Introduction: Kidney transplantation stands out as the optimal treatment for patients with end-stage kidney disease, provided they meet specific criteria for a secure outcome. With the exception of identical twin donor–recipient pairs, lifelong immunosuppression becomes imperative. Unfortunately, immunosuppressant drugs, particularly calcineurin inhibitors like tacrolimus, bring about adverse effects, including nephrotoxicity, diabetes mellitus, hypertension, infections, malignancy, leukopenia, anemia, thrombocytopenia, mouth ulcers, dyslipidemia, and wound complications. Since achieving tolerance is not feasible, patients are compelled to adhere to lifelong immunosuppressive therapies, often involving calcineurin inhibitors, alongside mycophenolic acid or mTOR inhibitors, with or without steroids. Area covered: Notably, these drugs, especially calcineurin inhibitors, possess narrow therapeutic windows, resulting in numerous drug-related side effects. This review focuses on the prevalent immunosuppressive drug-related side effects encountered in kidney transplant recipients, namely nephrotoxicity, post-transplant diabetes mellitus, leukopenia, anemia, dyslipidemia, mouth ulcers, hypertension, and viral reactivations (cytomegalovirus and BK virus). Additionally, other post-kidney-transplantation drugs such as valganciclovir may also contribute to adverse events such as leukopenia. For each side effect, we propose preventive measures and outline appropriate treatment strategies.

Conversion from calcineurin-inhibitors (CNIs) to belatacept can help kidney-transplant (KT) recipients avoid CNI-related nephrotoxicity. The risk of associated opportunistic infections (OPIs) is ill-defined. We conducted a multicentric cohort study across 15 French KT-centers in a real-life setting. Between 07-2010 and 07-2019, 453 KT recipients were converted from CNI- to belatacept-based therapy at 19 [0.13–431] months post-transplantation. Most patients, i.e., 332 (79.3%), were converted after 6-months post-transplantation. Follow-up time after conversion was 20.1 +/− 13 months. OPIs developed in 42(9.3%) patients after 14 +/− 12 months post-conversion. Eight patients (19%) had two OPI episodes during follow-up. Incidences of CMV DNAemia and CMV disease were significantly higher in patients converted before 6-months post-KT compared to those converted later (i.e., 31.6% vs. 11.5%; p < 0.001; and 11.6% vs. 2.4%, p < 0.001, respectively). Cumulative incidence of OPIs was 6.5 OPIs/100 person–years. Incidence of CMV disease was 2.8/100 person–years, of pneumocystis pneumonia 1.6/100 person–years, and of aspergillosis 0.2/100 person–years. Multivariate analyses showed that estimated glomerular filtration (eGFR) < 25 mL/min/1.73 m² at conversion was independently associated with OPIs (HR = 4.7 (2.2 − 10.3), p < 0.001). The incidence of EBV DNAemia was 17.3 events /100 person–years. At 1-year post-conversion, mean eGFR had significantly increased from 32.0 +/− 18 mL/min/1.73 m² to 42.2 +/− 18 mL/min/1.73 m² (p < 0.0001). Conversion to belatacept is an effective strategy with a low infectious risk.

Background.: Calcineurin inhibitors (CNIs) and steroids are strongly associated with new-onset diabetes after transplantation, worsening of pre-existing diabetes, and cardiovascular events. We assessed the benefit of conversion from CNI-based to belatacept-based immunosuppression in diabetic kidney-transplant (KT) recipients on glucose control and cardiovascular risk factors. Methods.: In this retrospective, noncontrolled single-study conducted between May 2016 and October 26, 2018, we recruited KT recipients converted from CNIs to belatacept at least 6 months after KT. The primary endpoint was the evolution of hemoglobin A1c (HbA1c) between baseline and after 6 months of treatment. Secondary endpoints included modifications to antidiabetic drugs, other cardiovascular risk factors, and renal function. Results.: One hundred and three KT recipients were included. Of these, 26 (25%) had type 2 diabetes. The patients were either receiving oral antidiabetic drugs (n = 21; 75%) or insulin therapy (n = 14; 54%). Overall HbA1c decreased significantly from 6.2 ± 1 to 5.8 ± 1%, P < 0.001. In diabetic patients, HbA1c decreased from 7.2 ± 1 to 6.5 ± 1%, P = 0.001. HbA1c significantly decreased in the subgroup of patients with new-onset diabetes after transplantation and whether diabetes was controlled at inclusion or not (ie, HA1c ≤7% or >7%). Moreover, no diabetic patient increased the number of oral antidiabetic drugs and the dose of basal insulin was not statistically different from baseline to 6 months (16 international unit at baseline and 16 international unit at 6 mo, P = 1). One patient had to start treatment by insulin pump. During follow-up, the renal function, body mass index, and hemoglobin level of all 103 patients remained stable, 2 patients presented acute cellular rejection, and no patient suffered from graft loss. Conclusions.: A late switch from CNI to belatacept was a valuable therapeutic option for diabetic kidney recipients and substantially improved glycemic parameters.

Nearly 18% of patients on a waiting list for kidney transplantation (KT) are highly sensitized, which make access to KT more difficult. We assessed the efficacy and tolerance of different techniques (plasma exchanges [PE], double-filtration plasmapheresis [DFPP], and immunoadsorption [IA]) to remove donor specific antibodies (DSA) in the setting of HLA-incompatible (HLAi) KT. All patients that underwent apheresis for HLAi KT within a single center were included. Intra-session and inter-session Mean Fluorescence Intensity (MFI) decrease in DSA, clinical and biological tolerances were assessed. A total of 881 sessions were performed for 45 patients: 107 DFPP, 54 PE, 720 IA. The procedures led to HLAi KT in 39 patients (87%) after 29 (15–51) days. A higher volume of treated plasma was associated with a greater decrease of inter-session class I and II DSA (p = 0.04, p = 0.02). IA, PE, and a lower maximal DSA MFI were associated with a greater decrease in intra-session class II DSA (p < 0.01). Safety was good: severe adverse events occurred in 17 sessions (1.9%), more frequently with DFPP (6.5%) p < 0.01. Hypotension occurred in 154 sessions (17.5%), more frequently with DFPP (p < 0.01). Apheresis is well tolerated (IA and PE > DFPP) and effective at removing HLA antibodies and allows HLAi KT for sensitized patients.

Background: Desensitization strategies improve access to transplantation in highly sensitized kidney transplant candidates. Tocilizumab could be a valuable addition to more traditional desensitization regimens. We investigated the effect of tocilizumab as an add-on therapy to our standard of care (SoC) desensitization strategy based on rituximab and apheresis. Methods: In this study, we prospectively included highly sensitized patients to receive monthly tocilizumab infusions for 6 months before our SoC regimen (Toci + SoC group). We compared the reductions in the mean fluorescent intensity (MFI) rebound at post-transplantation and kidney function at 1-year post-transplantation to patients treated by SoC (based on apheresis and two doses of rituximab). Results: Twenty-six patients were included in the SoC group; seven in the Toci + SoC group. Reductions in pre-transplantation MFI were similar between groups. At 1-year post-transplantation, there was no absolute difference in overall MFI rebounds, including donor-specific antibodies. Toci + SoC helped lower the rebound of antibodies with more elevated baseline MFIs. Graft function and survival rates were similar at one-year post-transplantation (median eGFR 62.8 vs. 65.6 mL/min/1.73 m² for SoC and Toci + SoC, respectively). Conclusions: Tocilizumab as an add-on to SoC desensitization may help control the post-transplantation rebound of antibodies with elevated baseline MFIs. However, reductions in pre-transplantation MFIs were similar with or without tocilizumab. Further studies are needed to validate this pilot study.

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.