Tacrolimus intrapatient variability linked with de novo donor-specific antibody formation
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Among pediatric patients who received a kidney-only transplantation, high tacrolimus intrapatient variability significantly correlated with de novo donor-specific antibody formation.
“Studies in adults strongly suggest that highly variable tacrolimus levels are associated with poor long-term outcomes in kidney transplant recipients,” Kim H. Piburn, DO, from the division of nephrology in the department of pediatrics at Stanford University in California, and colleagues wrote. They added, “However, baseline patterns of tacrolimus intrapatient variability in pediatric patients with kidney transplants have not been well described in the literature.”
In a retrospective pediatric cohort study, researchers observed 426 patients who underwent kidney-only transplantation at Lucile Packard Children’s Hospital Stanford between Jan. 1, 2004, and March 1, 2018. The study included a subgroup of patients who underwent transplantation when de novo screening was implemented. All patients completed at least a 12-month follow-up.
Researchers sought to characterize a baseline pattern of tacrolimus intrapatient variability among the patients and explore the risk threshold for tacrolimus intrapatient variability in relation to graft outcomes. They defined intrapatient variability using the coefficient of variation of all samples in a 6-month moving period.
Researchers conducted multivariable Cox regression models to assess the association of tacrolimus variability with C1q-binding de novo donor-specific antibody formation and secondary graft outcomes.
The final analysis included a total of 31,125 tacrolimus levels. Among the 426 patients, 51 patients formed C1q-binding de novo donor-specific antibodies, 20 of which researchers detected within the first 10 months after transplant. Those who formed de novo donor-specific antibodies experienced a higher intrapatient variability, with a mean of 38% compared with 28% for nondonor-specific antibody formers. Additionally, a total of 14 patients lost their graft due to immunologic causes.
Researchers observed patients with high tacrolimus intrapatient variability and a coefficient of variation greater than 30% showed a higher risk of de novo donor-specific antibody formation. Meanwhile, those in the top quartile of tacrolimus intrapatient variability with a coefficient of variation greater than 41% showed the strongest correlation with C1q-binding de novo donor-specific antibody formation.
In an accompanying editorial, Rachel Becker-Cohen, MD, from the Shaare Zedek Medical Center and Hebrew University School of Medicine in Jerusalem, Israel, wrote, “Questions remain on the effect of other immunosuppressive agents and drug combinations on the development of de novo [donor-specific antibodies], acute rejection and graft loss.”
Researchers suggested hospitals incorporate tacrolimus intrapatient variability into electronic health records to improve early intervention among high-risk transplant patients.
“These early interventions can include more frequent phone calls, in-person visits or further engaging the patients’ families to improve medication adherence, likely the most modifiable determinant of tacrolimus variability,” Piburn said in the press release. “High tacrolimus intrapatient variability may be due to periods of under-immunosuppression, thus putting patients at risk for donor-specific antibody formation and rejection. Minimizing variation in tacrolimus drug levels through these interventions may potentially help improve graft outcomes.”
References:
Becker-Cohen R. Clin J Am Soc Nephrol. 2022;doi:10.2215/CJN.06640622.
Immunosuppressive drug’s blood level variability may identify pediatric kidney transplant recipients at risk of rejection. https://www.eurekalert.org/news-releases/959574. Published July 26, 2022. Accessed July 26, 2022.
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