Induction therapy with thymoglobulin or interleukin-2 receptor antagonist for Chinese recipients of living donor renal transplantation: a retrospective study

Kidney transplantation remains the most optimal therapy for patients with irreversible chronic kidney failure [1]. According to the 2009 KDIGO (Kidney Disease: Improving Global Outcomes) guideline [2], immunosuppressive therapy is crucial for successful kidney transplantation, which purpose is to prevent rejection episodes, maintain the allograft function and minimize the risk of side effects and infection [3]. Immunosuppression regimens typically include a perioperative induction therapy and a life-long maintenance therapy. Induction treatment is capable of effectively reducing the incidence of acute graft rejection, a risk factor for the long-term outcomes of transplantation [4, 5]. Current options for induction therapy mainly include lymphocyte-depleting antibodies (such as polyclonal rabbit antithymocyte globulin [rATG, thymoglobulin]) and monoclonal antibodies against the interleukin-2 receptor (IL2-RA, such as basiliximab and daclizumab) which acts to inhibit T cell proliferation in response to IL-2 [6]. In China, rATG and basiliximab are two of the most commonly used induction therapy regimens.

Recipients of living donor renal transplantation are typically considered to have a relatively lower immunological risk as compared with those of deceased donor renal transplantation [7] due to the better compatibility between donor and recipient, shorter ischemic time and better quality of the graft. Nevertheless, the beneficial effect of induction therapy against acute rejection has also been observed in kidney transplantation with living donor [8]. Compared with rATG, IL2-RA is a less potent immunosuppressant and is recommended as the first-line induction therapy for living donor renal transplantation by the KIDGO guideline to reduce the risk of postoperative immunosuppression-related infections [2]. By contrast, the relatively-more-potent immunosuppressant rATG can reduce the risk of acute rejection as compared with IL2-RA, but also induces higher rates of infection and other side effects [9]. Therefore, rATG is recommended for patients at high risk of graft rejection according to the KIDGO guideline [2]. However, rATG induction has also been shown to be safe and effectively reduce the incidence of acute rejection and complications in living donor renal transplantation [10]. Hence, both rATG and IL2-RA are the options of induction therapy for living donor renal transplantation. Currently, the selection of induction therapy for living donor renal transplantation is commonly based on comprehensive assessment of immunological risk for individual patients. Independent factors associated with increased risk of acute graft rejection include the number of human leukocyte antigen (HLA) mismatches, younger recipient age, older donor age, panel reactive antibody (PRA) score > 0%, presence of a donor-specific antibody (DSA), blood group incompatibility, delayed onset of graft function and cold ischemia time > 24 h [2].

At present, the studies on comparing the safety and efficacy of different induction therapies for living donor renal transplantation are still limited, especially for the Chinese population. Thus, convincing evidence is still lacking to recommend the most appropriate treatment strategies for living donor renal transplantation. Therefore, this retrospective study aimed to compare the therapeutic efficacy and safety between IL2-RA and rATG induction therapies in Chinese recipients of living donor kidney transplantation.

In this study, we compared the therapeutic efficacy and safety between IL2-RA and rATG induction therapies in Chinese recipients of living donor kidney transplantation. The results demonstrated that the rATG group had a higher PRA score and more cases with complete HLA mismatches than IL2-RA group, suggesting a higher immunological risk. The incidences of clinically-suspected acute rejection and dn-DSA were not significantly different between the rATG and IL2-RA groups, but rATG group had a lower rate of BPAR than the IL2-RA group, when diagnostic biopsy was performed. Kaplan-Meier curve analysis showed that the graft survivals of two groups were comparable. In addition, the multivariate Cox regression analysis demonstrated that the method of induction therapy was not an influential factor associated with either clinically-suspected acute rejection or graft survival. The 1-year, 2-year, and 3-year graft survival rates were comparable between groups. Furthermore, the incidences of complications (infections, pneumonia, liver injury and myelosuppression) were all comparable between groups. Taken together, these results suggested that rATG could be a safe and efficient immunosuppressant and when used in a Chinese recipient population with a higher immunological risk in living donor renal transplantation.

Previous studies have demonstrated that patients receiving rATG induction therapy have an acute rejection rate of around 10% [6, 9‐13]. A multiple-center study by US transplant centers based on the data from 1816 patients in the Thymoglobulin Antibody Immunosuppression in Living Donor Recipients (TAILOR) Registry reported that the BPAR is 8.3% at 12 months post-transplantation [10]. Likewise, a retrospective cohort analysis of the Organ Procurement and Transplantation Network (OPTN) registry by Tanriover et al. have reported similar 1-year acute rejection rates (either biopsy-confirmed or clinically treated) of patients receiving rATG induction therapy with (9.6%, n = 8552) or without (9.0%, n = 4905) steroid maintenance therapy [9]. In this study, the rATG group had a rate of clinically-suspected acute rejection of 9.8%, which is consistent with the above reports. On the other hand, the IL2-RA group in this study had a clinically-suspected acute rejection rate of 8.8%, which is slightly lower than rates of acute rejection in Tanriover et al.’s study (11.7% in patient with steroid maintenance and 10.5% in those without steroid maintenance at 12 months) [9].

Our results showed that rATG group had a higher PRA score and more complete HLA mismatches than the IL2-RA group, indicating a higher immunological risk in the rATG group. However, after adjusting for the baseline confounders including PRA score and complete HLA mismatch, our multivariate Cox regression model still demonstrated that there were no differences in either the risk of clinically-suspected acute rejection or graft survival between the IL2-RA group and the rATG group. This finding is in line with a prospective study including 213 cases of living-donor renal transplantation by Huang et al. [14]. Their study reports that there are no significant differences in the acute rejection rates, DGF rates, graft loss and death between the IL2-RA group and the rATG group [14].

The 2009 KDOQI guideline suggests that IL2-RA induction therapy could reduce the rate of infection in renal transplantation as compared with the rATG induction therapy [2]. Consistently, the prospective study in living-donor renal transplantation by Huang et al. have reported that the rATG group has a significantly higher infection rate than the IL2-RA group (85.8% vs. 75.2%, P = 0.03) [14]. In contradiction to their observation, our result revealed that the post-transplantation infection rate was similar between the two treatment groups. This discrepancy may be attributed to the total cumulative dose of rATG is lower in our study (3 mg/kg) than in Huang et al.’s study (5 mg/kg) [14]. The rATG dose used in this study is the standard dose typically used in Chinese kidney transplant patients, with the purpose to reduce infectious complication [14‐16]. Moreover, although total cumulative dose of prophylactic intravenous ganciclovir within the first 2 weeks is lower in our study, however, the daily dose of oral ganciclovir in the following 90 days in our study (3 g/day) is twice as high as that in Huang et al.’s study (1.5 g/day) [14]. This may also contribute to the decrease in infection rate. rATG is a more potent immunosuppressant and could induce a higher risk of infection than IL2-AR [17]. However, our study showed that the incidence of infectious complication was lower in the rATG group than in the IL-2AR group, which may be attributed to the relatively young age of recipients in the rATG group or relatively small sample size of this study. Taken together, our observations indicated that rATG induction therapies in recipients of living donor kidney transplantation could simultaneously achieve low rates of post-transplantation infection and acute rejection, especially for the recipients with high immunological risk.

De novo formation of DSAs directed against HLA has been recognized as one of the major risk factors for allograft failure [18‐20]. In this study, the incidence of dn-DSA formation was comparable between the rATG and the IL2-RA groups (4.9% vs. 5.4%). A review article including 12 studies by Lionaki et al. has shown that the incidence rates of dn-DSA formation in kidney transplant recipients range from 5.5 to 32% [19]. The marked variation of incidence rates of dn-DSA formation among studies is due to the diversity of methods used for antibody detection [19]. Among the 12 reviewed studies, only 3 ones report the rate of dn-DSA lower than 10% [19]. Hence, the incidence of dn-DSA formation in this study was relatively low. However, Everly et al. have reported that 47 out of 189 (25%) patients developed dn-DSA within 10 years post-transplantation. Among them, there are 42.6, 36.2 and 21.3% of patients developing dn-DSA antibody within the first year, between 1 and 5 years and after 5 years post-transplantation, respectively [21]. Therefore, given the lack of long-term follow-up data in the present study, the rates of dn-DSA may have been under-estimated and a long-term follow-up is necessary.

There are several limitations of this study. Due to the retrospective nature, some patients had missing or incomplete data, resulting in inaccuracy of the data (such the date of acute rejection and graft survival outcome) which could affect the analysis results to some extent. However, multivariate Cox regression analysis adjusted for baseline characteristics was conducted to eliminate the confounding factors. In addition, the lack of systematic diagnostic biopsy for rejection is a major drawback of this study, since it has been suggested that a transplant renal biopsy should be carried out before treating an acute rejection episode [22]. The incidence of vascular rejection in the BPAR cases was high (66.7%,, 4/6), which may be due to the fact that our previous biopsies strategy was indication biopsies, in which biopsies was performed only when the patient had clinical symptoms and the treatment was not effective. This was a limitation. At present, our biopsies strategy has been improved to surveillance biopsies. In this study, the method of induction therapy was determined by the attending physician based on the immunological and infection risks of each patient. Nevertheless, the risk may be overestimated or underestimated in some patients, resulting in an inadequate induction therapy. This bias may interfere with the analysis results of this study. Therefore, a well-design prospective study with a large sample size is necessary to further validate the findings of this study. All these limitations should be addressed in future studies.

In summary, our findings demonstrated that rATG could be a safe and efficient immunosuppressant when used in a Chinese recipient population with a higher immunological risk in living donor renal transplantation.