Efficacy of Single Dose Anti-thymocyte Globulin in the Modulation of T Lymphocytes in Kidney Transplantation

Kidney transplantation is one of the major advances in medicine in the past 60 years. Currently, is considered the best treatment for terminal chronic kidney disease in the medium and long term, and the least costly. To obtain these successful outcomes, the immune response to the graft must be properly controlled and monitored since its implantation. T and B lymphocytes are crucial in the alloimmune response by mediating cellular and antibody-mediated rejections, respectively, and along with anti-HLA antibodies are the main effectors of acute and chronic rejections.

Anti-thymocyte globulin (ATG) has a key role in the immunosuppressive induction regimens used in kidney transplants as well as in the treatment of acute rejections. It is a purified solution that contains a variety of T cell-specific immunoglobulins, including CD2, CD3, CD4, CD8, CD11a, CD18, CD25, HLA-DR, and class I HLA (human leukocyte antigen). This solution is produced by immunizing rabbits with human thymocytes. The use of these agents is particularly important in inducing patients who are more predisposed to the nephrotoxic effects of calcineurin inhibitors (CI), allowing the delayed introduction of the CI. Induction with antibodies is also of great value in patients with higher immunological risk, such as pediatric, Afro-descendants, re-transplanted, and previously sensitized to HLA antigens recipients.

Polyclonal antibodies have definite benefits in kidney transplantation, but their use is associated with hematological, infectious, and neoplastic complications. The use of reduced doses of ATG has been the subject of recent studies, but still with inconclusive results.

The concept of monitoring T cells in patients receiving ATG was first proposed in 1975 to improve efficacy in preventing acute rejection and avoiding excessive immunosuppression. The dose regimen is guided by a daily count of peripheral blood TCD3+ lymphocytes. Monitoring the dose of thymoglobulin through its biological effects on T cells is a rational and safe method of titrating the dose of that antibody. This way, it is possible to reduce the total amount of drug administered to the patient and, consequently, reduce undesirable complications, as well as the cost of treatment, hopefully without losing effect on the benefit of immunosuppression.

A 60% reduction in the total dose of ATG and 58% reduction in therapy cost was observed in patients who were monitored using TCD3+ cell counts. Currently, the usual total dose of ATG for induction in kidney transplant patients is 6mg/kg, divided into 4 doses, which can be administered from day zero until day 14 (maximum) of transplantation. However, the ideal dose and duration of therapy are still the subject of investigation, with protocols between centers varying from total doses of 3 to 6 mg/kg, fractionated or single, to attempt to achieve the lowest dose with fewer undesirable effects, and with reduced length of inpatient stay. The use of ATG in a single dose of 3 mg/kg was successfully assessed for risks of infection and rejection in patients with low immunological risk.

Considering that the adverse effects associated with the use of ATG are relevant in the clinical context of kidney transplantation, the use of a lower dose, keeping its immunomodulatory effect, with a safer profile, is desirable.

The study evaluates the efficacy and safety of a single dose of 3mg/kg ATG for patients with low and standard immune risk, with TCD3+ lymphocyte monitoring, to assess the clinical efficacy and the modulation of the T cell response.

Inclusion criteria

• Kidney transplant patients from Hospital de Clínicas de Porto Alegre (HCPA) between October 2018 to March 2020 who received a single 3 mg/kg ATG dose at the immediate postoperative period. Recipients of standard and low immunological risk (PRA - panel reactive antibodies <50% and without donor-specific antibodies), regardless of the time of cold ischemia and the presence of kidney failure in the donor.
• Control group consisting of patients from the same and previous period, who received fractionated ATG dosing up to 6 mg/kg total dose.

Exclusion criteria

• Patients who used other induction strategies that did not include ATG in a single dose of 3 mg/kg or the fractionated dose of 6 mg/kg.
• Patients who died within 24 hours after transplantation.
• Patients who had a transplant nephrectomy within 24 hours after transplantation.
• Pediatric recipients (< 14 years old).
• Recipients with incomplete data.