Hashimoto Kazuhisa, Kimura Natsuka, Narita Jun, Ishii Ryo, Hirose Masaki, Hayashi Ken, Nishino Haruka, Ueyama Atsuko, Ueda Kazutoshi, Yoshihara Chika, Kitabatake Yasuji, Nagai Ryozo, Aizawa Kenichi, Ishida Hidekazu
Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan.
Division of Clinical Pharmacology, Department of Pharmacology, Jichi Medical University, Shimotsuke, Japan.
Pediatr Transplant. 2025 Jun;29(4):e70092. doi: 10.1111/petr.70092.
Management of immunosuppressive therapy after heart transplantation is typically guided by blood trough levels. Although tissue concentrations of immunosuppressive agents reportedly correlate with acute rejection in liver and kidney allografts, data in pediatric heart transplant recipients remain limited.
We enrolled 41 pediatric heart transplant recipients who underwent follow-up endomyocardial biopsy (EMB) between July 2021 and December 2023. For nine of those patients, serial data were collected up to 24 weeks post-transplantation. Myocardial tissue concentrations of tacrolimus (TAC), everolimus (EVR), mycophenolic acid (MPA), and mycophenolic acid glucuronide (MPAG) were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS), while blood concentrations were quantified by LC-MS/MS or immunoassays.
Significant correlations were observed between myocardial and blood concentrations at EMB for TAC (r = 0.73, p < 0.0001), MPA (r = 0.79, p < 0.0001), and MPAG (r = 0.50, p < 0.0001). However, for EVR there was no significant correlation. Longitudinal analysis demonstrated that the tissue-to-blood TAC and EVR ratios decreased with age. No significant rejection events were observed during the study period, precluding the analysis of rejection risk.
Myocardial TAC, MPA, and MPAG concentrations are associated with blood levels, whereas those of EVR showed no significant correlation. Further, the tissue perfusion efficiencies of TAC and EVR decreased with age. This study highlights the value of LC-MS/MS for immunosuppressant monitoring after pediatric heart transplantation.
心脏移植后免疫抑制治疗的管理通常以血药谷浓度为指导。尽管据报道免疫抑制剂的组织浓度与肝和肾同种异体移植中的急性排斥反应相关，但小儿心脏移植受者的数据仍然有限。
我们纳入了41例在2021年7月至2023年12月期间接受随访心内膜心肌活检（EMB）的小儿心脏移植受者。其中9例患者在移植后24周内收集了系列数据。通过液相色谱-串联质谱法（LC-MS/MS）测量他克莫司（TAC）、依维莫司（EVR）、霉酚酸（MPA）和霉酚酸葡糖苷酸（MPAG）的心肌组织浓度，而血药浓度通过LC-MS/MS或免疫测定法定量。
在EMB时，TAC（r = 0.73，p < 0.0001）、MPA（r = 0.79，p < 0.0001）和MPAG（r = 0.50，p < 0.0001）的心肌浓度与血药浓度之间存在显著相关性。然而，EVR没有显著相关性。纵向分析表明，组织与血液的TAC和EVR比值随年龄降低。在研究期间未观察到显著的排斥事件，无法进行排斥风险分析。
心肌TAC、MPA和MPAG浓度与血药水平相关，而EVR浓度无显著相关性。此外，TAC和EVR的组织灌注效率随年龄降低。本研究强调了LC-MS/MS在小儿心脏移植后免疫抑制剂监测中的价值。
