Use and Outcomes of Induction Therapy in Well-Matched Kidney Transplant Recipients

Abstract

Background and objectives 

The optimal induction treatment in low–immune risk kidney transplant recipients is uncertain. We therefore investigated the use and outcomes of induction immunosuppression in a low-risk cohort of patients who were well matched with their donor at HLA-A, -B, -DR, -DQB1 on the basis of serologic typing.

Design, setting, participants, & measurements 

Our study was an observational study of first adult kidney-only transplant recipients in the United States recorded by the Organ Procurement and Transplant Network.

Results 

Among 2976 recipients, 57% were treated with T cell–depleting antibodies, 28% were treated with an IL-2 receptor antagonist, and 15% were treated without induction. There was no difference in allograft survival, death-censored graft survival, or death with function between patients treated with an IL-2 receptor antagonist and no induction therapy. In multivariable models, patients treated with T cell–depleting therapy had a similar risk of graft loss from any cause, including death (hazard ratio, 1.19; 95% confidence interval, 0.98 to 1.45), compared with patients treated with an IL-2 receptor antagonist or no induction. The findings were consistent in subgroup analyses of Black recipients, patients grouped by calculated panel reactive antibody, and donor source. The incidence of acute rejection at 1 year was low (≤5%) and did not vary between treatment groups.

Conclusions 

Use of induction therapy with T cell–depleting therapy or IL-2 receptor antagonists in first kidney transplant recipients who are well matched with their donor at the HLA-A, -B, -DR, -DQB1 gene loci is not associated with improved post-transplant outcomes.

Visual Abstract

Introduction

International guidelines recommend the use of induction immunosuppression in kidney transplant recipients (¹). IL-2 receptor antagonists (IL2-RAs) are recommended as first-line therapy, with lymphocyte-depleting agents recommended in high–immunologic risk patients. The guidelines recommend that immunologic risk be determined by characteristics, including younger recipient age, older donor age, Black ancestry, panel reactive antibody (PRA) ≥0%, presence of donor-specific antibody (DSA) prior to transplantation, ABO blood group incompatibility, delayed graft function, and cold ischemic time >24 hours. The guidelines also acknowledged that in some low-risk patients, the benefits of IL2-RAs may be too small to outweigh the adverse effects or cost of these drugs (¹).

Advances in immunogenetics have improved the assessment of immunologic risk such that presence of pretransplant DSA rather than PRA is now used to indicate immunologic risk. Despite its simplicity, the cell-based PRA test is nonspecific and relatively insensitive (²). With the introduction of single-antigen bead testing, laboratories acquired the ability to detect and characterize anti-HLA antibodies with exquisite sensitivity and specificity. In turn, single-antigen bead testing enabled transplant centers to define specific HLA antibodies that their patients possessed (³). These advances led to the replacement of PRA with a calculated value (calculated panel reactive antibody [cPRA]) in October 2009 (⁴). Unlike PRA, which measures the breadth of recipient sensitization without donor specificity, entering cPRA values into the allocation system requires accurate determination and listing of unacceptable antigens to ensure that candidates will not be allocated organs with any of those antigens.

We sought to re-examine the association of induction immunosuppression with transplant outcomes in low–immunologic risk patients defined using contemporary methods. Because the recording of unacceptable HLA donor antigens is at the discretion of transplant centers, some patients may still undergo transplantation from a donor to which they have preformed DSA. To identify a patient cohort without preformed DSA prior to transplant, we focused on patients who were matched with their donors at the HLA-A, -B, -DR, -DQB1 gene loci and therefore are unlikely to have DSA.

Materials and Methods

The study was approved by the local hospital research ethics board and adheres to the principles of the Declaration of Helsinki. The clinical and research activities being reported are consistent with the Principles of the Declaration of Istanbul as outlined in the “Declaration of Istanbul on Organ Trafficking and Transplant Tourism.”

Data Sources

The standard analysis files of the United States Renal Data System were utilized for this analysis (⁵). These files are on the basis of data collected by the Organ Procurement and Transplant Network (OPTN).

The study population included patients ≥18 years of age who underwent a first living or deceased donor kidney-only transplant between January 2010 and October 2014 with follow-up through October 2017. Transplant dates were restricted to ensure that all patients and donors had recorded typing for HLAs at the A, B, DR, DQB1 loci; a cPRA value; and at least 3 years of post-transplant follow-up. The study was limited to patients with recorded pretransplant cPRA as well as complete donor and recipient typing at the HLA-A, -B, -DRB1, -DQB1 gene loci. Only transplants involving donor and recipients with identical HLA-A, -B, -DR, and -DQB1 antigen typing were included. Pairs were excluded when the HLA-DQB1 typing of the donor and/or recipient was broad (i.e., DQ1 instead of DQ5 or DQ6; DQ3 instead of DQ7, -8, or -9) and precise matching could not be ascertained. Patients with missing information regarding treatment with induction immunosuppression were excluded.

The study outcomes included graft loss from any cause, including death, graft loss censored for death, and death with a functioning graft. Because acute rejection events are not validated in the OPTN data, we determined acute rejection only during the first post-transplant year.

Analytical Methods

Patients were grouped by the type of induction treatment into those treated with T cell–depleting agents, including thymoglobulin (rabbit antithymocyte globlin), equine antithymocyte globulin, and alemtuzumab (Campath); those treated with IL2-RAs, including basiliximab and daclizumab; and those treated without any induction. Patients recorded as receiving both T cell–depleting agents and IL2-RAs (n=75) were included in the depleting antibody group. Patient characteristics were described using the medians and quartiles for continuous variables or frequencies and proportions for categorical variables. Donors were categorized by type into living donors and deceased donors stratified by kidney donor profile index (KDPI; 0%–85% and 86%–100%).

The times to graft failure from any cause, graft failure censored for patient death, and death with a functioning graft were determined by induction treatment group using the Kaplan–Meier method with group differences compared with the log rank test. Because the outcomes were similar between patients treated with IL2-RAs and no induction therapy, these groups were combined in subsequent analyses. The association of induction with graft survival was then determined in the following predefined patient subgroups: Black recipients, recipients grouped according to cPRA (0%, 1%–29%, 30%–79%, 80%–97%, and ≥98%), and recipients of living and deceased donor transplants.

The relative hazard of graft failure from any cause was determined using a Cox proportional hazards multivariable regression analysis that adjusted for group differences in established determinants of transplant outcome, including patient age, sex, race, diabetes as the cause of kidney failure, insurance type, dialysis vintage, donor source, cPRA, and deceased donor KDPI. KDPI is a numerical measure that combines ten donor factors to summarize into a single number the quality of deceased donor kidneys relative to other recovered kidneys (referenced to 2018) (⁶). Similar models were constructed for the outcomes of allograft failure censored for death and death with a functioning allograft. Model assumptions were tested with plots of the log of the negative log of the estimated survival density function versus the log of survival time, and no violations were identified. The frequency of missing data was low; n=1 (0.03%) missing insurance observation, n=3 (0.1%) missing warm ischemic time, and n=186 (6%) missing cold ischemic time. Data were not differentially missing between groups. In all models, variables with missing data were assigned a category of “missing” to allow inclusion of all patients in the models. All analyses were conducted using Stata Statistical Software: Release 17 (StataCorp LLC; College Station, TX; www.stata.com).

Results

Figure 1 shows the study cohort of 2976 zero HLA-A, -B, -DR, -DQB1 mismatched first kidney-only transplant recipients. This included 1689 (57%) patients who were treated with T cell–depleting antibody, 836 (28%) treated with IL2-RAs, and 451 (15%) who were treated without induction therapy.

Figure 1.: Assembly of the study cohort. IL2-RA, IL-2 receptor antagonist.

Table 1 shows patient characteristics by induction group. Among the 1689 patients who received T cell–depleting antibodies, 75% (n=1268) received thymoglobulin, 23% (n=387) received alemtuzumab (Campath), and 2% (n=34) received equine antithymocyte globulin. Among patients treated with IL2-RAs, 99% (n=826) received basiliximab, and 1% (n=10) received daclizumab. The vast majority of patients in all groups were treated with tacrolimus, mycophenolate mofetil/mycophenolate sodium, and corticosteroid maintenance immunosuppression.

Table 1. - Patient characteristics

Patient Characteristic	T Cell–Depleting Antibodies, n=1689	IL-2 Receptor Antagonists, a n=836	No Induction, n=451
Median age, yr (quartile 1 to quartile 3)	53 (42–62)	53 (41–63)	53 (41–61)
Men, n (%)	743 (44)	516 (62)	264 (59)
Recipient race, n (%)
White	1388 (82)	698 (83)	375 (83)
Black	213 (13)	83 (10)	47 (10)
Other	88 (5)	55 (7)	29 (6)
Diabetes-related kidney failure, n (%)	452 (27)	197 (24)	118 (26)
cPRA, n (%)
0	661 (39)	551 (66)	254 (56)
1–29	215 (13)	115 (14)	46 (10)
30–79	413 (24)	114 (14)	101 (22)
80–97	258 (15)	36 (4)	30 (7)
98–100	142 (8)	20 (2)	20 (4)
Insurance, n (%)
Medicare	884 (52)	381 (46)	199 (44)
Private	538 (32)	275 (33)	143 (32)
Other	266 (16)	180 (22)	109 (24)
Duration of pretransplant dialysis, yr (quartile 1 to quartile 3)	2 (0–3)	1 (0–3)	1 (0–3)
Maintenance immunosuppression, n (%)
Corticosteroids	1635 (97)	818 (98)	387 (86)
Maintenance tacrolimus	1568 (93)	774 (93)	411 (91)
Maintenance antimetabolite b	1613 (96)	807 (97)	409 (91)
Delayed graft function, n (%)	229 (14)	74 (9)	32 (7)
Median hospitalization, d (quartile 1 to quartile 3)	5 (4–6)	4 (4–5)	4 (4–6)
eGFR at 6 mo (quartile 1 to quartile 3)	51 (38–68)	54 (40–71)	51 (40–71)
Early graft loss (%)	14 (0.8)	3 (0.4)	3 (0.7)
Donor characteristics, n (%)
Living donor	434 (26)	421 (50)	227 (50)
Living related c	423 (25)	410 (49)	221 (49)
Living unrelated	11 (1)	11 (1)	6 (1)
Deceased donor	1255 (74)	415 (50)	224 (50)
Neurologic brain death	1154 (92)	379 (91)	204 (91)
Donation after circulatory death	101 (8)	36 (9)	20 (9)
Deceased donor KDPI, n (%)
0–20	403 (32)	117 (28)	83 (37)
21–50	466 (37)	176 (42)	82 (37)
51–85	341 (27)	109 (26)	53 (24)
86–100	45 (4)	13 (3)	6 (3)
Cold ischemic time ≥18 h (%)	697 (41)	149 (18)	104 (23)

cPRA, calculated panel reactive antibody; KDPI, kidney donor profile index.

^aIL-2 receptor antagonist included 826 patients treated with basiliximab and ten patients treated with daclizumab.

^bAntimetabolites: Imuran (n=15), CellCept, myfortic, generic mycophenolate mofetil, and generic myfortic.

^cLiving related donors include sibling, child, or parent donors.

Figure 2 shows the time to allograft failure from any cause, allograft failure censored for death, and death with a functioning allograft by induction treatment during the mean follow-up of 5±2 years. The time to these outcomes was similar in patients treated with IL2-RAs and no induction therapy. Compared with patients treated with IL2-RAs or no induction therapy, the time to graft loss from any cause was shorter in patients treated with T cell–depleting antibodies (Figure 2A), and this was due to a higher incidence of graft loss censored for death (i.e., return to dialysis or preemptive repeat transplantation) (Figure 2B), whereas the time to death with a functioning graft did not differ between the groups (Figure 2C). The number of patients at risk during follow-up is shown in Supplemental Table 1.

Figure 2.: Time to graft loss from any cause including death (A), graft loss censored for death (B), and death with a functioning graft (C) in zero HLA-A, -B, -DR, -DQB1 mismatched first adult kidney-only transplant recipients grouped by type of induction therapy. T cell depleting, n=1689; IL2-RAs, n=836; no induction, n=451. Supplemental Table 1 shows the number of patients at risk at various time points after transplantation.

Table 2 shows the association of induction immunosuppression with the study outcomes after adjustment for confounders. Because of similar outcomes in patients treated with IL2-RAs or no induction in unadjusted analysis (Figure 2) and multivariable models (Supplemental Table 2), these groups were combined into a single reference group. The adjusted hazard for graft loss from any cause in patients treated with T cell–depleting antibody induction (hazard ratio [HR], 1.19; 95% confidence interval [95% CI], 0.98 to 1.45) was not different from that in patients in the combined IL2-RA/no induction group. Patients treated with T cell–depleting antibody induction had a higher hazard for graft loss censored for death (HR, 1.46; 95% CI, 1.09 to 1.94) but were not at higher risk for death with a functioning graft (HR, 0.97; 95% CI, 0.13 to 1.27).

Table 2. - Association of induction therapy with the outcomes of graft loss from any cause, including death, graft loss censored for death, and death with a functioning graft

Patient Characteristic	No. (%) with Outcome	Graft Loss from Any Cause, Hazard Ratio (95% Confidence Interval)	No. (%) with Outcome	Graft Loss Censored for Death, Hazard Ratio (95% Confidence Interval)	No. (%) with Outcome	Death with Functioning Graft, Hazard Ratio (95% Confidence Interval)
Induction therapy
IL2-RAsa/no induction	304 (18)	Reference	163 (10)	Reference	141 (8)	Reference
Depleting antibody	171 (13)	1.19 (0.98 to 1.45)	75 (6)	1.46 (1.09 to 1.94)	96 (8)	0.97 (0.13 to 1.27)
Age at transplant, yr
18–39	67 (11)	Reference	56 (9)	Reference	11 (2)	Reference
40–60	215 (14)	1.11 (0.84 to 1.47)	118 (8)	0.72 (0.52 to 1.00)	97 (7)	3.08 (1.64 to 5.78)
61+	193 (23)	1.61 (1.20 to 2.16)	64 (8)	0.62 (0.42 to 0.91)	129 (15)	6.42 (3.42 to 12.06)
Men	253 (17)	1.31 (1.06 to 1.61)	124 (8)	1.23 (0.93 to 1.64)	129 (8)	1.33 (0.99 to 1.80)
Recipient race
White	394 (16)	Reference	194 (8)	Reference	200 (8)	Reference
Black	64 (19)	1.18 (0.90 to 1.54)	34 (10)	1.20 (0.83 to 1.75)	30 (9)	1.17 (0.79 to 1.72)
Other	17 (10)	0.68 (0.42 to 1.10)	10 (6)	0.84 (0.44 to 1.59)	7 (4)	0.58 (0.27 to 1.23)
Diabetes	183 (24)	1.55 (1.28 to 1.88)	78 (10)	1.30 (0.98 to 1.73)	105 (14)	1.72 (1.33 to 2.24)
Insurance
Medicare	277 (19)	Reference	118 (8)	Reference	159 (11)	Reference
Private	136 (14)	0.91 (0.74 to 1.13)	79 (8)	1.19 (0.88 to 1.62)	57 (6)	0.69 (0.51 to 0.94)
Other	62 (11)	0.87 (0.66 to 1.17)	41 (7)	1.14 (0.78 to 1.66)	21 (4)	0.61 (0.38 to 0.98)
Duration of pretransplant dialysis		1.03 (1.00 to 1.06)		1.00 (0.94 to 1.05)		1.05 (1.01 to 1.09)
cPRA
0	203 (14)	Reference	103 (7)	Reference	100 (7)	Reference
1–29	57 (15)	0.89 (0.66 to 1.20)	27 (7)	0.83 (0.54 to 1.28)	30 (8)	0.98 (0.65 to 1.49)
30–79	119 (19)	1.10 (0.86 to 1.41)	62 (10)	1.11 (0.79 to 1.56)	57 (9)	1.06 (0.75 to 1.51)
80–97	63 (19)	1.18 (0.86 to 1.62)	32 (10)	1.05 (0.68 to 1.64)	31 (10)	1.33 (0.84 to 2.11)
98–100	33 (18)	1.08 (0.72 to 1.62)	14 (8)	0.86 (0.47 to 1.57)	19 (10)	1.30 (0.75 to 2.25)
KDPI living donor		Reference		Reference		Reference
Deceased donor KDPI: 0–85	91 (8)	2.08 (1.61 to 2.69)	49 (5)	2.42 (1.69 to 3.47)	42 (4)	1.66 (1.15 to 2.41)
Deceased donor KDPI: 86–100	365 (20)	3.36 (2.01 to 5.63)	182 (10)	3.04 (1.33 to 6.93)	183 (10)	2.77 (1.43 to 5.39)

IL2-RA, IL-2 receptor antagonist; cPRA, calculated panel reactive antibody; KDPI, kidney donor profile index.

Subgroup Analyses

The unadjusted associations of induction with graft loss from any cause, including death, among Black recipients and deceased and living donor recipients are shown in Figure 3. Among Black recipients, there was no difference in the outcome of graft loss from any cause between patients treated with T cell–depleting antibody induction and patients treated with IL2-RAs/no induction. Among deceased donor recipients, there was no difference in graft loss between patients treated with T cell–depleting induction and those treated with IL2-RAs/no induction. Among living donor recipients, patients treated with T cell–depleting antibody induction had a shorter time to graft loss from any cause (P=0.02). The number of patients at risk during follow-up is shown in Supplemental Table 3. Figure 4 shows the association of induction with transplant outcomes in patients stratified by cPRA. In no cPRA group was T cell–depleting antibody associated with a longer time to graft loss from any cause. The number of patients at risk during follow-up is shown in Supplemental Table 4. In additional subgroup analyses, consistent results were found in patient subgroups defined by cPRA>80%, donation after circulatory death donor type, and cold ischemic time >18 hours (Supplemental Figures 1–3).

Figure 3.: Association of induction therapy with graft loss from any cause, including death, in selected patient subgroups. (A) Black recipients: T cell depleting, n=213; IL2-RAs/no induction, n=130. (B) Deceased donor recipients: T cell depleting, n=1255; IL2-RAs/no induction, n=639. (C) Living donor recipients: T cell depleting, n=434; IL2-RAs/no induction, n=648. Supplemental Table 2 shows the number of patients at risk at various time points after transplantation.

Figure 4.: Graft loss from any cause, including death, in patients grouped by calculated panel reactive antibody (cPRA). (A) cPRA 0% recipients: T cell depleting, n=661; IL2-RAs/no induction, n=805. (B) cPRA 1%–29% recipients: T cell depleting, n=215; IL2-RAs/no induction, n=161. (C) cPRA 30%–79% recipients: T cell depleting, n=413; IL2-RAs/no induction, n=215. (D) cPRA 80%–97% recipients: T cell depleting, n=258; IL2-RAs/no induction, n=66. (E) cPRA 98%–100%: T cell depleting, n=142; IL2-RAs/no induction, n=40. Supplemental Table 3 shows the number of patients at risk at various time points after transplantation.

Supplemental Figure 4 shows transplant outcomes in patients treated with thymoglobulin (n=1268) and alemtuzumab (n=387) compared with patients in the combined IL2-RA/no induction group. The outcomes in the thymoglobulin- and alemtuzumab-treated patients were similar.

Acute Rejection

There were 134 cases of acute rejection reported during the first post-transplant year. The incidence was similar in patients treated with T cell–depleting antibodies (4%; 95% CI, 4% to 5%), patients treated with IL2-RAs (5%; 95% CI, 4% to 7%), and patients treated without induction (4%; 95% CI, 3% to 7%).

Discussion

In this study of well-matched transplant recipients who shared HLA typing with their donor at the HLA-A, -B, -DR, and -DQB1 gene loci and therefore had a low probability of preformed DSA, the majority of patients were treated with T cell–depleting antibody therapy. Few patients in this low–immune risk cohort had additional immunologic risk factors, such as Black recipient race (12%), deceased donor KDPI ≥85% (2%), donation after circulatory death (9%), and cold ischemic time ≥18 hours (32%), to account for the high use of depleting antibody induction therapy. The findings suggest that the lack of precise recommendations on how to rank or combine individual immunologic risk factors when choosing induction therapy contributes to variation in clinical practice in the United States, where the use of depleting antibody induction is far more common than in other developed countries (^789–10).

The study found no difference in outcomes between patients treated with IL2-RAs and no induction therapy and suggests that any form of induction therapy may not be necessary in zero HLA-A, -B, -DR, -DQB1 mismatched first kidney-only transplant recipients. Because the number of patients treated without any induction therapy was limited, it is difficult to further specify patient subgroups in which induction therapy may be safely avoided altogether.

The study findings with regard to the use of IL2-RAs should be considered in the context of the pivotal IL2-RAs trials (^111213–14). These studies included low–immunologic risk patients defined by PRA, and they reported a lower risk of acute rejection and comparable 1-year allograft survival compared with placebo; however, they did not show a difference in long-term clinical outcomes. The majority of patients in the pivotal trials were treated with cyclosporin-based immunosuppression protocols, and none were treated with mycophenolate mofetil. The studies included in a 2010 meta-analysis that compared IL2-RAs with placebo consisted of 87% of patients treated with cyclosporin as opposed to tacrolimus; only 50% were treated with mycophenolate mofetil, and 22% were treated with double as opposed to triple therapy (¹⁵,¹⁶). Although these studies reported a benefit of IL2-RA on acute rejection and allograft survival at 1 year post-transplant, these benefits were not maintained thereafter. Subsequent retrospective analyses comparing IL2-RA with no induction in low–immune risk patients defined by PRA treated with tacrolimus and mycophenolate mofetil have demonstrated no difference in 5-year allograft survival, consistent with our findings (^1718–19). Our findings add to the existing literature by specifying a low–immune risk group defined by current immunogenetic testing methods in which IL2-RAs were not associated with improved outcomes compared with treatment without induction.

The study also found no difference in the outcome of graft loss from any cause and a higher risk of graft loss censored for death in patients treated with T cell–depleting induction compared with treatment with IL2-RA or no induction therapy. Subgroup analyses of patients with risk factors for rejection, including Black recipients, deceased donor recipients and patients with high cPRA, failed to identify a subset of patients in whom T cell depletion was associated with better outcomes. The majority of the patients treated with T cell–depleting induction received thymoglobulin, but the findings were consistent in alemtuzumab-treated patients. Importantly, in previous controlled studies comparing T cell–depleting induction with IL2-RAs in high–immune risk patients populations, T cell depletion was associated with a lower risk of rejection but was not associated with better graft or patient survival (^2021–22).

The finding of a higher risk of death-censored graft loss among patients treated with T cell–depleting therapy should be interpreted with caution. T cell–depleting induction is associated with a higher risk of administration reactions, infection, and malignancy compared with IL2-RAs, but we would not anticipate these differences to lead to a higher risk of death-censored graft loss (¹⁵). Unfortunately, the causes of graft failure are frequently missing in this dataset, making it impossible to speculate regarding mechanisms of graft loss. The study findings support previous studies and recommendations that T cell–depleting induction should be reserved for patients at high immune risk and are valuable in defining a low–immune risk population of zero HLA-A, -B, -DR, -DQB1 first transplant living donor recipients in whom T cell depletion may not be beneficial (¹⁹,²³,²⁴).

The study highlights the importance of reconsidering long-held clinical practice paradigms. It is notable that the Federal Drug Administration’s approval of the use of thymoglobulin for induction in kidney transplantation was not limited to patients at high immune risk, despite the fact that the approval was primarily on the basis of two randomized controlled trials in patients at risk for rejection or delayed graft function (²⁰,²⁵). In the context of evolving understanding regarding the characterization of immune risk, the broad approval of thymoglobulin for induction therapy should not limit efforts to define patient subgroups where depleting induction therapy may be particularly beneficial or unnecessary. In this regard, PRA has commonly been used as a laboratory measure of immune risk. The association of induction therapy with transplant outcomes in this study was consistent in patient subgroups defined by cPRA, in keeping with recent findings indicating that cPRA is not associated with transplant outcomes in the absence of DSA (^2627–28).

Black recipient race was not associated with outcomes in this study of well-matched transplant recipients. The association of induction therapy with transplant outcomes was also consistent in the subgroup of Black recipients. The basis for the association of Black race with a higher risk of transplant failure is multifactorial, including socioeconomic factors and donor and recipient HLA matching as well as differences in genetics and drug metabolism (²⁹). Studies in Black recipients outside the United States found no difference in transplant outcomes, suggesting that the higher risk among Black recipients in the United States may be largely due to health system or socioeconomic factors (³⁰,³¹). These study findings suggest that well-matched Black recipients are not at higher risk of graft loss and may not require depleting induction therapy in the absence of additional risk factors, supporting previous reports (³²). The association of induction therapy with transplant outcomes was also consistent in deceased donor recipients. There were too few recipients of high-KDPI deceased donor kidneys to identify variation in the association between induction and transplant outcomes as a function of KDPI.

Readers of this study should consider the inherent limitations of observational studies on the basis of registry data, including misclassification and the possibility of residual confounding. Because longitudinal information regarding maintenance immunosuppression is not reliably recorded after transplantation and there is no information on drug dosing or drug levels, our analyses do not account for potential differences in long-term maintenance immunosuppression. Additionally, the data do not allow us to precisely determine the timing of acute rejection or the type of rejection episodes. The restriction of the study population to zero HLA-A, -B, -DR, -DQB1 mismatched recipients allowed us to identify a cohort that should not develop DSA to these HLA antigens. However, our analysis is predominantly on the basis of HLA data with low resolution. Patients who are HLA matched with their donors on the basis of antigen-level typing may still develop allele-specific antibodies against their donors, which can lead to immune injury and graft loss. Further, the study findings in this cohort may not be applicable to nonzero HLA mismatched recipients without preformed DSA. The generalizability of the study findings outside the United States is also uncertain. Categorizing patients into high or standard immune risk is complex and may be influenced by additional factors not captured in our analysis. How individual providers respond to perceived risk may vary, and the choice of induction therapy may therefore be influenced by differences in risk perception, as well as the cost of induction therapy, regulatory requirements, and the ease of patient monitoring after transplantation.

In summary, most patients in this well-matched US cohort underwent induction with T cell–depleting antibodies. The findings suggest that in well-matched patients, depleting antibody induction offers no benefit over IL2-RAs, irrespective of the presence of other factors contributing to immune risk. Indeed, in well-matched living donor recipients, depleting antibody induction is associated with a higher risk of graft loss censored for death. Transplant outcomes were no different between patients treated with IL2-RAs or no induction, suggesting that any form of induction therapy may be unnecessary in this well-matched group. Further prospective studies to refine the use of induction immunosuppression in patients on the basis of contemporary methods of immunologic risk assessment are needed.

Disclosures

J.S. Gill reports employment with BC Transplant and serving as a scientific advisor or member of Canadian Blood Services, the Canadian Organ Replacement Register, the Canadian Society of Transplantation, and Health Canada. J.S. Gill reports receiving research funding from Astellas, receiving honoraria from Takeda, and serving as a scientific advisor or member of the American Society of Transplantation and the Declaration of Istanbul Custodial Group. L. McMichael reports serving as an editorial intern of American Journal of Kidney Diseases. All remaining authors have nothing to disclose.

Funding

R.D.R. Evans acknowledges fellowship support from the St. John Ambulance Air Wing and the Royal Free Hospital Transplant Fund. J.S. Gill is funded by a Canadian Institutes of Health Research Foundation Award. M. Kadatz is supported by the Vancouver Coastal Health Research Institute.