Early Acute Cellular Rejection Research Articles

A Single-Center Experience of the Optimal Initial Immunosuppressive Strategy for Preventing Early Acute Cellular Rejection in Orthotopic Heart Transplantation Associated With Renal Dysfunction.

Renal dysfunction is a common complication following heart transplantation that may be worsened by the early initiation of calcineurin inhibitors. Antithymocyte globulin (ATG) or basiliximab has been used to delay or avoid calcineurin inhibitors. The most effective strategy for preventing early acute cellular rejection in this context is uncertain. We retrospectively reviewed all heart transplant cases between January 2012 and June 2017. The standard therapy consisted of mycophenolate mofetil, prednisolone, and tacrolimus. In patients at high risk of post-transplant renal dysfunction, an early calcineurin inhibitor-free regimen with basiliximab and/or ATG was used. Patients were assigned to cohorts based on the initial immunosuppressive strategy. The primary end point was the freedom rate of acute cellular rejection within 4 weeks post-transplant. Of 93 cases, 21 patients received standard therapy, 64 patients received an initial calcineurin inhibitor-free regimen with basiliximab, and 8 patients received ATG and basiliximab. Freedom from acute rejection was greater in the ATG plus basiliximab group (all rejection free), compared to 40 (63%) of 64 patients treated with basiliximab and 10 (48%) of 21 patients treated with standard therapy (P < .05, log rank test). In patients treated with basiliximab, early administration (<24 hours) was associated with a higher freedom from acute rejection compared to ≥24 hours, (72% vs 29%, P < .05). The combination of ATG and basiliximab was more effective in preventing acute cellular rejection. In those patients treated with basiliximab, rejection rates were no worse than standard therapy; however, it was only effective when administered within 24 hours.

Effectiveness of Perioperative Immunologic Markers Monitoring for Predicting Early Acute Cellular Rejection After Living Donor Liver Transplantation

BackgroundThe objective of this study was to determine whether perioperative immunologic markers monitoring could predict early acute cellular rejection (ACR) after living donor liver transplantation (LDLT). Materials and methodsFrom September 2010 to June 2013, a total of 172 patients underwent LDLT at our transplant center. Of them, 26 patients were excluded because of infection. We retrospectively reviewed the remaining 146 patients. CD4 lymphocyte activity, T cell subsets test, and serum cytokine panel were checked on the day before transplantation and at 20 days after transplantation. These patients were divided into 3 groups: 1. normal liver function test (LFT) group; 2. increased LFT without rejection group; and 3. early ACR group. We excluded the increased LFT without rejection group in order to rule out multiple factors influencing immunologic factors. ResultsCD4 lymphocyte activity (P = .004) was significantly increased while CD4+/CD25+/FOXP3+ cells (P < .001) and interleukin (IL)-17 (P = .002) levels were significantly decreased during the perioperative period. Pretransplant IL-6 (P = .014) and IL-17 (P = .029) levels in the early ACR group were significantly lower than those in the normal LFT group. The proportion of patients with increased IL-6 during perioperative period in the early ACR group was higher than that in the normal LFT group, although the difference was not statistically significant (P = .065). ConclusionOur results suggest that IL-6 and IL-17 levels are associated with early ACR in LDLT patients. However, whether monitoring perioperative immunologic markers could predict early ACR remains unclear. Further prospective studies are needed to reach a definite conclusion.

Acute Cellular Rejection Early after Heart Transplantation Does Not Reduce Exercise Capacity in the First Year

BackgroundEarly graft dysfunction after orthotopic heart transplantation is associated with worse survival and functional outcomes. However, the prognostic implication of acute cellular rejection (ACR) early after transplant is less well defined. Here, we analyzed the association between early ACR and post-transplant exercise capacity.MethodsWe performed a retrospective analysis of all heart transplant patients who underwent cardiopulmonary exercise testing (CPET) within a year of transplant at a single large academic center between 2000 and 2011. Early ACR was defined as cellular grade 2R or 3R histopathology seen on biopsy within 3 months of transplant. Exercise capacity was assessed during CPET by 1) peak VO2 and 2) total exercise time. CPET performed prior to diagnosis of rejection were excluded. The association between early ACR or grade of ACR and exercise parameters was analyzed using linear regression.ResultsA total of 230 patients (median age 55 [IQR 45-61], 79.6% male) who received a heart transplantation at our institution between 2000 and 2011 underwent CPET during the 1st year. Of these, 12% (n=40) developed early grade 2R rejection and 5% (n=12) developed early grade 3R rejection. No antibody mediated rejection (including hyperacute) was seen in this timeframe among patients who later underwent CPET. Neither peak VO2 (p=0.95) nor total exercise time (p=0.54) were predicted by early ACR of any grade.ConclusionsEarly cellular rejection does not predict worse exercise capacity in the first year after heart transplant. This inference is limited to patients who are able to undergo CPET. Early graft dysfunction after orthotopic heart transplantation is associated with worse survival and functional outcomes. However, the prognostic implication of acute cellular rejection (ACR) early after transplant is less well defined. Here, we analyzed the association between early ACR and post-transplant exercise capacity. We performed a retrospective analysis of all heart transplant patients who underwent cardiopulmonary exercise testing (CPET) within a year of transplant at a single large academic center between 2000 and 2011. Early ACR was defined as cellular grade 2R or 3R histopathology seen on biopsy within 3 months of transplant. Exercise capacity was assessed during CPET by 1) peak VO2 and 2) total exercise time. CPET performed prior to diagnosis of rejection were excluded. The association between early ACR or grade of ACR and exercise parameters was analyzed using linear regression. A total of 230 patients (median age 55 [IQR 45-61], 79.6% male) who received a heart transplantation at our institution between 2000 and 2011 underwent CPET during the 1st year. Of these, 12% (n=40) developed early grade 2R rejection and 5% (n=12) developed early grade 3R rejection. No antibody mediated rejection (including hyperacute) was seen in this timeframe among patients who later underwent CPET. Neither peak VO2 (p=0.95) nor total exercise time (p=0.54) were predicted by early ACR of any grade. Early cellular rejection does not predict worse exercise capacity in the first year after heart transplant. This inference is limited to patients who are able to undergo CPET.

Pretransplant transcriptomic signature in peripheral blood predicts early acute rejection.

Commonly available clinical parameters fail to predict early acute cellular rejection (EAR, occurring within 6 months after transplant), a major risk factor for graft loss after kidney transplantation. We performed whole-blood RNA sequencing at the time of transplant in 235 kidney transplant recipients enrolled in a prospective cohort study (Genomics of Chronic Allograft Rejection [GoCAR]) and evaluated the relationship of pretransplant transcriptomic profiles with EAR. EAR was associated with downregulation of NK and CD8+ T cell gene signatures in pretransplant blood. We identified a 23-gene set that predicted EAR in the discovery (n = 81, and AUC = 0.80) and validation (n = 74, and AUC = 0.74) sets. Exclusion of recipients with 5 or 6 HLA donor mismatches increased the AUC to 0.89. The risk score derived from the gene set was also significantly associated with acute cellular rejection after 6 months, antibody-mediated rejection and/or de novo donor-specific antibodies, and graft loss in a cohort of 154 patients, combining the validation set and additional GoCAR patients with surveillance biopsies between 6 and 24 months (n = 80) posttransplant. This 23-gene set is a potentially important new tool for determination of the recipient's immunological risk before kidney transplantation, and facilitation of an individualized approach to immunosuppressive therapy.

The effect of maternal grafts in early acute cellular rejection after pediatric living-donor liver transplantation.

Living-donor liver transplantations (LDLTs) with maternal grafts can be more successful than those with paternal grafts because of their tolerance to non-inherited maternal antigens. We reviewed LDLT patients to investigate the relationship between acute rejection and donor sex. LDLT patients between January 2010 and November 2015 were enrolled. ACR was defined by a rejection activity index of > 3. Forty-six patients (22 males and 24 females), of whom 28 had biliary atresia, were enrolled. The median age of the patients was 2.8years and the donor types were maternal (n = 25) and paternal (n = 21). Acute cellular rejection (ACR) was observed in 22 patients. Twelve (48%) of the 25 patients in the maternal group had at least one episode of rejection compared with 10 (48%) of the 21 in the paternal group. Among the patients with ACR, the first rejection in the maternal group occurred significantly earlier than that in the paternal group (p < 0.01). In the multivariable analysis, the only variable significantly related to the first rejection day after LDLT was donor sex (male) (p < 0.005). Our results showed that maternal grafts had an effect on causing earlier ACR in LDLT.

Time to Therapeutic Tacrolimus Serum Concentrations and the Impact on Early Acute Cellular Rejection in Adult Lung Transplant Recipients

Purpose Acute cellular rejection (ACR) affects up to 55% of lung transplant recipients (LTR) within the first year post-transplant. Maintenance immunosuppression regimens include calcineurin inhibitors, antimetabolites, and corticosteroids. Previous studies have shown that early ACR can lead to more severe rejection episodes within the first year post-transplant. The aim of this study is to evaluate the relationship between the time to therapeutic tacrolimus trough concentrations immediately after lung transplant and early clinical ACR post lung transplant. Methods This was a single center, retrospective cohort study of 208 adult LTR transplanted between March 1, 2012 and December 31, 2015 at NewYork-Presbyterian Hospital, Columbia University Irving Medical Center. Recipients were stratified into four groups based on the time to therapeutic tacrolimus concentrations: 0-7, 8-14, 15-29, and ≥30 days post-transplant. Therapeutic tacrolimus trough concentrations were defined as two consecutive levels between 10-15 ng/mL. The primary outcome was the incidence of clinical ACR 6 weeks post-transplant. Clinical ACR included both biopsy proven rejection and treated rejection. Secondary outcomes included biopsy proven ACR 4 and 12 weeks post-transplant and the incidence of acute kidney injury 7, 14, and 30 days post-transplant. Multivariable logistic regression was performed to assess the primary outcome with adjustment for donor age, recipient age, recipient sex, primary graft dysfunction (PGD) within 72 hours post-transplant, and pre-transplant HLA sensitization. Results The incidence of clinical ACR within 6 weeks post-transplant did not differ between groups: 68%, 66%, 71%, and 71% in the 0-7, 8-14, 15-29, and ≥30 days post-transplant groups, respectively (p=0.94). No differences were seen in adjusted and unadjusted analysis. No difference was found in the incidence of AKI within 7 (p=0.25) or 30 (p=0.32) days post-transplant. The incidence of AKI within 14 days was higher in the 15-29 day group (26%), compared to 7%, 14%, 7% in groups 0-7, 8-14, and ≥30 days, respectively (p=0.05). Conclusion There was no difference in the incidence of early clinical ACR among adult LTR who achieved therapeutic tacrolimus trough concentrations 0-7, 8-14, 15-29, or ≥30 days post-transplant.

Impact of TBX21, GATA3, and FOXP3 gene polymorphisms on acute cellular rejection after liver transplantation.

The single nucleotide polymorphisms (SNPs) rs4794067, rs2275806, rs2232365, and rs3761548 map in the genes of TBX21, GATA3, and FOXP3 involved in mediating acute cellular rejection. We investigated whether these SNPs are associated with acute cellular liver transplant rejection. The SNPs were analyzed in recipients with early acute cellular rejection (n = 97), recipients with late acute cellular rejection (n = 49), and recipients without rejection (n = 149). There was no association between acute cellular rejection and SNPs rs4794067, rs2275806, and rs2232365. In contrast, the allele -3279A of FOXP3 SNP rs3761548 exhibited a higher frequency in recipients with late acute cellular rejection as compared with recipients without rejection. This result indicates that the allele -3279A of the SNP rs3761548 may predispose to the development of late acute cellular rejection.

Early Acute Cellular Rejection in Lung Transplant Recipients is Associated with Greater Variation in the Lung Allograft Microbiome

Describe the association between the early lung allograft microbiome and acute cellular rejection (ACR) in lung transplant recipients (LTRs).

Durable renal response after combination of bortezomib, corticosteroids, rituximab, and plasmapheresis for late antibody-mediated renal transplant rejection .

Consecutive patients who presented with biopsy-proven AMR and donor-specific anti-HLA antibodies (DSA) at a single institution between July 2011 and February 2015 were included. They received rituximab 375mg/m² on day1, bortezomib 1.3mg/m² and methylprednisolone on days 1, 4, 8, 11, and plasmapheresis on days -1, 4, 8, 11, 14, 15, 17, with herpes zoster prophylaxis. The primary outcome was graft survival independent of dialysis. Patients were prospectively assessed with serial monitoring of renal function and proteinuria, and neuropathy symptoms. Toxicity determination was made by medical record review for hospitalizations within 3months of therapy, or documentation of opportunistic infection. Eleven patients were treated for late AMR (diagnosed at a median of 38months post renal transplant) with this bortezomib-based protocol; 2 patients underwent the regimen twice. Of the 11patients, 9 have functioning allografts (82% graft survival) with a median creatinine of 2.1mg/dL (range 1.1-3.4mg/dL), at a median follow-up of 50months after AMR therapy (range 24-63months). One patient was re-transplanted at 4years post AMR treatment with no AMR recurrence to date at 2-years' follow-up, and a second patient re-initiated dialysis at 2years post AMR treatment. Patient survival is 91% (10/11): 1 patient relocated out of state and was reported to have died from complications of hypertensive encephalopathy. The majority of patients (7/11) had several class I and classII DSA specificities; of these, 4 patients had negative classI DSA but persistent classII DSAs at 2-3 months post therapy. Only 1 patient who was positive for classII DSAs alone (DR53 and DQ2) converted to negative DSA, although DSA testing was delayed to 2years' follow-up. Two patients were hospitalized within 1 month of the protocol, 1 for ileus and 1 for urinary tract infection and ruptured ovarian cyst. One other patient had herpes zoster. Renal allograft survival was 82% at 4years after bortezomib-based therapy for late onset AMR; toxicity profile of this regimen was acceptable. Eradication of DSAs may not be necessary for meaningful and durable renal response. .

Gut Permeability and Glucose Absorption Are Affected at Early Stages of Graft Rejection in a Small Bowel Transplant Rat Model.

Intestinal transplantation (ITx) faces many challenges due to the complexity of surgery and to the multiple immunological reactions that lead to the necessity of rigorous follow-up for early detection of acute cellular rejection (ACR). Our aim was to determine the kinetics of ACR using an experimental ITx model, with emphasis in the characterization of the process using different approaches, including the use of functional assays of absorptive and barrier function. ITx in rats conducting serial sampling was performed. Clinical monitoring, graft histology, proinflammatory gene expression, and nitrosative stress determination were performed. Also, glucose absorption, barrier function using ovalbumin translocation, and contractile function were analyzed. The model used reproduced the different stages of ACR. Allogeneic ITx recipients showed signs of rejection from postoperative day (POD) 5, with increasing severity until 12 POD. Histological evaluation showed mild rejection in early sampling and severe rejection at late stages, with alterations in all graft layers. IL-6, CXCL 10, IFNg, and nitrite plasmas levels showed behavior coincident with histopathology. Remarkably, allogeneic grafts showed a marked alteration of glucose absorptive capacity from POD 5 that was sustained until endpoint. Coincidently, barrier function alteration was evidenced by luminal ovalbumin translocation to serum. Contractile function was progressively impaired along ACR. Glucose absorption and barrier function are altered at early stages of ACR when histological alterations or gene expression changes were much subtle. This observation may provide simple evaluation tools that could be eventually translated to the clinics to contribute to early ACR diagnosis.

CTLA4-Ig in combination with FTY720 promotes allograft survival in sensitized recipients.

Despite recent evidence of improved graft outcomes and safety, the high incidence of early acute cellular rejection with belatacept, a high-affinity CTLA4-Ig, has limited its use in clinical transplantation. Here we define how the incomplete control of endogenous donor-reactive memory T cells results in belatacept-resistant rejection in an experimental model of BALB/c.2W-OVA donor heart transplantation into C57BL/6 recipients presensitized to donor splenocytes. These sensitized mice harbored modestly elevated numbers of endogenous donor-specific memory T cells and alloantibodies compared with naive recipients. Continuous CTLA4-Ig treatment was unexpectedly efficacious at inhibiting endogenous graft-reactive T cell expansion but was unable to inhibit late CD4+ and CD8+ T cell infiltration into the allografts, and rejection was observed in 50% of recipients by day 35 after transplantation. When CTLA4-Ig was combined with the sphingosine 1-phosphate receptor-1 (S1PR1) functional antagonist FTY720, alloantibody production was inhibited and donor-specific IFN-γ-producing T cells were reduced to levels approaching nonsensitized tolerant recipients. Late T cell recruitment into the graft was also restrained, and graft survival improved with this combination therapy. These observations suggest that a rational strategy consisting of inhibiting memory T cell expansion and trafficking into the allograft with CTLA4-Ig and FTY720 can promote allograft survival in allosensitized recipients.

Re-Transplantation, Higher Creatinine Levels in Hepatitis C Virus Patients, and Donor Age Are Predictors of Mortality in Long-Term Analysis of Late Acute Rejection in Liver Transplantation.

BACKGROUND Late acute rejection (LAR) differs in its clinical and histological presentation and management from early acute rejection. This clinical entity is not completely understood; thus, we aimed to identify significant prognostic factors that can influence post-transplant survival in LAR patients. The purpose of this study was to evaluate the incidence and post-transplant survival of patients from a single center with a focus on late acute rejection. MATERIAL AND METHODS From January 2002 to June 2013, all liver biopsies from patients with rejection were scored using the Banff criteria. The groups were compared, and simple and multiple logistic regression and survival curves were created. RESULTS A total of 779 liver transplants were performed; 585 patients with no rejections and 194 patients with rejections were analyzed. The overall incidence of LAR was 6.7%, and there was a higher prevalence of early acute cellular rejection than LAR. The mean time to LAR was 564 days (median 214 days, range 91-2642). LAR had a more severe grade (35.3%) than early acute rejection (23.5%). The survival rates were similar between both modalities for the long-term period. Worse mortality rates were observed in liver re-transplantation (HR 4.77; p<0.0001); in hepatitis C virus patients with increased creatinine levels (HR 22.48; p=0.016); and in donors >41 years of age (OR 2.1; p=0.047) in a long-term analysis of LAR. CONCLUSIONS Liver re-transplantation, higher creatinine levels in hepatitis C virus patients, and donor age were predictors of mortality in this long-term analysis of late acute rejection in liver transplantation.

Association of the Number of HLA-DR Mismatches With Early Post-transplant Acute Cellular Rejection Among Heart Transplantation Recipients: A Cohort Study in Japanese Population

BackgroundAlthough many risk factors are reported about graft rejection after heart transplantation (HTx), the effect of HLA mismatch (MM) still remains unknown, especially in the Japanese population. The aim of the present study was to investigate the influence of HLA MM on graft rejection among HTx recipients in Japan. MethodsWe retrospectively investigated the association of the number of HLA MM including class I (A, B) and class II (DR) (for each locus MM: 0 to 2, total MM: 0 to 6) and the incidence of moderate to severe acute cellular rejection (ACR) confirmed by endomyocardial biopsy (International Society for Heart and Lung Transplantation grade ≥ 3A/2R) within 1 year after HTx. ResultsBetween 2007 and 2014, we had 49 HTx cases in our institute. After excluding those with insufficient data and positive donor-specific antigen, finally 35 patients were enrolled. Moderate to severe ACR was observed in 16 (45.7%) patients. The number of HLA-DR MM was significantly associated with the development of ACR (ACR+: 1.50 ± 0.63, ACR−: 1.11 ± 0.46, P = .029). From univariate analysis, DR MM = 2 was the only independent risk factor for ACR episodes (P = .017). The frequency of ACR within 1 year was significantly higher in those with DR MM = 2 (DR MM = 0 to 1: 0.3 ± 0.47, DR MM = 2: 1.17 ± 1.34 times, P = .007). ConclusionsThe number of HLA-DR MMs was associated with the development and recurrence of ACR episodes among HTx recipients within 1 year after transplantation in Japanese population.

(511) - The Number of Human Leukocyte Antigen DR Mismatch Is Associated with Early Post-Transplant Acute Cellular Rejection Among Heart Transplantation Recipients

s S193 The purpose of the study was to evaluate T2, T1 and extracellular volume (ECV) quantification as novel tissue markers to diagnose acute cardiac rejection. Methods: CMR was prospectively performed in heart transplant patients before or just after routine EMB and before acute rejection therapy. Images were acquired on a 1.5 Tesla scanner including T2 mapping (T2 preparedSSFP) and T1 mapping using a modified look locker inversion recovery sequence ( MOLLI) at basal, mid and apical level in short axis view. T2 and T1 values were measured before and 15 minutes (for T1 mapping) after contrast administration. The results are expressed by the median and the 5th and the 95th percentiles. Results: twenty six patients (age 52±14 years) were included providing 40 comparisons CMR/EMB. Acute rejection (cellular, humoral or clinical symptoms) was diagnosed in 13 patients. Patients with AR had significantly higher global T2 values at 3 levels (58 ms [52-61] vs 55ms [49-55], P= 0.0049 at basal; 57 ms [54-61] vs 51 ms [5054], P= 0.0010 at median and 60 ms [54-66] vs 54 ms [50-57], P= 0.0119 at apical level). The area under the curve (AUC) for each level was: 0.78; 0.84 and 0.77 respectively. Patients with AR had significantly higher ECV at basal and median level: 35% [33-41] vs 27% [25-31] P= 0.0021 and 33% [28-38] vs 27%[24-31], P= 0.015 respectively. The AUC for each level was; 0.83 and 0.75 respectively. The sensitivity, specificity and diagnosis accuracy for basal T2 (cutoff : 58 ms) were 70%, 96 % and 79% respectively; basal ECV: (cutoff 31%) 89%, 77% and 81% respectively. The best AUC ( 0.88) was obtained when we combined basal T2 and basal ECV. Conclusion: In heart transplant patients, a combined CMR approach using T2 mapping and ECV quantification provides a high diagnostic accuracy for acute rejection diagnosis and could potentially decrease the number of routine EMB. Further studies are required to confirm these data.

Acute Rejection Clinically Defined Phenotypes Correlate With Long-term Renal Allograft Survival.

Classification of acute rejection (AR) based on etiology and timing may provide a means for enhancing therapeutic results and allograft survival. This study evaluated graft and patient survival after the first AR episodes among kidney transplant recipients with an early or late antibody-mediated rejection (AMR), acute cellular rejection (ACR) or mixed AR (MAR). A prospective institutional review board-approved database was queried to identify biopsy-proven first AR episodes occurring from January 2005 to October 2012. The ACR was defined by Banff criteria; borderline AR was excluded. The AMR was defined as 3 of 4 criteria: renal dysfunction, donor specific antibody, C4d positivity on biopsy, and histological changes. The MAR met criteria for both ACR and AMR. Early AR occurred within six months post-transplant. AR episodes were then assigned to 1 of the 6 categories--early AMR, early ACR, early MAR, late AMR, late ACR, and late MAR. One hundred eighty-two kidney transplant recipients identified with a first AR episode. Mean follow-up was 773 days (± 715 days). No difference was observed in patient survival. Death-censored graft survival was 84%. Death-censored graft loss was higher with late versus early AMR (P = 0.01) and late versus early ACR (P = 0.03), but not late versus early MAR (P = 0.3). The AR type demonstrated a hierarchy for graft survival with ACR better than MAR better than AMR, which persisted for both early and late AR. Improvement in long-term results of AR may require development of specific treatment for individual AR types.

Primary Graft Dysfunction After Zero-Mismatch Kidney Transplantation Secondary to Early Biopsy-Proven Acute Cell-Mediated Rejection: Case Report

We report a case of primary renal allograft dysfunction and early acute cell-mediated rejection after a 12/12 HLA antigen zero-mismatch (0MM) transplant. The recipient was a 40-year-old white man who was highly allosensitized, with a calculated panel reactive antibody score of 100%. In posteroperative day 1 the recipient remained anuric and underwent dialysis because of hyperkalemia. Graft biopsy showed early acute cellular rejection, Banff grade 2B. No evidence of antibody-mediated rejection was observed. To our knowledge, this case is the 1st to report early cell-mediated rejection after 12/12 HLA antigen 0MM kidney transplantation. This case suggests that highly sensitized candidates are at high immunologic risk even in the context of 0MM kidney transplantation.

Association of interleukin4 gene polymorphisms of recipients and donors with acute rejection following living donor liver transplantation

Little is known as to whether the interleukin4 (IL4) gene polymorphisms in recipients or donors affect the incidence of acute cellular rejection (ACR) following living donor liver transplantation (LDLT). Therefore, we determined the effect of IL4 T-33C polymorphisms in recipients and donors on ACR in a large cohort of patients that underwent LDLT. We examined 155 LDLT cases treated at Nagoya University or Kyoto University, Japan, between 2004 and 2009. IL4 T-33C polymorphisms were analyzed in recipients and donors. Forty-seven recipients (30.3%) developed early ACR. The genotype frequency of IL4 T-33C in the recipients was associated with ACR incidence (P=0.008, P<0.0125 considered significant). Patients with the IL4-33C carrier genotype (C/C or C/T) were significantly associated with a higher incidence of ACR relative to those with the T/T genotype (OR=3.27, 95% CI: 1.56-6.88, P=0.002). The genotype frequencies of IL4 T-33C in the donors were not associated with rejection incidence. In addition, there was no significant effect of IL4 T-33C genotype combinations on ACR incidence in donors and recipients. Genotyping of IL4 T-33C in recipients might be useful to stratify the liver transplant recipients according to their risk of ACR.

Pre-transplant donor-specific T-cell alloreactivity is strongly associated with early acute cellular rejection in kidney transplant recipients not receiving T-cell depleting induction therapy.

Preformed T-cell immune-sensitization should most likely impact allograft outcome during the initial period after kidney transplantation, since donor-specific memory T-cells may rapidly recognize alloantigens and activate the effector immune response, which leads to allograft rejection. However, the precise time-frame in which acute rejection is fundamentally triggered by preformed donor-specific memory T cells rather than by de novo activated naïve T cells is still to be established. Here, preformed donor-specific alloreactive T-cell responses were evaluated using the IFN-γ ELISPOT assay in a large consecutive cohort of kidney transplant patients (n = 90), to assess the main clinical variables associated with cellular sensitization and its predominant time-frame impact on allograft outcome, and was further validated in an independent new set of kidney transplant recipients (n = 67). We found that most highly T-cell sensitized patients were elderly patients with particularly poor HLA class-I matching, without any clinically recognizable sensitizing events. While one-year incidence of all types of biopsy-proven acute rejection did not differ between T-cell alloreactive and non-alloreactive patients, Receiver Operating Characteristic curve analysis indicated the first two months after transplantation as the highest risk time period for acute cellular rejection associated with baseline T-cell sensitization. This effect was particularly evident in young and highly alloreactive individuals that did not receive T-cell depletion immunosuppression. Multivariate analysis confirmed preformed T-cell sensitization as an independent predictor of early acute cellular rejection. In summary, monitoring anti-donor T-cell sensitization before transplantation may help to identify patients at increased risk of acute cellular rejection, particularly in the early phases after kidney transplantation, and thus guide decision-making regarding the use of induction therapy.

Effects of Preoperative Positive Cross-Match and HLA Mismatching on Early Acute Cellular Rejection and Graft Survival in Living Donor Liver Transplantation

BACKGROUND We evaluated the effects of preoperative positive cross-match and HLA mismatching on early acute cellular rejection and graft survival in living donor liver transplantation (LDLT). MATERIAL AND METHODS We retrospectively reviewed data of 286 patients who underwent LDLT from 2008 to 2013. Cross-matching tests were performed by complement-dependent lymphocytotoxicity (CDC) and flow cytometry (FCX) methods. The CDC cross-matching test was performed using the National Institutes of Health (NIH) standard cross-match and antiglobulin (AHG) cross-match methods. RESULTS NIH, AHG, and FCX were positive in T-lymphocytes from 18 (6.3%), 21(7.3%), and 23 (8.0%) patients, respectively. T-CDC (T-NIH or T-AHG) results were positive in 23 (8.0%) patients. CDC and FCX results were positive in B-lymphocytes from 18 (6.3%) and 35 (12.2%) patients. All positive cross-match results were significantly associated with acute cellular rejection. Only a positive T-CDC cross-match was significantly associated with decreased graft survival (P=0.035). In a multivariate analysis, a positive T-CDC cross-match was the only independent risk factor with a decreased graft survival rate (P=0.041). An HLA mismatch was not associated with acute rejection (p=0.468 for HLA-A, p=0.644 for HLA-B, and p=0.811 for HLA-DR), graft survival (p=0.895 for HLA-A, p=0.580 for HLA-B, and p=0.969 for HLA-DR), and overall survival (p=0.862 for HLA-A, p=0.634 for HLA-B, and p=0.917 for DLA-DR). CONCLUSIONS Although a further prospective study with a larger cohort is required, it is not wise nor safe to perform LDLT in the setting of a positive T-CDC cross-match result.

P115 : PRIMARY GRAFT DYSFUNCTION AFTER 0 MM KIDNEY TRANSPLANTATION SECONDARY TO ACUTE CELL MEDIATED REJECTION

Aim To present a highly sensitized patient with end stage renal disease who received his third kidney transplant from HLA-A, -B, -DR zero mismatched (0 MM) deceased donor (DD) and developed early acute cellular rejection (ACR – BANFF 2A) in absence of DSA. Methods Donor and recipient were HLA typed by RSSOP Luminex assay for HLA loci A, B and C, DRB1, DRB3/4/5, DQB1, DQA1, DPB1, and DPA1. HLA antibody identification were performed with One Lambda Luminex single antigen bead assay. Sera were tested untreated, treated with heat inactivation (HI) and 1:8 dilutions. CDC (with and without HI) and flow XM for T and B cells were tested at the day of transplant. Results A 40 years old man, highly sensitized (CPRA 100%) with a history of two previous renal transplants (lost due to non-immunological cause) with multiple class II DP antibodies with high MFI. The patient received a local zero mismatched donor was offered and with confirmatory testing an antigen level match for all HLA including DP. CDC and flow XM for T and B cells were negative. No DSA was detected pre or post-transplant. In post-operative day 1, the patient presented with anuria and hyperkalemia that mandated dialysis, and underwent dialysis throughout the rest of hospitalization as needed. Due to delayed graft function, he had a biopsy on post-operative day 8 that showed ACR – BANFF 2A – with negative C4d, peritubular capillaritis, and DSA. Treatment with anti-thymo globulin (ATG) did not show improvement. Consequently the patient received 3 sessions of plasmapheresis plus IvIG but the patient remained dialysis dependent. In post-operative day 50, biopsy showed chronic active T cell mediated rejection with no DSA. The graft remained non-functioning and graft nephrectomy was performed. This case suggests that highly sensitized kidney transplant candidates are at increased risk of cell mediated rejection and graft loss even in the context of 0 MM, negative DSA and flow crossmatch.