AECAs) are thought to be involved in the development of renal allograft rejection. To explore this further, we determine whether AECAs play a role both in predicting the incidence of allograft rejection and long-term outcomes by analysis of serum samples from 226 renal allograft recipients for AECAs pre- and post-transplant. Surprisingly, the presence of pre-existing AECAs was not associated with either an increased risk of rejection or a detrimental impact on recipient/graft survival. Subsequent de novo AECAs, however, were associated with a significantly increased risk of early acute rejection. Moreover, these rejections tended to be more severe with a significantly increased incidence of both steroid-resistant and multiple episodes of acute rejection. The acute rejections associated with de novo AECAs did not correlate with C4d deposition at the time of renal biopsy, but did demonstrate an association with the presence of glomerulitis and peritubular capillary inflammation. Significantly more patients with de novo AECAs developed graft dysfunction. Thus, our prospective study suggests the emergence of de novo AECAs is associated with transplant rejection that may lead to allograft dysfunction.

483: Significance of Pre Transplant Donor Specific HLA Antibodies and Post Transplant Cardiac Allograft Vasculopathy

Cardiac allograft vasculopathy (CAV) is the leading cause of late morbidity and mortality in heart transplant recipients. CAV is a complex multifactorial process caused by immune and non-immune mechanisms. Experimental evidence suggests that acute allograft rejection and CAV are closely related processes. The presence of anti-HLA antibodies specifically donor specific antibodies (DSA) by more sensitive solid phase assays like single antigen beads (SAB) at the time of heart transplantation has been shown to increase the risk of early acute rejection and decrease graft survival. The role of DSA detected by SAB at the time of transplant in the development of CAV is less well-established.

The role of alemtuzumab in facilitating maintenance immunosuppression minimization following solid organ transplantation

National registry data indicate a trend towards the incorporation of lymphocyte depletion antibody induction therapy into immunosuppressive regimens for solid organ transplantation. Depletional induction has been shown to reduce the risk of early acute rejection, but increase the risk of immune incompetence. As such, it recently has been paired with reduced maintenance immunosuppression in an effort to curb excessive immunosuppression without sacrificing low rejection rates. Alemtuzumab is a humanized CD52-specific monoclonal antibody that has been used in the setting of maintenance immunosuppression minimization. Although not specifically indicated for organ transplantation, it is now used off-label as an induction agent in approximately 10% of transplant recipients in the United States. In general, alemtuzumab is well tolerated and substantially reduces the risk of acute rejection in the first 6 months post-transplant in non-sensitized recipients. There is little evidence to support the notion that it uniquely promotes tolerance, and growing evidence that it is ineffective in the setting of allosensitization. Alemtuzumab-treated patients clearly remain dependent on maintenance immunosuppression. Long-term outcome data will be required to determine the magnitude and type of maintenance therapy that makes best use of alemtuzumab's depletional effects.

Identification of Patients at Risk of Acute Rejection by Pretransplantation and Posttransplantation Monitoring of Soluble CD30 Levels in Kidney Transplantation

In this study, we investigated the impact of pre- and posttransplantation sCD30 monitoring on early (<6 months) acute rejection (AR) risk and analyzed the effect of different immunosuppressive regimens on posttransplantation sCD30 levels in kidney recipients. Fifty patients receiving kidney allograft and 10 healthy donors were included in this retrospective cohort study. Eight patients developed biopsy-proven AR (19%). In pretransplantation samples, patients showed a significantly higher sCD30 than healthy controls. The pretransplantation and posttransplantation (day-15) sCD30 levels were significantly elevated in rejecting patients compared to non-rejecting patients. No significant differences among immunosuppressive regimens were found in posttransplantation sCD30 levels. High pretransplantation and posttransplantation (day 15) sCD30 levels are associated with increased risk of early AR, and sCD30 can be another tool to evaluate immunological risk prior to kidney transplantation. There was no difference in immunosuppressive regimens used in this study on posttransplantation sCD30 levels at the first month.

Anti-HLA antibody analysis and crossmatching in heart and lung transplantation

Although the clinical significance of anti-HLA antibodies in heart and lung transplantation is less well studied than in renal transplantation, several studies have shown that heart and lung recipients transplanted in the presence of donor-specific antibodies are at increased risk for early acute rejection and have a lower graft survival. In an effort to avoid any increase in organ ischemia time, heart and lung candidates with anti-HLA antibodies have to be identified prior to transplantation and crossmatches performed with donor materials obtained prior to organ recovery. Both class I and II antibodies have been found to be associated with chronic rejection, defined in heart transplantation as transplant-related coronary artery disease (TRCAV) and in lung transplantation as obliterative bronchiolitis (OB) or bronchiolitis obliterative syndrome (BOS). Post-transplant de novo development of donor antigen-specific class II antibodies has been found to be especially deleterious, significantly increasing the risk of chronic rejection and poor graft outcome. Based on the review of studies regarding the development of anti-HLA antibodies and thoracic organ allograft rejection several conclusions can be drawn. The presence of class I and II-directed anti-HLA antibodies, detected by any method, are associated with acute and chronic rejection in heart and lung transplantation. Different therapeutic strategies have been used pre-transplantation to decrease the level of anti-HLA antibodies and post-transplantation to maintain low antibody levels or treat rejection, thereby improving graft outcome. Thus, monitoring the presence and the level of anti-HLA antibodies is prognostic of graft outcome and allows for measurement of therapeutic efficacy.

Pre-transplant Th1 and post-transplant Th2 cytokine patterns are associated with early acute rejection in renal transplant recipients.

In this retrospective study, we tried to define pre- and post-transplant immunological parameters that identify patients at risk for early acute rejection. Lymphocyte subpopulations and plasma levels of cytokines and neopterin were determined pre- and post-transplant in 32 renal transplant recipients with biopsy-proven early acute graft rejection. Recipients without early acute rejection served as controls. High pre-transplant interferon-gamma (IFN-gamma) plasma levels (p = 0.006), consistently high levels of neopterin early post-transplant (p = 0.008), a post-transplant switch from a Th1 to a Th2 cytokine pattern with decreasing IFN-gamma (p = 0.02), low CD8+ lymphocyte counts (p = 0.006) and consistently high CD19+ B lymphocyte counts were associated with acute rejection. Our data suggest that patients with a pre-transplant Th1 and an early post-transplant Th2 cytokine pattern are pre-disposed for early acute rejection.

Donor-specific single cell detection of IFN-[g] production identifies renal recipients at high risk for early acute rejection

Donor-specific single cell detection of IFN-[g] production identifies renal recipients at high risk for early acute rejection

Low tacrolimus concentrations and increased risk of early acute rejection in adult renal transplantation.

A retrospective analysis was performed on adult renal transplant recipients to evaluate the relationship between tacrolimus trough concentrations and the development of rejection in the first month after transplant. A total of 349 concentrations from 29 patients, measured by enzyme-linked immunosorbent assay (ELISA), were recorded. Based on an increased serum creatinine, 12 patients were considered to have organ rejection. Rejection was confirmed by biopsy in five of these. The median trough concentration of tacrolimus over the first month of therapy, or until the time of first rejection was compared in rejecters vs non-rejecters. Median trough concentrations of tacrolimus were found to be lower in biopsy-proven rejecters vs non-rejecters (P=0.03) and all rejecters vs non-rejecters (P=0.04). The average median concentration (+/-SD) in the biopsy-proven rejecter group was 5.09+/-1.16 ng/ml, compared to 9.20+/-3.52 ng/ml in the non-rejecter group. After exclusion of an outlier, the average median concentration in all rejecters was 5.57+/-1.47 ng/ml, compared with 9.20+/-3.52 ng/ml in non-rejecters. A rejection rate of 55% was found for patients with a median trough concentration between 0 and 10 ng/ml. This compared with no observed rejection in patients with a median concentration between 10 and 15 ng/ml. A significant relationship exists between organ rejection and median tacrolimus trough concentrations in the first month post-transplant, with patients displaying low concentrations more likely to reject. In order to minimize rejection in the first month after renal transplantation, trough concentrations greater than 10 ng/ml must be achieved.

Preoperative detection of IGG non-cytotoxic antibodies identifies primary renal transplant recipients at risk for early acute rejection and graft loss

Preoperative detection of IGG non-cytotoxic antibodies identifies primary renal transplant recipients at risk for early acute rejection and graft loss