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.