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Original Clinical Science—General

The Influence of Antithymocyte Globulin Dose on the Incidence of CMV Infection in High-risk Kidney Transplant Recipients Without Pharmacological Prophylaxis

de Paula, Mayara I. PharmD, PhD1,2; Bae, Sunjae KMD, MPH2,3,4; Shaffer, Ashton A. BA2,3; Garonzik-Wang, Jacqueline MD, PhD2; Felipe, Claudia R. PharmD, PhD1; Cristelli, Marina P. MD, MHS1; Waldram, Madeleine M. BA2; Massie, Allan B. PhD2,3; Medina-Pestana, Jose MD, PhD1; Segev, Dorry L. MD, PhD2,3; Tedesco-Silva, Helio MD, PhD1

Author Information
doi: 10.1097/TP.0000000000003124

Abstract

INTRODUCTION

Antithymocyte globulin (ATG) induction therapy is commonly used in kidney transplantation (KT) to prevent acute rejection (AR) and protect against subsequent graft loss.1-3 Previous randomized trials and meta-analyses have found ATG use to be associated with lower rates of AR compared to no induction or induction with IL-2RA.4-7 In particular, ATG can benefit KT recipients with risk factors for AR, such as those who are highly sensitized (panel reactive antibody [PRA] ≥50%) or are recipients of expanded criteria donor (ECD) grafts.8,9 However, high doses and prolonged exposure to ATG can lead to an increased risk of infections,10 mainly cytomegalovirus (CMV),6,9 which is associated with significant post-KT morbidity and mortality.11 Since up to 60% of infections in KT recipients occur in the absence of prophylaxis, it is important to establish a treatment protocol that finds the right balance in ATG dosage, when preventive strategies are unavailable. Despite the fact that guidelines recommend the use of CMV prophylaxis in patients with high-risk of CMV infection/disease, the availability of a highly effective oral drug, valganciclovir, is perhaps the primary reason for the growing shift from preemptive therapy to universal CMV prophylaxis. Yet, drug-related toxicities, late CMV infection after discontinuation of prophylaxis, and costs are critical concerns.12

ATG dose reduction has been proposed as a strategy for minimizing the risk of excess immunosuppression and achieving comparable outcomes in KT recipients. Although ATG is approved by Food and Drug Administration for the prevention of post-KT AR, with recommended doses of 6–10.5 mg/kg, the appropriate regimen for patients considered at high-risk for AR and receiving no pharmacological CMV prophylaxis has not been defined. Clinical studies examining ATG doses ranging from 4.5 to 10.3 mg/kg in high-risk KT recipients, receiving CMV prophylaxis, found similar AR rates ranging from 8.8% to 11% with lower or comparable CMV infection rates ranging from 4.8% to 6.1%.8,13,14 A recently published clinical trial comparing an ATG dose of 4.5 mg/kg versus 6.0 mg/kg in KT recipients with CMV prophylaxis found lower CMV infections among KT recipients who received 4.5 mg/kg ATG dose compared to 6 mg/kg (16% versus 33%, P = 0.003), regardless of CMV prophylaxis used.15 A single 3 mg/kg dose was effective in reducing AR to 9.3%, but the safety and efficacy of this dose has not been explored in KT recipients at high-risk of AR with no CMV prophylaxis.

We hypothesized that a single 3 mg/kg dose of ATG would reduce CMV infections without increasing other adverse outcomes in KT recipients at high-risk for graft loss without CMV prophylaxis. At Hospital do Rim, Brazil, the introduction of a protocol, on June 17, 2014, changed induction therapy from the conventional dose (≥4 doses of 1–1.5 mg/kg/per dose) to a single dose (3 mg/kg) of ATG. Using this natural experiment, we studied KT recipients who were sensitized (PRA ≥50%) or received ECD grafts to compare the safety and efficacy of a single ATG dose versus conventional dose, examining the risks of CMV infection, rejection, death-censored graft loss, and mortality.

MATERIALS AND METHODS

Study Population

We conducted a retrospective cohort study of adult (>18 y old) KT recipients receiving induction therapy with ATG, maintenance immunosuppression therapy with tacrolimus (TAC), prednisone (PRED) and mycophenolic acid (MPA), and no CMV prophylaxis, from January 2, 2013 to May 21, 2015. Patients were considered at high-risk for graft loss if they received an ECD renal allograft or if they were sensitized (PRA ≥50%). None of the recipients had anti-HLA-A, B, and DR preformed donor specific antibodies. We excluded KT recipients with pretransplant serologies positive for HIV, hepatitis C virus (HCV), or hepatitis B virus surface antigen (HBsAg) and those who underwent simultaneous pancreas-kidney transplantation or received organs from living donors. The study was approved by the local Research Ethics Committee under registration C.A.A.E ID: 49776815.4.0000.5505.

Immunosuppression Protocol

On June 17, 2014, the study institution implemented an induction therapy protocol changing the dose of ATG used in high-risk KT recipients from the conventional dose (up to 5 doses of 1–1.5 mg/kg/per dose ATG) to a reduced dose (single dose of 3 mg/kg ATG), creating a natural experiment to compare the safety and efficacy of these 2 treatment regimens. To identify changes in the incidence of CMV infections and AR, we defined 2 eras relative to the protocol implementation date: a conventional dose era (January 02, 2013 to June 16, 2014) and a reduced dose era (June 17, 2014 to May 21, 2015). According to the institutional protocol, all high-risk KT recipients in the study period received ATG induction, administered intravenously beginning within the first 24 hours after graft revascularization. All recipients were initiated on intravenous methylprednisolone (500 mg) intraoperatively, followed by oral PRED (0.5 mg/kg) within the first 24 hours after graft revascularization, and MPA (720 mg twice daily). PRED was reduced to a once daily dose (5 mg/kg) by the end of the first month post-KT. All patients received trimethoprim-sulfamethoxazole prophylaxis for at least 12 months.

Conventional Dose Era

In the conventional dose era, 406 high-risk KTs were performed; of these, 313 received ECD grafts and 93 were sensitized. Patients receiving ECD allografts were treated with an ATG infusion of 1.5 mg/kg for up to 4 alternative days and TAC (0.05 mg/kg twice daily) was added to the regimen after the end of ATG induction therapy. Sensitized patients received ATG (1.0 mg/kg) for up to 5 consecutive days and TAC (0.1 mg/kg twice daily) beginning on the first day post-KT to maintain whole blood trough concentrations between 8 and 12 ng/mL.

Reduced Dose Era

In the reduced dose era, we studied 224 KT recipients who were treated with a single ATG infusion of 3 mg/kg; of these 155 received ECD grafts and 69 were sensitized. For patients receiving ECD allografts, TAC (0.05 mg/kg twice daily) was added to the regimen 24 hours after revascularization, and the dose was adjusted to maintain whole blood trough concentrations between 5 and 15 ng/mL. Sensitized patients received TAC (0.1 mg/kg twice daily) beginning on the first day post-KT to maintain whole blood trough concentrations between 5 and 15 ng/mL.

Incidence of CMV Infection or Disease

Our main outcome of interest was the cumulative incidence of CMV infection or disease. No patients received pharmacological prophylaxis for CMV infection; post-KT all patients were monitored for CMV antigenemia test every 2 weeks from week 3 to week 12. CMV infection was defined as the presence of >10 infected cells per 200 000 peripheral blood neutrophils in asymptomatic patients based on a CMV pp65 antigenemia assay. CMV disease was diagnosed based on evidence of related signs or symptoms, including fever, asthenia, myalgia, leukopenia, thrombocytopenia, or liver enzyme abnormalities, in the presence of any number of CMV pp65 infected cells.16 CMV infection or disease was treated with intravenous ganciclovir for at least 14 days with weekly monitoring of viral replication. Treatment was continued for 1 week after the first negative CMV pp65 antigenemia test.

Post-KT Outcomes

In addition to CMV incidence, we explored post-KT outcomes including: AR, delayed graft function (DGF), changes in estimated glomerular filtration rate (eGFR), death-censored graft loss, and mortality. AR was defined as any report of a clinical AR or biopsy proven AR (BPAR). Clinical AR was defined as graft dysfunction without histological evidence of rejection and was treated with methylprednisolone for at least 3 days. Episodes of BPAR were graded according to Banff 2009 criteria (IA or higher). As a sensitivity analysis, we also examined KT recipients with BPAR only. DGF was defined as the need for dialysis during the first week after KT, excluding a single dialysis for hypervolemia and/or hyperkalemia. eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation17 and assessed at 1 week, 1 month, 3 months, 6 months, and 1 year post-KT. We compared the cumulative incidence of death-censored graft loss and mortality in the reduced dose and conventional dose eras. Graft loss was defined as the need for permanent return to dialysis.

Statistical Analysis

All patients were followed up for a year following KT. We used Cox proportional hazards models to measure the association between ATG dosing protocols and the incidence of CMV infections and other post-KT outcomes, adjusting for recipient factors (age, race, sex, history of hypertension, history of diabetes, time on dialysis pre-KT, history of previous transplant, PRA class I and class II, time on dialysis post-KT, and CMV IgG serostatus), donor factors (age, race, sex, cause of death, terminal creatinine, history of hypertension, history of diabetes, and CMV IgG serostatus), transplant factors (cold ischemia time, number of HLA A, B, or DR mismatches), and temporal trend. The cumulative incidence of mortality and death-censored graft loss were estimated using the Kaplan–Meier method. We used a multivariable linear regression to compare eGFR. Confidence intervals were reported according to the method of Louis and Zeger.18 All statistical analyses were performed using Stata version 15.0 (StataCorp, College Station, TX) with 2-sided hypothesis testing and an α of 0.05 as the criterion for statistical significance.

Propensity Score Stratification

Propensity score (PS) stratification was used to account for potential differences in baseline covariates of patients in different treatment eras. To build the PS, we used a cutoff of 4 mg/kg of ATG, based on the cumulative ATG dose distribution observed among patients in the conventional dose era (Figure 1). Thus, each patient’s PS was modeled based on the baseline characteristics of those transplanted in the conventional dose era to estimate the probability of receiving an ATG dose >4 mg/kg. PS was modeled using multivariable logistic regression with recipient (age, race, sex, history of hypertension, history of diabetes, time on dialysis pre-KT, history of previous transplant, PRA class I and class II, time on dialysis post-KT, and CMV IgG serostatus), donor (age, race, sex, cause of death, terminal creatinine, history of hypertension, history of diabetes, and CMV IgG serostatus), and transplant characteristics (cold ischemia time and number of HLA A, B, or DR mismatches). Patients were then divided into 3 strata based on their PS, reflecting a low, intermediate, or high probability of receiving an ATG dose >4 mg/kg in the conventional dose era.

FIGURE 1.
FIGURE 1.:
Distribution of the cumulative ATG doses (mg/kg) administered to kidney transplant recipients in the reduced dose era and in the conventional dose era. ATG, antithymocyte globulin.

RESULTS

Study Population

During the study period, 1613 deceased donor KTs were performed at Hospital do Rim. Among these, 767 were treated with ATG, TAC, PRED, and MPA. We excluded 63 simultaneous kidney-pancreas transplant recipients, 7 pediatric KT recipients, 28 recipients with positive pretransplant serologies (17 HCV, 7 HIV, 3 HBsAg, 1 HCV/HBsAg), 7 recipients of non-ECD donors, 2 recipients with adverse events during ATG infusion, and 30 recipients enrolled in clinical trials. We identified 630 KT recipients at high-risk for rejection who were eligible for inclusion in our study cohort (Figure 2). In this cohort, the median age was 49 years old (interquartile range [IQR]: 38–57), 53.3% were men, 43.97% were Caucasian, 78.89% had hypertension, 18.89% had diabetes, 18.6% were sensitized, and the median time on dialysis was 42.4 months (IQR: 22–76). The most common cause of end-stage renal disease was undetermined (36.98%), 38.1% had 2 HLA mismatches, 11.43% had previously undergone a KT, and 93.01% of recipients had positive CMV serologies pre-KT.

FIGURE 2.
FIGURE 2.:
Disposition of the study population. ECD, expanded criteria donor; HBsAg, hepatitis B virus surface antigen; HCV, hepatitis C virus.

Patient Characteristics

When grouped by era, recipients in the conventional and reduced dose eras were similar with respect to sex, race, HLA mismatches, PRA, history of hypertension, history of diabetes and time on dialysis. The median (IQR) cumulative ATG dose was 5.5 (4.1–6.2) in the conventional dose era and 3.0 (2.9–3.1) in the reduced dose era (P < 0.001). The distribution of ATG doses in this cohort is shown in Figure 1. Compared to recipients in the conventional dose era, recipients in the reduced dose era had slightly longer cold ischemia time (24.0 [IQR: 20.0–31.0] versus 22.0 [IQR: 19.0–29.0] h; P = 0.02) and were more likely to have had a prior KT (17.4% versus 8.1%; P < 0.001). The majority of recipients (83.6%) were considered at moderate risk for CMV (Donor+/Recipient+), with 6.1% at higher risk (Donor+/Recipient−) (Table 1).12,16

TABLE 1. - Characteristics of the study population
Baseline characteristics Conventional dose era (N = 406) Reduced dose era (N = 224) P
ATG dose mg/kg, median (IQR) 5.5 (4.1–6.2) 3.0 (2.9–3.1) <0.001
Recipient characteristics
 Age, median (IQR) 49.0 (38.0–57.0) 49.0 (39.0–58.0) 0.6
 Male (%) 53.7 52.7 0.8
 Caucasian race (%) 43.3 45.1 0.7
 Primary cause of end-stage renal disease (%) 0.2
  Hypertension 14.8 13.4
  Glomerulonephritis 16.7 21.4
  Diabetes mellitus 14.3 16.5
  Undetermined 39.9 31.7
  Others 14.3 17.0
  Diabetes (%) 17.0 22.3 0.1
  Hypertension (%) 80.3 76.3 0.2
  PRA class I >50% (%) 18.2 21.9 0.3
  PRA class II >50% (%) 9.9 14.7 0.07
 Time on dialysis (mo), median (IQR) 42.0 (22.0–73.2) 43.0 (21.8–84.0) 0.6
 Previous transplant (%) 8.1 17.4 <0.001
 Pretransplant CMV serostatus (%) 0.04
  Donor (+)/Recipient (+) 79.3 87.9
  Donor (+)/Recipient (−) 6.9 5.4
  Donor (−)/Recipient (+) 13.1 6.3
  Donor (−)/Recipient (−) 0.7 0.4
 HLA mismatches (%) 0.2
  0 7.6 8.5
  1 14.0 17.4
  2 41.4 32.1
  3 24.9 29.9
  4 8.6 8.9
  5 2.5 3.1
  6 1.0 0.0
 Cold ischemia time, median (IQR) 22.0 (19.0–29.0) 24.0 (20.0–31.0) 0.02
Donor characteristics
 Age, median (IQR) 54.0 (46.0–61.0) 54.0 (45.0–62.0) 0.9
 Male (%) 59.1 51.8 0.08
 Caucasian race (%) 54.9 51.8 0.4
 Cause of death (%) 1.0
  Cerebrovascular 72.2 71.9
  Trauma 21.2 21.9
  Others 6.7 6.3
 Diabetes (%) 8.9 12.9 0.1
 Hypertension (%) 55.4 57.1 0.7
 Terminal creatinine, median (IQR) 1.8 (1.2–3.0) 1.9 (1.1–3.1) 0.9
ATG, antithymocyte globulin; CMV, cytomegalovirus; IQR, interquartile range; PRA, panel reactive antibody.

Post-KT Outcomes

Incidence of CMV Infection or Disease

Overall, 449 recipients (71.3%) developed CMV infection or disease (conventional dose era: 309 [76.1%]; reduced dose era: 140 [62.5%]). Recipients presented with CMV infection more often than CMV disease (66 versus 44%) and an AR episode preceded 7.8% of cases. In the unadjusted analyses of CMV infection/disease stratified by CMV serostatus combination, the D−/R− combination has just 4 cases and did not provide a meaningful HR. The HR was below 1 for all other combinations (including D−/R+) except for D(Unk)/R− combination, but sample size was only 15 and the HR was not significant. In the highest risk group CMV D+/R−, the unadjusted HR is 0.330.852.20 (P = 0.7) (Table S1, SDC, http://links.lww.com/TP/B867). Therefore, we did not include any new covariate in the multivariable analysis. There were 162 episodes of CMV diseases in total. The unadjusted HR is 0.640.881.22 (P = 0.4). The adjusted hazard ratio (aHR) is 0.510.961.84 (P = 0.9), and the aHR including TAC concentration at 1 month is 0.520.991.90 (P = 1.0). After adjusting for confounders, recipients in the reduced dose era were at a significantly lower hazard of developing CMV infection or disease than recipients in the conventional dose era (aHR: 0.420.630.93; P = 0.02) (Figure 3). After PS stratification and adjustment, the hazard of CMV infections or disease did not differ for patients with a low (aHR: 0.410.661.06; P = 0.1) or intermediate (aHR: 0.380.641.07; P = 0.1) probability of receiving a dose of ATG >4 mg/kg. However, in the highest PS tertile, recipients in the reduced dose era had a lower hazard of CMV infections or disease than those in the conventional dose era (aHR: 0.340.560.91; P = 0.02) (Table 2). Mean TAC whole blood trough concentrations at 1 month post-KT was 6.1 ng/mL (IQR = 4.5–8.5) in the conventional era and 7.5 ng/mL (5.9–9.9) in the reduced dose era (aHR: 0.420.620.92 [P = 0.02]). Adding TAC concentration at 1 month to the model did not change significantly the interpretation of the data.

TABLE 2. - Hazard of CMV infection/or disease, and acute rejection within the first y after kidney transplantation in the whole cohort and across propensity score stratification
Whole cohort Propensity score stratification
Lowest tertile (n = 210) Intermediate tertile (n = 210) Highest tertile (n = 210)
Outcomes Conventional dose era Reduced dose era Conventional dose era Reduced dose era Conventional dose era Reduced dose era Conventional dose era Reduced dose era
N 406 224 105 105 105 105 105 105
First episode of CMV infection Reference 0.420.630.93 Reference 0.410.661.06 Reference 0.380.641.07 Reference 0.340.560.91
First treated acute rejection Reference 0.471.162.83 Reference 0.200.621.91 Reference 0.421.314.08 Reference 0.772.306.86
Propensity score stratification characteristics include: Recipient (age, race, sex, history of diabetes, history of hypertension, time on dialysis, history of previous transplant, PRA class I and class II, time on post-KT dialysis), CMV IgG serostatus (Donor/Recipient), cold ischemia time, and number of HLA A, HLA B, HLA DR mismatches, and donor characteristics (age, race, sex, cause of death, terminal creatinine, history of hypertension and history of diabetes).
CMV, cytomegalovirus; KT, kidney transplantation; PRA, panel reactive antibody.

FIGURE 3.
FIGURE 3.:
Time to first CMV infection/or disease in high-risk recipients with no pharmacological CMV prophylaxis. Adjusted hazard ratio (aHR: 0.420.630.93; P = 0.02) of developing CMV infection or disease was lower for recipients in the reduced dose era compared to the conventional dose era. CMV, cytomegalovirus.

Acute Rejection

Overall, 116 recipients (18.4%) developed AR (conventional dose era: 92 [22.7%]; reduced dose era: 24 [10.7%]). After adjusting for potential confounders, the hazard of AR was similar for recipients in the reduced dose era, compared to the conventional era (aHR: 0.471.162.83; P = 0.8). Within PS strata, there were no statistically significant differences in the hazard of AR by era. However, compared to the conventional dose era, in the reduced dose era, there is a trend in the hazard of AR to be slightly lower among the low PS stratum (aHR: 0.200.621.91; P = 0.4), and slightly higher among the intermediate (aHR: 0.421.314.08; P = 0.6) and high PS strata (aHR: 0.772.306.86; P = 0.1), (Table 2).

Renal Function

Recipients in the conventional dose era had a higher incidence of DGF compared to recipients in the reduced dose era (75.4% versus 64.7%, P = 0.005). We found no significant difference in eGFR (in mL/min/1.73 m2) among recipients in the conventional and reduced dose eras at 1 week (12.9 versus 12.1, P = 0.88), 1 month (43.0 versus 38.8, P = 0.95), 3 months (51.5 versus 49.1, P = 0.58), 6 months (53.6 versus 52.4, P = 0.31), and 1 year (53.4 versus 52.6, P = 0.28) post-KT, respectively (Figure 4).

FIGURE 4.
FIGURE 4.:
Average eGFR, calculated using the Chronic Kidney Disease Epidemiology Collaboration equation, over the first y after kidney transplantation in the reduced dose era and the conventional dose era. eGFR, estimated glomerular filtration rate.

Death-censored Graft Loss and Mortality

Death-censored graft loss was also similar in the conventional dose and reduced dose eras at 3 months (2.7% versus 4.5%), 6 months (3.8% versus 5.0%), and 1 year (4.8% versus 5.0%) post-KT, respectively. Patient mortality was similar in the conventional dose and reduced dose eras at 3 months (1.0% versus 2.7%), 6 months (2.3% versus 3.2%), and 1 year (3.4% versus 4.7%) post-KT, respectively (Figure 5). Specific causes and timing of graft losses are shown in Table S2 (SDC, http://links.lww.com/TP/B867). In an adjusted Cox model, we also found no associations between dose era and patient mortality (aHR: 0.181.289.22; P = 0.8) or death-censored graft loss (aHR: 0.130.663,28; P = 0.6).

FIGURE 5.
FIGURE 5.:
Cumulative incidence of (A) death-censored graft loss and (B) mortality for high-risk recipients in reduced dose era vs conventional era in the first y after kidney transplantation.

DISCUSSION

In this single-center retrospective cohort study, we compare outcomes for 630 high-risk KT recipients across 2 distinct ATG dosing eras: a conventional dose (up to 5 doses of 1–1.5 mg/kg/per dose) era and a reduced dose (a single dose of 3 mg/kg) era. We observed that KT recipients in the reduced dose era experienced a 37% lower hazard of CMV infection or disease during the first year post-KT compared to those in the conventional dose era. Furthermore, we found no statistically significant increase in the hazard of AR among the recipients in the reduced dose era, despite their high baseline AR risk from sensitization or receipt of ECD kidneys. In addition, risk of mortality, death-censored graft loss, and renal function did not differ for recipients based on ATG dosing era.

The use of ATG induction in high-risk KT recipients is associated with reduced rates of BPAR.3,5,19 In 1999, Brennan et al7 conducted a landmark study which treated KT recipients with ATG doses starting at 10.5 mg/kg and continuing for 7 consecutive days at 1.5 mg/kg per day and found that the severity and incidence of AR were lower among those receiving ATG. Subsequently, given fears of increased risk of adverse events and infectious complications with high ATG doses, several trials have examined outcomes at different cumulative ATG doses.20-22 Experiences using ATG as an induction agent since the late 1990s have demonstrated that the high doses of ATG used in early clinical trials are not necessary to prevent AR.1,21,22 However, the ideal dose which balances side effects and efficacy is still controversial, particularly for recipients considered at high-risk for rejection and those receiving no CMV prophylaxis.

Our finding of reduced risk of CMV infection or disease in high-risk KT recipients is not consistent with previous studies in reducing ATG dosing, which reported similar rates of CMV infections regardless ATG doses. However, these previous studies used pharmacological CMV prophylaxis for all patients,21,22 which was not used among recipients in our study. More specifically, after PS stratification and adjustment for baseline characteristics and temporal transplant trends, we found that in the highest PS tertile, recipients in the reduced dose era had a lower hazard of CMV infections or disease than those in the conventional dose era (aHR: 0.340.560.91, P = 0.02). The lower incidence of CMV infections observed in the reduced dose era may be explained in part by the fact that the single 3 mg/kg ATG dose is at least half of what is used in current immunosuppressive regimens for patients considered to be at high-risk for rejection.

To date, this is the first study reporting the safety and efficacy of single dose of 3 mg/kg in a high-risk population with no pharmacological CMV prophylaxis. We found that induction therapy with 3 mg/kg of ATG in high-risk KT recipients was associated with a decreased risk of CMV infectious complications and similar risks of AR, graft loss, and mortality. It is consistent with reports from previous studies in this setting.23,24

Several prior studies have examined outcomes in KT recipients at different cumulative ATG doses and found that lower doses of ATG were comparable to higher doses in terms of AR rates.14,21,22,25 In each of these studies, the incidence of AR was comparable for recipients of lower doses and higher doses of ATG. The progressive increase of the HR for the first treated AR increases according to the tertile analysis but did not reach statistical significance. This suggests that more data and continuous monitoring of the efficacy of the low dose ATG in this subgroup, primarily comprised of highly sensitized and/or patients with prolonged DGF, is necessary. In our study, we observed similar rejection rates and satisfactory safety outcomes using doses of ATG that were even lower than those reported in any of these previous studies.

A single dose of 3 mg/kg has been previously described in patients considered at lower risk for rejection. Wong et al23 compared different cumulative dosages of ATG (3.0 versus 4.5 mg/kg) and found no difference in AR rate or graft function up to 24 months post-KT. More recently, Singh et al demonstrated that cumulative ATG doses of 3.0 and 4.5 mg/kg were associated with excellent patient and graft survival among KT recipients who were at a standard level of immunologic risk.26-28 A recent study conducted by Nafar et al15 similarly reported no difference in patient and graft survival in a set of low immunologic risk patients treated with ATG 4.5 mg/kg versus ATG 6.0 mg/kg. The survival rates we observed in the present study are in accordance with these previous studies. More specifically, 1-year death-censored graft loss was similar in the conventional dose and reduced dose eras (4.8% versus 5.0%), and 1-year patient mortality was 3.4% in the conventional dose era and 4.7% in the reduced dose era. Although visual inspection suggests higher rate of the early graft loss and mortality in the reduced era cohort, we did not detected a clear trend toward an early higher incidence of any specific cause of graft loss or death. Finally, the average savings comparing 3 (US$ 1555.00) versus 5.5 mg/kg (US$ 2851.00) mean ATG doses would be US$ 1296.00 per patient. The average savings per patient for the treatment of CMV infection/disease would be US$ 501.02, considering the average cost of US$ 3684.00 per episode and a 14% reduction in the CMV infection/disease, from 76.1% in the conventional era and 62.5%, in the reduced dose era. The estimated mean reduction on annual costs would be US$ 1797.20 per patient during the first year after transplantation.

Our study must be considered within the context of several limitations. The single-center nature of the study, retrospective design, demographic characteristics of the population, and lack of CMV prophylaxis, even for high-risk D+/R− KT, cannot exclude the potential for intervention bias or the role of unmeasured confounding variables. However, we elected to use PS stratification to ensure that we compared patients from the conventional era to those in reduced dose era who had a similar probability of receiving a higher dose of ATG if they had been transplanted in the conventional dose era. We also feel that the disadvantages of a retrospective study are mitigated by our ability to harness a natural experiment created by the introduction of an induction protocol change. Considering that all patients in this study did not have DSA, the results presented cannot be extrapolated to higher immunological risk patients with preformed DSA. Interestingly, decreasing ATG dose does not impact the incidence of AR in the whole cohort but significantly reduced CMV infection/disease. This may suggest that a single dose of 3 mg/kg could be optimal in terms of risk/benefit ratio. However, the incidence of CMV infection/disease is still high compared to the incidence of CMV in patients receiving pharmacological prophylaxis. It would be interesting to evaluate the effect of low dose ATG in combination with pharmacological prophylaxis for CMV infection. While it is anticipated that lymphocyte depletion duration is shorter with reduced dose of ATG, according to the study by Kho et al,13 we did not collect and analyze these data in both groups. Data of BK virus would be very informative. Yet, considering the retrospective nature of our analysis, no systematic screening for BK virus replication was obtained for both populations.

In summary, the results of this investigation of KT recipients considered at high-risk for graft loss suggest that induction therapy with single 3 mg/kg dose of ATG, with a maintenance therapy of TAC, PRED, MPA, and no pharmacological CMV prophylaxis, may effectively reduce the incidence of CMV while still preventing AR and maintaining low rates of graft loss and mortality within the first year post-KT.

ACKNOWLEDGMENTS

We thank the Epidemiology Research Group in Organ Transplantation for supporting the development of this study. The analyses described here are the responsibility of the authors alone and do not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the U.S. Government.

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