Sirolimus interferes with iron homeostasis in renal transplant recipients.
BACKGROUND
Sirolimus is an immunosuppressive drug whose use is frequently associated with anemia. A pathogenic link between sirolimus-induced anemia and the appearance of an inflammatory state was recently suggested. Because inflammation-related anemia is characterized by a functional iron deficiency, we investigated whether sirolimus may influence iron homeostasis and serum levels of hepcidin, a key mediator of inflammation-related anemia.


METHODS
To this purpose, 42 consecutive transplanted patients with biopsy-proven chronic allograft nephropathy were randomized (2:1 ratio) to receive either a 40% cyclosporine reduction (group A, 14 patients) or immediate cyclosporine withdrawal and sirolimus introduction (group B, 28 patients). Hemoglobin levels and iron status were evaluated 6 months before and after randomization.


RESULTS
The two groups had similar hemoglobin levels and iron status at baseline. We did not observe any significant change in hemoglobin and iron status in group A patients after randomization. On the contrary, we observed a significant reduction of hemoglobin without any change of red blood cell count after sirolimus introduction, with a significant reduction of mean corpuscular volume and mean corpuscular hemoglobin. Serum iron and transferrin saturation (TSAT) levels were markedly reduced after the switch, while ferritin serum concentrations remained stable. Although sirolimus-induced anemia was recently suggested to resemble inflammation-related anemia, hepcidin serum levels were similar in the two groups after randomization. None of group A and eight of group B patients presented a TSAT <20 and were given iron supplementation after randomization, in all of them oral iron therapy did not influence either hemoglobin or serum iron levels.


CONCLUSIONS
We demonstrated that sirolimus-induced anemia is independent of the drug antiproliferative effect and does not present the features of inflammation-related anemia. This event may be due to the direct influence of sirolimus on iron homeostasis.
Maiorano
Annamaria
A
Division of Nephrology, Department of Emergency and Transplantation, University of Bari, Italy.
Stallone
Giovanni
G
Schena
Antonio
A
Infante
Barbara
B
Pontrelli
Paola
P
Schena
Francesco Paolo
FP
Grandaliano
Giuseppe
G
D000328:Adult; D004906:Erythrocyte Count; D005260:Female; D006454:Hemoglobins / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007501:Iron / Q000378:metabolism*; D016030:Kidney Transplantation / Q000473:pathology / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D020123:Sirolimus / Q000627:therapeutic use*; D014184:Transplantation, Homologous
D006454:Hemoglobins; D007166:Immunosuppressive Agents; D007501:Iron; D020123:Sirolimus