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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2013  |  Volume : 24  |  Issue : 3  |  Page : 580-582
Fatal outcome due to sirolimus-induced acute hepatitis, myelosuppression and fever in a kidney allograft recipient

Department of Nephrology, Hedi Chaker Hospital, Sfax, Tunisia

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Date of Web Publication24-Apr-2013

How to cite this article:
Yaich S, El Aoud N, Zaghdane S, Charfeddine K, Kharrat M, Masmoudi M, Hachicha J. Fatal outcome due to sirolimus-induced acute hepatitis, myelosuppression and fever in a kidney allograft recipient. Saudi J Kidney Dis Transpl 2013;24:580-2

How to cite this URL:
Yaich S, El Aoud N, Zaghdane S, Charfeddine K, Kharrat M, Masmoudi M, Hachicha J. Fatal outcome due to sirolimus-induced acute hepatitis, myelosuppression and fever in a kidney allograft recipient. Saudi J Kidney Dis Transpl [serial online] 2013 [cited 2020 Jun 5];24:580-2. Available from: http://www.sjkdt.org/text.asp?2013/24/3/580/111072
To the Editor,

Sirolimus (SRL) is a macrolide lactone increa­singly being used in organ transplantation as an immunosuppressive drug. It is also used to avoid chronic rejection and calcineurin-related nephrotoxicity, and, recently, anti-tumor pro­perties has been reported with SRL. [1],[2] How­ever, the use of SRL has been limited by the high incidence of side-effects. The main ad­verse effects of this drug are hyperlipidemia, myelosuppression, interstitial pneumonitis, im­paired wound healing, lymphoceles and mouth ulcers. [3]

Herein, we report the case of a 33-year-old man, on peritoneal dialysis since 2008 secon­dary to an unknown nephropathy. He received kidney transplantation from a living donor (his wife, full HLA mismatch) on December 2009. Urine output was immediate and the post-ope­rative course was uneventful. He was discharged on the 14 th day with a stable renal function at 94 μmol/L on a triple immunosuppressive the­rapy of mycophenolate mofetil (MMF), cyclosporine with trough levels of 150-200 ng/mL and corticosteroids (10 mg/d). He was admitted one month later for cytomegalovirus (CMV) infection successfully treated with a 15-day ganciclovir course. On September 2010, he de­veloped cutaneous Kaposi sarcoma (KS). Check up for other location for KS involved thoracic, abdominal and pelvic CT scan, bone marrow biopsy, colonoscopy and gastroscopy, which showed a unique gastric lesion. Treatment consisted of a switch to cyclosporine/SRL with discontinuation of MMF.

One month later, he was admitted to the transplant unit with high-grade fever recorded up to 41°C. Clinical examination was essen­tially normal. Laboratory tests revealed serum creatinine 97 μmol/L, white blood count (WBC) 2700/mm 3 , hemoglobin level 12.5 g/dL, plate­let count 34,000/mm 3 , C-reactive protein 213 mg/L, cytolysis (alanine aminotransferase 85 IU/mL and aspartate aminotransferase 115 IU/mL) and cholestasis (γ glutamyl transferase 180 IU/mL, alkaline phosphatase 427 IU/mL). The blood level of SRL was 12 ng/mL. Patient serum was tested for viruses [Epstein-Barr virus (EBV); hepatitis B, C, E and A; herpes simplex virus; human herpes virus 8 (HHV8); HHV6, parvo B19; human immunodeficiency virus (HIV)], parasites and fungi (toxoplasma, leshmania, candida, aspergillus, pneumocystis) and bacteria (chlamydiae,  Brucella More Details, rickettsia, mycoplasma). Repeated pulmonary radiographs were normal. Urine analysis and fecal and re­peated blood cultures were negative. Cytomegalovirus (CMV) antigenemia pp65 was negative. Polymerase chain reaction CMV, parvo B19, hepatitis B and C were all negative as well. Sputum examinations performed for Mycobacterium tuberculosis for three conse­cutive days were negative. Antinuclear anti­bodies and antineutrophil cytoplasmic antibodies were negative. Anti-liver-kidney microsome antibody type 1 (anti-LKM1) and anti-smooth muscle and anti-mitochondria antibodies were also negative. Large broad-spectrum antibio­tics were prescribed but stopped after seven days as no clinical improvement was achieved. The cerebrospinal fluid was examined for bac­teria, tuberculosis, cryptococcus, toxoplasma and HSV, but was also negative. Thoracic, abdominal, pelvic and cerebral computerised tomogram (CT) scans were normal. Bone marrow examination (including cultures for bacteria, tuberculosis and leishmania) was nor­mal; specifically, there was no sign of hemophagocytosis. Cerebral magnetic resonance ima­ging was normal. Echocardiogram excluded infectious endocarditis. Bronchoalveolar lavage was negative for nocardia and pneumocystis. Drug fever was suspected and SRL was re­placed by tacrolimus. Fever decreased after 24 h but, unfortunately, he developed cough, re­currence of fever and crackles on lung exa­mination two days later. Laboratory tests revealed WBC 13,200/mm 3 and elevated procalcitonin. Chest X-ray revealed bilateral le­sions of the lower pulmonary field. Thoracic CT scan confirmed the presence of bilateral pneumonia. Broad-spectrum antibiotics were immediately instituted but the patient deve­loped multiorgan failure and died four days later.

SRL-related fever has already been reported. In fact, Aires et al described a renal transplant patient who developed fever one month after introduction of SRL. [2] Extensive investigations failed to reveal any focus of infection and SRL withdrawal resulted in a disappearance of fe­ver and complete resolution of inflammatory markers. [2] A similar case of SRL-induced drug fever in a liver transplant recipient has been reported by Schacherer et al. [4]

Fever has also been described as a side-effect of the novel rapamycin-derived immunosuppressant everolimus. Dorshner et al reported the case of a heart transplant recipient who re­ceived corticosteroids, cyclosporine and everolimus as immunosuppressive regimen and who suffered from intermittent fever during two years. [5] An extensive check up for infection focus was negative; therefore, everolimus was switched to azathioprine. Clinical improvement was obtained within two weeks and C-reactive protein was normalized.

Acute hepatitis is an uncommon side-effect of SRL, resulting in increasing of the trans­aminase levels. [6] Jacques et al reported a case of SRL-induced severe hepatitis in a renal transplant recipient confirmed by liver biopsy. [6] The occurrence of hepatitis rapidly after the introduction of SRL, the negative results of the extensive work up done and that of the liver biopsy and the improvement that occurred in transaminase levels after SRL discontinuation are in favor of the diagnosis of SRL-induced hepatitis. Niemczyk et al also described a case of a patient who developed elevated liver en­zymes 16 months after SRL introduction. [7] The causative relationship with SRL is less sugges­tive than that described by Jacques et al. [6] , [7] In fact, biopsy liver was not contributory; more­over, their patient had received other drugs that were likely to induce hepatotoxicity.

To the best of our knowledge, this is the first case of SRL toxicity that associates fever, acute hepatitis and myelosupression. The cau­sative relationship was considered after exten­sive check up for infection, immune-mediated diseases and malignancies. The decline of fever after discontinuation of SRL is in favor of this hypothesis. We thought that the bila­teral pneumonia that he developed later is a separate problem. This infection may be attri­buted to the profound immunosupression that our patient had as a consequence of concomi­tant myelosuppression and neutropenia. Unfor­tunately, the outcome was rapidly fatal and we did not have enough time to observe the evo­lution of temperature curve, blood cell count and liver enzymes after SRL discontinuation.

The mechanism by which SRL induces hepa­totoxicity is not well established. Reduction of hepatocyte regeneration by an increase of hepatocyte sensitivity to TGF β has been considered as a factor as well as an increase of sensitivity to TNF-related apoptosis-inducing ligand (TRAIL) and also interferon-induced apoptosis. [8]

Use of mammalian target of rapamycin inhi­bitors (mTOR) is increasing manifold. There­fore, awareness and an early recognition of fever and hepatitis as potential side-effects of these drugs is important to avoid such fatal outcome. A diagnosis of drug toxicity in a transplant recipient can only be made after ex­tensive and expensive investigations to rule out infections, auto-immune disorders and lymphoproliferative diseases.

   References Top

1.Thaunat O, Beaumont C, Chatenoud L, et al. Anemia after late introduction of sirolimus may correlate with biochemical evidence of a chronic inflammatory state. Transplantation 2005;80:1212-9.  Back to cited text no. 1
2.Aires I, Carvalho D, Remédio F, et al. Sirolimus-induced drug fever in a renal transplant pa­tient: A case report. Transpl Proc 2009;41:957-8.  Back to cited text no. 2
3.Stallone G, Infante B, Grandaliano G, Gesualdo L. Management of side effects of sirolimus therapy. Transplantation 2009;87(8 Suppl):23-6.  Back to cited text no. 3
4.Schacherer D, Zeitoun M, Buttner R, et al. Sirolimus-induced drug fever and ciclosporin-induced leukencephalopathia with seizures in one liver transplant recipient. World J Gastroenterol 2007;13:6090-3.  Back to cited text no. 4
5.Dorschner L, Speich R, Ruschitzka F, Seebach JD, Gallino A. Everolimus -induced drug fever after heart transplantation. Transplantation 2004;78:303-4.  Back to cited text no. 5
6.Jacques J, Dickson Z, Carrier P, et al. Severe sirolimus-induced acute hepatitis in a renal transplant recipient. Transplant Int 2010;23: 967-70.  Back to cited text no. 6
7.Niemczyk M, Wyzga³ J, Perkowska A, Porowski D, Paczek L. Sirolimus-associated hepatotoxicity in the kidney graft recipient. Transplant Int 2005;18:1302-3.  Back to cited text no. 7
8.Parent R, Kolippakkam D, Booth G, Beretta L. Mammalian target of rapamycin activation impairs hepatocytic differenciation and target genes moderating lipid homeostasis and hepatocellular growth. Cancer Res 2007;67: 4337-45.  Back to cited text no. 8

Correspondence Address:
Soumaya Yaich
Department of Nephrology, Hedi Chaker Hospital, Sfax
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DOI: 10.4103/1319-2442.111072

PMID: 23640637

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