Belatacept is a fusion protein composed of the heavy chain constant region of human IgG1 linked to the extracellular domain of human cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) that selectively inhibits T-cell activation through costimulation blockade. Since its approval by the U.S. Food and Drug Administration and the European Medicines Agency in 2011, belatacept has become widely used in kidney transplantation as an alternative to calcineurin inhibitors (CNIs) for maintenance immunosuppression [1, 2]. Belatacept is used as a de novo immunosuppressive therapy after kidney transplantation, but also as a conversion from calcineurin inhibitors [1, 2] in cases of CNI toxicity and/or side effects [3]. Belatacept should be administered intravenously every month under the supervision of a healthcare provider.

Coronavirus disease 2019 (COVID-19) has been particularly deleterious in kidney transplant recipients (KTRs), with a very high risk of severe disease associated with a high mortality rate [4, 5]. During the first wave of the pandemic, a lockdown order came into effect in France on 17 March 2020. Immunocompromised patients were asked to isolate themselves and outpatient clinic visits were dramatically reduced. Patients who have converted to belatacept for CNI toxicity are suspected to be at high risk of opportunistic infections [6, 7]. In order to avoid frequent clinic visits by belatacept-treated KTRs and prevent SARS-CoV-2 contamination during the initial pandemic period, and also to release some institutional resources to care for COVID-19-infected KTRs, we searched for a temporary alternative solution to monthly administration of belatacept. CNI conversion appeared to be a safer option because i) patients could take their treatment orally at home; ii) most of them had previously received tacrolimus or cyclosporine before belatacept conversion; and iii) CNIs significantly reduce acute rejection rates. However, this solution was not generalizable to all of our patients, due to some having a low estimated glomerular filtration rate (eGFR) or history of CNI toxicity and/or intolerance [8].

Abatacept is also genetically constructed by fusion of the external domain of human CTLA-4 to the heavy chain constant region of human IgG1. This drug was the predecessor of its higher-affinity evolution, belatacept, which was engineered to contain two amino acid substitutions to bind its ligands CD80 and CD86 with greater potency for use in kidney transplantation. Abatacept was approved by the Food and Drug Administration for use in adults with rheumatoid arthritis in 2005 [9] and in children with juvenile idiopathic arthritis in 2008 [10], and it can be used intravenously or subcutaneously [11]. Data on the use of abatacept after kidney transplantation are very scarce, but the results of a preclinical study using a primate kidney transplant model [12] and of a small report on nine patients [13] seemed reassuring.

Considering these results, and replicating the protocol used for rheumatoid arthritis [11], we believed that once-weekly subcutaneous injection of abatacept could be a safe, effective, and logistically feasible alternative to belatacept during the COVID-19 pandemic. Here, we report on a cohort of patients from two transplant centers who received abatacept during the initial stay-at-home order in France. Our aim was to assess short-term graft and patient outcomes, kidney allograft function, immunological features, and tolerance and safety of abatacept maintenance to provide a rationale for belatacept avoidance in the event of a prolonged crisis, and as an alternative in KTRs with problematic vascular access; these findings have even greater relevance in the current period of belatacept shortage.

To the best of our knowledge, we report here for the first time in a large cohort of KTRs the feasibility, safety, and efficacy of conversion from once-monthly intravenous infusion of belatacept to once-weekly subcutaneous injection of abatacept as a maintenance immunosuppression regimen. Tolerance was excellent and side effects were very uncommon in this fragile population. eGFR remained stable during the follow-up period, and cases of biopsy-proven TCMR after abatacept conversion were rare (1.1%). In comparison, conversion from belatacept to another immunosuppressive treatment in cases of CNI toxicity or intolerance is associated with a decrease in eGFR, as recently reported by [8]. In this cohort of 44 KTRs from five French transplantation centers, who were converted from maintenance belatacept to another regimen because of a complication (n = 28), by patient request, or due to belatacept shortage (n = 13), mean eGFR decreased from 44.2 ± 16 mL/min per 1.73 m² at conversion from belatacept to 35.7 ± 18.4 mL/min per 1.73 m² at last follow-up (p = 0.0002). Of note, eGFR decreased more severely in patients who were converted to CNIs.

As an alternative approach, we could have increased the spacing of the belatacept injections from 4 to 8 weeks, as reported by [16]; however, although the result was not statistically significant, rates of BPAR were twofold higher in patients administered belatacept every 8 weeks vs. every 4 weeks. Another alternative would have been to pursue in-hospital belatacept infusions with a specific infection control protocol, as reported by Kamar et al. [17]. Nevertheless, these measures were very restrictive and time-consuming, and they did not fully rule out the risk of nosocomial transmission of SARS-CoV-2. Our in-home attitude is also retrospectively supported by the low humoral and cellular immunogenicity induced by SARS-CoV-2 vaccination in belatacept-treated KTRs [18, 19], related to their profoundly immunocompromised condition and to their high risk of opportunistic infection [6, 7] and severe COVID-19.

Data on the use of abatacept after kidney transplantation are very scarce. Abatacept is a genetically constructed by fusion of the external domain of human CTLA-4 to the heavy chain constant region of human IgG1. This drug was the predecessor of its higher-affinity variant belatacept, which was engineered to contain two amino acid substitutions to bind its ligands CD80 and CD86 with greater potency for use in kidney transplantation. Apprehension toward its use after kidney transplantation is therefore related to its supposedly insufficient immunosuppressive capacity. The data reported in the present study are quite reassuring, with a low risk of rejection when abatacept is used in a conversion protocol beyond the first 6 months after kidney transplant. Although preclinical non-human primate (NHP) studies have shown superior results with belatacept in a kidney transplant model [20], abatacept has also exhibited efficacy in a kidney transplant model [12], as well as in an NHP allogeneic islet transplant model, as a de novo monotherapy or in combination with CD154‐ specific blockade [21]. It has also since been effectively used in the clinical setting to treat rheumatoid arthritis and, more recently, other autoimmune disorders [9]. While belatacept may be indeed more potent and the preclinical data on abatacept warrant caution regarding its immunosuppressive strength for the purpose of inhibiting alloreactivity, preclinical data from murine and primate models alike have proven not to be entirely predictive of clinical outcomes or directly translatable to humans [22]. Abatacept has been used after kidney transplantation for recurrence of focal and segmental glomerulosclerosis [23], but most publications are case reports [24, 25] and its effectiveness is widely debated [26, 27]. Recently; [13], have reported on a series of 9 CNI‐intolerant transplant recipients who were converted to abatacept early after transplant as a form of rescue immunosuppression during periods of belatacept shortage. A retrospective review revealed successful allograft salvage and 100% patient and graft survival (median 115 months) after conversion to abatacept. Patients received intravenous abatacept for a median duration of 82 months with stable, long‐term renal allograft function, a single cellular rejection episode, and no clinically apparent protective immunity concerns. Furthermore, CD86 receptor saturation levels (a pharmacodynamic measure of costimulation blockade proposed to correlate with inhibition of alloresponses [28]) did not differ between belatacept‐ and abatacept-treated patients tested after infusion. Although abatacept was originally formulated as an infusion, it is now available in a subcutaneous formulation, which has equal safety and efficiency in rheumatoid arthritis patients [11]. Nevertheless, only one patient was treated with once-weekly subcutaneous injections of abatacept, although this patient was treated under this regimen for 16 months without complications. Very recently, Uro-Coste et al. reported their experience with abatacept injection in 5 KTRs, suggesting that weekly subcutaneous administration of 125 mg abatacept may be an effective alternative to belatacept [29]. The data presented here on the use of subcutaneous injection of abatacept in a large cohort could be very useful for patients with CNI toxicity or intolerance and in need of conversion to belatacept but with poor vascular access, like many end-stage renal disease patients. This approach could also represent a solution in cases of belatacept shortage. Costimulation blockade with abatacept could potentially have a logistical advantage over belatacept in kidney transplant recipients. Nevertheless, our niche experience over 3 months does not allow us to make definitive assertions as to the potential benefits mentioned above.

Our work has several limitations. The short duration of our follow-up period (3 months) prevents us from drawing a firm conclusion on the risks of rejection and infection in patients treated with abatacept as a maintenance therapy. Nevertheless, the median half-life of belatacept is reported to be 8 days (range: 3.1–11.9) [30], and the very low incidence of TCMR during the weeks following abatacept initiation can be taken into account and is quite reassuring. Because of the ethical issues related to data scarcity on abatacept safety, and the possibility of in-home belatacept infusion, we could not accept the risk of continuing to pursue abatacept therapy once the first wave of SARS-CoV-2 had ended. The absence of a control group receiving ongoing belatacept injection is also problematic. However, our main goal was to avoid frequent hospital visits by immunocompromised KTRs during the initial period of the SARS-CoV-2 pandemic. Under these conditions, we chose to treat as many patients as possible with abatacept. A clinical trial NCT04955366 (https://clinicaltrials.gov/) was developed to answer the question of whether patients can be safely converted from monthly belatacept IV infusions to subcutaneous abatacept injections without a decrease in kidney function. The results of this study will be available in late 2024 or in 2025. In the meantime, the message of our work is not to treat all belatacept-converted patients with subcutaneous abatacept, as reflected by the questionnaire completed by the patients: 49% preferred in-hospital belatacept, and 43% did not find that abatacept was less restrictive than belatacept. Nevertheless, we would like to point out that before the COVID-19 pandemic, all patients on belatacept were receiving infusions in hospital. As a result of these treatment sessions, they were closely monitored on a monthly basis. The pandemic has taken patients away from the hospital, making them very anxious at times and most probably explaining the rather low acceptance rates and the rather high discontinuation rate over this short period. In this context of in-home subcutaneous abatacept injection, close monitoring with, for example, regular blood draws or regular teleconsultation could be reassuring for patients and represent an additional safety measure.

In conclusion, our study demonstrates for the first time, in a large cohort of belatacept-treated KTRs, that once-weekly injection of abatacept, used as a rescue therapy, appears to be feasible, safe, and effective in the short term (3 months). The current context of belatacept shortage makes this report even more important.