Antibody-mediated Rejection Rates Research Articles

De novo and recurrent post-transplant membranous nephropathy cases show similar rates of concurrent antibody-mediated rejection.

Membranous nephropathy (MN) can develop post-kidney transplant and is classified as a recurrent disease in patients with a history of MN in the native kidneys or as de novo disease in patients without such history. The mechanism of recurrent MN is thought to be like that of primary MN, but the mechanism of de novo MN is not well delineated. An association between de novo MN and antibody-mediated rejection (AMR) has been suggested. A search of the pathology database from our medical center identified 11 cases of recurrent and 15 cases of de novo MN, in which clinical and histologic findings were compared. No significant differences were identified in the demographic characteristics, serum creatinine and proteinuria trends, or rates of allograft failure between the recurrent and de novo MN groups. Rates of concurrent AMR were high in both groups (36% and 40%, respectively) but not statistically different from each other. PLA2R immunofluorescence (IF) positivity was seen in 64% of recurrent MN cases compared to 33% of de novo MN cases, suggesting a higher incidence of PLA2R-positive de novo MN than previously reported. No significant histologic differences were identified in the initial biopsies from the two groups, except mean IgG intensity by IF was higher in the recurrent group, suggesting a higher load of immune complex deposits at diagnosis in this group. The findings do not provide support for a specific association between AMR and de novo MN, but whether there is a possible link between both forms of post-transplant MN and AMR remains an unanswered question.

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.

Characteristics of Early Antibody Mediated Rejection in Antibody Incompatible Living Donor Kidney Transplantation.

Antibody incompatible transplantation (AIT) may be an only option for highly sensitized patients. Severe form of early antibody mediated rejection (AMR) adversely affects graft survival after AIT. The aim of this study was to identify individuals at risk of AMR. We analyzed 213 living donor AITs performed at our center. Among 120 ABOi, 58 HLAi and 35 DSA + FCXM-negative cases, the rates of early AMR were 6%, 31%, and 9%, respectively (p < 0.001). On multivariate analysis for graft loss, early AMR had a HR of 3.28 (p < 0.001). The HLAi group had worse death-censored graft survival (p = 0.003). In the HLAi group, Patients with aggressive variant AMR (AAMR) had greater percentage of C3d complement fixing DSA, higher baseline class I and total DSA MFI levels and B-cell FCXM RMF. C1q and C3d complement fixing DSA and strong positivity of baseline B- or T-cell FXCM as predictors of AAMR had 100% sensitivity. Early AMR is of significant clinical concern in AIT as it results in poor graft survival and is not well described in literature. An aggressive variant is characterized by massive rise in DSA levels at rejection. Baseline DSA, C1q, and C3d and baseline FCXM values can be used to risk-stratify candidates for AIT.

Sensitive HLA antibody testing and the risk of antibody-mediated rejection and graft failure.

Solid phase detection and identification of HLA antibodies in kidney transplantation currently relies on single antigen bead (Luminex®) assays, which is more sensitive than the previously used enzyme-linked immunosorbent assays (ELISA). To evaluate the impact of more sensitive HLA testing on antibody-mediated rejection (AMR) occurrence and allograft survival, we analysed 1818 renal allograft recipients transplanted between March 2004 and May 2021. In 2008, solid phase testing switched from ELISA to Luminex. We included 393 (21.6%) transplantations before and 1425 (78.4%) transplantations after transition from ELISA- to Luminex-based testing. For this study, bio-banked ELISA era samples were tested retrospectively with Luminex. Significantly less pretransplant DSA were found in patients transplanted with pre-existing HLA antibodies in the Luminex (109/387) versus the ELISA period (43/90) (28% vs. 48%, p < 0.01). Throughout histological follow-up, 169 of 1818 (9.3%) patients developed AMR. After implementing Luminex-based testing, the rate of AMR significantly decreased (p = 0.003). However, incidence of graft failure did not significantly differ between both eras. In conclusion, less patients with pretransplant DSA were transplanted since the implementation of Luminex HLA testing. Transition from ELISA- to Luminex-based HLA testing was associated with a significant decrease in AMR occurrence post-transplantation. Since the decline of AMR did not translate into improved graft survival, Luminex-based testing has the added value of preventing low-risk AMR cases. Therefore, Luminex' high sensitivity must be balanced against waiting time for a suitable organ.

The Effect of Induction Therapy on Antibody-Mediated Rejection in Kidney Transplantation: A Network Meta-Analysis Using Recent Data

Various induction regimens are available for kidney transplantation (KT); however, which is superior remains unclear. Moreover, although the induction regimens are effective and important for reducing side effects, their respective relationships with antibody-mediated rejection (AMR) after transplantation remain unclear. Therefore, this study aimed to elucidate the most effective induction regimen for AMR reduction through network analysis. We performed a comprehensive search of databases, including basiliximab, alemtuzumab, antithymocyte globulin (ATG), and daclizumab as induction regimens for KT from inception to September 1, 2022. Using a network meta-analysis, we investigated the priorities of 5 induction regimens for patient survival, graft failure, and graft rejection after ABO-incompatible KT. In total, 25 studies comprising 1768 people were included in this network meta-analysis. The primary outcome was the AMR rate of other induction regimens compared with that of basiliximab, whereas the secondary outcomes were heart failure, stroke, hospitalization, peripheral artery disease, myocardial infarction, anemia, leukopenia, herpes zoster, or adverse events. Notably, ATG reduced the AMR rate by 59% (odds ratio, 0.41; 95% credible interval, 0.20-0.90), whereas the other drugs did not show statistical significance. Furthermore, secondary outcomes did not significantly differ between the induction regimens. ATG is widely used in KT induction regimens. Our results showed that ATG reduced the risk of AMR in KT recipients when compared with other induction drugs; therefore, it appears to be an efficient choice of induction regimen to reduce AMR after KT.

The role of anticomplement therapy in the management of the kidney allograft.

As the number of patients living with kidney failure grows, the need also grows for kidney transplantation, the gold standard kidney replacement therapy that provides a survival advantage. This may result in an increased rate of transplantation from HLA-mismatched donors that increases the rate of antibody-mediated rejection (AMR), which already is the leading cause of allograft failure. Plasmapheresis, intravenous immunoglobulin therapy, anti-CD20 therapies (i.e., rituximab), bortezomib and splenectomy have been used over the years to treat AMR as well as to prevent AMR in high-risk sensitized kidney transplant recipients. Eculizumab and ravulizumab are monoclonal antibodies targeting the C5 protein of the complement pathway and part of the expanding field of anticomplement therapies, which is not limited to kidney transplant recipients, and also includes complement-mediated microangiopathic hemolytic anemia, paroxysmal nocturnal hemoglobinuria, and ANCA-vasculitis. In this narrative review, we summarize the current knowledge concerning the pathophysiological background and use of anti-C5 strategies (eculizumab and ravulizumab) and C1-esterase inhibitor in AMR, either to prevent AMR in high-risk desensitized patients or to treat AMR as first-line or rescue therapy and also to treat de novo thrombotic microangiopathy in kidney transplant recipients.

Impacts of Pre-transplant Panel-Reactive Antibody on Post-transplantation Outcomes: A Study of Nationwide Heart Transplant Registry Data.

The number of sensitized heart failure patients on waiting lists for heart transplantation (HTx) is increasing. Using the Korean Organ Transplantation Registry (KOTRY), a nationwide multicenter database, we investigated the prevalence and clinical impact of calculated panel-reactive antibody (cPRA) in patients undergoing HTx. We retrospectively reviewed 813 patients who underwent HTx between 2014 and 2021. Patients were grouped according to peak PRA level as group A: patients with cPRA ≤10% (n= 492); group B: patients with cPRA >10%, <50% (n=160); group C patients with cPRA ≥50% (n=161). Post-HTx outcomes were freedom from antibody-mediated rejection (AMR), acute cellular rejection, coronary allograft vasculopathy, and all-cause mortality. The median follow-up duration was 44 (19-72) months. Female sex, re-transplantation, and pre-HTx renal replacement therapy were independently associated with an increased risk of sensitization (cPRA ≥50%). Group C patients were more likely to have longer hospital stays and to use anti-thymocyte globulin as an induction agent compared to groups A and B. Significantly more patients in group C had positive flow cytometric crossmatch and had a higher incidence of preformed donor-specific antibody (DSA) compared to groups A and B. During follow-up, group C had a significantly higher rate of AMR, but the overall survival rate was comparable to that of groups A and B. In a subgroup analysis of group C, post-transplant survival was comparable despite higher preformed DSA in a desensitized group compared to the non-desensitized group. Patients with cPRA ≥50% had significantly higher incidence of preformed DSA and lower freedom from AMR, but post-HTx survival rates were similar to those with cPRA <50%. Our findings suggest that sensitized patients can attain comparable post-transplant survival to non-sensitized patients when treated with optimal desensitization treatment and therapeutic intervention.

Positive Long-Term Outcome of Kidney Allocation via Acceptable Mismatch Program in Highly Sensitized Patients

Introduction: Eurotransplant established the acceptable mismatch (AM) program to facilitate timely kidney transplantations of highly sensitized patients, but long-term granular clinical and immunological outcomes regarding overall graft survival and de novo DSA (dnDSA) formation are still intensively researched. The right choice of induction therapy in patients with differing immunological risk is not conclusively determined, as well as the impact of human leukocyte antigen (HLA) epitope matching on dnDSA formation. Methods: This monocentric, retrospective study analyzed 94 patients transplanted within the AM program between 2000 and 2019 compared to case-control matched cohorts of non- (PRA 0–5%; PRA-0) and intermediately sensitized (PRA 6–84%; PRA-6/84) patients transplanted through Eurotransplant Kidney Allocation System. Results: Estimated 10-year overall graft survival between the PRA-0 and AM cohorts was similar, whereas PRA-6/84 was significantly disadvantageous compared to PRA-0. Estimated 10-year incidence of antibody-mediated rejection rates was significantly lower in the PRA-0 group compared to AM and PRA-6/84 groups. Compared to the AM group, estimated incidence of de novo donor-specific antibody (dnDSA) was significantly lower in PRA-0 patients, with no differences between the AM and PRA-6/84 cohorts. The PRA-6/84 cohort was the only subgroup in which interleukin-2 receptor antagonist (IL2RA) induction was associated with longer overall graft survival, patient survival, and graft survival compared to depleting induction (ATG or OKT3). Broad HLA-A, -B, -DR mismatches (mmABDR) and HLA epitope mismatches determined by Eplets and PIRCHE-II were predictive for dnDSA formation in the total cohort, and the AM subgroup. Discussion: The high efforts expended on AM patients are justified to allow timely organ transplantation with acceptable risk profile and non-inferior outcomes. IL2RA induction in intermediately sensitized patients is associated with superior overall graft survival, patient survival, and graft survival compared to ATG/OKT3 induction, without negative effects on rejection episodes or dnDSA formation. In silico epitope matching might further help reduce dnDSA formation, particularly in high-risk AM patients.

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.

Early Cytomegalovirus Reactivation in Renal Recipients Is Associated with High Levels of B Cell Maturation Antigen Transcript Expression Prior to Transplantation.

Cytomegalovirus (CMV) infection is the most frequent infection episode in kidney transplant (KT) recipients. Reactivation usually occurs in the first three months after transplantation and is associated with higher cellular and/or antibody-mediated rejection rates and poorer graft performance. CMV induces the expression of BAFF (B-cell-activating factor, a cytokine involved in the homeostasis of B cells), which communicates signals for survival and growth to B cells and virus-specific plasma cells via the R-BAFF (BAFF receptor), TACI (the calcium modulator, the cyclophilin ligand interactor), and BCMA (B cell maturation antigen) receptors. These molecules of the BAFF system have also been suggested as biomarkers for the development of alloantibodies and graft dysfunction. This prospective study included 30 CMV-IgG seropositive KT recipients. The expression levels of the genes BAFF-R, transmembrane activator and CAML interactor (TACI), and B cell maturation antigen (BCMA) in peripheral blood leukocytes (PBL) pre-KT were determined using qPCR. qPCR was also used to monitor CMV reactivation in the first three months following KT. The remainder of the KT recipients were classified as CMV- reactivation, and those with more than 500 copies/mL in at least one sample were classified as CMV+ reactivation. There were no discernible variations in the BAFF-R and TACI transcript expression levels. In the CMV+ group, we examined the relationship between the transcript levels and peak viremia. Peak viremia levels and BCMA transcript levels showed a strong correlation. BAFF-R and TACI expressions showed no measurable differences. In patients with early CMV reactivation, high BCMA receptor expression was associated with increased plasmablast, lymphocyte B cell class-switched levels (LBCS), and viral load. Our findings demonstrate that pre-KT BCMA transcript levels increased in KT recipients with early CMV reactivation. These transcript levels positively correlate with peak viremia and weakly with plasmablast and LBCS levels in PBLs.

Effect of blood transfusion post kidney transplantation on de novo human leukocytes antigen donor-specific antibody development and clinical outcomes in kidney transplant recipients: A systematic review and meta-analysis

The relationship between blood transfusion following kidney transplantation (KT) and the development of de novo donor-specific antibodies (dnDSA) is controversial. This was investigated by conducting a meta-analysis of studies on patients who underwent KT with or without blood transfusion, and by evaluating the effect of post-KT blood transfusion on clinical outcomes of kidney transplant recipients. Relevant studies in the PubMed, EMBASE, and Cochrane Library databases were identified from inception to July 1, 2022. Two reviewers independently extracted data from the selected articles and estimated study quality. A fixed effects or random effects model was used to pool data according to the heterogeneity among studies. Data included in the meta-analysis were derived from 11 studies with a total of 19,543 patients including 6191 with and 13,352 without blood transfusion post-KT. We assessed the pooled associations between blood transfusion and occurrence of dnDSA and clinical outcomes of transplant recipients. Blood transfusion was strongly correlated with the development of dnDSA (relative risk [RR] = 1.40, 95% confidence interval [CI]: 1.17–1.67; P < 0.05). Patients with blood transfusion had a higher risk of developing anti-human leukocyte antigen (HLA) class I dnDSA than non-transfused patients (RR = 1.75, 95% CI: 1.14–2.69; P < 0.05) as well as significantly higher rates of antibody-mediated rejection (AMR) (RR = 1.41, 95% CI: 1.21–2.35; P < 0.05) and graft loss (RR = 1.75, 95% CI: 1.30–2.35; P < 0.05). There were no statistically significant differences between the two groups in the development of anti-HLA antibodies, anti-HLA class II dnDSA, and anti-HLA class I and II dnDSA; delayed graft function; T cell-mediated rejection; acute rejection; borderline rejection; or patient death. Our results suggest that blood transfusion was associated with dnDSA development in KT recipients. The findings of this systematic review also suggest that post-KT blood transfusion recipients have a higher risk of AMR, and graft loss compared with non-transfused patients. Evidence from this meta-analysis indicates that the use of blood transfusion post-KT is associated with a significantly higher risk of immunological sensitization. More and higher quality results from large randomized controlled trials are still needed to inform clinical practice.

Efficacy of bortezomib desensitization among heart transplant candidates.

Allosensitization is prevalent in heart transplant candidates and is associated with prolonged waiting times and poor outcomes following transplantation. We analyzed the efficacy of a desensitization regimen consisting of plasma exchange, intravenous immunoglobulin, and bortezomib among 25 consecutive sensitized waitlisted candidates at our center from 2016 to 2021. Following desensitization therapies, all C1q negative antibodies were removed from a candidate's unacceptable antigen list. There was a significant decrease in the median number of human leukocyte antigen (HLA) class I (21-15, p=.001) but not class II antibodies (7-6.5, p=.07). There was a significant corresponding decrease in median calculated panel reactive antibodies for class I (90%-74%, p=.004) but not class II (74.5%-75.5%, p=.30). Following desensitization, 76% of patients were transplanted at a median of 91 days. One-year survival following transplant was 89% with a 33% rate of antibody-mediated rejection (AMR). In conclusion, a bortezomib desensitization protocol was modestly effective for class I antibodies and allowed successful transplant in most cases when combined with selective crossing of C1q negative antigens.

Association Between De Novo C1q-Binding Donor-Specific Anti-HLA Antibodies and Clinical Outcomes After Kidney Transplantation: A Meta-Analysis

Donor-specific antibodies (DSAs) are recognized as an important factor of kidney allograft loss as a subsequent event of antibody-mediated rejection (AMR). The clinical relevance of de novo DSAs (dnDSAs) after kidney transplant, particularly in their ability to bind C1q, has been widely investigated to various extents among studies. A recent study was performed to examine the association between C1q-binding dnDSAs and succeeding clinical events after kidney transplant. A meta-analysis of studies published before April 2021 was conducted from PubMed, Science Direct, and Cochrane databases. Publications on dnDSA after kidney transplant focusing on differentiation between C1q-binding and non-C1q-binding were included. The outcomes analyzed were AMR rate and allograft loss. Studies using preformed DSA were excluded. The pooled risk ratio and 95% confidence interval (CI) were analyzed using Mantzel-Haenzel method, and the I2 value was used to determine the heterogeneity of the studies. Data analysis was conducted using Review Manager 5.3. A total of 535 patients from 13 studies who developed dnDSA after kidney transplant were analyzed. Among these, 239 (44.7%) had C1q-binding and 296 (55.3%) had non-C1q-binding dnDSA. Acute AMR was found in 59.2% (97/164) of the C1q-binding group and in 28.8% (49/170) of the non-C1q-binding group (risk ratio [RR], 0.58 [95% CI, 0.39-0.85], P = .006, I2=58%). Chronic AMR was found in 50% (19/38) of the C1q-binding group and in 16.9% (11/65) of the non-C1q-binding group (RR, 0.39 [95% CI, 0.21-0.71], P=.002, I2=0%). Allograft loss was found in 62.2% (74/119) of the C1q-binding group and in 34.1% (60/176) of the non-C1q-binding group (RR, 0.57 [95% CI, 0.38-0.85], P = .006, I2=61%). This meta-analysis demonstrates that patients who developed C1q-binding dnDSA display an increased risk of AMR and allograft loss compared with those with non-C1q-binding dnDSA. Therefore, C1q-binding dnDSAs are associated with inferior outcomes after kidney transplant.

Development of de novo donor-specific antibodies in renal transplant recipients with BK viremia managed with immunosuppression reduction.

Reduction of immunosuppression (IS) upon detection of Polyomavirus (BK) viremia is widely used to prevent BK virus nephropathy. This retrospective case-control study assesses the frequency of de novo donor-specific antibodies (dnDSA) in renal transplant recipients with IS modulation due to BK viremia and the associated risk of antibody mediated rejection. Our cohort included recipients of kidney transplantation between 2007 and 2017 with clinical, HLA antibody, and biopsy data. BK positivity was defined as viremia >10000 c/ml or biopsy proven BK nephropathy. A total of 190 BK cases matched our inclusion criteria, each case was matched with two controls based on gender, donor type, and transplant within 1 year (N = 396). Despite lower number of HLA antigen mismatches (mean = 3.5vs. 4.4, p < .001), dnDSA rates were higher in BK cases than in control group (22.1%vs. 13.9%, p = .02), with the majority detected following IS reduction for BK infection, and arising earlier posttransplant compared with no BK infection (294d vs. 434d, p < .001). Antibody mediated rejection rates were similar between cases and controls (8.9% and 8.3%, respectively), but rejection was more likely to occur earlier posttransplant in the BK cases (354d vs. 602d, p = .03). Our data suggest a link between IS reduction and the generation of dnDSA and/or rejection, supporting close monitoring for DSA in patients with reduced IS due to BK infection given their increased risk to develop dnDSA.

Higher levels of allograft injury in black patients early after heart transplantation.

Black patients suffer higher rates of antibody-mediated rejection and have worse long-term graft survival after heart transplantation. Donor-derived cell free DNA (ddcfDNA) is released into the blood following allograft injury. This study analyzed %ddcfDNA in 63 heart transplant recipients categorized by Black and non-Black race, during the first 200 days after transplant. Immediately after transplant, %ddcfDNA was higher for Black patients (mean [SE]: 8.3% [1.3%] vs 3.2% [1.2%], p=0.001). In the first week post-transplant, the rate of decay in %ddcfDNA was similar (0.7% [0.68] vs 0.7% [0.11], p=0.78), and values declined in both groups to a comparable plateau at 7 days post-transplant (0.46% [0.03] vs 0.45% [0.04], p=0.78). The proportion of Black patients experiencing AMR was higher than non-Black patients (21% vs 9% [hazard ratio of 2.61 [95% confidence interval: 0.651-10.43], p=0.18). Black patients were more likely to receive a race mismatched organ than non-Black patients (69% vs 35%, p=0.01), which may explain the higher levels of early allograft injury.

Outcome of ABO-incompatible kidney transplantation using a modified desensitization protocol without plasmapheresis.

Several controversies regarding desensitization strategies for successful ABO-incompatible (ABOi) kidney transplantation still exist. This study aimed to investigate whether pretransplant anti-A/B antibody removal is mandatory in an ABOi kidney transplant recipient with low baseline isoagglutinin titers. We adopted a modified desensitization protocol with two doses of rituximab (RTX, 100 mg/body) without pretransplant antibody removal for ABOi kidney transplant recipients with a titer of ≤1:64 (group A; n = 35) and investigated the feasibility of this protocol by comparing it with the clinical outcomes of patients undergoing standard pretransplant plasmapheresis (group B; n = 21). There was no significant difference in the rate of antibody-mediated rejection within the first month after transplantation between the two groups (11.4% in group A vs. 2% in group B, p = 0.6019). Moreover, no differences were observed in the short- and long-term graft outcomes between the groups. However, two major critical acute antibody-mediated events occurred in group A; one patient lost the graftdue to hyperacute rejection, and the other patient developed thrombotic microangiopathy after surgery. Risk factors predicting these perioperative complications were not identified. We conclude that not only B-cell depletion using RTX but also pretransplant antibody removal is still recommended even for patients with low isoagglutinin titers. In addition, a new diagnostic tool is needed for accurate risk stratification.

Deletion of the Natural Killer Cell Receptor NKG2C Encoding KLR2C Gene and Kidney Transplant Outcome.

Natural killer (NK) cells may contribute to antibody-mediated rejection (ABMR) of renal allografts. The role of distinct NK cell subsets in this specific context, such as NK cells expressing the activating receptor NKG2C, is unknown. Our aim was to investigate whether KLRC2 gene deletion variants which determine NKG2C expression affect the pathogenicity of donor-specific antibodies (DSA) and, if so, influence long-term graft survival. We genotyped the KLRC2 wt/del variants for two distinct kidney transplant cohorts, (i) a cross-sectional cohort of 86 recipients who, on the basis of a positive post-transplant DSA result, all underwent allograft biopsies, and (ii) 1,860 recipients of a deceased donor renal allograft randomly selected from the Collaborative Transplant Study (CTS) database. In the DSA+ patient cohort, KLRC2 wt/wt (80%) was associated with antibody-mediated rejection (ABMR; 65% versus 29% among KLRC2 wt/del subjects; P=0.012), microvascular inflammation [MVI; median g+ptc score: 2 (interquartile range: 0-4) versus 0 (0-1), P=0.002], a molecular classifier of ABMR [0.41 (0.14-0.72) versus 0.10 (0.07-0.27), P=0.001], and elevated NK cell-related transcripts (P=0.017). In combined analyses of KLRC2 variants and a functional polymorphism in the Fc gamma receptor IIIA gene (FCGR3A-V/F158), ABMR rates and activity gradually increased with the number of risk genotypes. In DSA+ and CTS cohorts, however, the KLRC2 wt/wt variant did not impact long-term death-censored graft survival, also when combined with the FCGR3A-V158 risk variant. KLRC2 wt/wt may be associated with DSA-triggered MVI and ABMR-associated gene expression patterns, but the findings observed in a highly selected cohort of DSA+ patients did not translate into meaningful graft survival differences in a large multicenter kidney transplant cohort not selected for HLA sensitization.

Comparing safety of proton‐pump inhibitors versus H2‐receptor antagonists in kidney transplant recipients: A systematic review and meta‐analysis

Multiple studies have been conducted to compare the safety of proton-pump inhibitors (PPIs) and H2-receptor antagonists (H2RAs) as acid-suppressive treatment in kidney transplant recipients with conflicting results. This systematic review and meta-analysis aimed to evaluate the risk of adverse effects in kidney transplant patients receiving PPIs compared to those treated with H2RAs. A systematic search was performed on the databases from inception to June 2021. The treatment effects were expressed as odds ratio (OR), weighted mean differences (WMD) and their 95% confidence intervals (CI) and pooled by a random-effects model. Eight studies, consisting 4,844 patients, were included. Patients were followed for a mean duration of 23.57months after transplantation. Compared with H2RAs, PPIs exposure was associated with similar rate of biopsy-proven acute rejection (BPAR) (OR= 1.05, 95% CI 0.83-1.34, p=0.67), mortality (OR=1.31, 95% CI 0.56-3.07, p=0.533), graft loss (OR=1.06, 95% CI 0.59-1.93, p=0.842), Clostridioides difficile infection (OR=1.37, 95% CI 0.49-3.85, p=0.545) and pneumonia (OR=1.83, 95% CI 0.95-3.52, p=0.072). The estimated glomerular filtration rate (eGFR) at 12months was lower in patients who received PPIs than those treated with H2RAs (WMD=-1.01, 95% CI -1.89 to -0.12ml/min/1.73m2 , p=0.02). The PPI-treated kidney transplant patients experienced higher rate of antibody-mediated rejection (AMR) (OR=1.87, 95% CI 1.03-3.04, p=0.039) and hypomagnesemia (OR=2.16, 95% CI 1.46-3.20, p˂0.001). Compared with H2RAs, PPIs were not associated with higher risks of BPAR, mortality, graft loss or infection-related outcomes. However, taking PPIs was associated with higher rates of AMR and hypomagnesemia, and lower eGFR at one year after transplantation. Further well-controlled studies are needed to assess the impact of acid-suppressive strategy on long-term outcomes in KTRs.

Living Donor Kidney Transplantation in Patients With Donor-Specific HLA Antibodies After Desensitization With Immunoadsorption.

Due to the current organ shortage, living donor kidney transplantation is increasingly performed across HLA (human leukocyte antigen) or ABO antibody barriers. There is still uncertainty about the risk of antibody-mediated rejection (AMR) episodes, which may limit long-term graft survival. From March 2007 to December 2016, 58 sensitized living donor kidney transplant candidates were identified and 38 patients eventually included in the study: 36 patients (95%) had pre-transplant and pre-desensitization Luminex-detected donor-specific HLA antibodies (DSA), and 17/36 patients (47%) in addition had a positive crossmatch result. Two patients had no detectable DSA but a positive CDC B-cell crossmatch result. Patients were treated with pre- and post-transplant apheresis and powerful immunosuppression including the anti-CD20 antibody rituximab (N = 36) in combination with thymoglobulin (N = 20) or anti-IL2 receptor antibody (N = 18). The results of the 38 successfully desensitized and transplanted patients were retrospectively compared to the results of 76 matched standard-risk recipients. Desensitized patients showed patient and graft survival rates similar to that of standard-risk recipients (P = 0.55 and P = 0.16, respectively). There was a trend toward reduced death-censored graft survival in desensitized patients (P = 0.053) which, however, disappeared when the 34 patients who were transplanted after introduction of sensitive Luminex testing were analyzed (P = 0.43). The incidence of rejection episodes without borderline changes were in desensitized patients with 21% similar to the 18% in standard-risk patients (P = 0.74). Thirty-six patients had pre-transplant HLA class I and/or II DSA that were reduced by 85 and 81%, respectively, during pre-transplant desensitization (P < 0.001 for both). On day 360 after transplantation, 20 of 36 (56%) patients had lost their DSA. The overall AMR rate was 6% in these patients, but as high as 60% in 5 (14%) patients with persistent and de novo DSA during year 1; 2 (40%) of whom lost their graft due to AMR. Eleven (31%) patients with persistent DSA but without de novo DSA had an AMR rate of 18% without graft loss while one patient lost her graft without signs of AMR. Our desensitization protocol for pre-sensitized living donor kidney transplant recipients with DSA resulted in good graft outcomes with side effects and rejection rates similar to that of standard-risk recipients. Adequate patient selection prior to transplantation and frequent immunological monitoring thereafter is critical to minimize rejection episodes and subsequent graft loss.

Predictive Potential of Flow Cytometry Crossmatching in Deceased Donor Kidney Transplant Recipients Subjected to Peritransplant Desensitization.

Recipient sensitization is a major risk factor of antibody-mediated rejection (ABMR) and inferior graft survival. The predictive effect of solid-phase human leukocyte antigen antibody testing and flow cytometry crossmatch (FCXM) in the era of peritransplant desensitization remains poorly understood. This observational retrospective single-center study with 108 donor-specific antibody (DSA)-positive deceased donor kidney allograft recipients who had undergone peritransplant desensitization aimed to analyze variables affecting graft outcome. ABMR rates were highest among patients with positive pretransplant FCXM vs. FCXM-negative (76 vs. 18.7%, p < 0.001) and with donor-specific antibody mean fluorescence intensity (DSA MFI) > 5,000 vs. <5,000 (54.5 vs. 28%, p = 0.01) despite desensitization. In univariable Cox regression, FCXM positivity, retransplantation, recipient gender, immunodominant DSA MFI, DSA number, and peak panel reactive antibodies were found to be associated with ABMR occurrence. In multivariable Cox regression adjusted for desensitization treatment (AUC = 0.810), only FCXM positivity (HR = 4.6, p = 0.001) and DSA number (HR = 1.47, p = 0.039) remained significant. In conclusion, our data suggest that pretransplant FCXM and DSA number, but not DSA MFI, are independent predictors of ABMR in patients who received peritransplant desensitization.