Redefining Immunosuppression in Older Kidney Transplant Recipients

In a recent JASN article, Sanders et al. report the results of “The OPen label multicenter randomized trial comparing standard IMmunosuppression with tacrolimus and mycophenolate mofetil with a low-exposure tacrolimus regimen In combination with everolimus in de novo renal transplantation in Elderly patients” (OPTIMIZE) trial.1 OPTIMIZE is an investigator-driven, randomized, multicenter, international, open-label, interventional trial that was conducted between July 2019 and April 2025 at six transplant centers in the Netherlands and one in Belgium. In OPTIMIZE, older kidney transplant recipients (65 years or older) were randomized to low dose once daily tacrolimus plus everolimus and prednisolone (TEP) versus standard dose once daily tacrolimus plus mycophenolate mofetil and prednisolone (TMP). Tacrolimus target trough levels in the TEP group were 5–7 ng/ml until 3 months, 2–4 ng/ml from 3 to 6 months, and 1.5–4 ng/ml from 6 months onwards. Tacrolimus target trough levels in the TMP group were 8–12, 6–10, and 5–8 ng/ml, respectively. Everolimus target trough levels were 3–6 ng/ml, and the mycophenolate mofetil (MMF) dose was 500 mg twice daily in the TMP group. All received induction with basiliximab. The primary end point of successful transplantation was being alive with a functioning graft with an eGFR above a predefined threshold at 2 years after transplantation. Predefined eGFR thresholds were 30 (stratum A) or 45 ml/min per 1.73 m2 (stratum B). Stratum A included older recipients (65 years or older) of kidneys from older deceased donors (65 years or older) within the Eurotransplant Senior Program. Stratum B included older recipients (65 years or older) of kidneys from living donors (all ages) or deceased donors younger than 65 years. OPTIMIZE randomized 379 patients: 198 in stratum A and 181 in stratum B. The median 24-hour trough levels for everolimus and tacrolimus were within the target range throughout the study. There was no significant difference in successful transplantation at 2 years between the TEP versus TMP groups: 50% versus 57%. There were also no significant differences in the predefined secondary outcomes in the TEP versus TMP groups: patient survival (89% versus 89%) and graft survival (83% versus 84%). Furthermore, there were no significant differences between the TEP versus TMP groups in biopsy-proven acute rejection (11% versus 8%) or in mean eGFR levels at 2 years (48±19 ml/min per 1.73 m2 versus 48±19 ml/min, respectively). The incidence of viral infections also did not differ significantly between the TEP (55%) and TMP (54%) groups. Specifically, there was no difference in the incidence of coronavirus disease 2019, CMV, or BKV infection between groups. The occurrence of malignancies tended to be lower in the TEP compared with TMP groups (9% versus 15.2%; P = 0.051). However, the proportion of participants with skin malignancies did not differ with TEP versus TMP (5% versus 7%). Edema was more common in TEP, and at 12 months post-transplantation, urinary protein/creatinine ratio and serum concentrations of LDL cholesterol and triglycerides were higher in the TEP group. Thus, despite achieving clear separation in tacrolimus exposure, and everolimus versus MMF, the study showed no significant difference in the primary successful transplantation end point at 2 years or in patient survival or graft function. There was also no increased risk of rejection with low tacrolimus levels, and there was no benefit of replacement of MMF with everolimus, a mammalian target of rapamycin inhibitor (mTORi), on CMV, BK, coronavirus disease 2019, or skin cancers. This negative study showed that low tacrolimus levels of 1.5–4 ng/dl were safe and effective at least when used in combination with everolimus as the mTORi. The use of everolimus, however, was associated with more edema, dyslipidemia, and proteinuria. Notably, the putative antioncogenic and antiviral effects of the mTORi were not realized. Very importantly, the use of appropriate MMF dosing at 500 mg twice daily was not associated with more rejection, but instead, less relative infection. Some strengths of this trial include (1) it was investigator-driven, real-world, and not influenced by industry or encumbered by government regulations; (2) it was multicenter, international, and randomized controlled; (3) the target tacrolimus and everolimus levels were achieved, and tacrolimus levels actually differed numerically and clinically between groups. There was no overlap or regression to the mean as seen in previous calcineurin inhibitor (CNI) avoidance trials; (4) the MMF dose was appropriate (500 mg twice daily) rather than excessive. Mycophenolate was originally approved at a dose of 1000 mg twice daily with cyclosporine, but MMF exposure is 2–4 times higher with tacrolimus than with cyclosporine (Figure 1).2 The investigators avoided the 1000 mg twice daily dose commonly used, which would have produced a toxic imbalance in immunosuppression, leading to more infection as seen in the TRANSFORM study.3 Finally, (5) the results were achieved without lymphocyte-depleting induction.Figure 1: MMF exposure is much higher (4×) with tacrolimus compared with cyclosporine. The proper dose of MMF with tacrolimus is 500 twice daily—maximum. Relationship between MMF dose and MPA 12 hours predose trough concentration in plasma of renal transplant patients with triple therapy of MMF, MEP, and CSA; open symbols or MMF, MEP, and TAC; closed symbols. Reprinted from ref. 2, with permission. MEP, methylprednisolone; MMF, mycophenolate mofetil.The results of the OPTIMIZE study in recipients older than 65 years are similar to those in the prior mTORi substitution for CNI study (TRANSFORM) in younger patients, where the average age was 49 years. The TRANSFORM study similarly showed noninferiority in efficacy, but more side effects compared with standard triple therapy with tacrolimus (standard dose), mycophenolate (common high dose), and steroids. The BENEFIT-EXT study was another attempt to replace the CNI with belatacept.4 The CNI in the standard arm was cyclosporine, which is much more nephrotoxic than tacrolimus.4 Thus, the comparator arm was not consistent with usual care, then or now, where tacrolimus was and remains the CNI of choice. Despite this bias, the BENEFIT-EXT study showed that belatacept in recipients of extended criteria donor kidneys was associated with only a 4–7 ml/min per 1.73 m2 improvement in GFR and more post-transplant lymphoproliferative disorder. Both regimens in the OPTIMIZE study were safe and effective with no post-transplant lymphoproliferative disorder, and thus, OPTIIMIZE can replace BENEFIT-EXT and belatacept as a CNI minimization strategy, at least in older recipients. The OPTIMIZE study also shows that skin cancers were not less with mTORi's as reported in the TUMORapa study.5 A careful review of the TUMORapa study shows it was not the use of the mTORi, but elimination of the CNI, which was primarily cyclosporine, that reduced the risk of skin cancer. Furthermore, the risk was only reduced if the recipient had no more than one skin cancer. The absence of a statistically significant difference between TEP and TMP at 2 years should not be dismissed as a failure of the mTORi-CNI minimization strategy, but rather interpreted as an important signal: in older kidney transplant recipients, an everolimus-based regimen that targets tacrolimus levels lower than in the ELITE-SYMPHONY study of 3–7 ng/ml or the Amsterdam, LEiden, GROningen study of 3–5 ng/ml delivers at least comparable outcomes with a standard tacrolimus, MMF (500 twice daily), prednisolone regimen.6,7 There are some minor concerns. The prestudy 14% noninferiority rate on which the study was powered seems high. But to give some perspective, the noninferiority rate for rejection in the BENEFIT-EXT was set at a very high level of 20%. Incorporating patient-reported outcomes may have improved the study because the two different immunosuppression regimens have different side effects and toxicities beyond the reported AEs. Ultimately, the OPTIMIZE trial delivers an important message: in kidney transplant recipients aged 65 years and older, the regimen of low-dose, once-daily tacrolimus plus everolimus did not outperform standard-dose tacrolimus plus reasonably dosed MMF at 2 years in achieving survival with functioning graft and eGFR above thresholds. Thus, the new standard regimen with slightly lower tacrolimus and lower MMF dosing than commonly used remains a robust choice in this population. I am frequently asked, “What do we need to do to make immunosuppression better?” My reply is, “Not much. We just need to use less of what we already have, better. Listen to your patient. When your patient tells you, “My hands are shaking and I got diarrhea,” lower the tacrolimus and stop the MMF.