Induction Therapy in Immunologically Well-Matched Recipients

Less May Be More

Administered perioperatively to reduce rejection risk, antibody induction is used in most US kidney recipients (¹). Induction therapies typically target T cells and are classified as depleting (e.g., rabbit antithymocyte globulin—Thymoglobulin), where T cells are lysed and depleted followed by gradual reconstitution, or nondepleting (e.g., basiliximab, an IL-2 receptor antagonist [IL-2RA]), which blocks IL-2 binding to its receptor but T cell populations remain intact (²). Studies have demonstrated lower early acute rejection rates with depleting agents compared with IL-2RA but higher risk of major infections and some malignancies, and their long-term benefit is not established (³,⁴). Guidelines recommend IL-2RA as first-line induction therapy, whereas depleting agents are recommended for patients considered at high risk for rejection (⁵). Although histocompatibility advancements are redefining immunologic risk assessment, traditional high–immunologic risk features include younger recipient age, recipients of African ancestry, presence of preexisting anti-HLA antibodies, older age donors, delayed graft function, cold ischemia time over 24 hours, or settings where recipients are either ABO blood group incompatible or less well HLA matched with their donors (⁵). For recipients with no HLA mismatches with their donors, a subgroup with superior allograft survival compared with recipients where there are HLA mismatches, the benefits of induction therapy are unclear.

In this issue of CJASN, Evans et al. (⁶) compared outcomes for well-matched recipients who received antibody induction with those of recipients who did not receive induction therapy. They used US Organ Procurement and Transplantation Network data and included adult recipients transplanted between 2010 and 2014. The study included 2976 recipients considered at lower immunologic risk for rejection (recipients matched with their donors at HLA-A, -B, -DR, and -DQB1), finding that 57% of these recipients received a depleting agent, 28% received IL-2RA, and 15% received no induction. The authors find that well-matched recipients had similar rejection and graft survival rates at 3 years after transplant regardless of induction therapy. They also find that depleting agents were associated with a higher death rate at 3 years post-transplant.

As the authors note, this is a registry-based retrospective study, limiting the ability to have granular data on immunosuppression decision-making processes, comorbidities, and pretransplant infection history. Subgroup analyses were limited by the small number of patients who did not receive induction; also, long-term immunosuppression management could not be ascertained, the validity of acute rejection data is of low quality, and the analysis was on the basis of low-resolution HLA typing. Notwithstanding these limitations inherent to registry data, the study’s findings are timely and important given the widespread use of induction therapy in this population.

There are over 250 US kidney transplant centers, and immunosuppression practice patterns vary widely (⁷). Data suggest that induction therapy use has increased from 80% in 2008 to 92% in 2019 (¹). Among the first transplant recipients with zero-HLA-antigen mismatched donor kidneys and no pretransplant HLA antibodies, induction therapy use approached 90% in 2019, with depleting therapy administered to almost half of this cohort (Figure 1). The approval of Thymoglobulin in 2017 by the US Food and Drug Administration (FDA) was on the basis of two randomized controlled trials that compared Thymoglobulin with basiliximab and compared Thymoglobulin with daclizumab, and these studies found reduction in acute rejection in the Thymoglobulin arm at 12 months post-transplant (³,⁴). For clinicians concerned about risk of infections or malignancies with induction therapy use, the uncertainty about optimal therapy for well-matched patients can contribute to variations in clinical practice across transplant centers. In the absence of randomized controlled, double-blind clinical trials comparing induction agents with each other or with placebo under contemporary maintenance immunosuppression, what should transplant clinicians do for well-matched, frequently lower–immunologic risk patients?

Figure 1.: Increasing use of induction therapy for low–immunologic risk patients in the United States. This image was restricted to patients who received a zero-HLA mismatch transplant, had 0% calculated panel reactive antibodies at transplant, received a kidney alone transplant, and did not receive a prior transplant. FDA, Food and Drug Administration; IL-2RA, IL-2 receptor antagonist.

The first few post-transplant months are a high-risk period for acute rejection, and immunologically well-matched patients can still develop this complication. Studies have demonstrated that Thymoglobulin depletes circulating T cell subsets for 3–6 months post-transplant, with an even longer delay for their return to pretransplant levels (⁸). Durable T cell depletion early post-transplant may provide immunosuppressive cover during a period when maintenance therapy targets and dosing are being sought, drug-related side effects are common, and a high pill burden may be a challenge for many patients. A second common rationale for durable T cell depletion immediately post-transplant is that it may facilitate early steroid withdrawal or permit downward titration of other maintenance therapies to mitigate their drug-specific toxicities. This includes the theoretical, although unproven, concern that tacrolimus, as a nephrotoxic drug, delays early post-transplant recovery of kidney allograft function and that lower than desired tacrolimus levels might be helpful in graft recovery. Finally, it has been hypothesized that Thymoglobulin administration initiated prior to reperfusion attenuates ischemia-reperfusion injury and may attenuate delayed graft function (⁹).

There is a paucity of data showing benefit of any induction therapy in patients with low risk of rejection. Although trials comparing the effect of basiliximab with placebo showed a reduction in the risk of acute rejection or graft loss, follow-up was short; participants were not restricted to lower immunologic risk; and cyclosporin was the calcineurin inhibitor used (without mycophenolate-based therapy), a maintenance regimen seldom used in contemporary practice. The pivotal trials that led to US FDA approval of Thymoglobulin were similarly not limited to patients with lower rejection risk. One European trial compared outcomes for Thymoglobulin with IL-2RA in lower–immunologic risk patients, demonstrating no difference in rejection, graft survival, or infectious complications at 12 months between the two agents in patients who underwent early steroid withdrawal (¹⁰). In a four-arm alemtuzumab induction trial where enrollment was stratified by immunologic risk, alemtuzumab showed superior prevention of rejection in lower-risk patients, but patients had persistent leukopenia (¹¹). Consistent findings in virtually all of these trials were higher rates of major infections (urinary tract infection, sepsis, and viral infections other than cytomegalovirus) and malignancies (such as post-transplant lymphoproliferative disorders).

Kidney transplant outcomes have improved in recent decades concomitant with plummeting early post-transplant rejection rates, a testament to more efficacious induction and maintenance immunosuppression. The high rates of cancer and infection in kidney transplant recipients, often due to overimmunosuppression, underscore that there are opportunities to improve immunosuppression protocols. Although the case for induction therapy in well-matched recipients is largely theoretical, the argument against its use has some evidence justification. In this context, the findings of Evans et al. (⁶) highlight the need to risk-stratify patients and consider the balance between reducing the 5% short-term risk of rejection with induction therapy and reducing the long-term risk of infections and malignancies (and higher risk of death) by avoiding induction therapy. However, registry-based retrospective studies can only inform us so far.

Multicenter, prospective, randomized controlled trials are needed to answer fundamental questions regarding induction therapy in low–immunologic risk patients. What is the optimal dose and type, if any? In the setting of depleting therapy, should regimens incorporate lower maintenance immunosuppression dosing given the durability of T cell depletion? Should decisions to use induction therapy account for donor and recipient cytomegalovirus and Epstein-Barr virus serostatus? Finally, it goes without saying that patient-reported outcomes should be considered as well. Until we can be better informed by clinically relevant trials, the important study by Evans et al. (⁶) in this issue should make us consider whether we have pushed too far in our quest to avoid rejection in well-matched recipients and that there are indeed clinical settings when less may be more.

Disclosures

R.D. Bloom reports consultancy agreements with Veloxis Pharmaceuticals; research funding from CareDx, CSL Behring, Natera, and Veloxis Pharmaceuticals; honoraria from Veloxis Pharmaceuticals; serving as a scientific advisor or member of Allovir, CareDx, Natera, Paladin Labs, and Veloxis Pharmaceuticals; royalties from UpToDate; and serving on the editorial board of American Journal of Kidney Diseases. V.S. Potluri is supported by a career development grant from the National Institutes of Health (National Institutes of Diabetes and Digestive and Kidney Diseases grant K08 DK127250).

Funding

This work was supported in part by Health Resources and Services Administration contract HHSH250-2019-00001C.