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HYPERLIPIDEMIA IN SOLID ORGAN TRANSPLANTATION

1997; Wolters Kluwer; Volume: 63; Issue: 3 Linguagem: Inglês

10.1097/00007890-199702150-00001

1534-6080

Jon Kobashigawa, Bertram L. Kasiske,

Hepatitis C virus research

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 United States: lovastatin, pravastatin, simvastatin, and fluvastatin. These agents are highly effective in lowering LDL cholesterol concentrations-the primary target of lipid-lowering therapy in most patients (2). Data from primary and secondary prevention studies in nontransplant hyperlipidemic patients treated with these agents have shown reductions in cardiac mortality (33% and 42% risk reduction, respectively) (58, 59). Several investigators have reported success with lovastatin in cardiac and renal allograft recipients with elevated lipid levels (see Table 2). Lovastatin doses of 10-20 mg/day for more than 1.5 months reduced total cholesterol by 21-29% and LDL cholesterol by 25-32%. Experience with pravastatin has been similar to that of lovastatin (see Table 2). Pravastatin doses of 10-40 mg/day for more than 1.5 months reduced total cholesterol by 11-21% and LDL cholesterol by 15-42%. In a primary prevention study, 97 heart transplant recipients were randomly assigned within 2 weeks after transplantation to receive either pravastatin 40 mg/day (n=47) or no lipid-lowering therapy (n=50) (60). Cholesterol levels at 3, 6, 9, and 12 months after transplantation were consistently lower in the pravastatin group (mean, 193 mg/dl vs. 248 mg/dl, P<0.001). The incidence of clinically severe rejection leading to hemodynamic compromise within 1 year was less frequent in the pravastatin group, which translated into a 1-year survival benefit of 94%, compared with 78% in the control group (P=0.02). The incidence of transplant CAD (diagnosed angiographically or at autopsy), and measurements of intimal thickness by intracoronary ultrasound were lower in the pravastatin group. Natural killer cell cytotoxicity was assessed in a subgroup of 20 patients and was significantly lower in pravastatin patients. The investigators hypothesized that the favorable effects of pravastatin may reflect the importance of early reduction of cholesterol, a direct immunosuppressive effect, or both. Similar work in kidney and liver transplantation from the same institution has corroborated lower natural killer cell cytotoxicity in those transplant patients treated with 20 mg of pravastatin per day. Katznelson et al. (61) randomly allocated 48 kidney transplant patients to pravastatin or no pravastatin and reported decreases in the incidence of acute rejection episodes (64% vs. 25% in the control group, P<0.01) and decreases in the use of both OKT3 and methylprednisolone. At the end of the 4-month study period, there was no difference in renal function between groups. Several investigators have reported significant lipid reduction using simvastatin in cardiac and renal transplant recipients. Simvastatin doses of 5-20 mg/day for more than 4 months reduced total cholesterol by 14-27% and LDL cholesterol by 18-40% (see Table 2). Wenke et al. (62) randomly allocated 70 heart transplant patients immediately after transplant to 5-20 mg of simvastatin per day (n=37) or no simvastatin (n=33). After 24 months, the LDL cholesterol levels were 110 mg/dl and 150 mg/dl in the simvastatin and control groups, respectively (P 200 mg/dl), fibric acid derivatives appear to be well tolerated and an effective option. The safe and efficacious use of combination pharmacologic therapy awaits further study. Current research efforts are focusing on modulation of immunosuppressive therapy and use of the HMG-CoA reductase inhibitors. From autopsy studies demonstrating early lipid deposition in transplant coronary arteries and recent small clinical trials, it may be beneficial to initiate cholesterol-lowering therapy with HMG-CoA reductase inhibitors early after heart or kidney transplant surgery. Acknowledgments. The authors thank Judith Cassem and Judy Neary for their dedication in preparing the manuscript.Figure 1: Potential cyclosporine effects are designated as "1." 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 corticosteroid effects are designated as "2" 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 levels.Figure 2: Initial treatment algorithm for hyperlipidemia in heart, kidney, and liver transplantation. (AHA, American Heart Association; flu, fluvastatin; lov, lovastatin; pra, pravastatin; sim, simvastatin).