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Hyperlipidemia: impact of therapy
Hyperlipidemia: Impact of Therapy W.C. Lye
P
ERSISTENT hyperlipidemia is a common complication in solid organ transplant recipients. It has been reported in 37% to 45% of renal transplant recipients, 60% to 80% of heart transplant recipients, and 45% of liver transplant recipients.1 The lipoprotein abnormalities include elevations in total cholesterol, LDL-cholesterol, apolipoprotein B, and triglyceride concentrations. There are also qualitative alterations in the lipoprotein fractions such as increased oxidative LDL and IDL particles and reduced HDL2 fraction. Hyperlipidemia is an established risk factor for cardiovascular events. In renal transplant recipients, up to 50% of deaths were cardiovascular related. Hyperlipidemia has also been implicated as a risk factor for transplant coronary vasculopathy in cardiac transplant recipients, chronic allograft dysfunction in renal transplant recipients, and the vanishing bile duct syndrome in liver transplant recipients. There are multiple lines of evidence on the role of hyperlipidemia in graft vasculopathy. In rabbit and rat cardiac transplant models, lipogenic diets accelerate coronary vasculopathy, and treatment with a HMG-CoA reductase inhibitor reduced cardiac allograft vasculopathy.2 Pravastatin has been shown to improve rat survival and decrease the incidence of chronic rejection in a rat orthotopic liver transplant model. Vascular lesions from renal allografts with chronic rejection contain apolipoproteins A-I, A-II, B and oxidized LDL in the vascular intima.3 Finally, in observational studies Isoniemi et al found that elevated total cholesterol, LDL-cholesterol, and triglyceride levels correlated with renal allograft dysfunction.4 Dimeny et al found that pretransplant cholesterol levels predicted late graft failure.5 Although there is no direct evidence confirming the benefits of treating hyperlipidemia in transplant patients, compelling evidence from studies involving the general population suggests that hyperlipidemia in transplant patients should be managed similarly. Effective lipid-lowering treatment may also promote allograft survival. Mild hyperlipidemia may be corrected with dietary treatment alone such as the American Heart Association Step I diet. HMGCoA reductase inhibitors arc highly effective in lowering LDL-cholesterol levels. The use of lovastatin, pravastatin, simvastatin, and fluvastatin have reduced LDL-cholesterol concentrations by 20% to 40% in heart and kidney transplant recipients.6 It is now generally accepted that low doses
of HMG-CoA reductase inhibitors are safe in patients treated with cyclosporine A. Other lipid-lowering agents have been less well studied. Gemfibrozil has been used for treatment of hypertriglyceridemia in heart transplant patients.7 Bile acid sequestrants are not well tolerated because of their gastrointestinal side effects. Theoretically, they could interfere with the intestinal absorption of cyclosporine A. Nicotinic acid has been shown to lower the LDL cholesterol and triglyceride concentrations and increase the HDL cholesterol concentration in renal transplant recipients.8 However, flushing and gastrointestinal side effects are commonly encountered. Finally, omega-3-polyunsaturated fatty acids in fish oil has been shown to lower serum triglyceride concentrations.9 Experimental models have shown that HMG-CoA reductase inhibitors have effects on different cell lines. They decrease the proliferation of mitogen-stimulated T-lymphocytes and cytotoxic T-lymphocytes. Other effects include diminished B-lymphocyte activation and decreased vascular smooth muscle cell migration and proliferation. The effects of HMG-CoA reductase inhibitors on monocyte chemotaxis, expression of adhesion molecules, and natural killer cell cytotoxicity were reversed by mevalonate.10 In clinical trials the use of pravastatin in heart transplant recipients significantly increased the 1-year patient survival and decreased the incidence of clinically severe acute rejection episodes.11 Pravastatin-treated patients also showed less progression of transplant coronary vasculopathy compared to controls. Similar findings were also shown by Wenke et al. The use of simvastatin in heart transplant patients was associated with significantly better long-term survival and a lower incidence of transplant coronary vasculopathy based on intracoronary ultrasound findings.12 In summary, hyperlipidemia is an important complication in solid organ transplant recipients. Correction of hyperlipidemia may prevent atherosclerotic vasculopathy and may retard the progressing of graft vasculopathy. HMG-CoA reductase inhibitors may also function as immunomodulators and have effects on the effector immunoreactive cells.
From Centre for Kidney Diseases, Mount Elizabeth Medical Centre, Singapore. Address reprint requests to W.C. Lye, Centre for Kidney Diseases, Mount Elizabeth Medical Centre, Singapore 22851.
© 2000 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
0041-1345/00/$–see front matter PII S0041-1345(00)01305-1
Transplantation Proceedings, 32, 1497–1498 (2000)
1497
1498
REFERENCES 1. Miller LW, Schlant RC, Kobashigawa J, et al: J Am Coll Cardiol 22:41, 1993 2. Meiser BM, Wenke K, Thiery J, et al: Transplant Proc 25:2077, 1993 3. Tanabe S, Ueda M, Han YS, et al: Transplant Proc 30:116, 1998 4. Isoniemi H, Nurminen M, Tikkanan M, et al: Transplantation 57:68, 1994 5. Dimeny E, Wahlberg J, Lithell H, et al: Eur J Clin Invest 25:574, 1995 6. Kobashigawa JA, Kasiske BL: Transplantation 63:331, 1997
LYE 7. Ballantyne CM, Rodavancevic B, Farmer JA, et al: J Am Coll Cardiol 19:1315, 1992 8. Lal SM, Hewett JE, Petroski GF, et al: Am J Kidney 25:616, 1995 9. Castro R, Queiros J, Fonseca JPS, et al: Nephrol Dial Transplant 12:2140, 1997 10. Katznelson S: Kidney Int 56:S117, 1999 11. Kobashigawa JA, Katznelson S, Laks H, et al: N Engl J Med 333:621, 1995 12. Wenke K, Meiser B, Thiery J, et al: Circulation 96:1398, 1997
P
ERSISTENT hyperlipidemia is a common complication in solid organ transplant recipients. It has been reported in 37% to 45% of renal transplant recipients, 60% to 80% of heart transplant recipients, and 45% of liver transplant recipients.1 The lipoprotein abnormalities include elevations in total cholesterol, LDL-cholesterol, apolipoprotein B, and triglyceride concentrations. There are also qualitative alterations in the lipoprotein fractions such as increased oxidative LDL and IDL particles and reduced HDL2 fraction. Hyperlipidemia is an established risk factor for cardiovascular events. In renal transplant recipients, up to 50% of deaths were cardiovascular related. Hyperlipidemia has also been implicated as a risk factor for transplant coronary vasculopathy in cardiac transplant recipients, chronic allograft dysfunction in renal transplant recipients, and the vanishing bile duct syndrome in liver transplant recipients. There are multiple lines of evidence on the role of hyperlipidemia in graft vasculopathy. In rabbit and rat cardiac transplant models, lipogenic diets accelerate coronary vasculopathy, and treatment with a HMG-CoA reductase inhibitor reduced cardiac allograft vasculopathy.2 Pravastatin has been shown to improve rat survival and decrease the incidence of chronic rejection in a rat orthotopic liver transplant model. Vascular lesions from renal allografts with chronic rejection contain apolipoproteins A-I, A-II, B and oxidized LDL in the vascular intima.3 Finally, in observational studies Isoniemi et al found that elevated total cholesterol, LDL-cholesterol, and triglyceride levels correlated with renal allograft dysfunction.4 Dimeny et al found that pretransplant cholesterol levels predicted late graft failure.5 Although there is no direct evidence confirming the benefits of treating hyperlipidemia in transplant patients, compelling evidence from studies involving the general population suggests that hyperlipidemia in transplant patients should be managed similarly. Effective lipid-lowering treatment may also promote allograft survival. Mild hyperlipidemia may be corrected with dietary treatment alone such as the American Heart Association Step I diet. HMGCoA reductase inhibitors arc highly effective in lowering LDL-cholesterol levels. The use of lovastatin, pravastatin, simvastatin, and fluvastatin have reduced LDL-cholesterol concentrations by 20% to 40% in heart and kidney transplant recipients.6 It is now generally accepted that low doses
of HMG-CoA reductase inhibitors are safe in patients treated with cyclosporine A. Other lipid-lowering agents have been less well studied. Gemfibrozil has been used for treatment of hypertriglyceridemia in heart transplant patients.7 Bile acid sequestrants are not well tolerated because of their gastrointestinal side effects. Theoretically, they could interfere with the intestinal absorption of cyclosporine A. Nicotinic acid has been shown to lower the LDL cholesterol and triglyceride concentrations and increase the HDL cholesterol concentration in renal transplant recipients.8 However, flushing and gastrointestinal side effects are commonly encountered. Finally, omega-3-polyunsaturated fatty acids in fish oil has been shown to lower serum triglyceride concentrations.9 Experimental models have shown that HMG-CoA reductase inhibitors have effects on different cell lines. They decrease the proliferation of mitogen-stimulated T-lymphocytes and cytotoxic T-lymphocytes. Other effects include diminished B-lymphocyte activation and decreased vascular smooth muscle cell migration and proliferation. The effects of HMG-CoA reductase inhibitors on monocyte chemotaxis, expression of adhesion molecules, and natural killer cell cytotoxicity were reversed by mevalonate.10 In clinical trials the use of pravastatin in heart transplant recipients significantly increased the 1-year patient survival and decreased the incidence of clinically severe acute rejection episodes.11 Pravastatin-treated patients also showed less progression of transplant coronary vasculopathy compared to controls. Similar findings were also shown by Wenke et al. The use of simvastatin in heart transplant patients was associated with significantly better long-term survival and a lower incidence of transplant coronary vasculopathy based on intracoronary ultrasound findings.12 In summary, hyperlipidemia is an important complication in solid organ transplant recipients. Correction of hyperlipidemia may prevent atherosclerotic vasculopathy and may retard the progressing of graft vasculopathy. HMG-CoA reductase inhibitors may also function as immunomodulators and have effects on the effector immunoreactive cells.
From Centre for Kidney Diseases, Mount Elizabeth Medical Centre, Singapore. Address reprint requests to W.C. Lye, Centre for Kidney Diseases, Mount Elizabeth Medical Centre, Singapore 22851.
© 2000 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
0041-1345/00/$–see front matter PII S0041-1345(00)01305-1
Transplantation Proceedings, 32, 1497–1498 (2000)
1497
1498
REFERENCES 1. Miller LW, Schlant RC, Kobashigawa J, et al: J Am Coll Cardiol 22:41, 1993 2. Meiser BM, Wenke K, Thiery J, et al: Transplant Proc 25:2077, 1993 3. Tanabe S, Ueda M, Han YS, et al: Transplant Proc 30:116, 1998 4. Isoniemi H, Nurminen M, Tikkanan M, et al: Transplantation 57:68, 1994 5. Dimeny E, Wahlberg J, Lithell H, et al: Eur J Clin Invest 25:574, 1995 6. Kobashigawa JA, Kasiske BL: Transplantation 63:331, 1997
LYE 7. Ballantyne CM, Rodavancevic B, Farmer JA, et al: J Am Coll Cardiol 19:1315, 1992 8. Lal SM, Hewett JE, Petroski GF, et al: Am J Kidney 25:616, 1995 9. Castro R, Queiros J, Fonseca JPS, et al: Nephrol Dial Transplant 12:2140, 1997 10. Katznelson S: Kidney Int 56:S117, 1999 11. Kobashigawa JA, Katznelson S, Laks H, et al: N Engl J Med 333:621, 1995 12. Wenke K, Meiser B, Thiery J, et al: Circulation 96:1398, 1997