Background.: Tacrolimus trough concentrations (mean/variability), as well as concentration-to-dose ratio (C/D ratio), affect kidney allograft outcomes. We investigated the link between the C/D ratio and death-censored kidney graft survival (DCGS). Methods.: We performed a retrospective study on 1029 kidney transplant patients (2004–2016) with the following criteria: tacrolimus-based immunosuppression, >1-year graft survival, no initial use of everolimus, and available anti–human leukocyte antigen antibody data. We analyzed the impact of the time-varying C/D ratio on DCGS. Fast metabolizers were defined by a C/D ratio < 1.05. We also investigated the effect of an early (mo 3 to mo 6 post transplantation) C/D ratio below 1.05. Cox survival analyses were performed, adjusting for potential confounders (tacrolimus trough, variability of tacrolimus trough, de novo donor-specific antibody development, cytochrome P450 3A5 genotype, pregraft sensitization, mo 3 glomerular filtration rate). Results.: Time-varying C/D ratio was significantly associated with DCGS (hazard ratio [HR], 2.35; P < 0.001) in a univariate model, on the full analysis set comprising 1029 patients. In the multivariate time-varying model, based on 666 patients with available cytochrome P450 3A5 genotypes, the effect of the C/D ratio remained significant (HR, 2.26; P = 0.015); even when glomerular filtration rate at month 3 < 30 mL/min/1.73 m² (HR, 2.61; P = 0.011), de novo donor-specific antibody development (HR, 4.09; P < 0.001) and continued steroid prescription (HR=2.08, P = 0.014) were taken into account (other covariates, including tacrolimus trough concentrations, were nonsignificant). In the same multivariate model, the effect of early C/D ratio (median at mo 3 and mo 6) remained significantly associated with DCGS (HR, 2.25; P = 0.041). Conclusions.: C/D ratio is an independent and early predictor of DCGS. Identification of fast metabolizers could be a strategy to improve graft survival, for example, by optimizing tacrolimus formulation. Mechanistic studies to understand the C/D ratio effect are required.

Introduction: Tacrolimus-based immunosuppression remains the immunosuppressive drug of choice in kidney transplantation. Areas covered: Its safety profile is closely linked to its pharmacokinetic properties. A narrow therapeutic range allows to limit under- and over-immunosuppression consequences. Minimization of tacrolimus exposure, using appropriate companion drugs, leads to the best renal outcomes in the long-term. Also, reducing tacrolimus exposure variability helps in reducing tacrolimus toxicity. The novel concept of tacrolimus concentration-to-dose ratio (C/D ratio) associates with renal outcomes as well and provides some new possible improvements on tacrolimus safety, possibly by identifying kidney transplant recipient subpopulations at higher risk of tacrolimus toxicity. Similarly, the incidence of new-onset diabetes after transplantation (NODAT), a major side-effect of tacrolimus, can also be reduced by optimizing tacrolimus exposure. In this review, the authors summarize the safety profile of tacrolimus when optimizing mean tacrolimus exposure, tacrolimus exposure variability and tacrolimus C/D ratio. The impact of these adjustments on nephrotoxicity and NODAT is reviewed. Using such prescription optimization, tacrolimus’ safety profile is positive. Expert opinion: Tacrolimus-based immunosuppression remains a valid option for kidney transplant recipients, and might even improve by individualizing prescriptions, the next frontier in transplant immunosuppression.

Introduction: Since the approval of belatacept in 2011 for use in the setting of de novo kidney transplantation, this CD80/86 – CD28 co-stimulation blocker has been shown to be a valuable treatment option for maintenance immunosuppression. Areas covered: In this setting, belatacept has been associated with superior glomerular filtration rate as compared to calcineurin inhibitor-based treatments because of the absence of nephrotoxicity. Additionally, belatacept avoids the cardiovascular side effects (e.g., hypertension and dyslipidemia) caused by a CNI-based-regimen. Nevertheless, belatacept-treated recipients have a higher rate of acute rejections and a higher risk of lymphoproliferative disorders. Expert opinion: Data suggest a benefit from early conversion vs. late conversion of belatacept in a conversion setting following CNI-related toxicity. Randomized studies are currently comparing belatacept to tacrolimus, instead of cyclosporine, as was done in the Belatacept Evaluation of Nephroprotection and Efficacy as a First-line Immunosuppression Trial (BENEFIT). The benefits and limitations of belatacept seem to be the same when tacrolimus is used instead of cyclosporine. Finally, we also report in this review on the immunological data available so far that explain belatacept’s limitations and the higher rate of acute rejection. The goal is to find the optimal immunosuppressive strategy to improve efficacy and safety at post-transplantation.

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.

Kidney-transplant candidates (KTCs) who are HLA highly-sensitized (calculated panel-reactive alloantibodies>95%) have poor access to deceased-kidney transplantation. In this single-center prospective study, 13 highly-sensitized desensitization-naïve KTCs received IV tocilizumab(8mg/kg) every 4-weeks. We evaluated tolerability as well as immune responses, i.e., T-cell-, B-cell-, T-follicular helper[Tfh]-subsets, blood cytokines (IL-6, soluble IL-6 receptor-sIL-6R-, IL-21), blood chemokines (CXCL10,CXCL13), and anti-HLA alloantibodies. Tocilizumab treatment was well-tolerated except in one patient that presented spondylodiscitis, raising a note of caution. Regarding immune parameters, there were no significant changes of percentages of lymphocyte subsets, i.e., CD3⁺-, CD3⁺/CD4⁺-, CD3⁺/CD8⁺-T-cells, and NK-cells. This was also the case for Tfh-cell subsets, B-cells, mature B-cells, plasma-cells, pre-germinal center (GC) B-cells, and post-GC B-cells, whereas we observed a significant increase in naïve B-cells (p=0.02) and a significant decrease in plasmablasts (p=0.046) over the tocilizumab treatment course. CXCL10, CXCL13, IL-21, total IgG, IgA, and IgM levels did not significantly change during tocilizumab therapy; conversely, there was a significant increase in IL-6 levels (p=0.03) and a huge increase in sIL-6R (p=0.00004). There was a marginal effect on anti-HLA alloantibodies (class-I and class-II). To conclude in highly sensitized KTCs, tocilizumab as a monotherapy limited B-cell maturation; however, it had almost no effect on anti-HLA alloantibodies.

Recent data from the World Population Prospects projects that, by 2050, nearly all regions in the world will have a quarter or more of the population aged 60 and above. Chronic kidney disease (CKD) has a high global prevalence (~13%) worldwide, and the prevalence of chronic kidney disease and end-stage kidney disease increase with age. Kidney transplantation remains the best therapeutic option for end-stage kidney disease, offering a survival benefit in comparison with dialysis maintenance for most patients. This review focuses on immunological aspects of kidney transplantation in older patients and marginal donors, i.e., 60 years or older deceased kidney donors or 50–59 years old deceased kidney donors with comorbidities. Clinical outcomes of kidney recipients in terms of renal and patient survival are more than acceptable even for patients over 70. In this population, the first cause of graft loss is death with a functional graft. However, the inherent issues of these transplantations are the acceptance or refusal of frail kidney from an old donor and the increased immunogenicity of these organs in balance with potential frail and immunosenescent recipients. Finally, the immunosuppressive regimen itself is a challenge for the future of the transplant, to prevent adverse effects such as nephrotoxicity and higher risk of infections or cancer in a population already at risk. Belatacept may have a good place in the immunosuppressive strategy to improve efficacy and the safety posttransplantation.