UNASSIGNED: Imlifidase, the IgG-degrading enzyme derived from Streptococcus pyogenes, can cleave all four human IgG subclasses with precise specificity. All IgG molecules can be inactivated for ~1-to-2 weeks, until new IgG synthesis is detected.
UNASSIGNED: Imlifidase was first studied for the desensitization of highly HLA-sensitized patients to enable kidney transplantation. It is currently being evaluated for kidney transplant recipients who have antibody-mediated rejection (AMR), those with acute kidney injury in the setting of anti-glomerular basement membrane disease, and those with Guillain-Barré syndrome. In 2020, imlifidase received conditional approval from the European Medicines Agency for use to desensitize deceased-donor kidney transplant recipients with a positive crossmatch. Literature search through PubMed revealed that so far, 39 crossmatched-positive patients, i.e. in the presence of donor-specific alloantibodies (DSA) on the transplantation day, have received imlifidase prior to kidney transplantation in four single-arm, open-label, phase II studies. Results at 3-year follow-up are good, i.e. allograft survival is 84%, despite 38% of patients presenting with acute AMR. Mean estimated glomerular filtration rate at 3 years was 55 mL/min/1.73 m2.
UNASSIGNED: The major hurdle now is how to prevent/avoid DSA rebound within days 5-15 post-transplantation. Thus, imlifidase represents a major breakthrough for highly HLA-sensitized kidney transplant candidates, particularly those that have calculated panel-reactive alloantibodies of ≥90%.

Advances in hematopoietic stem cell transplant (HSCT) have led to changes in the approach to donor selection. Many of these new approaches result in greater HLA loci mismatching, either through the selection of haploidentical donors or permissive HLA mismatches. Although these approaches increase the potential of transplant for many patients by expanding the number of acceptable donor HLA genotypes, they add the potential barrier of donor-specific HLA antibodies (DSA). DSA presents a unique challenge in HSCT, as it can limit engraftment and lead to graft failure. However, transient reduction of HLA antibodies through desensitization treatments can limit the risk of graft failure and facilitate engraftment. Thus, the consideration of DSA in donor selection and the management of DSA prior to transplant are playing an increasingly important role in HSCT. In this review, we will discuss studies addressing the role of HLA antibodies in HSCT, the reported impact of desensitization on DSA levels, and the implications for selecting donors for patients with DSA. We found that there is a clear consensus that moderate strength DSA should be avoided, while desensitization strategies are reported to be effective in most cases at reducing DSA to amenable levels. There is limited information regarding the impact of specific characteristics of DSA, such as HLA loci or overall level of sensitization, which could further aid in donor selection for sensitized HSCT candidates.

Chronic kidney disease (CKD) is a major public-health problem that increases the risk of end-stage kidney disease (ESKD), cardiovascular diseases, and other complications. Kidney transplantation is a renal-replacement therapy that offers better survival compared to dialysis. Antibody-mediated rejection (ABMR) is a significant complication following kidney transplantation: it contributes to both short- and long-term injury. The standard-of-care (SOC) therapy combines plasmapheresis and Intravenous Immunoglobulins (IVIg) with or without steroids, with or without rituximab: however, despite this combined treatment, ABMR remains the main cause of graft loss. IL-6 is a key cytokine: it regulates inflammation, and the development, maturation, and activation of T cells, B cells, and plasma cells. Tocilizumab (TCZ) is the main humanized monoclonal aimed at IL-6R and appears to be a safe and possible strategy to manage ABMR in sensitized recipients. We conducted a literature review to assess the place of the anti-IL-6R monoclonal antibody TCZ within ABMR protocols.
We systematically reviewed the PubMed literature and reviewed six studies that included 117 patients and collected data on the utilization of TCZ to treat ABMR.
Most studies report a significant reduction in levels of Donor Specific Antibodies (DSAs) and reduced inflammation and microvascular lesions (as found in biopsies). Stabilization of the renal function was observed. Adverse events were light to moderate, and mortality was not linked with TCZ treatment. The main side effect noted was infection, but infections did not occur more frequently in patients receiving TCZ as compared to those receiving SOC therapy.
TCZ may be an alternative to SOC for ABMR kidney-transplant patients, either as a first-line treatment or after failure of SOC. Further randomized and controlled studies are needed to support these results.

Antibody-mediated rejection (ABMR) at early or late post-transplantation remains challenging. We performed a single-center single-arm study where four cases of acute ABMR and nine cases of chronic active ABMR (defined by Banff classification) were treated with double-filtration plasmapheresis (two cycles of three consecutive daily sessions with a 4-day gap between). At the end of the third and sixth DFPP sessions, the patients received rituximab 375 mg/m2 . After a median follow-up of 1078 (61-1676) days, kidney-allograft survival was 50%. Before DFPP/rituximab therapy, the median donor-specific alloantibody (DSA) mean fluorescence intensity (MFI) was 9160 (4000-15 400); 45 days (D45) later it had significantly decreased to 7375 (215-18 100) (P = .018). In addition, at one-year (Y1) post-therapy, MFI had decreased further, that is, 4060 (400-7850) (P = .001). In two patients, DSA MFIs decreased and remained below 2000. The slope of estimated glomerular-filtration rate within the 6 months preceding intervention was -1.18 mL/min/month and remained unchanged at -1.29 mL/min/month within the year after intervention. Proteinuria remained unchanged. Baseline Banff scores on repeat allograft biopsies (post-therapy D45, Y1) did not show any improvement. Side-effects were mild to moderate. We conclude that the combined DFPP/rituximab significantly decreased DSAs in ABMR kidney-transplant recipients but did not improve renal function or renal histology at 1-year follow-up.

​Introduction: As tolerance is not yet achievable, the kidney-transplanted-patients have to take on a daily-basis immunosuppressive drugs in order to avoid acute rejection-AR-. The cornerstone of immunosuppression relies on tacrolimus-therapy which is potentially nephrotoxic. Areas Covered: We identified from the studies published in the recent years those who were reporting on AR in de novo kidney-transplant recipients under tacrolimus-based therapy, as well as those who reported on the attempt to minimize tacrolimus-therapy.
RESULTS: There are many formulations of tacrolimus: immediate-release (Prograf®), slow-release (Advagraf®), or extended-release (Envarsus®). All demonstrate a very good efficacy in preventing AR episodes. Studies in which tacrolimus was minimized or even weaned-off have shown that it was unsafe, i.e. in resulting in AR episode and/or de novo donor-specific alloantibodies. Recent data show that Tacrobell®, a generic of tacrolimus, was as efficient as Prograf® in the short- and long-term. Expert-opinion: Tacrolimus-based immunosuppression is very effective in preventing rejection in kidney-transplant recipients. It might be associated with nephrotoxicity, that can be reduced by avoiding tacrolimus trough levels too high in the long-term. Conversely, tacrolimus ultraminimization should not be attempted.

Chronic rejection in renal transplantation clinically manifests as slow deterioration in allograft function and is a major contributor of late renal graft loss. Most cases of chronic rejection involve chronic antibody-mediated rejection (ABMR) triggered by the interaction of donor-specific alloantibodies with endothelial cells of the microcirculation. The evolution of the Banff classification involved a major revision of the ABMR criteria during the 2000s and led to the inclusion of detailed pathological characteristics of chronic ABMR in the 2013 Banff scheme, including microcirculation damage observed as newly formed basement membranes and arterial fibrous intimal proliferation. Inflammation of microvasculature including glomeruli and/or peritubular capillaries is also seen in substantial cases of chronic ABMR, defined as chronic active ABMR. Chronic active T cell-mediated rejection (TCMR) results from chronic T cell-mediated injury involving renal arteries but is less characterized under the current Banff classification, mainly due to the expanding histological criteria of chronic active ABMR. Characteristics shared by these two chronic rejection types can potentially cause diagnostic confusion. Hence, the diagnostic criteria or categories of chronic renal rejection require amendment of the current Banff classification. Assessment of rejection cases with molecular phenotyping advanced the mechanistic understanding of various dysfunctions in renal allograft, including ABMR and TCMR. Identification of disease-specific changes in gene expression by immunohistological studies, especially in chronic ABMR, has already been validated by several studies, warranting potential application to the pathological diagnostic process. This review provides an overview of current pathological perspectives on chronic rejection of renal allografts and future directions.