Low Tacrolimus trough concentration and high intra-patient variability are associated with chronic lung allograft dysfunction and mortality in lung transplantation recipients

doi:10.21203/rs.3.rs-2867368/v1

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Research Article

Low Tacrolimus trough concentration and high intra-patient variability are associated with chronic lung allograft dysfunction and mortality in lung transplantation recipients

https://doi.org/10.21203/rs.3.rs-2867368/v1

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Background

Erratic tacrolimus (Tac) exposure is associated with poor long-term outcomes after kidney transplantation. However, detailed data on the association in lung transplant recipients are lacking.

Aim

We hypothesized that Tac intra-patient variability (Tac IPV) or mean concentration was associated with chronic lung allograft dysfunction (CLAD) and survival after lung transplantation.

Methods

Data from 132 lung transplant recipients were analyzed retrospectively. Tac trough concentration during 0–6, 6–12 and 12–24 months after transplantation were collected. Tac IPV was calculated based on coefficient of variation. Univariate and multivariate COX analyses were performed to identify risk factors for CLAD and survival.

Results

Of the 132 patients analyzed, 31 (23.5%) developed CLAD and 20 (15.2%) died. Patients received significantly more intensive monitoring of Tac concentration at 0–6 months and Tac IPV was the highest (median: 33.98%) at this period, while after 6 months it lowered to a relatively steady level. A higher mean concentration at 6–12 months [Hazard Ratio (HR) 0.358 (95% CI: 0.137–0.933)] and at 12–24 months [HR 0.351 (95% CI: 0.136–0.904)] was a protective factor for CLAD incidence, while a higher Tac IPV at 6–12 months [HR 2.839 (95% CI: 1.063–7.585)] was associated with increased risk of mortality.

Conclusion

Our data indicates that Tac mean concentration and IPV had significant impact on CLAD incidence and mortality in lung transplant recipients. Routine monitoring of Tac concentration and IPV may help identify in patients at increased risk for inferior long-term outcomes.

Tacrolimus

Intra-patient variability

CLAD

Lung transplantation

Keeping Tac concentration at a relatively higher level after the first 6 months post transplantation may protect patients from the risk of CLAD incidence.
Patients whose Tac concentration fluctuates greatly during 6–12 months may have increased risk of mortality after lung transplantation.
Incorporating algorithms that calculate Tac IPV into electronic medical records may help physicians recognize patients at higher risk for poor long-term outcomes after lung transplantation.

Tacrolimus (Tac) is the primary immunosuppressive agent for lung transplantation recipients [1]. It is characterized by high inter-individual variability in pharmacokinetics and narrow therapeutic window; therefore, frequent monitoring of trough concentration is required to maintain a therapeutic level [2]. However, even when the mean trough concentration is within the target range for certain time period, there is a risk of sub-therapeutic or supra-therapeutic fluctuations for each single measurement [3]. Hence, tacrolimus intra-individual variability (Tac IPV) has been proposed to be related to clinical outcomes in solid organ transplantation [4].

Tac IPV is the measurement of fluctuations of tacrolimus trough concentrations over a certain period of time. Borra et al first demonstrated a high Tac IPV was associated with poor allograft outcomes in adult kidney transplant recipients in 2010 [5]. After that, a number of studies and reviews appeared, confirming the correlation between high IPV and rejection, graft survival and mortality in kidney and liver transplantation [4, 6–8]. Meanwhile, similar studies in lung transplantation are limited, leaving a major void in this area.

Aim of the study

Based on current status, our study was designed to explore two research interests. First, how Tac mean concentration and IPV varies at different time periods after lung transplantation. Second, whether variation in Tac concentration could affect long-term outcomes in lung transplant recipients.

Ethics approval

All procedures in this study were in accordance with the 1964 Helsinki declaration and its amendments, and was approved by the Ethics Committee of China-Japan Friendship Hospital in June, 2022 (No. 2022-KY-056-1).

Patients

This was a single center, retrospective study. Two hundred and twenty patients undergone lung transplantation during January 2017 to December 2021 in China-Japan Friendship Hospital and received Tac-based immunosuppressive regimen after transplantation were recruited. Among them, patients who (1) survived less than 1 year after surgery; (2) had lung carcinoma before transplantation; (3) had missing data were excluded, leaving 132 patients for final analysis.

Immunosuppressive regimen

For induction therapy, patients received either methylprednisolone or in combination with basiliximab. Methylprednisolone was given intraoperatively at a dose of 500–1000 mg. Basiliximab were given both before transplantation and on post-operative day (POD) 4 at a dose of 20 mg.

Maintenance immunosuppressive regimen consists of Tac, mycophenolate mofetil (MMF) and prednisone. Tac was given on POD 1. Routine starting dose was 2 mg/d in 2 divided doses, except those with exceptionally high or low body weight, and dose adjustments were made according to whole-blood trough concentration. The target ranges of concentration were 8–10, 6–8 and around 6 ng/mL during 0–6, 6–12 and 12–24 months after lung transplantation, respectively. The initial dose of MMF was 1000 mg/d in 2 divided doses. Prednisone was given intravenously at 1 mg/kg/d during POD 1–3, and then switched to oral administration at 0.5 mg/kg/d, and gradually tapered to 5–10 mg/d for long-term maintenance.

Data collection

Patients’ data were collected by reviewing electronic medical records. Information including basic demographics (age, sex, height, weight, indication for transplant, comorbidities, transplant type and induction therapy) and post-operative data (Tac trough concentration (ng/mL), Forced expiratory volume in 1 second (FEV₁), and survival time) were obtained.

Tac trough concentration was determined using micro-particle enzyme immunoassay (ARCHITECT i1000SR immunoassay analyzer, Abbott U.S.). All the results in each of the post-transplant time periods of 0–6, 6–12 and 12–24 months were included. Tac mean concentration was calculated for each patient at each epoch, respectively. Tac IPV was calculated as coefficient of variation (CV%) according to the formula Tac IPV = (standard deviation/mean) × 100, as previously reported [9]. For each post-transplant epoch, at least 3 measurements were required to calculate Tac IPV. The patients were divided into low and high Tac mean concentration or IPV groups using the median value as the cutoff value in further analysis.

Outcome definitions

Our study outcomes were the incidence of chronic lung allograft dysfunction (CLAD) and mortality. CLAD was defined as a 20% fall from the best post-transplant FEV1 according to the International Society of Heart and Lung Transplant Guidelines [10]. In addition, we investigated the distribution characteristics of Tac exposure, which was represented by mean concentration and Tac IPV, across 3 different time periods (0–6, 6–12, 12–24 months).

Statistical analysis

Data was processed using Statistical Package for Social Science (SPSS) 19.0. Continuous variables were expressed as mean ± standard deviation (SD) or median (interquartile range, IQR). Categorical variables were presented as count (percentage). Comparisons between continuous variables were analyzed by Student’s t test or Mann–Whitney U test. Pearson’s chi-square test or Fisher’s exact test was used to compare differences in categorical variables. Incidence of CLAD or mortality stratified by mean concentration or IPV were analyzed by Kaplan-Meier analysis and compared using the log-rank test. Time from transplant to CLAD or death was modeled using Cox proportional hazard regression. Potential risk factors included age at transplant, sex, body mass index (BMI), comorbidities (hypertension, hyperlipidemia and diabetes), indication, transplant type, use of induction therapy, Tac mean concentration and IPV. All variables with a p < 0.1 in univariate analysis were incorporated into multivariate analysis which adopted a forward LR strategy. P < 0.05 was considered of statistical significance.

Patients’ characteristics

A total of 132 patients, 106 males (80.3%) and 26 females (19.7%), undergoing lung transplantation between 2017 and 2021 were included. Table 1 shows the baseline demographics of the study population. Median age at transplantation was 61 (IQR, 53–65) years old. All patients had at least 1-year follow-up and the median follow-up time was 43.6 (IQR, 32.7–53.2) months. Twenty patients died and 31 patients developed CLAD at census.

Table 1

Baseline demographic characteristics of LTx patients stratified by CLAD status
Parameters	All	CLAD-free	CLAD	p
n (%)	132 (100.0)	101 (76.5)	31 (23.5)
Transplant age (years)	61 (53–65)	60 (52–65)	62 (56–67)	0.244^a
Male, n (%)	106 (80.3)	78 (77.2)	28 (90.3)	0.109^b
BMI (kg/m²)	21.7 ± 4.1	21.4 ± 4.1	22.7 ± 4.1	0.122^c
Comorbidities (n (%))
Hypertension	33 (25.0)	23 (22.8)	10 (32.3)	0.286^b
Diabetes mellitus	47 (35.6)	33 (32.7)	14 (45.2)	0.204^b
Hyperlipidemia	23 (17.4)	18 (17.8)	5 (16.1)	0.828^b
Diagnosis (n (%))				0.813^d
COPD	21 (15.9)	16 (15.8)	5 (16.1)
ILD	93 (70.5)	70 (69.3)	23 (74.2)
Others	18 (13.6)	15 (14.9)	3 (9.7)
Transplant type (n (%))				0.143^b
Unilateral	70 (53.0)	50 (49.5)	20 (64.5)
Bilateral	62 (47.0)	51 (50.5)	11 (35.5)
Induction therapy (n (%))	61 (46.2)	51 (50.5)	10 (32.3)	0.075^b
Deceased at census (n (%))	20 (15.2)	14 (13.9)	6 (19.4)	0.567^d
Time to CLAD (months)	41.8 (26.4–47.8)	-	41.8 (26.4–47.8)
Follow-up time (months)	43.6 (32.7–53.2)	41.3 (31.9–51.6)	52.2 (39.7–58.7)	0.007^a
Categoric data are presented as number (%), continuous data are presented as mean with SD or median with IQR, depending on variable distribution
^aMann–Whitney U test
^bPearson’s chi-square test
^cStudent’s t test
^dFisher’s exact test

Variation of Tac exposure over time after transplantation

Tac exposure data was collected in 132, 132 and 111 patients for post-transplant time periods of 0–6, 6–12 and 12–24 months, respectively, and the corresponding mean concentration was 9.4 ± 1.3, 9.2 ± 1.5 and 8.4 ± 1.3 ng/mL, respectively. Tac mean concentration at 12–24 months was significantly lower than those in the first year (Fig. 1a). Tac IPV was 33.98% (IQR, 29.04–41.92%), 26.96% (IQR, 20.40–33.49%) and 25.25% (IQR, 19.54–31.89%) for 0–6, 6–12 and 12–24 months, respectively, and the value at 0–6 months was significantly higher than those in later time periods (Fig. 1b). We summarized the number of concentration measurements for different time periods and the median value was 25 (IQR, 20–32), 10 (IQR, 6–16) and 13(IQR, 7–20), respectively, indicating the monitoring of Tac concentration was significantly more intense at the early post-transplant period (Fig. 1c).

No correlation between mean concentration and IPV were found (data not shown). Positive correlation was found between the number of concentration measurements and Tac IPV at all time periods, and the correlation coefficient was 0.278 (p = 0.001), 0.244 (p = 0.005) and 0.228 (p = 0.016) for 0–6, 6–12 and 12–24 months. In contrast, only Tac mean concentration at 12–24 months showed negative correlation with its corresponding measurement counts (r = − 0.249, p = 0.005)

The patients were divided into low and high Tac mean concentration or IPV groups based on the median value at different time periods for further analysis. The baseline characteristics stratified by Tac IPV are summarized in Supplementary Table 1–3. No significant differences in baseline characteristics were found between the 2 cohorts.

Association of Tac exposure with CLAD

CLAD occurred in 23.5% transplant recipients who survived the first year after transplantation. According to Kaplan-Meier analysis, the impact of mean concentration at 6–12 months (p = 0.001), 12–24 months (p = 0.005) and Tac IPV at 12–24 months (p = 0.024) on CLAD was significant (Fig. 2).

Cox regression analysis was performed to identify risk factors for CLAD. Demographic characteristics including BMI (p = 0.048), Tac exposure data including Tac mean concentration at 6–12 months (p = 0.002) and 12–24 months (p = 0.008), Tac IPV at 12–24 months (p = 0.029) showed significance in univariate analysis. In the multivariate analysis, a high Tac mean concentration at 6–12 months (> 9.12 ng/mL) [HR 0.358 (95% CI: 0.137–0.933, p = 0.036] and 12–24 months (> 8.20 ng/mL) [HR 0.351 (95% CI: 0.136–0.904), p = 0.030] showed negative correlation with CLAD incidence (Table 2).

Table 2

Cox Proportional Hazards Regression analysis on the Influence of potential risk factors for CLAD
Potential risk factors	Univariate analysis		Multivariate analysis
Potential risk factors	OR (95% CI)	p	OR (95% CI)	p
BMI, kg/m²	0.919 (0.846–0.999)	0.048
Induction therapy	1.940 (0.880–4.276)	0.100
High mean concentration at 6–12 months	0.251 (0.106–0.594)	0.002	0.358 (0.137–0.933)	0.036
High mean concentration at 12–24 months	0.293 (0.119–0.721)	0.008	0.351 (0.136–0.904)	0.030
High Tac IPV at 6–12 months	2.083 (0.978–4.437)	0.057
High Tac IPV at 12–24 months	2.502 (1.099–5.696)	0.029

Association of Tac exposure with mortality

Twenty patients (15.2%) who survived the first year after lung transplantation died at census in our study. Tac mean concentration (p = 0.022) and IPV (p = 0.034) at 6–12 months exhibited significant impact on mortality in Kaplan-Meier analysis (Fig. 3). All potential risk factors for mortality were analyzed using Cox regression. Transplant type and Tac exposure at 6–12 months showed significance in univariate analysis. The final model using multivariate analysis is shown in Table 3. A high Tac IPV (> 26.96%) at 6–12 months was independently associated with mortality [HR 2.839 (95% CI: 1.063–7.585), p = 0.037].

Table 3

Cox Proportional Hazards Regression analysis on the Influence of potential risk factors for survival
Potential risk factors	Univariate analysis		Multivariate analysis
Potential risk factors	OR (95% CI)	p	OR (95% CI)	p
Transplant type
Unilateral	Reference		Reference
Bilateral	0.313 (0.104–0.937)	0.038	0.255 (0.084–0.772)	0.016
High mean concentration at 6–12 months	0.358 (0.144–0.893)	0.028	0.414 (0.165–1.040)	0.060
High Tac IPV at 6–12 months	2.709 (1.037–7.079)	0.042	2.839 (1.063–7.585)	0.037

Statement of key findings

In this study, we explored the impact of erratic Tac exposure on CLAD incidence and mortality in lung transplant recipients. We drew two major conclusions from the data: (1) a lower Tac mean concentration at 6–24 months could increase the risk of CLAD; (2) a higher Tac IPV at 6–12 months may impair long-term survival after lung transplantation.

Tac IPV has become recognized as a novel marker to identify transplant recipients at risk for inferior clinical outcomes [4, 11]. It is estimated to range from 5% to over 60% in solid organ transplantation, while most literature reported an IPV between 15% and 35% [11]. Few data on Tac IPV in lung transplant recipients are available for reference. Gallagher et al used SD to represent IPV and Evans et al only reported the median value around 30–40% [12, 13]. We observed a slightly wider distribution of IPV ranging from 2.1–71.0% throughout the first 2 years. The wide range in our study may be caused by the inclusion of early post-transplant period which is characterized by high variability, and the later post-transplant periods when patients received less frequent assessments of levels and possibly lead to lower variability.

Research on association between Tac exposure and clinical outcomes has always been focusing on 6–12 months post-transplant, which is commonly considered as a relatively steady state for patients [8, 14]. Borra et al was the first to evaluate the impact of high Tac IPV clearance during this time period on long-term chronic allograft nephropathy and graft loss after kidney transplantation. He conducted a single-center retrospective study with 297 patients and demonstrated high Tac IPV is associated with impaired graft survival [5]. Shuker et al. later conducted a study with a larger cohort of 808 kidney transplant patients and found a high tacrolimus IPV was an independent risk factor for adverse kidney transplant outcomes [15]. In our study, we found a lower Tac mean concentration was associated with increased risk of CLAD, while a higher Tac IPV was associated with mortality during 6–12 months, which was in parallel with Gallagher’s results in lung transplant recipients [13].

The early post-transplant period is marked by clinical instability of patients and frequent dose adjustments of Tacrolimus [16]. Patients received more intense monitoring and experienced significantly higher Tac IPV than in later time periods. However, no correlation between Tac IPV or mean concentration with CLAD or mortality was found in our study. Gallagher et al analyzed data at 0–6 months in 110 lung transplantation recipients, and reported Tac SD at this time period was not associated with CLAD or mortality [13]. Evens et al enrolled 229 lung transplant recipients and also found high tacrolimus variability at 0–3, 3–6, and 6–12 months was not associated with increased 12-month total acute rejection score [12]. Unlike results in lung transplantation, Rozen-Zvi et al found that high time-weighted coefficient variability (TWCV) of Tac in the early post transplantation period was associated with reduced graft survival in kidney transplantation [17]. Whether the contradictory results were caused by different graft type or calculation methods of Tac IPV needs further validation.

Literature reporting tacrolimus exposure beyond 12 months after transplantation is also limited. We found a lower tacrolimus mean concentration during 12–24 months could predict the incidence of CLAD. This can be explained by the insufficient immunosuppressive effect caused by low tacrolimus trough concentration, which may worsen allograft outcomes [3, 6, 18]. Previous studies have also shown the correlation between lower tacrolimus trough concentration and acute rejection and CLAD occurrence, although in earlier post-transplant periods [13, 18–20]. Judging from all the evidence, it is necessary to maintain a relatively high concentration of tacrolimus after transplantation in clinical practice.

The reason why Tac IPV affects allograft and patient outcome may be explained by the fact that patients with high IPV are more easily exposed to sub-therapeutic or supra-therapeutic drug concentrations than those with low IPV values. The sub-therapeutic exposure may be related to immune activation leading to rejection episodes and the supra-therapeutic exposure may exhibit drug toxicity, including nephrotoxicity, neurotoxicity and infections, and hence lead to inferior long-term outcomes [21, 22]. Reported causes of high IPV are non-adherence, food, drug-drug interactions, genetic factors and concomitant illnesses [23]. Adherence in lung transplant recipients is commonly perceived to be high, and we believe genetic factors such as CYP3A5 genotype, may affect IPV, but further studies are warranted to validate our hypothesis.

Apart from Tac exposure, transplant type also proved to be related to mortality in lung transplant recipients in multivariate analysis. Bilateral lung transplant was found to be a protective factor when compared with single lung transplant in our study. The Annual Data Report of the US Organ Procurement and Transplantation Network (OPTN) and the Scientific Registry of Transplant Recipients (SRTR) on Lung also reported a higher survival rate for recipients of bilateral transplant [24]. This survival benefit may be attributed by its prevention of early ventilation and perfusion mismatching, and thus avoiding the hyperinflation in the native lung following single lung transplant [25].

Strengths and weaknesses

In summary, despite the large number of studies addressing the impact of Tac IPV on clinical outcomes in kidney transplantation, whether it remains significant in lung transplant recipients remains was poorly understood [16, 26]. Besides, most research focuses on the time period between 6 and 12 months after transplantation, while the early phase and long-term evaluation of Tac IPV remain limited. In our study, we investigated the distribution of Tac IPV and mean concentration at 3 consecutive time periods, and demonstrated their correlation with clinical outcomes, respectively.

There are several limitations in our study. Firstly, the sample size is relatively small compared with previous research in kidney transplantation. The survival rate in lung transplant recipients is lower than in kidney transplant and since we needed to collect concentration data between 6 and 12 months, we excluded patients who did not survive the first year, and hence leaving the current sample size. Therefore, our conclusions might need to be validated in future study with longer observation time and larger sample size. Secondly, we did not exclude inpatient data. Lung transplant recipients may encounter infection more frequently and their follow-up examination is more complicated, leading to limited outpatient data, especially in the first year. So, in order to include more patients, we did not exclude inpatient data.

In conclusion, erratic tacrolimus exposure is associated with impaired long-term outcomes in lung transplant recipients. A low tacrolimus mean trough concentration during 6–24 months may increase the incidence of CLAD and a high Tac IPV during 6–12 months could increase the risk of mortality. Monitoring Tac concentration and IPV in routine clinical practice is a convenient tool that may assist in identifying patients at high risk for inferior long-term outcomes.

Acknowledgements We thank Prof. Wenhui Chen and her team from Department of Lung Transplantation in China-Japan Friendship Hospital for their assistance in conducting the study.

Funding The study was financed with National High Level Hospital Clinical Research Funding (2022-NHLHCRF-PY-15), National Natural Science Foundation Project (82273523), National High Level Hospital Clinical Research Funding (2022-NHLHCRF-LX-03), National Key Research and Development Program of China (2020YFC2005504), CAMS Innovation Fund for Medical Science (2021-I2M-1-049) and Capital's Funds for Health Improvement and Research (CFH 2020-1-2031). The funding sources had no effect on any part of the study, preparation, or submission of the manuscript.

Conflicts of interest All authors report no conflict of interest.

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Low Tacrolimus trough concentration and high intra-patient variability are associated with chronic lung allograft dysfunction and mortality in lung transplantation recipients

Status:

Version 1

Abstract

Figures

Impacts on practice

Introduction

Aim of the study

Ethics approval

Methods

Patients

Immunosuppressive regimen

Data collection

Outcome definitions

Statistical analysis

Results

Patients’ characteristics

Variation of Tac exposure over time after transplantation

Association of Tac exposure with CLAD

Association of Tac exposure with mortality

Discussion

Statement of key findings

Strengths and weaknesses

Conclusion

Declarations

References

Supplementary Files

Status:

Version 1