Donor-specific anti-HLA Antibodies Research Articles

IMMUNOSUPPRESSIVE OPTION WITH BELATACEPT IN HIV-POSITIVE KIDNEY TRANSPLANT RECIPIENTS

Kidney allograft survival in HIV-infected patients is lower than in the general population. Belatacept increases long-term patients and allografts survival compare to anticalcineurins (CNI). Its use in HIV-positive recipients is poorly documented. We retrospectively reported a French cohort of HIV-positive kidney allograft recipients treated with belatacept. Patient and allograft survivals, HIV immunovirological and clinical evolution, acute rejection, opportunistic infections (OI), and donor-specific anti-HLA antibodies (DSA) were analyzed and compared to an historical CNI control group. Fourteen patients were treated with belatacept: 2 (16%) de novo and 12 (84%) switches 10 [2-30] months after transplantation. One year after belatacept therapy patients’ and allografts survival were 91% and 92% respectively with two (17%) HIV viral rebound linked to antiretroviral therapy non-compliance while CD4+ and CD8+ T cell count remained over time. Serious adverse events included 2 (17%) acute steroid-resistant T-cell mediated rejections and 2 (17%) OI. Kidney allograft function increased significantly 12-months after switch (P=0.009) whereas proteinuria remained comparable. DSAs remained stable 12 months after treatment. Results were similar in control group. Belatacept can be used safely and could increase long-term kidney allograft survival in HIV+ kidney allograft recipients. These results need to be confirmed in a larger cohort.

DONOR HLA GENOTYPING BY NEXT GENERATION SEQUENCING OF DNA FROM URINE-DERIVED DONOR CELLS OF RENAL ALLOGRAFT RECIPIENTS

Introduction: Antibody-mediated rejection (AMR), dominantly induced by anti-HLA antibody, remains the most important cause of long-term graft loss after kidney transplantation. Donor-specific anti-HLA antibody (DSA) can’t often be determined at a specific allele level since historical donor DNA sample is not available and the existing donor HLA typing information is incomplete or even missing. Here, we developed a novel non-invasive technique by selectively expanding donor cells from urine of renal transplant recipients, and thus generating unlimited donor DNA to perform reliable allele-level HLA typing with next generation sequencing method for all HLA loci. Materials and Methods: This study enrolled 28 renal transplant recipients. The fresh midstream urine from each recipient was collected. After urine sample was centrifuged, the supernatant was discarded and washed twice with PBS. The resulting sediment was resuspended in the culture medium. The cells were plated and non-adherent cells were removed. DNA was extracted from the urine-derived donor cells (UDDCs). NGS sequencing is carried out to determine the HLA loci. Results: UDDCs from 26 patients were successfully isolated. High-resolution HLA results were unambiguously determined in 25 out of 26 DNA samples (25/26, 96%) and they are 100% concordant with donor HLA. We showed five HLA sequencing cases of UDDCs (Fig 1). The HLA typing of UDDCs is completely matched with HLA of donor peripheral blood. We further isolated UDDCs from a patient whose donor HLA information is missing at 10 years after kidney transplantation. Based on the UDDCs HLA typing and LSA results, DQA1*05:01 DQB1*02:01 were established as the culprit DSA loci of this patient (Fig 2). Discussion: DNA could be extracted from fresh kidney graft tissues for HLA genotyping; however, this approach is invasive and may aggravate graft injury. The amount of tissues obtained may be minimal and cannot yield sufficient quantity of DNA for HLA typing[1]. Other investigators extract DNA from paraffin embedded tissues or urinary sediments of KTx patients, and mismatched donor antigens could be deduced by subtracting the recipient’s HLA from the allograft HLA[2,3]. However, robust high-resolution HLA typing data can not be obtained by these methods. With an ex vivo expandable source of exfoliated cells, we provide a novel noninvasive urine-based molecular diagnostic method for donor HLA genotyping. Conclusion: The UDDCs-based HLA genotyping strategy successfully establishes complete donor DNA genotypes and provides a feasible and clinically relevant molecular diagnostic method that help to determine DSA loci for kidney transplant patients with historically insufficient donor HLA information.

Non-invasive screening for subclinical liver graft injury in adults via donor-specific anti-HLA antibodies

The majority of liver grafts exhibit abnormal histological findings late after transplantation, even when liver enzymes are normal. Such subclinical graft injuries were associated with rejection and fibrosis progression in recent studies. The identification of non-invasive biomarkers for subclinical graft injury might help to individualize immunosuppression. Therefore, graft injury was assessed in 133 liver biopsies with normal/near normal liver enzymes from a prospective liver biopsy program. Cytokeratin-18 cell death marker (M65) and donor specific anti-HLA antibodies (DSA) were measured as non-invasive markers in paired plasma samples in addition to routine parameters. M65 was associated with subclinical graft injury but this association was too weak for reasonable clinical application. DSA positivity was associated with more graft inflammation (OR = 5.4) and more fibrosis (OR = 4.2). Absence of DSA excluded fibrosis in 87–89%, while presence of DSA excluded histological criteria for immunosuppression minimization attempts in 92–97%. While CK18 cell death marker had no diagnostic value for the detection of subclinical liver graft injury, DSA testing can help to preselect patients for immunosuppression reduction in case of DSA negativity, while DSA positivity should prompt elastography or liver biopsy for the assessment of subclinical graft injury.

Trajectories of glomerular filtration rate and progression to end stage kidney disease after kidney transplantation

Although the gold standard of monitoring kidney transplant function relies on glomerular filtration rate (GFR), little is known about GFR trajectories after transplantation, their determinants, and their association with outcomes. To evaluate these parameters we examined kidney transplant recipients receiving care at 15 academic centers. Patients underwent prospective monitoring of estimated GFR (eGFR) measurements, with assessment of clinical, functional, histological and immunological parameters. Additional validation took place in seven randomized controlled trials that included a total of 14,132 patients with 403,497 eGFR measurements. After a median follow-up of 6.5 years, 1,688 patients developed end-stage kidney disease. Using unsupervised latent class mixed models, we identified eight distinct eGFR trajectories. Multinomial regression models identified seven significant determinants of eGFR trajectories including donor age, eGFR, proteinuria, and several significant histological features: graft scarring, graft interstitial inflammation and tubulitis, microcirculation inflammation, and circulating anti-HLA donor specific antibodies. The eGFR trajectories were associated with progression to end stage kidney disease. These trajectories, their determinants and respective associations with end stage kidney disease were similar across cohorts, as well as in diverse clinical scenarios, therapeutic eras and in the seven randomized control trials. Thus, our results provide the basis for a trajectory-based assessment of kidney transplant patients for risk stratification and monitoring.

Eplet Mismatch Load and De Novo Occurrence of Donor-Specific Anti-HLA Antibodies, Rejection, and Graft Failure after Kidney Transplantation: An Observational Cohort Study.

In kidney transplantation, evaluating mismatches of HLA eplets-small patches of surface-exposed amino acids of the HLA molecule-instead of antigen mismatches might offer a better approach to assessing donor-recipient HLA incompatibility and improve risk assessment and prediction of transplant outcomes. To evaluate the effect of number of eplet mismatches (mismatch load) on de novo formation of donor-specific HLA antibodies (DSAs) and transplant outcomes, we conducted a cohort study that included consecutive adult kidney recipients transplanted at a single center from March 2004 to February 2013. We performed retrospective high-resolution genotyping of HLA loci of 926 transplant pairs and used the HLAMatchmaker computer algorithm to count HLA eplet mismatches. De novo DSAs occurred in 43 (4.6%) patients. Multivariable analysis showed a significant independent association between antibody-verified eplet mismatch load and de novo DSA occurrence and graft failure, mainly explained by DQ antibody-verified eplet effects. The association with DQ antibody-verified eplet mismatches was linear, without a safe threshold at which de novo DSA did not occur. Odds for T cell- or antibody-mediated rejection increased by 5% and 12%, respectively, per antibody-verified DQ eplet mismatch. Eplet mismatches in HLA-DQ confer substantial risk for de novo DSA formation, graft rejection, and graft failure after kidney transplantation. Mismatches in other loci seem to have less effect. The results suggest that antibody-verified HLA-DQ eplet mismatch load could be used to guide personalized post-transplant immunosuppression. Adoption of molecular matching for DQA1 and DQB1 alleles could also help to minimize de novo DSA formation and potentially improve transplant outcomes.

Monitoring of Donor-specific Anti-HLA Antibodies and Management of Immunosuppression in Kidney Transplant Recipients: An Evidence-based Expert Paper.

Monitoring of Donor-specific Anti-HLA Antibodies and Management of Immunosuppression in Kidney Transplant Recipients: An Evidence-based Expert Paper.

Haploidentical transplants for patients with relapse after the first allograft.

Relapse after allogeneic hematopoietic stem-cell transplantation (AHSCT) is associated with very poor outcomes. A second transplant offers the possibility of long-term disease control. We analyzed outcomes with haploidentical donors for second allograft at our institution. All consecutive patients with hematological malignancies (N = 29) who relapsed after AHSCT and underwent a haploidentical transplant (haploSCT) as second transplant between February 2009 and October 2018 were included. Median age was 36 years (interquartile range (IQR) 24-60); 83% of patients had high/very high disease risk index; 61% of AML/MDS patients had high-risk cytogenetics; and only 24% were in complete remission at transplant. With a median follow-up of 46.9 months, the 3-year relapse, non-relapse mortality (NRM), progression-free survival (PFS) and overall survival (OS) were 30%, 39%, 31% and 40%, respectively. In multivariable analysis (MVA), comorbidity index (HCT-CI) and detectable donor-specific anti-HLA antibodies (DSA) prior to second transplant were significantly associated with worse outcomes. Patients with HCT-CI <3 and without DSA had 3-year PFS and OS of 53% and 60.3%, respectively. Our findings suggest that haploSCT as second AHSCT is feasible and potentially curative. Lower HCT-CI and no DSA were associated with lower NRM and improved survival. Haploidentical grafts might be a preferred donor source for second AHSCT as these are high-risk patients who frequently need to proceed urgently to transplant.

Monoclonal secondary reagents do not outperform polyclonal secondary reagents for detection of anti-HLA IgG using single antigen flow beads assays.

Luminex single antigen flow beads (SAFB) assays are used to monitor anti-HLA antibodies, which are associated with allograft loss. The primary antibody binding level is evaluated by the mean fluorescence intensity (MFI) provided by the tracing secondary antibody. The aim of this study was to compare the MFI obtained with two secondary antibodies and to evaluate their sensitivity to detect newly developed de novo anti-HLA donor-specific antibodies (dnDSA). A total of 23 and 46 different sera from 20 HLA-sensitized kidney transplant recipients were tested with class I and II SAFB, respectively, as well as sera from 17 patients with dnDSA. The conventional secondary antibody (IgHPolyFab) was the phycoerythrin (PE)-conjugated goat anti-human IgG constant heavy chain (HC)-binding polyclonal-F(ab')2. The alternate secondary antibody was a PE-conjugated anti-human IgG Fc-specific monoclonal IgG (FcMonoIgG). MFI of negative control sera were drastically lower with the FcMonoIgG than with IgHPolyFab, requesting a unique positivity threshold to be defined for each secondary antibody. MFI obtained with positive control sera were also lower with FcMonoIgG. In kidney transplant recipient's sera, the number of antigenic specificities detected by each secondary antibody was comparable, for dnDSA as well as for nonDSA. In conclusion, decision thresholds must be refined when changing the secondary tracing reagent in SAFB assays. FcMonoIgG did not demonstrate any superiority over IgHPolyFab for monitoring HLA antibodies.

Transcriptional Changes in Kidney Allografts with Histology of Antibody-Mediated Rejection without Anti-HLA Donor-Specific Antibodies.

Circulating donor-specific anti-HLA antibodies (HLA-DSAs) are often absent in serum of kidney allograft recipients whose biopsy specimens demonstrate histology of antibody-mediated rejection (ABMR). It is unclear whether cases involving ABMR histology without detectable HLA-DSAs represent a distinct clinical and molecular phenotype. In this multicenter cohort study, we integrated allograft microarray analysis with extensive clinical and histologic phenotyping from 224 kidney transplant recipients between 2011 and 2017. We used the term ABMR histology for biopsy specimens that fulfill the first two Banff 2017 criteria for ABMR, irrespective of HLA-DSA status. Of 224 biopsy specimens, 56 had ABMR histology; 26 of these (46.4%) lacked detectable serum HLA-DSAs. Biopsy specimens with ABMR histology showed overexpression of transcripts mostly related to IFNγ-induced pathways and activation of natural killer cells and endothelial cells. HLA-DSA-positive and HLA-DSA-negative biopsy specimens with ABMR histology displayed similar upregulation of pathways and enrichment of infiltrating leukocytes. Transcriptional heterogeneity observed in biopsy specimens with ABMR histology was not associated with HLA-DSA status but was caused by concomitant T cell-mediated rejection. Compared with cases lacking ABMR histology, those with ABMR histology and HLA-DSA had higher allograft failure risk (hazard ratio [HR], 7.24; 95% confidence interval [95% CI], 3.04 to 17.20) than cases without HLA-DSA (HR, 2.33; 95% CI, 0.85 to 6.33), despite the absence of transcriptional differences. ABMR histology corresponds to a robust intragraft transcriptional signature, irrespective of HLA-DSA status. Outcome after ABMR histology is not solely determined by the histomolecular presentation but is predicted by the underlying etiologic factor. It is important to consider this heterogeneity in further research and in treatment decisions for patients with ABMR histology.

Antibodies Against ARHGDIB and ARHGDIB Gene Expression Associate With Kidney Allograft Outcome.

The impact of donor-specific anti-HLA antibodies (DSA) on antibody-mediated rejection (AMR) and kidney allograft failure is well established. However, the relevance of non-HLA antibodies remains unclear. We investigated 13 pretransplant non-HLA antibodies and their association with histology of AMR (AMRh) and kidney allograft failure. We included single kidney recipients (n = 203) with AMRh, according to the Banff 2017 classification and matched AMRh-free controls (n = 219). Non-HLA antibodies were assessed using multiplex Luminex assay. Of the selected non-HLA antibodies (against agrin, adipocyte plasma membrane-associated protein, Rho GDP-dissociation inhibitor 2 [ARHGDIB], Rho guanine nucleotide exchange factor 6, angiotensin-II type 1 receptor, endothelin type A receptor, lamin B1, BPI fold-containing family B member 1, peroxisomal trans-2-enoyl-coenzyme A reductase, phospholipase A2 receptor, protein kinase C zeta type, tubulin beta-4B class IVb, vimentin), only antibodies against ARHGDIB (adjusted median fluorescence intensity [aMFI] ≥ 1000), a minor histocompatibility antigen, associated with graft failure, in univariate and multivariate models (hazard ratio = 2.7; 95% confidence interval [CI],1.3-5.4; P = 0.007). There was a 19.5-fold (95% CI, 6.0-63.9; P < 0.0001) increased risk of graft failure in patients positive for both DSA and anti-ARHGDIB antibodies (aMFI ≥ 1000) versus patients negative for both DSA and anti-ARHGDIB antibodies, compared with a 4.4-fold (95% CI, 2.4-8.2; P < 0.0001) increased risk in patients with only DSA, and a 4.1-fold (95% CI, 1.4-11.7; P = 0.009) increased risk in patients with only anti-ARHGDIB antibodies above 2000 aMFI. AMRh associated with increased intrarenal expression of the ARHGDIB gene. In the absence of AMRh and DSA, anti-ARHGDIB antibodies were not clearly associated with graft failure. The presence of pretransplant anti-ARHGDIB antibodies has an additive effect in patients with DSA on the risk of graft failure via AMRh. Other investigated non-HLA antibodies, including antibodies against angiotensin-II type 1 receptor, did not contribute to risk stratification and could not explain the histology of AMR in the absence of DSA.

Research Highlights

Research Highlights

Chronic Active Antibody-Mediated Rejection With Donor-Specific Anti–HLA-DP Antibodies Following Living Donor Kidney Transplantation: A Case Report

Posttransplant donor-specific anti-HLA antibodies (DSA) cause chronic antibody-mediated rejection. Anti-DR and anti-DQ DSAs have especially been shown to be associated with negative graft function. In contrast, the prevalence and significance of anti-DP DSA have not been well established and remain unclear. We report a case of living donor kidney transplantation. The level of serum creatinine gradually became elevated because of chronic active antibody-mediated rejection, which was considered to be caused by anti-DP DSA. In this report, we indicate the significance of pretransplant screening for HLA-DP in donors to evaluate more comprehensively the donor specificity of posttransplant HLA antibodies.

Importance des anticorps dans la prise en charge de la greffe de cellules souches hématopoïétiques : anticorps anti-HLA, anti-plaquettes, anti-granuleux, anti-érythrocytes et anti-MICA. Recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC)

The presence of allo-antibodies in the serum of a recipient awaiting hematopoietic stem cell transplantation (HSCT) may have an impact on transfusion efficiency and/or donor choice, especially in the absence of an identical sibling donor. Prior to transplantation, donor specific anti-HLA (Human Leukocyte Antigen) antibodies (DSA) have a recognized effect on transplant outcome, correlated with the increasing MFI value and with the ability of such antibody to fix the complement fraction. Anti-platelet antibodies (anti-HLA class I and anti-HPA [Human Platelet Antigen]) are better involved in transfusion inefficiency and can be responsible for refractory status. ABO incompatibilities require a specific treatment of the graft in presence of high titer to avoid hemolytic adverse effects. Investigations of these antibodies should be carried out on a regular basis in order to establish appropriate transfusion recommendation, select an alternative donor when possible or adapt the source of cells. After transplantation, in case of delayed recovery or graft rejection, long term aplasia, persistent mixed chimerism or late release, and after elimination of the main clinical causes, a biological assessment targeted on the different type of antibodies will have to be performed in order to orient towards the cause or the appropriate therapy. Further studies should be carried out to determine the impact of anti-MICA antibodies and recipient specific anti-HLA antibodies, on the outcome of the transplantation.

P1756ANTI-ABO ANTIBODY- VERSUS ANTI-HLA ANTIBODY-INDUCED ANTIBODY MEDIATED REJECTION IN ABO-INCOMPATIBLE KIDNEY TRANSPLANT PATIENTS: RELATIVE INCIDENCE AND PHENOTYPE DIFFERENCE

Abstract Background and Aims Antibody-mediated rejection(AMR) in ABO incompatible(ABOi) kidney transplant(KT) patients can either be due to donor-specific anti-HLA antibody(DSA) or anti-blood group antibody. The relative frequency and possible phenotype difference of these two types of AMR in ABOi KT patients have not been reported. Method Of 111 ABOi KT patients between 2007 and 2019 in our center, 15(13.5%) patients developed acute AMR diagnosed by indication biopsy. Since there is no histologic distinction between DSA- and anti-ABO-induced AMR, we assumed the causative antibody in each case based on anti-ABO level and DSA, measured in serum collected at the time of AMR. Results Of these 15 cases of acute AMR, 5 were attributable to anti-ABO(ABO-AMR) since anti-ABO titer was higher (≥16) and DSA was undetectable at the time of rejection. Five cases were attributable to DSA(DSA-AMR) since DSA was detectable and anti-ABO was lower during rejection. Another 3 cases with lower anti-ABO titer and undetectable DSA were also assumed to be DSA-induced, since this low level of anti-ABO is unlikely to cause rejection and DSA can be undetectable in DSA-induced AMR by adsorption of Ab on graft, as frequently seen in ABO-compatible patients Two cases with both higher anti-ABO titer and detectable DSA was regarded as undetermined. The onset of acute AMR was within 2 weeks in all cases(median 7.0 days) and comparable between DSA- and ABO-AMR. Initial anti-ABO titer was also not statistically different; median(range) 256(64-4096) in ABO-AMR and 64(16-256) in DSA-AMR. All the 5 patients with ABO-AMR had negative PRA before KT, whereas 5 of 8 patients with DSA-AMR had positive PRA before KT, and two DSA-AMR patients had preformed DSA before KT. There was no difference in peak creatinine and response to treatment. All the AMR were recovered by treatment and no graft was lost to rejection. No patient with ABO-AMR developed chronic AMR whereas one of DSA-AMR patients developed chronic AMR. Conclusion In summary, among 15 cases of acute AMR, 5 were ABO-AMR, 8 were DSA-AMR and 2 were undetermined. There was no difference in clinical feature between DSA- and ABO-AMR. No patient with ABO-AMR developed chronic AMR.

P1713A CASE OF DEVASTATING BARIATRIC SURGERY-RELATED ACUTE OXALATE NEPHROPATHY FIRST DIAGNOSED AFTER KIDNEY TRANSPLANTATION

Abstract Background and Aims Despite the obvious efficacy in achieving weight loss, traditional malabsorptive procedures (intestinal by-pass) used for the treatment of obesity, may be associated with enteric oxaluria. Enteric oxaluria, by causing calcium-oxalate stones and nephrocalcinosis, represents an under-recognized cause of end-stage kidney disease in patients with history of intestinal by-pass. Herein, we describe a patient with a long-standing history of intestinal by-pass who developed a devastating acute oxalate nephropathy first diagnosed after kidney transplantation. Method A white female aged 50, who started hemodialysis one year earlier because of tubule-interstitial nephritis on a kidney biopsy, and who had history of recurrent kidney stones (calcium oxalate), underwent urgent deceased-donor kidney transplantation because of exhausted vascular access for hemodialysis (tunneled CVC right giugular vein as the last resort). She had received intestinal by-pass surgery 20 yrs earlier, and had a pacemaker implantation in the left sublavian vein for AV block two years earlier. She was highly sensitized because of blood transfusions at the time of surgery. Results After transplantation, graft function had immediate recovery, serum creatinine decreasing to 2.0mg/dL (117 mmol/L) on post-operative day (POD) 3. Shortly after, serum creatinine started rising until it reached 4.0mg/dL (354mmol/L) on POD 5. Three graft biopsies (performed on POD 6, 9 and 15 post-transplant) revealed acute oxalate nephropathy ( Figure1-2 large oxalate crystals on fresh unfixed core of kidney tissue analyzed under bright field microscope using polarized light) with no sign of rejection. Serial monitoring of Luminex SAB did not reveal circulating anti-HLA donor specific antibodies. Fundus examination revealed two tiny mono-lateral retinal oxalate deposits, whereas bone biopsy did not reveal oxalate accumulation. Plasma oxalate levels were 43 mmol/L on POD 10 were urinary oxalate excretion was 29mg /day on POD 14. The patient slowly progressed to end-stage kidney disease 2-month post-transplantation despite daily high flux dialysis since POD 7, fat-free and oxalate-free diet, oral potassium and high dose pyridoxine supplements. Conclusion Patients on chronic dialysis with a previous history of bariatric surgery via intestinal by-pass may have oxalate nephropathy caused by enteric oxaluria as unknown primary renal disease. The disease may recur shortly after transplantation despite the adoption of prompt aggressive treatment for oxalate removal.

Non-donor specific anti-human leukocyte antigen (HLA) antibodies are not associated with poor outcome in hematopoietic stem cell transplant recipients

Testing for anti-human leukocyte antigen (HLA) antibodies has now become standard practice in allogeneic hematopoietic stem cell transplantation (HSCT), and anti-HLA antibodies (both donor specific and non-donor specific) are being identified and have many potential consequences. Most studies suggest that donor-specific HLA antibodies lead to adverse outcomes, though little is reported on non-donor specific anti-HLA antibodies. We present the results of a retrospective cohort analysis of 157 patients who received HSCT at the University of Rochester over a period of four years. We identified 45 patients (28.7%) who had detectable anti-HLA antibodies, while only one patient (0.6%) had donor-specific anti-HLA antibodies. Patients with prior pregnancies and multiple transfusions were at increased risk to develop antibodies. In our cohort, the presence of non-donor specific anti-HLA antibodies did not significantly impact overall survival, progression free survival, graft failure, or transplant-related mortality.

Clinical importance of extended second field high-resolution HLA genotyping for kidney transplantation.

The need for extended second field high‐resolution (2F‐HR) HLA genotyping in kidney transplantation is debated. In a cohort of 1000 kidney transplants, we evaluated the impact of different HLA genotyping levels on the assignment of donor‐specific anti‐HLA antibodies (DSA) and investigated whether inference of 2F‐HR genotypes from low‐resolution (LR) genotypes could be used to correctly assign DSA. Based on LR genotypes, 224 pretransplant DSAs were present in 140 patients and absent in 860 patients (DSAneg group). With extended 2F‐HR HLA genotyping, we confirmed 173 DSA (77.2%) in 108 (77.1%) patients (2F‐HRposLRposDSA group) and excluded DSA in 32 patients (22.9%) (2F‐HRnegLRposDSA group). Kaplan‐Meier curves showed that 10‐year graft survival rates were similar between the DSAneg and 2F‐HRnegLRposDSA groups (82.4% vs 93.8%; P = .27) and confirmed that DSA determined using LR typing but not confirmed using 2F‐HR typing were indeed misclassified. By inferring 2F‐HR genotypes using HaploStats, DSA still could not be correctly assigned in 23.3% of cases. We conclude that extended 2F‐HR typing of the donor‐recipient pairs is relevant for the correct assessment of DSA. Although inference of 2F‐HR genotypes may improve the assessment of DSA in some cases, significant misclassification occurs, and warrants caution in using inferred HLA results for clinical and research purposes.

Intravenous immunoglobulin significantly reduces exposure of concomitantly administered anti-C5 monoclonal antibody tesidolumab.

Awareness of drug-drug interactions is critical in organ transplant recipient management. However, biologic agents interfering with monoclonal antibodies is not widely considered. We report the effect of high-dose intravenous immunoglobulin (IVIg) on safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of the human anti-C5 monoclonal antibody tesidolumab (LFG316) in end-stage renal disease patients awaiting kidney transplant. In this single-center, phase 1, open-label, parallel-group study, 8 patients were assigned to receive either single-dose tesidolumab+IVIg or tesidolumab alone, with 56-day follow-up. Within-group PK parameters were consistent. Mean tesidolumab exposure decreased 34%, clearance increased 63%, and half-life decreased 41% comparing tesidolumab+IVIg to tesidolumab alone. IVIg influence on tesidolumab elimination was most evident in the first 3weeks. Complete suppression of both total and alternative complement activities was maintained for 4weeks in the tesidolumab alone group and for 2weeks in the tesidolumab+IVIg group. Tesidolumab was well tolerated. IVIg infused before tesidolumab affected tesidolumab PK and PD, resulting in a shortened period of full complement activity inhibition. These findings suggest a clinically relevant impact of IVIg on monoclonal antibody clearance and indirectly hint at an IVIg mechanism of action in treating autoimmune diseases and allosensitization by accelerating pathogenic IgG antibody degradation. Trial registration number: NCT02878616.

Rituximab for desensitization during HLA-mismatched stem cell transplantation in patients with a positive donor-specific anti-HLA antibody.

To define the efficacy of a single dose of 375 mg/m2 rituximab for DSA-positive patients with 2000 ≤ MFI < 10,000, we enrolled a prospective clinical cohort including patients with positive DSA treated with rituximab (n = 55, cohort A), a matched-pair cohort including cases with negative DSA (n = 110, cohort B) and a historical cohort including subjects with 2000 ≤ MFI < 10,000 without receiving any treatment for DSA (n = 22, cohort C). The incidences of primary poor graft function (PGF) in cohort A and cohort B were 5% and 1% (P = 0.076), respectively, both of which were lower than that in cohort C (27%, P < 0.001, for all). Rituximab was associated with a reduced incidence of primary PGF (HR 0.200, P = 0.023). The 3-year nonrelapse mortality of patients in cohort A and cohort B were 23% and 24%, respectively, both of which were lower than that in the cohort C (37%), although no statistical significance was observed. These results led to a low 3-year overall survival in patients in the cohort C (58%) compared with those in the cohort A (71%) and the cohort B (73%). We suggest that a single dose of rituximab could be effectively used to prevent the onset of primary PGF. The prospective cohort of this study is registered at http://www.chictr.org.cn/ChiCTR-OPC-15006672.

Beyond 10years, with or without an intestinal graft: Present and future?

Long-term outcomes in children undergoing intestinal transplantation remain unclear. Seventy-one children underwent intestinal transplantation in our center from 1989 to 2007. We report on 10-year posttransplant outcomes with (group 1, n=26) and without (group 2, n=9) a functional graft. Ten-year patient and graft survival rates were 53% and 36%, respectively. Most patients were studying or working, one third having psychiatric disorders. All patients in group 1 were weaned off parenteral nutrition with mostly normal physical growth and subnormal energy absorption. Graft histology from 15 late biopsies showed minimal abnormality. However, micronutrient deficiencies and fat malabsorption were frequent; biliary complications occurred in 4 patients among the 17 who underwent liver transplantation; median renal clearance was 87mL/min/1.73m2 . Four patients in group 1 experienced late acute rejection. Among the 9 patients in group 2, 4 died after 10years and 2 developed significant liver fibrosis. Liver transplantation and the use of a 3-drug regimen including sirolimus or mycophenolate mofetil were associated with improved graft survival. Therefore, intestinal transplantation may enable a satisfactory digestive function in the long term. The prognosis of graft removal without retransplantation is better than expected. Regular monitoring of micronutrients, early psychological assessment, and use of sirolimus are recommended.