HLA-incompatible Transplantation Research Articles

Outcomes of Kidney Transplantation in Highly HLA-Sensitized Patients Treated with Intravenous Immuno-Globulin, Plasmapheresis and Rituximab: A Meta-Analysis.

(1) Background: We aimed to investigate the outcomes of human leukocyte antigen (HLA)-incompatible transplantation for patients who received desensitization with intravenous immunoglobulins (IVIg), plasmapheresis, and rituximab. (2) Methods: A comprehensive search of multiple electronic databases to identify studies that utilized desensitization was conducted. The random-effects model was used to calculate the pooled rates and the 95% confidence interval (CI). (3) Results: A total of 1517 studies were initially identified. From these, 16 studies met the inclusion criteria, encompassing 459 patients, with a mean age of 45 years, of whom 40.8% were male. CDC crossmatch was positive in 68.3% (95% CI: 43.5-85.8; I2 87%), and 89.4% (95% CI: 53.4-98.4%; I2 89.8%) underwent living-donor transplantation. The 1-year graft survival pooled rate was 88.9% (95% CI: 84.8-92; I2 0%) and the 5-year graft survival rate was 86.1% (95% CI: 81.2-89.9; I2 0%). The 1-year patient survival rate was 94.2% (95% CI: 91-96.3; I2 0%), and the 5-year patient survival rate was 88.9% (95% CI: 83.5-92.7%; I2 7.7%). The rate of antibody-mediated rejection was 37.7% (95% CI: 25-52.3; I2 80.3%), and the rate of acute cell-mediated rejection was 15.1% (95% CI: 9.1-24; I2 55%). (4) Conclusions: Graft and patient survival are favorable in highly sensitized patients who undergo desensitization using IVIg, plasmapheresis, and rituximab for HLA-incompatible transplantation.

Comparative outcomes of DSA positive, crossmatch negative living donor kidney transplants versus remaining on the waitlist for an HLA compatible deceased donor

IntroductionThe clinical relevance of preformed donor specific antibodies in the setting of a negative crossmatch (DSA + XM-) remains controversial. In this study we investigate the outcomes of patients with a DSA + XM- living donor (LDi) who proceeded with an HLA-incompatible (HLAi) transplant compared with those who waited for an HLA-compatible deceased donor (DDc). Materials and methodsWe investigated 359 patients on the transplant waiting list who had at least one potential HLAi living donor, from which 203 DSA + XM- pairs were identified and outcomes analysed. ResultsOut of 203 patients, 96 (47.3%) received a LD transplant: 52/96 (54.2%) a LDi, and 44/96 (45.8%) an alternative compatible LD. In addition, 107 patients out of 203(52.7%) waited for a DDc, of which 47(43.9%) were subsequently transplanted. Our adjusted analysis showed that the LDi transplantation did not offer a superior patient survival over waiting for a DDc transplant. For those transplanted, there was no difference in patient (p = 0.065) or death censored allograft survival (p = 0.37) between DDc and LDi recipients. However, there was a higher incidence of acute allograft rejection (p = 0.043) and antibody-mediated rejection (p = 0.005) in the LDi group. Having a high pre-transplant calculated reaction frequency and preformed DSA to both class I and class II antigens were associated with inferior outcomes in the LDi transplants. ConclusionsGiven the lack of difference in allograft survival between LDi and DDc transplants, in the absence of an alternative compatible living donor, proceeding with a LDi should be supported despite a higher rejection risk, providing individual risk assessment and shared decision making is undertaken.

BK Viremia and Viruria Does Not Depend on the Type of Double-J Stent Used During Kidney Transplantation.

BK virus is a major cause of chronic renal allograft failure.Transplant ureteral stent use has been reported as a risk factorfor BK virus infection. Recently, the use of a new type of ureteral stent (Magnetic Black Star) was reported in kidney transplant recipients. The aim ofthis preliminary report was to compare BK virus viremia and viruria occurrence depending on the type of double-J stent (standard versus Magnetic Black Star). We included all kidney transplants performed in our center from January to December 2022. Each case had double-J stent placement. Indwelling stents were either a 6- or 7-Fr standard double-J stent or a 6-Fr Magnetic Black Star double-J stent. The type of double-J stent was chosen according to the surgeon's preference. A standard BK virus screening protocol was followed during the study period, which consisted of routine polymerase chain reaction examination of plasma and urine samples during monthly follow-ups. We assessed 120 patients without missing data: 92 patients received standard double-J stents and 28 patients received Magnetic Black Star stents. Patients were mostly male in the standard group (70.7%) versus the Magnetic Black Star group (42.9%) (P = .01). ABO- and HLA-incompatible transplant rates were similar in both groups. BK viremia occurrence and BK viruria occurrence were similar between groups at 1 month, 3 months, and 6 months. This preliminary study showed no differences concerning BKvirus infection depending on the type of double-J stents used during kidney transplant.

The impact of IdeS (imlifidase) on allo-specific, xeno-reactive, and protective antibodies in a sensitized rhesus macaque model.

Highly sensitized patients face many barriers to kidney transplantation, including higher rates of antibody-mediated rejection after HLA-incompatible transplant. IdeS, an endopeptidase that cleaves IgG nonspecifically, has been trialed as desensitization prior to kidney transplant, and successfully cleaves donor-specific antibody (DSA), albeit with rebound. IdeS was generated and tested (2mg/kg, IV) in two naïve and four allosensitized nonhuman primates (NHP). Peripheral blood samples were collected at regular intervals following IdeS administration. Total IgG, total IgM, and anti-CMV antibodies were quantified with ELISA, and donor-specific antibody (DSA) and anti-pig antibodies were evaluated using flow cytometric crossmatch. B cell populations were assessed using flow cytometry. IdeS successfully cleaved rhesus IgG in vitro. In allosensitized NHP, robust reduction of total, DSA, anti-pig, and anti-CMV IgG was observed within one day following IdeS administration. Rapid rebound of all IgG antibody populations was observed, with antibody levels returning to baseline around day 14 post-infusion. Total IgM level was not affected by IdeS. Interestingly, a comparable reduction in antibody populations was observed after the second dose of IdeS. However, we have not observed any significant modulation of B cell subpopulations after IdeS. This study evaluated efficacy of IdeS in the allosensitized NHP in IgG with various specificities, mirroring antibody kinetics in human patients. The efficacy of IdeS on preexisting anti-pig antibodies may be useful in clinical xenotransplantation. However, given the limitation of IdeS on its durability as a monotherapy, optimization of IdeS with other agents targeting the humoral response is further needed.

Améliorer l’accès à la transplantation rénale des sujets hyperimmunisés : quelle place pour un blocage de la voie de l’IL-6 dans les protocoles de désimmunisation ?

BackgroundDesensitization allows kidney transplantation for HLA highly sensitized subjects. Due to the central role of IL-6 in immunological response, tocilizumab (monoclonal antibody directed against IL-6 receptor) could probably improve desensitization efficacy. MethodsPubmed systematic review by using MeSH terms: tocilizumab, clazakizumab, interleukin-6 blockade, kidney transplantation, kidney graft and desensitization. StudiesIL-6 plays a role in humoral response (plasmocyte differentiation induced by lymphocyte T, IL-21 secretion) as well as in cellular response (differentiation of LT Th17 rather than T reg). In desensitization field, tocilizumab was first studied as second-line treatment after failing of standard-of-care (apheresis, rituximab ± IgIV). Recent study showed that tocilizumab as a monotherapy attenuated anti-HLA antibodies rates but was not sufficient to allow transplantation. However, lymphocyte immunophenotyping showed that tocilizumab hindered B cells maturation. Thereby, tocilizumab could improve long-term efficacy of desensitization, by limiting the anti-HLA rebound and so avoiding antibody-mediated rejection. This hypothesis is supported by a recent study which used clazakizumab (monoclonal antibody directed against IL-6) in association with standard-of-care. In that study, clazakizumab was continued after kidney transplantation. Results were encouraging because 9/10 patients were transplanted and there was no donor-specific antibody at 6 months post-transplantation. ConclusionIL-6 pathway blockade as a monotherapy fails to desensitize HLA highly sensitized kidney transplant candidates. In association with standard-of-care, it does not seem to significatively improve kidney allograft access (short-term efficacy) vs. standard-of-care only. However, it could improve long-term prognosis of HLA incompatible transplantation by orienting the response towards a tolerogenic profile, by hindering B-cell maturation and, thereby, avoiding DSA rebounds after transplantation. This hypothesis needs to be proven by further studies.

Comparison of kidney transplant outcomes in HLA compatible and incompatible transplantation: A national cohort study.

Reports of HLA incompatible (HLAi) kidney transplant outcomes are inconclusive, especially in the context of lower level Donor Specific Antibodies (DSA). Multi-centre national cohort study of HLAi kidney transplant recipients matched in 1:2 ratio with HLA compatible (HLAc) kidney transplant recipients. HLAi defined as DSA identified by Luminex. Antibody mediated rejection (AMR) and transplant-survival were analysed using Kaplan-Meier plots. Propensity score (PS) matching was used to compare recipient and transplant survival between groups. We included 61 HLAi and 122 HLAc recipients; mean age 46 years; 60% female. MFIT0 : 3327 (IQR 1352-6458), 23 (38%) were Flow cytometry crossmatch positive (FC-XMPOS ). DSAPOS /FC-XMPOS transplantation carried an increased risk of AMR at 1year (52%) compared to DSAPOS /FC-XMNEG (27%) and HLAc (0%). Unadjusted death censored graft loss at 3 years was 13% (HLAi) and 8% (HLAc). Three-year patient survival was 95% in HLAc, 84% in DSAPOS /FC-XMNEG and 69% in DSAPOS /FC-XMPOS recipients; 58% of HLAi deaths were infection-related. HLA incompatibility was associated with a decreased 3-year survival in our PS-matched cohort. In kidney transplantation, DSA and positive FC-XM carries an increased risk of AMR. Despite inferior transplant and survival outcomes compared to HLAc transplantation, it remains a realistic option for highly sensitized patients facing prolonged waiting times and reduced survival on dialysis.

Successful ABO and HLA incompatible kidney transplantation in children in the UK

BackgroundThere is increasing evidence of good short-term and medium-term outcomes of ABO incompatible (ABOi) and HLA incompatible (HLAi) kidney transplantation with pre-transplant positive crossmatches in paediatric practice. However, there remain concerns regarding the higher risks of infective complications and antibody-mediated rejections. The aim of our study is to show longer-term follow-up on all ABOi and HLAi paediatric kidney transplant recipients (pKTR) in the UK.MethodsQuestionnaires specifying kidney transplant type, desensitisation requirement and kidney allograft function were sent to 13 paediatric nephrology centres that performed kidney transplantation in children and young people under 18 years of age who received an ABOi and/or HLAi transplant between 1 January 2006 and 31 December 2016. Patient and kidney allograft survival were compared between ABOi, HLAi and ABO/HLA compatible (ABOc/HLAc) groups.ResultsAmong 711 living donor kidney transplants performed in the UK, 23 were ABOi and 6 were HLAi. Patient survival was 87%, 100% and 96% in ABOi, HLAi and ABOc/HLAc groups, respectively, at median follow-up of 6.8 (3.6–14.0) years post-transplant. Death-censored kidney allograft survival was 100% in all 3 groups at last follow-up. There were no cases of primary non-function in ABOi or HLAi groups, but 2% in the ABOc/HLAc group. There was one reported case of Epstein-Barr viral-induced post-transplant lymphoproliferative disorder.ConclusionLonger term follow-up has shown that ABOi and HLAi kidney transplantation are feasible for pKTR where no compatible donors are available, and that minimising desensitisation should be achieved where possible.Graphical abstractA higher resolution version of the Graphical abstract is available as Supplementary information.

Tocilizumab and Desensitization in Kidney Transplant Candidates: Personal Experience and Literature Review.

Desensitization (DES) allows kidney transplantation for highly HLA-sensitized subjects. Due to the central role of IL-6 in the immunological response, tocilizumab may improve DES efficacy. Thus, we conducted a PubMed systematic review using the MeSH terms tocilizumab, interleukin-6, kidney transplantation, and desensitization. Tocilizumab (TCZ) was first studied for DES as the second-line treatment after failure of a standard DES protocol (SP) (apheresis, rituximab +/− IVIg). Although TCZ (as a monotherapy) attenuated anti-HLA antibody rates, it did not permit transplantation. However, lymphocyte immuno-phenotyping has shown that TCZ hinders B-cell maturation and thus could improve the long-term efficacy of DES by limiting anti-HLA rebound and so avoid antibody-mediated rejection. This hypothesis is supported by a recent study where clazakizumab, a monoclonal antibody directed against IL-6, was continued after kidney transplantation in association with an SP. Nine out of ten patients were then eligible for transplantation, and there were no donor-specific antibodies at 6 months post-transplantation. In association with an SP, tocilizumab does not seem to significantly improve kidney-allograft access (short-term efficacy) vs. a SP only. However, it could improve the long-term prognosis of HLA-incompatible transplantation by hindering B-cell maturation and, thereby, avoiding donor-specific antibody rebounds post-transplantation.

HLA Antibody Incompatible Renal Transplantation: Long-term Outcomes Similar to Deceased Donor Transplantation.

Background.HLA incompatible renal transplantation still remains one of best therapeutic options for a subgroup of patients who are highly sensitized and difficult to match but not much is known about its long-term graft and patient survival.Methods.One hundred thirty-four HLA incompatible renal transplantation patients from 2003 to 2018 with a median follow of 6.93 y were analyzed retrospectively to estimate patient and graft survivals. Outcomes were compared with groups defined by baseline crossmatch status and the type and timings of rejection episodes.Results.The overall patient survival was 95%, 90%, and 81%; and graft survival was 95%, 85%, and 70% at 1, 5, and 10 y, respectively. This was similar to the first-time deceased donor transplant cohort. The graft survival for pretreatment cytotoxic-dependent crossmatch (CDC) positive crossmatch group was significantly low at 83%, 64%, and 40% at 1, 5, and 10 y, respectively, compared with other groups (Bead/CDC, P = 0.007; CDC/Flow, P = 0.001; and microbead assay/flow cytometry crossmatch, P = 0.837), although those with a low CDC titer (<1 in 2) have comparable outcomes to the CDC negative group. Female patients in general fared worse in both patient and graft survival outcomes in each of the 3 groups based on pretreatment crossmatch, although this did not reach statistical significance. Antibody-mediated rejection was the most frequent type of rejection with significant decline in graft survival by 10 y when compared with no rejection (P < 0.001). Rejection that occurred or continued to occur after the first 2 wk of transplantation caused a significant reduction in graft survivals (P < 0.001), whereas good outcomes were seen in those with a single early rejection episode.Conclusions.One-, 5-, and 10-y HLA incompatible graft and patient survival is comparable to deceased donor transplantation and can be further improved by excluding high-CDC titer cases. Antibody-positive female patients show worse long-term survival. Resolution of early rejection is associated with good long-term graft survival.

Current Approaches to Desensitization in Solid Organ Transplantation.

Major advancements in the development of HLA antibody detection techniques and our understanding of the outcomes of solid organ transplant in the context of HLA antibody have occurred since the relevance of sensitization was first recognized nearly 50 years ago. Additionally, kidney paired donation programs (KPD) have become widespread, deceased donor allocation policies have changed, and several new therapeutic options have become available with promise to reduce HLA antibody. In this overview we aim to provide thoughtful guidance about when desensitization in kidney transplantation should be considered taking into account the outcomes of HLA incompatible transplantation. Novel therapeutics, desensitization endpoints, and strategies for future study will also be discussed. While most of our understanding about desensitization comes from studying kidney transplant candidates and recipients, many of the concepts discussed can be easily applied to desensitization in all of solid organ transplantation.

ABO-Incompatible Living-Donor Kidney Transplantation in a Developing Country: A Multicenter Experience in Malaysia

Malaysia has a low deceased-donor donation rate and has not embarked on a paired kidney exchange program; therefore, ABO-incompatible and HLA-incompatible transplantation remain the main contributor to the sustainability of the national kidney transplantation (KT) program. There were 26 cases of ABO-incompatible KTs performed from 2011 to 2018 in 3 major transplant centers, namely, Hospital Kuala Lumpur, University Malaya Medical Centre, and Prince Court Medical Centre. We collected perioperative and follow-up data through June 2019. The desensitization protocol varies and is center specific: the localized Japanese protocol and Swedish protocol with a target anti-A/B isoagglutinin titer of 16 or 32 on the day of transplant. The induction and tacrolimus-based maintenance protocol was nearly identical. The median follow-up time was 62.3 months (interquartile range, 37.0-79.7). Fifteen subjects had the highest predesensitization anti-A/B titer of ≥32 (57.7%). The acute cellular rejection and antibody-mediated rejection incidence were 12.5% (3 cases) and 8.3% (2 cases), respectively. Patient, graft, and death-censored graft survival rates were 96.2%, 92.3%, and 96.0%, respectively, 1 year post-living-donor KT (LDKT) and 96.2%, 87.2%, and 90.7%, respectively, 5 years post-LDKT. Our experience shows that ABO-incompatible LDKT using a suitable desensitization technique could be a safe and feasible choice for LDKT even with varied desensitization regimens for recipients with relatively high baseline isoagglutinin titers.

Infection Related Immunoglobulin-M Antibodies Cross Reactive with Human Leucocyte Antigens

Objective: The first required feature for the patients, who will undergo allotransplantation, is HLA compatibility between donor and the recipient. In this study, it was aimed to indicate whether IgM antibodies that are produced during acute infection phase affect crossmatch tests or not, in addition to hitches that can occur in HLA incompatible transplants. Methods: Eighty-two patients with acute infection due to only one infectious agent and high serum IgM antibody levels were involved in this study. The patients had no alloimmunization (blood transfusion, pregnancy, and/or previous transplants). Fifty-five healthy individuals were used as HLA antigen source in order to evaluate Ab-Ag lymphocytotoxicity reactions. Results: The infectious agent distribution in the sera samples were as 25.6% Anti-Epstein-Barr virus capsid antigen (EBV VCA), 14.6% Anti-Cytomegalovirus (CMV), 17.1% Anti-Toxoplasma, 11% Anti-Hepatitis A Virus (HAV), 7.3% Anti-Rubella, 7.3% Anti-Varicella zoster virus (VZV), 4.9% Anti-Brucella, 3.7% Anti-Mumps, 2.97% Anti-Parvovirus B19, 1.9% Anti-Herpes simplex virus (HSV)-1, and 3.7% Anti-HBc. IgM antibody and HLA antigen reactions were analyzed by lymphocytotoxicity method in terasaki plates using peripheral blood lymphocytes of 55 healthy individuals. Conclusion: In lymphocytotoxicity test, the distribution of reactions that IgM antibodies gave to HLA antigens without class I-II differentiation according to infections were identified as 50% Brucella, 50% VZV, 44.4% HAV, 41.7% CMV, 42.9% EBV, 35.7% Toxoplasma, and 33.3% Rubella.

Clinical outcome of living donor kidney transplantation across simultaneous ABO and HLA incompatibility: Single center experience of first ten cases

Background and aimsPreconditioning using different protocols has been tested to prevent antibody mediated rejection (ABMR) individually for ABO and HLA incompatibility. However, simultaneous presence of both barriers is still less explored. The aim of this study was to report outcomes of institutional desensitization protocol in renal transplant recipients with simultaneous ABO and HLA incompatibility. Materials and methodsThis was a retrospective study conducted from October 2015 to December 2018. All patients with a clinical diagnosis of dialysis dependent chronic kidney disease (CKD), who were prospective coexistent HLA and ABO incompatible renal transplant recipients were included in the study. Patients were followed up and graft function and patient survival was assessed at 1 y from the date of transplant. ResultsMedian and mode baseline anti-A titers were 64, while median and mode baseline anti-B titers were 256. All recipients were discharged by tenth postoperative day. None of the patients had any bleeding complications. Post transplant infection rate was found to be 20 %. A total of 54 therapeutic plasma exchange (TPE) procedures were performed before transplant and 8 were performed after transplant. Graft survival and patient survival was 100 % at 3, 6, 9, and 12 months. Range and mean follow-up period was 15–42 months and 23 months respectively. Mean glomerular filtration rate (GFR) at 1 y using the CKD-EPI equation was 85.25 ± 13.76 mL/min. Biopsy proven ABMR was observed in one case only which was managed with TPE and immunosuppression. ConclusionSimultaneous ABO and HLA incompatibility in renal transplant recipients can be managed successfully with adequate preconditioning and careful monitoring.

Outcomes of Living-Donor Kidney Transplantation in Female Recipients with Possible Pregnancy-Related Pre-Sensitization According to Donor Relationship.

BackgroundGiven that pregnancy is an immune-sensitizing event, female kidney transplant recipients who receive allografts from their offspring or husbands may have a higher risk of rejection and graft failure due to pre-sensitization acquired during pregnancy or childbirth. We investigated the association between donor relatedness (i.e., offspring, husband, unrelated) and graft survival among female living-donor kidney transplant (LDKT) recipients with pregnancy histories.Material/MethodsFrom January 2009 to January 2018, a total of 2060 LDKTs were performed at Asan Medical Center, Seoul, Korea. After excluding HLA-incompatible transplantation, re-transplantation, and those without a clear history of childbirth, 390 female recipients were included and categorized into group I (offspring-to-mother, n=175), group II (husband-to-wife, n=159), and group III (unrelated, n=56). The primary endpoint was biopsy-proven acute rejection (BPAR) and graft survival. We also evaluated delayed graft function (DGF), death-censored graft failure, and mortality.ResultsGroup I had the lowest number of HLA mismatches (p<0.001), and group II had the highest number of ABO-incompatible transplantations (p=0.005). At 5 years after transplant, graft survival and death-censored graft survival did not significantly differ among the 3 groups (graft survival: 96.0% vs. 95.5% vs. 93.3%, p=0.685; death-censored graft survival: 98.3% vs. 97.5% vs. 100%, p=0.732). Five-year BPAR-free survival showed no significant differences among the 3 groups (88.6 vs. 88.7 vs. 88.6%, p=0.842). Group II had the highest rate of clinical rejection (p=0.103) and DGF (p=0.174), but the difference was not statistically significant.ConclusionsFemale LDKT recipients with possible pregnancy-related pre-sensitization who received grafts from offspring or husbands did not show significantly worse clinical outcomes than those who received grafts from unrelated donors.

Donor specific anti HLA sensitization is associated with inferior short term outcome in ABO- incompatible renal transplantation

Sixty six patients were evaluated for donor specific anti HLA sensitization before they received ABO incompatible kidney transplantation. Each recipient was evaluated by complement dependent cytotoxicity (CDC) crossmatch, flow cytometric crossmatch, single antigen bead assay (SAB) and lysate based solid phase crossmatch .The desensitization protocol was started10 to 12 days prior kidney transplant for ABO incompatible and anti HLA incompatible transplants at our center. Patients were evaluated for antibody mediated rejection (ABMR), donor specific anti HLA sensitization, graft survival with anti HLA DSA positivity in ABO-incompatible kidney transplant recipients.Antibody mediated rejection (ABMR) was seen in five (7.5%) out of 66 patients. In non-sensitized group-A, ABMR was seen in 4.0% and in sensitized group (group-B) ABMR was seen in 18.75% with DSA positivity. Graft loss within one month post-transplant was seen in 2 patients due to ABMR in the sensitized group -B with pre-transplant positive DSA and in none in the non-sensitized group-A (p value = 0.05). Both these two patients sensitized group -B had flow CM, SAB DSA and Lysate CM positivity, with total MFI strength by SAB was above 5000, these two patients with CDC and flow CM negative after desensitization and had SAB DSA MFI strength came down to ≤1000.In this study patient survival was 97% and graft survival was 95% at one year, at four years Patient survival was 91.6% and graft survival was 91.5% follow up period. Anti HLA DSA positivity with ABO- incompatibility is associated with poor graft survival.

P1791HLA DESENSITIZATION- INDIAN EXPERIENCE

Abstract Background and Aims There are many barriers to kidney transplant and one of them is presence of donor specific antibodies (DSAs) in the recipients. Presence of strong DSA is considered a relative contraindication for kidney transplantation, however, if DSAs are of weak to moderate then desensitization is attempted in many centres with good success rate. Desensitizing such patients can be an acceptable approach to increase the donor pool and facilitating transplants. This is a retrospective analysis of patients who underwent desensitization at our centre after availability of luminex single antigen (LSA) assay Method Between April 2014 and December 2018, 825 patients underwent kidney transplantation at our centre. Patients who were CDC negative but positive FCXM were further analysed with LSA to know the presence and strength of DSAs. Our protocol for desensitization consisted of plasmapheresis (PP) 1.5 volume by double filtration on alternate day and low dose IV IG 100 mg/kg after each PP. Whenever MFI was &amp;lt;1000 and/or FCXM was negative, patient was taken for transplant with thymoglobulin induction of 1.5 mg/kg for 2-3 doses. All patients were maintained on triple immunosuppression consisting of tacrolimus, mycophenolate mofetil and corticosteroids. We did not routinely followed DSAs in these patients post-transplant if there was no clinical indication. All adverse events during follow up including new onset diabetes after transplant (NODAT), infections, acute rejections (AR), graft loss and death Results Out of 825 patients, 15 underwent HLA incompatible transplants, of which, 8 were males. All patients were first transplant and 11/13 had history of some sensitizing events in the form of blood transfusion and/or pregnancy. The mean dialysis duration was 8.6 ±14.6 months. FCXM was positive in all the patients with 5 patients had T cell flow positive, 8 had B cell flow positive and 2 had both T &amp; B cell FCXM positivity. Most patients had weak to moderate positive flow cross match. On further evaluation by LSA, all these patients had DSAs, with 3/15 had MFI &amp;lt;1000, 6 had MFI between1000-2000, and remaining 6 had MFI &amp;gt;2000, out of which one patient had MFI of 7195 and six patients had multiple DSAs. These patients underwent desensitization with PP and IVIG and the end point of treatment was either MFI &amp;lt; 1000 or FCXM negative. Post- transplant DSAs were done in patients with high MFI or clinically indicated. Two patients had increase in post-transplant DSA titres requiring post-transplant plasmapheresis. The mean follow up was 29±6 months. On follow up, only 1 patient developed borderline cellular rejection one year after transplant, which responded with pulse steroids. Three patients had biopsy for asymptomatic rise in creatinine but it showed patchy ATN with no evidence of rejection.. One patient developed transient CMV viremia, one patient developed lymph node tuberculosis (TB) and two patients had UTI, all of them responded to treatment. There was no graft or patient loss till last follow up. Conclusion This study shows that HLA desensitisation is feasible and successful in if patients are selected carefully and evaluate thoroughly. HLA incompatible transplant can provide a new lease of life to those patients who would otherwise not get a kidney due to lack of paired exchange and deceased donor program

RATG Versus rATG Combined With Intravenous Immunoglobulin (IVIG) Induction Immunosuppression in HLA Incompatible Transplantation (INHIBIT)

rATG Versus rATG Combined With Intravenous Immunoglobulin (IVIG) Induction Immunosuppression in HLA Incompatible Transplantation (INHIBIT)

Molecular Patterns Discriminate Accommodation and Subclinical Antibody-mediated Rejection in Kidney Transplantation

Accommodation in ABO-incompatible (ABOi) transplantation and subclinical antibody-mediated rejection in HLA-incompatible (HLAi) transplantation share several morphological similarities. Because the clinical long-term outcomes differ, we hypothesized different molecular processes involved in ABOi transplantation and subclinical antibody-mediated rejection. Using Illumina Human HT-12 v4 Expression BeadChips, the whole transcriptome was evaluated based on 3-month protocol C4d+ biopsies in otherwise stable ABOi and HLAi kidney grafts, as well as in C4d-negative HLA-compatible grafts exhibiting normal histological findings. Top differently regulated genes were further validated using real-time quantitative polymerase chain reaction in another patient cohort and complement regulatory proteins by immunohistochemistry. In the case of genes involved in immune response-related biological processes, ABOi and HLAi cohorts had similar transcriptomic profiles to C4d-negative controls. The majority of deregulated genes in the ABOi and HLAi groups consisted of metallothioneins and epithelial transporter genes. Increased expression of epithelial transporters (SLC4A1, SLC4A9, SLC17A3, SLC12A3, and SLC30A2) and class 1 metallothioneins (MT1F, MT1G, and MT1X) in HLAi transplantation was validated by real-time quantitative polymerase chain reaction. In comparison to controls, both incompatible cohorts were characterized by the upregulation of intrarenal complement regulatory genes. CD46 and CD59 transcripts were increased in the ABOi cohort, whereas CD46 solely in HLAi group, and CD59 protein expression was similar in both incompatible groups. Several epithelial transporters and metallothioneins discriminate subclinical antibody-mediated rejection in HLAi transplantation from accommodation in ABOi transplantation, which suggest different involved downstream mechanisms and increased risk of injury in HLAi settings. Metallothioneins with their antioxidative properties may help to attenuate the inflammation response induced by donor-specific anti-HLA antibody binding.

Desensitization in HLA Incompatible Transplantation

Desensitization in HLA Incompatible Transplantation

Transfusion of leukoreduced blood products and risk of antibody-mediated rejection of renal allografts.

Antibody-mediated rejection (AMR) is a major barrier to the long-term function of renal allografts. White blood cells, which may be present in red blood cell (RBC) units, and platelets (PLTs) express HLA antigens that may increase the risk of AMR by inducing or increasing humoral sensitization to HLA. A retrospective cohort study of HLA-incompatible (HLAi) renal transplant recipients between 2004 and 2015 was conducted. Data on apheresis PLT and leukoreduced RBC transfusions within 4 weeks of transplantation, demographic information, and biopsy-proven AMR were collected from medical records and the Scientific Registry of Transplant Recipients. Patients were evaluated until they showed evidence of AMR or until 1 year posttransplant, whichever came first. Multivariable analysis with Cox modeling was performed. Of 244 individuals, 182 (74.6%) received RBCs and 20 (8.2%) of those also received PLTs. During the first year posttransplant, 97 (39.8%) had AMR. RBC-alone or RBC and PLT transfusions were not associated with increased risk of AMR after adjustment for panel-reactive antibody, years on dialysis, HLA antibody strength, and number of therapeutic plasma exchange treatments (adjusted hazard ratio [adjHR] 1.00, 95% confidence interval [95% CI] 0.59-1.69; and adjHR 0.68, 95% CI 0.28-1.68, respectively). For each 1-unit increase in RBC transfusions, there was no association with AMR (adjHR 0.94, 95% CI 0.85-1.05). Only HLA antibody strength before transplantation was associated with AMR (adjHR 2.23, 95% CI 1.10-4.52; cytotoxic crossmatch compared to crossmatch negative but detectable donor-specific HLA antibodies). Patients who receive an HLAi transplant who are transfused with leukoreduced RBCs or PLTs in the peritransplant period are at no higher risk of AMR than nontransfused patients.