scholarly journals From Humoral Theory to Performant Risk Stratification in Kidney Transplantation

2017 ◽  
Vol 2017 ◽  
pp. 1-8 ◽  
Author(s):  
C. Lefaucheur ◽  
D. Viglietti ◽  
M. Mangiola ◽  
A. Loupy ◽  
A. Zeevi
Keyword(s):  
Kidney Transplantation ◽  
Risk Stratification ◽  
Binding Capacity ◽  
Wide Spectrum ◽  
Predictive Performance ◽  
Clinical Implementation ◽  
Transplant Outcomes ◽  
Antibody Mediated Rejection ◽  
Risk Stratification Model ◽  
Allograft Loss

The purpose of the present review is to describe how we improve the model for risk stratification of transplant outcomes in kidney transplantation by incorporating the novel insights of donor-specific anti-HLA antibody (DSA) characteristics. The detection of anti-HLA DSA is widely used for the assessment of pre- and posttransplant risks of rejection and allograft loss; however, not all anti-HLA DSA carry the same risk for transplant outcomes. These antibodies have been shown to cause a wide spectrum of effects on allografts, ranging from the absence of injury to indolent or full-blown acute antibody-mediated rejection. Consequently, the presence of circulating anti-HLA DSA does not provide a sufficient level of accuracy for the risk stratification of allograft outcomes. Enhancing the predictive performance of anti-HLA DSA is currently one of the most pressing unmet needs for facilitating individualized treatment choices that may improve outcomes. Recent advancements in the assessment of anti-HLA DSA properties, including their strength, complement-binding capacity, and IgG subclass composition, significantly improved the risk stratification model to predict allograft injury and failure. Although risk stratification based on anti-HLA DSA properties appears promising, further specific studies that address immunological risk stratification in large and unselected populations are required to define the benefits and cost-effectiveness of such comprehensive assessment prior to clinical implementation.

scholarly journals Intensity of de novo DSA detected by Immucor Lifecodes assay and C3d fixing antibodies are not predictive of subclinical ABMR after Kidney Transplantation

PLoS ONE ◽  
2021 ◽  
Vol 16 (4) ◽  
pp. e0249934
Author(s):  
Dominique Bertrand ◽  
Rangolie Kaveri ◽  
Charlotte Laurent ◽  
Philippe Gatault ◽  
Maïté Jauréguy ◽  
...  
Keyword(s):  
Kidney Transplantation ◽  
Prognostic Value ◽  
De Novo ◽  
Added Value ◽  
Multicentric Study ◽  
Specific Antibodies ◽  
Antibody Mediated Rejection ◽  
Single Antigen ◽  
Donor Specific Antibodies ◽  
Allograft Loss

De novo donor-specific antibodies (dnDSA) are associated with antibody-mediated rejection (ABMR) and allograft loss. We tested Immucor* (IM) Luminex Single-antigen beads (LSAB) assay and C3d-fixing antibodies in the setting of dnDSA and subclinical (s) ABMR. This retrospective multicentric study included 123 patients biopsied because of the presence of subclinical de novo DSA detected by One Lamda* Labscreen (MFI > 1000). In 112 patients, sera of the day of the biopsy were available and tested in a central lab with IM Lifecodes LSAB and C3d fixing antibodies assays. In 16 patients (14.3%), no DSA was detected using Immucor test. In 96 patients, at least one DSA was determined with IM. Systematic biopsies showed active sABMR in 30 patients (31.2%), chronic active sABMR in 17 patients (17.7%) and no lesions of sABMR in 49 KT recipients (51%). Intensitity criteria (BCM, BCR and AD-BCR) of DSA were not statistically different between these 3 histological groups. The proportion of patients with C3d-fixing DSA was not statistically different between the 3 groups and did not offer any prognostic value regarding graft survival. Performing biopsy for dnDSA could not be guided by the intensity criteria of IM LSAB assay. C3d-fixing DSA do not offer added value.

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

2020 ◽  
Vol 31 (9) ◽  
pp. 2193-2204 ◽  
Author(s):  
Aleksandar Senev ◽  
Maarten Coemans ◽  
Evelyne Lerut ◽  
Vicky Van Sandt ◽  
Johan Kerkhofs ◽  
...  
Keyword(s):  
Cohort Study ◽  
Kidney Transplantation ◽  
Graft Failure ◽  
De Novo ◽  
Multivariable Analysis ◽  
Hla Antibodies ◽  
Transplant Outcomes ◽  
Antibody Mediated Rejection ◽  
Kidney Recipients ◽  
Hla Dq

BackgroundIn 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.MethodsTo 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.ResultsDe 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.ConclusionsEplet 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.

scholarly journals Coordinated Circulating T Follicular Helper and Activated B Cell Responses Underlie the Onset of Antibody-Mediated Rejection in Kidney Transplantation

2020 ◽  
Vol 31 (10) ◽  
pp. 2457-2474
Author(s):  
Kevin Louis ◽  
Camila Macedo ◽  
Elodie Bailly ◽  
Louis Lau ◽  
Bala Ramaswami ◽  
...  
Keyword(s):  
Kidney Transplantation ◽  
B Cells ◽  
B Cell ◽  
Rna Sequencing ◽  
Kidney Transplant Recipients ◽  
Antibody Mediated Rejection ◽  
Follicular Helper ◽  
Allograft Loss ◽  
Activated B Cells

BackgroundAlthough antibody-mediated rejection (ABMR) has been long recognized as a leading cause of allograft failure after kidney transplantation, the cellular and molecular processes underlying the induction of deleterious donor-specific antibody (DSA) responses remain poorly understood.MethodsUsing high-dimensional flow cytometry, in vitro assays, and RNA sequencing, we concomitantly investigated the role of T follicular helper (TFH) cells and B cells during ABMR in 105 kidney transplant recipients.ResultsThere were 54 patients without DSAs; of those with DSAs, ABMR emerged in 20 patients, but not in 31 patients. We identified proliferating populations of circulating TFH cells and activated B cells emerging in blood of patients undergoing ABMR. Although these circulating TFH cells comprised heterogeneous phenotypes, they were dominated by activated (ICOS+PD-1+) and early memory precursor (CCR7+CD127+) subsets, and were enriched for the transcription factors IRF4 and c-Maf. These circulating TFH cells produced large amounts of IL-21 upon stimulation with donor antigen and induced B cells to differentiate into antibody-secreting cells that produced DSAs. Combined analysis of the matched circulating TFH cell and activated B cell RNA-sequencing profiles identified highly coordinated transcriptional programs in circulating TFH cells and B cells among patients with ABMR, which markedly differed from those of patients who did not develop DSAs or ABMR. The timing of expansion of the distinctive circulating TFH cells and activated B cells paralleled emergence of DSAs in blood, and their magnitude was predictive of IgG3 DSA generation, more severe allograft injury, and higher rate of allograft loss.ConclusionsPatients undergoing ABMR may benefit from monitoring and therapeutic targeting of TFH cell–B cell interactions.

Transplant outcomes in kidney recipients with lupus nephritis, and systematic review

Lupus ◽  
2020 ◽  
Vol 29 (3) ◽  
pp. 248-255 ◽  
Author(s):  
J E Kim ◽  
Y C Kim ◽  
S-l Min ◽  
H Lee ◽  
J Ha ◽  
...  
Keyword(s):  
Kidney Transplantation ◽  
Lupus Nephritis ◽  
Graft Survival ◽  
Graft Failure ◽  
Patient Survival ◽  
Survival Rates ◽  
Transplant Outcomes ◽  
Antibody Mediated Rejection ◽  
Kidney Recipients ◽  
And Control

Background Despite improved survival of patients with lupus nephritis (LN), some require kidney transplantation because of progression to end-stage renal disease (ESRD). However, the transplant outcomes of these patients and other recipients have not been thoroughly compared. Methods In total, 1848 Korean kidney recipients who underwent transplantation from 1998 to 2017 at two tertiary referral centers were evaluated retrospectively. Among them, 28 recipients with LN, and 50 control recipients matched by age, sex, and donor type, were compared with respect to graft and patient survival. We pooled our data with 17 previous cohort studies in which the graft survival of recipients with LN was described in detail. Results During the median follow-up period of 9.5 years (maximum 21 years), graft failure (GF) occurred in 10.7% and 16.0% of LN and control recipients, respectively. No differences were found in the rates of GF and death-censored graft failure or patient survival between the two groups. The risks of acute T cell-mediated and antibody-mediated rejection were also similar between the two groups. The pooled analysis showed similar 1- and 5-year graft survival rates between LN and control recipients. Conclusions Kidney transplantation is an acceptable option in patients with concurrent LN and ESRD.

Acute Rejection Following Kidney Transplantation: State-of-the-Art and Future Perspectives

2020 ◽  
Vol 26 (28) ◽  
pp. 3468-3496
Author(s):  
Emilio Rodrigo ◽  
Marcio F. Chedid ◽  
David San Segundo ◽  
Juan C.R. San Millán ◽  
Marcos López-Hoyos
Keyword(s):  
Kidney Transplantation ◽  
Acute Rejection ◽  
Rescue Therapy ◽  
Standard Of Care ◽  
Rejection Rate ◽  
New Drugs ◽  
High Dose ◽  
Current Standard ◽  
Antibody Mediated Rejection ◽  
Cellular Rejection

: Although acute renal graft rejection rate has declined in the last years, and because an adequate therapy can improve graft outcome, its therapy remains as one of the most significant challenges for pharmacists and physicians taking care of transplant patients. Due to the lack of evidence highlighted by the available metaanalyses, we performed a narrative review focused on the basic mechanisms and current and future therapies of acute rejection in kidney transplantation. : According to Kidney Disease/Improving Global Outcomes (KDIGO) guidelines, both clinical and subclinical acute rejection episodes should be treated. Usually, high dose steroids and basal immunosuppression optimization are the first line of therapy in treating acute cellular rejection. Rabbit antithymocytic polyclonal globulins are used as rescue therapy for recurrent or steroid-resistant cellular rejection episodes. Current standard-of-care (SOC) therapy for acute antibody-mediated rejection (AbMR) is the combination of plasma exchange with intravenous immunoglobulin (IVIG). Since a significant rate of AbMR does not respond to SOC, different studies have analyzed the role of new drugs such as Rituximab, Bortezomib, Eculizumab and C1 inhibitors. Lack of randomized controlled trials and heterogenicity among performed studies limit obtaining definite conclusions. Data about new direct and indirect B cell and plasma cell depleting agents, proximal and terminal complement blockers, IL-6/IL-6R pathway inhibitors and antibody removal agents, among other promising drugs, are reviewed.

scholarly journals B-cell activating factor BAFF as a novel alert marker for the immunological risk stratification after kidney transplantation

2021 ◽  
Author(s):  
Antonia Margarete Schuster ◽  
N. Miesgang ◽  
L. Steines ◽  
C. Bach ◽  
B. Banas ◽  
...  
Keyword(s):  
Kidney Transplantation ◽  
B Cell ◽  
Graft Function ◽  
Risk Profile ◽  
Kidney Transplant Recipients ◽  
Post Transplantation ◽  
Antibody Mediated Rejection ◽  
B Cell Activating Factor ◽  
Medium Risk ◽  
Patients At Risk

AbstractThe B cell activating factor BAFF has gained importance in the context of kidney transplantation due to its role in B cell survival. Studies have shown that BAFF correlates with an increased incidence of antibody-mediated rejection and the development of donor-specific antibodies. In this study, we analyzed a defined cohort of kidney transplant recipients who were treated with standardized immunosuppressive regimens according to their immunological risk profile. The aim was to add BAFF as an awareness marker in the course after transplantation to consider patient’s individual immunological risk profile. Included patients were transplanted between 2016 and 2018. Baseline data, graft function, the occurrence of rejection episodes, signs of microvascular infiltration, and DSA kinetics were recorded over 3 years. BAFF levels were determined 14 d, 3 and 12 months post transplantation. Although no difference in graft function could be observed, medium-risk patients showed a clear dynamic in their BAFF levels with low levels shortly after transplantation and an increase in values of 123% over the course of 1 year. Patients with high BAFF values were more susceptible to rejection, especially antibody-mediated rejection and displayed intensified microvascular inflammation; the combination of high BAFF + DSA puts patients at risk. The changing BAFF kinetics of the medium risk group as well as the increased occurrence of rejections at high BAFF values enables BAFF to be seen as an awareness factor. To compensate the changing immunological risk, a switch from a weaker induction therapy to an intensified maintenance therapy is required.

scholarly journals Safety and Efficacy of Tandem Hemodialysis and Selective Plasma Exchange in Pretransplant Desensitization of ABO-Incompatible Kidney Transplantation

2021 ◽  
pp. 1-8
Author(s):  
Ako Hanaoka ◽  
Toshihide Naganuma ◽  
Daijiro Kabata ◽  
Daichi Morii ◽  
Yoshiaki Takemoto ◽  
...  
Keyword(s):  
Kidney Transplantation ◽  
Plasma Exchange ◽  
Treatment Time ◽  
Venous Pressure ◽  
Transmembrane Pressure ◽  
Safety And Efficacy ◽  
Antibody Mediated Rejection ◽  
Tandem Therapy ◽  
Internal Pressures ◽  
Over Time

<b><i>Introduction:</i></b> In patients requiring both hemodialysis (HD) and apheresis, the 2 treatments can be performed simultaneously. At our hospital, selective plasma exchange (SePE) is often performed along with HD for removal of isoagglutinins before ABO-incompatible (ABOi) kidney transplantation. The 2 treatments can be completed within the HD schedule, which allows the treatment time to be shortened. This approach is also less stressful for patients because fewer punctures are required. In this study, we investigated the safety and efficacy of tandem HD and SePE. <b><i>Methods:</i></b> A total of 58 SePE sessions in 30 ABOi kidney transplant recipients were investigated. The SePE circuit was connected in parallel with the HD circuit, and tandem HD and SePE therapy was performed using filtration methods. The SePE sessions were divided into 2 groups: those with SePE monotherapy (group S, <i>n</i> = 20) and those with tandem therapy (group T, <i>n</i> = 38). Changes in transmembrane pressure (TMP), arterial pressure (AP), venous pressure (VP), and decrease in isoagglutinin titers over time were compared between the groups with adjustment for background data. <b><i>Results:</i></b> The internal pressures (AP and VP) were higher in group T, and there were significant differences in changes of TMP and AP over time between groups T and S. Membrane exchange was required in 1 case in group T due to coagulation. There was a more significant decrease of immunoglobulin G isoagglutinin titers in group T compared to group S. No case had antibody-mediated rejection after transplantation. <b><i>Discussion/Conclusion:</i></b> In HD/SePE tandem therapy, internal pressures were higher and TMP and AP tended to increase more compared to SePE monotherapy, but we were able to perform the 2 treatments without any functional problems. Tandem therapy was also effective in decreasing isoagglutinin titers, which suggests that this may be a beneficial treatment modality as apheresis before ABOi kidney transplantation.

scholarly journals Preceding T-Cell-Mediated Rejection Is Associated with the Development of Chronic Active Antibody-Mediated Rejection by de Novo Donor-Specific Antibody

Nephron ◽  
2020 ◽  
pp. 1-5
Author(s):  
Takahiro Tsuji ◽  
Sari Iwasaki ◽  
Keishi Makita ◽  
Teppei Imamoto ◽  
Naomichi Ishidate ◽  
...  
Keyword(s):  
T Cell ◽  
Specific Antibody ◽  
De Novo ◽  
Control Group ◽  
Antibody Mediated Rejection ◽  
Peritubular Capillaries ◽  
The Mean ◽  
Microvascular Inflammation ◽  
Renal Allograft Loss ◽  
Allograft Loss

<b><i>Aim:</i></b> Chronic active antibody-mediated rejection (CAABMR) is an important cause of late-stage renal allograft loss. Early inflammatory events such as acute rejection and infection after transplantation are considered to be the risk factors of de novo donor-specific antibody (dnDSA) production. In this study, we investigated the relationship between pre­disposing T-cell-mediated rejection and dnDSA-positive CAABMR. <b><i>Methods:</i></b> We recruited 365 patients who underwent ABO-compatible renal transplantation at our hospital. Among them, 16 patients diagnosed as having dnDSA-positive CAABMR were designated as a CAABMR group, and 38 randomly selected patients were designated as a control group. All biopsies from 1 month after transplantation were included in the study. The presence or absence of borderline changes (BLCs), acute T-cell-mediated rejection (ATMR), microvascular inflammation (MVI), and C4d positive on peritubular capillaries (C4d-P) was examined. <b><i>Results:</i></b> In the CAABMR group, BLC/ATMR was found in 12 cases (75%), and the mean duration until appearance of BLC/ATMR was 282.7 ± 328.7 days. C4d-P was found in 11 cases (68.8%), and the mean duration until its appearance was 1,432 ± 1,307 days. MVI was found in all cases, and the mean duration until its appearance was 1,333 ± 1,126 days. The mean duration until diagnosis of CAABMR was 2,268 ± 1,191 days. In the control group, BLC/ATMR was found in 13 cases (34.2%), and the mean duration until the appearance of BLC/ATMR was 173.1 ± 170.4 days. C4d-P was found in 2 cases (5.3%), and the durations until its appearance were 748 and 1,881 days. No cases of MVI were found in the control group. The frequency of BLC/ATMR was significantly higher in the CAABMR group (<i>p</i> &#x3c; 0.01). <b><i>Conclusion:</i></b> Preceding BLC/ATMR is associated with the development of CAABMR with dnDSA.

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