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Volume: 15 Issue: 1 February 2017 - Supplement - 1


Sirolimus-Induced Combined Posterior Reversible Encephalopathy Syndrome and Lymphocytic Pneumonitis in a Renal Transplant Recipient: Case Report and Review of the Literature

The mammalian target of rapamycin inhibitor siro­limus was introduced into clinical transplant practice in 1999. Dose-related myelosuppression and hyper­lipidemia are the most common adverse effects. Pulmonary toxicity has been reported since 2004 and can cause interstitial pneumonitis, organizing pneu­monia, and alveolar hemorrhage. Moreover, it can occasionally induce posterior reversible encep­halopathy syndrome, as documented in scarce reports. To our knowledge; this is the 1st report of combined posterior reversible encephalopathy syndrome and lymphocytic pneu­monitis to be induced by sirolimus. Here, we present a renal transplant recipient with reversible sirolimus-induced brain lesions who was diagnosed after exclusion of infections (viral, bacterial, and fungal), tumors, sarcoidosis, and autoimmune disorders. Both brain lesions and pneumonitis resolved completely after sirolimus discontinuation with excellent patient and graft outcome. Early and gradual sirolimus withdrawal can reverse posterior reversible encephalopathy syn­drome and lymphocytic pneumonitis with preservation of stable graft function.

Key words : Mammalian target of rapamycin, Neuro-pulmonary, Outcome


The mammalian target of rapamycin inhibitor (mTORi) sirolimus was introduced into clinical transplant practice in 1999.1 Sirolimus is often used to achieve adequate immunosuppression while de­creasing the dose and possible toxicity of primary agents, such as calcineurin inhibitors.2,3 Dose-related myelosuppression and hyperlipidemia are the most common adverse effects.1 Pulmonary toxicity has been reported since 2004 and can cause interstitial pneumonitis, organizing pneumonia, and alveolar hemorrhage.4 To date, there have been only a few case reports of granulomatous interstitial pneu­monitis associated with sirolimus.

With increased world-wide exposure to this drug, there have been sporadic reports of lung syndromes associated with its use, most typically pneumonitis or bronchiolitis obliterans organizing pneumonia. One case series highlighted these complications from one transplant center.3 In this series, risk factors for these complications were thought to be high drug levels and late exposure to sirolimus (eg, “switch” patients).

Sirolimus has reduced the risks for overall and nonmelanoma skin cancer by 40% and 56%. However, this benefit has been confined to patients switching to sirolimus from other treatments. The most striking finding was an increased risk of death (driven by increased cardiovascular deaths and deaths related to infection) among patients taking sirolimus in both de novo and conversion studies. This is a new finding, and one that puts the future of sirolimus, and other mTORi agents, at the center of a difficult trade-off between risks and benefits in the setting of kidney transplant.5

The mechanism of sirolimus-induced interstitial pneumonitis is still unclear. A cell-mediated auto­immune response may have a role when cryptic pulmonary antigens are exposed, and this causes lymphocytic alveolitis and interstitial pneumonitis. T-cell mediated, delayed-type hypersensitivity may be another pathogenic mechanism.6

Although posterior reversible encephalopathy syndrome (PRES) has been commonly associated with calcineurin inhibitors, only a few reports of PRES associated with mTORi administration have been published.7-11 As such, no combined brain and pulmonary lesions have been reported. To our knowledge, this is the 1st report concerning combined PRES and pneumonitis in a renal transplant recipient.

Case Report

Our patient, a 21-year-old Kuwaiti female with end-stage kidney disease secondary to possible hyper­tensive nephrosclerosis, started hemodialysis in June 2011 via right internal jugular vein permcath. Her blood pressure was controlled by 2 drugs. She also had secondary hyperparathyroidism with negative thrombophilia screen and anti-cytomegalovirus antibodies. In November 2011, she underwent renal transplant from a deceased donor. She developed delayed graft function possibly due to vasculopathy of intrarenal graft arteries that resulted in upper and lower polar infarcts. Intraoperative protocol graft biopsy showed ischemic necrosis. She received thymoglobulin as induction, and she was maintained on steroids, tacrolimus, and mycophenolate mofetil.

A 2nd graft biopsy 2 weeks later revealed thrombotic microangiopathy with negative C4d. In view of the slow recovery of graft function and the result of an additional graft biopsy (after another 2 weeks, which showed severe acute and chronic thrombotic microangiopathy), as well as bipolar renal infarcts, our team decided on nephron-sparing maintenance immunosuppression by avoiding calcineurin inhi­bitors. Therefore, her maintenance immunosup­pression was tailored by changing from tacrolimus to sirolimus, with a goal trough level of 3 to 6 ng/mL. Her recovery improved, and the patient demonstrated a mildly impaired graft function with fluctuating creatinine of around 200 μmol/L.

In 2014, the patient’s hypovitaminosis D was successfully treated by 6 intramuscular injections of vitamin D. In March 2015, she complained of vomiting, headache, and diplopia, and papilledema was confirmed. Magnetic resonance imaging of the brain showed multiple heterogeneous isointense mass lesions involving the left thalamus, genu and body of corpus callosum, right caudated nucleus, right insular gyrus, right temporal lobe, and right occipital lobe (Figure 1). These lesions showed peripheral hyperintensity on T1-weighted images and restriction on diffusion-weighted image. The lesions were associated with vasogenic edema compromising the right lateral and third ventricles, with midline shift to left by 3 mm. The neurologist kept her on dexamethasone and phenytoin for several weeks, and the neurosurgeon advised to proceed to brain biopsy as the lesions were accessible.

The patient had nonsignificant posterior cervical lymphadenopathy, but she was afebrile. Chest and abdomen were evaluated by contrasted computed tomography, and we found 2 pulmonary nodules: the 1st was on the right upper lung lobe (subpleural) and the 2nd was on the left upper lobe. In view of a risky brain biopsy procedure (which was refused by the patient), we decided to proceed with an endoscopic lung biopsy. Biopsy results revealed fibrinous and organizing pneumonia with lymphocytic interstitial pneumonia (Figure 2). The pathologist recommended testing for viral infections, which were all negative (Cytomegalovirus, Epstein-Barr virus, human im­munodeficiency virus, herpes simplex virus, and hepatitis B virus) and to conduct fungal serology (concerning aspergillosis and toxoplasmosis).

Meanwhile, we minimized her immunosup­pressive medications by holding mycophenolate mofetil (for 2 mo) and gradually tapering rapamycin until complete discontinuation over 2 weeks. Within 2 months, she had clinically improved concerning her appetite, headache, diplopia, and papilledema. We started gradual tapering of dexamethasone and phenytoin with reintroduction of prednisolone and increasing doses of mycophenolate mofetil until full dosage was reached. Repeated follow-up magnetic resonance imaging and computed tomography brain scans (Figures 1 and 3) showed marked impro­vement, with nearly complete disappearance of her brain legions. At last follow-up, the patient is showing more stable graft function with creatinine level of around 170 μmol/L and without any neurologic or pulmonary symptoms or lesions on imaging studies.


Care of solid-organ recipients is complex because of the early posttransplant increased risk of infections, late onset of cardiovascular complications, and possible malignancy, as well as drug interactions and toxicities. The risk of infections (bacterial, mycobacterial, fungal, and viral) is increased as a result of the immunosuppressive medications. These medications can also add to cardiovascular risk and are the major source of drug interactions, allergies, and toxicities. Interstitial shadowing on radiologic assessment has frequently considered a differential diagnosis of infection (eg, Cytomegalovirus and pneumocystis pneumonia)12 and even rare drug-induced syndromes.

There are many case reports of sirolimus-induced interstitial lung disease (early and late), with the largest number written by Morelon and associates from Paris,6 which confirmed diagnosis by bron­choalveolar lavage. In these cases, bronchoalveolar lavage showed an excess of CD4-positive cells. Biopsies in other cases were confirmed by bronchiolitis obliterans organizing pneumonia. The study also excluded other causes of infections (including Cytomegalovirus, pneumocystis pneumonia, and fungal and mycobacterial infections) using appropriate tests before sirolimus was considered as the offending agent.

In our patient, chest symptoms were very mild and of insidious onset. This was similarly reported in one case by Haydar and associates.13 Because the main symptoms in our patient were neurologic, we started the investigations with brain magnetic resonance imaging scans, which revealed multiple space-occupying lesions (Figure 1). The provisional diagnosis was brain malignancy (primary or secondary) followed by fungal or viral infections. Malignancy was excluded by absence of significant lymph node enlargement, negative blast cells in complete blood counts, normal lymphocytic count, negative Epstein-Barr virus, and lactate dehydro­genase test. Fungal infection was excluded by negative fungal serology and absence of consti­tutional manifestations.

The possibility of tuberous sclerosis was remote because of absence of other organ lesions (skin, kidney, and heart). In our patient, the isolated lung and brain lesions resolved after discontinuation of sirolimus, which is contrary to that reported by Miller and associates, who showed marked improvement rather than deterioration with mTORi administration.14

Sarcoidosis could be considered as an important differential diagnosis in this case, especially in the absence of infections, presence of lymph nodes, and multisystem effects.15 However, a lack of bilateral lymph nodes in the lungs, absence of granuloma, and normal angiotensin-converting enzyme level and disease development in the presence of maintenance immunosuppressive drugs can exclude this im­portant diagnosis.

Other drugs used in transplant procedures have been linked with pulmonary disease, including azathioprine, cyclosporin, lipid-lowering agents, amiodarone, and beta blockers.16 Our patient was off of these drugs. Therefore, findings in our patient were consistent with PRES.

During care of our patient, we felt that it was unethical to expose our patient to a risky procedure like brain biopsy as we determined that we may be able to diagnose her condition through endoscopic lung biopsy, a less risky but still invasive procedure. Lung biopsy revealed fibrinous and organizing pneumonia with lymphocytic interstitial pneumonia. A diagnosis was confirmed to be due to rapamycin, after exclusion of infections and diseases as discussed, and because of its complete resolution (together with all brain lesions) after sirolimus withdrawal. However, the speed of symptom resolution after discontinuation of sirolimus, especially but not entirely with steroid therapy, debates against other causes.

The presentation of our patient was mild and insidious, which was different from symptoms detailed in the few previous reports in the literature. Our patient had sirolimus levels monitored consistently and carefully (Figure 4). In contrast, one report had no monitoring of sirolimus13 or monitoring was only mentioned in general terms.6 In our patient, the median sirolimus levels fell within the range recommended by the current European summary of product characteristics.

In contrast to previous reports, the blood sirolimus levels in our patient were not high (Figure 4), the presentation was clinically diverse, and there were rapid improvements in clinical and radiologic findings after sirolimus withdrawal. The postulated mechanism could be either a cell-mediated autoimmune response, which causes lymphocytic infiltration of the brain tissue, or a T-cell-mediated, delayed-type hypersensitivity reaction.

Concerning the possibility of PRES, our patient was not hypertensive during the entire period of care, which matches reports showing that only a minority of patients (30%) are not hypertensive.17-19 Our clinical scenario and favorable outcome as­sociated with discontinuation of sirolimus supported the diagnosis.


Early and gradual sirolimus withdrawal can reverse PRES and lymphocytic pneumonitis with pre­servation of stable graft function.


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Volume : 15
Issue : 1
Pages : 170 - 174
DOI : 10.6002/ect.mesot2016.P36

PDF VIEW [302] KB.

From the 1Urology and Nephrology Center, Mansoura University, Mansoura, Egypt; the 2Hamed Al-Essa Organ Transplant Center, Sabah Area, Kuwait; and the 3Pathology Department, Sabah Hospital, Sabah Area, Kuwait
Acknowledgements: The authors declare that they have no sources of funding for this study, and they have no conflicts of interest to declare.
Corresponding author: Osama Gheith, Hamed Al-Essa Organ Transplant Center, Sabah area, Kuwait
Phone: +965 6664 1967