Early steroid withdrawal: a niche for anti-interleukin 2 receptor monoclonal antibodies?

Early steroid withdrawal: a niche for anti-interleukin 2 receptor monoclonal antibodies? The majority of kidney transplant centres routinely use antibody induction therapy, such as monoclonal interleukin 2 receptor antibodies (IL2RA) or T-lymphocyte depleting agents [most commonly rabbit-derived antithymocyte globulin (rATG)] [1–3], as part of their treatment regimen. The rationale for this strategy is based on randomized trials performed in the 1990s and early 2000s, in which these agents were shown to reduce acute rejection (AR) rates. Consequently, the 2009 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines for the care of kidney transplant patients strongly recommended (Grade 1B) routine use of IL2RA as a first-line therapy, and suggested lymphocyte-depleting agents be reserved for high-risk cases (Grade 2B) [1]. Today, however, the routine use of induction therapy is debatable, as we argued recently [4]. In fact, the clinical trials on which the 2009 KDIGO guidelines based their recommendations mostly used outdated maintenance regimens. Current triple immunosuppressive therapy with steroids, tacrolimus (Tac) and mycophenolate (MPA) results in a much lower incidence of AR than observed with older therapeutic regimens and, consequently, it is highly likely that induction therapy is now redundant in transplant recipients with a standard immunological risk profile [3, 5–8]. Induction therapy is clearly more important in patients with higher immunological risk, in whom rATG has been shown to be superior to IL2RA in preventing AR [9–12]. We therefore questioned the role of IL2RA, which may no longer be useful in patients with standard risk profiles and has been shown to be inferior to rATG in patients with higher immunological risk [4]. Recent data on early steroid avoidance regimens, however, suggest that there may still be a niche for IL2RA use. Interest in early steroid withdrawal (stopping steroids on Days 5–10 post-transplantation) or steroid avoidance (no or only one steroid dose on the day of transplantation) regimens has increased following reports of the long-term safety of this approach and a possible reduction in post-transplant complications [13, 14]. This treatment method could, however, be considered as a form of high-risk transplantation, necessitating induction therapy in order to avoid unacceptably high early AR rates. This possibility was illustrated by the ATLAS study, in which 151 kidney transplant recipients received Tac with MPA without induction therapy and only a single perioperative dose of steroids [6]. These patients had a very high rate of biopsy-proven acute rejection (BPAR) in the first 6 months after transplant (30.5%), compared with only 8.5% in the control arm receiving Tac, MPA and long-term steroids without induction. Although the high rejection rate did not seem to translate into worse outcomes at 3 years post-transplantation [15], it is still a matter of concern. Transplant centres therefore generally include induction therapy in the immunosuppressive regimen when early steroid withdrawal is used. Several studies, all using antibody induction therapy (mostly IL2RA), have investigated the most appropriate maintenance therapy in the context of steroid withdrawal. The FREEDOM study was an intercontinental trial that evaluated two steroid-avoidance regimens [a steroid-free regimen (n = 112) and a regimen of steroid withdrawal at Day 7 (n = 116)], with basiliximab induction, enteric-coated MPA (1440 mg/day) and cyclosporine (CsA) [16]. Disappointingly, the 1-year BPAR rate was significantly higher in the steroid-free (32%) and steroid-withdrawal (26%) groups than in a control group in whom steroids were continued (15%). The severity of rejection in the steroid-free and steroid-withdrawal groups was generally mild, and 1-year graft survival and glomerular filtration rates (GFRs) were comparable to those in the control group. Nevertheless, this study suggested that treatment using IL2RA induction, CsA and MPA led to suboptimal control of rejection in the context of early steroid avoidance, even in a population with standard immunological risk (first transplant, 99% non-black). Studies using Tac, instead of CsA, showed better results. For example, in the European CARMEN study, a regimen of daclizumab, Tac and MPA and only one intraoperative bolus of steroids (n = 260) was associated with equivalent rejection rates compared with a control group treated with Tac, MPA and maintenance steroids (6-month BPAR was 16.5% in both groups) [17]. In a trial conducted in the US by Woodle et al. in which kidney transplant recipients were treated with induction (either IL2RA or rATG), Tac, MPA and steroids up to Day 7 (n = 191), BPAR rates were acceptable (BPAR 17.8% at 5 years, <10% at 6 months), although the BPAR rate was even lower in patients in the control group in whom steroids were continued (10.8% at 5 years, P = 0.04) [18]. A recent systematic review and meta-analysis reported that early steroid avoidance was associated with an increased risk of rejection in trials in which CsA was used, but not in those in which Tac was used [13]. Regardless of whether CsA or Tac was used, this meta-analysis, as well as a more recent meta-analysis by the Cochrane collaboration, showed that steroid-avoidance regimens did not have a negative impact on graft or patient survival compared with controls [13, 14]. It remains unclear, however, which induction agent is preferable in the context of early steroid withdrawal. Until recently, no randomized controlled trials (RCTs) had been conducted comparing IL2RA and rATG in this setting. The best approximation came from the study by Woodle et al. mentioned earlier [18]. Patients randomized to the early steroid withdrawal arm were treated with IL2RA or rATG according to centre preference. In a post hoc analysis, the risk of BPAR after early steroid withdrawal tended to be higher with IL2RA induction than with rATG (24.2% versus 14.4%; P = 0.09). A multivariable analysis combining the results of this trial with those from three other prospective trials by the same investigators also showed a tendency towards a lower risk of AR when early steroid avoidance was preceded by rATG induction compared with no rATG [odds ratio 0.61, 95% confidence interval (CI) 0.30–1.27] [19]. Finally, a recent large retrospective analysis of national US registry data from kidney transplant recipients discharged on steroid-free maintenance immunosuppression showed a lower adjusted graft loss with rATG than with IL2RA induction (hazard ratio 1.19, 95% CI 1.01–1.39) [20]. In December 2016, however, Thomusch et al. reported the results of the HARMONY study, a large multicentre RCT (n = 615) conducted in Germany, in which renal transplant recipients were randomized 1:1:1 to receive IL2RA induction with Tac, MPA and steroid maintenance therapy (arm A), IL2RA induction and rapid corticosteroid withdrawal on Day 8 (arm B) or rATG induction and rapid corticosteroid withdrawal on Day 8 (arm C) [21] (Table 1). The BPAR rates were similar in all three arms (11.2% in arm A, 10.6% in arm B and 9.9% in arm C) and 1-year graft and patient survival rates were excellent and equivalent in all arms. Hence, although previous data had suggested that rATG may be superior to IL2RA in early steroid-withdrawal regimens, there were no differences in the HARMONY study. Results from the recently published ADVANCE study confirm the potential value of IL2RA induction in early steroid withdrawal protocols [22]. The ADVANCE study was an RCT (n = 1081) in which two steroid minimization strategies [steroid withdrawal at Day 10 versus avoidance (i.e. only one intraoperative steroid dose)] were compared, with both arms receiving IL2RA induction, prolonged-release Tac and MPA therapy (Table 1). Six-month BPAR rates were significantly lower in the 10-day steroid withdrawal arm than in the avoidance arm (8.7% versus 13.6%; P = 0.006). Non-biopsy-proven rejection rates were also reported, with a total of 18.2% (withdrawal) versus 25.9% (avoidance) (P = 0.001) ‘clinical’ AR episodes. Because patients in the single-steroid dose arm required more rescue steroids, the cumulative steroid dose at 6 months was comparable between groups. Although the HARMONY and ADVANCE studies were conducted in two very similar European cohorts with standard immunological risk, the results in terms of rejection seem to be less favourable in the ADVANCE study, especially in the arm with only one perioperative steroid dose. What could be the explanation for these observations? First, we should consider how the BPAR and clinical AR rates were reported to avoid comparing ‘apples with oranges’. In terms of BPAR rates, the HARMONY and ADVANCE studies both had good results, which were comparable to outcomes in other studies with contemporary Tac/MPA/steroid maintenance regimens [7, 23] (Symphony: 12.3%, OSAKA: 10.3–16.1%). A possible criticism of the HARMONY study is that it did not report non-biopsy-proven AR rates. It is well known that many transplant centres report, in addition to cases of BPAR, a substantial number of cases of non-biopsy-proven AR, which may reflect reluctance to perform a biopsy in some patients, or a low threshold for treatment in patients with doubtful or borderline rejection. For example, in the Tac arm of the Symphony study there was a 1-year clinical AR rate of 17.2% (whereas the BPAR rate was 12.3%), and in the OSAKA trial the three arms receiving Tac, MPA and steroids had clinical AR rates at 24 weeks ranging from 18.5% to 25.0% (whereas the BPAR rate was 10.3–16.1%) [7, 23]. The BPAR and clinical AR rates reported in the ADVANCE study may, therefore, not be so different from those achieved with current standard of care. Nevertheless, based on the ADVANCE study, one could conclude that it seems advisable to continue steroid therapy during the first week after transplantation, rather than stopping on Day 1. Additionally, it could be argued that the relatively low dose of MPA in the ADVANCE study (2 g/day for the first 14 days, 1 g/day thereafter) compared with that used in the HARMONY study (2 g/day throughout the first year) may have impacted on the risk of AR, suggesting that maintaining a high MPA dose may be preferable when using steroid withdrawal as the treatment regimen. Table 1 Recent RCTs on early steroid withdrawal in kidney transplantation Study characteristics HARMONY (Thomusch et al. [21]) ADVANCE (Mourad et al. [22]) Population Inclusion criteria: recipient age 18–75 years, LD or DD, first TX or second TX provided, first allograft not lost because of rejection within first year Inclusion criteria: recipient age ≥18 years, LD or DD, first TX or second TX provided first allograft not lost because of rejection within first year Exclusion: PreTX DSA, PRA ≥30%, DCD donor, multiorgan TX, CIT ≥30 h, primary FSGS or MPGN, auto-immune disease requiring steroid therapy Exclusion: peak PRA >20%, DCD donor, multiorgan TX, CIT ≥30 h, diabetes mellitus preTX, underlying disease requiring systemic immunosuppressive therapy Immunosuppression Arm A (n = 206) Basiliximab 2 × 20 mg Tac (slow-release)  Target trough levels   1st month: 7–12 ng/mL   2nd–3rd month: 6–10 ng/mL   4th–12th month: 3–8 ng/mL MPA: 2000 mg/day Prednisolone   500 mg on Day 0   100 mg on Day 1   75 mg on Day 2   50 mg on Day 3   25 mg on Days 4–7   Taper to 10 mg/day by Week 4   Maintain 2.5–5 mg/day after 3 months Arm B (n = 189) Basiliximab 2 × 20 mg Tac (slow-release)  Target trough levels   1st month: 7–12 ng/mL   2nd–3rd month: 6–10 ng/mL   4th–12th month: 3–8 ng/mL MPA: 2000 mg/day Prednisolone   500 mg on Day 0   100 mg on Day 1   75 mg on Day 2   50 mg on Day 3   25 mg on Days 4–7   STOP on Day 8 Arm C (n = 192) rATG (Thymoglobulin®) Days 0–3, aimed at total dose of 6 mg/kg Tac (slow-release)  Target trough levels   1st month: 7–12 ng/mL   2nd–3rd month: 6–10 ng/mL   4th–12th month: 3–8 ng/mL MPA: 2000 mg/day Prednisolone   500 mg on Day 0   100 mg on Day 1   75 mg on Day 2   50 mg on Day 3   25 mg on Days 4–7   STOP on Day 8 Arm 1 (n = 528) Basiliximab 2 × 20 mg Tac (slow-release)  Target trough levels   Days 0–21: 11–15 ng/mL   Days 22–42: 8–12 ng/mL   Days 43–168: 5–9 ng/mL MPA   Days 0–14: 2 × 1000 mg/day   Days >14: 2 × 500 mg/day Prednisolone   Max 1000 mg on Day 0   20 mg on Days 1–4   15 mg on Days 5–6   10 mg on Days 7–8   5 mg on Days 9–10   STOP on Day 11 Arm 2 (n = 553) Basiliximab 2 × 20 mg Tac (slow-release)  Target trough levels   Days 0–21: 11–15 ng/mL   Days 22–42: 8–12 ng/mL   Days 43–168: 5–9 ng/mL MPA   Days 0–14: 2 × 1000 mg/day   Days >14: 2 × 500 mg/day Prednisolone   Max 1000 mg on Day 0   STOP on Day 1 Follow-up time 1 year after transplantation 24 weeks after transplantation BPAR (excl. borderline) BPAR: 11% Steroid-resistant BPAR: 2% AMR: 1% BPAR: 11% Steroid-resistant BPAR: 3% AMR: 2% BPAR: 10% Steroid-resistant BPAR: 2% AMR: 2% BPAR: 8.7% Steroid-resistant BPAR: 3.4% AMR: 2.7% BPAR: 13.6% Steroid-resistant BPAR: 3.8% AMR: 2.6% Clinical AR Not reported AR 18.2% (12.5% received steroids for AR) Steroid-resistant AR: 4.4% AR 25.9% (21.0% received steroids for AR) Steroid-resistant AR: 5.5% PS 95% at 1 year 97% at 1 year 97% at 1 year 98.4% at 24 weeks 99.0% at 24 weeks GS Overall GS: 91% at 1 year Death censored GS: 96% at 1 year Overall GS: 94% at 1 year Death censored GS: 97% at 1 year Overall GS: 93% at 1 year Death censored GS: 96% at 1 year 95.6% at 24 weeks 95.0% at 24 weeks GFR CKD-EPI: 46.3 mL/min Cockcroft–Gault: 57.3 mL/min CKD-EPI: 47.4 mL/min Cockcroft–Gault: 58.0 mL/min CKD-EPI: 50.2 mL/min Cockcroft–Gault: 62.9 mL/min MDRD: 47.1 mL/min/1.73 m2 Cockcroft–Gault: 53.8 mL/min MDRD: 47.3 mL/min/1.73 m2 Cockcroft–Gault: 51.7 mL/min Steroids at end of study At 1 year: 90% At 1 year: 16% At 1 year: 17% At 24 weeks: 14.2% At 24 weeks: 17.2% Post-transplant diabetes (ADA criteria) At 1 year: 39.2% (P = 0.0004) At 1 year: 23.9% At 1 year: 22.7% At 24 weeks: 17.4% At 24 weeks: 16.6% Study characteristics HARMONY (Thomusch et al. [21]) ADVANCE (Mourad et al. [22]) Population Inclusion criteria: recipient age 18–75 years, LD or DD, first TX or second TX provided, first allograft not lost because of rejection within first year Inclusion criteria: recipient age ≥18 years, LD or DD, first TX or second TX provided first allograft not lost because of rejection within first year Exclusion: PreTX DSA, PRA ≥30%, DCD donor, multiorgan TX, CIT ≥30 h, primary FSGS or MPGN, auto-immune disease requiring steroid therapy Exclusion: peak PRA >20%, DCD donor, multiorgan TX, CIT ≥30 h, diabetes mellitus preTX, underlying disease requiring systemic immunosuppressive therapy Immunosuppression Arm A (n = 206) Basiliximab 2 × 20 mg Tac (slow-release)  Target trough levels   1st month: 7–12 ng/mL   2nd–3rd month: 6–10 ng/mL   4th–12th month: 3–8 ng/mL MPA: 2000 mg/day Prednisolone   500 mg on Day 0   100 mg on Day 1   75 mg on Day 2   50 mg on Day 3   25 mg on Days 4–7   Taper to 10 mg/day by Week 4   Maintain 2.5–5 mg/day after 3 months Arm B (n = 189) Basiliximab 2 × 20 mg Tac (slow-release)  Target trough levels   1st month: 7–12 ng/mL   2nd–3rd month: 6–10 ng/mL   4th–12th month: 3–8 ng/mL MPA: 2000 mg/day Prednisolone   500 mg on Day 0   100 mg on Day 1   75 mg on Day 2   50 mg on Day 3   25 mg on Days 4–7   STOP on Day 8 Arm C (n = 192) rATG (Thymoglobulin®) Days 0–3, aimed at total dose of 6 mg/kg Tac (slow-release)  Target trough levels   1st month: 7–12 ng/mL   2nd–3rd month: 6–10 ng/mL   4th–12th month: 3–8 ng/mL MPA: 2000 mg/day Prednisolone   500 mg on Day 0   100 mg on Day 1   75 mg on Day 2   50 mg on Day 3   25 mg on Days 4–7   STOP on Day 8 Arm 1 (n = 528) Basiliximab 2 × 20 mg Tac (slow-release)  Target trough levels   Days 0–21: 11–15 ng/mL   Days 22–42: 8–12 ng/mL   Days 43–168: 5–9 ng/mL MPA   Days 0–14: 2 × 1000 mg/day   Days >14: 2 × 500 mg/day Prednisolone   Max 1000 mg on Day 0   20 mg on Days 1–4   15 mg on Days 5–6   10 mg on Days 7–8   5 mg on Days 9–10   STOP on Day 11 Arm 2 (n = 553) Basiliximab 2 × 20 mg Tac (slow-release)  Target trough levels   Days 0–21: 11–15 ng/mL   Days 22–42: 8–12 ng/mL   Days 43–168: 5–9 ng/mL MPA   Days 0–14: 2 × 1000 mg/day   Days >14: 2 × 500 mg/day Prednisolone   Max 1000 mg on Day 0   STOP on Day 1 Follow-up time 1 year after transplantation 24 weeks after transplantation BPAR (excl. borderline) BPAR: 11% Steroid-resistant BPAR: 2% AMR: 1% BPAR: 11% Steroid-resistant BPAR: 3% AMR: 2% BPAR: 10% Steroid-resistant BPAR: 2% AMR: 2% BPAR: 8.7% Steroid-resistant BPAR: 3.4% AMR: 2.7% BPAR: 13.6% Steroid-resistant BPAR: 3.8% AMR: 2.6% Clinical AR Not reported AR 18.2% (12.5% received steroids for AR) Steroid-resistant AR: 4.4% AR 25.9% (21.0% received steroids for AR) Steroid-resistant AR: 5.5% PS 95% at 1 year 97% at 1 year 97% at 1 year 98.4% at 24 weeks 99.0% at 24 weeks GS Overall GS: 91% at 1 year Death censored GS: 96% at 1 year Overall GS: 94% at 1 year Death censored GS: 97% at 1 year Overall GS: 93% at 1 year Death censored GS: 96% at 1 year 95.6% at 24 weeks 95.0% at 24 weeks GFR CKD-EPI: 46.3 mL/min Cockcroft–Gault: 57.3 mL/min CKD-EPI: 47.4 mL/min Cockcroft–Gault: 58.0 mL/min CKD-EPI: 50.2 mL/min Cockcroft–Gault: 62.9 mL/min MDRD: 47.1 mL/min/1.73 m2 Cockcroft–Gault: 53.8 mL/min MDRD: 47.3 mL/min/1.73 m2 Cockcroft–Gault: 51.7 mL/min Steroids at end of study At 1 year: 90% At 1 year: 16% At 1 year: 17% At 24 weeks: 14.2% At 24 weeks: 17.2% Post-transplant diabetes (ADA criteria) At 1 year: 39.2% (P = 0.0004) At 1 year: 23.9% At 1 year: 22.7% At 24 weeks: 17.4% At 24 weeks: 16.6% LD, living donor; DD, deceased donor; TX, transplant; DSA, donor-specific antibodies; PRA, panel reactive antibodies; DCD, donation after cardiac death; CIT, cold ischemia time; FSGS, focal segmental glomerulosclerosis; MPGN, membranoproliferative glomerulonephritis; MPA, mycophenolic acid; AMR, antibody-mediated rejection; PS, patient survival; GS, graft survival; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; MDRD, Modification of Diet in Renal Disease; ADA, American Diabetes Association. Table 1 Recent RCTs on early steroid withdrawal in kidney transplantation Study characteristics HARMONY (Thomusch et al. [21]) ADVANCE (Mourad et al. [22]) Population Inclusion criteria: recipient age 18–75 years, LD or DD, first TX or second TX provided, first allograft not lost because of rejection within first year Inclusion criteria: recipient age ≥18 years, LD or DD, first TX or second TX provided first allograft not lost because of rejection within first year Exclusion: PreTX DSA, PRA ≥30%, DCD donor, multiorgan TX, CIT ≥30 h, primary FSGS or MPGN, auto-immune disease requiring steroid therapy Exclusion: peak PRA >20%, DCD donor, multiorgan TX, CIT ≥30 h, diabetes mellitus preTX, underlying disease requiring systemic immunosuppressive therapy Immunosuppression Arm A (n = 206) Basiliximab 2 × 20 mg Tac (slow-release)  Target trough levels   1st month: 7–12 ng/mL   2nd–3rd month: 6–10 ng/mL   4th–12th month: 3–8 ng/mL MPA: 2000 mg/day Prednisolone   500 mg on Day 0   100 mg on Day 1   75 mg on Day 2   50 mg on Day 3   25 mg on Days 4–7   Taper to 10 mg/day by Week 4   Maintain 2.5–5 mg/day after 3 months Arm B (n = 189) Basiliximab 2 × 20 mg Tac (slow-release)  Target trough levels   1st month: 7–12 ng/mL   2nd–3rd month: 6–10 ng/mL   4th–12th month: 3–8 ng/mL MPA: 2000 mg/day Prednisolone   500 mg on Day 0   100 mg on Day 1   75 mg on Day 2   50 mg on Day 3   25 mg on Days 4–7   STOP on Day 8 Arm C (n = 192) rATG (Thymoglobulin®) Days 0–3, aimed at total dose of 6 mg/kg Tac (slow-release)  Target trough levels   1st month: 7–12 ng/mL   2nd–3rd month: 6–10 ng/mL   4th–12th month: 3–8 ng/mL MPA: 2000 mg/day Prednisolone   500 mg on Day 0   100 mg on Day 1   75 mg on Day 2   50 mg on Day 3   25 mg on Days 4–7   STOP on Day 8 Arm 1 (n = 528) Basiliximab 2 × 20 mg Tac (slow-release)  Target trough levels   Days 0–21: 11–15 ng/mL   Days 22–42: 8–12 ng/mL   Days 43–168: 5–9 ng/mL MPA   Days 0–14: 2 × 1000 mg/day   Days >14: 2 × 500 mg/day Prednisolone   Max 1000 mg on Day 0   20 mg on Days 1–4   15 mg on Days 5–6   10 mg on Days 7–8   5 mg on Days 9–10   STOP on Day 11 Arm 2 (n = 553) Basiliximab 2 × 20 mg Tac (slow-release)  Target trough levels   Days 0–21: 11–15 ng/mL   Days 22–42: 8–12 ng/mL   Days 43–168: 5–9 ng/mL MPA   Days 0–14: 2 × 1000 mg/day   Days >14: 2 × 500 mg/day Prednisolone   Max 1000 mg on Day 0   STOP on Day 1 Follow-up time 1 year after transplantation 24 weeks after transplantation BPAR (excl. borderline) BPAR: 11% Steroid-resistant BPAR: 2% AMR: 1% BPAR: 11% Steroid-resistant BPAR: 3% AMR: 2% BPAR: 10% Steroid-resistant BPAR: 2% AMR: 2% BPAR: 8.7% Steroid-resistant BPAR: 3.4% AMR: 2.7% BPAR: 13.6% Steroid-resistant BPAR: 3.8% AMR: 2.6% Clinical AR Not reported AR 18.2% (12.5% received steroids for AR) Steroid-resistant AR: 4.4% AR 25.9% (21.0% received steroids for AR) Steroid-resistant AR: 5.5% PS 95% at 1 year 97% at 1 year 97% at 1 year 98.4% at 24 weeks 99.0% at 24 weeks GS Overall GS: 91% at 1 year Death censored GS: 96% at 1 year Overall GS: 94% at 1 year Death censored GS: 97% at 1 year Overall GS: 93% at 1 year Death censored GS: 96% at 1 year 95.6% at 24 weeks 95.0% at 24 weeks GFR CKD-EPI: 46.3 mL/min Cockcroft–Gault: 57.3 mL/min CKD-EPI: 47.4 mL/min Cockcroft–Gault: 58.0 mL/min CKD-EPI: 50.2 mL/min Cockcroft–Gault: 62.9 mL/min MDRD: 47.1 mL/min/1.73 m2 Cockcroft–Gault: 53.8 mL/min MDRD: 47.3 mL/min/1.73 m2 Cockcroft–Gault: 51.7 mL/min Steroids at end of study At 1 year: 90% At 1 year: 16% At 1 year: 17% At 24 weeks: 14.2% At 24 weeks: 17.2% Post-transplant diabetes (ADA criteria) At 1 year: 39.2% (P = 0.0004) At 1 year: 23.9% At 1 year: 22.7% At 24 weeks: 17.4% At 24 weeks: 16.6% Study characteristics HARMONY (Thomusch et al. [21]) ADVANCE (Mourad et al. [22]) Population Inclusion criteria: recipient age 18–75 years, LD or DD, first TX or second TX provided, first allograft not lost because of rejection within first year Inclusion criteria: recipient age ≥18 years, LD or DD, first TX or second TX provided first allograft not lost because of rejection within first year Exclusion: PreTX DSA, PRA ≥30%, DCD donor, multiorgan TX, CIT ≥30 h, primary FSGS or MPGN, auto-immune disease requiring steroid therapy Exclusion: peak PRA >20%, DCD donor, multiorgan TX, CIT ≥30 h, diabetes mellitus preTX, underlying disease requiring systemic immunosuppressive therapy Immunosuppression Arm A (n = 206) Basiliximab 2 × 20 mg Tac (slow-release)  Target trough levels   1st month: 7–12 ng/mL   2nd–3rd month: 6–10 ng/mL   4th–12th month: 3–8 ng/mL MPA: 2000 mg/day Prednisolone   500 mg on Day 0   100 mg on Day 1   75 mg on Day 2   50 mg on Day 3   25 mg on Days 4–7   Taper to 10 mg/day by Week 4   Maintain 2.5–5 mg/day after 3 months Arm B (n = 189) Basiliximab 2 × 20 mg Tac (slow-release)  Target trough levels   1st month: 7–12 ng/mL   2nd–3rd month: 6–10 ng/mL   4th–12th month: 3–8 ng/mL MPA: 2000 mg/day Prednisolone   500 mg on Day 0   100 mg on Day 1   75 mg on Day 2   50 mg on Day 3   25 mg on Days 4–7   STOP on Day 8 Arm C (n = 192) rATG (Thymoglobulin®) Days 0–3, aimed at total dose of 6 mg/kg Tac (slow-release)  Target trough levels   1st month: 7–12 ng/mL   2nd–3rd month: 6–10 ng/mL   4th–12th month: 3–8 ng/mL MPA: 2000 mg/day Prednisolone   500 mg on Day 0   100 mg on Day 1   75 mg on Day 2   50 mg on Day 3   25 mg on Days 4–7   STOP on Day 8 Arm 1 (n = 528) Basiliximab 2 × 20 mg Tac (slow-release)  Target trough levels   Days 0–21: 11–15 ng/mL   Days 22–42: 8–12 ng/mL   Days 43–168: 5–9 ng/mL MPA   Days 0–14: 2 × 1000 mg/day   Days >14: 2 × 500 mg/day Prednisolone   Max 1000 mg on Day 0   20 mg on Days 1–4   15 mg on Days 5–6   10 mg on Days 7–8   5 mg on Days 9–10   STOP on Day 11 Arm 2 (n = 553) Basiliximab 2 × 20 mg Tac (slow-release)  Target trough levels   Days 0–21: 11–15 ng/mL   Days 22–42: 8–12 ng/mL   Days 43–168: 5–9 ng/mL MPA   Days 0–14: 2 × 1000 mg/day   Days >14: 2 × 500 mg/day Prednisolone   Max 1000 mg on Day 0   STOP on Day 1 Follow-up time 1 year after transplantation 24 weeks after transplantation BPAR (excl. borderline) BPAR: 11% Steroid-resistant BPAR: 2% AMR: 1% BPAR: 11% Steroid-resistant BPAR: 3% AMR: 2% BPAR: 10% Steroid-resistant BPAR: 2% AMR: 2% BPAR: 8.7% Steroid-resistant BPAR: 3.4% AMR: 2.7% BPAR: 13.6% Steroid-resistant BPAR: 3.8% AMR: 2.6% Clinical AR Not reported AR 18.2% (12.5% received steroids for AR) Steroid-resistant AR: 4.4% AR 25.9% (21.0% received steroids for AR) Steroid-resistant AR: 5.5% PS 95% at 1 year 97% at 1 year 97% at 1 year 98.4% at 24 weeks 99.0% at 24 weeks GS Overall GS: 91% at 1 year Death censored GS: 96% at 1 year Overall GS: 94% at 1 year Death censored GS: 97% at 1 year Overall GS: 93% at 1 year Death censored GS: 96% at 1 year 95.6% at 24 weeks 95.0% at 24 weeks GFR CKD-EPI: 46.3 mL/min Cockcroft–Gault: 57.3 mL/min CKD-EPI: 47.4 mL/min Cockcroft–Gault: 58.0 mL/min CKD-EPI: 50.2 mL/min Cockcroft–Gault: 62.9 mL/min MDRD: 47.1 mL/min/1.73 m2 Cockcroft–Gault: 53.8 mL/min MDRD: 47.3 mL/min/1.73 m2 Cockcroft–Gault: 51.7 mL/min Steroids at end of study At 1 year: 90% At 1 year: 16% At 1 year: 17% At 24 weeks: 14.2% At 24 weeks: 17.2% Post-transplant diabetes (ADA criteria) At 1 year: 39.2% (P = 0.0004) At 1 year: 23.9% At 1 year: 22.7% At 24 weeks: 17.4% At 24 weeks: 16.6% LD, living donor; DD, deceased donor; TX, transplant; DSA, donor-specific antibodies; PRA, panel reactive antibodies; DCD, donation after cardiac death; CIT, cold ischemia time; FSGS, focal segmental glomerulosclerosis; MPGN, membranoproliferative glomerulonephritis; MPA, mycophenolic acid; AMR, antibody-mediated rejection; PS, patient survival; GS, graft survival; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; MDRD, Modification of Diet in Renal Disease; ADA, American Diabetes Association. In summary, current data suggest that early steroid-withdrawal regimens do not increase the risk of AR when the remaining immunosuppressive therapy is sufficiently potent, which can be achieved using a combination of Tac, MPA 2 g/day and antibody induction therapy, and preferably by continuing steroids for the first week after transplantation. Based on the most recent studies, IL2RA may be the induction agent of choice, because it appeared to be as effective as rATG and is generally associated with fewer adverse effects. Having said this, we should, however, be aware of the limitations of the current evidence. First, the HARMONY and ADVANCE studies were both conducted in Europe, in a predominantly white population with standard immunological risk. It cannot be ruled out that rATG is superior in patients with higher immunological risk, although these patients are usually not considered to be suitable candidates for steroid withdrawal. Secondly, the main advantage of early steroid-avoidance regimens, as supported by the HARMONY and ADVANCE studies, may be the reduction in post-transplant diabetes. The long-term consequences, however, remain unclear [14]. We have no definitive data to prove that steroid-avoidance improves long-term renal function or graft survival, nor that it decreases cardiovascular events or mortality [14, 24]. There are no data on the development of de novo donor-specific antibodies (dnDSA) or of chronic antibody-mediated rejection in this setting, which may theoretically have a counterproductive effect on long-term outcomes. The limited data also mean that we cannot exclude the possibility that rATG may eventually be shown to be preferable to IL2RA in early steroid-avoidance regimens if it is better at preventing the development of dnDSA [25]. Thirdly, if the main reason for choosing an early steroid-withdrawal regimen is the reduction in occurrence of post-transplant diabetes, it may make sense to choose a regimen that includes CsA instead of Tac, as the latter is known to be more diabetogenic. Although studies on early steroid withdrawal combined with CsA have shown suboptimal results [16, 26], it is conceivable that a CsA-based regimen with withdrawal of steroids after 7 days, high-dose MPA (e.g. 2500 mg/day) and antibody induction may also keep AR rates low and may perhaps be even better at preventing new onset diabetes mellitus after transplantation than Tac-containing regimens such as those used in the HARMONY and ADVANCE studies. This should be an area of future research. Again, possible differences in efficacy of rATG and IL2RA should be addressed in such settings. In summary, we believe that the 2009 KDIGO guidelines on induction therapy after kidney transplantation no longer reflect the current evidence in patients with standard and high immunological risk or in patients managed with early steroid-withdrawal regimens. In standard risk transplantation using Tac, MPA and maintenance steroids, induction therapy now seems redundant. In patients with high immunological risk, rATG is superior to IL2RA. However, there may still be a niche for IL2RA use in the context of early steroid-withdrawal regimens, at least in low-risk recipients maintained on Tac and MPA. Updated guidelines based on the latest evidence are eagerly awaited. Future studies should focus on a better understanding and quantification of immunological risk, which may help guide decisions regarding which induction therapy to choose, if any, for individual patients. KEY POINTS Antibody induction therapy may be redundant in standard-risk kidney transplant recipients maintained on Tac, MPA and steroids. rATG is preferable to IL2RA in kidney transplant recipients with high immunological risk. When choosing a regimen with early steroid withdrawal: Antibody induction therapy is advisable IL2RA and rATG are equally effective in standard-risk recipients remaining on Tac and MPA. Given the balance of benefits and risks, IL2RA may be preferred over rATG in this setting. Maintenance therapy should be sufficiently potent: Steroid withdrawal after 7 days may be preferable to one preoperative dose. Consider to use Tac instead of CsA. Maintaining a high dose of MPA during the first year may be advisable. CONFLICT OF INTEREST STATEMENT None declared. REFERENCES 1 Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group . KDIGO clinical practice guideline for the care of kidney transplant recipients . Am J Transpl 2009 ; 9 (Suppl 3) : S1 – S155 2 Hart A , Smith JM , Skeans MA et al. OPTN/SRTR 2015 Annual report . Am J Transpl 2017 ; 17 : 1 – 564 3 Opelz G , Unterrainer C , Süsal C et al. Efficacy and safety of antibody induction therapy in the current era of kidney transplantation . Nephrol Dial Transplant 2016 ; 31 : 1730 – 1738 Google Scholar CrossRef Search ADS PubMed 4 Hellemans R , Bosmans J-L , Abramowicz D. Induction therapy for kidney transplant recipients: do we still need anti-IL2 receptor monoclonal antibodies? Am J Transplant 2017 ; 17 : 22 – 27 Google Scholar CrossRef Search ADS PubMed 5 Tanriover B , Jaikaransingh V , MacConmara MP et al. Acute rejection rates and graft outcomes according to induction regimen among recipients of kidneys from deceased donors treated with tacrolimus and mycophenolate . Clin J Am Soc Nephrol 2016 ; 11 : 1650 – 1661 Google Scholar CrossRef Search ADS PubMed 6 Vítko S , Klinger M , Salmela K et al. Two corticosteroid-free regimens-tacrolimus monotherapy after basiliximab administration and tacrolimus/mycophenolate mofetil-in comparison with a standard triple regimen in renal transplantation: results of the Atlas study . Transplantation 2005 ; 80 : 1734 – 1741 Google Scholar CrossRef Search ADS PubMed 7 Albano L , Banas B , Klempnauer JL et al. OSAKA trial: a randomized, controlled trial comparing tacrolimus QD and BD in kidney transplantation . Transplantation 2013 ; 96 : 897 – 903 Google Scholar CrossRef Search ADS PubMed 8 van den Hoogen MWF , Kamburova EG , Baas MC et al. Rituximab as induction therapy after renal transplantation: a randomized, double-blind, placebo-controlled study of efficacy and safety . Am J Transplant 2015 ; 15 : 407 – 416 Google Scholar CrossRef Search ADS PubMed 9 Noel C , Abramowicz D , Durand D et al. Daclizumab versus antithymocyte globulin in high-immunological-risk renal transplant recipients . J Am Soc Nephrol 2009 ; 20 : 1385 – 1392 Google Scholar CrossRef Search ADS PubMed 10 Hellemans R et al. Daclizumab versus rabbit antithymocyte globulin in high-risk renal transplants: five-year follow-up of a randomized study . Am J Transplant 2015 ; 15 : 1923 – 1932 Google Scholar CrossRef Search ADS PubMed 11 Brennan DC , Daller JA , Lake KD et al. Rabbit antithymocyte globulin versus basiliximab in renal transplantation . N Engl J Med 2006 ; 355 : 1967 – 1977 Google Scholar CrossRef Search ADS PubMed 12 Brennan DC , Schnitzler MA. Long-term results of rabbit antithymocyte globulin and basiliximab induction . N Engl J Med 2008 ; 359 : 1736 – 1738 Google Scholar CrossRef Search ADS PubMed 13 Pascual J , Royuela A , Galeano C et al. Very early steroid withdrawal or complete avoidance for kidney transplant recipients: a systematic review . Nephrol Dial Transplant 2012 ; 27 : 825 – 832 Google Scholar CrossRef Search ADS PubMed 14 Haller MC , Royuela A , Nagler EV et al. Steroid avoidance or withdrawal for kidney transplant recipients (Review) . Cochrane Database Syst Rev 2016 ; 8 : CD005632 15 Krämer BK , Klinger M , Vítko Š et al. Tacrolimus-based, steroid-free regimens in renal transplantation . Transplant J 2012 ; 94 : 492 – 498 Google Scholar CrossRef Search ADS 16 Vincenti F , Schena FP , Paraskevas S et al. A randomized, multicenter study of steroid avoidance, early steroid withdrawal or standard steroid therapy in kidney transplant recipients . Am J Transplant 2008 ; 8 : 307 – 316 Google Scholar CrossRef Search ADS PubMed 17 Rostaing L , Cantarovich D , Mourad G et al. Corticosteroid-free immunosuppression with tacrolimus, mycophenolate mofetil, and daclizumab induction in renal transplantation . Transplantation 2005 ; 79 : 807 – 814 Google Scholar CrossRef Search ADS PubMed 18 Woodle ES et al. A prospective, randomized, double-blind, placebo-controlled multicenter trial comparing early (7 day) corticosteroid cessation versus long-term, low-dose corticosteroid therapy . Ann Surg 2008 ; 248 : 564 – 577 Google Scholar PubMed 19 Woodle ES , Alloway RR , Buell JF et al. Multivariate analysis of risk factors for acute rejection in early corticosteroid cessation regimens under modern immunosuppression . Am J Transplant 2005 ; 5 : 2740 – 2744 Google Scholar CrossRef Search ADS PubMed 20 Sureshkumar KK , Thai NL , Hussain SM et al. Influence of induction modality on the outcome of deceased donor kidney transplant recipients discharged on steroid-free maintenance immunosuppression . Transplantation 2012 ; 93 : 799 – 805 Google Scholar CrossRef Search ADS PubMed 21 Thomusch O , Wiesener M , Opgenoorth M et al. Rabbit-ATG or basiliximab induction for rapid steroid withdrawal after renal transplantation (Harmony): an open-label, multicentre, randomised controlled trial . Lancet 2016 ; 388 : 3006 – 3016 Google Scholar CrossRef Search ADS PubMed 22 Mourad G et al. Incidence of posttransplantation diabetes mellitus in de novo kidney transplant recipients receiving prolonged-release tacrolimus-based immunosuppression with 2 different corticosteroid minimization strategies: ADVANCE, a randomized controlled trial . Transplantation 2017 ; 101 : 1924 – 1934 Google Scholar CrossRef Search ADS PubMed 23 Ekberg H , Tedesco-Silva H , Demirbas A et al. Reduced exposure to calcineurin inhibitors in renal transplantation . N Engl J Med 2007 ; 357 : 2562 – 2575 Google Scholar CrossRef Search ADS PubMed 24 Pascual J , Zuckermann A , Djamali A et al. Rabbit antithymocyte globulin and donor-specific antibodies in kidney transplantation—A review . Transplant Rev 2016 ; 30 : 85 – 91 Google Scholar CrossRef Search ADS 25 Brokhof MM , Sollinger HW , Hager DR et al. Antithymocyte globulin is associated with a lower incidence of de novo donor-specific antibodies in moderately sensitized renal transplant recipients . Transplantation 2014 ; 97 : 612 – 617 Google Scholar CrossRef Search ADS PubMed 26 Cantarovich D , Rostaing L , Kamar N et al. Early corticosteroid avoidance in kidney transplant recipients receiving ATG-F induction: 5-year actual results of a prospective and randomized study . Am J Transplant 2014 ; 14 : 2556 – 2564 Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Nephrology Dialysis Transplantation Oxford University Press

Early steroid withdrawal: a niche for anti-interleukin 2 receptor monoclonal antibodies?

Nephrology Dialysis Transplantation , Volume Advance Article (7) – Mar 27, 2018

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Oxford University Press
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© The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
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0931-0509
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Abstract

The majority of kidney transplant centres routinely use antibody induction therapy, such as monoclonal interleukin 2 receptor antibodies (IL2RA) or T-lymphocyte depleting agents [most commonly rabbit-derived antithymocyte globulin (rATG)] [1–3], as part of their treatment regimen. The rationale for this strategy is based on randomized trials performed in the 1990s and early 2000s, in which these agents were shown to reduce acute rejection (AR) rates. Consequently, the 2009 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines for the care of kidney transplant patients strongly recommended (Grade 1B) routine use of IL2RA as a first-line therapy, and suggested lymphocyte-depleting agents be reserved for high-risk cases (Grade 2B) [1]. Today, however, the routine use of induction therapy is debatable, as we argued recently [4]. In fact, the clinical trials on which the 2009 KDIGO guidelines based their recommendations mostly used outdated maintenance regimens. Current triple immunosuppressive therapy with steroids, tacrolimus (Tac) and mycophenolate (MPA) results in a much lower incidence of AR than observed with older therapeutic regimens and, consequently, it is highly likely that induction therapy is now redundant in transplant recipients with a standard immunological risk profile [3, 5–8]. Induction therapy is clearly more important in patients with higher immunological risk, in whom rATG has been shown to be superior to IL2RA in preventing AR [9–12]. We therefore questioned the role of IL2RA, which may no longer be useful in patients with standard risk profiles and has been shown to be inferior to rATG in patients with higher immunological risk [4]. Recent data on early steroid avoidance regimens, however, suggest that there may still be a niche for IL2RA use. Interest in early steroid withdrawal (stopping steroids on Days 5–10 post-transplantation) or steroid avoidance (no or only one steroid dose on the day of transplantation) regimens has increased following reports of the long-term safety of this approach and a possible reduction in post-transplant complications [13, 14]. This treatment method could, however, be considered as a form of high-risk transplantation, necessitating induction therapy in order to avoid unacceptably high early AR rates. This possibility was illustrated by the ATLAS study, in which 151 kidney transplant recipients received Tac with MPA without induction therapy and only a single perioperative dose of steroids [6]. These patients had a very high rate of biopsy-proven acute rejection (BPAR) in the first 6 months after transplant (30.5%), compared with only 8.5% in the control arm receiving Tac, MPA and long-term steroids without induction. Although the high rejection rate did not seem to translate into worse outcomes at 3 years post-transplantation [15], it is still a matter of concern. Transplant centres therefore generally include induction therapy in the immunosuppressive regimen when early steroid withdrawal is used. Several studies, all using antibody induction therapy (mostly IL2RA), have investigated the most appropriate maintenance therapy in the context of steroid withdrawal. The FREEDOM study was an intercontinental trial that evaluated two steroid-avoidance regimens [a steroid-free regimen (n = 112) and a regimen of steroid withdrawal at Day 7 (n = 116)], with basiliximab induction, enteric-coated MPA (1440 mg/day) and cyclosporine (CsA) [16]. Disappointingly, the 1-year BPAR rate was significantly higher in the steroid-free (32%) and steroid-withdrawal (26%) groups than in a control group in whom steroids were continued (15%). The severity of rejection in the steroid-free and steroid-withdrawal groups was generally mild, and 1-year graft survival and glomerular filtration rates (GFRs) were comparable to those in the control group. Nevertheless, this study suggested that treatment using IL2RA induction, CsA and MPA led to suboptimal control of rejection in the context of early steroid avoidance, even in a population with standard immunological risk (first transplant, 99% non-black). Studies using Tac, instead of CsA, showed better results. For example, in the European CARMEN study, a regimen of daclizumab, Tac and MPA and only one intraoperative bolus of steroids (n = 260) was associated with equivalent rejection rates compared with a control group treated with Tac, MPA and maintenance steroids (6-month BPAR was 16.5% in both groups) [17]. In a trial conducted in the US by Woodle et al. in which kidney transplant recipients were treated with induction (either IL2RA or rATG), Tac, MPA and steroids up to Day 7 (n = 191), BPAR rates were acceptable (BPAR 17.8% at 5 years, <10% at 6 months), although the BPAR rate was even lower in patients in the control group in whom steroids were continued (10.8% at 5 years, P = 0.04) [18]. A recent systematic review and meta-analysis reported that early steroid avoidance was associated with an increased risk of rejection in trials in which CsA was used, but not in those in which Tac was used [13]. Regardless of whether CsA or Tac was used, this meta-analysis, as well as a more recent meta-analysis by the Cochrane collaboration, showed that steroid-avoidance regimens did not have a negative impact on graft or patient survival compared with controls [13, 14]. It remains unclear, however, which induction agent is preferable in the context of early steroid withdrawal. Until recently, no randomized controlled trials (RCTs) had been conducted comparing IL2RA and rATG in this setting. The best approximation came from the study by Woodle et al. mentioned earlier [18]. Patients randomized to the early steroid withdrawal arm were treated with IL2RA or rATG according to centre preference. In a post hoc analysis, the risk of BPAR after early steroid withdrawal tended to be higher with IL2RA induction than with rATG (24.2% versus 14.4%; P = 0.09). A multivariable analysis combining the results of this trial with those from three other prospective trials by the same investigators also showed a tendency towards a lower risk of AR when early steroid avoidance was preceded by rATG induction compared with no rATG [odds ratio 0.61, 95% confidence interval (CI) 0.30–1.27] [19]. Finally, a recent large retrospective analysis of national US registry data from kidney transplant recipients discharged on steroid-free maintenance immunosuppression showed a lower adjusted graft loss with rATG than with IL2RA induction (hazard ratio 1.19, 95% CI 1.01–1.39) [20]. In December 2016, however, Thomusch et al. reported the results of the HARMONY study, a large multicentre RCT (n = 615) conducted in Germany, in which renal transplant recipients were randomized 1:1:1 to receive IL2RA induction with Tac, MPA and steroid maintenance therapy (arm A), IL2RA induction and rapid corticosteroid withdrawal on Day 8 (arm B) or rATG induction and rapid corticosteroid withdrawal on Day 8 (arm C) [21] (Table 1). The BPAR rates were similar in all three arms (11.2% in arm A, 10.6% in arm B and 9.9% in arm C) and 1-year graft and patient survival rates were excellent and equivalent in all arms. Hence, although previous data had suggested that rATG may be superior to IL2RA in early steroid-withdrawal regimens, there were no differences in the HARMONY study. Results from the recently published ADVANCE study confirm the potential value of IL2RA induction in early steroid withdrawal protocols [22]. The ADVANCE study was an RCT (n = 1081) in which two steroid minimization strategies [steroid withdrawal at Day 10 versus avoidance (i.e. only one intraoperative steroid dose)] were compared, with both arms receiving IL2RA induction, prolonged-release Tac and MPA therapy (Table 1). Six-month BPAR rates were significantly lower in the 10-day steroid withdrawal arm than in the avoidance arm (8.7% versus 13.6%; P = 0.006). Non-biopsy-proven rejection rates were also reported, with a total of 18.2% (withdrawal) versus 25.9% (avoidance) (P = 0.001) ‘clinical’ AR episodes. Because patients in the single-steroid dose arm required more rescue steroids, the cumulative steroid dose at 6 months was comparable between groups. Although the HARMONY and ADVANCE studies were conducted in two very similar European cohorts with standard immunological risk, the results in terms of rejection seem to be less favourable in the ADVANCE study, especially in the arm with only one perioperative steroid dose. What could be the explanation for these observations? First, we should consider how the BPAR and clinical AR rates were reported to avoid comparing ‘apples with oranges’. In terms of BPAR rates, the HARMONY and ADVANCE studies both had good results, which were comparable to outcomes in other studies with contemporary Tac/MPA/steroid maintenance regimens [7, 23] (Symphony: 12.3%, OSAKA: 10.3–16.1%). A possible criticism of the HARMONY study is that it did not report non-biopsy-proven AR rates. It is well known that many transplant centres report, in addition to cases of BPAR, a substantial number of cases of non-biopsy-proven AR, which may reflect reluctance to perform a biopsy in some patients, or a low threshold for treatment in patients with doubtful or borderline rejection. For example, in the Tac arm of the Symphony study there was a 1-year clinical AR rate of 17.2% (whereas the BPAR rate was 12.3%), and in the OSAKA trial the three arms receiving Tac, MPA and steroids had clinical AR rates at 24 weeks ranging from 18.5% to 25.0% (whereas the BPAR rate was 10.3–16.1%) [7, 23]. The BPAR and clinical AR rates reported in the ADVANCE study may, therefore, not be so different from those achieved with current standard of care. Nevertheless, based on the ADVANCE study, one could conclude that it seems advisable to continue steroid therapy during the first week after transplantation, rather than stopping on Day 1. Additionally, it could be argued that the relatively low dose of MPA in the ADVANCE study (2 g/day for the first 14 days, 1 g/day thereafter) compared with that used in the HARMONY study (2 g/day throughout the first year) may have impacted on the risk of AR, suggesting that maintaining a high MPA dose may be preferable when using steroid withdrawal as the treatment regimen. Table 1 Recent RCTs on early steroid withdrawal in kidney transplantation Study characteristics HARMONY (Thomusch et al. [21]) ADVANCE (Mourad et al. [22]) Population Inclusion criteria: recipient age 18–75 years, LD or DD, first TX or second TX provided, first allograft not lost because of rejection within first year Inclusion criteria: recipient age ≥18 years, LD or DD, first TX or second TX provided first allograft not lost because of rejection within first year Exclusion: PreTX DSA, PRA ≥30%, DCD donor, multiorgan TX, CIT ≥30 h, primary FSGS or MPGN, auto-immune disease requiring steroid therapy Exclusion: peak PRA >20%, DCD donor, multiorgan TX, CIT ≥30 h, diabetes mellitus preTX, underlying disease requiring systemic immunosuppressive therapy Immunosuppression Arm A (n = 206) Basiliximab 2 × 20 mg Tac (slow-release)  Target trough levels   1st month: 7–12 ng/mL   2nd–3rd month: 6–10 ng/mL   4th–12th month: 3–8 ng/mL MPA: 2000 mg/day Prednisolone   500 mg on Day 0   100 mg on Day 1   75 mg on Day 2   50 mg on Day 3   25 mg on Days 4–7   Taper to 10 mg/day by Week 4   Maintain 2.5–5 mg/day after 3 months Arm B (n = 189) Basiliximab 2 × 20 mg Tac (slow-release)  Target trough levels   1st month: 7–12 ng/mL   2nd–3rd month: 6–10 ng/mL   4th–12th month: 3–8 ng/mL MPA: 2000 mg/day Prednisolone   500 mg on Day 0   100 mg on Day 1   75 mg on Day 2   50 mg on Day 3   25 mg on Days 4–7   STOP on Day 8 Arm C (n = 192) rATG (Thymoglobulin®) Days 0–3, aimed at total dose of 6 mg/kg Tac (slow-release)  Target trough levels   1st month: 7–12 ng/mL   2nd–3rd month: 6–10 ng/mL   4th–12th month: 3–8 ng/mL MPA: 2000 mg/day Prednisolone   500 mg on Day 0   100 mg on Day 1   75 mg on Day 2   50 mg on Day 3   25 mg on Days 4–7   STOP on Day 8 Arm 1 (n = 528) Basiliximab 2 × 20 mg Tac (slow-release)  Target trough levels   Days 0–21: 11–15 ng/mL   Days 22–42: 8–12 ng/mL   Days 43–168: 5–9 ng/mL MPA   Days 0–14: 2 × 1000 mg/day   Days >14: 2 × 500 mg/day Prednisolone   Max 1000 mg on Day 0   20 mg on Days 1–4   15 mg on Days 5–6   10 mg on Days 7–8   5 mg on Days 9–10   STOP on Day 11 Arm 2 (n = 553) Basiliximab 2 × 20 mg Tac (slow-release)  Target trough levels   Days 0–21: 11–15 ng/mL   Days 22–42: 8–12 ng/mL   Days 43–168: 5–9 ng/mL MPA   Days 0–14: 2 × 1000 mg/day   Days >14: 2 × 500 mg/day Prednisolone   Max 1000 mg on Day 0   STOP on Day 1 Follow-up time 1 year after transplantation 24 weeks after transplantation BPAR (excl. borderline) BPAR: 11% Steroid-resistant BPAR: 2% AMR: 1% BPAR: 11% Steroid-resistant BPAR: 3% AMR: 2% BPAR: 10% Steroid-resistant BPAR: 2% AMR: 2% BPAR: 8.7% Steroid-resistant BPAR: 3.4% AMR: 2.7% BPAR: 13.6% Steroid-resistant BPAR: 3.8% AMR: 2.6% Clinical AR Not reported AR 18.2% (12.5% received steroids for AR) Steroid-resistant AR: 4.4% AR 25.9% (21.0% received steroids for AR) Steroid-resistant AR: 5.5% PS 95% at 1 year 97% at 1 year 97% at 1 year 98.4% at 24 weeks 99.0% at 24 weeks GS Overall GS: 91% at 1 year Death censored GS: 96% at 1 year Overall GS: 94% at 1 year Death censored GS: 97% at 1 year Overall GS: 93% at 1 year Death censored GS: 96% at 1 year 95.6% at 24 weeks 95.0% at 24 weeks GFR CKD-EPI: 46.3 mL/min Cockcroft–Gault: 57.3 mL/min CKD-EPI: 47.4 mL/min Cockcroft–Gault: 58.0 mL/min CKD-EPI: 50.2 mL/min Cockcroft–Gault: 62.9 mL/min MDRD: 47.1 mL/min/1.73 m2 Cockcroft–Gault: 53.8 mL/min MDRD: 47.3 mL/min/1.73 m2 Cockcroft–Gault: 51.7 mL/min Steroids at end of study At 1 year: 90% At 1 year: 16% At 1 year: 17% At 24 weeks: 14.2% At 24 weeks: 17.2% Post-transplant diabetes (ADA criteria) At 1 year: 39.2% (P = 0.0004) At 1 year: 23.9% At 1 year: 22.7% At 24 weeks: 17.4% At 24 weeks: 16.6% Study characteristics HARMONY (Thomusch et al. [21]) ADVANCE (Mourad et al. [22]) Population Inclusion criteria: recipient age 18–75 years, LD or DD, first TX or second TX provided, first allograft not lost because of rejection within first year Inclusion criteria: recipient age ≥18 years, LD or DD, first TX or second TX provided first allograft not lost because of rejection within first year Exclusion: PreTX DSA, PRA ≥30%, DCD donor, multiorgan TX, CIT ≥30 h, primary FSGS or MPGN, auto-immune disease requiring steroid therapy Exclusion: peak PRA >20%, DCD donor, multiorgan TX, CIT ≥30 h, diabetes mellitus preTX, underlying disease requiring systemic immunosuppressive therapy Immunosuppression Arm A (n = 206) Basiliximab 2 × 20 mg Tac (slow-release)  Target trough levels   1st month: 7–12 ng/mL   2nd–3rd month: 6–10 ng/mL   4th–12th month: 3–8 ng/mL MPA: 2000 mg/day Prednisolone   500 mg on Day 0   100 mg on Day 1   75 mg on Day 2   50 mg on Day 3   25 mg on Days 4–7   Taper to 10 mg/day by Week 4   Maintain 2.5–5 mg/day after 3 months Arm B (n = 189) Basiliximab 2 × 20 mg Tac (slow-release)  Target trough levels   1st month: 7–12 ng/mL   2nd–3rd month: 6–10 ng/mL   4th–12th month: 3–8 ng/mL MPA: 2000 mg/day Prednisolone   500 mg on Day 0   100 mg on Day 1   75 mg on Day 2   50 mg on Day 3   25 mg on Days 4–7   STOP on Day 8 Arm C (n = 192) rATG (Thymoglobulin®) Days 0–3, aimed at total dose of 6 mg/kg Tac (slow-release)  Target trough levels   1st month: 7–12 ng/mL   2nd–3rd month: 6–10 ng/mL   4th–12th month: 3–8 ng/mL MPA: 2000 mg/day Prednisolone   500 mg on Day 0   100 mg on Day 1   75 mg on Day 2   50 mg on Day 3   25 mg on Days 4–7   STOP on Day 8 Arm 1 (n = 528) Basiliximab 2 × 20 mg Tac (slow-release)  Target trough levels   Days 0–21: 11–15 ng/mL   Days 22–42: 8–12 ng/mL   Days 43–168: 5–9 ng/mL MPA   Days 0–14: 2 × 1000 mg/day   Days >14: 2 × 500 mg/day Prednisolone   Max 1000 mg on Day 0   20 mg on Days 1–4   15 mg on Days 5–6   10 mg on Days 7–8   5 mg on Days 9–10   STOP on Day 11 Arm 2 (n = 553) Basiliximab 2 × 20 mg Tac (slow-release)  Target trough levels   Days 0–21: 11–15 ng/mL   Days 22–42: 8–12 ng/mL   Days 43–168: 5–9 ng/mL MPA   Days 0–14: 2 × 1000 mg/day   Days >14: 2 × 500 mg/day Prednisolone   Max 1000 mg on Day 0   STOP on Day 1 Follow-up time 1 year after transplantation 24 weeks after transplantation BPAR (excl. borderline) BPAR: 11% Steroid-resistant BPAR: 2% AMR: 1% BPAR: 11% Steroid-resistant BPAR: 3% AMR: 2% BPAR: 10% Steroid-resistant BPAR: 2% AMR: 2% BPAR: 8.7% Steroid-resistant BPAR: 3.4% AMR: 2.7% BPAR: 13.6% Steroid-resistant BPAR: 3.8% AMR: 2.6% Clinical AR Not reported AR 18.2% (12.5% received steroids for AR) Steroid-resistant AR: 4.4% AR 25.9% (21.0% received steroids for AR) Steroid-resistant AR: 5.5% PS 95% at 1 year 97% at 1 year 97% at 1 year 98.4% at 24 weeks 99.0% at 24 weeks GS Overall GS: 91% at 1 year Death censored GS: 96% at 1 year Overall GS: 94% at 1 year Death censored GS: 97% at 1 year Overall GS: 93% at 1 year Death censored GS: 96% at 1 year 95.6% at 24 weeks 95.0% at 24 weeks GFR CKD-EPI: 46.3 mL/min Cockcroft–Gault: 57.3 mL/min CKD-EPI: 47.4 mL/min Cockcroft–Gault: 58.0 mL/min CKD-EPI: 50.2 mL/min Cockcroft–Gault: 62.9 mL/min MDRD: 47.1 mL/min/1.73 m2 Cockcroft–Gault: 53.8 mL/min MDRD: 47.3 mL/min/1.73 m2 Cockcroft–Gault: 51.7 mL/min Steroids at end of study At 1 year: 90% At 1 year: 16% At 1 year: 17% At 24 weeks: 14.2% At 24 weeks: 17.2% Post-transplant diabetes (ADA criteria) At 1 year: 39.2% (P = 0.0004) At 1 year: 23.9% At 1 year: 22.7% At 24 weeks: 17.4% At 24 weeks: 16.6% LD, living donor; DD, deceased donor; TX, transplant; DSA, donor-specific antibodies; PRA, panel reactive antibodies; DCD, donation after cardiac death; CIT, cold ischemia time; FSGS, focal segmental glomerulosclerosis; MPGN, membranoproliferative glomerulonephritis; MPA, mycophenolic acid; AMR, antibody-mediated rejection; PS, patient survival; GS, graft survival; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; MDRD, Modification of Diet in Renal Disease; ADA, American Diabetes Association. Table 1 Recent RCTs on early steroid withdrawal in kidney transplantation Study characteristics HARMONY (Thomusch et al. [21]) ADVANCE (Mourad et al. [22]) Population Inclusion criteria: recipient age 18–75 years, LD or DD, first TX or second TX provided, first allograft not lost because of rejection within first year Inclusion criteria: recipient age ≥18 years, LD or DD, first TX or second TX provided first allograft not lost because of rejection within first year Exclusion: PreTX DSA, PRA ≥30%, DCD donor, multiorgan TX, CIT ≥30 h, primary FSGS or MPGN, auto-immune disease requiring steroid therapy Exclusion: peak PRA >20%, DCD donor, multiorgan TX, CIT ≥30 h, diabetes mellitus preTX, underlying disease requiring systemic immunosuppressive therapy Immunosuppression Arm A (n = 206) Basiliximab 2 × 20 mg Tac (slow-release)  Target trough levels   1st month: 7–12 ng/mL   2nd–3rd month: 6–10 ng/mL   4th–12th month: 3–8 ng/mL MPA: 2000 mg/day Prednisolone   500 mg on Day 0   100 mg on Day 1   75 mg on Day 2   50 mg on Day 3   25 mg on Days 4–7   Taper to 10 mg/day by Week 4   Maintain 2.5–5 mg/day after 3 months Arm B (n = 189) Basiliximab 2 × 20 mg Tac (slow-release)  Target trough levels   1st month: 7–12 ng/mL   2nd–3rd month: 6–10 ng/mL   4th–12th month: 3–8 ng/mL MPA: 2000 mg/day Prednisolone   500 mg on Day 0   100 mg on Day 1   75 mg on Day 2   50 mg on Day 3   25 mg on Days 4–7   STOP on Day 8 Arm C (n = 192) rATG (Thymoglobulin®) Days 0–3, aimed at total dose of 6 mg/kg Tac (slow-release)  Target trough levels   1st month: 7–12 ng/mL   2nd–3rd month: 6–10 ng/mL   4th–12th month: 3–8 ng/mL MPA: 2000 mg/day Prednisolone   500 mg on Day 0   100 mg on Day 1   75 mg on Day 2   50 mg on Day 3   25 mg on Days 4–7   STOP on Day 8 Arm 1 (n = 528) Basiliximab 2 × 20 mg Tac (slow-release)  Target trough levels   Days 0–21: 11–15 ng/mL   Days 22–42: 8–12 ng/mL   Days 43–168: 5–9 ng/mL MPA   Days 0–14: 2 × 1000 mg/day   Days >14: 2 × 500 mg/day Prednisolone   Max 1000 mg on Day 0   20 mg on Days 1–4   15 mg on Days 5–6   10 mg on Days 7–8   5 mg on Days 9–10   STOP on Day 11 Arm 2 (n = 553) Basiliximab 2 × 20 mg Tac (slow-release)  Target trough levels   Days 0–21: 11–15 ng/mL   Days 22–42: 8–12 ng/mL   Days 43–168: 5–9 ng/mL MPA   Days 0–14: 2 × 1000 mg/day   Days >14: 2 × 500 mg/day Prednisolone   Max 1000 mg on Day 0   STOP on Day 1 Follow-up time 1 year after transplantation 24 weeks after transplantation BPAR (excl. borderline) BPAR: 11% Steroid-resistant BPAR: 2% AMR: 1% BPAR: 11% Steroid-resistant BPAR: 3% AMR: 2% BPAR: 10% Steroid-resistant BPAR: 2% AMR: 2% BPAR: 8.7% Steroid-resistant BPAR: 3.4% AMR: 2.7% BPAR: 13.6% Steroid-resistant BPAR: 3.8% AMR: 2.6% Clinical AR Not reported AR 18.2% (12.5% received steroids for AR) Steroid-resistant AR: 4.4% AR 25.9% (21.0% received steroids for AR) Steroid-resistant AR: 5.5% PS 95% at 1 year 97% at 1 year 97% at 1 year 98.4% at 24 weeks 99.0% at 24 weeks GS Overall GS: 91% at 1 year Death censored GS: 96% at 1 year Overall GS: 94% at 1 year Death censored GS: 97% at 1 year Overall GS: 93% at 1 year Death censored GS: 96% at 1 year 95.6% at 24 weeks 95.0% at 24 weeks GFR CKD-EPI: 46.3 mL/min Cockcroft–Gault: 57.3 mL/min CKD-EPI: 47.4 mL/min Cockcroft–Gault: 58.0 mL/min CKD-EPI: 50.2 mL/min Cockcroft–Gault: 62.9 mL/min MDRD: 47.1 mL/min/1.73 m2 Cockcroft–Gault: 53.8 mL/min MDRD: 47.3 mL/min/1.73 m2 Cockcroft–Gault: 51.7 mL/min Steroids at end of study At 1 year: 90% At 1 year: 16% At 1 year: 17% At 24 weeks: 14.2% At 24 weeks: 17.2% Post-transplant diabetes (ADA criteria) At 1 year: 39.2% (P = 0.0004) At 1 year: 23.9% At 1 year: 22.7% At 24 weeks: 17.4% At 24 weeks: 16.6% Study characteristics HARMONY (Thomusch et al. [21]) ADVANCE (Mourad et al. [22]) Population Inclusion criteria: recipient age 18–75 years, LD or DD, first TX or second TX provided, first allograft not lost because of rejection within first year Inclusion criteria: recipient age ≥18 years, LD or DD, first TX or second TX provided first allograft not lost because of rejection within first year Exclusion: PreTX DSA, PRA ≥30%, DCD donor, multiorgan TX, CIT ≥30 h, primary FSGS or MPGN, auto-immune disease requiring steroid therapy Exclusion: peak PRA >20%, DCD donor, multiorgan TX, CIT ≥30 h, diabetes mellitus preTX, underlying disease requiring systemic immunosuppressive therapy Immunosuppression Arm A (n = 206) Basiliximab 2 × 20 mg Tac (slow-release)  Target trough levels   1st month: 7–12 ng/mL   2nd–3rd month: 6–10 ng/mL   4th–12th month: 3–8 ng/mL MPA: 2000 mg/day Prednisolone   500 mg on Day 0   100 mg on Day 1   75 mg on Day 2   50 mg on Day 3   25 mg on Days 4–7   Taper to 10 mg/day by Week 4   Maintain 2.5–5 mg/day after 3 months Arm B (n = 189) Basiliximab 2 × 20 mg Tac (slow-release)  Target trough levels   1st month: 7–12 ng/mL   2nd–3rd month: 6–10 ng/mL   4th–12th month: 3–8 ng/mL MPA: 2000 mg/day Prednisolone   500 mg on Day 0   100 mg on Day 1   75 mg on Day 2   50 mg on Day 3   25 mg on Days 4–7   STOP on Day 8 Arm C (n = 192) rATG (Thymoglobulin®) Days 0–3, aimed at total dose of 6 mg/kg Tac (slow-release)  Target trough levels   1st month: 7–12 ng/mL   2nd–3rd month: 6–10 ng/mL   4th–12th month: 3–8 ng/mL MPA: 2000 mg/day Prednisolone   500 mg on Day 0   100 mg on Day 1   75 mg on Day 2   50 mg on Day 3   25 mg on Days 4–7   STOP on Day 8 Arm 1 (n = 528) Basiliximab 2 × 20 mg Tac (slow-release)  Target trough levels   Days 0–21: 11–15 ng/mL   Days 22–42: 8–12 ng/mL   Days 43–168: 5–9 ng/mL MPA   Days 0–14: 2 × 1000 mg/day   Days >14: 2 × 500 mg/day Prednisolone   Max 1000 mg on Day 0   20 mg on Days 1–4   15 mg on Days 5–6   10 mg on Days 7–8   5 mg on Days 9–10   STOP on Day 11 Arm 2 (n = 553) Basiliximab 2 × 20 mg Tac (slow-release)  Target trough levels   Days 0–21: 11–15 ng/mL   Days 22–42: 8–12 ng/mL   Days 43–168: 5–9 ng/mL MPA   Days 0–14: 2 × 1000 mg/day   Days >14: 2 × 500 mg/day Prednisolone   Max 1000 mg on Day 0   STOP on Day 1 Follow-up time 1 year after transplantation 24 weeks after transplantation BPAR (excl. borderline) BPAR: 11% Steroid-resistant BPAR: 2% AMR: 1% BPAR: 11% Steroid-resistant BPAR: 3% AMR: 2% BPAR: 10% Steroid-resistant BPAR: 2% AMR: 2% BPAR: 8.7% Steroid-resistant BPAR: 3.4% AMR: 2.7% BPAR: 13.6% Steroid-resistant BPAR: 3.8% AMR: 2.6% Clinical AR Not reported AR 18.2% (12.5% received steroids for AR) Steroid-resistant AR: 4.4% AR 25.9% (21.0% received steroids for AR) Steroid-resistant AR: 5.5% PS 95% at 1 year 97% at 1 year 97% at 1 year 98.4% at 24 weeks 99.0% at 24 weeks GS Overall GS: 91% at 1 year Death censored GS: 96% at 1 year Overall GS: 94% at 1 year Death censored GS: 97% at 1 year Overall GS: 93% at 1 year Death censored GS: 96% at 1 year 95.6% at 24 weeks 95.0% at 24 weeks GFR CKD-EPI: 46.3 mL/min Cockcroft–Gault: 57.3 mL/min CKD-EPI: 47.4 mL/min Cockcroft–Gault: 58.0 mL/min CKD-EPI: 50.2 mL/min Cockcroft–Gault: 62.9 mL/min MDRD: 47.1 mL/min/1.73 m2 Cockcroft–Gault: 53.8 mL/min MDRD: 47.3 mL/min/1.73 m2 Cockcroft–Gault: 51.7 mL/min Steroids at end of study At 1 year: 90% At 1 year: 16% At 1 year: 17% At 24 weeks: 14.2% At 24 weeks: 17.2% Post-transplant diabetes (ADA criteria) At 1 year: 39.2% (P = 0.0004) At 1 year: 23.9% At 1 year: 22.7% At 24 weeks: 17.4% At 24 weeks: 16.6% LD, living donor; DD, deceased donor; TX, transplant; DSA, donor-specific antibodies; PRA, panel reactive antibodies; DCD, donation after cardiac death; CIT, cold ischemia time; FSGS, focal segmental glomerulosclerosis; MPGN, membranoproliferative glomerulonephritis; MPA, mycophenolic acid; AMR, antibody-mediated rejection; PS, patient survival; GS, graft survival; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; MDRD, Modification of Diet in Renal Disease; ADA, American Diabetes Association. In summary, current data suggest that early steroid-withdrawal regimens do not increase the risk of AR when the remaining immunosuppressive therapy is sufficiently potent, which can be achieved using a combination of Tac, MPA 2 g/day and antibody induction therapy, and preferably by continuing steroids for the first week after transplantation. Based on the most recent studies, IL2RA may be the induction agent of choice, because it appeared to be as effective as rATG and is generally associated with fewer adverse effects. Having said this, we should, however, be aware of the limitations of the current evidence. First, the HARMONY and ADVANCE studies were both conducted in Europe, in a predominantly white population with standard immunological risk. It cannot be ruled out that rATG is superior in patients with higher immunological risk, although these patients are usually not considered to be suitable candidates for steroid withdrawal. Secondly, the main advantage of early steroid-avoidance regimens, as supported by the HARMONY and ADVANCE studies, may be the reduction in post-transplant diabetes. The long-term consequences, however, remain unclear [14]. We have no definitive data to prove that steroid-avoidance improves long-term renal function or graft survival, nor that it decreases cardiovascular events or mortality [14, 24]. There are no data on the development of de novo donor-specific antibodies (dnDSA) or of chronic antibody-mediated rejection in this setting, which may theoretically have a counterproductive effect on long-term outcomes. The limited data also mean that we cannot exclude the possibility that rATG may eventually be shown to be preferable to IL2RA in early steroid-avoidance regimens if it is better at preventing the development of dnDSA [25]. Thirdly, if the main reason for choosing an early steroid-withdrawal regimen is the reduction in occurrence of post-transplant diabetes, it may make sense to choose a regimen that includes CsA instead of Tac, as the latter is known to be more diabetogenic. Although studies on early steroid withdrawal combined with CsA have shown suboptimal results [16, 26], it is conceivable that a CsA-based regimen with withdrawal of steroids after 7 days, high-dose MPA (e.g. 2500 mg/day) and antibody induction may also keep AR rates low and may perhaps be even better at preventing new onset diabetes mellitus after transplantation than Tac-containing regimens such as those used in the HARMONY and ADVANCE studies. This should be an area of future research. Again, possible differences in efficacy of rATG and IL2RA should be addressed in such settings. In summary, we believe that the 2009 KDIGO guidelines on induction therapy after kidney transplantation no longer reflect the current evidence in patients with standard and high immunological risk or in patients managed with early steroid-withdrawal regimens. In standard risk transplantation using Tac, MPA and maintenance steroids, induction therapy now seems redundant. In patients with high immunological risk, rATG is superior to IL2RA. However, there may still be a niche for IL2RA use in the context of early steroid-withdrawal regimens, at least in low-risk recipients maintained on Tac and MPA. Updated guidelines based on the latest evidence are eagerly awaited. Future studies should focus on a better understanding and quantification of immunological risk, which may help guide decisions regarding which induction therapy to choose, if any, for individual patients. KEY POINTS Antibody induction therapy may be redundant in standard-risk kidney transplant recipients maintained on Tac, MPA and steroids. rATG is preferable to IL2RA in kidney transplant recipients with high immunological risk. When choosing a regimen with early steroid withdrawal: Antibody induction therapy is advisable IL2RA and rATG are equally effective in standard-risk recipients remaining on Tac and MPA. Given the balance of benefits and risks, IL2RA may be preferred over rATG in this setting. Maintenance therapy should be sufficiently potent: Steroid withdrawal after 7 days may be preferable to one preoperative dose. Consider to use Tac instead of CsA. Maintaining a high dose of MPA during the first year may be advisable. CONFLICT OF INTEREST STATEMENT None declared. REFERENCES 1 Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group . KDIGO clinical practice guideline for the care of kidney transplant recipients . 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Antithymocyte globulin is associated with a lower incidence of de novo donor-specific antibodies in moderately sensitized renal transplant recipients . Transplantation 2014 ; 97 : 612 – 617 Google Scholar CrossRef Search ADS PubMed 26 Cantarovich D , Rostaing L , Kamar N et al. Early corticosteroid avoidance in kidney transplant recipients receiving ATG-F induction: 5-year actual results of a prospective and randomized study . Am J Transplant 2014 ; 14 : 2556 – 2564 Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

Journal

Nephrology Dialysis TransplantationOxford University Press

Published: Mar 27, 2018

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