Sirolimus changes lipid concentrations and lipoprotein metabolism in kidney transplant recipients.
BACKGROUND
Sirolimus (Rapammune, rapamycin, RAPA) is a strong immunosuppressive agent that reduces kidney transplant rejection. Hyperlipidemia is a significant side effect of sirolimus treatment and often leads to vascular disease. We have studied the repeatability, reversibility, and dose dependence of the plasma lipid and apoprotein changing effects of sirolimus and attempted to determine the mechanism by which sirolimus induces hypertriglyceridemia in some kidney transplant recipients.


METHODS
Six patients with renal allografts maintained on cyclosporine A and prednisone were selected on the basis of their previous hyperlipidemic response to short-term (14 days) sirolimus administration. For longer-term treatment, each patient was started on 10 mg/d sirolimus and continued as tolerated for 42 days to reinduce hyperlipidemia. Timed blood samples were analyzed for lipid, apoprotein, and sirolimus levels.


RESULTS
During sirolimus administration, mean total plasma cholesterol increased from 214 to 322 mg/dL (+50%); low density lipoprotein-cholesterol levels changed in a similar pattern. Mean triglyceride level rose from 227 to 432 mg/dL (+95%). ApoB-100 concentration rose from 124 to 160 mg/dL (+28%). ApoC-III level increased from 28.9 to 55.5 mg/dL (+92%). These lipid and apoprotein changes were found to be repeatable, reversible, and dose dependent. [(13)C(4)]-palmitate metabolic studies in four patients with hypertriglyceridemia indicated that the free fatty acid pool was expanded by sirolimus treatment (mean = 42.3%). Incorporation of [(13)C(4)]-palmitate into triglycerides of very low density lipoprotien, intermediate density lipoprotein, low density lipoproteins was decreased 38.3%, 42.1%, and 38.4%, respectively, by sirolimus treatment of these patients.


CONCLUSIONS
These results suggest that sirolimus alters the insulin signaling pathway so as to increase adipose tissue lipase activity, decrease lipoprotein lipase activity, or both, resulting in increased hepatic synthesis of triglyceride, increased secretion of VLDL, and increased hypertriglyceridemia.
Department of Medicine, Baylor College of Medicine, Houston, Texas, USA. morrisset@bcm.tmc.edu
J D
JD
Morrisett
G
G
Abdel-Fattah
B D
BD
Kahan
D000328:Adult; D002102:Cadaver; D002784:Cholesterol / Q000097:blood; D016572:Cyclosporine / Q000627:therapeutic use; D005260:Female; D006801:Humans; D006949:Hyperlipidemias / Q000139:chemically induced / Q000453:epidemiology*; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D016030:Kidney Transplantation / Q000276:immunology / Q000502:physiology*; D008055:Lipids / Q000097:blood*; D008074:Lipoproteins / Q000097:blood*; D019520:Living Donors; D008297:Male; D008875:Middle Aged; D011241:Prednisone / Q000627:therapeutic use; D020123:Sirolimus / Q000009:adverse effects / Q000627:therapeutic use*; D014019:Tissue Donors; D014184:Transplantation, Homologous; D014280:Triglycerides / Q000097:blood
D007166:Immunosuppressive Agents; D008055:Lipids; D008074:Lipoproteins; D014280:Triglycerides; D016572:Cyclosporine; D002784:Cholesterol; D011241:Prednisone; D020123:Sirolimus