NDT Advance Access published online on July 25, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn401
© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org
Severe everolimus-associated pneumonitis in a renal transplant recipient
Simona Alexandru1,
Alberto Ortiz1,
Sonia Baldovi1,
Jose Maria Milicua2,
Elena Ruíz-Escribano2,
Jesús Egido1 and
Juan José Plaza1
1 Nephrology Unit
2 Intensive Care Unit, Fundación Jiménez Díaz-Capio, Universidad Autónoma, Madrid, Spain
Correspondence and offprint requests to:
Simona Alexandru, Nephrology Unit, Fundación Jiménez Díaz-Capio, Av Reyes Catolicos 2, 28040 Madrid, Spain. Tel: +34-9155-04940; Fax: +34-9155-42636; E-mail: salexandru{at}fjd.es, simona_amely{at}yahoo.com
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Abstract
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Inhibitors of mTOR (mammalian target of rapamycin) are immunosuppressants
with less nephrotoxic potential than calcineurin inhibitors
and antiproliferative effects, which are advantageous in the
case of malignancy. However, a series of adverse events has
been reported with the first-generation mTOR inhibitor sirolimus
that includes hypersensitivity-like interstitial pneumonitis.
To our knowledge, only one case of a pneumonitis associated
with everolimus in a heart transplant patient has been reported,
and it was related to elevated trough blood levels. We report
herein the first case of a kidney graft recipient who developed
everolimus-associated pneumonitis with normal trough blood levels
that was completely reversed after drug withdrawal.
Keywords: everolimus; pneumonitis; sirolimus; transplantation
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Introduction
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The novel mTOR (mammalian target of rapamycin) inhibitor everolimus
(Certican Novartis Pharma AG, Basel, Switzerland) represents
the latest generation of proliferation signal inhibitors. It
is used as an immunosuppressant in solid organ transplants combined
with low-dose cyclosporine. There are also positive experiences
using everolimus without calcineurin inhibitors in order to
avoid its well-known nephrotoxic effect or for its antiproliferative
effect in patients with tumours. Inhibitors of mTOR, sirolimus
and everolimus, share a similar side-effect profile, with one
notable exception. Hypersensitivity-like interstitial pneumonitis
is mostly related to sirolimus. Many reports have documented
this side effect in renal, liver and heart transplant recipients
[
1–8]. Furthermore, resolution of sirolimus-induced pneumonitis
following conversion to everolimus has been reported [
9]. This
raises doubts about the potential of everolimus to induce pulmonary
toxicity. To our knowledge, only one case of pneumonitis associated
with everolimus has been reported in a heart transplant recipient,
which was ascribed to supratherapeutic concentrations of the
drug [
5]. We report a case of everolimus-induced pneumonitis
in a renal transplant recipient with normal trough blood levels.
Pneumonitis was completely reversed after drug withdrawal.
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Case
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A 57-year-old man received a second renal transplant in 1999
for end-stage renal disease secondary to type I membranoproliferative
glomerulonephritis. Immunosuppressive treatment consisted of
cyclosporine and mycophenolate mophetil until March 2006, when
he was switched to everolimus and mycophenolate mophetil, in
order to prevent long-term anticalcineurin nephrotoxicity. No
renal biopsy was performed before the conversion. Renal function
had been stable (creatinine clearance 50 ml/min and serum creatinine
2.1 mg/dl) and proteinuria absent, and no changes were observed
following the switch. In June 2006, he was admitted for cough,
progressive dyspnoea and fever. Laboratory findings showed leucocytes
3440/µl (77% neutrophils), haemoglobin 9.7 g/dl, platelets
228 000/µl, serum creatinine 2.24 mg/dl, serum sodium
143 mEq/l, serum potassium 5.22 mEq/l and everolimus blood levels
6.5 ng/ml (therapeutic range 3–8 ng/ml). Chest X-ray and
pulmonary CT scan showed bilateral pulmonary infiltrates, mostly
in the left lung and inferior lobes (Figure
1). Urinary
Streptococcus pneumoniae and
Legionella pneumophila antigens; cultures of
blood, urine and sputum; tests for cytomegalovirus antigen,
anti-
Chlamydia pneumoniae IgG and
Aspergillus galactomannan were negative. Empiric treatment with broad-spectrum antibiotics,
antifungal and antiviral drugs did not improve the lung condition.
A bronchoalveolar lavage (BAL) disclosed lymphocytic infiltrates.
Eosinophils were not observed, ruling out hypersensitivity pneumonitis.
BAL cultures for bacteria, fungi, virus and
Mycobacterium tuberculosis were negative. The lung biopsy showed lymphocytic infiltrates,
where CD8 cells predominated over CD4 lymphocytes. Severe respiratory
failure required admission to the intensive care unit and mechanical
ventilation. Pharmacological pneumonitis was suspected and everolimus
was stopped. A spectacular clinical improvement was obtained
after drug withdrawal and steroid treatment with prednisone
20 mg twice a day, tapering the dose after 2 weeks. The patient
was discharged 10 days later, with an immunosuppressive regime
consisting of cyclosporine and mycophenolate mophetil. The resolution
of pulmonary infiltrates was documented 8 months later. Renal
function remained stable.
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Discussion
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Interstitial pneumonitis associated with sirolimus was first
reported in 2000 by Mahalati [
11] and Morelon [
12]. A series
of eight renal transplant recipients who developed pneumonitis
while on sirolimus therapy was published in 2001 [
1]. This new
entity was characterized by general symptoms, bilateral interstitial
pulmonary infiltrates, lymphocytic alveolitis, in the absence
of any infectious or alternative pulmonary disease and resolution
in all cases within 3 months after drug withdrawal or dose reduction.
Dose-dependent toxicity and immune-mediated toxicity were suggested
as causative mechanisms. In that series trough sirolimus blood
levels ranged between 15 and 30 ng/ml, considered therapeutic
at that time. Additional series of sirolimus pneumonitis in
renal transplant recipients were published in subsequent years
[
2–4]. The three cases reported by Haydar
et al. had therapeutic
sirolimus trough blood levels (11.2, 9.7 and 8.3 ng/ml, respectively),
and all of them rapidly improved after drug discontinuation
[
2]. More recently, it has been suggested that pneumonitis related
to sirolimus could be dose-independent, appearing in patients
with trough blood levels ranging from 6.2 to 38.7 ng/ml [
4].
Sirolimus-related pneumonitis has also been reported in patients
with heart or liver transplants [
5–8]. In a large series
of 186 liver recipients 2.2% developed pneumonitis, with blood
levels ranging from 7 to 19.5 ng/ml [
7]. Thus, whether there
is any dose-related effect is still controversial.
Although the clinical experience with everolimus is limited, everolimus-associated pneumonitis appears to be extremely infrequent. Moreover, several cases of pneumonitis associated with sirolimus resolved after switching to everolimus [9]. To our knowledge, only one case of pneumonitis associated with everolimus was reported in a heart transplant recipient, which completely resolved after drug withdrawal [5]. Blood levels were 22.6 ng/ml (therapeutic range 8–10 ng/ml). A mild case of localized bronchiolitis obliterans organizing pneumonia resolved with a transient increase in an oral prednisone dose without everolimus discontinuation [10]. The present case report suggests that everolimus can also induce pneumonitis at therapeutic blood levels after switching from calcineurin inhibitors, and is consistent with a class-related side effect of mTOR inhibitors.
Conflict of interest statement. None declared.
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References
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- Morelon E, Stern M, Israel-Biet D, et al. Characteristics of sirolimus-associated interstitial pneumonitis in renal transplant patients. Transplantation (2001) 5:787–790.
- Haydar A, Denton M, West A, et al. Sirolimus-induced pneumonitis: three cases and a review of the literature. Am J Transplant (2004) 4:137–139.[CrossRef][Web of Science][Medline]
- Champion L, Stern M, Israel-Biet D, et al. Brief communication: sirolimus-associated pneumonitis: 24 cases in renal transplant recipients. Ann Intern Med (2006) 144:505–509.[Abstract/Free Full Text]
- Weiner S, Sellin L, Vonend O, et al. Pneumonitis associated with sirolimus: clinical characteristics, risk factors and outcome-a single-center experience and review of the literature. Nephrol Dial Transplant (2007) 22:3631–3637.[Abstract/Free Full Text]
- David S, Kumpers P, Shin H, et al. Everolimus-associated interstitial pneumonitis in a patient with a heart transplant. Nephrol Dial Transplant (2007) 22:3363.[Free Full Text]
- Hamour IM, Mittal TK, Bell AD, et al. Reversible sirolimus-associated pneumonitis after heart transplantation. J Heart Lung Transplant (2006) 25:241–244.[CrossRef][Web of Science][Medline]
- Roberts RJ, Wells AC, Unitt E, et al. Sirolimus-induced pneumonitis following liver transplantation. Liver Transplant (2007) 13:853–856.[CrossRef][Web of Science][Medline]
- De Simone P, Petruccelli S, Precisi A, et al. Switch to everolimus for sirolimus-induced pneumonitis in a liver transplant recipient—not all proliferation signal inhibitors are the same: a case report. Transplant Proc (2007) 39:3500–3501.[CrossRef][Web of Science][Medline]
- Rehm B, Keller F, Mayer J, et al. Resolution of sirolimus-induced pneumonitis after conversion to everolimus. Transplant Proc (2006) 38:711–713.[CrossRef][Web of Science][Medline]
- Carreño CA, Gadea M. Case report of a kidney transplant recipient converted to everolimus due to malignancy: resolution of bronchiolitis obliterans organizing pneumonia without everolimus discontinuation. Transplant Proc (2007) 39:594–595.[CrossRef][Web of Science][Medline]
- Mahalati K, Murphy DM, West ML. Bronchiolitis obliterans and organizing pneumonia in renal transplantation recipients. Transplantation (2000) 69:1531.[CrossRef][Web of Science]
- Morelon E, Stern M, Kreis H. Inrterstitial pneumonitis associated with sirolimus therapy in renal transplant recipients. N Engl J Med 3000. 343:225.
Received for publication: 17. 3.08
Accepted in revised form: 24. 6.08
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Abstract
Introduction