Hyperlipidemia in Solid Organ Transplantation

In the past decade, improved management strategies in solid organ transplantation have dramatically increased allograft survival and reduced early posttransplant morbidity. However, these advances have been accompanied by the emergence of a new group of complications. One of these complications, hyperlipidemia, is an important concern in heart and kidney transplant recipients and may also be a concern in the liver transplant population (1). Because of the well-established correlation between lipid levels and atherosclerosis in nontransplant populations (2), it is logical to expect that transplant recipients would also be placed at increased risk for cardiovascular events. In addition, there is emerging evidence linking elevated lipid levels to allograft vasculopathy, an unusually accelerated form of atherosclerotic vascular disease (3). In fact, this complication has emerged as one of the primary causes of morbidity and mortality in long-term transplant survivors, surpassing even infection. In this Overview, the mechanisms and clinical implications of hyperlipidemia in the heart, kidney, and liver transplant populations are discussed, with comments specific for each of these three transplant groups, and treatment options are reviewed. POTENTIAL CAUSES OF HYPERLIPIDEMIA Potential causes of hyperlipidemia in transplant recipients include diet, genetic predisposition, and immunosuppressive medications. Many patients are at or below their ideal body weight before transplantation, but become obese after successful procedures. Obesity in heart transplantation has been closely associated with the development of hyperlipidemia (4). Some patients with preoperative diagnosis of atherosclerotic cardiovascular disease have familial hyperlipidemia. This genetic predisposition contributes to the posttransplant hyperlipidemic state (5). Immunosuppressive agents, such as corticosteroids and cyclosporine, are implicated in the development of hyperlipidemia, and possible mechanisms are described in Figure 1. It has been suggested that cyclosporine may inhibit the enzyme 26-hydroxylase, which is important in the bile acid synthetic pathway (6). Cyclosporine would thereby decrease the synthesis of bile acids from cholesterol and subsequently the transport of cholesterol to the intestines. Cyclosporine is also reported to bind to the low-density lipoprotein (LDL*) receptor, which results in increased serum levels of LDL cholesterol (6). It is also thought that cyclosporine increases hepatic lipase activity and decreases lipoprotein lipase activity, resulting in impaired clearance of very low-density lipoprotein (VLDL) and LDL. Corticosteroids are reported to enhance the activity of acetyl-coenzyme A carboxylase and free fatty acid synthetase, increase hepatic synthesis of VLDL, down-regulate LDL receptor activity, increase the activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, and inhibit lipoprotein lipase (7-9). This results in increased levels of VLDL, total cholesterol, and triglyceride levels, and decreased high-density lipoprotein (HDL) levels. POSSIBLE CONSEQUENCES OF POSTTRANSPLANT HYPERCHOLESTEROLEMIA Hypercholesterolemia in organ transplant recipients may be associated with an increased risk for allograft vasculopathy. In cardiac transplant recipients, transplant vasculopathy takes the form of transplant coronary artery disease (CAD); in renal transplant recipients, vasculopathy manifests as chronic rejection; in hepatic transplantation, it manifests as vanishing bile duct syndrome (3). Atherosclerotic vascular disease in nontransplant vessels is another possible consequence. It has been reported that 55% of deaths in renal transplant recipients with functioning allografts were cardiovascular related (10). Peripheral vascular disease has been reported in 10% of heart transplant recipients (11). HEART TRANSPLANT RECIPIENTS Lipid abnormalities are reported in 60-80% of heart transplant patients receiving the standard triple-drug regimen consisting of cyclosporine, azathioprine, and prednisone (12). Several groups have examined the patterns of lipid abnormalities following cardiac transplantation. Studies in this population show that increases in total cholesterol, LDL cholesterol, apolipoprotein B, and triglyceride levels develop at 3-18 months (13, 14). Some studies suggest that these lipid levels slowly fall as the time after transplantation lengthens (4). The reports are more variable regarding levels of HDL cholesterol (15, 16). Interestingly, lipoprotein(a) levels have been found to decrease by almost 40% after cardiac transplantation (16). Ballantyne et al. (13) reported that mean total cholesterol values in 100 cardiac transplant recipients increased from pretransplant levels of 168±7 mg/dl to 234±7 mg/dl at 3 months after transplantation. During this same period, LDL cholesterol rose from 111±6 mg/dl to 148±6 mg/dl, HDL cholesterol rose from 34±1 mg/dl to 47±1 mg/dl, and triglyceride levels rose from 107±6 mg/dl to 195±10 mg/dl. There were no further significant rises after the 3-month evaluation, but LDL cholesterol and triglyceride levels remained elevated in 64% and 41% of patients, respectively, 6 months after dietary therapy was instituted. The development of transplant CAD in cardiac allografts is one of the major causes of graft failure in long-term survivors of cardiac transplantation and is a primary contributor to overall patient morbidity and mortality. The incidence of this disease ranges from 1% to 18% at 1 year to 20% to 50% at 3 years (17, 18). Numerous immune and nonimmune risk factors are associated with the development of transplant CAD. Immune risk factors (12, 19) as a cause for transplant CAD is evidenced by increased levels of cytotoxic B-cell antibodies, increased anti-HLA antibodies, a correlation between disease development and increased incidence of acute cellular rejection and humoral (antibody-mediated) rejection, cytomegalovirus infection, sensitization to monoclonal antibody OKT3, and detection of early and persistently elevated interleukin 2 receptor levels. Nonimmune risk factors (15) include hyperlipidemia, recipient age and gender, obesity, pretransplant diagnosis, and donor ischemic time. Among nonimmune risk factors for transplant CAD, the most consistently described relationship has been with cholesterol. In an autopsy study, McManus et al. (20) performed morphometric, immunohistochemical, ultrastructural, and biochemical studies in 23 explanted allografts and donor agematched native coronary artery controls. Mean total cholesterol, esterified cholesterol, and free cholesterol content in the transplant arteriopathic coronaries were greater than 10-fold higher than in comparable native coronary segments. The extent of lipids in the arterial walls was highly correlated with digitized percent luminal narrowing. The authors concluded that lipid accumulation is an important early and persistent phenomenon in the development of transplant CAD. The relationship of elevated triglyceride levels to transplant CAD risk has not been fully defined (15). Winters et al. (21) showed that higher versus lower triglycerides (328 mg/dl vs. 145 mg/dl) were associated with a marked difference in luminal narrowing through inspection of failed allografts. Valantine (22) reported a correlation of elevated triglycerides and low HDL cholesterol to increasing intimal thickness from a multicenter intracoronary ultrasound study. RENAL TRANSPLANT RECIPIENTS Abnormalities in circulating lipoproteins are common after renal transplantation. These abnormalities include elevations in total and LDL cholesterol, as well as increases in VLDL and triglycerides (23-25). Vathsala et al. (24) studied 500 cyclosporine-treated renal transplant recipients and found a 37% incidence of cholesterol levels ≥300 mg/dl, which occurred within 6 months in the majority of patients. Interestingly, HDL cholesterol levels were usually normal or even high (26, 27), although the composition of HDL may not be normal (26, 28). In addition to increased levels of commonly measured lipoproteins, other more subtle abnormalities may make lipoproteins particularly atherogenic in renal transplant recipients. For example, LDL appears to be more susceptible to oxidation, and antioxidant levels are lower in renal transplant patients treated with cyclosporine (29-31). Studies examining lipoprotein(a) levels in renal transplant recipients have so far produced conflicting results (32-38). It is not only the incidence but also the duration of lipoprotein abnormalities that has important implications for renal transplant recipients. Most studies have shown that lipoprotein abnormalities persist into the very late posttransplant period. For example, hyperlipidemia (total and LDL cholesterol >240 mg/dl and 145 mg/dl, respectively) was a persistent problem in a cohort of over 700 transplant recipients followed for a mean period of 7 years (39). Others reported increased lipid levels after more than 10 years of follow-up (40). A growing amount of circumstantial evidence has linked hyperlipidemia with cardiovascular disease in renal transplant recipients (41, 42). It has been reported that the prevalence of cardiovascular disease events is approximately 20% by 15 years after renal transplantation (43-45) There are no strong reasons to believe that the risk of hyperlipidemia in the general population, now well established in many large clinical trials, would be any less in renal transplant recipients who have a higher than normal incidence of both hyperlipidemia and cardiovascular disease. The most characteristic histologic finding in chronic renal allograft rejection is a marked, concentric, fibrointimal proliferation that occurs in medium and large intrarenal arteries (42). It is tempting, therefore, to speculate that risk factors for systemic atherosclerosis could also contribute to the pathogenesis of chronic rejection. The vascular lesions of chronic rejection have been shown to contain foam cells and lipoprotein deposits (42). Two studies have measured total and LDL cholesterol levels in renal transplant recipients with stable grafts and in recipients with chronic rejection. Dimeny et al. (46) and Isoniemi et al. (47) both showed that total and LDL cholesterol levels were significantly higher in patients with chronic rejection than in patients with stable graft function. However, renal dysfunction, proteinuria, and the additional immunosuppression often used in patients with chronic rejection may explain the association with hyperlipidemia without implicating lipid abnormalities in the pathogenesis of chronic rejection. Clearly, controlled intervention trials will be needed to prove that hyperlipidemia causes or contributes to chronic rejection after renal transplantation. LIVER TRANSPLANT RECIPIENTS Fewer data have been collected about the impact of hyperlipidemia in liver transplantation. Mathe et al. (48) measured serum lipoprotein levels in 86 subjects aged 15-67 years. Most patients were receiving triple immunosuppressive therapy with prednisone, cyclosporine, and azathioprine. Total cholesterol levels >250 mg/dl occurred in 17% of subjects. A further 28% had cholesterol levels 150 mg/dl. Overall, dyslipoproteinemia was observed in 45% of patients following liver transplantation. Although immunosuppressive therapy was not directly correlated with lipid abnormalities, the authors reported a correlation between lipid levels and renal function tests, suggesting an indirect effect of the immunosuppressive drugs. Also, liver function was impaired in some patients with elevated lipids and may have been related to reduced clearance of VLDL cholesterol and LDL cholesterol and subsequent accumulation of atherogenic lipids in the serum. McDiarmid et al. (49) conducted a longitudinal cohort study in 102 pediatric liver recipients, whose median age was 6 years. Cholesterol levels were >170 mg/dl (75th percentile) in 47% of subjects. Wiesner et al. (50) evaluated cardiovascular risk factors in 529 adult liver transplant recipients who were randomly assigned to receive immunosuppression with standard triple therapy of cyclosporine, azathioprine, and prednisone or FK506 in combination with low-dose corticosteroids. During 12 months of follow-up, total cholesterol and LDL cholesterol levels rose steadily in the cyclosporine group but not in the FK506 group. At study end, the difference in lipoprotein levels between the two groups was significant (P<0.0001 and P<0.01 for total cholesterol and LDL cholesterol, respectively). Onset of diabetes mellitus occurred in 0.8% and 2.1% of the cyclosporine and FK506 groups, respectively, a difference that did not reach statistical significance. In two other reports, Jindal et al. (51) and Imagawa et al. (UCLA Medical Center, personal communication, 1996) also evaluated the effect of cyclosporine versus FK506 in 63 and 45 liver transplant recipients, respectively. Both total and LDL cholesterol levels were significantly higher in the cyclosporine patients. In contrast, Steinmüller et al. (52) evaluated 101 liver transplant recipients receiving cyclosporine or FK506 and found a significant increase in total cholesterol in both transplant groups. It has yet to be determined whether hyperlipidemia is associated with vanishing bile duct syndrome. Two possible mechanisms have been identified for this phenomenon: (1) direct immunologic attack on bile duct cells and (2) immunologic attack on arterial endothelium, resulting in formation of lipid-laden macrophages that eventually block the vasculature, causing ischemic damage to the bile duct. TREATMENT OF HYPERLIPIDEMIA Clinical assessment for hyperlipidemia should be initiated soon after transplantation. It is controversial whether therapy for hyperlipidemia in transplant patients should follow the guidelines recommended for the general population and detailed in the report of the second Adult Treatment Panel of the National Cholesterol Education Program (NCEP) (2). In transplant patients, potential strategies include dietary therapy, reduced doses of immunosuppressive agents, and lipid-lowering agents. Diet In the transplant population, dietary modification is the safest form of treatment for elevated LDL cholesterol. Patients should be asked to comply with the American Heart Association Step I or Step II Diet as recommended by the NCEP (2). However, it has been shown that, despite dietary intervention, many patients have persistently high lipid levels. Ballantyne et al. (13) measured mean plasma lipid values in 100 patients at 1, 3, 6, and 12 months after heart transplantation. All patients were given instructions on the American Heart Association Step I Diet before hospital discharge. Lipid values did not change significantly during the 3 months in which patients were asked to comply with the Step I Diet, and many patients had persistent elevations of LDL cholesterol and triglyceride levels. It is likely that despite dietary intervention and optimal medical management for hypertension and immunosuppression, many patients may have high lipid levels and require pharmacologic intervention. Immunosuppressive Therapy As discussed previously, both cyclosporine and prednisone have been independently linked with increased risk for hyperlipidemia; therefore, one strategy to reduce hyperlipidemia is to modify the dosage of one or both of these drugs. Several heart transplant programs have reported decreases in cholesterol levels after withdrawal of corticosteroids from the maintenance immunosuppressive regimen (53-56). Effects on cholesterol reduction at 1 year after stopping corticosteroids range between 6% and 26%. However, not all patients may benefit from this strategy; steroid withdrawal in heart transplant patients was successfully performed in 56-89% of patients (53-55). Hricik et al. (57) measured lipid profiles in 34 renal and 9 renal-pancreas recipients after complete withdrawal of prednisone from their immunosuppressive regimens. All 43 patients were maintained on cyclosporine and azathioprine with reductions in levels of total and LDL cholesterol of 17% and 16%, respectively. However, there was an 18% reduction in HDL cholesterol levels. The investigators concluded from these data that withdrawal of prednisone from an immunosuppressive regimen may not necessarily be associated with an improvement in the patients' cardiovascular profile. In the future, newer immunosuppressive agents, such as FK506 or mycophenolate mofetil, may allow clinicians to more safely reduce or discontinue agents that increase plasma lipids. Drug Therapy for Cholesterol Lowering The NCEP guidelines regarding lipid-lowering drug therapy are based, for the most part, on three major drug classes: the HMG-CoA reductase inhibitors, bile acid sequestrants, and nicotinic acid. The fibric acid derivatives are indicated for patients with very high triglyceride levels, and probucol is suggested only for those patients who have not tolerated or responded to the other cholesterol-lowering drugs. Potential interactions with immunosuppressive regimens should be considered when using lipid-lowering drugs in transplant recipients and are described in Table 1. HMG-CoA reductase inhibitors. These drugs inhibit HMG-CoA reductase, a key rate-limiting enzyme in the pathway for cholesterol biosynthesis; at therapeutic doses, they reduce but do not completely inhibit cholesterol synthesis. Four agents are currently available in the and These agents are highly in LDL cholesterol primary of lipid-lowering therapy in most patients (2). from primary and studies in nontransplant hyperlipidemic patients treated with these agents have shown reductions in cardiac mortality and risk respectively) Several investigators have reported with in cardiac and renal allograft recipients with elevated lipid levels Table doses of for more than months reduced total cholesterol by and LDL cholesterol by with has been to that of Table doses of for more than months reduced total cholesterol by and LDL cholesterol by In a primary study, heart transplant recipients were randomly assigned within 2 after transplantation to receive or no lipid-lowering therapy Cholesterol levels at 3, 6, and 12 months after transplantation were consistently lower in the group mg/dl vs. mg/dl, The incidence of rejection to within 1 year was less in the which into a survival benefit of with in the group The incidence of transplant CAD or at and of intimal thickness by intracoronary ultrasound were lower in the group. was in a of patients and was significantly lower in patients. The investigators that the of may the of early reduction of cholesterol, a direct immunosuppressive or in kidney and liver transplantation from the same has lower in those transplant patients treated with of et al. randomly kidney transplant patients to or no and reported decreases in the incidence of acute rejection vs. in the and decreases in the of both and At the of the study period, there was no difference in renal function between groups. Several investigators have reported significant lipid reduction using in cardiac and renal transplant recipients. doses of for more than months reduced total cholesterol by and LDL cholesterol by Table et al. randomly heart transplant patients after transplant to of or no the LDL cholesterol levels were mg/dl and mg/dl in the and groups, benefit in rejection or survival was Fewer reports have been about but results Table to those of other agents in this Several reports in the in cyclosporine-treated heart transplant recipients receiving These patients high doses therapy with or The increased risk of with HMG-CoA reductase in transplant recipients is most likely to increased serum of HMG-CoA reductase in patients receiving cyclosporine It is now that low doses of HMG-CoA reductase be used safely in patients treated with acid acid and bind with bile bile acid and increase hepatic bile acid synthesis and LDL receptor activity (2). There are reasons to believe that these agents may with the of cyclosporine In a study of heart transplant recipients treated with et al. reported a reduction in total cholesterol levels. These investigators also cyclosporine and found that the the cyclosporine the patients, from a decrease to a 55% increase from but did not cyclosporine levels. and found no effect of bile acid on cyclosporine levels in kidney transplant patients. acid Two are available in the and (2). Ballantyne et al. (13) reported the of as a in a group of cardiac transplant recipients, resulting in marked reductions in triglycerides and reductions in total and LDL cholesterol levels. In this was well tolerated and was not observed to with immunosuppressive Two newer fibric acid and are study in reports in heart transplant recipients have suggested possible with to a cyclosporine et al. did not report with of a dosage that was as in cholesterol in cardiac transplant patients with 10 of lipid-lowering A of clinical trials have examined the and of other lipid-lowering agents. A the of for hyperlipidemia in renal transplant recipients Most of these trials were and of the results using a of a large of clinical trials and suggest that and a HMG-CoA reductase is the therapy acid LDL and increases HDL cholesterol levels bile acid sequestrants, triglyceride levels (2). Clinical studies of this drug in transplantation have been most likely to the many Table both total and LDL cholesterol levels to a It has been used in heart transplant patients and found to reduce both LDL and HDL cholesterol levels by it did not a significant change in the of LDL cholesterol to HDL cholesterol The authors reported a 28% decrease in cyclosporine levels in heart transplant patients receiving probucol is no available in the The of LDL cholesterol in combination with and 10 has in transplant CAD. trials are in for this lipid-lowering strategy lipid levels have been reported in more than of heart or kidney transplant recipients and in of liver transplant recipients. Diet, genetic predisposition, and immunosuppressive agents have been identified as factors in elevated cholesterol levels in the transplant lipid levels have been correlated with an increased risk for cardiovascular disease in kidney transplant recipients. lipid levels have also been associated with atherosclerotic disease of the graft vessels in kidney and heart atherosclerotic disease in the nontransplant population, allograft vasculopathy and become significant within 1 A in vanishing bile duct a form of allograft vasculopathy in liver transplant recipients, has also been for elevated lipid levels. no regarding The of the NCEP guidelines is controversial they may not the for lipid-lowering therapy following solid organ transplantation. therapy is the safest but has had It appears that the most agents to reduce cholesterol levels are the HMG-CoA reductase there is concern regarding associated and on the high cardiovascular risk of transplant patients, an treatment of and HMG-CoA reductase inhibitors, organ is shown in Figure For those transplant patients with to fibric acid derivatives to be well tolerated and an The and of combination pharmacologic therapy further study. are on of immunosuppressive therapy and of the HMG-CoA reductase inhibitors. autopsy studies early lipid in transplant coronary arteries and clinical trials, it may be to cholesterol-lowering therapy with HMG-CoA reductase early after heart or kidney transplant The authors and for their in the Potential cyclosporine are as Cyclosporine is suggested to inhibit the enzyme 26-hydroxylase, which is important in the bile acid synthetic pathway (6). This would decrease the synthesis of bile acids from cholesterol and subsequently the transport of cholesterol to the intestines. Cyclosporine is also reported to bind to the LDL receptor, which results in increased serum levels of LDL cholesterol (6). Potential are as and are reported to enhance the activity of acetyl-coenzyme A carboxylase and free fatty acid synthetase, and inhibit lipoprotein lipase (7-9). This results in increased levels of VLDL, total cholesterol, and triglyceride treatment for hyperlipidemia in heart, kidney, and liver transplantation. American Heart