Key words : Induction treatment, Living donor transplantation, Renal transplantation

Introduction

Induction treatment is associated with favorable outcomes, such as lower rates of acute rejection and delayed graft function, as well as improved short-term graft survival in kidney transplant.^1,2 On the other hand, adverse effects such as infection, cardiovascular problems, and malignancy, in addition to drug-specific adverse effects, raise concerns about widespread use of induction treatment.³ The 2 main types of induction agents presently used in clinical practice are T-cell-depleting antibodies, such as antithymocyte globulin (ATG), and interleukin-2 receptor antagonists (IL2-RA), such as basiliximab.⁴

Antithymocyte globulin is a more potent im-munosuppressive agent than basiliximab.5 However, basiliximab was found to be as effective as ATG to prevent acute rejection and delayed graft function and to improve graft survival, especially among patients with a low immunological risk. Additionally, basiliximab has a better safety profile in terms of infectious complications and malignancy.^6-9 Previous studies have demonstrated the superiority of ATG and basiliximab versus induction-free regimens for prevention of acute rejection episodes.¹⁰ Hence, the Kidney Disease Improving Global Outcomes guidelines recommend induction treatment as a routine element of care for renal transplant recipients. According to these guidelines, IL2-RA agents should be used as a first-line option, with ATG reserved for immunologically high-risk patients.¹¹

The need for induction treatment was evaluated generally in studies with cyclosporine-based mainte-nance immunosuppression and in the setting of deceased donor transplant. The advent of modern immunosuppressive drugs for maintenance treatment, including tacrolimus and mycophenolic acid derivatives, also have contributed to the improvement of short-term graft survival, with fewer episodes of acute rejection.¹² Therefore, the role of induction treatment in kidney transplant should be reconsidered in the tacrolimus era.¹³

In this study, we analyzed the efficacy and safety of ATG and basiliximab versus an induction-free regimen in a cohort of living donor kidney transplant recipients who received tacrolimus-based triple therapy.

Materials and Methods

Study design and setting
We performed a cross-sectional study in the transplant department of a tertiary care university hospital from November 2021 to March 2022. We constructed 3 groups according to the presence and type of induction therapy. The first group consisted of patients who received ATG, and the second group received basiliximab. The third group comprised patients who did not receive any induction treatment.

The study was approved by the local medical ethics committee (approval No. BSC176Y3K3) and was conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from patients or their guardians.

Patients and data collection
Adult patients (>18 years of age) who had a living donor kidney transplant with tacrolimus and mycophenolic acid-based maintenance immunosup-pression were included in the study. All donors and recipients were ABO compatible. Donors were first-degree or second-degree relatives of recipients. All donors and recipients were evaluated by a dedicated team composed of a nephrologist, transplant surgeons, and transplant coordinators for the eligibility of candidates according to established international guidelines. Patients who had previously undergone renal transplant were excluded.

We examined the baseline data regarding demographic, clinical, and laboratory parameters at the time of transplant and within the first year after transplant. We collected follow-up data that included creatinine level at discharge from the hospital, at 6 months, and at the end of the first posttransplant year; rejection episodes; hospitalization episodes; infection episodes including cytomegalovirus (CMV) infection and bacterial infections; delayed graft function; and graft survival within first year. We established 3 chronological periods to examine the infectious outcomes and rejections: 0 to 1 month, 2 to 6 months, and 7 to 12 months. Data were obtained from the electronic medical records and from patient files.

We collected the data of renal transplant recipients who had undergone renal transplant from January 2010 through March 2021 at our transplant center. Most of the patients received induction treatment during this period according to guideline recommendations. Therefore, to construct an induction-free regimen group, we extracted data from medical records of the patients who underwent renal transplant from 2001 through the end of 2009.

Immunosuppression protocol
We used ATG-F (Fresenius) or basiliximab (Novartis) for the induction. Antithymocyte globulin was administered before patients went to the operating room, with administration continued at daily doses of 1 to 2 mg/kg. The duration of the treatment was based on the physician’s preference based on clinical and laboratory parameters. Basiliximab (20 mg/d) was also administered before patients went to the operating room, followed by a second infusion on postoperative day 4.

Both groups received maintenance oral immuno-suppression treatment consisting of mycophenolate mofetil, prednisolone, and tacrolimus. Methylp-rednisolone (500-1000 mg) was administered intravenously on day 0. Methylprednisolone dose was reduced to one-half of the original dose, then switched to prednisone on postoperative day 3, and subsequently tapered to 5 mg of oral prednisolone at the beginning of month 3 and continued until the end of month 6.

Mycophenolate mofetil was administered at 1000 mg twice daily. The dose was reduced or the drug was discontinued for cases of neutropenia (absolute neutrophil count <1.3 × 10³ cells/μL), and the drug dose was adjusted according to gastrointestinal side effects. Tacrolimus was initiated with a dose of =0.15 mg/kg with a target level of 10 μg/L for the first month, then 7 μg/L for the remainder of the first year. Blood tacrolimus level was measured periodically to adjust dosage. All patients received prophylactic oral valganciclovir or acyclovir for 3 months, cotrimoxazole for 9 months, and isoniazid for 6 months if the purified protein derivative skin test showed positive results for tuberculosis infection.

The choice of induction treatment versus induction-free treatment was based on the preference of our transplantation council, according to the following factors: human leukocyte antigen (HLA) matching, previous transplant history, panel reactive antibody (PRA) titer, and donor type. Induction treatment was preferred for second transplant, HLA matching less than 1 haplotype, previous cross-matching >20% PRA positivity, and deceased donor transplant. A flow chart of these selection criteria, which we follow in general, is shown in Figure 1.

Definitions
Delayed graft function was defined as “the temporary need for dialysis following transplantation.” Graft loss was defined as “the initiation of renal replacement therapy or death of the recipient.” Acute rejection episodes were either diagnosed clinically or confirmed with a renal biopsy according to the Banff criteria. Hospitalization was defined as “staying at the hospital more than 1 day.” A quantitative buffy coat CMV polymerase chain reaction of >1000 copies/ng of DNA was accepted as confirmation of CMV infection.¹⁴ Bacterial infection was defined according to (1) the records of the physician who followed the patient or (2) culture positivity.

Statistical analyses
Continuous variables are expressed according to respective distributions, as either mean values (with SD) or median values (with minimum to maximum range). Categorical variables are presented as numbers (with %). Continuous variables were evaluated for normality distribution using the Shapiro-Wilk test. One-way analysis of variance tests were performed for comparison of the ATG group, the basiliximab group, and the induction-free group if continuous outcomes were normally distributed. The Kruskal-Wallis test was used for nonnormally distributed continuous outcomes. Categorical variab-les were compared with the chi-square test for proportions.

All significance tests were 2 tailed, and P < .05 was considered statistically significant. All statistical analyses were performed with SPSS software (version 21).

One patient in the ATG group, 1 patient in the basiliximab group, and 3 patients in the induction-free group failed to fulfill the follow-up visits. We used available data for those patients. However, in the evaluation of graft loss, these patients were accepted to have graft loss.

Results

Baseline data
We examined 126 patients (mean age 35 ± 12 years, 65% male). Baseline demographic, clinical, and laboratory data of the study groups are shown in Table 1. Basiliximab was administered to 52 patients, ATG was administered to 25 patients, and 49 patients did not receive any induction treatment. Patients in the ATG group were older but had a similar sex distribution versus the patients in the induction-free group. Hemodialysis vintage was older and hospital stay during the operation period was longer in the induction-free group versus the 2 groups of patients who received induction. The cause of end-stage renal disease was unknown in most patients (31%), but the most common causes were congenital urological abnormalities (21%) and glomerulonephritis (15%).

Despite the ongoing debate regarding the ideal number of HLA mismatches, a full HLA match has been associated with the least risk for acute rejection.¹¹ There was no statistically significant difference in terms of full HLA-matched patients among the 3 groups. The PRA class I status was similar in all groups, whereas PRA class II positivity was more frequent in the ATG group. The PRA test was unavailable for most of the patients in the induction-free group; therefore, we performed a second analysis to compare only the ATG group and the basiliximab group (Table 1).

Follow-up data
Clinical data collected during the follow-up are summarized in Table 2. Kidney biopsy and acute rejection rates were similar among the 3 groups during all time periods and cumulatively. Delayed graft function, graft loss, and hospitalization duration during the first year were also similar among the 3 groups; however, hospitalization duration was lower in the induction-free group. The main cause of hospitalization in all groups was infection, especially urinary tract infections, followed by the increase in creatinine level.

Creatinine levels and estimated glomerular filtration rates are shown in Table 3. Discharge creatinine levels were higher in the induction-free group, with a borderline statistical significance. However, the follow-up creatinine levels were similar in all groups. One-way analysis of variance and the Kruskal-Wallis test were applied to evaluate repetitive values for estimated glomerular filtration rates, and we did not find any statistically significant difference.

Follow-up data regarding infections are listed in Table 3. Bacterial infectious complications were lower in the induction-free group from posttransplant month 2 through month 6. However, there were no significant differences for bacterial infection in the other time periods and cumulatively among the 3 groups. The incidence of CMV infection was also similar among all groups.

In 1 patient from the basiliximab group, we observed antibody-mediated rejection between posttransplant month 2 and month 6. He was treated with plasmapheresis and intravenous immunog-lobulin and rituximab. One patient had borderline rejection in the induction-free group, and thus we increased this patient’s steroid dose. All other patients received pulse/high-dose steroid treatment in case of rejection episodes. Unfortunately, data on proteinuria were not available for the induction-free group because 24-hour urine collection was not a standard of routine clinical practice during their treatment. Two patients who received induction treatment and who had a rejection episode within the first year showed proteinuria in excess of 500 mg/day at the end of the first posttransplant year.

Discussion

According to our findings, induction treatment does not offer additional benefit regarding delayed graft function, first-year graft survival, and acute rejection episodes in kidney transplant recipients who have received tacrolimus-based triple maintenance treatment. Our cohort was composed of living donor kidney transplant recipients for whom this was their first kidney transplant. Preoperative results from a complement-dependent cytotoxicity crossmatch were negative. The PRA test was conducted in 86 of the 126 patients, and 5% of the 86 patients tested positive for PRA class I and 6% tested positive for PRA class II. Therefore, our study population was composed of patients who were characterized as immunologically low-risk patients.

Our results are in agreement with large registry data studies from the United States, Australia, and the United Kingdom, which have been performed in the tacrolimus era to evaluate induction treatment in recipients with low risk or standard risk. Tanriover and colleagues reported that IL2-RA treatment did not reduce acute rejection and did not improve graft survival compared with the induction-free treatment in living donor transplant recipients who received maintenance treatment with tacrolimus and mycophenolate mofetil.¹⁵ Ali and colleagues included standard-risk recipients with tacrolimus-based maintenance treatment and found similar graft survival rates and estimated glomerular filtration rates between the patients who received no induction and patients who received IL2-RA. In that study, standard-risk transplants were defined as patients with <2 DR mismatch, a calculated reaction frequency <20%, living donors or donors after brain death, and patients with no previous renal transplant.¹⁶ Lim and colleagues noted that IL2-RA was not associated with a reduction in acute rejection in low-risk (?2 HLA mismatches and PRA <10%) and intermediate-risk (subsequent grafts or >2 HLA mismatches or PRA >25%) patients treated with tacrolimus.¹⁷ Furthermore, a recent study by Evans and colleagues showed that induction treatment with either ATG or basiliximab at the first renal transplant from a well-matched HLA donor did not improve the posttransplant outcomes.¹⁸

In a study from Spain, Gavela Martinez and colleagues concluded that basiliximab provided neither a reduction in acute rejection episodes nor a prolongation of graft survival among patients who had low immunological risk and received tacrolimus.¹⁹ Janigen and colleagues reported similar biopsy-proven acute rejection rates and 10-year graft survival rates between the IL2-RA and induction-free groups in low-risk recipients (defined as ABO compatibility, first transplant, PRA = 10, and HLA mismatches = 3).20 The main limitation of these previous studies was the lack of an established definition of low/standard/high risk; all of those definitions were physician dependent or center dependent. According to these previous studies, PRA negativity, less than 3 HLA mismatches, and first kidney transplant from a living donor could be defined as low risk, and such patients could be considered appropriate candidates for induction-free regimens. We also generally used an induction-free regimen in our low-risk patients, as defined by PRA negativity, less than 1 haplotype HLA mismatch, and first living donor transplant.

Infectious complications and hospitalization were the important safety aspects of induction treatment. In previous studies, ATG was associated with enhanced risk of bacterial infection, including urinary tract infection and CMV infection, in renal transplant recipients.^21,22 We observed a higher risk of infection between postoperative month 2 and month 6 in the ATG and basiliximab groups versus the induction-free group. However, the incidence rates of cumulative infectious complications were similar in all groups. Likewise, Baek and colleagues performed a prospective study on recipients treated with tacrolimus-based immunosuppression with well-matched HLA (defined as 1-3 HLA mismatches) and found that, despite the lower tendency for infectious complications in the induction-free group, the overall prevalence of infections was not significantly different versus patients who received induction treatment.²³ We found a higher rate of hospitalization among patients who received induction treatment. However, Sandes-Frietas and colleagues have shown that the overall frequency of hospitalization was not statistically significant.²⁴

The limitations of our study are as follows: relatively small sample size, retrospective nature of the data collection, and low prevalence of PRA testing that was related to the period difference of the induction-free group. However, this study remains important as it provides data from a country in which the kidney transplants are performed mainly from living donors.

Our data demonstrate that neither basiliximab nor ATG had superiority versus induction-free regimens with regard to acute rejection, delayed graft function, and first-year graft survival in living donor kidney transplant recipients with tacrolimus-based immunosuppression. Although overall infectious complications were similar among all groups, hospitalization due to any reason was more frequent in patients who received induction treatment. In conclusion, induction-free regimens should be considered in the first transplant for living donor kidney recipients.

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