Introduction
During the past few decades, nondepleting monoclonal antibody agents specifically targeting activated T cells have been developed, which are intended to provide effective immunosuppression without the adverse effects of profound and aspecific T lymphocyte depletion that are associated with polyclonal antibody agents (1). Basiliximab (Simulect®) is a high affinity, chimeric monoclonal antibody, with murine variable and human constant regions, directed against the α-chain (also known as CD25 subunit) of the interleukin (IL)-2 receptor on T lymphocytes (2). The expression of CD25 is specific to activated T cells; thus, basiliximab selectively targets activated lymphocytes and does not affect resting cells (3). The chimerization of the murine antibody with human immunoglobulin G1 is associated with reduced immunogenicity.
Basiliximab has been widely used as an induction therapy in kidney transplantation, with a two-dose regimen of 20 mg on days 0 and 4, respectively. However, pharmacokinetic studies have shown that the half-life of basiliximab is 7.2±3.2 days in adults, suggesting that a shorter regimen might be effective as an induction therapy (4). Recently, a single-dose regimen of basiliximab has been described in cadaveric kidney transplantation, with good efficacy and safety (4).
The objective of the present study was to observe the efficacy and safety of induction immunosuppression with single-dose basiliximab in 33 patients with donation after cardiac death (DCD) kidney transplantation in a single hospital.
Discussion
Renal transplantation is the preferred treatment for the majority of patients with ESRD because transplantation markedly improves the length and quality of life for dialysis patients (7). At the end of 2013, according to data from the Chinese Renal Data Registration System, the number of patients in mainland China receiving dialysis was 326,000 (280,000 hemodialysis and 46,000 peritoneal dialysis patients), accounting for ~20% of the global ESRD population; however, the donor supply for kidney transplantation in China is rather limited (8). The discrepancy between renal transplant supply and demand in China is expected to grow as the population ages, as the prevalence of hypertension, diabetes increases, and with the increasing number of patients whose previous allograft loses function. Allografts from DCD donors are increasingly being used (9). It has been reported that long-term results equivalent to those with deceased donors can be achieved using kidneys from DCD donors. To further improve these results, the use of induction therapy continues to be investigated in DCD kidney transplantation (10).
Induction therapy in kidney transplantation is considered to be important for reducing acute rejections, despite the potential for adverse effects. Induction therapies include polyclonal anti-lymphocyte antibodies, monoclonal anti-lymphocyte antibodies and anti-IL-2 receptor monoclonal antibody (7). The chimeric IL-2 receptor antibody basiliximab has been widely used as an effective, safe and economical induction therapy for kidney transplantation. Basiliximab is directed against the CD25 subunit, which prevents acute cellular rejection (ACR) by inhibiting IL-2-driven T-cell proliferation (11). Basiliximab is one of the most commonly used induction agents due to the following advantages: i) Evidence of reduced overall cost demonstrated by pharmacoeconomic analysis; ii) ease of administration; iii) short-term use; iv) no need for blood level monitoring; and v) lack of major toxicity.
Studies have shown that induction therapy with basiliximab leads to greater graft and patient survival rates (12,13). In a large prospective placebo-controlled trial of basiliximab in 700 adult renal transplant patients in Europe, the result showed a significant reduction in rejection in the first year after transplantation, with a 32% reduction in biopsy-proven acute rejection in the first 6 months (from 44% with placebo to 30% with basiliximab) and a 57% reduction in steroid-resistant rejection with the use of basiliximab (1).
Similarly, a large meta-analysis reported a rate of acute rejection of 40% in patients receiving placebo or no induction, with a reduction in the risk of acute rejection of 34% (relative risk, 0.66) using basiliximab (14). Thus, for every 100 patients treated with IL-2 receptor antagonist, it was expected that 14 fewer patients would experience acute rejection, and 7 patients would need to be treated to prevent one rejection episode [number needed to treat (NNT) acute rejection = 7]. An updated analysis found a 38% incidence of rejection in the placebo/no induction arm, and suggested an NNT of 9 patients to prevent one episode of acute rejection (15).
In the present study, 33 renal transplantations from DCD donors using a single-dose basiliximab induction strategy were evaluated. The 1-year graft survival rate was 90.9%, similar to that observed by Ledinh et al (16). An intraoperative 20-mg single-dose of basiliximab was used in the present study, which is lower than that used by Matl et al (4), who demonstrated that the efficacy, safety and tolerability of a 40-mg single-dose basiliximab regimen were comparable to those of the conventional 2 × 20 mg two-dose regimen. Since Chinese people may be considered to have a smaller body size than westerners, this 20 mg single-dose regimen of basiliximab in DCD kidney transplantation in Chinese patients is valid.
Infection is an important complication after transplantation that could affect the life quality and survival of recipients. Induction therapy in renal transplantation is prone to increase the risk for infection. In the present study, 8 patients developed infection, including 6 cases of pulmonary infection, 1 case of urinary tract infection and 1 case of Mycosis pilorum infection in the renal vein. This infection rate described in these DCD recipients is not specific to these particular patients but is typical of patients in the transplantation setting in China. Of note, for the recipient diagnosed with Mycosis pilorum infection in the renal vein, the donor was drowned in a muddy pool; and after further investigation, it was found that the recipient receiving the other kidney underwent graft nephrectomy for rupture and severe bleeding of the allograft in the third postoperative week (in another hospital). One patient succumbed to Guillain-Barré syndrome (GBS) at 3 months post-transplantation. This patient's HLA loci matched well with the donor who also died of GBS; they had only one HLA mismatch. The 36-year-old patient had excellent renal function after transplantation; but 10 weeks later, he was readmitted due to progressive, symmetrical weakness of the lower limbs, paresthesia and dysphagia, and in the next few days he developed acute respiratory failure requiring mechanical ventilation. At the time of his death, his transplant was functioning well. Our evaluation of infectious complications did not show a significant difference in incidence or its role as a cause of mortality/graft loss. These data are consistent with the meta-analysis of Adu et al (17).
During the study period, 10 patients experienced DGF, a common complication in the immediate post-transplant period, with an incidence of 30.3%. The incidence of DGF after transplantation from DCD donors has been described as 25 to 90% (18). Several studies have documented that one of the potential problems with kidneys from DCD donors is the potential for a higher rejection rate and a higher risk for graft failure due to the higher incidence of DGF (19,20). In addition, DGF leads to extended hospital stays, resulting in increased costs (19). The commonly accepted explanation for the increased risk of DGF in DCD kidney transplantation is warm ischemia, which results in reperfusion injury, acute tubular necrosis and graft dysfunction. The variable period of warm ischemia that occurs prior to organ procurement is a major disadvantage of DCD organ donation. While the interval from asystole to cross-clamp and organ perfusion is readily determined, warm ischemia occurring during the withdrawal phase prior to asystole is much more difficult to quantify (21). In the present study, the duration of warm ischemia was taken as being from the time of persistent systolic blood pressure <60 mmHg to the time of organ reperfusion with cold preservation solution. The outcome would be improved by any intervention that could preserve the function of the graft and reduce the incidence of DGF; improved methods for organ recovery and reduction of drug toxicity may, therefore, further improve the outcome of DCD kidney transplantation. Basiliximab has been reported to be associated with reduced DGF incidence, mainly when calcineurin inhibitor administration has been reduced or delayed to avoid nephrotoxicity to ischemic kidneys recovering from cold storage (22).
It has been reported that basiliximab does not cause lymphocyte depletion, with an incidence of cytopenia lower than that with depleting agents such as ATG or alemtuzumab, and partial humanization structurally decreases the development of inhibitory antibodies (23). It is administered peripherally and is less expensive than ATG in China. The incidence of infusion reactions is also lower with basiliximab than with depleting agents (24). In the present study cohort, increasing ALT/AST was considered to be associated with basiliximab in only 2 patients, and they both recovered satisfactorily. This clinical study demonstrated that the application of single-dose of basiliximab as an induction therapy in DCD kidney transplantation is very well tolerated.
The shortcomings of the present study include it being a single-center evaluation, with a relatively small population and short duration of study, as well there being as lack of comparison between single-dose and conventional two-dose basiliximab regimens in DCD kidney transplantation. Furthermore, in future studies, pre-operative evaluation of the match of the donor and recipient requires further improvement, including construction of better inclusion criteria and exclusion criteria, in order to reduce the number of mismatches between the donor and recipient.
The present study of single-dose of basiliximab as an induction therapy in DCD kidney transplantation showed that favorable clinical outcomes within 1 year were achieved in terms of graft survival and function. The single-dose regimen in a larger population as well as in comparison with a conventional two-dose regimen in DCD kidney transplant recipients requires further investigation.