Prolonged Administration of Twice-Daily Bolus Intravenous Tacrolimus in the Early Phase After Lung Transplantation

Abstract

Background

Although administration of tacrolimus, whether by the enteric, sublingual, or continuous intravenous routes, has some limitations, twice-daily bolus intravenous tacrolimus administration has been shown to be beneficial in optimizing efficacy and safety after lung transplantation. However, at present, the duration of bolus intravenous tacrolimus administration is limited, and the effects of prolonged bolus intravenous tacrolimus administration remain unknown. Our study was aimed at assessing the safety and efficacy of prolonged twice-daily bolus intravenous tacrolimus administration in the early phase after lung transplantation.

Material/Methods

We retrospectively investigated the data of 62 recipients of lung transplantation who had received twice-daily bolus intravenous administration of tacrolimus, followed by oral tacrolimus, after lung transplantation at our institution between January 2011 and October 2015.

Results

The median duration of bolus intravenous tacrolimus administration was 19 days (4–72 days). The target trough level was achieved in 89% of the patients by day 3. Acute kidney injury occurred in 27% of the patients during bolus intravenous tacrolimus. Two patients (3%) had neurotoxicity, necessitating discontinuation of tacrolimus. Suspected acute rejection requiring steroid pulse therapy occurred in 21% of patients during the follow-up period. Eight patients (13%) developed chronic lung allograft dysfunction during the follow-up period. The 1-year and 5-year survival rates after lung transplantation were 95% and 76%, respectively.

Conclusions

These results suggest that prolonged bolus intravenous tacrolimus administration in the early phase after lung transplantation is a safe and effective alternative to enteric, sublingual, or continuous intravenous administration.

Background

Tacrolimus has been used as a primary immunosuppressive agent after lung transplantation (LTx) as well as other types of solid organ transplantation, because among the calcineurin inhibitors, tacrolimus has a more powerful immunosuppressive effect than cyclosporine [1]. According to the registry of the International Society for Heart and Lung Transplantation (ISHLT), tacrolimus, rather than cyclosporine, is currently used for the prophylaxis of lung allograft rejection in more than 80% of LTx recipients [2]. Moreover, early establishment of therapeutic blood levels of tacrolimus is important to prevent acute rejection and chronic lung allograft dysfunction (CLAD) after LTx [3].

To establish the desired therapeutic levels of tacrolimus early after LTx, the route of administration is considered as a key factor. Tacrolimus could be administered via the enteric (oral or nasogastric), sublingual or intravenous (IV) routes; however, each of these routes has its own limitations. When tacrolimus is administered by the enteric route, even including via the nasogastric route, after LTx, impairment of intestinal peristalsis or absorption prevents the establishment of therapeutic levels. Furthermore, because genetic polymorphisms have been shown to be associated with the intestinal absorption of tacrolimus, tacrolimus bioavailability after enteric administration might vary among individuals [4]. Sublingual administration has been shown to be associated with practical drug delivery issues and particularly poor absorption after LTx [3]. Although continuous IV administration for 24 hours is recommended by the manufactures after transplantation [5,6], continuous IV administration is not practical as it requires a dedicated central venous line, especially in young children.

Twice-daily bolus IV tacrolimus administration, as a means to overcome this problem, has recently been shown to be safe and beneficial after LTx [3]. In one previous study, using this method, significantly higher target levels were obtained earlier, with lower acute rejection rates and acceptable safety [3]; nevertheless, in this study, the duration of bolus IV administration was short, being limited to 5 days after LTx [3]. Prolonged bolus IV tacrolimus administration might be useful for maintaining the target drug levels in critically ill recipients with intestinal dysmotility or malabsorption after LTx. However, the effects of prolonged bolus IV tacrolimus administration, including nephrotoxicity and neurotoxicity, remain unknown. With regard to nephrotoxicity, acute kidney injury (AKI) has recently been shown to be associated with mortality after LTx [7–9]. Currently, sustaining renal function over the long term remains a major concern after LTx [10]. In this study, we report our experience of prolonged twice-daily bolus IV tacrolimus administration in the early post-LTx period at our institution.

Material and Methods

Patients

In this study, we conducted a retrospective review of patients who underwent LTx for various end-stage lung diseases at Okayama University Hospital. Between January 2011 and October 2015, 62 recipients of LTx, including 42 cases of cadaveric LTx and 20 cases of living-donor lobar LTx, received twice-daily bolus IV tacrolimus administration, followed by oral tacrolimus administration, after LTx. Of these, 13 of pediatric patients (age <18 years) and 49 of adult patients (age ≥18 years) were included. The study protocol (No. 1604-002) was approved by the institutional review board of Okayama University Hospital. The patient characteristics, trough levels and effects of tacrolimus, and the postoperative results, including the occurrence of acute rejection episodes, development of CLAD, and survival after LTx, were assessed. The lung allocation score (LAS) of each patient was retrospectively calculated using the LAS calculator on the OPTN website (https://optn.transplant.hrsa.gov/resources/allocation-calculators/las-calculator/) in November 2015, to determine the recipients’ pretransplant severity.

Donor and recipient selection, and transplantation procedures

Patients requiring cadaveric LTx were registered at the Japan Organ Transplantation Network. The LAS system has not yet been adopted in Japan, and the allocation system of organs from brain-dead donors was still based on the waiting time. For critically ill patients who cannot await cadaveric LTx, living-donor lobar LTx is considered. All patients for living-donor lobar LTx must meet the criteria for cadaveric LTx, and only blood-relatives within the third degree or a spouse are accepted as living donors at our hospital. The size-matching protocol and transplant procedures have been described previously [11].

Postoperative care

The postoperative management of the LTx recipients, including the immunosuppressive and prophylactic therapies for viral and fungal infections, has been described previously [11]. Magnesium supplementation was routinely used to prevent hypomagnesemia after the LTx. Initial broad-spectrum antibiotic coverage was rapidly tapered to culture-specific coverage or discontinued within 1 week. For prophylaxis against cytomegalovirus (CMV) infection, oral valganciclovir was administered daily for 2 months from day 21 after the LTx, followed by oral acyclovir therapy. If the recipient is negative for CMV antibodies and the donor is positive (CMV-mismatched pair), a high titer of anti-CMV globulin is routinely injected during transplantation. Further, a daily venous infusion of ganciclovir is initiated from day 1 for 3 weeks and the patient is switched to oral valganciclovir. Prophylaxis against Pneumocystis carinii consisted of trimethoprim-sulfamethoxazole given twice a week from day 21 after the LTx. Acute rejection was diagnosed only on the basis of clinical and radiographic findings, including repeated computed tomography; this is because we prefer not to use transbronchial biopsy to identify acute rejection, especially in cases with living-donor lobar LTx recipients, to avoid unexpected intragraft bleeding [11]. The acute rejection was treated by bolus IV corticosteroid administration for 3 days. CLAD was diagnosed using the ISHLT classification system [12].

Administration and measurement of tacrolimus

All LTx recipients received triple-immunosuppression therapy, consisting of tacrolimus, mycophenolate mofetil and a corticosteroid. A pre-LTx dose of 0.2–2 mg of tacrolimus and 125–750 mg of mycophenolate mofetil was routinely given orally according to the body weight 3 hours preoperatively. Basiliximab (Novartis Pharmaceuticals, Tokyo, Japan) was given to patients who were identified as being at a higher risk of developing renal dysfunction on postoperative day 1 and day 4. On postoperative day 1, a multiple-lumen catheter, the PreSep Oximetry Catheter (Edwards Lifesciences Corporation, Tokyo, Japan), was inserted in place of a Swan-Ganz catheter (Edwards Lifesciences Corporation, Tokyo, Japan), and 1 channel of the catheter was used only for the administration of IV tacrolimus. Preparation of bolus IV tacrolimus was carefully double-checked by skilled nurses to prevent fluctuation of the trough levels. IV tacrolimus twice daily as a 3-hour bolus infusion, followed by oral tacrolimus. The starting IV dose of tacrolimus was 0.05–0.7 mg twice daily according to body weight, with a 1: 3 conversion to oral tacrolimus as recommended by the manufacturer after transplantation. Tacrolimus trough concentrations in the whole blood were measured twice daily by the chemiluminescence enzyme immunoassay method using a Dimension Xpand Plus-HM (Siemens Healthcare Diagnostics Inc, Tokyo, Japan) during bolus IV tacrolimus, aiming for a target trough level between 8–13 ng/ml. The target trough level was clinically modified in the presence of renal impairment or infection. Conversion from IV to oral tacrolimus was performed in patients who were assured of adequate oral intake to minimize the fluctuation of the trough levels.

Toxicity assessment

AKI was defined as an increase of the serum creatinine by ≥0.3 mg/dl, >1.5-fold rise of the serum creatinine, or renal replacement therapy initiation ≤48 hours from the baseline during bolus IV tacrolimus administration and classified according to the Acute Kidney Injury Network (AKIN) classification into stage 1 (AKIN 1), stage 2 (AKIN 2), and stage 3 (AKIN 3) [9,13] (Table 1). Hepatotoxicity was defined as ≥3x the upper limit of normal liver enzyme levels. Posterior reversible leuko-encephalopathy syndrome (PRES) was defined as any evidence of altered sensorium with seizure activity accompanied by characteristic changes on brain magnetic resonance imaging [14,15]. Neurotoxicity was defined as PRES or persistent minor neurotoxic effects, including headache, paresthesias, mood changes, and sleep disturbances [14]. Hyperglycemia was defined as a fasting blood glucose level of more than 150 mg/dl. CMV antigenemia was defined as ≥1 CMV antigen-positive cells/50,000 leukocytes by using a monoclonal antibody (C7-HRP) against a CMV structural protein of the 65-kDa lower matrix phosphoprotein (pp65) [16] (SRL Inc., Tokyo, Japan). The results were analyzed as of January 31, 2017.

Table 1.

Patient characteristics.

	Total	Age <18 years	Age ≥18 years	p-value
Number of patients	62	13	49	–
Median age, years (range)	38 (2–64)	10 (2–15)	43 (18–64)	–
Gender, Male: Female	34: 28	8: 5	26: 23	0.76
Median body mass index	17.5 (12.2–32.2)	15.6 (12.2–18.6)	19.3 (12.4–32.2)	0.0015
Diagnoses
Interstitial pneumonia	19 (31%)	3 (23%)	16 (33%)
Pulmonary graft-versus host disease	13 (21%)	5 (38%)	8 (16%)
Pulmonary hypertension	9 (15%)	4 (31%)	5 (10%)
Bronchiectasis	5 (8%)	0	5 (10%)
Emphysema	4 (6%)	0	4 (8%)
Lymphangioleiomyomatosis	4 (6%)	0	4 (8%)
Chronic lung allograft dysfunction	3 (5%)	0	3 (6%)
Other diseases	5 (8%)	1 (8%)	4 (8%)	–
Median lung allocation score	38.2 (30.3–89.3)	42.7 (34.4–89.3)	38.1 (30.3–75.5)	0.17
Lung transplant donor
Deceased donor	42 (68%)	2 (15%)	40 (82%)
Living donor	20 (32%)	11 (85%)	9 (18%)	<0.0001
Lung transplant procedure
Bilateral	44 (71%)	7 (54%)	37 (76%)
Single	18 (29%)	6 (46%)	12 (24%)	0.17
Cardiopulmonary bypass	52 (84%)	11 (85%)	41 (84%)	1.00
Meidan total ischemic time (min)	462 (74–787)	144 (97–551)	517 (74–787)	0.0002
Cytomegalovirus donor/recipient serostatus
Donor (+)/Recipient (+)	48 (77%)	7 (54%)	41 (84%)
Donor (+)/Recipient (−)	6 (10%)	3 (23%)	3 (6%)
Donor (−)/Recipient (+)	4 (6.5%)	1 (8%)	3 (6%)
Donor (−)/Recipient (−)	4 (6.5%)	2 (15%)	2 (4%)	–
Basiliximab usage	32 (52%)	11 (85%)	21 (43%)	0.011

Statistical analysis

All statistical analyses were performed using GraphPad Prism5 software (San Diego, CA, USA). Tacrolimus trough levels and suspected acute rejection episodes are expressed as means ± standard deviations. Suspected acute rejection episodes were evaluated using Student’s t test. Bivariate comparison of other continuous variables was performed with the Mann-Whitney U Test. Associations between categorical variables were tested by Fisher’s exact test. The postoperative survival rate was analyzed using the Kaplan-Meier method.

Results

The patient characteristics are shown in Table 1. Their ages ranged from 2 to 64 years with a mean age of 38 years at the time of the LTx. The male to female ratio was 1: 0.8. The median body mass index of the recipients was 17.5 (12.2–32.2). The underlying diagnoses for LTx included interstitial pneumonia (n=19, 31%), pulmonary graft-versus-host disease after hematopoietic stem cell transplantation (n=13, 21%), pulmonary hypertension (n=9, 14%), bronchiectasis (n=5, 8.1%), emphysema (n=4, 6.5%), lymphangioleiomyomatosis (n=4, 6.5%), chronic lung allograft dysfunction after LTx (n=3, 4.8%), and other diseases (n=5, 8.1%). The median LAS was 38.2 (30.3–89.3). Forty-two patients (68%) underwent cadaveric LTx, while the remaining 20 patients (32%) underwent living-donor lobar LTx. In pediatric patients, living-donor lobar LTx was predominantly performed because pediatric donation was extremely limited in Japan. As a result, median total ischemic time was significantly shorter in pediatric patients (p=0.0002). Bilateral LTx was performed in 44 patients (71%), and single LTx was performed in 18 patients (29%). Basiliximab was used in 32 patients (52%) and 85% of pediatric patients received basiliximab therapy.

The median duration of bolus IV tacrolimus was 19 days (4–72 days) after the LTx. More than 60% of the patients received bolus IV tacrolimus within 3 weeks after the LTx, including 9 patients (15%) within 1 week, 14 patients (22%) within 2 weeks, and 16 patients (26%) within 3 weeks after the LTx (Figure 1). On the other hand, 14 patients (22%) received bolus IV tacrolimus more than 4 weeks. The mean trough level of tacrolimus was established early after LTx, and stabilized within 28 days after the LTx (Figure 2). The target trough level was achieved in 50% of the patients by day 1 and 89% by day 3 (Figure 3), and all 62 patients achieved the target trough level by day 9. During the observation period, suspected acute rejection requiring 3 days of bolus IV corticosteroid administration was noted in 13 patients (21%), including 4 patients (6.5%) within the 1^st week, 6 patients (9.7%) within the 2^nd week, 1 patient (1.6%) within the 3^rd week, and 2 patients (3.2%) more than 4 weeks after the LTx (Figure 4). The mean number of suspected acute rejection episodes requiring bolus IV corticosteroid administration was 0.31±0.75 per patient during the follow-up period. There was no significant difference in suspected acute rejection episodes between the patients with basiliximab therapy and those without basiliximab therapy (0.38±0.54 vs. 0.23±0.92, p=0.47). In addition, suspected acute rejection episodes of the patients with living-donor lobar LTx were similar to those with cadaveric LTx (0.55±1.16 vs. 0.19±0.39, p=0.08).

Figure 1.

Duration of bolus intravenous tacrolimus administration after lung transplantation. The median duration of bolus intravenous tacrolimus administration was 19 days (4–72 days).

Figure 2.

Mean trough level of tacrolimus after lung transplantation. The mean trough level of tacrolimus stabilized within 28 days after the transplantation. The trough levels were expressed as means ± standard deviations.

Figure 3.

Achievement of the target trough level. The target trough level was achieved in 50% of the patients by day 1 and 89% of patients by day 3.

Figure 4.

Suspected acute rejection requiring bolus intravenous corticosteroid administration during the observation period. Suspected acute rejection occurred in 13 patients (21%) after lung transplantation.

The clinical outcomes of the patients are shown in Table 2. The time-since-transplant ranged from 529 to 2221 days, with a mean time of 1196 days. No patient died during the bolus IV tacrolimus administration method or within 90 days after the LTx. AKI occurred in only 18 patients (29%) during the bolus IV tacrolimus administration period, including AKIN 1 in 13 patients (21%) and AKIN 2–3 in 5 patients (8.1%) (Figure 5). Of these, only one patient required continuous hemodiafiltration in the short-term during the bolus IV tacrolimus administration period. AKI developed in 12 of 32 patients with additional basiliximab therapy and 6 of 30 patients with tacrolimus only. There was no significant difference in the incidence of AKI between the patients with basiliximab therapy and those without basiliximab therapy (p=0.17). Hepatotoxicity was observed in 10 patients (16%) the during bolus IV tacrolimus administration period, which resolved with discontinuation or switch to other medications, but not bolus IV tacrolimus. Persistent minor neurotoxicity developed in 2 patients (3.2%), without evidence of PRES on head magnetic resonance imaging during bolus IV tacrolimus administration, requiring a switch of the calcineurin inhibitor from tacrolimus to cyclosporine. Hyperglycemia developed in 4 patients (6.5%) who had received preoperative treatment with corticosteroids for underlying diseases, necessitating temporary insulin therapy. None of the patients developed anaphylactic reactions immediately after bolus IV tacrolimus administration. CMV antigenemia occurred in 8 patients (13%), who recovered with ganciclovir therapy, and none of the patients developed symptomatic CMV disease. In the patients with CMV antigenemia, 5 of 8 patients had received basiliximab therapy and 2 patients had received steroid pulse therapy for acute rejection. None of the patients developed any fatal infections. Eight patients (13%) developed chronic lung allograft dysfunction (CLAD) during the follow-up period after the LTx. CLAD occurred in 1 of 8 patients with living-donor lobar LTx and 7 of 42 patients with cadaveric LTx, and the incidence of CLAD was similar in the patients with living-donor lobar LTx and cadaveric LTx (p=0.42). The 1-year and 5-year survival rates after LTx were 95% and 76%, respectively (Figure 6).

Table 2.

Clinical outcomes.

	Total	Age <18 years	Age ≥18 years	p-value
Time since transplant to follow-up (median days)	529–2221 (1196)	545–1968 (1212)	529–2221 (1107)	0.99
Deaths <90 days	0	0	0	–
Primary graft dysfunction grade 2 or 3 at 48 and 72 hours after transplant	20 (32%)	4 (31%)	16 (33%)	1.00
Toxicity noted with bolus intravenous tacrolimus
Acute kidney injury	18 (29%)	5 (38%)	13 (27%)	0.50
Dialysis	1 (1.6%)	0	1 (2%)	1.00
Hepatotoxicity	10 (16%)	3 (23%)	7 (14%)	0.42
Neurotoxicity	2 (3.2%)	0	2 (4%)	1.00
Posterior reversible leuko-encephalopathy syndrome	0	0	0	–
Hyperglycemia	4 (6.5%)	0	4 (8%)	0.57
Anaphylactic reaction	0	0	0	–
Cytomegarovirus antigenemia	8 (13%)	2 (15%)	6 (12%)	0.67
Fatal infection	0	0	0	–
Chronic lung allograft dysfunction	8 (13%)	0	8 (16%)	0.19
Obstructive	7 (11%)	0	7 (14%)	0.33
Restrictive	1 (1.6%)	0	1 (2%)	1.00

Figure 5.

Acute kidney injury during bolus intravenous tacrolimus. Acute kidney injury developed in 18 patients (29%).

Figure 6.

Survival after lung transplantation. The 1-year and 5-year survival rates after lung transplantation were 95% and 76%, respectively.

Discussion

The efficacy of twice-daily bolus IV tacrolimus administration was recently reported, as compared to sublingual and oral administration in the early postoperative period [3]. This pioneering work encouraged us to introduce bolus IV tacrolimus administration to LTx recipients at our hospital. In contrast to a previous report on short-term bolus IV tacrolimus administration [3], we adopted bolus IV tacrolimus treatment for a prolonged period after LTx because of the stabilized trough levels and low toxicity rates. To the best of our knowledge, this is the first report of prolonged twice-daily bolus intravenous tacrolimus administration in the early phase after LTx.

The characteristics of the patients at our hospital also led us to use bolus IV tacrolimus treatment for a prolonged period after LTx. Firstly, our patients were underweight, with a median body mass index of 17.5, who are considered to have a higher risk of mortality after LTx than the normal-weight patients [17]. Secondly, regarding the diagnosis of the underlying disease in the recipients, while the number of emphysema patients was small (6.5%), 52% of the patients had diseases associated with a higher mortality risk after LTx, including interstitial pneumonia (31%) and pulmonary graft-versus-host disease (21%) [2,18,19]. Finally, the median LAS (38.8) in this study was as high as that reported from the United States [20] and Germany [21], and 20 recipients (32%), who could not await cadaveric LTx, underwent living-donor lobar LTx. In general, critically ill patients could be susceptible to intestinal dysmotility or malabsorption in the postoperative period [22]. When enteric administration of tacrolimus is adopted, the intestinal impairment could result in lower levels of tacrolimus than expected, resulting in the development of acute rejection. Additionally, when tacrolimus is enterically administered concomitantly with P-glycoprotein inhibiting or activating agents, the intestinal absorption of tacrolimus can vary due to the drug interaction, because tacrolimus is a substrate of P-glycoprotein [4]. To ensure early achievement of therapeutic levels of tacrolimus, we used bolus IV tacrolimus until the patients became capable of adequate oral intake.

Consistent with the results of a previous report [3], bolus IV tacrolimus led to early achievement of the target trough level. The target trough level was achieved by day 3 in 89% of patients, a higher percentage than that reported previously [3]. Moreover, the duration of bolus IV tacrolimus administration in this study, which was 2–3 weeks in 48% of patients, with the longest duration of 72 days, was much longer than the longest duration of 5 days in the previous study [3]. The longer duration of IV tacrolimus administration in our study was to avoid fluctuation of the tacrolimus levels and decrease the risk of acute rejection, because oral tacrolimus was initiated after the patients’ condition stabilized without any major post-transplant complications. The concept of this strategy might be supported by recent basic research [23], showing a link between innate and adaptive immune responses after LTx that emergency granulopoiesis could cause acute rejection. According to this report, because post-transplant complications associated with neutrophilic leukocytosis, such as primary graft dysfunction and infection, could cause subsequent acute rejection, we avoided conversion to oral treatment until the post-transplant complications resolved. Despite the duration of bolus IV tacrolimus administration, the trough level of tacrolimus remained stable throughout the IV administration period. Even after conversion to oral treatment, the trough level remained stable under close monitoring. In addition, there was no difficulty in adjusting the dose of the bolus IV tacrolimus for obtaining therapeutic levels of the drug. Thus, even during prolonged bolus IV tacrolimus administration, early achievement and stabilization of the target trough level is beneficial.

Bolus IV tacrolimus administration for a prolonged period seemed to provide similar results in terms of the suspected acute rejection rate (21%) reported from a previous study (15%) [3], which was low by historical standards [24–26]. The mean number of suspected acute rejection episodes (0.3) in this study was lower than that of our historical control (1.8) in the study using enteric administration of calcineurin inhibitors a decade ago [11] determined using the same diagnostic approach. While the strategies for perioperative management of LTx have improved over time, bolus IV tacrolimus administration might play an important role in preventing acute rejection. Moreover, the rate of CLAD in this study was low (13%) as compared to that in the ISHLT report [2], although the follow-up period was still intermediate. Because acute rejection is one of the risk factors for CLAD [24,25,27], including primary graft dysfunction [28], gastroesophageal reflux disease [29] and CMV infection [30], lower rates of acute rejection could be advantageous for preventing the development of CLAD. Furthermore, the lower rates of CLAD contributed to better survival rates after LTx in this study, as compared with that in the ISHLT report [2]. Because AKI has recently been shown to have an impact on the survival after LTx, the lower rates of AKI in this study could also contribute to better survival after LTx. Taken together, our results suggest that prolonged bolus IV tacrolimus administration could be a useful option to prevent acute rejection and CLAD after LTx.

A major concern in regard to prolonged bolus IV tacrolimus administration was the toxicity of the drug, including nephrotoxicity and neurotoxicity. In this study, the incidence of AKI (29%) during bolus IV tacrolimus was lower than that in a previous report (65%) [9]. Our results indicate that prolonged bolus IV tacrolimus administration did not increase the risk of nephrotoxicity under meticulous management of the trough levels. The additional use of basiliximab in 52% of our patients could have contribute to decreasing the risk of nephrotoxicity. In this study, basiliximab was used for patients who were identified as being at a higher risk of developing renal dysfunction. Because LAS of pediatric patients tended to be higher than that of adult patients, pediatric patients received basiliximab therapy more frequently. As a result, the incidence of AKI in pediatric patients was comparable to that in adult patients despite the severe condition. Moreover, the incidence of AKI was not significantly different between patients with additional basiliximab therapy and those with tacrolimus only. A low incidence of neurotoxicity without evidence of PRES (3.2%) was also acceptable in the patients receiving prolonged bolus IV tacrolimus administration. Hepatotoxicity, seen in 10 patients (16%), resolved without the discontinuation of the bolus IV tacrolimus injections and was not a major problem. Hyperglycemia (6.5%) during bolus IV tacrolimus administration seemed to be associated with the pretransplant use of corticosteroids. CMV antigenemia (13%) might be affected by not only the bolus IV tacrolimus administration, but also by basiliximab therapy and steroid pulse therapy. The prevalence of these side effects was acceptable and similar to those reported previously [3,15]. Furthermore, the excellent survival rates of 90 days (100%) and 1 year (95%) lend support to the low risk of toxicity associated with prolonged bolus IV tacrolimus administration in the early phase after LTx. We speculated that bolus IV administration could reduce dose requirement of tacrolimus for achieving of therapeutic levels as compared to enteral and sublingual administration, leading to minimization of the risk of adverse effects. Also, normal post-dose peak and pre-dose trough in bolus IV administration may contribute to enhanced efficacy and decreased toxicity, compared with continuous IV administration [3].

Our study had several limitations. This study was a retrospective observational study conducted at a single transplant center. The number of recipients was small, because the number of donations from brain-dead donors is still limited in Japan. Basiliximab was used in 52% of patients in an effort to reduce the risk of critically ill patients after LTx. Acute rejection was diagnosed based on clinical and radiographic findings, without transbronchial biopsy, to minimize the risk of unexpected bleeding, especially in cases with living-donor lobar LTx at our hospital. Preparation of bolus IV tacrolimus necessitates careful handling and supervision of skilled nurses to prevent fluctuation of the trough levels. From the point of view of medical economics, IV tacrolimus is more expensive than oral tacrolimus. The follow-up period was still intermediate, and longer-term follow-up is required for further evaluation of CLAD.

Conclusions

Prolonged bolus IV tacrolimus administration appears to be safe and effective in the early phase after LTx. Bolus IV tacrolimus administration for a prolonged period after LTx might be a better option, especially in critically ill recipients or recipients suffering from life-threatening post-transplant complications, even in recipients with intestinal dysmotility.