Tailored Rabbit Antithymocyte Globulin Induction Dosing for Kidney Transplantation

Abstract

BackgroundRabbit antithymocyte globulin (rATG) is the most widely used kidney transplant induction immunotherapy in the United States. It was recently Food and Drug Administration approved for this indication with typical dose recommendations of 1.5 mg/kg for up to 7 days given via a central line.MethodsWe theorized that reduced rATG dosing when compared with conventional dosing (6-10.5 mg/kg) is safe and effective, leading to development of a risk-stratified treatment protocol. Five-year data from a retrospective cohort of 224 adult kidney transplants (2008-2013) with follow-up through 2015 is presented. Cumulative rATG doses of 3 mg/kg were administered peripherally to nonsensitized living donor recipients, 4.5 mg/kg to nonsensitized deceased donor recipients. A subset of higher immunologic risk recipients (defined as history of prior transplant, panel reactive antibody greater than 20%, or flow cytometry crossmatch positivity) received 6 mg/kg.ResultsThere were no differences in patient or graft survival between the 3 groups. One-year rejection rates in the first 2 groups were 8.3% and 8.8%, respectively, comparable to contemporaneous rates reported to the Scientific Registry of Transplant Recipients. Dose tailoring permitted substantial cost savings estimated at US $1 091 502. Mean length of stay fell by almost 3 days as the protocol was refined. There were no episodes of phlebitis. Infection rates were comparable with those reported to the Scientific Registry of Transplant Recipients.ConclusionsThe novel findings of the current study include peripheral administration, reduced dosing, favorable safety, excellent allograft outcomes, and clear associative data regarding reduced costs and length of stay.

Reassessing Rabbit Antithymocyte Globulin Induction in Kidney Transplantation (RETHINK): An Analysis of the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) Registry

“…Several studies have demonstrated excellent 1-year graft outcomes with low-dose rATG induction strategies. In a comparison to conventional rATG exposure targets of 6–10 mg/kg, Singh et al 6 reviewed their outcomes using a tailored rATG cumulative exposure target of 3–6 mg/kg over a 5-year period and found comparable outcomes to those reported in the Scientific Registry of Transplant Recipients. Another study by Grafals et al 12 utilizing a much lower rATG cumulative exposure target of either 2.25 or 3.75 mg/kg demonstrated a biopsy-proven acute rejection rate of 10% and 17%, respectively, at 1-year follow-up and similar T-cell subpopulation depletion and repopulation kinetics in both groups.…”

“… 4 However, the lack of specific dosing recommendations until very recently has led to many immunosuppressive protocols in the adult transplant literature with an overall trend toward a lower cumulative exposure in the most recent era. 6 , 10 – 12 By utilizing the NAPRTCS registry, a large voluntary database that collects information on pediatric kidney transplants performed across North America, 8 we provide a contemporary assessment of the prevailing practice patterns at 37 participating centers with regards to rATG use for induction therapy. We demonstrate a wide variability in rATG cumulative exposure between individual centers, yet an overall trend toward lower exposure in the most recent era.…”

“…5 This may have contributed to wide variation in “standard” dosing practice, as it related to cumulative exposure targets for induction in kidney transplant recipients as each transplant center adopted its own standards and practice. 4 Significant cost savings can be realized with lower cumulative rATG exposure, 6 and the inherent risk of infection and leukopenia with its use in conjunction with other immunosuppressive drugs favors a more judicious approach in dosing and administration. 2 However, a lower dosing strategy may carry with it a higher risk of acute rejection given rATG’s established superiority in preventing acute rejection episodes at a relatively high cumulative dosing threshold of 7.5 mg per kg of body weight.…”

Memory T‐cell exhaustion and tolerance in transplantation

“…When CD8 + T cells undergo homeostatic proliferation they take on the phenotype of memory T cells (socalled pseudo-memory T cells) without ever having been exposed to antigen, including a decreased dependence on IL-2 and costimulation through CD28. 25 They also elegantly show that B cells are necessary to the process of homeostatic proliferation, but not through antigen presentation, since MHC knock out on B cells has no effect T-cell repopulation, but global MHC-I KO completely prevents T-cell expansion. 25 They also elegantly show that B cells are necessary to the process of homeostatic proliferation, but not through antigen presentation, since MHC knock out on B cells has no effect T-cell repopulation, but global MHC-I KO completely prevents T-cell expansion.…”

“…26 promotes the memory phenotype of expanding T cells during homeostatic proliferation, but blocking the IL-27 receptor prevents the expansion of any T cells after depletion in mouse models. 25 They also elegantly show that B cells are necessary to the process of homeostatic proliferation, but not through antigen presentation, since MHC knock out on B cells has no effect T-cell repopulation, but global MHC-I KO completely prevents T-cell expansion. Finally, they go on to show that the cytokine production by B cells is the critical component to CD8 T-cell reconstitution following depletion by mATG.…”