Introduction
acrolimus, a calcineurin inhibitor, is the
major immunosuppressive medication used in the treatment of patients after
liver transplantation. It has been used with low doses or without steroids in
children receiving liver transplants.1 Tacrolimus has a
mode of action similar to that of cyclosporine, but is 10 – 100 times as potent
and is associated with fewer rejection episodes.2,3
The major side effects of
tacrolimus in children include: anemia, renal toxicity, hyperkalemia,
gastrointestinal symptoms, allergic reactions, and post-transplant
lymphoproliferative disease.4 Compared
with cyclosporine, however, gingival hyperplasia, hirsutism, coarsening of the facial
features and hypertension solely due to tacrolimus are notably absent.4
In clinical trials, tacrolimus has been shown to be better
tolerated and associated with fewer rejection episodes, in addition to better
graft and patient survival compared with cyclosporine.1. The US Multicenter Liver Study
Group, , A comparison of tacrolimus (FK506) and cyclosporine for
immunosuppression in liver transplantation. N Engl J Med 332 (1994), pp. 1110–1115. Therefore, tacrolimus has been
increasingly used by many transplant centers as the primary immunosuppressive
agent immediately after transplantation.5 It has been reported that tacrolimus can cause cardiac
toxicity.4,6,7 The potential cardiac toxicity of tacrolimus has been
found in rabbits and baboons during animal studies.8 Cardiotoxicity
has been described in a group of pediatric patients receiving tacrolimus as a
part of immunosuppression for orthotopic liver transplantation.7
This study was performed
to evaluate cardiac toxicity in post-liver transplant patients who received
tacrolimus for more than six months.
Patients and Methods
This study approved by local institutional review
board. Patients and for children parents or legal guardians signed approved
informed consents to participate in study.
We prospectively studied
63 liver transplant recipients who underwent liver transplantation between
September 2006 and September 2007, and received tacrolimus as the main immuno-suppressive
medication.
All patients had a normal
cardiac examination, normal electrocardiogram (ECG), chest X-ray and
echocardiography which were performed before transplantation by our
cardiologists. All children were visited by pediatric cardiologists.
Echocardiographic examination was performed using the GE VIVID 3
echocardiographic machines by probe 3 MHz.
Oral tacrolimus was
started one day after the operation with a dose of 0.1 – 0.15 mg/kg/day. The
whole blood trough levels of tacrolimus were monitored, with target levels of
10 – 20 ng/mL.
All patients received 20 –
25 mg/kg intravenous methyl prednisolone for three consecutive days and then a 1
mg/kg/day oral prednisolone taper during the three month post-transplant period.
All patients were visited
by the same cardiologists three and six months after liver transplantation and
underwent full cardiovascular evaluation including ECG and echocardiography.
Tacrolimus trough levels
were checked during these visits.
In addition, 50 patients
who underwent liver transplantation prior to September 2006 and received
cyclosporine as the main immunosuppressive medication were evaluated as the
control group. These patients were also evaluated by the same cardiologists and
underwent full cardiac evaluation and echocardiography.
Results
There were 63 tacrolimus
treated recipients (42, 66.7% male and 21, 33.3% female) with a mean age of
27.8±16.1 years (range, 2 – 58 years).
We studied 19 (30%)
pediatric patients (age under 18) and 44 (70%) adult patients.
The indications for liver
transplantation included: HBV cirrhosis (n=12, 19%), Wilson disease (n=12,
19%), autoimmune cirrhosis (n=11, 17.5%), cryptogenic cirrhosis (n=10, 15.9%),
primary sclerosing cholangitis (n=4, 6.3%), progressive familial intrahepatic
cholestasis (n=4, 6.3%), Caroli disease (n=2, 3.2%), tyrosinemia (n=2, 3.2%), HCV cirrhosis, primary biliary cirrhosis, Budd-Chiari syndrome, biliary
atresia, neonatal hepatitis and biliary hypoplasia, all of which had one case
(n=1, 1.6%) each.
There were 52 (81.3%)
patients who received a whole graft from deceased donors and 3 (4.7%) cases that
underwent split liver transplantation.
The remaining 8 (12.5%)
patients received a graft from living donors (their parents).
The mean tacrolimus
levels of patients at three and six months after liver transplantation were
11.2±5.8 ng/mL (range 1 – 32.1) and 7.5±4.5 ng/mL (range 2.1 – 31.5),
respectively.
Cardiac evaluation, ECG
and echocardiography three months post-surgery were normal in all cases with
the exception of two children. The first case was a two year old boy who
underwent split liver transplantation due to tyrosinemia with multiple
hypoechoic nodules in the liver. He received tacrolimus at a dose of 0.15 mg/kg/day
and prednisolone (5 mg/day). Three months after the operation, he developed a fever
and dyspnea. On physical examination, he had high blood pressure (150/80 mmHg)
and a heart murmur. ECG showed tachycardia, left axis deviation and left
ventricular hypertrophy. Echocardiography showed obstructive hypertrophic
cardiomyopathy with asymmetric hypertrophy of the interventricular septum, left
ventricular hypertrophy and aortic valve stenosis. The tacrolimus trough level
of the patient at this time was 32.1 ng/mL. He also had cervical
lymphadenopathy and a lymph node excision biopsy was performed which indicated
post-transplant lymphoproliferative disorder. Tacrolimus was discontinued and
sirolimus was started but the patient did not respond and died one month later.
The second case was a five year-old girl, a case of biliary atresia without any
signs and symptoms of a cardiac problem, but echocardiography three months
after liver transplantation showed aortic stenosis and mitral and tricuspid
regurgitation. The tacrolimus trough level of this case was 30.3 ng/mL. We
adjusted the dose of tacrolimus and her echocardiography became normal six
months after the liver transplant.
Cardiac evaluations and
echocardiography were normal in the remaining patients six months after liver
transplantation.
In the control group which
included 15 (30%) children and 35 (70%) adult patients who received
cyclosporine, cardiac evaluations and echocardiography results were all normal.
Discussion
Tacrolimus is a potent
immunosuppressive agent with a mechanism of action similar to that of
cyclosporine.9 It is 10 to 100 times more potent than cyclosporine.3
This potency has contributed to its superiority in preventing allograft
rejection and has allowed most patients to be weaned off corticosteroids.10
Tacrolimus has significant adverse effects; namely renal toxicity,
neurotoxicity, anemia, gastrointestinal symptoms and post transplant diabetes
mellitus.4,11
In 1995, Atkinson et al.12
reported the first series of five pediatric patients (two liver transplant
recipients) who developed tacrolimus associated symmetric hypertrophy of the
left ventricle or concentric hypertrophic cardiomyopathy. Later, other authors
reported a few cases of cardiac toxicity related to tacrolimus.7,9,10,12–15
A number of mechanisms have been proposed to explain the cardiotoxicity of
tacrolimus, including arteritis of cardiac arteries and extensive calcification
of cardiac tissue,14 tacrolimus mediated hypertension,7
and a reduced serum selenium level.16 However, the true underlying
mechanism of tacrolimus related cardiomyopathy is not completely understood.
It is likely that the
cardiotoxicity due to tacrolimus is related to high blood levels of this
medication, particularly at levels greater than 20 ng/mL.17
There are no prospective
control studies on a large group of liver transplant recipients with tacrolimus
cardiotoxicity with a six months follow- up.
Nakata et al.18 evaluated
32 patients who underwent living related liver transplantation for evidence of
tacrolimus associated cardiotoxicity. None of their patients developed this
complication despite some having the same blood level of tacrolimus as our
patients (12.2 ng/mL vs. 11.2 ng/mL). This may be due to the shorter duration
of follow-up in the Nakata et al.18 report in comparison to the
present study (four weeks vs. six months).
Our study showed two
cases of tacrolimus associated cardiac toxicity in pediatric patients. Therefore,
long term follow-up is needed to determine whether or not tacrolimus induces
cardiomyopathy.
Our first case is similar
to a case that was reported by Pappas et al.19 who did not respond
to sirolimus therapy.
Turska-Kmiec et al.20
reported a case of tacrolimus associated hypertrophic cardiomyopathy who was
responsive to sirolimus treatment.
The levels of tacrolimus
in both cases in our study with cardiac problems were high (32.1 and 30.3
ng/mL), in comparison to previous studies.18,19
Hypertrophic cardiomyopathy
has also been reported to arise from the administration of steroids.21
One of our cases received a low dose of prednisolone and the other did not
receive steroids. The cardiomyopathy of steroids was correlated to its
immunomodulating effects in addition to some of its side effects such as fluid
retention and hypertension. Pappas et al.19 have reported that
concurrent use of steroids and tacrolimus may accelerate the development of
hypertrophic cardiomyopathy. In our center, the adult patients received
steroids for a longer period than the pediatric patients due to potential
growth impairment, with no cases of cardiotoxicity in the adult patients
despite the fact that 70% of our cases were adults and only 30% were children.
This finding is consistent with a previous study.22 Considering
previous studies and our findings, it seems that cardiotoxicity of tacrolimus
is seen almost exclusively in pediatric patients, as four of our adult patients
had tacrolimus levels above 20 ng/mL but none of them developed cardiac problems.
The differences between the adult and pediatric population need further
investigation.
It is imperative to
develop guidelines for clinical evaluation and follow-up to monitor the
potential cardiac effects of tacrolimus, especially in children.
References
1
Tzakis AG,
Reyes J, Todo S, Nour B, Shapiro R, Jordan M, et al. Two-year experience with
FK 506 in pediatric patients. Transplant Proc. 1993; 25: 619 – 621.
2
Textor SC,
Wiesner R, Wilson DJ, Porayko M, Romero JC, Burnett JC Jr, et al. Systemic and renal hemodynamic differences between
FK506 and cyclosporine in liver transplant recipients. Transplantation.
1993; 55:
1332 – 1339.
3
The US
Multicenter FK506 liver Study Group. A comparison of tacrolimus (FK 506) and
cyclosporine for immunosuppression in liver transplantation. N Engl J Med.
1994; 331: 1110 – 1115.
4
Chang RK,
Alzona M, Alejos J, Jue K, McDiarmid SV. Marked
left ventricular hypertrophy in children on tacrolimus (FK506) after orthotopic
liver transplantation. Am J Cardiol. 1998; 81: 1277 – 1280.
5
Pham SM,
Kormos RL, Kawai A, Murali S, Hattler BG, Demetris AJ, et al. Tacrolimus
(FK506) in clinical cardiac transplantation: a five-year experience. Tranplant
Proc. 1996; 28: 1002 – 1004.
6
Chang RK,
McDiarmid SV, Alejos JC, Drant SE, Klitzner TS. Echocardiographic findings of hypertrophic cardiomyopathy in children
after orthotopic liver transplantation. Pediatr Transplant. 2001; 5: 187 – 191.
7
Roberts
CA, Stern DL, Radio SJ. Asymmetric cardiac
hypertrophy at autopsy in patients who received FK506 (tacrolimus) or
cyclosporine A after liver transplant. Transplantation. 2002; 74:
817 – 821.
8
Nomoto S,
Fujiwara H, Ban T, Ohara K. Cardiotoxicity of long-term intravenous
administration of FK506 in rabbits: dose relationship and recovery after discontinuance.
Transplant Proc. 1994: 26: 855 – 857.
9
Peters DH,
Fitton A, Plosker GL, Faulds D. Tacrolimus. A review of its pharmacology, and
therapeutic potential in hepatic and renal transplantation. Drugs. 1993;
46:
746 – 794.
10
Cox KL,
Freese DK. Tacrolimus (FK506): the pros and cons of its use as an
immunosuppressant in pediatric liver transplantation. Clin Invest Med.
1996; 19: 389 – 392.
11
Shapiro R. Tacrolimus in pediatric renal
transplantation: a review. Pediatr Transplan. 1998; 2: 270 – 276.
12
Atkison P,
Joubert G, Barron A, Grant D, Paradis K, Seidman E, et al. Hypertrophic
cardiomyopathy associated with tacrolimus in paediatric transplant patients. Lancet.
1995; 345: 894 – 896.
13
Uchida N,
Taniguchi S, Harada N, Shibuya T. Myocardial
ischemia following allogeneic bone marrow transplantation: possible implication
of tacrolimus overdose. Blood. 2000; 96:
370 – 372.
14
Atkison
PR, Joubert GI, Guiraudon C, Armstrong R, Wall W, Asfar S, et al. Arteritis and
increased intracellular calcium as a possible mechanism for tacrolimus-related
cardiac toxicity in a pediatric transplant recipient. Transplantation.
1997; 64:
773 – 775.
15
Cox KL,
Lawrence-Miyasaki LS, Garcia-Kennedy R, Lennette ET, Martinez OM, Krams SM, et
al. An increased incidence of Epstein-Barr
virus infection and lymphoproliferative disorder in young children on FK506
after liver transplantation. Transplantation. 1995; 59:
524 – 529.
16
Dhawan A,
Mack DR, Langnas AN. Immunosuppressive drugs and hypertrophic cardiomyopathy
(letter). Lancet. 1995; 345: 1644.
17
Uemoto S,
Inornata Y, Egawa H. Effects of tacrolimus on cardiac function after living
related liver transplantation in pediatric patients. Paper presented at 15th
Annual Meeting of the American Society of Transplant Physicians; May 26 – 30,
1996; Dallas, TX. May 26 – 30, 1996: 196.
18
Nakata Y,
Yoshibayashi M, Yonemura T, Uemoto S, Inomata Y, Tanaka K, et al. Tacrolimus
and myocardial hypertrophy.Transplantation. 2000; 69: 1960 – 1962.
19
Pappas PA, Weppler D, Pinna AD,
Rusconi P, Thompson JF, Jaffe JS, et al. Sirolimus in pediatric
gastrointestinal transplantation: the use of sirolimus for pediatric transplant
patients with tacrolimus-related cardiomyopathy. Pediatr Transplant.
2000; 4: 45 – 49.
20
Turska-Kmieć
A, Jankowska I, Pawłowska J, Kaliciński P, Kawalec W, Tomyn M, et al. Reversal of
tacrolimus-related hypertrophic cardiomyopathy after conversion to rapamycin in
a pediatric liver transplant recipient. Pediatr Transplant. 2007; 11:
319 – 323.
21
Brand PL,
Brus F. Immunosuppressive drugs and hypertrophic cardiomyopathy. Lancet.
1995; 345: 1644.
22 Coley KC,
Verrico MM, McNamara DM, Park SC, Cressman MD, Branch RA. Lack of
tacrolimus-induced cardiomyopathy. Ann Pharmacother. 2001; 35:
985 – 989.
AIM
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