Early post-lung transplant calcineurin inhibitor management varies widely: an international survey

Calcineurin inhibitors (CNI) are critical for preventing allograft rejection after lung transplantation, but have known nephrotoxic and other adverse effects.^1,2 There are limited data and no consensus guidelines to inform dosing, target levels, and associated risks in the early post-transplant period, a timeframe when recipients may be particularly vulnerable to adverse CNI effects such as acute kidney injury (AKI).³ We therefore conducted an anonymous international survey of clinicians, exempted by the University of Pennsylvania institutional review board, regarding CNI practices during the first 2 weeks after lung transplantation. From October-November 2020, we invited clinicians to participate via REDCap weblink posted to the International Society for Heart and Lung Transplantation (ISHLT) lung transplant and pharmacy discussion groups and the Lung Transplant Outcomes Group investigator listserv.

Survey respondents (n=77) were primarily pulmonologists and pharmacists from North America (Figure 1A). Tacrolimus was the initial CNI used by 73 (94.8%) respondents. Sixty-three (81.8%) reported use of induction agents (55 basiliximab, 5 antithymocyte globulin, 3 alemtuzumab) while 14 (18.2%) used none, similar to ISHLT Registry data.⁴

Figure 1.

Responses to questions of a survey of lung transplant clinicians (respondent n=77). A. Professional position and geographic region of survey respondents (APP=advanced practice provider; US=United States; NZ=New Zealand). B. Timing of calcineurin inhibitor (CNI) initiation relative to the time of allograft reperfusion. C. Reported target ranges of tacrolimus concentrations during the first 14 days post-transplant among respondents who use this CNI initially (n=73). Each bar represents a single response. D. Reported overall level of concern as well as concern for specific lung transplant recipient outcomes regarding out-of-range CNI levels during the first 14 days post-transplant (AKI=acute kidney injury; ACR=acute cellular rejection; AMR=antibody-mediated rejection; CLAD=chronic lung allograft dysfunction).

CNI dosing practices in the first two post-transplant weeks were heterogeneous. Figure 1B shows substantial variability in time of initiation, from before to >72 hours after allograft reperfusion. Similarly, tacrolimus target concentrations during the first 14 days varied considerably (Figure 1C). The most common target range was 10–15 ng/ml (n=24, 31.2%), but nearly one-fifth of respondents reported non-overlapping ranges: 6 specified an upper limit of 10 ng/ml, while 9 reported a lower limit of 12 ng/ml. Although CNIs exhibit substantial pharmacokinetic variability, partly explained by inherited differences in cytochrome P450 (CYP) metabolism,³ 60 (77.9%) respondents used uniform initial CNI dosing, and only 5 (6.5%) reported using CYP genotyping to inform early dosing.

Clinicians reported significant concern regarding out-of-range CNI levels during the first 14 post-transplant days (Figure 1D), particularly regarding AKI risk: 58 (75.3%) were “concerned” or “very concerned.” This contrasted with only 30 (39.0%) respondents who expressed similar levels of concern about acute cellular rejection (ACR) risk, though an additional 24 (31.2%) stated that they were “somewhat concerned.” Over 95% indicated that they would consider delayed initiation or reduced post-operative CNI trough level target as part of a kidney-sparing regimen in at-risk patients, while 36 (46.8%) stated that they would consider less aggressive targeting of post-operative negative fluid balance. Four (5.2%) respondents described early use of belatacept as a CNI-sparing intervention in select patients.

This survey has limitations. We cannot estimate survey response rate since we posted it to a broadly accessed message board. Respondent anonymity prevents definitively assessing clustered responses from multiple practitioners at a single center, though this would likely bias away from our findings of practice variability. Further, there were >55 unique sets of responses when considering reported induction and CNI practices as well as country, suggesting that we captured data from a substantial number of centers. Finally, the survey was designed to assess typical early CNI dosing practices. A more extensive survey and larger sampling would be needed to robustly assess how patient-level factors such as age, induction therapy, and interacting medications alter these practices.

Despite these limitations, our findings shed significant light on variable CNI dosing strategies and target levels in the early post-lung transplant time period. Clinical concern is high for the impact of early CNI levels on AKI, a common early transplant complication associated with increased mortality.⁵ Concern is somewhat less for the association of low early CNI levels with ACR and other medium- and long-term allograft dysfunction syndromes, perhaps due both to a less certain causal link and the relative amenability of ACR to treatment. Further study is warranted to fully elucidate acute and long-term risks to both allograft and kidneys associated with early CNI levels, establish an optimal post-operative target range to minimize these risks, and potentially individualize early dosing based on recipient-specific risk profiles and CNI pharmacokinetics.

Abbreviations:

CNI

calcineurin inhibitor

ISHLT

International Society for Heart & Lung Transplantation

CYP

cytochrome P450

AKI

acute kidney injury

Data availability statement:

The data that support the findings of this study are available from the corresponding author upon reasonable request.