PMID- 20703217
OWN - NLM
STAT- MEDLINE
DCOM- 20110225
LR  - 20211203
IS  - 1523-1755 (Electronic)
IS  - 0085-2538 (Linking)
VI  - 78
IP  - 11
DP  - 2010 Dec
TI  - Sirolimus for calcineurin inhibitors in organ transplantation: contra.
PG  - 1068-74
LID - 10.1038/ki.2010.268 [doi]
AB  - Sirolimus (SRL) is an antiproliferative agent inhibiting the mammalian target of 
      rapamycin (mTOR) proposed as a non-nephrotoxic alternative to calcineurin 
      inhibitors for the prevention of acute rejection in renal transplantation. 
      Despite initial encouraging results, enthusiasm faded with large trials showing 
      an increased risk of acute rejection with this molecule that did not provide 
      superior graft function over cyclosporin or tacrolimus. Recent data showed that 
      SRL, along with an immunosuppressive activity on CD4+ T cells, exerts a 
      paradoxical stimulatory effect on innate immunity, which may explain its 
      incomplete control of alloimmune response. Moreover, SRL therapy is burdened by a 
      concerning safety profile including high risk of delayed graft function and onset 
      of proteinuria. This adds to many other adverse effects, including dyslipidemia, 
      diabetes, myelosuppression, delayed wound healing, infertility, ovarian cysts, 
      and mouth ulcers, that further limit the use of this molecule. Severe cases of 
      interstitial pneumonia have also been reported with this therapy, raising 
      additional concerns. Incomplete control of immune response, along with a poor 
      tolerability, makes SRL far from being the ideal antirejection drug. Progressive 
      restrictions of SRL indication in renal transplantation have, however, been 
      paralleled by evidence showing mTOR abnormalities involved in many pathogenic 
      conditions, thus opening the avenue to new possible applications of this 
      molecule.
FAU - Cravedi, Paolo
AU  - Cravedi P
AD  - Mario Negri Institute for Pharmacological Research, Bergamo--Unit of Nephrology, 
      Azienda Ospedaliera Ospedali Riuniti, Bergamo, Italy.
FAU - Ruggenenti, Piero
AU  - Ruggenenti P
FAU - Remuzzi, Giuseppe
AU  - Remuzzi G
LA  - eng
PT  - Journal Article
PT  - Review
DEP - 20100811
PL  - United States
TA  - Kidney Int
JT  - Kidney international
JID - 0323470
RN  - 0 (Calcineurin Inhibitors)
RN  - 0 (Immunosuppressive Agents)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - *Calcineurin Inhibitors
MH  - Delayed Graft Function/chemically induced
MH  - Graft Survival/drug effects
MH  - Humans
MH  - Immunosuppressive Agents/*adverse effects
MH  - *Organ Transplantation/adverse effects
MH  - Proteinuria/chemically induced
MH  - Risk Assessment
MH  - Risk Factors
MH  - Sirolimus/*adverse effects
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors
MH  - Treatment Outcome
EDAT- 2010/08/13 06:00
MHDA- 2011/02/26 06:00
CRDT- 2010/08/13 06:00
PHST- 2010/08/13 06:00 [entrez]
PHST- 2010/08/13 06:00 [pubmed]
PHST- 2011/02/26 06:00 [medline]
AID - S0085-2538(15)54436-0 [pii]
AID - 10.1038/ki.2010.268 [doi]
PST - ppublish
SO  - Kidney Int. 2010 Dec;78(11):1068-74. doi: 10.1038/ki.2010.268. Epub 2010 Aug 11.