Chronic Active Antibody-mediated Rejection Research Articles

Is Lack of Consensus on the Management of Chronic Active Antibody-Mediated Rejection Harming Renal Transplant Recipients?

In 2022, over 92,000 kidney transplants were performed globally. With advancements in transplant science, 1-year graft survival rates have reached 94.3% for deceased donor kidney transplant recipients, and 97.8% for living recipients. However, 5-year graft survival remains at 76.3% and 86.5%. Antibody-mediated rejection (AMR) is one of the most common causes of immune-related allograft rejection. Chronic active AMR (CABMR) typically develops 6–12 months post-transplant; 76% of kidney transplant recipients with CABMR experience graft loss 1.9 years after diagnosis. Despite these alarming figures, consensus guidelines on the management of post-transplant patients have not been updated with advancements in testing and protocol biopsies, and there is currently no consensus in Europe on CABMR management.

Back to the future: the uncharted role of T cells in chronic and unexplained microvascular inflammation

The 2022 Banff classification for kidney allograft pathology introduced the category "microvascular inflammation DSA-negative and C4d-negative" for cases without evidence of a humoral cause. Many questions remain about the etiology, prognosis, and treatment of this phenotype. Cristoferi etal. performed a molecular comparison of chronic active antibody-mediated rejection and its seronegative counterpart and suggest a central role for T cells in chronic donor-specific antibody-negative, C4d-negative microvascular inflammation. These results further question how we should classify rejection.

Tocilizumab in chronic active antibody-mediated rejection: rationale and protocol of an in-progress randomized controlled open-label multi-center trial (INTERCEPT study)

BackgroundChronic active antibody-mediated rejection (caAMR) in kidney transplants is associated with irreversible tissue damage and a leading cause of graft loss in the long-term. However, the treatment for caAMR remains a challenge to date. Recently, tocilizumab, a recombinant humanized monoclonal antibody directed against the human interleukin-6 (IL-6) receptor, has shown promise in the treatment of caAMR. However, it has not been systematically investigated so far underscoring the need for randomized controlled studies in this area.MethodsThe INTERCEPT study is an investigator-driven randomized controlled open-label multi-center trial in kidney transplant recipients to assess the efficacy of tocilizumab in the treatment of biopsy-proven caAMR. A total of 50 recipients with biopsy-proven caAMR at least 12 months after transplantation will be randomized to receive either tocilizumab (n = 25) added to our standard of care (SOC) maintenance treatment or SOC alone (n = 25) for a period of 24 months. Patients will be followed for an additional 12 months after cessation of study medication. After the inclusion biopsies at baseline, protocol kidney graft biopsies will be performed at 12 and 24 months. The sample size calculation assumed a difference of 5 ml/year in slope of estimated glomerular filtration rate (eGFR) between the two groups for 80% power at an alpha of 0.05.The primary endpoint is the slope of eGFR at 24 months after start of treatment. The secondary endpoints include assessment of the following at 12, 24, and 36 months: composite risk score iBox, safety, evolution and characteristics of donor-specific antibodies (DSA), graft histology, proteinuria, kidney function assessed by measured GFR (mGFR), patient- and death-censored graft survival, and patient-reported outcomes that include transplant-specific well-being, adherence to immunosuppressive medications and perceived threat of the risk of graft rejection.DiscussionNo effective treatment exists for caAMR at present. Based on the hypothesis that inhibition of IL-6 receptor by tocilizumab will reduce antibody production and reduce antibody-mediated damage, our randomized trial has a potential to provide evidence for a novel treatment strategy for caAMR, therewith slowing the decline in graft function in the long-term.Trial registrationClinicalTrials.gov NCT04561986. Registered on September 24, 2020

Higher Donor Age and Severe Microvascular Inflammation Are Risk Factors for Chronic Rejection After Treatment of Active Antibody-Mediated Rejection.

Recent developments in intensive desensitization protocols have enabled kidney transplantation in human leukocyte antigen (HLA)-sensitized recipients. However, cases of active antibody-mediated rejection (AABMR), when they occur, are difficult to manage, graft failure being the worst-case scenario. We aimed to assess the impact of our desensitization and AABMR treatment regimen and identify risk factors for disease progression. Among 849 patients who underwent living-donor kidney transplantation between 2014 and 2021 at our institution, 59 were diagnosed with AABMR within 1year after transplantation. All patients received combination therapy consisting of steroid pulse therapy, intravenous immunoglobulin, rituximab, and plasmapheresis. Multivariable analysis revealed unrelated donors and preformed donor-specific antibodies as independent risk factors for AABMR. Five-year death-censored graft survival rate was not significantly different between patients with and without AABMR although 27 of 59 patients with AABMR developed chronic AABMR (CABMR) during the study period. Multivariate Cox proportional hazard regression analysis revealed that a donor age greater than 59years and microvascular inflammation (MVI) score (g + ptc) ≥4 at AABMR diagnosis were independent risk factors for CABMR. Our combination therapy ameliorated AABMR; however, further treatment options should be considered to prevent CABMR, especially in patients with old donors and severe MVI.

Multiomic profiling of transplant glomerulopathy reveals a novel T-cell dominant subclass

Kidney transplant (KTx) biopsies showing transplant glomerulopathy (TG) (glomerular basement membrane double contours (cg) > 0)) and microvascular inflammation (MVI) in the absence of C4d staining and donor-specific antibodies (DSA)s do not fulfill the criteria for chronic active antibody-mediated rejection (CA-AMR) diagnosis and do not fit into any other Banff category. To investigate this, we initiated a multicenter intercontinental study encompassing 36 cases, comparing the immunomic and transcriptomic profiles of 14 KTx biopsies classified as cg+MVI DSA-/C4d- with 22 classified as CA-AMR DSA+/C4d+ through novel transcriptomic analysis using the NanoString Banff-Human Organ Transplant (B-HOT) panel and subsequent orthogonal subset analysis using two innovative 5-marker multiplex immunofluorescent panels. Nineteen genes were differentially expressed between the two study groups. Samples diagnosed with CA-AMR DSA+/C4d+ showed a higher glomerular abundance of natural killer cells and higher transcriptomic cell type scores for macrophages in an environment characterized by increased expression of complement-related genes (i.e., C5AR1) and higher activity of angiogenesis, interstitial fibrosis tubular atrophy, CA-AMR, and DSA-related pathways when compared to samples diagnosed with cg+MVI DSA-/C4d-. Samples diagnosed with cg+MVI DSA-/C4d- displayed a higher glomerular abundance and activity of T-cells (CD3+, CD3+CD8+, and CD3+CD8-). Thus, we show that using novel multiomic techniques, KTx biopsies with cg+MVI DSA-/C4d- have a prominent T-cell presence and activity, putting forward the possibility that these represent a more T-cell-dominant phenotype.

Transcriptomic signatures of chronic active antibody-mediated rejection deciphered by RNA sequencing of human kidney allografts

Natural killer (NK) cells mediate spontaneous cell-mediated cytotoxicity and antibody-dependent cell-mediated cytotoxicity. This dual functionality could enable their participation in chronic active antibody-mediated rejection (CA-ABMR). Earlier microarray profiling studies have not subcategorized antibody-mediated rejection into CA-ABMR and active-ABMR, and the gene expression pattern of CA-ABMR has not been compared with that of T cell-mediated rejection (TCMR). To fill these gaps, we RNA sequenced human kidney allograft biopsies categorized as CA-ABMR, active-ABMR, TCMR, or No Rejection (NR). Among the 15,910 genes identified in the biopsies, 60, 114, and 231 genes were uniquely overexpressed in CA-ABMR, TCMR, and active-ABMR, respectively, compared to NR, 50 genes were shared between CA-ABMR and active-ABMR, and 164 genes between CA-ABMR and TCMR. The overexpressed genes were annotated to NK cells and T cells in CA-ABMR and TCMR, and to neutrophils and monocytes in active-ABMR. The NK cell cytotoxicity and allograft rejection pathways were enriched in CA-ABMR. Genes encoding perforin, granzymes, and death receptor, were overexpressed in CA-ABMR versus ABMR but not compared to TCMR. NK cell cytotoxicity pathway gene set variation analysis score was higher in CA-ABMR compared to active-ABMR but not in TCMR. Principal component analysis of the deconvolved immune cellular transcriptomes separated CA-ABMR and TCMR from active-ABMR and NR. Immunohistochemistry of kidney allograft biopsies validated a higher proportion of CD56+ NK cells in CA-ABMR than in active-ABMR. Thus, CA-ABMR was exemplified by the overexpression of the NK cell cytotoxicity pathway gene set and, surprisingly, molecularly more like TCMR than active-ABMR.

Post-Transplant Monoclonal Gammopathy of Renal Significance: A Case Report

The term monoclonal gammopathy of renal significance has been used to classify the presence of a monoclonal gammopathy or lymphoproliferative disorders that do not meet hematological criteria for myeloma but instead cause kidney damage. Mostly, post-transplant monoclonal gammopathy of renal significance occurs due to recurrent disease. In contrast, the incidence of de novo post-transplant monoclonal gammopathy of renal significance has not been established, as it is considered a rare disease, presenting a unique challenge in terms of diagnosis, management, and potential impact on graft survival. Here, we report a case of de novo monoclonal gammopathy of renal significance diagnosed after kidney transplantation and its complexity due to a concomitant chronic active antibody-mediated rejection.

Chronic Active Antibody-mediated Rejection: Opportunity to Determine the Role of Interleukin-6 Blockade.

Chronic active antibody-mediated rejection (caAMR) is arguably the most important cause of late kidney allograft failure. However, there are no US Food and Drug Administration (FDA)-approved treatments for acute or chronic AMR and there is no consensus on effective treatment. Many trials in transplantation have failed because of slow and/or inadequate enrollment, and no new agent has been approved by the FDA for transplantation in over a decade. Several lines of evidence suggest that interleukin-6 is an important driver of AMR, and clazakizumab, a humanized monoclonal antibody that neutralizes interleukin-6, has shown promising results in phase 2 studies. The IMAGINE trial (Interleukin-6 Blockade Modifying Antibody-mediated Graft Injury and Estimated Glomerular Filtration Rate Decline) (NCT03744910) is the first to be considered by the FDA using a reasonably likely surrogate endpoint (slope of estimated glomerular filtration rate decline >1 y) for accelerated approval and is the only ongoing clinical trial for the treatment of chronic rejection. This trial offers us the opportunity to advance the care for our patients in need, and this article is a call to action for all transplant providers caring for patients with caAMR.

Difficult-to-Treat Rejections in Kidney Transplant Recipients: Our Experience with Everolimus-Based Quadruple Maintenance Therapy.

All chronic and treatment-resistant acute rejections are "difficult-to-treat" and lead to progressive loss of graft function in kidney transplant recipients (KTR), as no effective treatment exists for such rejections to date. We review our experience with a novel strategy to treat such rejections by adding everolimus as a "rescue" to conventional triple maintenance therapy with prednisolone, mycophenolate mofetil and calcineurin inhibitor. We retrospectively analysed data in 28 KTR who received everolimus-based quadruple therapy at our institution for biopsy-proven chronic active T cell-mediated or antibody-mediated rejection (n = 19) or treatment-resistant acute rejections (n = 9) between 2011-2017. The primary outcome was 5-year death-censored graft survival. Main secondary outcomes were response to treatment defined by stable or improved graft function, 5-year patient survival and discontinuation rate of treatment. The Kaplan-Meier estimate for 5-year death-censored graft survival was 79% in all patients, 90% for patients with chronic active T cell-mediated rejections, 78% for chronic active antibody-mediated rejection and 67% for acute rejections. Response to treatment was achieved in 43% and 5-year patient survival was 94%. Treatment was stopped in 12 (43%) patients due to adverse events. Everolimus-based maintenance quadruple therapy, despite high rate of everolimus discontinuation due to adverse events, may be a valid approach in a subset of kidney transplant recipients with such difficult-to-treat rejections, which otherwise would lead to a high rate of graft loss.

Non-meningeal, non-pulmonary cryptococcosis with limited posterior uveitis in a kidney organ transplant recipient with antibody-mediated rejection: a case report

BackgroundCryptococcosis is one of the most frequent fungal eye infections in patients with immunosuppression. Currently, treatment approaches for non-meningeal, non-pulmonary cryptococcosis are based on those used for cryptococcal meningitis or pneumonia.Case presentationWe present a rare case of non-meningeal, non-pulmonary cryptococcosis with clinical manifestations limited to one eye of a cadaveric kidney transplant recipient with chronic-active antibody-mediated rejection. Typical manifestations, diagnosis, and treatments, including antifungal therapies, adjunctive therapies, and immunosuppression reduction, are discussed. After timely diagnosis and treatment, her visual acuity recovered to baseline without recurrence or sequelae of cryptococcosis.ConclusionsClinicians should be aware of rare presentations of fungal infections, especially when a kidney transplant recipient with rejection has been treated with intensive immunosuppressants. Early diagnosis with individualized therapies may have a favorable prognosis.

Novel transcriptomic signatures associated with premature kidney allograft failure

The power to predict kidney allograft outcomes based on non-invasive assays is limited. Assessment of operational tolerance (OT) patients allows us to identify transcriptomic signatures of true non-responders for construction of predictive models. In this observational retrospective study, RNA sequencing of peripheral blood was used in a derivation cohort to identify a protective set of transcripts by comparing 15 OT patients (40% females), from the TOMOGRAM Study (NCT05124444), 14 chronic active antibody-mediated rejection (CABMR) and 23 stable graft function patients ≥15 years (STA). The selected differentially expressed transcripts between OT and CABMR were used in a validation cohort (n=396) to predict 3-year kidney allograft loss at 3 time-points using RT-qPCR. Archetypal analysis and classifier performance of RNA sequencing data showed that OT is clearly distinguishable from CABMR, but similar to STA. Based on significant transcripts from the validation cohort in univariable analysis, 2 multivariable Cox models were created. A 3-transcript (ADGRG3, ATG2A, and GNLY) model from POD 7 predicted graft loss with C-statistics (C) 0.727 (95% CI, 0.638-0.820). Another 3-transcript (IGHM, CD5, GNLY) model from M3 predicted graft loss with C 0.786 (95% CI, 0.785-0.865). Combining 3-transcripts models with eGFR at POD 7 and M3 improved C-statistics to 0.860 (95% CI, 0.778-0.944) and 0.868 (95% CI, 0.790-0.944), respectively. Identification of transcripts distinguishing OT from CABMR allowed us to construct models predicting premature graft loss. Identified transcripts reflect mechanisms of injury/repair and alloimmune response when assessed at day 7 or with a loss of protective phenotype when assessed at month3. Supported by the Ministry of Health of the Czech Republic under grant NV19-06-00031.

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.

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.

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.

Regulatory B Cells Profile in Kidney Transplant Recipients With Chronic-Active Antibody-Mediated Rejection

This study aims to reveal the relationship between regulatory B cell (Breg) subsets and chronic-active antibody-mediated rejection (c-aABMR) in renal transplant recipients. Our study involved 3 groups of participants: renal transplant recipients with biopsy-proven c-aABMR as the chronic rejection group (c-aABMR, n=23), recipients with stable graft functions as the patient control group (PC; n=11), and healthy volunteers (HV; n=11). Breg subsets, immature/transitional B cells, plasmablastic cells, B10 cells, and BR1 cells were isolated from venous blood samples by flow cytometry. The median values of Breg frequencies in the total lymphocyte population were analyzed. There were no significant differences between the study groups for immature and/or transitional B cell frequencies. Plasmablastic cell frequencies of the c-aABMR group (7.80 [2.10-27.40]) and the PC group (6.00 [1.80-55.50]) were similar, but both of these values were significantly higher than the HVs' (3.40 [1.20-8.50]), (respectively, P=.005 and P=.039). B10 cell frequencies were also similar, comparing the c-aABMR (4.20 [0.10-7.40]) and the PC groups (4.10 [0.10-5.90]), whereas the HVs (5.90 [2.90-8.50]) had the highest B10 cell frequency with an only statistical significance against the PC group (respectively, P=.09 and P=.028). The c-aABMR and the PC groups were similar regarding BR1 cell frequencies. However, the HV group significantly had the highest frequency of BR1 cells (5.50 [2.80-10.80]) than the other groups (P < .001 for both). We demonstrated that frequencies of B10 and BR1 cells were higher in HVs than in transplant recipients, regardless of rejection state. However, there was no significant relation between Breg frequencies and the c-aABMR state.

A Case of Chronic Active Antibody-Mediated Rejection Caused by a Pre-Existing Anti-DQ Donor-Specific Antibody in a Systemic Lupus Erythematosus Recipient Without History of Sensitization: A Case Report

Systemic lupus erythematosus (SLE) is reported to produce anti-HLA antibodies. We report a case of chronic active antibody-mediated rejection caused by pre-existing donor-specific antibody (DSA) in a patient with SLE without a history of sensitization. The case was a 29-year-old man with end-stage renal disease due to lupus nephritis. Cross-match with the mother was negative, but low titer anti-DQ DSA was detected, although he had no prior history of sensitization. After desensitization with rituximab and mycophenolate mofetil, a living donor kidney transplant was undergone, and his early postoperative period was uneventful. However, his renal function started to decline at 2 years post-transplant. Although there was no rejection on the biopsy at 2.5 years post-transplant, his renal function continued to decline after that. At 7 years, he had failed his graft due to chronic active antibody-mediated rejection. Retrospective analysis of human leukocyte antigen antibody tests revealed that anti-DQ DSA had disappeared at 1 year post-transplant, but high titer DSA was detected again with complement-binding capacity at 2 years and after that. Careful monitoring might be warranted in an SLE patient with pre-existing DSA, even though the titer was low and without any prior histories of sensitization events.

Tocilizumab for treatment of chronic active antibody-mediated rejection in kidney transplant recipients.

The optimal treatment for chronic active antibody-mediated rejection (ca-AMR) remains unclear. Tocilizumab (TCZ), a monoclonal antibody against IL-6, has been proposed as a therapeutic option. We reported our experience treating ca-AMR with TCZ either as the first line option or as a rescue therapy. We studied 11 adult kidney transplant recipients with biopsy-proven ca-AMR and preserved kidney function (eGFR 57 ± 18) who were treated with TCZ (8 mg/kg IV monthly). All biopsies were prompted by abnormal surveillance biomarker testing with DSA and/or dd-cfDNA. Clinical monitoring included dd-cfDNA and DSA testing every 3 months during the treatment with TCZ. In this cohort, ca-AMR was diagnosed at a median of 90 months (range 14-224) post-transplant, and 4 of 11 patients had DSA negative ca-AMR. Patients received a minimum of 3 months of TCZ, with 6 patients receiving at least 12 months of TCZ. Dd-cfDNA was elevated in all patients, with a median 2.24% at the start of TCZ treatment. After 6 months of TCZ treatment, 8/11 patients had dd- cfDNA <1%, and 3/11 had values <0.5%. Among those who completed at least 12 months of TCZ, dd-cfDNA decreased by 29% at 6 months (p=.05) and 47% by 12 months (p=.04). DSA also stabilized and, by 12 months, was reduced by 29% (p=.047). Graft function remained stable with no graft loss during treatment. There was a nonsignificant trend towards proteinuria reduction. During the course of treatment with tocilizumab, two patients experienced moderate to severe infections. In our early short-term experience, TCZ appears to reduce graft injury as measured by dd-cfDNA and modulate the immune response as evident by a modest reduction in immunodominant DSA MFI. Allograft function and proteinuria alsostabilized.

Mesangiolysis in Pathological Chronic Active Antibody-Mediated Rejection in Kidney Transplant Biopsies

Introduction: This study aimed to determine if immune or nonimmune and acute or chronic lesions associated with mesangiolysis (MGLS) occurred in biopsy-proven pathological chronic active antibody-mediated rejection (P-CAABMR) in kidney transplant biopsies. Methods: We evaluated MGLS in 41 patients with biopsy findings of P-CAABMR from January 2016 to December 2019. Histological scoring was evaluated by Banff classification. Multivariate logistic regression analysis was performed using a forward selection method. Results: Fifteen of the 41 P-CAABMR biopsies (36.6%) cases showed MGLS. The estimated glomerular filtration rate (eGFR) was significantly lower in the MGLS-positive compared with the MGLS-negative group, and proteinuria was significantly higher in the MGLS-positive compared with the MGLS-negative group. In the clinical model, multivariate analysis was performed using covariates of eGFR and duration after transplantation significantly correlated with MGLS by simple analysis, in addition to type of calcineurin inhibitor use (tacrolimus or cyclosporine), donor-specific antibodies, diabetes, and hypertension grade defined by use of antihypertensive therapy or/and blood pressure level. Only hypertension grade was significantly correlated with MGLS. In the pathological model, multivariate analysis was performed using the presence of FSGS and the aah and cg scores significantly correlated with MGLS by simple analysis, in addition to g and ptc scores. The cg score was significantly correlated with hypertension grade, duration after transplantation, g, ah, and aah. Conclusion: Lower graft function and higher proteinuria was observed in MGLS of P-CAABMR. The Banff cg score was independently related to MGLS in multivariate analysis. Sustained glomerulitis, calcineurin inhibitor nephrotoxicity, and hypertension may cause Banff cg lesions, leading to MGLS in P-CAABMR.

Clazakizumab for the treatment of chronic active antibody-mediated rejection (AMR) in kidney transplant recipients: Phase 3 IMAGINE study rationale and design

BackgroundChronic active antibody-mediated rejection (AMR) is a major cause of graft loss with no approved drugs for its treatment. Currently, off-label regimens are used, reflecting the high unmet need for effective therapies based on well-controlled trials. Clazakizumab is a high-affinity, humanized monoclonal antibody that binds interleukin-6 and decreases donor-specific antibody (DSA) production and inflammation. Phase 2 pilot studies of clazakizumab in kidney transplant recipients with chronic active AMR suggest modulation of DSA, stabilization of glomerular filtration rate (GFR), and a manageable safety profile. We report the design of the Phase 3 IMAGINE study (NCT03744910) to evaluate the safety and efficacy of clazakizumab for the treatment of chronic active AMR.MethodsIMAGINE is a multicenter, double-blind trial of approximately 350 kidney transplant recipients with chronic active AMR (Banff chronic glomerulopathy [cg] >0 with concurrent positive human leukocyte antigen DSA) randomized 1:1 to receive clazakizumab or placebo (12.5 mg subcutaneous once every 4 weeks). The event-driven trial design will follow patients until 221 occurrences of all-cause graft loss are observed, defined as return to dialysis, graft nephrectomy, re-transplantation, estimated GFR (eGFR) <15 mL/min/1.73m2, or death from any cause. A surrogate for graft loss (eGFR slope) will be assessed at 1 year based on prior modeling validation. Secondary endpoints will include measures of pharmacokinetics/pharmacodynamics. Recruitment is ongoing across North America, Europe, Asia, and Australia.DiscussionIMAGINE represents the first Phase 3 clinical trial investigating the safety and efficacy of clazakizumab in kidney transplant recipients with chronic active AMR, and the largest placebo-controlled trial in this patient population. This trial includes prognostic biomarker enrichment and uniquely utilizes the eGFR slope at 1 year as a surrogate endpoint for graft loss, which may accelerate the approval of a novel therapy for patients at risk of graft loss. The findings of this study will be fundamental in helping to address the unmet need for novel therapies for chronic active AMR.Trial registrationClinicalTrials.govNCT03744910. Registered on November 19, 2018.