PMID- 21785038
OWN - NLM
STAT- MEDLINE
DCOM- 20120913
LR  - 20211203
IS  - 1460-2385 (Electronic)
IS  - 0931-0509 (Linking)
VI  - 27
IP  - 2
DP  - 2012 Feb
TI  - mTOR inhibition and erythropoiesis: microcytosis or anaemia?
PG  - 537-41
LID - 10.1093/ndt/gfr318 [doi]
AB  - BACKGROUND: Anaemia and microcytosis are common post kidney transplantation. The 
      aim of this study was to evaluate the potential role of mammalian target of 
      rapamycin (mTOR) inhibition in the development of anaemia and microcytosis in 
      healthy animals and in human erythroid cultures in vitro. METHODS: Rats with 
      normal kidney function were treated with sirolimus (n = 7) or vehicle (n = 8) for 
      15 weeks. Hemograms were determined thereafter. In the sirolimus withdrawal part 
      of the study, rats received sirolimus (SRL) for 67 days (n = 4) 1 mg/kg three 
      times per week or for 30 days (n = 4) and were observed until Day 120. Hemograms 
      were performed regularly. Peripheral blood mononuclear cells from healthy 
      controls (HC; n = 8), kidney transplant patients with sirolimus treatment with 
      (SRL + MC; n = 8) or without microcytosis (SRL - MC; n = 8) were isolated and 
      cultured in the absence or presence of SRL (5 ng/mL). RESULTS: SRL-treated 
      animals had a reduced mean corpuscular volume (MCV) and elevated erythrocyte 
      count compared with control animals after 15 weeks of treatment. This effect was 
      evident as early as 4 weeks (MCV: 61.5 +/- 1.8 versus 57 +/- 1.7 fL; P = 0.0156; Red 
      blood count 7.4 +/- 0.3 x 10(9)/L versus 8.6 +/- 0.5 x 10(9)/L; P = 0.0156) and was 
      reversible 90 days after SRL withdrawal. SRL in the culture medium of erythroid 
      cultures led to fewer colonies in cultures from HC as well as from kidney 
      transplant patients (without SRL: 34.2 +/- 11.4 versus with SRL: 27.5 +/- 9.9 
      BFU-E-derived colonies P = 0.03), regardless if the cultures were derived from 
      recipients with normocytic or with microcytic erythrocytes. The presence of 
      tacrolimus in the culture medium had no influence on the number and size of 
      colonies. CONCLUSION: mTOR inhibition induces microcytosis and polyglobulia, but 
      not anaemia in healthy rats. This might be caused by growth inhibition of 
      erythroid precursor cells.
FAU - Diekmann, Fritz
AU  - Diekmann F
AD  - Department of Nephrology and Kidney Transplantation, Laboratori Experimental de 
      Nefrologia i Transplantament, Hospital Clinic, Barcelona, Spain. 
      fdiekman@clinic.ub.es
FAU - Rovira, Jordi
AU  - Rovira J
FAU - Diaz-Ricart, Maribel
AU  - Diaz-Ricart M
FAU - Arellano, Edgar Marcelo
AU  - Arellano EM
FAU - Vodenik, Barbara
AU  - Vodenik B
FAU - Jou, Josep Maria
AU  - Jou JM
FAU - Vives-Corrons, Joan Lluis
AU  - Vives-Corrons JL
FAU - Escolar, Gines
AU  - Escolar G
FAU - Campistol, Josep M
AU  - Campistol JM
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20110722
PL  - England
TA  - Nephrol Dial Transplant
JT  - Nephrology, dialysis, transplantation : official publication of the European 
      Dialysis and Transplant Association - European Renal Association
JID - 8706402
RN  - 0 (Immunosuppressive Agents)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Anemia/blood/*physiopathology
MH  - Animals
MH  - Cells, Cultured
MH  - Disease Models, Animal
MH  - Dose-Response Relationship, Drug
MH  - Erythrocyte Count
MH  - Erythrocyte Indices
MH  - Erythroid Precursor Cells/cytology/drug effects
MH  - Erythropoiesis/*drug effects/physiology
MH  - Hematologic Diseases/blood
MH  - Humans
MH  - Immunosuppressive Agents
MH  - Infusions, Parenteral
MH  - Kidney Transplantation
MH  - Leukocytes, Mononuclear/cytology/*drug effects
MH  - Male
MH  - Random Allocation
MH  - Rats
MH  - Rats, Wistar
MH  - Reference Values
MH  - Sirolimus/*pharmacology
MH  - Statistics, Nonparametric
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors/metabolism
EDAT- 2011/07/26 06:00
MHDA- 2012/09/14 06:00
CRDT- 2011/07/26 06:00
PHST- 2011/07/26 06:00 [entrez]
PHST- 2011/07/26 06:00 [pubmed]
PHST- 2012/09/14 06:00 [medline]
AID - gfr318 [pii]
AID - 10.1093/ndt/gfr318 [doi]
PST - ppublish
SO  - Nephrol Dial Transplant. 2012 Feb;27(2):537-41. doi: 10.1093/ndt/gfr318. Epub 
      2011 Jul 22.