Effect of sirolimus on the metabolism of ApoB100-containing lipoproteins in renal transplant patients

Background. Sirolimus (Rapamune, rapamycin, RAPA) is a potent immunosuppres sive drug that has reduced the rate of acute rejection episodes by more tha n 40% in phase III trials when added to an immunosuppression regimen of cyc losporine (CsA) and prednisone. However, RAPA treatment tends to increase l ipid levels, particularly among patients with pre-existing hyperlipidemia. Methods. To identify the metabolic pathway(s) leading to RAPA-mediated hype rlipidemia, five patients with renal transplants maintained on CsA+/-predni sone+/- azathioprine (AZA) were studied before and after 6 weeks of treatme nt with RAPA (off RAPA and on RAPA, respectively). Each study patient was i nfused with a single bolus of [H-2(4)]-lysine to derive metabolic parameter s for apoB100-containing lipoproteins by using kinetic analysis based upon quantitation of isotopic enrichment by gas chromatography-mass spectrometry . Results. Serial lipid measurements revealed that four patients displayed in creased plasma triglyceride levels after RAPA treatment, which coincided wi th significantly higher plasma VLDL-apoB100 concentrations (21.7 +/- 12.1 m g/dl off RAPA vs. 38.7 +/- 14.8 mg/dl on RAPA, mean+/-SD, P<0.05). Kinetic analysis showed that the RAPA-induced increase in VLDL-apoB100 concentratio ns was due to a significant reduction in the fractional catabolic rate TCR) of very low-density lipoprotein (VLDL) apoB100 (0.83+/-0.65 off RAPA vs. 0 .24+/-0.10 on PAPA, mean SD, P<0.05), rather than an enhanced VLDL-apoB100 synthesis. In one patient, RAPA treatment induced hypercholesterolemia but not hypertriglyceridemia. This hypercholesterolemia. was due to elevated lo w-density lipoprotein (LDL) cholesterol levels, which coincided with a decr eased FCR of LDL-apoB100. Heparin-induced lipoprotein lipase activity was s ignificantly lower in the immunosuppressed hyperlipidemic patients than in normolipidemic controls. However, RAPA treatment did not significantly alte r basal lipoprotein lipase activity in renal transplant patients in this st udy. Conclusions. This study indicates that for renal transplant patients in who m RAPA treatment induces hyperlipidemia, this effect is the result of reduc ed catabolism of apoB100-containing lipoproteins.