Infection Risks With Thymoglobulin Use for Delayed Graft Function in Deceased Donor Kidney Transplantation: Research Letter

Abstract

Anti-thymocyte globulin (ATG) is often used when delayed graft function (DGF) occurs post-transplantation. The ATG may be associated with an increased risk of infections but may also decrease rejection risk in high-immunological risk recipients. The safety of ATG for the indication of DGF in low-immunological risk recipients has not been well characterized. We conducted a retrospective cohort study of deceased donor kidney transplant recipients deemed low-immunological risk and not planned for ATG induction, from June 2019 to June 2023 (N = 139). Participants switched to ATG post-transplant due to DGF (exposure; N = 68) were compared to those who did not receive ATG for induction (controls; N = 71 basiliximab only induction). Outcomes examined included BK, cytomegalovirus (CMV), and serious infection as well as acute rejection, graft loss, and death. Participants who received ATG for DGF, compared to controls, were older (63.9 vs 59.7 years), more often had diabetes as cause of kidney failure (45.5% vs 33.8%) were more often recipients of death determination by circulatory criteria donor (70.5% vs 30.9%) and extended criteria donor kidneys (48.5% vs 32.3%). There was no significant difference in the probability of BK (22.1% vs 21.1%, P = .89), CMV (20.6% vs 9.9%, P = .08), serious infections (44.1% vs 43.6%, P = .96), acute rejection, graft loss, or death. The use of ATG for DGF following kidney transplantation did not significantly increase infection risk nor did it improve graft outcomes. Further studies are needed to clarify the risk-benefit trade-off of using ATG for DGF.

Introduction

Delayed graft function (DGF) after deceased donor kidney transplantation is considered a high-immunological risk condition.^1,2 The risk for, or development of, DGF after transplantation may alter the choice of induction immunosuppression to mitigate this risk. Lymphocyte-depleting induction therapies such as anti-thymocyte globulin (ATG) provide greater immunosuppression than non-depleting agents such as basiliximab. ³ In deceased donor kidney transplant recipients at high risk for rejection or DGF, ATG may decrease acute rejections but may increase infections. ⁴ In otherwise low-immunological risk recipients who develop DGF, it is It is unclear whether the potential benefit of ATG over basiliximab to reduce rejection outweighs the potential infection risk, particularly in the current era of maintenance immunosuppression with tacrolimus and mycophenolate. At our center, low-immunological risk recipients are initially planned for basiliximab induction but are switched to ATG if DGF occurs. We examined the infection risks and graft outcomes in low-immunological risk deceased donor kidney transplant recipients who developed DGF treated with ATG compared to those who did not develop DGF or did not receive ATG.

Methods

Study design, participants, and setting

This was a retrospective cohort study of adult recipients of deceased donor kidney-only transplants performed at The Ottawa Hospital (TOH) between June 1, 2019 and June 30, 2023. We included recipients initially deemed low-immunological risk for rejection planned for basiliximab induction, as per our protocol. At TOH, a deceased donor recipient is considered low immune risk when they have no high-immunological risk features (re-transplantation, cumulative panel reactive antibody >20%). No patients were excluded. The study methods and analysis plan were determined prior to availability of data. Research ethics board approval was obtained and due to the retrospective nature of our study and use of deidentified information, the need for informed consent was waived. Participants were identified through our renal transplant database. Chart review was done to capture baseline characteristics, exposure, and outcomes. All participants were followed from date of transplant until February 29, 2024.

Exposure and control groups

The exposure group consisted of eligible participants who received ATG induction due to DGF after transplant, whereas the control group was those who did not receive ATG induction immunosuppression (either did not develop DGF or had DGF but ATG was not given). The ATG typically starts within the first 12 to 24 hours post-transplant when the recipient is noted to have oligo-anuria, insufficient drop in serum creatinine, or require dialysis.

Outcomes and covariates

The primary outcomes were the occurrence of infections post-transplant. We examined BK infection (detectable and quantifiable viremia or confirmed infection through histopathologic examination of the allograft), cytomegalovirus (CMV) infection (detectable and quantifiable viremia or confirmed infection through histopathologic examination of an affected organ), EBV infection (detectable and quantifiable EBV viremia or post-transplant lymphoproliferative disorder [PTLD] confirmed through histopathologic examination of an affected organ or tissue), and serious infection (requiring treatment with IV antimicrobials or any infection leading to hospital encounter), bacterial, viral, or fungal. Secondary outcomes were the occurrence of rejection, graft failure (re-transplantation, nephrectomy, or need for continuous dialysis for ≥12 weeks post-transplantation), or death. Clinically relevant patient characteristics, determined a priori and available in the chart, were gathered. At our center, all kidney transplant recipients undergo routine BK screening in the first 2 years and receive valganciclovir prophylaxis for 3 months (recipient CMV serostatus positive) or 6 months (CMV serostatus mismatch: donor positive/recipient negative) post-transplantation.

Statistical analysis

Baseline characteristics and outcomes were determined for the entire study cohort and for the exposure and control groups (continuous variables as mean with standard deviation or median with interquartile range [IQR] and categorical variables as numbers with percentages). We compared outcomes between the 2 groups using chi-square, with P < .05 considered significant, and by calculating relative risks (RRs) with 95% confidence intervals (95% CIs).

Results

Patient characteristics

There were 139 participants who met eligibility during the study period: 68 received ATG for DGF and 71 received basiliximab only (controls; 70 did not have DGF and 1 had DGF but still received only basiliximab). Those who received ATG for DGF, compared to controls, were older (63.9 vs 59.7 years), more often male (79.4% vs 70.4%), and more often had diabetes as original disease (45.5% vs 33.8%). The donor type was more often death determination by circulatory criteria and confirmed extended criteria donor in the ATG group vs controls (70.5% vs 30.9% and 48.5% vs 32.3%, respectively). The mean dose of ATG was 363.6 mg. In both groups, 95% of participants received tacrolimus, mycophenolate, and prednisone maintenance immunosuppression. The CMV serostatus was donor positive/recipient negative in 13% of ATG and 28% of controls and recipient positive in 66% of ATG and 49% of controls.

Infections

The number of BK infections was similar between ATG and controls (22.1% vs 21.1%, respectively, P = .89). The severity of BK viremia based on median peak viremic level was also was similar between ATG and controls (21 955 vs 33 025). One patient in each group (1.5% vs 1.4%) had biopsy-proven BK nephropathy. There was a higher probability of CMV infection in the ATG group (20.6% vs 9.9%, P = .08), but the difference was not statistically significant. Median peak CMV viremia level was higher in ATG than controls (48 750 vs 7810). Among participants who developed CMV, characteristics were similar in age and CMV donor/recipient serostatus between the 2 groups (ATG: 57.1% recipient positive and 42.9% donor positive/recipient negative; controls: 42.9% recipient positive and 57.1% donor positive/recipient negative). Occurrence of EBV infection (2.9% vs 2.8%, P = .97) and serious infection (44.1% vs 43.6%, P = .96) was not significantly different between ATG and controls, respectively (Table 1).

Table 1.

Outcomes by ATG exposure.

	ATG (68)	Control (71)	RR (95%CI)	P
BK infection, N (%)	15 (22.1)	15 (21.1)	1.04 (0.55, 1.97)	.89
CMV infection, N (%)	14 (20.6)	7 (9.9)	2.15 (0.93, 5.00)	.08
EBV infection, N (%)	2 (2.9)	2 (2.8)	1.04 (0.15, 7.20)	.97
Serious infection, N (%)	30 (44.1)	31 (43.7)	1.01 (0.69, 1.47)	.96
Serious infection types, N a	UTI 11 Bacterial pneumonia 6 COVID 5 SSTI 5 Invasive fungal 4 Bacteriemia 3 C Diff 2 Herpes/zoster 2 Nocardia 1 Tuberculosis 1	UTI 12 Bacterial pneumonia 3 COVID 8 SSTI 8 Invasive fungal 4 Bacteriemia 1 CMV 2 PJP 1
Acute rejection, N (%)	3 (4.4)	6 (8.5)	0.52 (0.14, 2.00)	.33
Graft loss, N (%)	2 (2.9)	3 (4.2)	0.70 (0.12, 4.04)	.68
Death, N (%)	12 (17.6)	9 (12.7)	1.39 (0.63, 3.09)	.41

Abbreviations: ATG, anti-thymocyte globulin; C Diff, clostridium difficile; CMV, cytomegalovirus; EBV, Epstein-Barr virus; PJP, pneumocystis jiroveci pneumonia; SSTI, skin or soft tissue infection; UTI, urinary tract infection; RR, relative risk.

a

Number of patients who had various types of serious infections (numbers do not add up to total N of serious infections because a single patient could have had more than 1 serious infection).

Graft outcomes

There was no significant difference in acute rejection (4.4% vs 8.5%, P = .33), graft loss (2.9% vs 4.2%, P = .68), or death (17.6% vs 12.7%, P = .41) between participants receiving ATG vs controls, respectively (Table 1).

Discussion

In this single-center study examining the use of ATG for DGF in kidney transplant recipients initially deemed low-immunological risk, there was no significant difference in the probability of BK, CMV, or serious infections post-transplant, nor was there any significant difference in acute rejection, graft loss, or death.

Although the difference did not reach statistical significance, the risk of CMV infection was double that in controls. For recipients who developed CMV viremia, the peak titer was higher in the ATG group, suggesting increased severity of infection. Limited sample size may have limited our ability to find a significant difference. While hypothesis generating, this may still be an important finding. Our study population had low rates of rejection with no significant difference between ATG and controls. Mourad et al ⁵ conducted a trial comparing ATG to basiliximab for induction therapy (not for DGF) in low-immunological risk recipients and found a doubling of CMV in those treated with ATG, with low rejection rates similar between the 2 groups. Our findings of CMV and rejection risk are consistent with this study. In a high-immunological risk population, Brennan et al ⁴ found that ATG was associated with higher rates of infections but lower rates of rejection compared to basiliximab. Interestingly, CMV was less common in the ATG group, possibly from patients treated with basiliximab having more rejection requiring increased immunosuppression. We found numerically less acute rejections with ATG, but this was not significant given the low number of events. Therefore, in otherwise low-immunological risk recipients with low baseline probability of rejection, the potential CMV risks from ATG for DGF may outweigh potential benefits.

The occurrence of non-CMV infections was not greater in patients who received ATG. Why ATG would affect CMV and not other common infections such as BK or serious infections is unclear. Such discrepancies have also been noted in other studies.^5,6 The ATG may lead to leukopenia. ⁷ In recipients at risk of CMV who receive valganciclovir prophylaxis, leukopenia may prompt holding valganciclovir, which could predispose to CMV viremia and disease. Also, when DGF occurs, kidney function may take weeks or even months to reach steady state, which can lead to under-dosing valganciclovir, predisposing to breakthrough viremia. Therefore, the signal for CMV infection may simply be due to confounding.

While this was a single-center study, it was performed in a Canadian academic teaching hospital and the patient population would be representative of those found in similar centers. A major limitation of our study is the nature of the control group. The ideal control group would have been recipients who developed DGF but did not receive ATG. We had only 1 such patient. If the control group had more such patients, there could have been more rejection in controls and perhaps a benefit seen from ATG. Furthermore, our control group (younger and better-quality donors) may have been at inherently lower risk of infection. However, it is unclear how this could have affected our findings since ATG use did not impact all infection risks the same way. Finally, we did not capture the duration of DGF in the ATG group; therefore, it is unclear to what extent DGF could have affected graft outcomes.

Conclusions

Our study found no significantly increased risk for infection or clear benefit for rejection from ATG for DGF in otherwise low-immunological risk recipients. There may be a signal for increased risk for CMV. Therefore, it may be prudent to adopt a case-by-case approach when considering the use of ATG for DGF in a low-immunological risk setting, accounting for other factors that may impact CMV risk. The use of CMV-specific immune assays, if available, to guide decisions or CMV monitoring post-prophylaxis for delayed onset post-prophylaxis CMV disease may be considered. Further studies would be needed to clarify the safety and efficacy of using ATG for DGF compared to basiliximab. A randomized controlled trial would be challenging; however, it would be interesting to compare our findings to other centers’ that do not routinely use ATG for DGF.