Changing of therapeutic trends between the 1st and 2nd wave did not reduce COVID-19 related mortality of renal transplant recipients: a national registry study.

SARS-CoV-2 pandemic evolved in two consecutive waves over 2020 (for France: 1st wave from March 1 to July 31; and 2nd wave from August 1 to December 31). Improvements in the management of COVID-19 led to a reduction of mortality rates in hospitalized patients during the second wave. Whether this progress also benefited to kidney transplant recipients (KTR), a population particularly vulnerable to severe COVID-19, remained unclear. In France, 957 KTR were hospitalized for COVID-19 in 2020 and their data were prospectively collected in the French SOT COVID registry. The presentation, management, and outcomes of the 359 KTR diagnosed during the 1st wave were compared to those of the 598 of the 2nd wave. Baseline comorbidities were largely similar between KTR of the 2 waves. Maintenance immunosuppression was reduced in most patients but withdrawal of antimetabolite (73.7% vs 58.4%, p<0.001) or CNI (32.1% vs 16.6%, p<0.001) was less frequent during the 2nd wave. Hydroxychloroquine and azithromycin that were commonly used during the 1st wave (21.7% and 30.9%, respectively) were almost abandoned during the 2nd. In contrast, the use of high dose corticosteroids doubled (19.5% vs. 41.6%, p<0.001). Despite these changing trends in COVID-19 management, 60-day mortality was not statistically different between the 2 waves (25.3% vs. 23.9%; Log Rank, p=0.48). We conclude that changing of therapeutic trends during 2020 did not reduce COVID-19 related mortality in KTR. Our data indirectly support the importance of vaccination and monoclonal neutralizing anti-SARS-CoV-2 antibodies to protect KTR from severe COVID-19.

Immunosuppression as a Risk Factor for De Novo Angiotensin II Type Receptor Antibodies Development after Kidney Transplantation

(1) Background: Angiotensin II type I receptor antibodies (AT1R-Ab) represent a topic of interest in kidney transplantation (KT). Data regarding the risk factors associated with de novo AT1R-Ab development are lacking. Our goal was to identify the incidence of de novo AT1R-Ab at 1 year after KT and to evaluate the risk factors associated with their formation. (2) Methods: We conducted a prospective cohort study on 56 adult patients, transplanted between 2018 and 2019. Recipient, donor, transplant, treatment, and complications data were assessed. A threshold of >10 U/mL was used for AT1R-Ab detection. (3) Results: De novo AT1R-Ab were observed in 12 out of 56 KT recipients (21.4%). The median value AT1R-Ab in the study cohort was 8.5 U/mL (inter quartile range: 6.8–10.4) and 15.6 U/mL (10.8–19.8) in the positive group. By multivariate logistic regression analysis, induction immunosuppression with anti-thymocyte globulin (OR = 7.20, 95% CI: 1.30–39.65, p = 0.02), maintenance immunosuppression with immediate-release tacrolimus (OR = 6.20, 95% CI: 1.16–41.51, p = 0.03), and mean tacrolimus trough level (OR = 2.36, 95% CI: 1.14–4.85, p = 0.01) were independent risk factors for de novo AT1R-Ab at 1 year after KT. (4) Conclusions: De novo AT1R-Ab development at 1 year after KT is significantly influenced by the type of induction and maintenance immunosuppression.

Induction of Immune Tolerance in Islet Transplantation Using Apoptotic Donor Leukocytes

Allogeneic islet transplantation has become an effective treatment option for severe Type 1 diabetes with intractable impaired awareness due to hypoglycemic events. Although current immunosuppressive protocols effectively prevent the acute rejection associated with initial T cell activation in recipients, chronic rejection has remained an obstacle for achieving long-term allogeneic islet engraftment. The development of donor-specific immune tolerance to the allograft is the ultimate goal given its potential ability to overcome chronic rejection and disregard the need for maintenance immunosuppression, which may be toxic to islet grafts. Recently, a breakthrough in tolerance induction during allogeneic islet transplantation using apoptotic donor lymphocytes (ADLs) in a non-human primate model had been reported. Several studies have suggested that the clonal depletion, anergy, and expansion of the antigen-specific regulatory immune network are the mechanisms for donor-specific tolerance with ADLs, which act synergistically to induce robust transplant tolerance. This achievement represents a huge step forward toward the clinical application of immune tolerance induction. We herein summarize the reported operational induction therapies in islet transplantation using the ADLs. Moreover, a few obstacles for the engraftment of transplanted islets, such as islet immunogenicity and instant blood-mediated response, which need to be resolved in the future, are also discussed.

Belatacept Use after Kidney Transplantation and Its Effects on Risk of Infection and COVID-19 Vaccine Response

Introduction: Belatacept is a common immunosuppressive therapy used after kidney transplantation (KT) to avoid calcineurin-inhibitor (CNI) use and its related toxicities. It is unclear whether its use exposes KT recipients (KTx) to a greater risk of infection or a poorer response to vaccines. Areas covered: We reviewed PubMed and the Cochrane database. We then summarized the mechanisms and impacts of belatacept use on the risk of infection, particularly opportunistic, in two settings, i.e., de novo KTx and conversion from CNIs. We also focused on COVID-19 infection risk and response to SARS-Cov-2 vaccination in patients whose maintenance immunosuppression relies on belatacept. Expert opinion: When belatacept is used de novo, or after drug conversion the safety profile regarding the risk of infection remains good. However, there is an increased risk of opportunistic infections, mainly CMV disease and Pneumocystis pneumonia, particularly in those with a low eGFR, in older people, in those receiving steroid-based therapy, or those that have an early conversion from CNI to belatacept (i.e., <six months post-transplantation). Thus, we recommend, if possible, delaying conversion from CNI to belatacept until at least six months post-transplantation. Optimal timing seems to be eight months post-transplantation. In addition, KTx receiving belatacept respond poorly to SARS-CoV-2 vaccination.

Conversion from Calcineurin Inhibitor– to Belatacept-Based Maintenance Immunosuppression in Renal Transplant Recipients: A Randomized Phase 3b Trial

BackgroundCalcineurin inhibitors (CNIs) are standard of care after kidney transplantation, but they are associated with nephrotoxicity and reduced long-term graft survival. Belatacept, a selective T cell costimulation blocker, is approved for the prophylaxis of kidney transplant rejection. This phase 3 trial evaluated the efficacy and safety of conversion from CNI-based to belatacept-based maintenance immunosuppression in kidney transplant recipients.MethodsStable adult kidney transplant recipients 6–60 months post-transplantation under CNI-based immunosuppression were randomized (1:1) to switch to belatacept or continue treatment with their established CNI. The primary end point was the percentage of patients surviving with a functioning graft at 24 months.ResultsOverall, 446 renal transplant recipients were randomized to belatacept conversion (n=223) or CNI continuation (n=223). The 24-month rates of survival with graft function were 98% and 97% in the belatacept and CNI groups, respectively (adjusted difference, 0.8; 95.1% CI, −2.1 to 3.7). In the belatacept conversion versus CNI continuation groups, 8% versus 4% of patients experienced biopsy-proven acute rejection (BPAR), respectively, and 1% versus 7% developed de novo donor-specific antibodies (dnDSAs), respectively. The 24-month eGFR was higher with belatacept (55.5 versus 48.5 ml/min per 1.73 m2 with CNI). Both groups had similar rates of serious adverse events, infections, and discontinuations, with no unexpected adverse events. One patient in the belatacept group had post-transplant lymphoproliferative disorder.ConclusionsSwitching stable renal transplant recipients from CNI-based to belatacept-based immunosuppression was associated with a similar rate of death or graft loss, improved renal function, and a numerically higher BPAR rate but a lower incidence of dnDSA.Clinical Trial registry name and registration number: A Study in Maintenance Kidney Transplant Recipients Following Conversion to Nulojix® (Belatacept)-Based, NCT01820572

Structural and functional markers of optic nerve damage in myelin oligodendrocyte glycoprotein antibody-associated optic neuritis

Background Optic neuritis (ON) occurs in immune-mediated disorders including multiple sclerosis (MS), aquaporin-4 antibody-positive (AQP4) neuromyelitis optica spectrum disorder (AQP4-NMOSD) and myelin oligodendrocyte glycoprotein (MOG) antibody-associated demyelination (MOGAD). Accurate determination of aetiology is critical for appropriate treatment and prognostication. Objective To evaluate demyelination and axonal loss in MOG-ON to facilitate differentiation from MS-ON and AQP4-ON. Methods 15 MOGAD patients with previous ON (25 eyes) underwent multifocal visual evoked potential (mfVEP) recordings and optical coherence tomography scans. Comparison was made to previously reported MS patients ( n = 67, 69 eyes) and AQP4-NMOSD patients ( n = 15, 23 eyes) with prior ON and healthy controls ( n = 37, 74 eyes). Results MOG-ON patients had less retinal nerve fibre layer (RNFL) loss than AQP4-ON patients ( p < 0.05) and less mfVEP latency prolongation than MS-ON patients ( p < 0.01). Number of ON episodes in MOGAD was associated with reduced RNFL thickness (global, p = 0.07; temporal, p < 0.001) and mfVEP amplitude ( p < 0.001). There was no abnormality in non-ON eyes. Conclusions Our study demonstrated a distinct pattern of damage in MOG-ON compared to AQP4-ON and MS-ON. ON in MOGAD produces less axonal loss than AQP4-NMOSD. Damage accumulates with relapses, supporting the role of maintenance immunosuppression to induce remission. Compared to MS, MOGAD causes less demyelination.

Belatacept for Simultaneous Calcineurin Inhibitor and Chronic Corticosteroid Immunosuppression Avoidance

Immunosuppressive therapy in kidney transplantation is associated with numerous toxicities. CD28-mediated T cell costimulation blockade using belatacept may reduce long-term nephrotoxicity, compared with calcineurin inhibitor-based immunosuppression. The efficacy and safety of simultaneous calcineurin inhibitor avoidance and rapid steroid withdrawal were tested in a randomized, prospective, multi-center study. MethodsAll kidney transplants were performed using rapid steroid withdrawal immunosuppression. Recipients were randomized to 1:1:1 to receive belatacept with alemtuzumab induction, belatacept with rabbit antithymocyte globulin (rATG) induction, or tacrolimus with rATG induction. The composite endpoint consisted of death, kidney allograft loss, or an MDRD calculated eGFR of <45 ml/min/1.73m2 at 2 years. ResultsThe composite endpoint was observed for 11/107 (10%) participants assigned to belatacept/alemtuzumab, 13/104 (13%) assigned to belatacept /rATG, and 21/105 (21%) assigned to tacrolimus/rATG (belatacept/alemtuzumab vs tacrolimus/rATG p = 0.99: belatacept/rATG vs tacrolimus/rATG p = 0.66). Patient and graft survival rates were similar between all groups. eGFR <45 ml/min/1.73m2 was observed for 9/107 (8%) participants assigned to belatacept/alemtuzuab, 8/104 (8%) participants assigned to belatacept/rATG, and 20/105 (19%) participants assigned to tacrolimus/rATG (p<0.05 for each belatacept group vs tacrolimus/rATG). Biopsy-proven acute rejection was observed for 20/107 (19%) participants assigned to belatacept/alemtuzuab, 26/104 (25%) participants assigned to belatacept/rATG, and 7/105 (7%) participants assigned to tacrolimus/rATG (belatacept/alemtuzumab vs tacrolimus/rATG p = 0.006: belatacept/rATG vs tacrolimus/rATG p < 0.001). Gastrointestinal and neurologic adverse events were less frequent with belatacept versus calcineurin based immunosuppression. ConclusionsOverall two-year outcomes were similar comparing maintenance immunosuppression based on belatacept versus tacrolimus, each protocol with rapid steroid withdrawal. The incidence of eGFR <45 ml/min/1.73m2 was significantly lower but the incidence of biopsy proven acute rejection significantly higher with belatacept compared with tacrolimus.