In kidney transplantation, ongoing alloimmune processes-commonly triggered by HLA incompatibilities-can trigger chronic transplant rejection, affecting the microcirculation and the tubulointerstitium. Continuous inflammation may lead to progressive, irreversible graft injury, culminating in graft dysfunction and accelerated transplant failure. Numerous experimental and translational studies have delineated a complex interplay of different immune mechanisms driving rejection, with antibody-mediated rejection (AMR) being an extensively studied rejection variant. In microvascular inflammation, a hallmark lesion of AMR, natural killer (NK) cells have emerged as pivotal effector cells. Their essential role is supported by immunohistologic evidence, bulk and spatial transcriptomics, and functional genetics. Despite significant research efforts, a substantial unmet need for approved rejection therapies persists, with many trials yielding negative outcomes. However, several promising therapies are currently under investigation, including felzartamab, a monoclonal antibody targeting the surface molecule CD38, which is highly expressed in NK cells and antibody-producing plasma cells. In an exploratory phase 2 trial in late AMR, this compound has demonstrated potential in resolving molecular and morphologic rejection activity and injury, predominantly by targeting NK cell effector function. These findings inspire hope for effective treatments and emphasize the necessity of further pivotal trials focusing on chronic transplant rejection.

Renal transplant recipients with donor-specific anti-HLA antibodies are at an increased risk of antibody-mediated rejection (ABMR). Early protocolized renal biopsies may serve as a strategy to improve diagnosis in this patient population.

We evaluated 155 highly sensitized renal transplant recipients with cPRA class I + II >90% pre-transplant from 2015 to 2022. Patients with protocol biopsies within the first 2 weeks post-transplant were included.

A total of 122 patients were included in the study. Of these, 13 (10.6%) were diagnosed with very early antibody-mediated rejection (veABMR) within the first 2 weeks post-transplant. This corresponds to 52% (13/25 patients) of all ABMR cases reported during the follow-up of this population. The graft survival rates at 1 and 3 years were significantly lower in patients with veABMR (P < .001) compared with patients without rejection in the early protocol biopsy. In terms of severity, the veABMR cohort exhibited a hazard ratio (HR) of 10.33 (95% confidence interval 3.23-33.06, P < .001) for graft failure. The presence of donor-specific antibodies class II on the day of transplantation and a higher percentage of eplet mismatch (EpMM), particularly EpMM DQA1, correlated with the development of veABMR.

Early protocol biopsies play a pivotal role in the early detection of veABMR in high-risk immunological patients. Patients with veABMR face significant risks of graft loss, despite early treatment of rejection.

Background: Artificial intelligence is rapidly advancing within the domains of medicine and transplantology. In this comprehensive review, we provide an in-depth exploration of current AI methodologies, with a particular emphasis on machine learning and deep learning techniques, and their diverse subtypes. These technologies are revolutionizing how data are processed, analyzed, and applied in clinical decision making. Methods: A meticulous literature review was conducted with a focus on the application of artificial intelligence in kidney transplantation. Four research questions were formulated to establish the aim of the review. Results: We thoroughly examined the general applications of AI in the medical field, such as feature selection, dimensionality reduction, and clustering, which serve as foundational tools for complex data analysis. This includes the development of predictive models for transplant rejection, the optimization of personalized immunosuppressive therapies, the algorithmic matching of donors and recipients based on multidimensional criteria, and the sophisticated analysis of histopathological images to improve the diagnostic accuracy. Moreover, we present a detailed comparison of existing AI-based algorithms designed to predict kidney graft survival in transplant recipients. In this context, we focus on the variables incorporated into these predictive models, providing a critical analysis of their relative importance and contribution to model performance. Conclusions: This review highlights the significant advancements made possible through AI and underscores its potential to enhance both clinical outcomes and the precision of medical interventions in the field of transplantology.

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.

Blockade of interleukin-6 (IL-6) has emerged as a promising therapeutic option for antibody-mediated rejection. Subtherapeutic anti-IL-6 antibody level or treatment cessation following prolonged cytokine neutralization may result in proinflammatory rebound phenomena via accumulation of IL-6 and/or modulated gene expression of major components of the IL-6/IL-6 receptor (IL-6R) axis.

We evaluated biologic material obtained from a randomized controlled, double-blind phase 2 trial designed to evaluate the safety and efficacy of the anti-IL-6 monoclonal antibody clazakizumab in late antibody-mediated rejection. Twenty kidney transplant recipients, allocated to clazakizumab or placebo, received 4-weekly doses over 12 wks, followed by a 40-wk extension where all recipients received clazakizumab. Serum proteins were detected using bead-based immunoassays and RNA transcripts using quantitative real-time polymerase chain reaction (peripheral blood) or microarray analysis (serial allograft biopsies).

Clazakizumab treatment resulted in a substantial increase in median total (bound and unbound to drug) serum IL-6 level (1.4, 8015, and 13 600 pg/mL at 0, 12, and 52 wks), but median level of free (unbound to drug) IL-6 did not increase (3.0, 2.3, and 2.3 pg/mL, respectively). Neutralization of IL-6 did not boost soluble IL-6R or leukocyte or allograft expression of IL-6, IL-6R, and glycoprotein 130 mRNA. Cessation of treatment at the end of the trial did not result in a meaningful increase in C-reactive protein or accelerated progression of graft dysfunction during 12 mo of follow-up.

Our results argue against clinically relevant rebound phenomena and modulation of major components of the IL-6/IL-6R axis following prolonged IL-6 neutralization with clazakizumab.

Antibody-mediated rejection (ABMR) is a leading cause of kidney allograft failure. Its therapy continues to be challenge, and no treatment has been approved for the market thus far.

In this article, we discuss the pathophysiology and phenotypic presentation of ABMR, the current level of evidence to support the use of available therapeutic strategies, and the emergence of tailored drugs now being evaluated in systematic clinical trials. We searched PubMed, Clinicaltrials.gov and Citeline's Pharmaprojects for pertinent information on emerging anti-rejection strategies, laying a focus on phase II and III trials.

Currently, we rely on the use of apheresis for alloantibody depletion and intravenous immunoglobulin (referred to as standard of care), preferentially in early active ABMR. Recent systematic trials have questioned the benefits of using the CD20 antibody rituximab or the proteasome inhibitor bortezomib. However, there are now several promising treatment approaches in the pipeline, which are being trialed in phase II and III studies. These include interleukin-6 antagonism, CD38-targeting antibodies, and selective inhibitors of complement. On the basis of the information that has emerged so far, it seems that innovative treatment strategies for clinical use in ABMR may be available within the next 5-10 years.

Due to the optimal results obtained in kidney transplantation and to the lack of interest of the industries, new innovative drugs in kidney transplantation are difficult to be encountered. The best strategy to find the new drugs recently developed or under development is to search in the sections of kidney transplantation still not completely covered by the drugs on the market. These unmet needs are the prevention of delayed graft function (DGF), the protection of the graft over the long time and the desensitization of preformed anti human leukocyte antigen antibodies and the treatment of the acute antibody-mediated rejection. These needs are particularly relevant due to the expansion of some kind of kidney transplantation as transplantation from non-heart beating donor and in the case of antibody-incompatible grafts. The first are particularly exposed to DGF, the latter need a safe desensitization and a safe treatments of the antibody mediated rejections that often occur. Particular caution is needed in treating these drugs. First, they are described in very recent studies and the follow-up of their effect is of course rather short. Second, some of these drugs are still in an early phase of study, even if in well-conducted randomized controlled trials. Particular caution and a careful check need to be used in trials launched 2 or 3 years ago. Indeed, is always necessary to verify whether the study is still going on or whether and why the study itself was abandoned.

Antibody-mediated rejection (AMR) is one of the leading causes of graft loss in kidney transplant recipients but little is known about the associated cost and healthcare burden of AMR.

We developed an algorithm to detect AMR using the 2006-2011 Centers for Medicare & Medicaid Services (CMS) using ICD-10 and billing codes as there is no specific ICD-10 or procedure code for AMR. We then compared healthcare utilization, cost, and risk of graft failure or death in AMR. patients versus matched controls.

The algorithm had a 39.4% true-positive rate (69/175) and a 4.1% false-positive rate (110/2,655). We identified 5,679/101,554 (5.6%) with AMR, who had a nearly 3-fold higher risk of graft failure (hazard ratio [HR], 2.75, 95% confidence interval [CI], 2.50 to 3.03; p < .0001) and death (HR, 2.59; 95% CI, 2.35 to 2.86; p < .0001) at 2 years, nearly 5 times the hospitalizations in the 60 d before AMR diagnosis, and increased nephrology and emergency department visits. Mean AMR attributable healthcare costs were 4 times higher than matched controls, at $13,066 more per patient in the 60 d before AMR diagnosis and $35,740 per patient per year higher in the 2 years after AMR diagnosis.

US kidney transplant recipients with AMR have substantially greater healthcare utilization and higher costs and risk of graft loss and mortality.