Even if kidney graft survival has improved during the last two decades, highly immunized pediatric waitlisted patients are an emerging problem. Patients who received their first kidney transplant as young children frequently need another transplant during adolescence or adultness, ultimately impacting on the number of sensitized patients on the waiting lists. About 20-40% of adult patients on the waiting list present alloantibodies before transplantation; no data about the prevalence of hyperimmunized pediatric patients are available. These patients are at higher risk of acute antibody mediated rejection (AMR), with an incidence of about 30%; Episodes of AMR are treated with intravenous immunoglobulin (IVIG), Rituximab and plasmapheresis (PP). In rare cases in which these approaches failed to stop the immunological response, other therapeutic strategies have been used, such as Bortezomib or Eculizumab. Eculizumab is a humanized mAb which binds to C5, suppressing membrane attack complex formation. It is currently used in paroxysmal nocturnal hemoglobinuria, but it is now emerging as a therapeutic option for rheumatic diseases and humoral rejection. (Jordan SC )
We describe a caucasian 17-year old male, transplanted at three years of age because of ESRD due to congenital nephrotic syndrome (Finnish type), who lost his first graft due to chronic allograft nephropathy. While on the waiting list, he presented a progressive rise in Panel Reactive Antibodies levels (PRA 99.61%). The patient received a desensitization protocol based on plasmapheresis (PP), immunoglobulins and Rituximab, with minor response (post desensitization PRA 75%). He was enrolled in a National Protocol for organs allocation to immunized patients and received his second non-living HLA-compatible kidney transplant at the age of 16. He had prompt function of his allograft. On postoperative day 30 he developed a biopsy-proven antibody-mediated rejection (AMR) [Figure 1].
Post-transplant immunological monitoring showed donor-specific anti-DQ5 antibodies (DSA) that were already present at the time of transplantation. The patient received three methylprednisolone pulses and 45 PP sessions, starting with daily sessions, gradually reduced to twice per week. A stabilization of creatinine levels was observed, but a raise in creatinine and DSA levels occurred after PP’s frequency reduction. PP sessions were then enhanced; a second graft biopsy [Figure 2] demonstrated a persistent C4d positive AMR.
Therefore, in the light of histological findings, clinical PP-resistant AMR and the previous administration of two Rituximab doses that preclude other anti-CD20 infusions, the patient was offered the option of receiving Eculizumab. Four consecutive Eculizumab infusions (600 mg each, POD 168/175/189/203) were performed after the administration of meningococcal, pneumococcal and H. Influenzae vaccines [Figure 3].
After the fourth infusion graft function was normal and a third percutaneous biopsy showed the resolution of AMR [Figure 4]. Taking into account graft function stabilization and the improvement of histological features, Eculizumab infusions were continued.
Eculizumab is a humanized mAb which binds to C5, suppressing membrane attack complex formation. It is currently used in paroxysmal nocturnal hemoglobinuria, but it is now emerging as a therapeutic option for rheumatic diseases and humoral rejection. Randomized control trials to determine Eculizumab safety and efficacy profile are still lacking. However, positive results are described in single case-reports of adult kidney or kidney-pancreas transplant recipients. (Locke JE, Magro CM ; Lonze BE, Dagher NN )
Eculizumab allowed our patient to stop PP therapy. One year after transplantation, in a monthly infusion regimen, graft function is still normal and stable. Anti C5 therapy may represent an effective therapeutic option also in pediatric patients with persistent PP-resistant AMR. However, Randomized Control Trials are needed to determine Eculizumab efficacy and safety in a larger cohort of patients.