Antibody-mediated rejection (AMR) is the leading cause of kidney transplant failure, accounting for 50% of death-censored graft losses.1 The major risk factor for developing AMR is hypersensitization against human leukocyte antigens (HLAs) epitopes, an event that is secondary to previous transplants, blood transfusions, or pregnancy. The management of immunosuppression in hypersensitized kidney transplant recipients is challenging and is based on aggressive induction therapy with lymphocyte-depleting agents. Maintenance therapy usually includes a calcineurin inhibitor (CNI; either tacrolimus or cyclosporine), mycophenolic acid (MPA), and steroids. However, the combination of this schedule with aggressive induction is associated with higher rates of infections in the posttransplant period (especially cytomegalovirus [CMV]) and possibly worse long-term outcomes in term of cancer development.2,3 The possibility to substitute MPA with an mTOR inhibitor (mTORi; either everolimus or sirolimus) may reduce the burden of these complications, given the beneficial effects that mTORi have in terms of infection and neoplasia control.4 However, there is a generalized feeling that mTORis have to be avoided in hypersensitized kidney transplant recipients as it is perceived that they are associated with increased risk of developing AMR. This is derived from the results obtained by some pivotal trials, especially the SYMPHONY study, in which the use of sirolimus was associated with increased risk of rejection and worse graft survival. However, it has to be highlighted that sirolimus was used as a substitute of a CNI and not in combination with it.5 On the contrary, the last 10 years of clinical research have pointed out that the best way to take advantage of the beneficial effects of mTORi without increasing the risk of rejection is to use them at an optimal dose (trough levels of 3–8 ng/mL) in combination, and not as a substitution, of CNI. The results of the recently published TRANSFORM trial confirmed that this approach is not inferior to a classical regimen based on MPA.6 However, this trial and almost all those that compared mTORi and MPA in combination with a CNI excluded hypersensitized kidney transplant recipients from enrollment,7-17 thus limiting the applicability of this finding to this delicate piece of population. In an attempt to shed light on this issue, we revised our experience in hypersensitized kidney transplant recipients, comparing these 2 maintenance schedules in terms of development of biopsy-proven acute rejection (BPAR).
MATERIALS AND METHODS
From June 2013 to December 2016, 442 patients received a solitary kidney graft at the Hospital Clínic of Barcelona. Recipients of a living donor who received desensitization before transplant for a positive crossmatch (donor-specific antibody [DSA]) were excluded from this analysis (n = 18), as well as HLA-identical transplants (n = 6) and patients whose immunosuppression was cyclosporine and azathioprine based (n = 4). All the other patients transplanted in this period with a cPRA against class I and II HLA antigens (cPRA I+II) < 50% were not included in this analysis (n = 343). The final population consisted therefore of 71 patients with a cPRA I+II ≥ 50% (Figure 1). Recipients of a deceased donor were transplanted only if complement-dependent cytotoxicity (CDC) was negative. In the case of positive flow-cytometry crossmatch or in the presence of a DSA, a single dose of Rituximab (Mabthera, 400 mg; Roche, Basel, Switzerland) was administered according to the individual risk of the recipient. Induction was based on a lymphocyte-depleting agent (either Thymoglobuline 1.25 mg/Kg [Sanofi-Aventis, Paris, France], or Grafalon 2.5 mg/Kg [Neovii, Rapperswil, Switzerland]) for 5 days starting from the day of transplant or, alternatively, on Basiliximab (Simulect, Novartis, Basel, Switzerland), 20 mg on the day of the transplant and 20 mg on day 4.
Maintenance therapy was based on Tacrolimus (Advagraf 0.15 mg/kg/daily, Astellas, Tokyo, Japan) starting before transplantation and, either MPA (Myfortic 720 mg bid [Novartis]) or an mTORi (either everolimus 1 mg bid [Certican, Novartis] or sirolimus 2 mg daily [Rapamune; Pfizer, New York, NY]) always in combination with steroids. The dose of mTORi was later adjusted to reach trough levels of 3–8 ng/ml. As a “rule of thumb” the sum of tacrolimus and mTORi trough levels has to be 10–12 ng/ml during the first six months and 8–12 ng/ml thereafter. In our center, patients are given an mTORi as concomitant treatment of tacrolimus and independently of their immunological risk. Patients with contraindications to receive mTOR (eg, obesity, FSGS as cause of kidney disease, development of adverse reactions in previous transplants and chronic lung disease) are given MPA instead. The clinical protocol for ABO-incompatible living donors is based on MPA too.
Renal biopsies were performed per-indication whenever there was a suspicion of an ongoing rejection and per-protocol at 3 and 12 months. BPAR was classified according to Banff 2017 criteria.18 Active AMR was treated with Rituximab (400 mg at the beginning and at the end of the cycle), 5 sessions of plasmapheresis (1 total blood volume for each session) and intravenous human immunoglobulins after the second and the fifth exchange (Plangamma, 200 mg/kg for session, Institute Grifols, Barcelona, Spain). Anti-HLA antibodies were assessed before transplantation, at the moment of rejection and at 3 and 12 months through Luminex-based technology.19 Briefly, antibodies were tested using Single Antigen Bead test (LIFECODES Single Antigen, Immucor, GA). An allele was considered positive if the median fluorescent intensity was over 1500 and 4 times higher than the lowest reactive antigen (LRA) of the same locus cPRA was calculated by identifying if at least one of the alleles considered to be positive was present in each one of the 500 not related individuals from local population, typed for A, B, C, DRB1, and DQB1 in high resolution (2 fields) by sequence-based typing. Delayed graft function (DGF) was defined as the need of dialysis during the first week after transplantation.
Basal characteristics of the patients as well as one-year outcomes were collected. Continuous variables have been described as mean with SD. Categorical variables have been described as absolute frequencies or percentages. Relations between baseline variables have later been explored with Student’s t-test for continuous variables and with Fisher’s exact test for categorical variables. Univariable and multivariable tacrolimus and mTORi trough levels along the first year after kidney transplantation were analyzed using generalized estimating equations models with an unstructured matrix to account for intraindividual correlation, considering group, time and interaction group by time as independent factors for the estimation of means and inferential analysis. Cox-regression analysis of survival has been performed for the chosen outcome of interest (1-y BPAR). All statistical tests have been conducted with a 95% confidence interval (CI) and a P < 0.05 has been considered significant. To carry out all the above mentioned analysis, the software SPSS v.25 (SPSS Inc., Chicago, IL) has been used. Rejection-free survival curve was censored at death or at last follow-up visit and was designed with GraphPad v.5 (GraphPad Software, La Jolla, CA). The Institutional Ethics Committee approved the study.
Baseline characteristics of the patients are listed in Table 1. Thirty-eight patients received MPA along with tacrolimus and prednisone, while 33 patients received an mTORi in place of MPA. The only difference was related to the higher percentage of living donors in the MPA group (52.6% versus 24.2%, P = 0.017). Almost 90% of patients in both groups received induction with a lymphocyte-depleting agent. Four recipients of an ABO-incompatible graft were present in the MPA group. Five patients in each group received rituximab for a positive flow-cytometry crossmatch or a DSA (P = n.s).
Immunological characteristics are summarized in Table 2. The global risk was equal, being mean cPRA 86.71 ± 15.28 for MPA and 84.55 ± 15.61 for mTORi (P = 0.558). HLA (A-B-DR) mismatches were equally distributed between groups as well (means 3.68 ± 1.31 and 3.64 ± 1.36 for MPA and mTORi, respectively, P = 0.881). Flow-cytometry crossmatch was positive in 3 and 5 patients of the MPA and mTORi group, respectively. DSA before transplant was present in 12 patients in the MPA group (31.6%) and 12 patients in the mTORi group (36.4%) (P = 0.802).
Clinically relevant outcomes of the whole population are summarized in Table 3, while a subgroup analysis on patients with a positive crossmatch and/or a DSA before transplantation is depicted in Table S1 (SDC, http://links.lww.com/TP/B834). There was only one primary nonfunction in the MPA group. During the first year, there was one more graft loss in the MPA group in a patient with cardiorenal syndrome and none in the mTORi group. Two patients died for septic shock and 2 for unknown causes (equally distributed between groups). One-year creatinine was not different between groups (1.65 ± 0.69 versus 1.46 ± 0.69 mg/dl for MPA and mTORi, respectively, P = 0.272). Regarding BPAR, it occurred in 14 patients in the MPA group (36.8%) and in 5 patients in the mTORi group (15.2%), with the majority being antibody-mediated and C4d positive. There was no difference in the number of renal biopsies during the first year between the two groups. Only in two cases BPAR was asymptomatic and discovered casually in a protocol biopsy. Subgroup analysis of patients with positive crossmatch and/or DSA before transplantation provided comparable results (Table S1, SDC, http://links.lww.com/TP/B834). Mean time from transplant to BPAR development was 114.00 ± 138.65 days for MPA and 108.40 ± 149.65 days for mTORi group (P = 0.940). Cox-regression analysis demonstrated better 1-year rejection-free survival for patients receiving mTORi versus MPA (hazard ratio [HR] 0.32 [0.11–0.90], P = 0.031) (Figure 2) at univariable analysis. Use of rituximab, a positive crossmatch and/or the presence of a DSA before transplant, type of donor, medication intolerance, age and sex of donors and recipients, and ABO incompatibility were not associated with AMR at Cox-regression analysis. The only parameters associated at univariable analysis with the development of BPAR were DGF (HR 2.76 [0.98–7.75], P = 0.054]) and a cPRA ≥ 90% (HR 2.64 [0.87–7.99], P = 0.084]). In the multivariable model based on these 3 parameters; finally, only the use of mTORi was inversely associated with AMR development (HR 0.34 [0.12–0.95], P = 0.040]). All these findings were confirmed at the analysis performed in the per-protocol population (Table 4).
DSA de-novo appeared in 6 patients of the MPA group and in 4 patients of the mTORi group during the first year (18.2% versus 12.1%, respectively, P = 0.408). Hospitalization due to any infection was required in 23 and 18 patients of the MPA and mTORi group (52.6% versus 54.5%, P = 1.0). CMV reactivation occurred in 17 and 9 patients of the two groups (42.1% versus 27.3% for MPA and mTORi, respectively, P = 0.221). Other common immunosuppression-related side effects are listed in Table S2 (SDC, http://links.lww.com/TP/B834). It has to be highlighted that there were no statistical differences between groups in terms of 1-year triglycerides, lymphocele, surgical scar infection, and proteinuria. Total 1-year cholesterol was higher in the mTOR group compared with MPA (221.44 ± 57.53 versus 184.07 ± 40.30, P = 0.007). BK reactivation occurred in 3 patients receiving MPA, with 1 of them eventually developing BK nephropathy, while none of the mTOR patients experienced BK replication. Banff scores of 3- and 12-month protocol renal biopsies are listed in Table 5 (no differences).
During the first year 6 patients in the MPA group (15.8%) and 9 patients in the mTORi group (27.3%) changed immunosuppression (P = 0.260). It has to be highlighted that two patients within the mTORi group developed AMR after conversion to MPA. Conversely, no patients in the MPA developed AMR after conversion to mTORi (Table 6).
Mean tacrolimus and mTOR trough levels during the first year are depicted in Table 7, along with mean dose of MPA. There was an observed tendency toward lower levels of tacrolimus in the mTORi group, although without reaching statistical significance apart from month 9. mTORi levels were within the recommended range (3–8 ng/mL) all throughout the study period. At the moment of rejection, tacrolimus trough levels were 8.12 ± 2.59 and 7.24 ± 1.84 ng/ml in the MPA and mTORi groups, respectively (P = 0.502), while mTORi levels were 3.80 ± 1.38 ng/ml. Mycophenolic acid dose was 894.55 ± 375.10 mg/day at one year and 1041.42 ± 447.52 mg/day at the moment of rejection.
In the present study, we have analyzed the incidence of BPAR in a cohort of high-immunological risk kidney transplant recipients treated with either MPA or mTORi in a immunosuppressive schedule based on tacrolimus and steroids. Basal demographic characteristics were comparable, apart from the higher percentage of living donors in the MPA group (Table 1). Immunological features of the two groups demonstrated a similar risk profile (Table 2). The number of BPAR rejection episodes was higher in the MPA group (34.1% versus 15.2%, Table 3) and rejection-free survival significantly favored patients receiving mTORi. This finding was confirmed at the multivariable analysis in which the contribution of mTORi was analyzed along with the other parameters associated with BPAR at the univariate analysis, namely, DGF and cPRA I+II > 90%. Per-protocol analysis revealed even better results (Table 4). Chronicity scores at 3- and 12-month renal biopsies revealed no differences between groups (Table 5). Drug discontinuation tended to be higher in the mTORi group (27.3% versus 15.8%, Table 6) and mTORi trough levels were within recommended range along the study period. Tacrolimus trough levels were not statistically different between groups, apart from month 9 in which were significantly lower in the mTORi group (Table 7).
The attempt to refine immunosuppression in this particular cohort of transplant population is far from being irrelevant. Especially, in the last years, given to the global increase in the transplant population and the increasing rate of retransplantation, the percentage of hypersensitized recipients on the waiting list has increased steadily. According to the 2015 annual report of the United Network for Organ Sharing/Scientific Registry of Transplant Recipients (UNOS/SRTR), 15.6% of transplanted patients had a cPRA I+II > 80%.20 Only 6.5% of hypersensitized patients get transplanted every year21 and 5-year survival is poor for those who remain on dialysis.22 The choice of the optimal immunosuppression is therefore vital for those hypersensitized patients who finally get transplanted, considering their high risk to develop AMR. Historically, high-immunological risk patients have been treated with aggressive induction based on lymphocytes-depleting antibodies. Maintenance therapy on turn has been classically based on CNI, MPA, and steroids. However, while results for BPAR and short-term outcomes are satisfactory, long-term results are undermined by CNI nephrotoxicity, infectious, and neoplastic complications.2,3 The ongoing quest to improve this immunosuppressive schedule has highlighted the role of mTORi in low-risk kidney transplant recipients. The recently published TRANSFORM trial pointed out that everolimus, when used at an optimal dose in conjunction with CNI, is noninferior to MPA in terms of rejection and renal function and is associated with improved rates of infections.6 However, it is difficult to apply these results to hypersensitized patients, as they were excluded by this and almost every trial that compared mTORi to MPA in a CNI- and prednisone-based regimen (Table 8). Clinical trials’ design has probably been affected by the results of the SYMPHONY study, in which sirolimus was associated with increased rates of BPAR.5 It has to be highlighted that was a CNI-free regimen and when mTORi were used in association with CNI, incidence of rejection was substantially similar to that associated with the combination of MPA with CNI.12,23 However, the only trial that compared these two prescriptions and did not exclude hypersensitized patients from enrollment gave conflicting results, as in mTORi patients incidence of BPAR was higher while graft loss was lower.24 Moreover, in this trial hypersensitization was defined by a PRA > 20%, so many patients with low-to-moderate immunological risk may have been included within this category.24
On turn, in our experience in selected high-risk patients, the use of mTORi was associated with a lower number of BPAR episodes and an improved rejection-free survival (Tables 3 and 4). This difference may also be explained by drugs’ trough levels during the first year after transplant. While mTORi trough levels were within recommended range in both studies (3–8 ng/mL), tacrolimus trough levels were significantly lower in the study by Qazi et al,24 given that in the mTORi group tacrolimus minimization was planned. A possible deduction is that in high-immunological risk patients treated with mTORi, tacrolimus should not be minimized as in the general transplant population. In our cohort, apart from the first three months, we have maintained mean tacrolimus trough levels between 7 and 8 ng/ml (Table 7). This combination indeed may prove to be more potent than the classical combination of tacrolimus and MPA in inhibiting the B-cell response. In vitro studies demonstrated that both MPA and mTORi are capable of inhibiting humoral responses directly and indirectly via inhibition of T-cell help.25,26 However, while both sirolimus and everolimus strongly reduce B cell proliferation, high doses of MPA are needed to reduce it.25,27-29 Moreover, only mTORi are capable to reduce the proliferation of IgM and IgG producing cells, whereas MPA does not.24,27 As CNIs have minimal effect on B-cells proliferation regardless of the stimulus (L-CD40L cells plus interleukins or anti-CD40 plus interleukins),27,28 the addition of mTORi may theoretically provide an added protection on the B-cells compartment. When moving to animal models, we have previously demonstrated that rapamycin reduces C4d deposition and could partially slow the progression of an already established humoral alloimmune response in a renal allotransplantation rat model.30 In addition, Vogelbacher et al31 could also demonstrate the decrease in circulating alloantibodies in rats treated with sirolimus. Finally, Jin et al32 demonstrated that mTOR inhibition, being everolimus more effective than rapamycin, reduce HLA-dependent endothelial cell proliferation in transplant vasculopathy. Therefore, it is reasonable to conclude that in a “normal-range” tacrolimus prescription, the addition of mTORi at 3–8 ng/ml may be useful in blocking B cell activity more effectively than MPA. This may provide an added benefit of mTORi versus MPA, which needs to be used at full dose to exert the same effect on B cells.28
To our knowledge, this is the first study that specifically analyzes the clinical results of an mTORi-based immunosuppression in high-immunological risk kidney transplant recipients. However, given its retrospective nature, results should be interpreted with extreme caution. Even if groups were well matched in terms of immunological risk, allocation bias cannot be ruled out, as some baseline characteristics (primary glomerular disease, obesity, ABO-incompatibility, etc.) influenced group assignation; given the small sample size, even few patients could skew the results. Apart from lack of randomization and the small sample size, other weak points were the short follow-up and the limited number of events that reduce the strength of the multivariable analysis, including the lower-than-expected incidence of T-cell–mediated rejection. The higher conversion rate in the mTORi group should also be highlighted, as some side effects (mTOR-associated pneumonia, thrombotic microangiopathy) are worth of concern. Another weakness of this study lied in the possible sub-optimal dose of MPA during the first year; this could have influenced the results leading to an increased incidence of BPAR in this group. However, it is worthy to note that in common clinical practice MPA is often lowered by the physician to the best tolerated dose to minimize side effects such as diarrhea or leucopenia. On the other side, a good point of our experience relies in immunological follow-up, with control of DSAs and protocol biopsies along the first year after transplant.
In conclusion, in contrast to what is commonly believed, our clinical experience suggests that the combination of tacrolimus and mTORi represents a feasible option in high-immunological risk kidney transplant recipients. Given the nature of this study, results are not conclusive and it is desirable to include this delicate piece of population in future clinical trials to definitively establish the efficacy and the risk/benefit ratio of mTORi in this setting.
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