Risk Of Antibody-mediated Rejection Research Articles

Short-Term Outcomes of ABO-Incompatible Living Donor Kidney Transplantation With Uniform Protocol: Significance of Baseline Anti-ABO Titer

Antibody-mediated rejection (AMR) is one of the major causes of poor outcomes in ABO-incompatible kidney transplantation (ABOi KT). Studies investigating AMR risk factors found that anti-ABO titer is a major issue. However, the significance of antibody titer has been debated. This retrospective study analyzed AMR risk factors in 59 patients who underwent ABOi KT between August 2010 and January 2015. We also analyzed AMR risk factors in recipients with high anti-ABO baseline titers (≥1:64 on dithiothreitol at 37°C phase or ≥1:256 on antihuman globulin phase). The 2-year patient survival rate was 95.8%, and the 2-year graft survival rate was 94.9%. Nine patients (15.3%) experienced clinical (6 of 59 [10.2%]) or subclinical (3 of 59 [5.1%]) AMR. One patient experienced graft loss from hyperacute rejection. AMR risk factor analysis revealed that baseline antibody titer was associated with incidence of AMR. In patients with high baseline titers, low doses of rituximab (200-mg single-dose), an antibody against CD20, was predictive for AMR. Six patients who received pretransplant intravenous immunoglobulin did not experience AMR even when they had high baseline antibody titers. Our results indicate that a high baseline antibody titer affected the incidence of AMR. ABOi KT candidates with high baseline titers need to undergo an intensified preconditioning protocol, including high-dose rituximab (375 mg/m2) and intravenous immunoglobulin.

The Impact of Bortezomib in Renal Transplantation

Kidney transplantation is one of the most common solid organ transplants that improves quality of life and promotes longevity of the patients. However, the access to transplantation is limited by the shortage of deceased donor organs and the presence of HLA antibodies prior transplantation. Many efforts have been made to promote living kidney donation due to the better survival rates, and desensitization protocols have been developed in order to abrogate or reduce the titers of anti-HLA antibodies. Several regimens can be used, including pretransplantation induction therapy and post-operative immunosuppression to prevent graft rejection, reduce morbidity and complications. Immunosuppressant drugs currently used against allorejection are calcineurin inhibitors, corticosteroids, antimetabolites, and mTOR inhibitors. Unmet treatment needs have recently hastened investments in alternative approaches. Along this line, bortezomib, which is a proteasome inhibitor and is already approved by FDA for the treatment of multiple myeloma, has been proposed for conversion of the sensitized status of the patients. This agent is now also used as a rescue treatment for antibody-mediated rejection (AMR). In this mini-review, I aim to discuss recent studies on bortezomib in renal transplant recipients with donor-specific antibodies (DSA) and increased risk for AMR. The role of the drug is not clearly defined on the course of late AMR, awaiting final results from the BORTEJECT trial, and large multicenter dose-response studies are required.

Impact of preformed donor-specific antibodies against HLA class I on kidney graft outcomes: Comparative analysis of exclusively anti-Cw vs anti-A and/or -B antibodies.

AIMTo analyze the clinical impact of preformed antiHLA-Cw vs antiHLA-A and/or -B donor-specific antibodies (DSA) in kidney transplantation.METHODSRetrospective study, comparing 12 patients transplanted with DSA exclusively antiHLA-Cw with 23 patients with preformed DSA antiHLA-A and/or B.RESULTSOne year after transplantation there were no differences in terms of acute rejection between the two groups (3 and 6 cases, respectively in the DSA-Cw and the DSA-A-B groups; P = 1). At one year, eGFR was not significantly different between groups (median 59 mL/min in DSA-Cw group, compared to median 51 mL/min in DSA-A-B group, P = 0.192). Moreover, kidney graft survival was similar between groups at 5-years (100% in DSA-Cw group vs 91% in DSA-A-B group, P = 0.528). The sole independent predictor of antibody mediated rejection (AMR) incidence was DSA strength (HR = 1.07 per 1000 increase in MFI, P = 0.034). AMR was associated with shortened graft survival at 5-years, with 75% and 100% grafts surviving in patients with or without AMR, respectively (Log-rank P = 0.005).CONCLUSIONOur data indicate that DSA-Cw are associated with an identical risk of AMR and impact on graft function in comparison with “classical” class I DSA.

Current status of the evaluation and management of antibody-mediated rejection in kidney transplantation

Antibody-mediated rejection (AMR) has come to the forefront of clinical and research challenges in clinical transplantation. Despite the major progress made over the past two decades, there remains a large number of unanswered diagnostic, prognostic, and therapeutic questions. Here we review the recent studies that have helped improve our understanding of AMR. Complement binding capacity of the HLA antibodies using modified single antigen bead Luminex assays to detect C1q, C4d, or C3d binding, has been associated with risk of AMR and graft failure. However, this property correlates with the antibody mean fluorescent intensity, and, in many cases, may not add additional insight. The use of molecular methods to examine expression profiles in the kidney biopsy specimens, in peripheral mononuclear cells, or urinary chemokine signature, has improved our understanding of the mechanisms of AMR-induced injury and refined our current diagnostic tools. On the treatment front, monoclonal antiinterleukin 6 receptor antibody, and C1 esterase inhibitor have shown promising results in the pilot studies but further larger trials are needed to evaluate their safety and efficacy. We are making constant progress in the pursuit of a better understanding the AMR process and finding new diagnostic and therapeutic options.

High strength HLA-DPA1 donor-specific antibodies cause positive CDC B-cell crossmatch but weak positive B-cell flow crossmatch

DPA1 antibodies were shown to be a risk of antibody-mediated rejection (AMR). We present a case showing high MFI DPA1 donor-specific antibodies (DSA) causing +ve CDC crossmatch (CxM), but -ve flow xM (FxM). At the time of deceased donor offer, we perform prospective FxM if the intended candidate displays strong DP DSA. This particular case received first kidney transplant in 2004 from a 8/10 mismatched donor. Luminex single antigen bead assay (One Lambda) revealed strong antibodies to all mismatched donor’s HLA and CREG, and thus had 100% CPRA. The patient also displayed strong antibodies to several DPs including to the alpha chains, DPA1∗01 and DPA1∗03. The patient received a deceased donor offer in May 2015. Virtual xM (VxM) identified 3 strong DSAs directed to DPA1∗01(MFI = 16282), DPA1∗03(MFI = 13167) and DPB1∗04(MFI = 19568), and predicted positive B FxM. Contrary to the prediction, the donor-specific FxM was -ve (T cell MCS = 29; B cell MCS = 110). Kidney offer was declined because of multiple high MFI DSAs. To have better insights on our failed VxM prediction, we performed pronase as well as CxMs. The pronase B FxM was weakly +ve with a MCS = 209 (+ve cutoff > 120 MCS), which is within the range relates to -ve CxM. Unexpectedly, the B CxM with and without DTT-treated sera were turned to be strongly +ve. Additional xMs with a surrogate donor cells expressing a single target DPA1∗01:03 also produced similar results, i.e., +ve pronase B FxM with MCS=178 and +ve B CxM. We confirmed DP antibodies assignment using Immucor single antigen beads, and typed previous donor and patient for DPA1 and DPB1 loci. These results ruled out DPB1∗04:01 antibody, but cannot confirm DPB1∗04:02, because DPB1∗04:02 beads in both venders’ systems were paired with DQA1∗01:03. It is more likely the patient has only DPA1∗01 and DPA1∗03 antibodies. Unambiguous assignment of DPA1 antibodies will remain challenging until the single antigen bead array includes multiple DP antigen series with different alpha and beta chain pairs. In conclusion, comprehensive antibody analyses by single antigen beads, and high-resolution typing of DPB1 and DPA1 of donor and recipient are necessary to define DPA1 antibodies. CDC xM is a critical test to determine the risk of hyper acute AMR in patients having strong DPA1 DSAs, and FxM may yield false negative results in these cases.

Multiple high MFI Class I DSA can cause acute AMR of kidney allograft in simultaneous liver and kidney transplant recipients: outcome analysis from a single-center

Aim Crossmatch (xM) positive (+ve) simultaneous liver and kidney transplant (SLKT) recipients remain at risk for antibody-mediated rejection (AMR) of the kidney allograft. To investigate the risk associated with donor-specific HLA antibodies (DSA), we studied 23 consecutive patients who received a SLKT at UCSF since 12/2013. Methods Donors and recipients were HLA-typed using Luminex rSSO. Recipient sera collected pre-tx, 1 wk and 3 mo post-tx were analyzed for HLA antibodies using Luminex single antigen beads. CPRA was determined using 2000 MFI cutoff. Immunosuppression was steroids, tacrolimus, and mycophenolate without induction. AMR was diagnosed by kidney biopsy. Results Among 23 patients (pts), 17 (74%) had CPRA>1%; 6 (26%) had CPRA>85%. Eight pts had pre-tx DSA: 6 with class I only; 1 had class II only, and 1 had both class I+II. Four pts had > 2 DSAs. Most DSAs (and CREG) were lost by 1 wk post-tx but non-DSAs persisted >3 mos (Figure). Two pts with 0% CPRA developed a de novo DSA at 3 mos: 1 had B44 (MFI 5589), other had DQA05 (MFI 2303). Two pts developed early kidney AMR. Pt 1 (CPRA100%) with 5 high MFI (>20K MFI) class I DSAs (A1, A24, B7, B37, Cw7) and +ve CDC & +ve Flow TB previous liver tx recipient) received SLKT from a well-matched (1C, 2DR, 2DQ, 1DP; no repeat mismatch) donor with +ve CDC and weakly +ve Flow T&B cell xMs. Allo-xM with 3rd party donors and auto-xM were CDC +ve but Flow -ve. All CDC xMs were -ve with heat-inactivated complement. xM with a 3rd party endothelial cell-line was weakly +ve. Renal allograft function recovered with AMR treatment. Conclusion Reduction of circulating HLA antibody titers after SLKT appears to be donor HLA (and CREG) specific. Kidney AMR occurred with multiple high MFI Class I DSAs or complement-fixing non-HLA IgG antibodies. Longitudinal analyses show the specificity, kinetics, and stability of HLA antibody absorption by liver allografts. Download : Download full-size image

OR21 Is circulating angiotensin II receptor a potential marker of renal allograft injury?

Aim Angiotensin II receptor-1 (AngII) is a membrane-bound protein in vascular endothelium that is responsible for vasoconstriction and blood pressure regulation. Current data suggests AngII may be a target of antibody mediated rejection (AMR) following renal transplantation. We speculated that detection of AngII in the peripheral circulation might reflect allograft injury and be a marker for AMR. Methods This retrospective study selected 20 patients without evidence of anti-HLA antibody and graft survival ⩾ 1 year: Ten patients were AMR-free and blood tested at 0, 6 and 12 months post-transplant. Ten patients had AMR and blood was tested pretransplant, during and after AMR). Blood was also collected from 63 healthy volunteers. AngII was measured by commercial elisa (Cusabio). Results AngII was absent in 63/63 volunteers (100%). In contrast, circulating AngII was detected in half the AMR (4/10) and AMR-free (6/10) patients pretransplant ( p p = ns). Posttransplant, circulating AngII declined from 6/10 to 4/10 non-AMR patients by 6 months. In addition, AngII concentration declined to 84 ± 135 and 22 ± 50 pg/ml by 6 and 12 months posttransplant. In contrast, AngII was present in 7/10 patients during AMR ( p p Conclusions This pilot study showed that circulating AngII is lacking among healthy volunteers but present in half of patients awaiting renal transplantation. Neither the presence or the concentration of AngII pretransplant predicted risk of AMR. However, the demonstration that circulating AngII was common during AMR and resolved upon clinical stability and the finding that de novo AngII expression was only seen among patients with AMR suggests that circulating AngII might be a useful marker in detection and treatment of AMR, particularly when anti-HLA DSA are not present.

Clinical Implications of Angiotensin II Type 1 Receptor Antibodies in Antibody-mediated Rejection Without Detectable Donor-specific HLA Antibodies After Renal Transplantation

BackgroundSolid-phase immunoassays have improved detection sensitivity for donor-specific HLA antibody (DSHA) and permitted the accurate diagnosis of antibody-mediated rejection (AMR). However, DSHA is not always sufficient to explain the cause of AMR. Consequently, a means of assessing non-HLA antibodies is required to determine the cause of AMR. The aim of the present study was to evaluate the clinical implications of antibodies (Abs) targeting angiotensin II type I receptor (AT1R) in recipients with AMR but without serum DSHA. MethodsNon-HLA AMR cases diagnosed between January 2011 and June 2014 were included. Levels of anti-AT1R Abs (U/mL) were quantified by using AT1R assay kits (One Lambda, Calif, United States) with collected sera pretransplantation and at biopsy (cut-off value: 15 U/mL). ResultsSeventy-two patients were diagnosed with AMR during the above-mentioned period. Of them, 12 recipients (16.7%) had no DSHA. The sera of these 12 patients were tested (2 patients were only checked at time of biopsy). Nine patients (9/10) were presensitized for anti-AT1R Abs (median, 25.0 U/mL; range, 12.9 to 50.0 U/mL). Ten patients (10/12) were anti-AT1R− positive at time of biopsy (median, 23.2 U/mL; range, 11.4 to 50.0 U/mL). The mean time from transplantation to biopsy was 73 months. Eight patients experienced acute AMR, and 4 developed chronic AMR. Four patients showed negative C4d staining in peritubular capillaries (4/12). Patients were treated with plasmapheresis, low-dose intravenous immunoglobulin, and/or rituximab. ConclusionsAT1R Abs may play a significant role in AMR without detectable DSHA. Pretransplantation detection of AT1R Abs may be helpful for assessing the risk for non-HLA AMR.

De novo donor-specific human leukocyte antigen antibodies early after kidney transplantation.

Our aim was to determine the incidence of de novo donor-specific human leukocyte antigen (HLA) antibody (dnDSA) during the first year after kidney transplantation and the impact of early dnDSA on acute rejection and protocol biopsy findings. We selected all patients who received a kidney transplant at our center between July 2010 and March 2012. Single antigen bead assay was performed at 1, 4 and 12 months after transplantation. Only DSAs with a mean fluorescence intensity (MFI) of greater 999 were included. We included 245 kidney transplant recipients who did not have a DSA before transplantation. At 12 months, 8.2% of the patients developed dnDSA; 2.4% of them were to HLA class I and 6.5% to HLA class II. Of the 32 patients with a dnDSA at 1 or 4 months, only 8 (25%) persisted at 12 months. The risk of antibody-mediated rejection (AMR) was higher in the dnDSA group. For the dnDSA group with MFI of 3,000 or greater (compared with the group with MFI<3,000), the hazard ratio for AMR was 10.6 (95% confidence interval, 2.27-49.5). The cumulative incidence of AMR or mixed rejection at 1 year was 30% in the group with dnDSA MFI level of 3,000 or greater but only 4% for the group with dnDSA with MFI less than 3,000. On 1-year protocol biopsies, the dnDSA group showed more interstitial inflammation, tubulitis, and glomerulitis. We conclude that dnDSA occurring during the first posttransplantation year may be transient, and the risk of AMR is higher in patients with a dnDSA MFI level that is greater than 3,000.

Alemtuzumab Induction and Antibody-Mediated Rejection in Kidney Transplantation

BackgroundInduction therapy improves graft outcomes in kidney transplant recipients (KTRs). We aimed to compare the incidences of antibody-mediated rejection (AMR) and acute cellular rejection (ACR) as well as graft and patient outcomes in KTRs who underwent induction with alemtuzumab versus rabbit-antithymocyte globulin (r-ATG). MethodsThis was a single-center retrospective study involving patients who underwent kidney transplantation between January 2009 and December 2011 after receiving induction therapy with either alemtuzumab or r-ATG. Maintenance immunosuppression included tacrolimus and mycophenolate mofetil with early steroid withdrawal. Acute rejection was diagnosed using allograft biopsy. ResultsAmong the 108 study patients, 68 received alemtuzumab and 40 got r-ATG. There was a significantly higher incidence of AMR (15% vs 2.5%; P = .008) and similar incidence of ACR (4.4% vs 10%; P = .69) for alemtuzumab versus r-ATG groups. One-year serum creatinine levels (l.68 ± 0.8 mg/dL vs 1.79 ± 1.8 mg/dL; P = .66) as well as graft (91.1 ± 3.5% vs 94.5 ± 3.8%; P = .48) and patient (93.8 ± 3.0% vs 96.4 ± 3.5%; P = .92) survivals were similar for the alemtuzumab versus the r-ATG groups. ConclusionOur study showed a higher incidence of AMR and similar incidence of ACR in KTRs who underwent induction with alemtuzumab compared with those who received r-ATG and were maintained on tacrolimus and MMF. This was despite a lower HLA mismatch in the alemtuzumab group. One-year graft survival, patient survival, and allograft function were similar. Inadequate B-cell suppression by alemtuzumab as well as altered phenotypic and functional properties of repopulating B cells could be contributing to heightened risk of AMR in these patients.

Dynamics of anti‐human leukocyte antigen antibodies after renal transplantation and their impact on graft outcome

The purpose of this study was to sequentially monitor anti-HLA antibodies and correlate the results with antibody-mediated rejection (AMR), graft survival (GS), and graft function (GF). We collected sera from 111 kidney transplant recipients on transplant days 0, 7, 14, 30, 60, 90, 180, and 360 and analyzed PRA levels by ELISA. DSAs were analyzed by single-antigen beads in rejecting kidneys. At pre-transplant, 79.3% of the patients were non-sensitized (PRA=0%) and 20.7% were sensitized (PRA>1%). After transplant, patients were grouped by PRA profile: no anti-HLA antibodies pre- or post-transplant (group HLApre-/post-; n=80); de novo anti-HLA antibodies post-transplant (group HLApre-/post+; n=8); sensitized pre-transplant/increased PRA post-transplant (group HLApre+/post↑; n=9); and sensitized pre-transplant/decreased PRA post-transplant (group HLApre+/post↓; n=14). De novo anti-HLA antibodies were detected at 7-180d. In sensitized patients, PRA levels changed within the first 30d post-transplant. Incidence of AMR was higher in HLApre-/post+ and HLApre+/post↑ than in HLApre-/post-, and HLApre+/post↓ (p<0.001) groups. One-yr death-censored GS was 36% in group HLApre+/post↑, compared with 98%, 88% and 100% in groups HLApre-/post-, HLApre-/post+, and HLApre+/post↓, respectively (p<0.001). Excluding first-year graft losses, GF and GS were similar among the groups. In conclusion, post-transplant antibody monitoring can identify recipients at higher risk of AMR.

Antibody-mediated rejection: analyzing the risk, proposing solutions.

Antibody-mediated rejection: analyzing the risk, proposing solutions.

Pretransplant DSA But Not Complement Fixing HLA Antibodies Are Associated with Increased Risk for Antibody Mediated Rejection in Kidney Transplantation.

It is still not fully elucidated whether kidney transplant recipients with preformed donor-specific human leukocyte antigen (HLA) antibodies (DSA) detectable by Luminex Single Antigen Beads (SAB) are at increased risk of reduced allograft function early after transplantation. Especially the effect of complement fixing DSA detected by the C1q SAB assay remains unclear. Regarding the C1q assay recent studies indicated controversial results, possibly related to centre effects or the size of the patient cohorts analyzed. The aim of our retrospective analysis was to evaluate the early impact of C1q fixing DSA in a large single centre study. We included a cohort of 262/289 renal transplant recipients transplanted in a short period between January 2011 and December 2012 at the local kidney transplantation program in this analysis. All transplantations were performed with a CDC negative crossmatch. For living donation also flow cytometric crossmatches were performed. The pretransplant HLA antibody status determined by Luminex SAB was not systematically considered for transplant decisions. In addition, we analysed all indication biopsies performed within the first one to two years of follow-up for histological signs of antibody mediated rejection (AMR). Pretransplant SAB DSA were present in 40 patients (25 with anti-HLA-class I, 11 with class II, and 4 with class I+II specificities, respectively). In total 27/262 patients showed signs of AMR, 14 of 222 patients without DSA (6.3%, RR 0.2) compared to 13/40 patients with DSA (32.5%, RR 5.2). The C1q fixing capacity was positive in 6/40 patients with DSA, but only in 1/27 patients with AMR. Follow-up data for graft survival and function are pending. Although still preliminary, our study could clearly confirm pretransplant Luminex DSA as a significant risk factor for the occurrence of early AMR after renal transplantation. C1q-binding capacity of DSA at the time of transplantation seems to be not predictive for the occurrence of AMR during early follow-up.

Desensitization Protocols in Immunologic High Risk Pediatric Recipients.

Renal transplantation (Tx) is the modality of choice for renal replacement in children with ESKD. Sensitized recipients have increased significantly and in this group renal tx rate is extremely low. Currently therapies that modulate antiHLA antibodies such as intravenous inmune globuline (IVIG), plasmapheresis (PP) and rituximab have improved their transplantation's chances. We report our desensitization protocols,the outcome of the sensitized patients after tx, and the immunologic post tx monitoring. We has been used two protocols, IGEV 2gr/kg for 3 months (2/6) and IGEV 2 gr/kg two doses plus one dose of rituximab 375 mg/m2 (4/6). Sensitized patients in waiting list for DD received one of these protocols. After one month they were included in a medical urgency list for tx. After tx they received another dose of IGEV 2 gr/kg and prophylactic PP. Donor specific alloantibody (DSA) was monitorized. Induction therapy was timoglobulin, and maintenance:prednisone, MMF and tacrolimus. Antibody mediated rejection (AMR) or T- cell mediated rejection (ACR) were defined by Banff classification. Between January 2009 and December 2013, 160 patients underwent kidney Tx. Six highly sensitized, with PRA more than 40% went into pretransplant desensitization. After 12 months (3-20) they received a kidney from DD. PRA pre desensitization 89,3% (100-71), post desensitization 79,3% (97-39). All the patients had negative CDCXM pretx and 2/6 had positive CFXM pretx. Rejection incidence 33%: 1 cellular acute rejection (CAR), 1 humoral acute rejection (HAR), 1 mixed rejection. 1/6 had a BK nephritis. Observation period was 26,5 month (6-48). Renal function determined by creatinine was: 1.2, 1.0, 1.3 mg/dl at one, three and twelve month postx. At the end of observation period creatinine was 1.3 mg/dl (0,81-2,62). One patient had proteinuria.Patients survival was 100%, graft survival 83,3%. One patient lost the graft for an AMR. Sensitization to HLA antigens is a significant barrier to renal transplantation. New protocols for desensitization with IVIG, PP and antiCD20 antibodies has become sucessfull to allow tx in this group of patients. The highly sensitized patients should be closely monitorized because they have and increase risk of AMR. The same therapies can be usefull to treat AHR.

Risk of Antibody-Mediated Rejection in Kidney Transplant Recipients With Anti-HLA-C Donor-Specific Antibodies

Anti-HLA donor-specific antibodies (DSAs) cause acute and chronic antibody-mediated rejection (AMR). However, the clinical relevance of anti-HLA-C antibodies remains unclear. We evaluated the clinical relevance of the presence of anti-HLA-C DSA at day 0 in renal transplant recipients. In this retrospective, case-controlled study, 608 patients who underwent kidney transplantation between August 2008 and March 2012 were screened for the presence of isolated anti-HLA-C DSA at day 0. A total of 22 renal transplant recipients were selected and followed for a period of 1 year. AMR was classified according to the Banff classification. The 22 patients were compared with 88 immunized patients. Acute AMR was diagnosed in six patients (27.3%). The median level of DSA at day 0 was 1179 (530-17,941). The mean fluorescence intensity in the anti-C group was 4966 (978-17,941) in the AMR group and 981 (530-8012) in the group of patients without AMR. Acute AMR was diagnosed less frequently in the 88 immunized individuals (9.1%) than in the DSA anti-C group (p = 0.033). The level of DSA at day 0 was predictive for AMR (p = 0.017). Patients with a high level of pretransplant anti-HLA-C DSAs are likely to develop acute AMR during the first year after transplantation.

PREDICTIVE SIGNIFICANCE OF ANTI-HLA AUTOANTIBODIES IN HEART TRANSPLANT RECIPIENTS

Aim. The aim of this study was to de fi ne the role of preformed anti-HLA antibodies (anti-HLA) in antibody-mediated rejection (AMR) and cardiac allograft vasculopathy (CAV) after heart transplantation. Materials and Methods. 140 heart transplant recipients were followed after heart transplantation performed for 106 dilated and 34 – ischemic cardiomyopathy. Anti-HLA was determined before transplantation by ELISA. Results. Recipients were divided into 2 groups: anti-HLA positive (n = 45, 32,1%) and anti-HLA negative (n = 95, 67,9%). The incidence of AMR in anti-HLA positive group was 12 (26,67%) and 11 (11,58%) in anti-HLA negative group. Risk of AMR was signi fi cantly higher in anti-HLA positive recipients (RR 2,3: 95% CI 1,02–4,81, р = 0,03). During fi rst three years after transplantation CAV was diagnosed in 9 (20%) of anti-HLA positive recipients and in 7 (6,8%) of patients without anti-HLA. (RR 2,7: 95% CI 1,08–6,82, р = 0,03). Survival in freedom from CAV in anti-HLA negative recipients was much higher than in anti-HLA positive recipients (0,89 ± 0,07, 0,72 ± 0,06, resp. (p = 0,02)). Conclusions. The presence of preformed anti-HLA antibodies in candidates for heart transplantation increase the risk of AMR and CAV post transplantation in 2,3 and 2,7 times, respectively.

Preformed Donor-Specific Antibodies and Risk of Antibody-Mediated Rejection in Repeat Renal Transplantation

Allograft outcomes in patients undergoing repeat renal transplantation are inferior compared to first-time transplant recipient outcomes. Donor-specific antibodies detected by solid-phase assays (DSA-SPA) may contribute to the worse prognosis. The influence of DSA-SPA on repeat renal transplantation outcomes has not been previously studied in detail. This study reports the findings in 174 patients who underwent repeat renal transplantation between years 2007 and 2012. These included 62 patients with preformed DSA-SPA detected by Luminex at the time of transplantation. Patients received standard and consistent immunosuppression and were monitored closely for evidence of rejection. Recipients who underwent desensitization were excluded from this analysis. Endpoints included development of biopsy-proven acute rejection and analysis of graft survival and function. Patients in the DSA-SPA-positive and DSA-SPA-negative groups received similar immunosuppression, and a similar proportion of recipients had a peak panel reactive antibody greater than 20%; the two groups differed with respect to human leukocyte antigen mismatches (4.7 ± 1.1 vs. 4.1 ± 1.7, P=0.024). Recipients with preformed DSA-SPA had higher rejection rates (54.8% vs. 34.8%, P=0.01), including higher rates of antibody-mediated rejection (AMR) (32.3% vs. 7.1%, P<0.001). Recipients who were DSA-SPA-positive and flow cytometry crossmatch (FCXM)-positive had a higher incidence of both AMR (OR 4.6, P=0.009) and of acute rejection (OR 3.57, P=0.02) as compared to those who were DSA-SPA-positive and FCXM-negative. Overall allograft survival was similar in the DSA-SPA-positive and DSA-SPA-negative groups (log-rank test=0.63, P=0.428). Differences in allograft function were detectable after 2 years (32.8 ± 13.1 vs. 47 ± 20.2 mL/min/1.73 m(2), P=0.023) and may be reflective of more AMR among DSA-SPA-positive patients. This analysis suggests that DSA-SPA increases the overall risk of acute rejection but does not appear to adversely impact allograft survival during the early follow-up period. Close monitoring of renal function and early biopsy for AMR detection appear to allow for satisfactory short-term allograft outcomes in repeat transplant recipients.

(322) - C1q Testing in Pediatric Heart Transplant Recipients at Risk for Antibody Mediated Rejection

(322) - C1q Testing in Pediatric Heart Transplant Recipients at Risk for Antibody Mediated Rejection

HLA-C antibodies are associated with irreversible rejection in kidney transplantation: Shared molecular eplets characterization

We report an interesting case concerning an irreversible antibody-mediated rejection (AMR), associated with anti-HLA-C DSA, which occurred after a second kidney transplantation despite having determined a low number of antibodies directed against HLA-C antigens (MFI<1000) in the previous transplantation (which was then considered to be an indicator of low risk of AMR). A 63-year-old woman was re-transplanted with pre-transplant (PrT) sensitization. On day 7 post-transplantation, oligoanuria occurred and increased MFIs for the detected PrT antibodies and other antibodies (non-detected or detected with very low PrT MFI) were observed. SAB assay also showed antibodies against the second donor HLA-C mismatches and other HLA-C antigens. Nephrologists suspected AMR and the patient was therefore treated with methylprednisolone/plasmapheresis/IVIG/anti-CD20 without improvement, which led to transplantectomy. Histologic analysis confirmed acute AMR. Interestingly, it was possible to define exactly the potential immunizing epitopes whose recognition determines the specific antibody production. So, 1st donor DSAs (detected PrT with low MFI), 2nd donor DSAs (detected PTP), and non-DSA detected PTP have several shared eplets, being the 11AVR eplet the only one present on all alleles. Thus, the recognition of 11AVR eplet in the first transplant modeled the patient’s antibody response. Therefore, we propose that donor HLA-C typing should always be performed for recipients with anti-HLA-C antibodies, and specific shared-eplets should be investigated in order to determine previous transplant mismatches.

Kidney Transplantation: Evaluation and Clinical Outcome of 237 Recipients at Low, Medium, High, or Strong Immunological Risk of Rejection

BackgroundDonor-specific antibodies (DSAs) play a fundamental role in kidney transplantation. The identification of DSAs is an essential rejection parameter. Patients and MethodsWe evaluated a protocol in 237 patients receiving kidneys from living (LDs) and deceased donors (DDs). Recipients were classified as being at low (LR), medium (MR), high (HR), or strong (SR) risk of rejection based on Luminex panel reactive antibody (PRA)–single antigen beads (SABs). Grafts that survived for 1 year were evaluated. ResultsOf the 237 transplanted patients, 129 (54.43%) received a kidney from an LD and 108 (45.57%) from a DD. Of 95 LR recipients receiving kidneys from LDs, 2 patients lost the graft due to non-immunological causes. Of 34 MR recipients, 13 had rejection episodes, and 2 lost the graft by AMR and one by cellular rejection (CR). Of 108 recipients receiving a kidney from a DD, 59 (54.63%) were LR, 31 (28.70%) MR, 11 (10.19%) HR, and 7 (6.48%) SR. Twenty of all transplanted recipients lost their grafts; 4 were due to clinical causes, 4 by cellular rejection, and 12 by antibody-mediated rejection (AMR) with PRA-SAB mean fluorescent intensity of 530 to 12,591. One-year graft survival for LD transplanted LR and MR patients was 97.6% and 94.1%, respectively (P = .004). In DD recipients, the LR vs MR SD was P = .011, and for LR vs HR + SR it was P = .001. For MR vs HR+SR no SD was found (P = .323). ConclusionRejections were detected in 51 patients (21.52%). Graft failure occurred in 16 patients (6.75%). A total of 218 (91.98%) recipients maintained good kidney function after 1 year. This protocol based on fluxogram risk assessment of AMR provided fast and precise immunological evaluation of recipients and donors and stratification by immunological risk of AMR.