Low-Dose Immunosuppression Fails to Beat Standard Therapy in Older Kidney Transplant Patients

Older adults make up a growing share of people on dialysis and receiving kidney transplants. Compared with younger recipients, they are more frail and carry more comorbidity. Their outcomes are driven less by graft failure than by death from cardiovascular disease, cancer, and infection. Immunosenescence may also lower their rejection risk. Many receive kidneys from older donors, which may be especially vulnerable to calcineurin inhibitor toxicity. This raised the possibility that less immunosuppression would serve them better.

The OPTIMIZE trial tested that idea. It was an investigator-driven, open-label, multicenter randomized trial run from July 2019 to April 2025 at six Dutch centers and one Belgian center. It enrolled 379 de novo kidney transplant recipients aged 65 or older, in two strata. Stratum A (198 patients) received kidneys from deceased donors aged 65 or older. Stratum B (181 patients) received kidneys from living donors or from deceased donors younger than 65. Patients were randomized 1:1 to TEP or TMP.

Both groups received basiliximab induction. The TEP arm (low-dose tacrolimus, everolimus, prednisolone) had tacrolimus trough targets of 5–7 ng/ml to 3 months, 2–4 ng/ml from 3 to 6 months, and 1.5–4 ng/ml thereafter, with everolimus at 3–6 µg/L. The TMP arm (standard-dose tacrolimus, mycophenolate mofetil, prednisolone) had targets of 8–12, 6–10, and 5–8 ng/ml. Median drug levels stayed within target ranges throughout the study, so the planned exposure difference was achieved.

The primary endpoint was successful transplantation at two years, defined as being alive with a functioning graft and an eGFR above a threshold. The threshold was 30 ml/min per 1.73 m² in stratum A and 45 in stratum B. Success occurred in 94 TEP patients (50%) and 110 TMP patients (57%). The reported difference was 7% (95% CI −17 to 3; P = 0.91), so the low-dose regimen did not produce a higher success rate. If anything, the point estimate favored standard therapy, though the interval includes no difference.

Secondary outcomes also showed no advantage. Patient survival was 89% in both arms (167 vs 171 patients; P = 0.95). Graft survival was 83% with TEP and 84% with TMP (155 vs 162; P = 0.65). The key points also report no better kidney function and no fewer infections with the low-dose regimen. Neither stratum showed significant differences in any endpoint. The rationale came from the TRANSFORM trial, which used everolimus with reduced CNI exposure in younger recipients (mean age 49) and saw fewer infections. That benefit did not carry over to this older population.

The clinical message is that reducing tacrolimus and swapping mycophenolate for everolimus is not clearly better in older recipients, including those with older donor kidneys. Standard-dose TMP remains a reasonable default. Caveats include the open-label design and the fact that only the abstract and early methods were available for this summary. The study was partly funded by Chiesi Farmaceutici, and the results apply to a selected population that excluded high-immunologic-risk patients.