Introduction
(Article introduction authored by Conquest Editorial Team)
The ELITE-Symphony study findings have influenced KDIGO guidelines for renal transplant immunosuppressive therapy. Current recommendations include induction therapy with tacrolimus, mycophenolate, and steroids.
However, studies, including the Symphony trial, link tacrolimus blood levels to nephrotoxic effects and delayed graft function. While some advocate for lower tacrolimus levels, concerns about rejection risk persist.
A large study found no significant correlation between tacrolimus levels and acute rejections. The lack of a clear therapeutic window complicates dosing, leading to potential overdosing and associated risks.
The hypothesis proposes early low and fixed tacrolimus dosing as a safe alternative. The study aims to compare this approach with the standard method, assessing non-inferiority in a combined endpoint of biopsy-proven acute rejections, graft loss, and death at six months post-transplant.
Methods
The study was a prospective, randomized, open-label, multicenter trial involving adult renal transplant recipients in fourteen German centers. It adhered to the Declaration of Helsinki and Good Clinical Practice guidelines. Two study arms, Standard Care and Slow & Low, were compared.
Patients received induction therapy with basiliximab, prolonged-release tacrolimus, mycophenolate mofetil, and prednisolone. The Standard Care arm followed conventional tacrolimus dosing, while the Slow & Low arm used a fixed 5 mg dose initially.
The primary endpoint was the combined incidence of biopsy-proven acute rejection, graft loss, and death at six months post-transplant. The study included external monitoring and a data safety monitoring board. Randomization was computer-generated, and sample size was calculated for non-inferiority.
Analyses were based on intention-to-treat, with statistical methods including Fisher’s exact test, Wilcoxon-Mann-Whitney U-test, and Kaplan-Meier curves. Per-protocol analysis and subgroup analyses were also conducted.
Results
Patient population
From Nov ’14 to Jul ’18, 14 German centers randomized 432 patients, with 398 receiving allocated treatment.
Of these 398 patients, 202 patients received treatment in the Standard Care control arm, 196 patients in the Slow & Low arm (Fig. 1). 92% of all study patients reached the regular end of study at 6 months, without differences between arms (Fig. 1). Only 3.0% (12/398) of all study participants withdrew
informed consent after renal transplantation before regular end of study, one patient was excluded due to incompliance, one-by investigator decision, one by violation of exclusion/inclusion criteria, and 4.3% (17/398) underwent either graft loss or death (Fig. 1).
Target trough levels for tacrolimus were within the predefined therapeutic window in the Standard Care arm but only during the first month in the Slow & Low arm (see Fig. 2), thereafter tacrolimus trough levels became more overlapping with the Standard Care arm.
Efficacy end points
At 6 months, the combined primary endpoint of biopsy-proven acute rejection (BPAR), graft loss, and death was similar between the Slow & Low (22.1%) and Standard Care (20.7%) study arms, meeting non-inferiority criteria.
The one-sided test of equivalence with a non-inferiority margin of 12.5% showed non-inferiority (p = 0.004). Per-protocol analysis confirmed a similar outcome (Slow & Low 20.3%, Standard Care 18.8%), with a risk difference of 1.5% (p = 0.008).
Non-inferiority was consistent across various definitions of BPAR and inclusion/exclusion of borderline rejection, as well as protocol biopsy findings. The Slow & Low arm demonstrated non-inferiority in rates of graft loss/mortality and rejections.
Secondary analyses
In the Slow & Low arm, most primary endpoint events, such as biopsy-proven acute rejections (BPAR) and graft losses, occurred within the first month (83.3%), while in the Standard Care arm, events were more evenly distributed over six months (42.5% in the first month).
Graft survival after 6 months was similar in both arms (94.2% Slow & Low vs. 95.7% Standard Care). Fourteen graft losses were mainly due to non-function or technical problems, with only two linked to chronic graft rejection.
While overall BPAR rates were comparable, a post-hoc analysis revealed a significant difference in the severity of T-cell mediated BPAR, with the Slow & Low arm showing higher-grade incidences. Rates of antibody-mediated rejections were similar in both groups.
Secondary end points
At six months, the development of donor-specific antibodies was low and comparable in both arms. The occurrence of any anti-HLA antibodies was numerically reduced in the Slow & Low arm (9.9%) compared to Standard Care (16.8%), though not statistically significant.
The frequency of delayed graft function (DGF) did not differ between the groups, with rates of 10.8% in Slow & Low and 10.9% in Standard Care based on one definition, and 16.0% in Slow & Low versus 20.9% in Standard Care according to center assessment. Kidney function, assessed using different formulas, was similar across all examined time points.
Safety end points
In terms of safety endpoints, both study arms exhibited similar incidences of adverse events and serious adverse events. The total number of adverse events and serious adverse events was comparable between the Slow & Low and Standard Care arms.
The overall incidence of infections, including CMV or BKV infections, did not differ significantly between the two arms. Biopsy-proven BKV nephropathy was rare and occurred at similar rates in both groups, with a tendency toward a reduced incidence in the Slow & Low arm.
Cancer development was observed only in the Slow & Low arm, with a significant difference noted. Neurotoxicity and anemia incidences were comparable between the arms.
Regarding metabolic profiles, the occurrence of post-transplant diabetes mellitus (PTDM) was similar in both arms.
The incidence of prediabetes also showed no significant difference between the Slow & Low and Standard Care arms. Arterial hypertension, cholesterol levels, and other metabolic parameters were similar in both groups.
Subgroup analyses indicated non-inferiority of the Slow & Low arm compared to the Standard Care arm, especially in postmortem donor transplantation and donors with extended criteria.
However, results were less convincing in the small group of living donations, where recipient age appeared to play a significant role.
Overall, the study demonstrated that the Slow & Low arm had comparable safety outcomes to the Standard Care arm, with some notable differences in cancer development and neurotoxicity.
Discussion
This study aimed to compare the efficacy and safety of a fixed-dose, bottom-up, slowly incremental tacrolimus saturation approach (Slow & Low) with the standard immunosuppressive protocol after renal transplantation.
The Slow & Low arm demonstrated non-inferiority in the combined endpoint of biopsy-proven acute rejection, graft loss, and death compared to the Standard Care arm.
The study revealed a marked simplification of the tacrolimus drug saturation process, eliminating the need for therapeutic drug monitoring within the first week.
Despite differences in tacrolimus trough levels, the Slow & Low approach was comparable in safety outcomes and demonstrated efficacy across various transplant recipient groups, suggesting it as a potential cost-effective alternative.
Limitations include potential bias due to lack of blinding and a relatively short follow-up period. The study highlights the adaptability of the Slow & Low approach, especially in deceased or extended criteria donors, and suggests its applicability for older recipients.
Overall, the simplified drug regimen demonstrated effectiveness and safety, raising the possibility of replacing the current standard drug monitoring approach.
References
1. 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
2. Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group KDIGO clinical practice guideline for the care of kidney transplant recipients.
Am J Transplant. 2009; 9: S1-S155
3. Frei U. Daloze P. Vítko S. et al.
Acute rejection in low-toxicity regimens: clinical impact and risk factors in the Symphony study. Clin Transplant. 2010; 24: 500-509
4. Ekberg H. van Gelder T. Kaplan B. et al.
Relationship of tacrolimus exposure and mycophenolate mofetil dose with renal function after renal transplantation. Transplantation. 2011; 92: 82-87
5. Bouamar R. Shuker N. Hesselink D.A. et al.
Tacrolimus predose concentrations do not predict the risk of acute rejection after renal transplantation: a pooled analysis from three randomized-controlled clinical trials. Am J Transplant. 2013; 13: 1253-1261
6. 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
7. Crespo M. Mir M. Marin M. et al.
De novo kidney transplant recipients need higher doses of Advagraf compared with Prograf to get therapeutic levels. Transplant Proc. 2009; 41: 2115-2117
8. Solez K. Colvin R.B. Racusen L.C. et al.
Banff ́05 Meeting report: differential diagnosis of chronic allograft injury and elimination of chronic allograft nephropathy (“CAN”). Am J Transplant. 2007; 7: 518-526
9. Levey A.S. Stevens L.A. Schmid C.H. et al.
A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009; 150: 604-612
10. Ciancio G. Burke G.W. Gaynor J.J. et al.
A randomized trial of three renal transplant induction antibodies: early comparison of tacrolimus, mycophenolate mofetil, and steroid dosing, a newer immune-monitoring. Transplantation. 2005; 80: 457-465
11. Ter Meulen C.G. van Riemsdijk I. Hene R.J. et al.
Steroid-withdrawa at 3 days after renal transplantation with anti-Il-2 Rreceptor α therapy: a prospective, randomized, multicenter study. Am J Transplant. 2004; 4: 803-810
12. Borrows R. Loucaidou M. Tromp J.V. et al.
Steroid sparing with tacrolimus and mycophenolate mofetil in renal transplantation. Am J Transplant. 2004; 4: 1845-1851
13. Metzger R.A. Delmonico F.L. Feng S. Port K.K. Wynn J.J. Merion R.M. Expanded criteria donors for kidney transplantation.
Am J Transplant. 2003; 3: 114-125
