Failure of Calcineurin Inhibitor (Tacrolimus) Weaning Randomized Trial in Long-Term Stable Kidney Transplant Recipients

Abstract

Long-term renal transplant outcome is limited by side effects of immunosuppressive drugs, particularly calcineurin inhibitor (CNI). We assumed that some patients selected for a "low immunological risk of rejection" could be eligible and benefit from a CNI weaning strategy. We designed a prospective, randomized, multicenter, double-blind placebo-controlled clinical study (Eudract: 2010-019574-33) to analyze the benefit-risk ratio of tacrolimus weaning on highly selected patients (≥4 years of transplantation, normal histology, stable graft function, no anti-HLA immunization). The primary endpoint was improvement of renal function. Fifty-two patients were scheduled in each treatment arm, placebo compared to the CNI maintenance arm. Only 10 patients were eligible and randomized. Five patients were assigned to the placebo arm and five were assigned to the tacrolimus maintenance arm. In the tacrolimus maintenance arm, all patients maintained stable graft function and no immunological events occurred. Contrastingly, in the placebo arm, all five patients had to reintroduce a full dose of tacrolimus since three of them presented an acute rejection episode (one humoral, one mixed, and one borderline) and two displayed anti-HLA antibodies without histological lesion (one donor-specific antibodies [DSA] and one non-DSA). Clearly, tacrolimus withdrawal must be avoided even in long-term highly selective stable kidney recipients.

A composite score associated with spontaneous operational tolerance in kidney transplant recipients

“…Nevertheless, because immunosuppression has been shown to alter gene expression 41, 42, 52, 53 and particularly circulating B cells 54 , immunosuppression may affect cSoT. Unfortunately, samples before immunosuppression withdrawal are not available notably as TOL are mainly non-compliant and as intentional immunosuppression withdrawal trials have failed 18, 20 . However, several elements argue against that.…”

“…To date, no parameter has been identified that will safely permit weaning off immunosuppression, even in trials based on a stringent selection of non-sensitized recipients 18–20 . Thus, the intentional replication of immunosuppression withdrawal in renal transplantation requires the integration of appropriate clinical parameters and new laboratory tests.…”

B Cell Receptor Genes Associated With Tolerance Identify a Cohort of Immunosuppressed Patients With Improved Renal Allograft Graft Function

“…Consequently, changes in immunosuppression for individuals are often based upon patient demographics, clinical variables, or physician experience. Two recent studies attempting to withdrawal CNI from carefully selected recipients were both halted prematurely due to high rates of acute rejection and the de novo formation of DSA (8, 10). These experiences highlight the need to develop biomarkers capable of better identifying those individuals in whom immunosuppressive minimization or even withdrawal is safe.…”

Higher calcineurin inhibitor levels predict better kidney graft survival in patients with de novo donor-specific anti-HLA antibodies: a cohort study

“…Historically, large multicenter clinical trials focusing on management of de novo anti‐HLA antibodies, such as the Clinical Trials in Organ Transplantation (CTOT)‐02 trial, were unsuccessful in the enrollment of patients in their intervention phases, largely because of concerns about the toxicity of therapies proposed to patients with otherwise stable graft function . However, the widespread practice of reducing immunosuppression, particularly CNIs, in the early 2000s, has now largely fallen of favor: trials of CNI withdrawal, reduction or avoidance produced mixed results, with some reporting high incidences of acute rejection and dnDSA development even in very low‐risk patients . For instance, following fifteen years of follow‐up, a multicenter trial recently reported that a CNI‐free regimen was not associated with a lower incidence of death by malignancy or cardiovascular disease, but led to a worse death‐censored graft survival .…”