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Received 24 September 2010. Accepted 14 December 2010. Copyright © 2011 by Lippincott Williams & Wilkins ISSN 0041-1337/11/9107-806 DOI: 10.1097/TP.0b013e31820c4574
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World Health Organization. Control of leishmaniasis. Geneva: World Health Organization; 2007. Available at: http://apps.who.int/gb/ ebwha/pdf_files/WHA60/A60_10-en.pdf. Accessed March 25, 2010. Herwalt BL. Leishmaniasis. Lancet 1999; 354: 1191. Antinori S, Cascio A, Parravicini C, et al. Leishmaniasis among organ transplant recipients. Lancet Infect Dis 2008; 8: 191. Badaro R, Jones TC, Carvalho EM, et al. New perspectives on a subclinical form of visceral leishmaniasis. J Infect Dis 1996; 154: 1003. Campos-Varela I, Len O, Castells L, et al. Visceral leishmaniasis among liver transplant recipients: An overview. Liver Transplant 2008; 14: 1816. Murray HW, Berman JD, Davies CR, et al. Advances in leishmaniasis. Lancet 2005; 366: 1561.
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Horber FF, Lerut JP, Reichen J, et al. Visceral leishmaniasis after orthotopic liver transplantation: Impact of persistent splenomegaly. Transpl Int 1993; 6: 55. Hernandez-Perez J, Yebra-Bango M, JimenezMartinez E, et al. Visceral leishmaniasis (kala-azar) in solid organ transplantation: Report of five cases and review. Clin Infect Dis 1999; 29: 918. Halkic N, Ksontini R, Scholl B, et al. Recurrent cytomegalovirus disease, visceral leishmaniasis, and Legionella pneumonia after liver transplantation: A case report. Can J Anaesth 2004; 51: 84. Tsiodras S, Zafiropoulou R, Giotakis J, et al. Deep sinus aspergillosis in a liver transplant recipient successfully treated with a combination of caspofungin and voriconazole. Transplant Infect Dis 2004; 9: 37. Basset D, Faraut F, Marty P, et al. Visceral leishmaniasis in organ transplant recipients: 11 new cases and review of the literature. Microbes Infect 2005; 7: 1370. Ozcan D, Seckin D, Allahverdiyev AM, et al. Liver transplant recipient with concomitant cutaneous and visceral leishmaniasis. Pediatr Transplant 2007; 11: 228. Murray HW. Treatment of visceral leishmaniasis (Kala-Azar): A decade of progress and future approaches. Int J Infect Dis 2000; 4: 158.
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Clemente WT, Couto CA, Ribeiro DD, et al. An atypical course of visceral leishmaniasis (Kala-azar) in a liver transplant recipient. Transplantation 2007; 83: 368. Brasil, Ministe´rio da Sau´de. Leishmaniose Visceral Grave. Brasília, 2006. Available at: http:// portal.saude.gov.br/portal/arquivos/pdf/ manual_lv_grave_nc.pdf. Accessed March 18, 2010. Brasil, Ministe´rio da Sau´de. Leishmaniose visceral. Recomendac¸o˜es clínicas para reduc¸a˜o da letalidade. Brasília, 2009. Oliveira CMC, Oliveira MLMB, Andrade SCA, et al. Visceral leishmaniasis in renal transplant recipients: Clinical aspects, diagnostic problems, and response to treatment. Transplant Proc 2008; 40: 755. Lo´pez-Ve´lez R, Videla S, Ma´rquez M, et al. Spanish HIV-leishmania study group. Amphotericin B lipid complex versus no treatment in the secondary prophylaxis of visceral leishmaniasis in HIV-infected patients. J Antimicrob Chemother 2004; 53: 540. Ferna´ndez-Guerrero ML, Robles P, Rivas P, et al. Visceral leishmaniasis in immunocompromised patients with and without AIDS: A comparison of clinical features and prognosis. Acta Trop 2004; 90: 11.
Minimal But Essential Doses of Immunosuppression: A More Realistic Approach to Improve Long-Term Outcomes for Pediatric Living-Donor Liver Transplantation The majority of transplant (Tx) patients remain dependent on the chronic administration of immunosuppression (IS) regardless of its associated complications. Tolerance (long-term acceptance of a transplanted organ after the complete cessation of IS) is the ultimate goal. No less than 15% of all pediatric patients who underwent livingdonor liver Tx in Kyoto were weaned off IS. Such cases are referred as showing “operational tolerance” in the absence of any histologic definition (1). Currently, two distinct types of mechanism are documented in tolerance: (a) deletional mechanisms in which T cells potentially reactive to donor antigens are eliminated from the immune repertoire and (b) nondeletional mechanisms in which such T cells are physically present, but inhibited by certain mechanisms. Immunologic analyses of our IS-free patients demonstrated that regulatory T cells (Tregs) would be likely to suppress the existing reactive T cells through intragraft Th2 cytokine immune deviation, and, thereby, nondeletional mechanisms play a determi-
nant role in operational tolerance (2–5). We performed protocol biopsy on IS-free patients to examine whether accepted grafts exhibit a normal histology. Approximately 50% of IS-free patients, albeit showing a normal liver test, exhibited graft fibrosis to a greater extent than those on maintenance IS (6). For fear of the progression of fibrosis, we reintroduced minimal maintenance immunosuppression (MMIS) for IS-free patients or patients who exhibited fibrosis during the process of weaning IS. Follow-up biopsy was performed after the reintroduction of MMIS to examine how MMIS effects on fibrosis. In most patients, fibrosis did not progress. In 52% of them, fibrosis was improved, and in 38% of them, it did not change. It is debatable whether graft fibrosis observed in stable pediatric liver Tx recipients can be prevented by MMIS. One IS-free patient did not start MMIS despite the presence of fibrosis (6). This patient exhibits rapid progression of fibrosis within a year, which was not observed in patients who started MMIS. Our results suggest that, at least in part,
fibrosis can be prevented by MMIS. Therefore, this implies that, in accordance with the recommendation of The Banff Working Group, operational tolerance necessitates Working Histopathologic Criteria (A. Demetris, personal communication Banff ’09, Banff, Alberta, Canada, August 9 –14, 2009). Of course, one must be cautious as to whether one biopsy sample would always represent the overall condition of grafts, especially in partial liver Tx. When the sample is obtained from the area near the cut surface, nonimmunologic surgical effects can affect the histologic findings. Nondeletional mechanisms mediated by Tregs may not always be sufficient to control low-grade destructive immune responses. Alternatively, specific cytokines (e.g., transforming growth factor-), which are produced by Tregs, may be responsible for fibrosis, as recently discussed by Magee (7). The other possibility is that operational tolerance associated with both a Treg-mediated mechanism and intragraft Th2 immune deviation, albeit important for the
Letters to the Editor
© 2011 Lippincott Williams & Wilkins
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TABLE 1. The reintroduction of minimal maintenance immunosuppression
Patient no. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Mean
Tacrolimus (mg/d/body)
Tacrolimus (mg/kg/d)
BW (kg)
Tacrolimus trough (ng/mL)
Reasons for reintroduction of MMIS
Off31.0/1.0 Off31.0/— Off31.0/— Off30.5/0.5 Off30.5X3/wk Off30.5/0.5 0.5/2 wk30.5/— Off31.0/— 0.5/mo30.5/— Off30.5/— 1.0/wk31.0/— 0.5/wk30.5/— 1.0/mo31.0/— 0.5/—30.5/0.5 0.5/wk30.5/0.5 0.2/2 wk30.2/— 0.5⫻2/wk30.5/— 0.5/—30.5/0.5 0.5/wk30.5/— 0.2⫻2/wk30.5/0.5 0.2/wk30.5/—
0.04 0.02 0.02 0.02 0.01 0.02 0.01 0.02 0.02 0.01 0.02 0.01
48 50 51 48 24 45 47 55 23 47 53 55 — — 23 25 30 32 59 31 23
Not detectable Not detectable 2.8 Not detectable Not detectable Not detectable Not detectable Not detectable Not detectable Not detectable Not detectable Not detectable Not detectable 4 4 Not detectable Not detectable 4 Not detectable 2 Not detectable
Advanced fibrosis Advanced fibrosis Progression of fibrosis Progression of fibrosis Progression of fibrosis Progression of fibrosis Progression of fibrosis Progression of fibrosis Progression of fibrosis Advanced fibrosis Progression of fibrosis Advanced fibrosis Progression of fibrosis Advanced fibrosis Advanced fibrosis Progression of fibrosis Progression of fibrosis Progression of fibrosis Progression of fibrosis Progression of fibrosis Progression of fibrosis
0.04 0.01 0.02 0.03 0.01 0.03 0.02 0.02
Follow-up time (mo)
Change in fibrosis
Side effect
12 4 27 11 14 12 12 16 12 12 12 19 17 18 54 12 13 10 5 12 10 15.0
No change Improved Worse Improved No change Improved Worse No change Improved No change No change Improved No change Improved Improved No change Improved Improved Improved Improved No change
Absence Absence Absence Absence Absence Absence Absence Absence Absence Absence Absence Absence Absence Absence Absence Absence Absence Absence Absence Absence Absence
MMIS has been reintroduced in 8 IS-free patients and 13 patients during the process of weaning IS, who exhibited graft fibrosis. Doses of tacrolimus (mg/kg BW, mg/kg/d), trough levels, the follow-up time, presence or absence of side effects, reasons for the reintroduction of MMIS, and changes in fibrosis are described. Except for two patients, fibrosis improved or did not progress. MMIS, minimal maintenance immunosuppression; BW, body weight.
establishment of in vivo hyporesponsiveness and protection against acute rejection, may correlate with the development of antibody-mediated rejection by promoting humoral responses, as shown by our experiment (8). In fact, our preliminary study demonstrated the deposition of C4d within the graft in some IS-free patients, but such deposition was decreased or disappeared in cases where MMIS was effective in improving fibrosis (H. Egawa, personal communication, 14th European Society for Organ Transplantation Congress, Paris, France, August 30 to September 2, 2009). It may well be that true tolerance requires more robust deletional mechanisms, notably through the creation of mixed chimerism, which has been successfully established in renal Tx by the Boston group (T. Kawai, personal communication, XXIII Interna-
tional Congress of TTS, Vancouver, Canada August 15–19, 2010). In this letter, we propose the following guidelines for the management of patients in whom graft fibrosis is observed using protocol biopsy after stopping IS or during the process of weaning IS, based on our experiences of MMIS in patients with graft fibrosis (Table 1). 1. Criteria for the reintroduction of MMIS: a. Advanced fibrosis (Ishak’s modified staging ⱖ3, focal moderate perivenular fibrosis (⬎30-m thickness)). b. Progression of fibrosis. 2. MMIS: 0.01 to 0.04 mg/kg of tacrolimus monotherapy once a day. 3. Close follow-up by protocol biopsy every 6 to 12 months.
In conclusion, although the complete cessation of IS represents the ultimate goal, use of minimal but essential doses of IS can be a more realistic approach in some patients in whom the complete cessation of IS has been attempted. This is in accordance with the concept first described by Calne et al. (9). ACKNOWLEDGMENTS The authors thank Drs. E. Kobayashi, J. Pirenne, and A. Demetris for their helpful discussions and the critical reading of this article, and Dr. Parker and Ms. Nakanishi for manuscript preparation. Hidenori Ohe1 Ying Li2 Hanaa Nafady-Hego1 Waki Kayo3 Shimon Sakaguchi2
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Kathryn Wood4 Roy Calne5 Shinji Uemoto1 Takaaki Koshiba1 1 Department of Surgery Graduate School of Medicine Kyoto University Kyoto, Japan 2 Department of Experimental Pathology Institute for Frontier Medical Science Kyoto University Kyoto, Japan 3 Department of Ubiquitous Health Informatics Graduate school of Medicine The University of Tokyo Tokyo, Japan 4 Transplantation Research Immunology Group Nuffield Department of Surgery University of Oxford John Radcliffe Hospital Headington, Oxford, United Kingdom 5 Department of Surgery & Medicine University of Cambridge United Kingdom and National University of Singapore, Singapore This work was supported by the ATC International Young Investigator Award (2009) (H.O.). The authors declare no conflict of interest.
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Presented, in part, at the American Transplant Congress (ATC) 2009, May 30 –June 3, 2009, Boston, MA; the 14th European Society for Organ Transplantation Congress 2009, August 30 –September 2, 2009, Paris, France; and the ATC 2010, May 1–5, 2010, San Diego, CA. Address correspondence to: Takaaki Koshiba, M.D., Ph.D., Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawara-Cho, Shogoin, Sakyo-ku, Kyoto 6068507, Japan. E-mail:
[email protected] H.O., T.K., Y.L., and H.N.-H. carried out research; H.O., T.K., S.S., K.J.W., R.C., and K.W. wrote the article; T.K. participated in the research design; H.O. conducted the data analysis; and S.U. directed transplant program. Received 13 September 2010. Accepted 6 January 2011. Copyright © 2011 by Lippincott Williams & Wilkins ISSN 0041-1337/11/9107-808 DOI: 10.1097/TP.0b013e31820f07de
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