PracticeUpdate Conference Series ISN WCN 2019

Lower Dose Tacrolimus Remains Effective Immunosuppressive Strategy Following Kidney Transplant Acute rejection rates did not increase with the lower dose. P atients given a lower-than-standard dose of tacrolimus as part of an immunosuppressive regimen following kidney transplantation were less likely to have supratherapeutic levels of the drug in the days following transplant surgery and did not have an increased risk of organ rejection, according to a single center experience. “The SYMPHONY study established low-dose tacrolimus, mycophenolate, prednisolone, and IL-2 receptor antagonist induction as standard of care for immunosuppression in kidney transplant recipients,” the authors wrote in their abstract. The study was led by Justin Chua, MD, of Austin Health in Melbourne. The study investigators reduced the starting tacrolimus dose from 0.075mg/ kg twice daily to 0.05 mg/kg twice daily among their kidney transplant patients, in an effort to minimize supratherapeutic tacrolimus levels in the early post-transplant period. Dr. Chua and his colleagues conducted a retrospective study of 127 kidney transplant recipients who were treated at their institution while they were still using higher dose tacrolimus (n=64; Nov 1, 2015 to October 31, 2016) as well as after they switched to the lower dose (n=63; December 1, 2016 to November 30, 2017). Multiorgan transplant recipients were excluded. The standard immunosuppression regimen used throughout was tacrolimus, mycophenolate mofetil, prednisolone and basiliximab. The two groups of patients were well-matched for age (mean 52.1 ± 12.1 years), gender (63% male) and pre-transplant diabetes mellitus (18.9%). Compared with those who received the higher dose of tacrolimus, those who received the lower dose had significantly lower mean tacrolimus levels during day 1 to 3 (10.8 ± 4.6 vs 15.3 ± 6.4 mcg/L; P < .001), day 4 to 7 (7.5 ± 2.4 vs 9.5 ± 3.4 mcg/L; P < .001) and day 8 to 14 (7.3 ± 1.4 vs 8.4 ± 2.2 mcg/L; P = .002), but not at day 21 or day 28. A higher proportion of patients on the lower dose of tacrolimus achieved therapeutic levels, defined as 6 to 10 mcg/L, during day 1 to 3 (36.1% vs 18.8%; P = .0022), day 4 to 7 (50.8% vs 40.6%; P = .0011), and day 8 to 14 (83.6% vs 71.7%; P = .025). In addition, those on the higher dose were more likely to have supratherapeutic levels, defined as levels >10 mcg/L, during day 1 to 3 (54.1% vs 79.7%, P = .0022). There were no significant differences between the two treatment groups with respect to rates of treated acute rejection at 6 months (26.4% vs 25.4%), delayed graft function (47.6% vs 46.8%), or post-transplant diabetes mellitus (38.2% vs 39.0%). In a comment on the study, session moderator Toby Coates, MD, of the University of Adelaide, told Elsevier’s PracticeUpdate that, “Tacrolimus is associated with transplant kidney nephrotoxicity. Therefore, a lower dose, if it could be achieved [without compromising efficacy], would reduce the damage of the drug to the kidney,” which in turn could help improve the graft outcome. Dr. Coates called these findings “very promising” but noted that they will need to be confirmed in a larger, more diverse population before any recommended changes to standard care can be made.

ratio (UACR) >300 mg/g. This was the trial’s defini- tion of proteinuric diabetic kidney disease. Of the 7020 EMPA-REG OUTCOME participants, 643 (9.2%) met CREDENCE criteria for proteinuric diabetic kidney disease. As with the overall cohort, the use of empagliflozin versus placebo showed consistent treatment effects, with a hazard ratio of 0.46 (95% CI 0.31–0.68) for the cardiorenal outcome. Outcomes in the subgroup of patients who met CREDENCE criteria were similar to the overall cohort with respect to the positive effects of empagliflozin on cardiovascular death and the composite of cardiovascular death and hospital- ization for heart failure. Similar to the overall population, there was no increased risk with empagliflozin versus placebo in events consistent with acute renal failure (12.6% vs 16.7%) or hyperkalemia (3.6% vs 7.2%). Based on these findings and those from the CREDENCE study also presented at the WCN conference, Dr. Wanner concluded that, “SGLT2 inhibitors are effective in lower ranges of kidney function, a range which is not covered by current labels in most parts of the world.”

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WCN 2019 • PRACTICEUPDATE CONFERENCE SERIES