Kidney Transplant Rejection

The purpose of this open-label, randomized, active-comparator-controlled study is to determine the efficacy and safety of frexalimab subcutaneous administrations up to 5 years compared to tacrolimus capsules in adults undergoing kidney transplantation. Participants aged 18 to 70 years who have low-to-moderate immunologic risk of graft rejection and receive their first kidney transplant are eligible if they meet all inclusion and no exclusion criteria. Study details include: * The study and treatment duration will be up to approximately 5 years. * The number of visits will be approximately 38.

Kidney transplant rejection remains a significant challenge to long-term graft survival. While histological biopsy continues to be the gold standard for diagnosing rejection, noninvasive biomarkers such as donor-derived cell-free DNA (dd-cfDNA) have gained traction for their ability to detect allograft injury. However, dd-cfDNA may lack sensitivity in certain clinical scenarios particularly in cases of localized immune activation leading to false negatives despite biopsy-confirmed rejection.

Antibody mediated rejection (ABMR) is a major cause of graft loss after kidney transplantation (KT) and is mainly associated with preformed anti-HLA donor specific antibodies (DSAs) (phenotype 1) or de novo DSAs (dnDSAs) (phenotype 2). Preexisting DSA-associated ABMR have superior graft survival compared with dnDSA-associated ABMR, which could partly be explained by the fact that patients with de novo DSA-associated ABMR have biopsy later, when graft dysfunction and/or proteinuria are already present. ABMR is a progressive process with an early stage called subclinical ABMR (sABMR), in which histological lesions are present in the kidney graft without clinical graft dysfunction. These early lesions are now well recognized as risk factors for transplant glomerulopathy and poor graft survival in phenotype 1 ABMR (ref 5). The impact of sABMR associated with dnDSA at any time post-transplant has been less studied and reported. Recently, a retrospective multicenter study was published, within the Spiesser Group that included 123 patients without graft dysfunction who underwent graft biopsy because of the presence of dnDSA (One Lambda, MFI \> 1000). Performing a kidney graft biopsy after dnDSA indentification without renal dysfunction leads to the diagnosis of active sABMR in 35 % of cases. Nevertheless, no effect of standard of care treatment in active sABMR was observed. Very recently, an expert consensus for the recommended treatment for ABMR after KT was published. It was conclude that the clear lack of evidence but a standard of care for ABMR was nevertheless defined. Therefore, the current proposal is to evaluate a new strategy for active sABMR, testing a conversion from calcineurin inhibitor (CNI) to belatacept associated with the recently recommended standard of care (SOC) compared to continuing CNI. Belatacept might help to manage nonadherence, decrease the toxicity of CNI on an endothelium already affected by microvascular inflammation, and reduce DSA titers. The monitoring of dnDSA after KT and an indication graft biopsy in case of appearance, even in the absence of graft dysfunction, is not part of a routine clinical practice in all KT centers. This strategy could be a valuable option, in order to begin treatment of ABMR before graft dysfunction occurs, and therefore to improve prognosis associated with phenotype 2 ABMR. Parajuli et al.4 suggested that early diagnosis and treatment of sABMR with SOC, using DSA monitoring may improve outcomes after KT, but this is a retrospective and no-randomized study. This study will be the first prospective randomized study in the context of de novo DSA. The objective is to evaluate a new combination of treatment for ABMR in the context of dnDSA with subclinical lesions and in the same time may help to determine the real incidence of sABMR in KT recipients with subclinical dnDSA. The use of belatacept in the context of sABMR to improve the non-adherence and to decrease the endothelial toxicity had never been evaluated in a prospective way.

Demonstrate the relationship between DD-cfDNA levels and HLA antibodies in blood, and the Molecular Microscope® (MMDx) Diagnostic System results in indication biopsies.

The purpose of this study is to evaluate the safety and efficacy of carfilzomib and belatacept, administered with steroids and maintenance immunosuppression, in kidney transplant recipients with donor-specific antibody (DSA)-associated graft injury. Participants will be followed for 52 weeks after starting investigational therapy, including protocol biopsies at 3 months and 12 months after start of investigational therapy. The study will also assess changes in immune cell responses, blood and urine biomarkers, and biopsy-based pathomic features associated with antibody-mediated graft injury.

The goal of this clinical trial is to determine whether belimumab can improve detection of circulating HLA-specific memory B cells to support safer and more effective donor organ allocation in highly sensitized kidney transplant candidates. The main questions it aims to answer are: Does treatment with belimumab change the antigen specificity profile of circulating HLA-specific memory B cells compared to pre-treatment measurements? Does a delisting strategy that incorporates mobilized memory B cells improve the probability of donor organ allocation and reduce time to transplantation? Participants will: Receive a short course of belimumab treatment Provide blood samples before and during treatment to assess memory B-cell profiles Undergo evaluation for potential adjustment of unacceptable HLA specificities (delisting) based on test results Be followed for donor organ allocation and transplantation outcomes

The objective of the proposed study it to perform a pilot clinical trial both to establish feasibility of applying a computational, augmented intelligence based approach, Phenotypic Precision Medicine (PPM), to optimizing combination drug therapy and to gather preliminary data to support a larger fully powered multi-center clinical trial. The key rationale for this clinical selection is that we have the technical, biological, and medical expertise in this disease, a wealth of experience in the use of PPM in both in vitro and the clinical setting, and a robust and integrated transplant program with a well-functioning clinical trial infrastructure.

Mesenchymal stem cell (MSCs) therapy has already been studied in kidney transplant recipients (KTRs), and the available data showed that it is safe and well tolerated. The aim of this study was to evaluate the safety and efficacy of autologous MSCs in combination with standard therapy in KTRs with biopsy-proven chronic active antibody-mediated rejection (AMR). Patients with biopsy-proven chronic active AMR received treatment with autologous bone marrow-derived MSCs (3 × 106 cells/kg iv) after completion of standard therapy and were followed for up to 12 months. The primary endpoints were safety by assessment of adverse events. Secondary endpoints included assessment of kidney graft function, immunological and histological changes related to AMR activity and chronicity assessed by conventional microscopy and molecular transcripts. A total of 3 patients were enrolled in the study before it was terminated prematurely because of adverse events. We found that AMR did not improve in any of the patients after treatment with MSCs. In addition, serious adverse events were observed in one case when autologous MSCs therapy was administered in the late phase after kidney transplantation, which requires further elucidation.

Chronic active antibody mediated rejection (CAMR) is a therapeutic challenge in transplant recipients that does not respond well to conventional treatments for acute antibody mediated rejection (AMR). Annually, 5000 kidney transplants are lost in the United States due to CAMR. The two-year graft survival rate in CAMR is approximately 20%, highlighting the need for a more efficient therapy for CAMR and directly targeting donor specific antibody (DSA) producing cells and reducing CAMRThere is no established treatment for this problem. While many centers intensify and optimize the dosage of immunosuppressive drugs, treatments such as plasmapheresis, IVIG, and rituximab, although effective in treating AMR, have not been successful in reducing DSA or improving kidney graft survival in CAMR patients. Despite these treatments, two-year graft survival can increase up to 55%. The use of anti-plasma cell treatments like bortezomib has also yielded inconsistent results.

The study titled "Platelet Aggregation in the Diagnosis of Acute Graft Rejection" is a pilot observational study evaluating whether alterations in platelet function can serve as non-invasive markers of acute rejection in kidney transplant recipients. Platelet aggregation is assessed using optical aggregometry, flow-cytometric P-selectin (CD62-P) expression, and soluble P-selectin levels before kidney transplantation and at the time of protocol biopsies performed at 3 and 12 months after kidney transplantation. Patients with suspected graft dysfunction undergoing indication biopsy are also included. Platelet activation markers are correlated with histopathological findings, donor-specific antibodies, metabolic parameters, and clinical outcomes. The goal is to determine whether platelet activation profiles can identify acute cellular or antibody-mediated rejection and contribute to the development of a non-invasive diagnostic tool.

The goal of this observational study is to learn if the donor-derived cell-free DNA (dd-cfDNA) test can assess rejection in kidney transplant recipients. Participants will have blood and urine collected at their study visit. Researchers will compare results of the GraftAssureDx to rejection detected by standard-of-care graft biopsies.

This is an observational, prospective, multi-center trial designed to evaluate clinical outcomes in kidney transplant recipients undergoing TruGraf and TRAC monitoring. Approximately 15 U.S. sites

The goal of the Australian Genomics of Chronic Allograft Dysfunction (AUSCAD) study is a single centre (Westmead Hospital), prospective, observational study, which enrols patients at time of kidney (or kidney-transplant) transplant and tracks the post transplant course. The AUSCAD study aims to generate new knowledge and improve outcomes following kidney transplantation. The primary aim is to determine whether important outcomes (including chronic rejection and graft loss) are correlated with patterns of allograft reactivity, gene expression and susceptibility profiles.

This clinical trial investigates the transplantation of donor kidneys that have been genetically modified ex vivo using CRISPR-Cas9 genome editing to reduce immunogenicity and transplant rejection. Donor kidney grafts will have key human leukocyte antigen (HLA) genes disrupted - specifically, knockout of HLA class I heavy chains HLA-A and HLA-B, along with disabling HLA class II expression by targeting the CIITA gene (a master regulator of HLA-DR/DQ/DP). Approximately 90 adult end-stage renal disease patients will receive a CRISPR-edited donor kidney transplant. The primary objectives are to assess the safety and feasibility of this novel intervention, while secondary objectives evaluate the reduction in immune responses (immunogenicity), graft function, and the practicality of implementing ex vivo gene-edited organ transplantation in humans. By knocking out major donor HLA molecules, the trial aims to reduce T-cell and antibody-mediated recognition of the graft, potentially lowering rejection rates and reliance on high-dose immunosuppressants. Safety, including any off-target effects or unanticipated immune reactions, will be closely monitored, and transplant outcomes will be tracked for one year post-transplant.

Identification of a bacterial signature in the blood or stool that may be associated with acute rejection in patients treated with Nulojix during their first year of transplant.

The renal biopsy (RB) represents the gold-standard for the diagnosis of acute renal transplant rejection (AR), and allows early verification of a so-called "subclinical" rejection, ie without any clinical or biological abnormality detectable in a stable kidney transplant patient. The RB also makes it possible to certify a strictly normal renal histology and thus to motivate the withdrawal of corticosteroid therapy. It is this 3-month post-transplant protocol RB protocol that has been effective since 2007 at the CHU Liège. However, RB is an invasive procedure, contraindicated in patients taking anticoagulants, and carrying a significant risk of complications. The potential complications associated with RB motivate the identification and validation of other diagnostic means. In the present project, the investigators propose to study the relevance of positron emission tomography (PET), coupled with conventional tomography (CT), after intravenous injection of 18-fluoro-deoxy-glucose (18FDG) in the overall protocol of the renal transplant patient at 3 months post-transplant to: (i) allow protocol renal biopsy only in patients with suspicion of an acute rejection (ii) be a decision maker for withdrawal from corticosteroids in the absence of rejection In practice, the investigators suggest performing 18FDG PET / CT imaging on the day of the surveillance biopsy, which is systematically performed in all kidney transplant patients at University Hospital of Liège 3 months after transplant. The investigators are considering 3 scenarios: * Scenario 1. The renal biopsy shows signs of humoral rejection: the patient is excluded from the study and is treated "as usual" on the basis of the histological results. * Scenario 2. The renal biopsy does not show signs of humoral rejection but the 18FDG PET / CT shows a high metabolic activity of the graft (\> 2.4): the patient is treated "as usual" on the basis of histological findings. * Scenario 3. The renal biopsy does not show signs of humoral rejection and the 18FDG PET / CT shows a weak metabolic activity of the graft (\<2.4): the immunosuppressive treatment is gradually weaned off corticosteroids. This clinical research project is interested in a major health problem in the follow-up of renal transplant patients, and could make it possible to improve the management of a subclinical rejection of the renal transplant and to increase the withdrawal of corticosteroids including side effects are well known.

Investigator led, prospective, observational cohort study to detect genomic features which can predict outcomes following kidney transplantation. 1. Determine non-HLA genomic mismatches between donor-recipient pairs which impact kidney allograft survival following transplantation 2. Derive polygenic risk scores on pre-transplant blood and/or kidney biopsy samples which predict kidney allograft dysfunction 3. Derive polygenic risk scores on post-transplant blood and/or kidney biopsy samples which predict kidney allograft dysfunction

The ATDC-PICI study is a Phase Ib, single-arm, prospective, non-randomized, multicentric trial, to evaluate the safety of ATDC cell product as adjunctive therapy to standard of care (SOC) in highly sensitized kidney transplant recipients.

The purpose of this study is to assess a new test to detect antibodies which may form following kidney transplant. These antibodies can be difficult to detect as they do not cause any symptoms but can lead to kidney damage. A new blood test will be performed alongside existing antibody tests to see how well the test functions in comparison and to see how well it is able to distinguish between inflammation caused by antibodies and other sorts of inflammation such as a urinary tract infection. The investigators also want to determine whether it is predictable whom will develop antibodies after a transplant and use these results to change the current way patients are monitored for antibodies after receiving a transplant. In addition to this, the investigators want to establish if patients over 60 years of age are relatively protected against immunological events such as rejection compared to patients who are under 60 years of age. The results could potentially lead to using a different immunosuppression regime based on which population age group patients belong to and lowering the risks associated with these drugs.

Prospective, follow-up study of kidney transplant recipients treated with alemtuzumab anti-rejection therapy for severe or glucocorticoid-resistant kidney transplant rejection.

The purpose of this study was to explore the accuracy of sentinel skin grafts from the same donor source in diagnosing renal allograft rejection, and to provide new ideas and options for the later clinical diagnosis of renal allograft rejection. Further, try to provide timing guidance for early immunization intervention.