Late Acute Rejection Research Articles

Primary cytomegalovirus infection after liver transplantation is associated with attenuated T cell alloreactivity and lower incidence of late acute rejections

Primary cytomegalovirus infection after liver transplantation is associated with attenuated T cell alloreactivity and lower incidence of late acute rejections

Depleting antibody induction in simultaneous pancreas-kidney transplantation: a prospective single-center comparison of alemtuzumab versus rabbit anti-thymocyte globulin

Background: The study purpose was to analyze midterm outcomes in a prospective trial of alemtuzumab (Alem) versus rabbit anti-thymocyte globulin (rATG) induction in simultaneous pancreas-kidney transplantation (SPKT).Methods: From February 2005 to October 2008, 46 SPKTs (45 portal-enteric drainage) were prospectively randomized as part of a larger kidney transplant study to receive either single-dose Alem (30 mg intraoperatively) or multiple-dose rATG antibody induction (starting intraoperatively, minimum three doses administered) with tacrolimus/mycophenolate ± steroids.Results: Of 222 kidney transplant patients enrolled in the study, 46 received SPKTs; 28 (61%) received Alem and 18 (39%) rATG induction. Follow-up ranged from 67 to 111 months (mean 80 months). There were no significant differences between the two groups in 5 years actual patient (86% Alem vs 89% rATG), kidney (82% Alem vs 61% rATG, p = 0.17) or pancreas (68% Alem vs 56% rATG) graft survival rates. Five years death-censored kidney (92% Alem vs 69% rATG, p = 0.09) and pancreas (76% Alem vs 56% rATG, p = 0.198) graft survival rates were slightly higher in patients receiving Alem. Acute rejection (21% Alem vs 44% rATG, p = 0.12) and major infection (39% Alem vs 67% rATG, p = 0.13) rates were slightly lower in the Alem group; cytomegalovirus infections were significantly lower (0 Alem vs 17% rATG, p = 0.05). The incidence of late acute rejection was low in both groups. There were no differences in early pancreas thrombosis (3.6% Alem vs 11% rATG), postoperative bleeding (11% Alem vs 0 rATG), other surgical complications, readmissions or freedom from steroids between groups. In patients with functioning grafts, 5 years mean serum creatinine (1.4 Alem vs 1.6 mg/dl rATG), calculated abbreviated modification of diet in renal disease glomerular filtration rate (55 Alem vs 52 ml/min/1.73 m2 rATG), hemoglobin A1c (both 5.4%) and C-peptide (2.6 Alem vs 2.3 ng/ml rATG) levels were similar.Conclusions: Single-dose Alem and multiple-dose rATG induction provide similar midterm patient survival and graft functional outcomes with no major differences in morbidity or resource utilization.

Effects of interleukin 2 receptor blockers on patient and graft survival in renal-transplanted children.

Background:Monoclonal antibodies block interleukin-2 receptors on alloantigen-reactive T-Lymphocytes and induce selective immunosuppression. It is postulated that induction therapy with these agents in pediatric transplantation may decrease acute rejection and improve graft survival with no significant side effect or increase in the incidence of viral infections.Objectives:The aim of this study was to examine the effects of interleukin 2 receptor blockers on patient and graft survival in renal-transplanted children.Patients and Methods:One hundred and eighty six children aged 7-13 years who received renal transplantation in university-affiliated hospital between 2003 and 2012 were enrolled in the study. All patients received prednisolone, cyclosporine and mycophenolate mofetil or azathioprine as basic immunosuppressive therapy. Patients were divided into two groups according to receiving induction therapy with IL2-receptor blockers. We investigated for acute rejection episodes, Cytomegalovirus (CMV) and BK virus infection and one and three year’s survival of the patients and the graftsResults:From 186 renal-transplanted children included in this study, 36 patients were in treated group (group 1) and 150 patients in control group (group 2). The mean age of the patients was 10.4 ± 2 years and 55.6% were males. In first six months of transplantation, eight patients in group one had one episode of acute rejection and no one had two episodes. Early acute rejection rate was 8.36 (22%). In the control group, 37 patients had one episode and three patients had two episodes of acute rejection (rejection rate 28.6%). Therefore, early acute rejection rates were lower in group one. Late acute rejection rates did not show any difference in group 1 and group 2 (27.7% vs. 27.3% respectively). There was lower prevalence of steroid-resistance rejection in group 1 patients (5.5%) compared with 6.6% in group 2, but it did not reach statistical significance. None of the patients in IL2-R blocker group died at one year follow-up (patient survival 100%). However, in control group, four (2.6%) patients died toward the end of first year (patient survival 97.4%). When patients in group 1 and group 2 were age and sex matched with equal number the difference was significant (P < 0.05).Conclusions:Induction therapy with IL2-R blockers reduced the rate of early acute rejection, but had no effect on late acute rejections. Patient and graft survival were better in treated group, but did not reach statistical significance. A longer period of follow-up may be required to discern a clear advantage for induction therapy with these agents.

IL-17 Producing CD4+ Cells Infiltrate the Graft During Early Rejection Episodes.

IL-17 is regarded as a major effector cytokine with pro-inflammatory actions in autoimmune diseases. IL-17 has pleiotropic and environmental specific functions by promoting adaptive cytotoxic T-lymphocyte responses during inflammation. Therefore, it is tempting to speculate that IL-17 is important in inflammatory responses seen after organ transplantation. We determined IL-17 mRNA expression in the transplanted heart during early and late acute rejection episodes, and during immunological quiescence. Additionally, we analysed whether IL-17 is derived from graft-infiltrating lymphocytes. Endomyocardial biopsies (EMBs: n=41) from heart transplant recipients (n=29) who experienced an early (≤3 months) or late (>3 months) acute rejection episode or during an immunological quiescence period, were analysed for the presence of IL-17 mRNA. IL-17 production determined by flowcytometry was analysed in cultures of graft-infiltrating lymphocytes (GILs) derived from acute rejection (n=5) and non-rejection (n=5) EMBs stimulated with PMA and ionomycine. Twenty-two percent (9/41) of EMBs were positive for IL-17 mRNA. All (9/26) were observed in the early period after transplantation, while none (0/15) of the late biopsies expressed IL-17 mRNA (p=0.02). During early acute rejection, 56% (5/9) of the EMBs did express IL-17 mRNA, while EMBs from late acute rejections (0/5) did not express IL-17 mRNA (p=0.09). Only CD4+ cells from GIL cultures produced IL-17. In 60% of GIL cultures from acute rejection EMBs a significant proportion of CD4+ cells produced IL-17, while only one GIL culture from non-rejection EMBs contained CD4+IL-17+ cells. All CD4+IL-17+ cells expressed CD161, a cell surface expression marker of Th17 cells. CD8+ cells did not produce IL-17 neither expressed CD161. In conclusion, particularly early after heart transplantation IL-17 producing CD4+ T-cells home to the graft contributing to the acute rejection process.

Primary Cytomegalovirus Infection After Liver Transplantation Is Associated With Attenuated T Cell Alloreactivity and Lower Incidence of Late Acute Rejections.

Cytomegalovirus (CMV) infection can induce long-lasting changes of T cell subsets in peripheral blood and is thought to generate alloreactive T cells. However its association with allograft rejection remains controversial in LTx patients. The aim of this study is to determine the effects of CMV primary infection on circulating T cell subsets and T cell alloreactivity after LTx. We monitored peripheral blood CD4+ and CD8+ naïve(TN), central memory(TCM), effector memory(TEM), and late-differentiated effector memory(TEMRA) T cells in 36 patients before, and at 1 and 6 months after LTx. Frequencies of alloreactive T cells, which were defined as T cells specifically upregulate CD137 upon allogeneic stimulation by donor or 3rd-party splenocytes, were compared between CMV primary infection patients (D+/R- with CMV viremia) and CMV naïve patients (D-/R-). As most CMV infections occur within 3 months after LTx, we further retrospectively analyzed the cumulative incidence of clinically relevant late acute rejections (biopsy proven and treated acute rejections occurring more than 3 months after LTx) in our center by Kaplan-Meier method. Six months after LTx, we found CMV primary infection resulted in an expansion of circulating CD8+ TEMRA (from 15% to 57%; p=0.0002), while no difference was observed in CMV naïve patients. CD8+ T cells from CMV primary infection patients (n=14) developed donor-specific hyporesponsiveness (donor-reactive: 0.38%, 3rd party-reactive: 1.00%, p=0.02), while donor and 3rd party-reactive CD8+ T cell frequencies were similar in CMV naïve patients (n=11). CD4+ TEM from CMV primary infection patients contained lower frequencies of both donor and 3rd party-reactive T cells compared to CMV naïve patients (donor-reactive: 2.9% and 6.3% respectively, p=0.02; 3rd party-reactive: 3.6% and 6.6% respectively, p=0.03). In the retrospective analysis, the cumulative incidence of late acute rejections was significantly lower in D+/R- patients (n=119) compared to D-/R- patients (n=114) (3.4% and 14.0% respectively, p=0.01). In conclusion, we found primary CMV infection after LTx is associated with attenuated T cell alloreactivity and lower incidence of late acute rejections. Primary CMV infection may contribute to the development of tolerance to liver grafts.

High-Intrapatient Tacrolimus Variability in a Low-Dose Tacrolimus Regimen Predicts Worse Long-Term Outcomes After Renal Transplantation.

Background Tacrolimus has been the mainstay of immunosuppression for the last decade. Subtherapeutic levels may lead to acute rejection (AR) whilst high levels result in toxicity. Reports prior to the Symphony study associate high intra-patient tacrolimus variability (IPTV) with worse outcomes. The lower target levels widely used since the Symphony study was published may magnify any effect of IPTV. We investigated the effects of IPTV in renal transplant (RTx) patients. Endpoints were graft survival, AR, and eGFR 1,2,3, and 4 years post transplantation. Methods The study included patients undergoing RTx between 01/01/07 and 31/12/2011. Exclusions were allograft loss or death within the 1st post transplant year, loss to follow-up, or conversion to other immunosuppression. All patients received Basiliximab induction and prednisolone plus mycophenolate in addition to tacrolimus. Target tacrolimus trough levels were 5-8μg/L. Median IPTV 6 -12 months post transplant was calculated by the following formula: {[(Xmean - X1) + (Xmean - X2)…..+(Xmean - Xn)] / n} / Xmean*100 = intra individual variability (%) Patients ≥ the IPTV median were considered high variability (HV) and patients < were considered low variability (LV). LV and HV groups were compared for the study primary endpoints outlined above. Results 376 patients were included in the study with a mean follow-up of 1495 days (± 551). Median IPTV was 16%. 181 patients were allocated to LV and 195 to HV. Baseline characteristics of the groups were not significantly different. HV patients suffered more episodes of 1 year AR (36/159 vs 14/167: p = 0.002) and late AR, after 1st year (21/174 vs 9/172: p =0.038). MDRD GFR at 1, 2, 3 and 4 years post transplant was worse in the HV group (p = <0.001 at 1, 2, 3 years and 0.028 at 4 years). Allograft survival (p= 0.002) was worse in the HV group. Discussion In RTx patients, managed with low dose tacrolimus, with > 4 years follow-up, we report high IPTV to be associated with worse outcomes by multiple clinical end-points. The causal nature of this relationship is unproven. Many factors contribute to IPTV, including adherence, lifestyle, diet etc. High IPV may identify a population of patients at increased risk for rejection and or graft loss. Such patients may benefit from increased surveillance and/or targeted interventions including specific immunosuppression protocols and patient education. DISCLOSURE:Clancy, M.: Grant/Research Support, Astellas.

Intermediate Term Outcomes of Early and Late Acute Antibody-Mediated Rejection After Kidney Transplantation.

Intermediate Term Outcomes of Early and Late Acute Antibody-Mediated Rejection After Kidney Transplantation.

Early Versus Late Acute Antibody-Mediated Rejection in Thai Kidney Transplant Patients: The Two Distinct Clinical Syndromes.

Background: Acute antibody-mediated rejection (AMR) is the leading cause of early and late renal allograft dysfunction. The purpose of this study was to compare the clinico-pathological features between early and late acute AMR in Thai kidney transplant patients. Method: We examined our kidney transplant recipients for acute AMR demonstrated on biopsy between January 2005 and December 2013. Patients who had glomerulitis and/or peritubular capillaritis were enrolled and stratified by early (≤ 3 months) and late acute AMR (> 3 months after transplantation). Results: Of 64 patients with biopsy-proven acute AMR, 27 cases of early acute AMR were analyzed for associated factors compared with 37 cases of late acute AMR. Early acute AMR was more common in older patients (46.5 ± 10.0 vs. 34.9 ± 9.8; p < 0.001), female recipients (66.7% vs. 32.4%; p = 0.007), deceased donor allografts (70.4% vs. 37.8%; p = 0.01), and highly sensitized patients (74.1% vs. 13.5%; p = 0.01). Non-adherence was observed in 9 cases (24.3%) with late acute AMR whereas none with early acute AMR (p = 0.01). Endothelialitis was more prevalent in early acute AMR (77.8% vs. 10.8%; p < 0.001). Transplant glomerulopathy and interstitial fibrosis/tubular atrophy, the pathological features of chronic changes, were already demonstrated in late acute AMR (70.3% and 13.5%, respectively) but none in early acute AMR (p < 0.001 and 0.05, respectively). Peritubular capillary C4d deposition were commonly revealed in late acute (70.3% vs. 25.9%; p <0.001, respectively). Donor specific antibodies (DSA) were significantly evidenced in late acute AMR (67.6% vs 37%; p = 0.01). Anti-HLA class II (mostly anti-HLA DQ) was more common than class I (62.2% vs 21.6%; p = 0.003) in late acute AMR while anti-HLA class I (mostly anti-HLA A) was more prevalent than class II (29.6% vs 11.1%; p = 0.09) in early acute AMR. The patients with stable graft function at one year after anti-humoral treatment were observed in 21 cases (77.8%) with early acute AMR but only 13 cases (35.1%) with late acute AMR (p = 0.001). Conclusion: Despite similar pathological findings, early and late acute AMR are distinct clinical syndromes. Late acute AMR has worse prognosis than early acute AMR.

Kidney Retransplant After Graft Loss From Nonadherence - The Effect of a Contract.

Background: Non-adherence (NA) is associated with rejection and graft loss(GL) after transplant(Tx). When a kidney Tx recipient loses a graft to NA, our practice has been to require that the patient admits the NA behavior, pledges and has a strategy for how to maintain adherence to all labs, medications and appointments in order to be considered for reTx. We hypothesized that addition of an actual written contract may help decrease repeat NA after reTx. Methods: We studied kidney reTx done after GL from prior NA since 9/2003. Beginning in 2009 we began requiring completion of a written contract for those with prior GL due to NA, thus dividing the recipients into a no contract group (NCG) (N=29) and a contract group (CG) (N=17). We compared these two groups to determine if the addition of a contract was associated with any change in postTx outcome. Results: Demographics are shown in Table 1. The NCG had decreased AR-free survival (p=0.18) and death censored graft survival (DCGS)(0.15) when compared to the CG. Importantly, the CG had significantly decreased late (>6 mo) acute rejection (LAR) (7.7%) vs the NCG (45.8%)(p=0.03) with a trend toward better LAR-free survival at 36 months (p=0.12). Patient survival was not different (p=0.46). No GL in either group was due to repeat NA, but 3 patients (10%) in the NCG had repeat NA behaviors vs 0 in the CG.Table: No Caption available.Figure: No Caption available.Conclusion: Tools for improving adherence may result in improved postTx outcomes, especially in those known to be at risk for NA. When reTxs were done after GL from NA, recipients who had participated in a written contract had less LAR, and trends toward less AR and increased DCGS, which may be due to improved adherence. Because of these observations, we will continue to require successful completion of a contract in order to achieve reTx after prior graft loss due to NA.

5-Year Results of a Prospective, Randomized, Single-Center Study of Alemtuzumab Compared With Rabbit Antithymocyte Globulin Induction in Simultaneous Kidney–Pancreas Transplantation

IntroductionThe study purpose was to analyze 5-year outcomes in a prospective, randomized trial of alemtuzumab (ALEM) versus rabbit antithymocyte globulin (rATG) induction in simultaneous kidney–pancreas transplantation (SKPT). Patients and MethodsFrom February 2005 through October 2008, a total of 46 SKPTs (45 portal-enteric drainage) were prospectively randomized to receive either single-dose ALEM (30 mg intraoperatively) or multiple-dose rATG antibody induction (starting intraoperatively, minimum of 3 doses administered) with tacrolimus/mycophenolate and/or steroids. ResultsOf 222 kidney transplant patients enrolled in the study, 46 received SKPTs; 28 (61%) received ALEM and 18 (39%) received rATG induction. Follow-up ranged from 54 to 98 months (mean, 69 months). There were no significant differences between the 2 groups in 5-year patient (82% ALEM vs 89% rATG), kidney graft (79% ALEM vs 72% rATG), or pancreas graft (64% ALEM vs 56% rATG) survival rates. Death-censored kidney (90% ALEM vs 75% rATG) and pancreas (71% ALEM vs 56% rATG) graft survival rates were likewise comparable (both, P = NS). Acute rejection (21% ALEM vs 44% rATG; P = .11) and major infection (39% ALEM vs 67% rATG; P = .13) rates were slightly lower in the ALEM group; cytomegalovirus infections were significantly lower (0% ALEM vs 17% rATG; P = .05). The incidence of late acute rejection was low in both groups. There were no differences in early pancreas thromboses (3.6% ALEM vs 11% rATG), postoperative bleeding (11% ALEM vs 0% rATG), other surgical complications, or readmissions between groups. In patients with functioning grafts, 5-year mean serum creatinine (1.4 ALEM vs 1.6 mg/dL rATG), calculated abbreviated Modification of Diet in Renal Disease glomerular filtration rate (55 ALEM vs 52 mL/min/1.73 m2 rATG), glycosylated hemoglobin (both 5.4%), and C-peptide (2.2 ALEM vs 2.3 ng/mL rATG) levels were similar. ConclusionsSingle-dose ALEM and multiple dose rATG induction provided similar medium-term patient, kidney, and pancreas graft function and survival rates. ALEM induction may be associated with less acute rejection and major infection over the long term.

Clinicopathological Characteristics and Impact of Late Acute Rejection On Renal Transplant Outcomes.

Clinicopathological Characteristics and Impact of Late Acute Rejection On Renal Transplant Outcomes.

LATE RENAL GRAFT REJECTION: PATHOLOGY AND PROGNOSIS

Rejection has always been one of the most important cause of late renal graft dysfunction. Aim of the study was to analyze the prevalence of different clinico-pathological variants of rejection that cause late graft dysfunction, and evaluate their impact on long-term outcome. Materials and methods. This is a retrospective study that analyzed 294 needle core biopsy specimens from 265 renal transplant recipients with late (48,8 ± 46,1 months after transplantation) allograft dysfunction caused by late acute rejection (LAR, n = 193) or chronic rejection (CR, n = 78) or both (n = 23). C4d staining was performed by immunofl uorescence (IF) on frozen sections using a standard protocol. Results. Peritubular capillary C4d deposition was identifi ed in 36% samples with acute rejection and in 62% cases of chronic rejection (including 67% cases of transplant glomerulopathy, and 50% – of isolated chronic vasculopathy). 5-year graft survival for LAR vs CR vs their combination was 47, 13 and 25%, respectively. The outcome of C4d– LAR was (p &lt; 0,01) better than of C4d+ acute rejection: at 60 months graft survival for diffuse C4d+ vs C4d − was 33% vs 53%, respectively. In cases of chronic rejection C4d+ vs C4d– it was not statistically signifi cant (34% vs 36%). Conclusion. In long-term allograft biopsy C4d positivity is more haracteristic for chronic rejection than for acute rejection. Only diffuse C4d staining affects the outcome. C4d– positivity is associated with worse allograft survival in cases of late acute rejection, but not in cases of chronic rejection.

Clinicopathologic Characteristics and Outcomes of Late Acute Antibody-Mediated Rejection in Thai Kidney Transplant Recipients: A Single-Center Experience

BackgroundLate antibody-mediated rejection (ABMR) has worse prognosis than early ABMR. The objective of this study was to examine the clinical and pathological features of late acute ABMR in our experience. MethodWe retrospectively reviewed all patients who underwent kidney transplantation (KT) between January 2001 and December 2012. Patients who had glomerulitis and/or peritubular capillaritis on kidney biopsy performed 6 months after KT were enrolled. ResultsOf 592 patients, late acute ABMR was diagnosed in 34 cases (5.74%) with a mean onset of 49.2 ± 30.2 months post-KT. Six patients (17.6%) had nonadherence. Allograft histopathology demonstrated concomitant transplant glomerulopathy in 23 patients (67.6%) and positive peritubular C4d staining in 25 patients (73.5%). Donor-specific antibody (DSA) was detected in 25 patients (73.5%). Anti-HLA class II antibody was more prevalent than class I (67.6% vs 20.6%; P = .003) and most of them were anti-HLA DQ. We prescribed intravenous immunoglobulin (IVIG) 1–2 g/kg for 30 patients (88.2%), plasma exchange (PE) for 27 patients (79.4%), and rituximab 375 mg/m2 for 18 patients (52.9%). We repeated treatment with PE and IVIG in 12 refractory cases. For clinical outcome, 21 patients (61.7%) had deterioration of graft function; 9 of them (26.5%) eventually lost their graft. Thirteen patients (38.2%) had stable graft function. ConclusionLate acute ABMR has unsatisfactory prognosis in spite of aggressive standard antihumoral treatment. Surveillance of late ABMR using DSA monitoring may be helpful in early detection and management.

PKP-011 Pharmacokinetics of everolimus in combination with mycophenolate sodium and clinical outcomes in renal transplant recipients previously treated with calcineurin inhibitors

BackgroundDespite advances in immunosuppressive treatment, long-term renal transplantation outcomes have not improved significantly over the last decade. The nephrotoxicity of calcineurin inhibitors (CNIs) is still associated with chronic allograft loss....

Impact of donor-specific antibodies on the outcomes of kidney graft: Pathophysiology, clinical, therapy

Allo-antibodies, particularly when donor specific, are one of the most important factors that cause both early and late graft dysfunction. The authors review the current state of the art concerning this important issue in renal transplantation. Many antibodies have been recognized as mediators of renal injury. In particular donor-specific-Human Leukocyte Antigens antibodies appear to play a major role. New techniques, such as solid phase techniques and Luminex, have revealed these antibodies from patient sera. Other new techniques have uncovered alloantibodies and signs of complement activation in renal biopsy specimens. It has been acknowledged that the old concept of chronic renal injury caused by calcineurine inhibitors toxicity should be replaced in many cases by alloantibodies acting against the graft. In addition, the number of patients on waiting lists with preformed anti-human leukocyte antigens (HLA) antibodies is increasing, primarily from patients with a history of renal transplant failure already been sensitized. We should distinguish early and late acute antibody-mediated rejection from chronic antibody-mediated rejection. The latter often manifets late during the course of the post-transplant period and may be difficult to recognize if specific techniques are not applied. Different therapeutic strategies are used to control antibody-induced damage. These strategies may be applied prior to transplantation or, in the case of acute antibody-mediated rejection, after transplantation. Many new drugs are appearing at the horizon; however, these drugs are far from the clinic because they are in phase I-II of clinical trials. Thus the pipeline for the near future appears almost empty.

Late acute rejection: Incidence, risk factors, and effect on graft survival and function

Long-term graft survival and function has not kept pace with short-term success in kidney transplant (Tx) recipients. LAR ≥6 months post-Tx may contribute to lack of improvement; risk factors for LAR are not well known. Of 64 Tx recipients followed over six yr, 23 (35.9%) had LAR (LAR group) and 41 had no LAR (no LAR group). Of all variables, significant risk factors for LAR included DGF, (43.4% LAR vs. 14.6% in no LAR group, p = 0.0096); de novo DSA (65.2% vs. 26.8%, p = 0.003); mean COV% of TAC (41.8% vs. 34.6%, p = 0.03); and non-adherence (34.8% vs. 7.3%, p = 0.0043). DGF and DSA remained statistically significant (p = 0.002 and 0.003, respectively); COV% TAC had borderline significance (p = 0.057), and non-adherence was not significant on multivariate regression analysis. Patients with LAR had inferior graft survival and function, whereas graft function was stable in the no LAR group over a mean follow-up of 31.2 months. Patients with de novo DSA and DGF should be considered at risk of LAR; an early diagnosis and treatment of LAR may improve graft survival and function.

HLA-DR Overexpression in Tubules of Renal Allografts During Early and Late Renal Allograft Injuries

We sought to discover which types of injuries were related to human leukocyte antigen DR expression in acute rejection and late chronic injury in renal allografts. Ninety-two recipients were separated into the early acute rejection group, the late monocyte infiltration group, and the late chronic injury group. Ten subjects with acute cellular rejection received a repeat biopsy. All samples were stained with CD4, CD8, CD20, CD68, and human leukocyte antigen DR by immunochemical staining. Levels of these markers were compared among the subgroups of each group. Human leukocyte antigen DR expression was greater in the early C4d-negative acute rejection group than it was in the early C4d-positive acute rejection group. Human leukocyte antigen DR expression was greater during acute rejection than that was on a repeat biopsy. Human leukocyte antigen DR expression was accord with the infiltration of monocyte infiltration in the acute cellular rejection group. Human leukocyte antigen DR expression was greater during late acute rejection than it was in BK virus nephropathy, which was not in accord with monocyte infiltration. Human leukocyte antigen DR expression was greater during chronic rejection than it was in IgAN, BK virus nephropathy, and TA/IF groups, and even in tubular atrophy. Human leukocyte antigen DR expression in renal tubular cells was associated with early acute cellular rejection and was in accord with monocyte infiltration. Human leukocyte antigen DR expression in renal tubular cells during the late phase (especially in tubular atrophy) was a marker of chronic rejection, but was not in accord with monocyte infiltration in renal allografts.

53-OR

The role of donor-specific HLA antibodies (DSA) following liver transplantation (LTx) is not clearly established. Our aim was to assess the presence of DSA in pediatric LTx recipients. We hypothesized that DSA would be detected (+DSA) in patients with late allograft dysfunction due to de-novo autoimmune hepatitis (d-AIH). Serum was collected at routine clinic visits from 50 pediatric LTx recipients a mean of 11.8 ± 5.3 years post LTx, and classified into four clinical phenotypes: non-tolerant with biopsy-proven late acute cellular rejection (n = 6) and/or d-AIH (n = 12); stable with normal liver function on maintenance tacrolimus (n = 25); tolerant with normal liver function off immunosuppression ⩾2 years (n = 7). Samples were blinded and antibody detection was performed using LABScreen HLA Class I and II Single Antigen beads (One Lambda) and Luminex multiplex technology. Descriptive statistics and multivariate logistic regression were performed with results reported as means and odds ratios (OR). HLA antibodies were detected in 28/50 (56%) of patients, with the majority of DSA directed against HLA Class II DR or DQ loci (40% and 52%, respectively). Patients with +DSA had a mean of 1.8 (range 1-4) DSA with a mean MFI of 11681 ± 8227. Patients with +DSA were younger at LTx (2.4 ± 2.9 vs 5.4 ± 5.4 years, p = 0.01). There were no differences in other clinical variables including sex, primary diagnosis, history of re-LTx, and early acute rejection. Age in years at LTx (OR 0.5, p = 0.01), history of post transplant lymphoproliferative disorder (OR 0.1, p = 0.01) and late rejection (OR 27, p = 0.02) are the strongest predictors of +DSA. Patients with d-AIH tended to be +DSA (10/12 patients, p = 0.05), a trend that was not observed in the other phenotypes. +DSA is the strongest multivariate predictor of d-AIH (OR 19, p = 0.03). DSA are common after pediatric LTx and detected more frequently in patients with d-AIH, suggesting d-AIH may be a form of antibody-mediated rejection.

CD20+ B-Cell Infiltration Is Related to the Time After Transplant and Poor Prognosis of Acute Cellular Rejection in Renal Transplant

This study sought to determine the relation between CD20+ B-cell infiltration and time after transplant and outcome of acute cellular rejection in renal allografts. Fifty-five patients with acute cellular rejection were categorized into 3 groups: very early, early, and late rejection. The density of CD4+, CD8+, CD20+, and CD68+ cells and HLA-DR expression were characterized and quantified using immunohistochemical staining. Histologic changes were compared between high-density and low-density CD20+ B-cell groups. Poor prognosis factors were analyzed with Cox proportional regression. Density of CD20+ cells in the very-early rejection group was lower than it was in the early- and late-acute rejection groups (P = .03); the density of CD4+, CD8+, and CD68+ cells and HLA-DR expression did not differ between the groups. Mesangial matrix increase, tubular atrophy, arteriolar hyaline thickening, and tubulitis were more prevalent in the high CD20+ density group. Cox regression analysis demonstrated that HLA-DR expression on the tubules, arteriolar hyaline thickening, and CD20+ cell density were associated with an elevated risk of acute cellular rejection. Expansion aggregation of CD20+ B cells occurred mostly after 2 weeks. When combined with HLA-DR expression and arteriolar hyaline thickening, these influence the outcome of acute cellular rejection in renal allograft.

Rejection after conversion to a proliferation signal inhibitor in chronic heart transplantation

We sought to determine the incidence, risk factors, and consequences of acute rejection (AR) after conversion from a calcineurin inhibitor (CNI) to a proliferation signal inhibitor (PSI) in maintenance heart transplantation. Relevant clinical data were retrospectively obtained for 284 long-term heart transplant recipients from nine centers in whom CNIs were replaced with a PSI (sirolimus or everolimus) between October 2001 and March 2009. The rejection rate at one yr was 8.3%, stabilizing to 2% per year thereafter. The incidence rate after conversion (4.9 per 100 patient-years) was significantly higher than that observed on CNI therapy in the pre-conversion period (2.2 per 100 patient-years). By multivariate analysis, rejection risk was associated with a history of late AR prior to PSI conversion, early conversion (<5 yr) after transplantation and age <50 yr at the time of conversion. Use of mycophenolate mofetil was a protective factor. Post-conversion rejection did not significantly influence the evolution of left ventricular ejection fraction, renal function, or mortality during further follow-up. Conversion to a CNI-free immunosuppression based on a PSI results in an increased risk of AR. Awareness of the clinical determinants of post-conversion rejection could help to refine the current PSI conversion strategies.