4 Discussion
Our findings have revealed that a combination of Low C0 and High IPV of TAC, assessed between 3 and 12 months after transplantation, was associated with an increased risk of donor-specific antibodies (DSA), as well as mortality among lung transplant recipients. Furthermore, we observed that the CYP3A5 genotype influenced TAC C0 and IPV during the early post-transplantation period; however, no correlation was found with clinical outcomes (Supplementary Figure 2).
We concluded that patients with an average C0 below 8 ng/mL during 3–12 months are at higher risk for DSA and mortality. Previous studies investigating the correlation between C0 and graft outcomes in lung transplantation have yielded inconsistent findings. Ryu et al. reported an increased risk of mortality with a C0 below 10 ng/ mL within one month post-transplantation, 15 while Gallagher found a negative association between mean TAC C0 (median (IQR): 9.8 (8.56–10.75) ng/mL) between 6–12 months and CLAD.7 Darley et al. reported a significantly higher proportion of rejection biopsies (85.7% versus 31.9%) with C0 fell below their target range of 12–15 ng/mL within the first three months after transplantation.21 The discrepancies in lower limits of TAC C0 may be attributed to variations in target ranges employed across different studies. In our center, where a substantial number of elderly patients undergo transplantation and face high risk of infection resulting in mortality, we have observed a significant association between C0 < 8 ng/mL and inferior outcomes, thereby suggesting this lower limit remains acceptable. Meanwhile, higher TAC concentration has been linked to increased drug toxicity such as acute kidney injury, chronic kidney disease and post-transplant diabetes mellitus; 22, 23 however, limited studies exist to assess the upper limit of TAC C0 in lung transplant recipients, thus further investigations are warranted.
In addition to routine C0 monitoring, TAC IPV has emerged as a novel marker for identifying transplant recipients at risk for suboptimal clinical outcomes.24 Various methodologies have been proposed to assess IPV, including coefficient of variation (CV), standard deviation (SD) and time in therapeutic range (TTR).25 In our study, we employed the most prevalent parameter in solid organ transplantation, CV, and observed that patients with CV >= 30% during 3–12 months was associated with increased risk of mortality. Meanwhile, current studies on evaluating TAC IPV in lung transplantation used different methodologies, and conclusions remains controversial.
Gallagher conducted a retrospective analysis of 110 lung transplant recipients, using SD to characterize IPV. Their findings suggest that TAC SD calculated during 6–12 months independently predicted the time to development of CLAD and mortality. With each unit increase in SD, there was a corresponding 46% and 27% increase in the risk of CLAD and death, respectively. 7 Ensor et al. conducted a retrospective study involving 292 patients and reported that a 10% increase in TTR was significantly associated with reduced risk of acute cellular rejection (ACR), CLAD and mortality at 1 year.9 In contrast, Kao et al analyzing TTR in 157 lung transplant patients during the first 6 months, did not find any correlation between TTR and ACR. 8These studies differed in their target ranges; Ensor and his colleagues employed a narrower range of 12–15 ng/mL for 0–6 months followed by 10–12 ng/mL for 6–12 months, while Kao used a range of 10–15 ng/mL throughout the first year. Due to TAC’s high variability, maintaining a strict therapeutic range can be challenging; therefore, adopting a more liberal range may allow more time within the therapeutic range without adverse effect on ACR, leading to negative outcomes.
The majority of studies evaluating the impact of TAC exposure on clinical outcomes have primary focused on the stable period, typically defined as at least 3 months post-transplantation. During the early post-transplant phase, patients experience clinical instability and necessitate frequent dose adjustments of TAC. This results in highly variable concentrations, which can introduce biases in statistical analysis and complicate result interpretation. Nonetheless, efforts have been made to investigate this phenomenon. Gallagher et al. found no association between TAC SD within 0–6 months and CLAD or mortality. Similarly, Evens et al. reported that high TAC variability within 0-3 months did not correlate with an increased acute rejection score at 12 months. In our study, we also observed no correlation between TAC IPV during 0–3 months and DSA, CLAD, or mortality (data not shown). Furthermore, there is limited literature exploring long-term TAC exposure beyond 12 months after lung transplantation. Our data suggest TAC exposure during 3–12 months predicted the developing trend of exposure in the second year, which aligns with previous study.7
The average C0 effectively reflects the levels over specific time periods, while IPV captures fluctuations between high and low levels, similar to accuracy and precision in analytical science. Hence, a combination of C0 and IPV may provide a more comprehensive characterization of TAC exposure. Stefanović et al enrolled 104 Caucasian kidney transplant patients, and found patients with high IPV/low C0/D during 6–12 months had significantly reduced graft survival compared to the other combinations.16 Park et al further validated this conclusion in a larger cohort with 1080 kidney transplant recipients, by reporting higher incidences of death censored graft loss (DCGL), biopsy-proven allograft rejection (BPAR) and overall graft loss in the high IPV/low C/D group. 17 Our study was the first study in lung transplantation to investigate the combinational effect of TAC C0 and IPV, and we also observed a stronger predictive power of Low C0/High IPV combination than TAC C0 or IPV alone.
The impact of CYP3A5 polymorphism on TAC metabolism has been extensively studied; however, the definitive association betweenCYP3A5 genotype and TAC IPV remains to be established.26 Seiber et al reported each additional loss-of-function allele (CYP3A5*3 , *6 and *7) reduced TAC CV by 1.82% in the first six months following kidney transplantation in European Americans. 18 On the other hand, studies conducted between 6 and 12 months suggested no significant influence ofCYP3A5 genotype on TAC IPV. 27, 28 Similarly, we only observed a higher IPV in CYP3A5 expressers within the first three months. Other factors such as noncompliance, drug-drug or drug-food interactions may play a more prominent role in determining IPV during the stable phase after transplantation.
There are several limitations in our study. Firstly, the study design was single-center, retrospective and observational. Secondly, the sample size is relatively small compared to previous research in kidney transplantation. Thirdly, we did not exclude inpatient data in our study. Lung transplant recipients usually face higher risk of infection compared to other solid organ transplantation and have a high likelihood of hospital readmission, particularly within the first year. To maintain an adequate sample size, we included all measurements in our study.
In conclusion, the present study suggested using a combination of Low C0 (< 8 ng/mL) and High IPV (>=30%) of TAC calculated during 3–12 months after lung transplantation may help predict adverse clinical outcomes. Monitoring TAC C0 and IPV in routine clinical practice is a convenient tool that may assist in identifying patients at high risk for inferior long-term outcomes.