Chronic Antibody-mediated Rejection Research Articles

Evidence for Alloimmune Sinusoidal Injury in De Novo Nodular Regenerative Hyperplasia After Liver Transplantation.

Posttransplant nodular regenerative hyperplasia (NRH) mostly remains unexplained. Microvascular injury due to antibody-mediated rejection (AMR) is suspected, but lack of donor specific antibody (DSA) testing makes it difficult to prove. Centered around a 1-year period of routine DSA testing, concomitant protocol, and indicated posttransplant liver biopsies (LB), recipients with NRH (n = 18) were compared with a matched control group (n = 36). All index, previous, and subsequent LB were reviewed. Both groups were similar in terms of demographics, timing of index LB, and DSA. In the index LB, the NRH group had higher sinusoidal C4d positivity (p = 0.029) and perisinusoidal fibrosis (p = 0.034), both independently associated with NRH (p = 0.038 and 0.050, respectively). Features of "possible" chronic AMR were detected in 28.5% of the NRH group without a known cause and 0% of the control group (p = 0.009). The NRH group had more preceding indicated LB with increased incidence of rejection and biliary obstruction pattern. In the follow-up histology, overall, sinusoidal and portal C4d positivity, sinusoidal microvasculitis, and perisinusoidal fibrosis were also higher (all p < 0.050). In conclusion, we provide evidence towards the hypothesis that some cases of posttransplant NRH are related to preceding active and persistent AMR. Large multicenter studies with protocol DSA testing are required to confirm.

Emerging Therapies for Antibody-Mediated Rejection in Kidney Transplantation.

Despite the advances in immunosuppressive medications, antibody-mediated rejection (AMR) continues to be a major cause of kidney allograft failure and remains a barrier to improving long-term allograft survival. Recently, there have been significant advances in the understanding of the pathophysiological process of AMR, along with the development of new therapeutic options. Additionally, surveillance protocols with donor-derived cell-free DNA and gene profile testing have been established, leading to the early detection of AMR. A multitude of clinical trials are ongoing, opening numerous opportunities for improving outcome in kidney transplant recipients. In this brief review, we discuss the emerging therapies for managing both active and chronic active AMR and highlight the ongoing clinical trials.

Post-Transplant Surveillance and Management of Chronic Active Antibody-Mediated Rejection in Renal Transplant Patients in Europe.

Antibody mediated rejection (ABMR) is the leading cause of immune-related allograft failure following kidney transplantation. Chronic active ABMR (CABMR) typically occurs after one-year post-transplant and is the most common cause of late allograft failure. This study was designed to assess common practices in Europe for post-transplant surveillance 1year after kidney transplant, as well as the diagnosis and management of CABMR. A 15-minute online survey with 58 multiple choice or open-ended questions was completed by EU transplant nephrologists, transplant surgeons and nephrologists. Survey topics included patient caseloads, post-transplant routine screening and treatment of CABMR. The results indicated that observing clinical measures of graft function form the cornerstone of post-transplant surveillance. This may be suboptimal, leading to late diagnoses and untreatable disease. Indeed, less than half of patients who develop CABMR receive treatment beyond optimization of immune suppression. This is attributable to not only late diagnoses, but also a lack of proven efficacious therapies. Intravenous Immunoglobulin (IVIG), steroid pulse and apheresis are prescribed by the majority to treat CABMR. While biologics can feature as part of treatment, there is no single agent that is being used by more than half of physicians.

Targeting the Complement Pathway in Kidney Transplantation.

The complement system is paramount in the clearance of pathogens and cell debris, yet is increasingly recognized as a key component in several pathways leading to allograft injury. There is thus a growing interest in new biomarkers to assess complement activation and guide tailored therapies after kidney transplantation (KTx). C5 blockade has revolutionized post-transplant management of atypical hemolytic uremic syndrome, a paradigm of complement-driven disease. Similarly, new drugs targeting the complement amplification loop hold much promise in the treatment and prevention of recurrence of C3 glomerulopathy. Although unduly activation of the complement pathway has been described after brain death and ischemia reperfusion, any clinical attempts to mitigate the ensuing renal insults have so far provided mixed results. However, the intervention timing, strategy, and type of complement blocker need to be optimized in these settings. Furthermore, the fast-moving field of ex vivo organ perfusion technology opens new avenues to deliver complement-targeted drugs to kidney allografts with limited iatrogenic risks. Complement plays also a key role in the pathogenesis of donor-specific ABO- and HLA-targeted alloantibodies. However, C5 blockade failed overall to improve outcomes in highly sensitized patients and prevent the progression to chronic antibody-mediated rejection (ABMR). Similarly, well-conducted studies with C1 inhibitors in sensitized recipients yielded disappointing results so far, in part, because of subtherapeutic dosage used in clinical studies. The emergence of new complement blockers raises hope to significantly reduce the negative effect of ischemia reperfusion, ABMR, and nephropathy recurrence on outcomes after KTx.

Lowering maintenance immune suppression in elderly kidney transplant recipients; connecting the immunological and clinical dots.

The management of long-term immune suppressive medication in kidney transplant recipients is a poorly explored field in the area of transplant medicine. In particular, older recipients are at an increased risk for side effects and have an exponentially increased risk of infection-related death. In contrast, an aged immune system decreases the risk of acute T-cell-mediated rejection in older recipients. Recent advances in alloimmunity research have shown a rapid and substantial decline in polyfunctional, high-risk CD4+ T cells post-transplantation. This lowers the direct alloreactivity responsible for T-cell-mediated rejection, also known as donor-specific hyporesponsiveness. Chronic antibody-mediated rejection (c-aABMR) is the most frequent cause of kidney graft loss in the long term. However, in older adults, c-aABMR as a cause of graft loss is outnumbered by death with a functioning graft. In addition, DSA development and a diagnosis of c-aABMR plateau ~10 years after transplantation, resulting in a very low risk for rejection thereafter. The intensity of immune suppression regimes could likely be reduced accordingly, but trials in this area are scarce. Tacrolimus monotherapy for 1 year after transplantation seems feasible in older kidney transplant recipients with standard immunological risk, showing the expected benefits of fewer infections and better vaccination responses.

Vitamin D supplementation reduced blood inflammatory cytokines expression and improved graft function in kidney transplant recipients.

Chronic allograft dysfunction(CAD) is the leading cause of graft loss in kidney transplant recipients (KTRs). Inflammatory process is believed to be one of the major contributors to CAD. The aim of this study is to explore the anti-inflammatory effect of vitamin D (VD) supplementation in KTRs and its role in the graft function improvement(protection). A retrospective cohort of 39 KTRs with chronic antibody mediated rejection(CAMR)or stable renal function and a prospective cohort of 42 KTRs treated or untreated with VD were enrolled. Serum levels of vitamin D metabolism and serum inflammatory cytokines, renal graft function, and routine blood biomarkers were tested and dynamically tracked within 12 months post-transplant. Compared with the stable group, the CAMR group exhibited significantly elevated serum levels of inflammatory cytokines IL-1β, IFN-γ, IL-2, IL-10, IP-10, and HMGB1 (P <0.05). The supplementation of vitamin D effectively increased the serum concentration of vitamin D in kidney transplant recipients (KTRs) in the treated group. During the course of treatment, the treated group exhibited a gradual increase in eGFR levels, which were significantly higher than those observed in the untreated group at 12 months post-transplant (p<0.05). Notably, as eGFR improved, there was a significant decrease in levels of IL-1β, IFN-γ, IL-2, IL-10, IP-10 and HMGB1 in the treated group compared to the untreated group (P<0.05). This study confirmed that immune-inflammation is a crucial factor in the development of CAD in KTRs.VD deficiency impairs its anti-inflammatory activity. By assisting in the regulation of excessive immune inflammation and restoration of immune homeostasis, effective VD supplementation contributes to protection and maintenance of graft function in KTRs.

Early conversion to belatacept-based immunosuppression regimen promotes improved long-term renal graft function in kidney transplant recipients

BackgroundBelatacept has been demonstrated as an effective alternative immunosuppressant in kidney transplant recipients. This study focuses on outcomes of early and late conversion to Belatacept-based immunosuppression after kidney transplant. Materials and methodsThis retrospective analysis of a prospectively collected database included all adult kidney transplants patients at SUNY Upstate Medical Hospital from 1 January 2014 to 30 December 2022. Early conversion was defined as all conversions done at <6 months after kidney transplantation, and late conversion to belatacept was defined as conversion at >6 months after kidney transplantation. ResultsOut of 61 patients included in this study, 33 patients (54%) were in the early conversion group, and 28 patients (46%) were in the late conversion group. The mean eGFR in the early conversion group was 26.73 ± 16.26 ml/min/1.73 m2 before conversion to belatacept, which improved to 45.3 ± 21.01 ml/min/1.73 m2 at one-year post-conversion (p = 0.0006). Furthermore, eGFR changes in the late conversion group were insignificant, with 46.30 ± 15.65 ml/min/1.73 m2 before conversion to belatacept, and 44.76 ± 22.91 ml/min/1.73 m2 after one year of follow-up (p = 0.72). All four biopsy-proven allograft rejections in the early conversion group were acute T-cell-mediated rejections (ATMR). In the late conversion group, out of three biopsy-proven rejections, one was chronic antibody-mediated rejection (CAMR), one was ATMR, and one was mixed ATMR/CAMR. All four patients with ATMR rejection received mycophenolic acid (MPA) as part of their immunosuppressive regimen, and none received tacrolimus. The one-year post-conversion allograft survival rate in early and late conversion groups was 100%. However, the one-year post-conversion patient survival rate was 90.9% in the early conversion group and 100% in the late conversion group (P = 0.11). ConclusionsEarly post-transplant conversion to belatacept can improve the eGFR more meaningful when compared to late conversion. Patients who receive belatacept and MPA rather than tacrolimus may have increased rates of T-cell-mediated rejection.

Performance and Advancement of the Kidney Solid Organ Response Test.

The kidney solid organ response test (kSORT) has been investigated for the prediction of acute rejection in kidney transplant recipients with conflicting results. We aimed to investigate if the kSORT assay score is associated with rejection or immune quiescence. The blinded association between rejection and kSORT > 9 were investigated. Optimization of kSORT prediction was evaluated after unblinding to determine the optimal prediction cutoff value of kSORT score. Additionally, the predictive capability of the kSORT gene set was assessed using blinded normalized gene expression data from microarray (Affymetrix) and qPCR assays. Of the 95 blood samples analyzed, 18 patients had blood samples before transplant, 77 patients after transplant and 71 had clinically indicated biopsies of which 15 biopsies showed acute rejection and 16 showed chronic active antibody-mediated rejection. When 31 patients with rejection were compared to the remaining 64 patients, positive predictive value (PPV) was 54.29% and negative predictive value (NPV) was 75% when stratified using a kSORT score > 9, and PPV was 57.89% and NPV was 78.95% when stratified using a kSORT score > 5. Using the kSORT assay for detection of rejection showed an area under the curve value of 0.71. Microarray data improved prediction accuracy with PPV of 53% and NPV of 84% compared to qPCR results (PPV and NPV were 36% and 66%), respectively. The kSORT assay has the potential to be used as a predictive tool for active rejection and/or immune quiescence, but additional studies will be useful in improving and refining the kSORT assay, in particular the prediction algorithm.

#5108 SUSTAINED IL-6 SECRETION CAN LEAD TO AN AMPLIFIED INFLAMMATORY RESPONSE, MEDIATED BY THE ACTIVATION OF STAT3 AND NFKB VIA THE IL-6 AMPLIFIER LOOP

Abstract Background and Aims Organ transplants are the preferred treatment for end-stage organ failure. Potent and specific immunosuppressive agents have significantly decreased acute allograft rejection following renal transplantation. A significant barrier to long-term kidney allograft outcomes is chronic antibody-mediated rejection (CABMR). Chronic inflammation is a major cause of late graft loss that is mediated by soluble mediators released by immune and non-immune cells. IL-6 is a crucial cytokine that plays a central role in developing chronic inflammation. Non-immune cells, such as fibroblasts, have recently been identified as mediating chronic allograft rejection by activating the IL-6 amplifier loop (IL-6+IL-17). Our Aim of the study: -to study the effect of IL-6+IL-17 on secretion of IL-6 in the culture supernatant of fibroblasts derived from renal biopsy of chronic antibody mediated rejection (CABMR) patients; -to see the effect of anti-IL-6 (Tocilizumab)and anti-IL-17 on the secretion of IL-6 from the fibroblasts derived from kidney tissue of chronic antibody mediated rejection (CABMR) patients; and -to elucidate the pro-inflammatory pathway leading to increased IL-6 secretion by induction of Amplifier loop. Method Fibroblasts from grafted kidney from CABMR patients (n = 6) were cultured and stimulated with IL-6 (20ng/ µl), IL-17(50ng/ µl), IL-6 plus IL-17 for 24 hours. Levels of IL-6, MCP-1 and CCL20 were estimated in culture supernatants by ELISA as marker of IL-6 amplifier loop activation. mRNA expression of IL-6, MCP1, CCL20, and SOCS3 genes were measured in the stimulated fibroblasts. Stimulated Renal fibroblast cells from CABMR patients were lysed with Lysis buffer and subjected to SDS–PAGE and western blotting with anti-phospho-STAT3 and anti-phospho-NFκB p65. Additionally, IL-6, MCP1, and CCL20 levels were measured in Healthy control (n = 10), CABMR (n = 20), and non-CABMR (n = 30) patients. Results IL-6 and IL-17 synergistically induced more IL-6, CCL-20 &amp; MCP-1 production from fibroblasts in culture supernatant. Gene expression analysis of IL-6, MCP1, and CCL20 was significantly higher with synergistic activation of IL-6 and IL-17 as compared to either IL-6 or IL-17 alone, while SOCS3 gene expression was downregulated. Our results also suggested that IL-6 Amplifier loop activation induces the NFκB and STAT3 signalling pathway activation in the non-immune cells like fibroblast derived from CABMR patients. Additionally, concentrations of IL-6, CCL-20 &amp; MCP-1 in sera were significantly higher in CABMR patients compared to non-CABMR patients (p&amp;lt;0.001). There was a significant reduction in IL-6 concentration in culture supernatant with IL-6 and IL-17 inhibitor together and mRNA expression of IL-6, CCL20 and MCP-1 was significantly reduced while SOCS3 gene expression was upregulated. Conclusion In humans after kidney transplantation, IL-6 amplifier activation plays an active role in chronic rejection responses. Inhibition of IL-6 with Anti-IL-6 (Tocilizumab) and inhibition of IL-17 with Anti-IL-17 together reduces markers of tissue injury (IL-6, MCP1, CCL20) and rejection of allografts. so, IL-6 amplifier may be a therapeutic target for Chronic transplant rejection.

#4251 KIDNEY TRANSPLANTATION WITH DONOR-SPECIFIC ANTIBODIES: A GROWING NEED

Abstract Background and Aims Preformed donor specific antibodies in kidney transplant (KT) recipients are associated with higher risk of antibody mediated rejection (ABMR) and poorer graft survival. However, remaining a long time on the waiting list is strongly related to worse patient outcomes. We aimed to analyze KT recipients with preformed DSA with mean intensity fluorescence (MFI) who received induction therapy adapted to their higher immunological risk. Method We conducted a cohort retrospective study. All KT with preformed DSA performed in our center since May 2010 until March 2021 were included in the analysis. The presence of DSA was evaluated through Luminex Single Antigen (SA®) technology. All KT were performed with cadaveric kidney donor and with previous negative test by CDC crossmatch. The induction therapy in the presence of DSA included steroids, thymoglobulin, rituximab, plasmapheresis and standard treatment with tacrolimus and mycophenolate. Results During the study period 27 KT with preformed DSA were carried out. Recipient median age was 49 (IQR 40-62) years and 70,2% were women. Dialysis vintage was 5.8 (IQR 2.3-10.2) years. 63% were blood group A and 29,5% blood group 0. 29.6% were also included in the Hypersensitized National Programme (PATHI). The main causes of sensitization were previous KT (55.6%), pregnancy (29.6%) and blood transfusions (3.7%). 63% received KT with preformed DSA class I (median MFI 2218) and 37% with preformed DSA class II (median MFI 1900). Median calculated PRA was 90.5% (IQR 80.6-98.3). Median follow up time was 32.5 (IQR 12.3-61.2) months. Seventeen kidney biopsies were carried out. The most frequent findings were acute tubular necrosis (35.3%) and active ABMR (23.5%). DSA disappeared in most of the cases in successive analysis (81%) without any differences between both DSA classes. Median serum creatinine was 1.25 (IQR 0.97-1.75) mg/dl at 12 months and 1.65 (IQR 1.1-1.81) mg/dl at 24 months. In the post-transplantation period 2 patients were diagnosed with malignant solid organ tumors, 3 developed BK nephropathy, 5 CMV asymptomatic reinfection, and 9 recurrent urinary tract infections. During the observation time, 8 grafts were lost (29.6%): 3 due to patient deaths with functioning grafts and 5 due to graft failure (3 chronic ABMR, 1 active ABMR and 1 BKV nephropathy). Graft survival was 98% and 12 months and 92% at 24 months, respectively. Conclusion DSA with MFI low levels must be considered as a risk factor of ABMR and not as a contraindication to perform KT. A reinforced induction immunosuppression therapy enables KT to patients with high immunological risk and avoid prolonged time on the waiting list.

#2683 NEXT GENERATION SEQUENCING: FROM BANFF SCORE MOLECULAR SIGNATURES AND CLASSIFIERS TO PREDICTED HISTOLOGICAL ARCHETYPES OF KIDNEY BIOPSIES

Abstract Background and Aims To improve risk stratification in kidney transplantation, molecular diagnostic tools are increasingly investigated for their feasibility and gain in diagnostic power. Nonetheless, previously published studies focused on sequencing technologies and gene panels with limited vision of the transcriptome (pathogenesis-based transcripts [PBTs], Banff Human Organ Transplant [BHOT] panel). The EU-TRAIN consortium was built to discover new predictive and informative biomarkers for kidney transplant histology and rejection diagnoses, leveraging a next generation sequencing technology. Method EU-TRAIN (NCT03652402) is a prospective multicentric study including unselected kidney transplant cohorts from 11 centres from 4 countries (France, Spain, Germany, Switzerland). We performed a bulk RNA sequencing on the polyadenylated probes of 770 kidney biopsies (n = 540 kidney recipients) collected between 2018 and 2021. Differential gene expression analyses were computed to obtain a molecular signature for all Banff score lesions. We then derived three different feature selections by either i) training an ElasticNet model on all differentially-expressed genes (DEGs), or by taking the top 30 ii) overall DEGs or iii) the top 30 DEGs focusing on transcripts included in the BHOT gene panel. From them, we trained four machine learning (ML) classifiers through a 10-times repeated 3-fold cross-validation. Models’ performances were assessed on a hold-out test set accounting for 30% of the total samples. Finally, we derived prototypic histological profiles using an archetypal analysis on the samples’ predicted Banff score probabilities from the best classifier. Results The ElasticNet feature selection lowered the number of DEGs to be included from a range of [859; 10,839] to [52; 867]. These selections were composed of a mixture of PBTs [55.2%; 84.2%], BHOT genes [2.2%;13.5%] and new transcripts [12.4%; 37.2%]. Based on these findings, four ML classifiers (Naïve Bayes, Extreme Gradient Boosting, Linear Support Vector Machine and K-Nearest Neighbours) were trained on the three different feature selections and their performances in predicting Banff score lesions were compared using the precision-recall area under the curve (PRAUC). In all settings, the ElasticNet feature selection outperformed the other two methods with a minimal/maximal increase in PRAUC of 0.068 (t) / 0.726 (cg). Excluding the ah score, the best discriminations were obtained with the Linear Support Vector Machine with a PRAUC in the interval [0.708; 0.980] (t/ptc). Excluding cv and ah, all models calibrated properly (Hosmer and Lemeshow goodness of fit p-value &amp;gt; 0.05). The archetypal analysis resulted in 8 profiles: acute and chronic antibody-mediated rejection (presence of circulating donor-specific antibodies, C4d deposition, g, ptc and cg lesions), acute T-cell mediated rejection (i, t and ti lesions), chronic TCMR (i, t, ti, ci, ct and i-IFTA lesions), mixed rejection (g, ptc, i, t and ti lesions), vascular injuries (cv and ah), fibrosis (ci and ct lesions, older donors with history of hypertension), minimal fibrotic change (ci and ct) and minor changes (no lesions). Conclusion From new transcripts, we managed to develop models that predict accurately the Banff score lesions and 8 profiles were identified among these predictions. External validation and archetypes’ association with graft loss will be addressed in the future.

#2938 DE NOVO DSA IS ASSOCIATED WITH HUMAN PERIPHERAL BLOOD CXCR5+PD-1+CD8+ T CELLS AND PD-1 PD-L1 MRNA EXPRESSION IN KIDNEY TRANSPLANT PATIENTS

Abstract Background and Aims Donor-specific antibody (DSA) development is mainly responsible for chronic antibody-mediated rejection. The immunological events that cause the development of DSA is not fully elucidated. The relationship between the Follicular Cytotoxic T cell subgroup and the development of DSA is unknown. In this study we aimed to examine CD8+CXCR5+PD-1+ follicular cytotoxic T cell levels and expression levels of PD1/PD-L1 genes in peripheral blood lymphocytes in recipients who de-novo DSA positive or negative after kidney transplantation (KTX). Method In this study, the expression levels of PD-1, PD-L1 genes were determined using the Real-Time Quantitative PCR method from peripheral blood samples of 22 KTX patients with de-novo DSA positive, 20 KTX patients with DSA negative and 21 healthy control (Table 1). Our patient groups were PRA negative before transplantation. Expression (%) levels of target cells were evaluated by flow cytometry method. IBM SPSS Statistics for Windows Version 22 and R.3.3.2 software were used to evaluate the data. Results PD-1 expression level was higher in the KTX patients with de-novo DSA positive compared to the KTX patients with DSA negative group (p:0.006 CT: 0,84±0,23). According to the results of flow cytometry, CD8+CXCR5+PD-1+ cell expression (%) levels were found to be significantly higher in patients (3,06±1,98) compared to the transplant control group (0,52±0,40) (p: 0.001) (Figure 1). Conclusion It shows that there may be a direct correlation between DSA and PD-1 / PDL-1 mRNA level and CXCR5+PD1+CD8+ follicular cytotoxic T cell in transplant patients after kidney transplantation.

#3654 ABO-INCOMPATIBLE KIDNEY TRANSPLANTATION LOWERS INCIDENCES OF DE NOVO DONOR-SPECIFIC ANTIBODIES AND CHRONIC ANTIBODY-MEDIATED REJECTION

Abstract Background and Aims ABO-incompatible kidney transplantation has been associated with an increased risk for antibody-mediated rejection (ABMR) and early graft loss attributable to isoagglutinins. Its impact on the development of de novo donor-specific HLA antibodies (DSA) and DSA-induced chronic ABMR, however, remains less well studied. Method We analyzed 297 kidney transplant recipients (KTRs) who underwent living donor transplantation at the University Hospital Zurich from 2009 to 2021. 58 ABO-incompatible (iABO) KTRs were compared to 239 ABO-compatible (cABO) KTRs concerning the development of de novo donor-specific antibodies (DSA) and antibody-mediated rejection (ABMR). ABO desensitization was performed using rituximab and antigen-specific immunoadsorption. The HLA-derived epitope-mismatches were calculated per HLA-locus and in total using the Predicted Indirectly Recognizable HLA-Epitopes (PIRCHE-II) algorithm. High-resolution re-typing was performed from protocol kidney allograft biopsies if necessary. Results The incidence of TCMR/ABMR in the first post-transplant year was comparable between iABO KTRs (19%) and cABO KTRs (13%; p = 0.207). De novo DSA were detected in only 1 of 58 iABO KTRs but 12 of 239 cABO KTRs in the first post-transplant year and 2 of 58 iABO KTRs but 50 of 239 cABO KTRs in the long-term follow-up (p = 0.001). ABMR was diagnosed in only 1 of 58 iABO KTRs but 28 of 239 cABO KTRs after the first post-transplant year (p = 0.021). iABO kidney transplantation decreased the risk of de novo DSA development (HR 7.222, CI 1.755-29.722, p = 0.006) and ABMR (HR 7.362, CI 1.000-54.239; p = 0.050) after the first-post-transplant year independent from the presence of preformed DSA. Total PIRCHE-II scores and PIRCHE-II scores per locus were not associated with the development of de novo DSA in all 297 living-donor KTRs (p&amp;gt;0.05). Conclusion Our findings suggest that iABO kidney transplantation is associated with a lower incidence of de novo DSA and ABMR in the long term, independent from the HLA-derived epitope mismatch load. Whether this protective effect offers new therapeutic options against kidney allograft injury needs to be investigated in future studies.

#4610 LACK OF EFFICACY AND SAFETY OF ECULIZUMAB FOR TREATMENT OF ANTIBODY-MEDIATED REJECTION FOLLOWING RENAL TRANSPLANTATION

Abstract Background and Aims We evaluated the efficacy and safety of eculizumab in comparison with plasmapheresis and intravenous immunoglobulin therapy in renal transplant recipients diagnosed with antibody-mediated rejection (AMR). Method This was a multicenter, open-label, prospective, randomized analysis. The patients were randomized by therapy type (eg, eculizumab infusions or standard of care [SOC]: plasmapheresis/intravenous immunoglobulin). The patients (ie, eculizumab arm: 7 patients, SOC arm: 4 patients) were evaluated for the continued presence of donor-specific antibodies (DSAs) and C4d (staining on biopsy), as well as histologic evidence, using repeat renal biopsy after treatment. Results The allograft biopsies revealed that eculizumab did not prevent the progression to transplant glomerulopathy. Cases of AMR were diagnosed in the early post-transplantation period in 2 patients (eculizumab arm: 1 patient, SOC arm: 1 patient) and in the late period in 9 patients. Most of the reports show that eculizumab, in combination with other therapeutic measures such as PP and/or IVIG, effectively reversed rejection. However, eculizumab alone could not treat AMR effectively. Only 2 patients in the SOC arm experienced rejection reversal, and no graft losses occurred in either group. After AMR treatment, the DSA titers generally decreased compared to titers taken at the time of AMR diagnosis. There were no serious adverse effects in the eculizumab arm. Conclusion Eculizumab alone cannot treat AMR effectively and does not prevent acute AMR from progressing to chronic AMR or transplant glomerulopathy. However, it should be considered as a potential alternative therapy because it may be associated with decreased DSA levels.

Mechanism and treatment for chronic antibody-mediated rejection in kidney transplant recipients.

Chronic antibody-mediated rejection of kidney transplantation is a major cause of late-stage graft loss. Donor-specific antibodies are the main cause of antibody-mediated rejection; in particular, de novo donor-specific antibodies are a risk factor for chronic active antibody-mediated rejection. The level of de novo donor-specific antibodies tends to increase with time throughout long-term graft survival. Donor-specific antibodies induce humoral rejection through complement activation, which results in tissue injury and coagulation. Additionally, complement activation promotes the migration of inflammatory cells through the innate immune response, causing endothelial injury. This inflammatory response may cause persistent glomerulitis and peritubular capillaritis, leading to fixed pathological lesions that impair graft function. No treatment has been established for chronic antibody-mediated rejection, a condition in which antibody-mediated rejection becomes irreversible. Thus, antibody-mediated rejection must be detected and treated while it is still reversible. In this review, we discuss the development of de novo donor-specific antibodies and the mechanisms leading to chronic antibody-mediated rejection and summarize the current treatment options and the latest biomarkers for detecting chronic antibody-mediated rejection at an earlier stage.

Development and nationwide validation of kidney graft injury markers using urinary exosomes and microvesicles (complete English translation of the Japanese version)

BackgroundNon-invasive, prompt, and proper detection tools for kidney graft injuries (KGIs) are awaited to ensure graft longevity. We screened diagnostic biomarkers for KGIs following kidney transplantation using extracellular vesicles (EVs; exosomes and microvesicles) from the urine samples of patients.MethodsOne hundred and twenty-seven kidney recipients at 11 Japanese institutions were enrolled in this study; urine samples were obtained prior to protocol/episode biopsies. EVs were isolated from urine samples, and EV RNA markers were assayed using quantitative reverse transcription polymerase chain reaction. Diagnostic performance of EV RNA markers and diagnostic formulas comprising these markers were evaluated by comparison with the corresponding pathological diagnoses.ResultsEV CXCL9, CXCL10, and UMOD were elevated in T-cell-mediated rejection samples compared with other KGI samples, while SPNS2 was elevated in chronic antibody-mediated rejection (cABMR) samples. A diagnostic formula developed through Sparse Logistic Regression analysis using EV RNA markers allowed us to accurately (with an area under the receiver operator characteristic curve [AUC] of 0.875) distinguish cABMR from other KGI samples. EV B4GALT1 and SPNS2 were also elevated in cABMR, and a diagnostic formula using these markers was able to distinguish between cABMR and chronic calcineurin toxicity accurately (AUC 0.886). In interstitial fibrosis and tubular atrophy (IFTA) urine samples and those with high Banff chronicity score sums (BChS), POTEM levels may reflect disease severity, and diagnostic formulas using POTEM detected IFTA (AUC 0.830) and high BChS (AUC 0.850).ConclusionsKGIs could be diagnosed with urinary EV mRNA analysis with relatively high accuracy.

Tocilizumab for antibody-mediated rejection treatment in lung transplantation

Tocilizumab (TCZ), an IL-6 inhibitor, has shown promise in the treatment of donor-specific antibodies (DSA) and chronic antibody-mediated rejection (AMR) in renal transplant recipients. However, its use in lung transplantation has not been described. This retrospective case-control study compared AMR treatments containing TCZ in 9 bilateral lung transplant recipients to 18 patients treated for AMR without TCZ. Treatment with TCZ resulted in more clearance of DSA, lower recurrence of DSA, lower incidence of new DSA, and lower rates of graft failure when compared to those treated for AMR without TCZ. The incidence of infusion reactions, elevation in transaminases, and infections were similar between the 2 groups. These data support a role for TCZ in pulmonary AMR and establish preliminary evidence to design a randomized controlled trial of IL-6 inhibition for the management of AMR.

Evaluation and management of abnormal liver enzymes in the liver transplant recipient: When, why, and what now?

Evaluation and management of abnormal liver enzymes in the liver transplant recipient: When, why, and what now?

Asymptomatic Allograft Fibrosis in Pediatric Liver Transplantation: Potential Clinical Implications.

Asymptomatic Allograft Fibrosis in Pediatric Liver Transplantation: Potential Clinical Implications.

Impact of ABO incompatibility and early antibody-mediated rejection on chronic antibody-mediated rejection in kidney transplant patients.

Early antibody-mediated rejection has been reported to increase chronic antibody-mediated rejection and decrease graft survival in kidney transplantation. However, the impact of early antibody-mediated rejection in ABO-incompatible kidney transplantation remains unclear. We retrospectively analyzed living-donor kidney transplantation patients from two Korean centers. Patients were categorized based on ABO compatibility and early antibody-mediated rejection within 1 year. The primary outcome was chronic antibody-mediated rejection. The secondary outcomes were production of de novo donor-specific antibody and composite kidney outcome, defined as graft loss or a decline in estimated glomerular filtration rate to below 30mL/min/1.73 m2. A total of 1639 patients were analyzed, including 1292 patients who underwent ABO-compatible kidney transplantation and 347 patients who underwent ABO-incompatible kidney transplantation. ABO-incompatible kidney transplantation had a lower risk of de novo donor-specific antibody production (hazard ratio [HR] 0.68, 95% confidence interval [CI] 0.48-0.95) and chronic antibody-mediated rejection (HR 0.33, 95% CI 0.12-0.92) with a comparable risk of the composite kidney outcome (HR 1.06, 95% CI 0.71-1.59) compared to ABO-compatible kidney transplantation. When outcomes of ABO-incompatible kidney transplantation were analyzed according to early antibody-mediated rejection, ABO-incompatible kidney transplantation without antibody-mediated rejection had a lower risk of de novo donor-specific antibody production (HR 0.60, 95% CI 0.41-0.88) and chronic antibody-mediated rejection (HR 0.28, 95% CI 0.09-0.91) than ABO-compatible kidney transplantation without antibody-mediated rejection. However, ABO-incompatible kidney transplantation with antibody-mediated rejection showed a higher risk of de novo donor-specific antibody production and similar risk of chronic antibody-mediated rejection compared to ABO-compatible kidney transplantation without antibody-mediated rejection. ABO-incompatible kidney transplantation showed a lower risk of de novo donor-specific antibody production and chronic antibody-mediated rejection compared to ABO-compatible kidney transplantation; however, early antibody-mediated rejection abrogated these beneficial effects of ABO-incompatible kidney transplantation.