Dyslipidemia or Hyperlipidemia after Solid Organ Transplantation

Ravinder K. Wali

Department of Medicine, Division of Nephrology, University of Maryland School of Medicine, Baltimore, Maryland 21201

BACKGROUND

During the past 2 decades, innovative developments in the immunosuppression regimens for prevention and treatment of acute rejection after successful organ transplantation has markedly improved patient and graft survival at 1 year. However, after the first year of transplantation, cardiovascular morbidity and mortality are the major causes of death with a functioning graft. Overall, among middle-aged individuals 45-64 years of age, the death due to coronary artery disease for transplant patients is approximately 0.6% per year (1). This event rate is more than five times that for the general population of similar age (2). More than half of the recipients of renal transplants in North America and Europe die of cardiovascular disease after the first year of transplantation (3, 4, 5). Kasiske et al. reported that cumulative incidence of coronary artery disease, cerebrovascular disease and peripheral vascular disease at 15 years after transplantation was 23%, 15%, and 15%, respectively (6). Similar adverse events have been reported in the recipients of liver transplants (7).

Organ transplant recipients have an increased risk for cardiovascular (CV) events (both morbidity and mortality) due to an unfavorable cardiovascular risk profile, which most frequently includes new onset or worsening of already existing dyslipidemia and the onset of complex metabolic syndrome (insulin resistance syndrome) after successful transplantation. In addition, dyslipidemia plays a significant role for chronic allograft dysfunction (8). The prevalence of lipid abnormalities in solid organ transplant recipients have been reported to range from 60% to 80% during the first year following renal transplant (9), 58% of patients after liver transplant (10), and up to 80% of recipients of cardiac transplants (11).

Premature death is the most common cause of death with a functioning graft (DWF) (12) mostly due to accelerated atherosclerosis (13). Lipid abnormalities in the posttransplant period are one of many risk factors that lead to accelerated atherosclerosis after successful organ transplantation. There are several factors that lead to new changes in lipid abnormalities in the posttransplant period:

1) Dyslipidemia sets in at the time of development of chronic kidney disease (CKD) in recipients of renal allografts and new onset renal disease in recipients of nonrenal organ transplants (14).

2) Changes or modifications in low-density lipoprotein (LDL) such as the production of oxidized-LDL (ox-LDL) that is considered to be more atherogenic in nature (15).

3) Patient survival after transplantation is directly proportional to the duration of dialysis (16, 17, 18), as dialysis therapy results in the vasculopathic state.

4) During the posttransplant period, the burden of cardiovascular disease increases further due to development of hypertension and use of diuretic agents (19, 20, 21).

5) The majority of transplant recipients have pre-existent cardiovascular disease at the time of undergoing transplantation (6,22).

6) New onset impaired glucose tolerance and posttransplant diabetes mellitus (23).

7) Onset of complex metabolic syndrome (insulin resistance syndrome) (24).

The results of recent studies have generated a new debate about the terms of hyperlipidemia or dyslipidemia and the current validity of National Cholesterol Education Program (NCEP) guidelines regarding the optimum lipid control in patients at high risk for cardiovascular disease. The results of studies such as the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) study (25), the Comparison of Intensive and Moderate Lipid Lowering with Statin after Coronary Syndrome (PROVE IT) study (26), the Heart Protection Study (HPS) (27) and the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) trials established the fact that there is no data point to a leveling off of coronary heart disease risk anywhere along the cholesterol continuum.

In view of these robust epidemiological studies in the general population, it is safe to assume that lipid abnormalities could be equally strong risk factors for atherosclerosis and atherosclerotic cardiovascular disease after organ transplantation, since these patients have a higher than normal incidence of hyperlipidemia/dyslipidemia and atherosclerotic disease. However, whether lipid-lowering therapies that have been demonstrated to reduce the cardiovascular events in the general population could be equally effective and safe in the recipients of organ transplantation are under evaluation (the Assessment of Lescol in Renal Transplantation [ALERT] trial [28] and others studies) (see Table 18.1).

Dyslipidemia is a frequently observed metabolic abnormality after organ transplantation, particularly so after kidney transplantation (29,30). The lipoprotein profile abnormalities develop immediately in the posttransplant period (19,29,31,32); and the peak incidence of hypercholesterolemia occurs at 6 months posttransplantation (33).

The prevalence of hypercholesterolemia and hypertriglyceridemia after transplantation has been reported to be as high as 60% and 35%, respectively. An increase in total cholesterol by approximately 30% or so is fairly common and seen in more than 80% of heart and lung (34), 60% to 70% of renal (35), and 45% of liver (36,37) transplant recipients in the immediate posttransplant period.

Whether hyperlipidemia per se adversely affects the patient and graft survival in recipients of organ transplants remains debatable (13,38). However, several retrospective and case control studies have demonstrated increased risk of cardiovascular disease and death among patients with hypercholesterolemia compared with those with normal cholesterol (33,38, 39, 40).

The improved survival in the general population following treatment with lipid lowering agents has been attributed to their pharmacological effects to lower the cholesterol level (41,42). Similarly the role of lipid lowering agents in the posttransplant period has been demonstrated to their potent effects to reduce the total cholesterol levels (28,43, 44, 45, 46, 47, 48). Early studies failed to demonstrate any significant association between the lipid levels and cardiovascular morbidity and mortality (49) and lack of association between posttransplant lipidemia and patient or graft survival (38,50).

CHANGING PARADIGMS OF DYSLIPIDEMIA IN RECIPIENTS OF ORGAN TRANSPLANTATION

It is difficult to explore the exact prevalence and type of hyperlipidemia in the posttransplant period because of differences in definition of hyperlipidemia, different series from different centers, different relative proportion of patients with or without diabetes mellitus, frequency and severity of lipid abnormalities related to the timing posttransplant and inter- and intracenter variations in immunosuppression drug therapy.

We are observing new paradigms in the degree and the types of dyslipidemia in recipients of organ transplantation with the recent introduction of new immunosuppression agents; such as replacement of azathioprine and cyclosporine with mycophenolate mofetil and tacrolimus, respectively, use of combination therapy with sirolimus with either cyclosporine or tacrolimus, or the evolving other maintenance immunosuppression agents such as FTY-772 and RAD-based therapy. As a result of these changes, the lipidemic profile following organ transplantation may also continue to change.

Dyslipidemia in the Era of Azathioprine and Corticosteroid-based Immunosuppression

During early 1980s when kidney transplant recipients were maintained on azathioprine and corticosteroid-based immunosuppression, hypertriglyceridemia was reported in up to 80% of patients after the first 3 months of transplantation, and that would continue to worsen during the next 6 months or so (13,51, 52, 53). On the other hand, in the era of cyclosporine (CsA)-based immunosuppression, more than half of the patients developed hypercholesterolemia at 3 months posttransplant, and this increase in total cholesterol was reported to be far higher than observed in patients on azathioprine alone (54, 55, 56). In a single center cohort study, Vathsala et al. reported severe hypercholesterolemia (total cholesterol >300 mg/dL) and severe hypertriglyceridemia (fasting triglyceride levels >500 mg/dL) during the first 6 months following transplantation in nearly 38% and 15% of patients, respectively (33), followed by slow decrease during the next 36 months. It was argued that improvement in the lipid profile during the second year posttransplant could be due to decrease in the dose of corticosteroids.

Dyslipidemia in the Era of Calcineurin Inhibitor-based Therapy

The use of calcineurin inhibitors (CNIs) (CsA or tacrolimus) results in an increase in total cholesterol, LDL-cholesterol
and apolipoprotein B (Apo B) from baseline values, but these levels persist at relatively higher levels in the group treated with CsA as compared to tacrolimus-treated patients. In addition, the use of CsA is associated with an increased tendency to LDL-oxidation with increased levels of ox-LDL as compared to patients treated with tacrolimus. CsA monotherapy (without use of corticosteroids) for 1 year is associated with increased levels of triglycerides, lower levels of high-density lipoprotein (HDL) and increased levels of lipoprotein (a) Lp(a) as compared to the group on azathioprine and prednisone (57).

Several comparative studies between the use of CsA and tacrolimus have shown that the degree of lipidemia on maintenance immunosuppression with tacrolimus may result in less severe degree of hyperlipidemia in the posttransplant period as compared to those receiving CsA-based therapy (10). Direct comparison of the frequency of lipidemia at 6 months and at 1 year after transplantation in patients on tacrolimus-based therapy was reported to be 30% and 26% as compared to 68% and 67% in CsA-treated patients, respectively (58). In addition, the severity of lipidemia was less intense in patients treated with tacrolimus as compared to CsA-treated patients (59).

Dyslipidemia of Sirolimus-based Immunosuppression

With the advent of sirolimus and its use in different types of organ transplantations, the exact frequency and severity of lipidemia remains as yet poorly understood and sparsely reported. However, early studies have demonstrated that the use of sirolimus in combination with CsA and prednisone is associated with a significant degree of hypertriglyceridemia, as the most frequent lipid abnormality in the first 3 months as compared to patient who were treated with CsA- and prednisone-based therapy (60,61).

Compositional Changes in Lipid Subfractions (Lipoprotein Subtypes)

There is a dynamic change in lipoprotein subtypes with the onset of CKD along the continuum with progression in renal failure and while on renal replacement therapy (dialysis) followed by further changes in these lipoprotein subtypes after kidney transplantation. Patients treated with azathioprine and corticosteroids show increased concentration of very low density lipoprotein (VLDL) and increased levels of LDL and high-density lipoprotein (HDL) cholesterol (51,62,63). Patients treated with CsA and corticosteroids demonstrate increased concentrations of LDL- and mild increase in HDL-cholesterol and normal to mild increase in VLDL levels (64,65). In addition, as in the general population, studies of Apo concentrations in renal transplant recipients have demonstrated close correlation between Apo B and LDL levels, Apo A1 and HDL levels. Ratio of Apo C-II and C-III are invariably decreased and inversely related to serum triglyceride levels. These changes in the apo levels are only available in the era of treatment with CsA and steroids (66, 67, 68). In addition, we still do not know the effects of different types of immunosuppression on the lipid particle size, as it has become clear that increase in VLDL size and decrease in the particle size of LDL and HDL potentiate the risk of atherosclerosis (69).

These qualitative and conformational changes may be more important than the simple quantitative changes, as qualitative abnormalities render these molecules more atherogenic and less responsive to contemporary antilipidemic therapy in the presence of normal or near normal lipid profiles.

Increased levels of ox-LDL (70,71) and increased levels of Lp(a) are also independently associated with increased risk for cardiovascular events (72, 73, 74). Some studies have indicated that Lp(a) may not change in the posttransplant period; however, these inconsistencies may be due to different types of assays used for the measurement of Lp(a). Since Lp(a) exists in two different isoforms (low and high molecular weight), patients with low molecular weight isoforms have increased levels of Lp(a) in the posttransplant period (75).

Another notable lipid conformational change associated with organ transplantation is decreased levels of HDL2-subfraction, which in turn decreases the antiatherosclerotic and cardioprotective effects of HDL (76).

PATHOGENESIS OF DYSLIPIDEMIA AFTER ORGAN TRANSPLANTATION

Steroids

Corticosteroids are known to affect lipid metabolism in several different ways. Depending upon the dose and duration of corticosteroid therapy, steroids induce insulin resistance that leads to hyperinsulinism. The atherogenic dyslipidemia associated with an insulin resistant state is characterized by hypertriglyceridemia; an increase in VLDL secretion from the liver; an increase in atherogenic LDL; and a decrease in HDL cholesterol. Each of these lipid abnormalities is an independent risk factor for coronary artery disease (CAD), and in concert, the cardiovascular risk is magnified (77). Hyperinsulinism also leads to increased uptake of free fatty acids, and free fatty acids are the main substrate for the synthesis of VLDL and high levels of triglycerides and low levels of HDL. Kinetic studies with stable isotope-labeled amino acid precursors have shown that the development of visceral obesity, as well as type 2 diabetes, leads to overproduction of the apo B-100 and VLDL. Insulin resistance syndrome is associated with significant decrease in the activity of LPL, thus decreasing the catabolism of triglycerides and VLDL (78).

Insulin resistance is generally accompanied by low HDL cholesterol and high plasma triglycerides, which are major cardiovascular risk factors (79). Several enzymes including lipoprotein lipase (LPL), hepatic lipase (HL) and lecithin: cholesterol acyltransferase (LCAT), as well as
cholesteryl ester transfer protein (CETP) and phospholipid transfer protein (PLTP) participate in HDL metabolism and remodeling. LPL hydrolyzes lipoprotein triglycerides, thus providing lipids for HDL formation. HL reduces HDL particle size by hydrolyzing its triglycerides and phospholipids. A decreased postheparin plasma LPL/HL ratio is a determinant of low HDL2 cholesterol in insulin resistance state. The esterification of free cholesterol by LCAT increases HDL particle size. CETP facilitates the transfer of cholesterol ester of HDL to VLDL and LDL and then returns to the liver to be excreted in the form of bile acids and cholesterol, completing the process of reverse cholesterol transport (80). Specific CETP inhibitors are under development that exert major HDL cholesterol-raising effects in humans and retard atherosclerosis in animal models (81).

Calcineurin inhibitors

CsA-induced hyperlipidemia is due to several mechanisms of action of CsA on lipid metabolism and may indeed be dose and duration related. Studies in nonorgan transplant subjects treated with CsA for autoimmune diseases showed that CsA use is associated with increased levels of LDL-cholesterol (82). In addition, CsA use leads to decreased synthesis of bile acids, which in turn leads to hypercholesterolemia due to down regulation of LDL receptors, with or without conformational changes in LDL receptor and decreased clearance of peripheral cholesterol. Whether these changes in the LDL receptor are due to the use of steroids or CsA or a combination of the two remain unclear. The use of calcineurin inhibitors (CNIs) is associated with ox-LDL, and replacement of CsA with azathioprine is associated with decreased level of ox-LDL (70,83,84).

Serial measurements of lipid profiles after discontinuation of either CsA or steroids is associated with changes in the lipid profile. Discontinuation of CsA is associated with a decrease in the total cholesterol and triglyceride levels even though the patient continues to remain on steroids. Discontinuation of CsA invariably leads to increase in GFR. It is being argued that these changes in lipids could be at least partly related to improvement in kidney function. Similarly, cessation of steroids is associated with a decrease in total cholesterol and triglyceride levels. However, decrease in LDL is often associated with a corresponding decrease in HDL-cholesterol following steroid withdrawal (85).

The effects of tacrolimus on the lipid profile are somewhat different than the effects of CsA. The effects of CsA and tacrolimus on serum lipids were compared in recipients randomized to CsA (15 patients) and tacrolimus (17 patients). Serum lipid levels in both groups were significantly increased at 1 month after renal transplantation. In the CsA-treated group, there were significant increases in cholesterol contents in VLDL, LDL2 and HDL2 fractions; whereas, in the tacrolimus group, cholesterol content was increased in VLDL and HDL2 fractions.

Lipid abnormalities in renal transplant recipients treated with either CsA or tacrolimus in combination with azathioprine and prednisone after excluding those subjects with diabetes mellitus, on lipid lowering therapy (either statin or fish oil supplements) or taking antioxidant vitamins were compared with lipid levels in normal subjects (12 males and 4 females) used as controls. Patients on CsA had significantly increased levels of total cholesterol, LDL-cholesterol, and Apo B levels at 3, 6, and 10 months posttransplantation as compared to those receiving tacrolimus-based therapy. Compared to the baseline, there was an increase in serum cholesterol by 5% to 7% in the tacrolimus group as compared to twofold increase (15-18%) in the CsA group. In addition, use of either agent resulted in an increase in LDL-cholesterol, CsA (11-16%) and Prograf (3-5%), as compared to baseline as well as to healthy controls.

Although use of either type of CNI is associated with an increase in LDL-cholesterol and B levels, the changes in the lipid profile in the posttransplant period may be to some extent related to the pretransplant lipid abnormalities.

Sirolimus

Sirolimus use is associated with an increase in serum triglyceride and total cholesterol levels when used concomitantly with either CsA or tacrolimus (60). Although posttransplant hyperlipidemia has been associated with the use of CsA alone (85,86), the incidence and severity of hyperlipidemia is more pronounced when sirolimus is used in combination with CsA and prednisone in the posttransplant period. Both corticosteroids and CsA are known to reduce LDL receptor affinity (87) and onset of subclinical cholestasis (86) by impairing glucose metabolism (55).

The combination therapy with sirolimus, CsA and prednisone is associated with a 1.5-fold greater overall risk of hypercholesterolemia and hypertriglyceridemia within 1 to 3 months after transplantation (from a baseline cholesterol and triglyceride levels of 240 mg/dL and 200 mg/dL, respectively). At 4 years after transplantation, the relative risks remained at 1.5-fold and 2.0-fold, respectively. Based on these definitions of hypercholesterolemia and hypertriglyceridemia, the incidence of hypercholesterolemia was as high as 60% to 80% at 2 years posttransplant, and 50% at 4 years after transplantation if maintained on combination therapy with sirolimus and CsA. The percentage of patients that need either statin, fibrates or fish oil, either alone or in combination, to lower serum cholesterol or triglycerides decreased from nearly 50% and 60% at 6 months to nearly less than 40% at 4 years, respectively.

Chueh et al compared the frequency of dyslipidemia in 118 CsA-treated patients as compared to 280 renal transplant recipients treated with a combination of CsA, sirolimus and prednisone (88). Dyslipidemia defined as an increase in cholesterol of greater than 240 mg/dL and triglyceride levels of greater than 500 mg/dL, was noted in 43% to 78% of sirolimus-treated patients during the first 6
months of posttransplantation. The increase in both cholesterol and triglyceride levels was noted within 1 month of use of sirolimus, peaked at the third month and remained elevated during the first year of transplantation. Although there was some decrease in the levels of total cholesterol and triglycerides after the first year of transplantation and at the end of the fourth year, these levels remained higher than the baseline values. On the contrary, the incidence of cardiovascular events during the follow-up of 4 years after transplantation among patients treated with or without sirolimus was similar (88).

The effects of sirolimus on plasma lipids was analyzed in 1,295 renal allograft recipients randomized in a multicenter study (phase III trial), and sirolimus was randomly assigned in a 2:2:1 ratio to treatment with sirolimus 2 mg/day, sirolimus 5 mg/day as compared to azathioprine in US patients or placebo in non-US centers. All patients received corticosteroids and CsA microemulsion (Neoral). At the time of entry into the study, pretransplant fasting serum triglyceride level was ≤500 mg/dL and a fasting cholesterol level was ≤350 mg/dL. The total cholesterol peaked at month 2 and decreased during the remainder of the 12-month follow-up period in all treatment groups. There was a dose-dependent increase in mean cholesterol and triglyceride levels, and this increase was significantly higher for each of the sirolimus groups at months 3, 6, and 12 as compared to those who were not on sirolimus. This difference stabilized at month 6 of transplantation with a trend towards improvement in mean cholesterol during the first year after transplantation. Similarly, mean triglyceride values were highest at month 2 or 3 in all the groups, and these levels continued to decrease in both sirolimus groups (either dose groups), but remained unchanged in the nonsirolimus groups after third month of transplantation.

Thus there is a dose dependent increase in cholesterol and triglyceride levels in the sirolimus groups, but indeed these levels decreased over time. Only 0.4% and 2.5% of patients in the sirolimus dose groups of 2 mg/day and 5 mg/day, respectively, had to stop sirolimus because of worsening or persistent hyperlipidemia. The frequency of the use of statins was 20% to 25% higher in the sirolimus group than in the control group. Statin use was associated with a significant decrease in total cholesterol in the sirolimus as well as in the control groups. There was no adverse event such as rhabdomyolysis reported with the use of statin in combination with sirolimus, a complication that is observed with increased frequency when statins are used with CNIs (89). Hypertriglyceridemia is known to produce several complications such as pancreatitis, cardiovascular events (acute coronary syndrome, strokes), but none of these events were significant in the sirolimus versus control groups.

The long-term effects of sirolimus-associated hyperlipidemia is not well known, a recent retrospective study showed no difference in the incidence of cardiovascular events (defined as strokes, acute myocardial infarction, congestive heart failure, arrhythmias, amputations) at 4 years after transplantation in the groups treated with CsA/sirolimus combination as compared to CsA/prednisone combination therapy (88,90, 91). Although none of these studies (either the sirolimus pivotal study or the retrospective study by Cheuh) were powered to look for these cardiovascular events, data was extrapolated from the initial pivotal studies (91,92) and correlation with the Framingham risk model demonstrated significant association of sirolimus related dyslipidemia and the risk of coronary artery disease and death (2).

The effects of combination therapy with tacrolimus and sirolimus on lipid metabolism may be different than in patients with combination therapy of CsA and sirolimus. Preliminary results indicate that combination of tacrolimus and sirolimus may be associated with less intense degree of hyperlipidemia (93). However, the impact of tacrolimus on the glucose metabolism remains the major risk factor that can impact lipid metabolism in patients at high risk for posttransplant diabetes mellitus.

The pathogenesis of lipidemic effects of sirolimus is not precisely known. However, it appears to be due to multiple factors. These include increased hepatic production of triglyceride- and cholesterol-rich lipoproteins (94), decreased clearance either in the transport mechanisms in the cell (95) or clearance from plasma (96), and reduced catabolism as evidenced with increase in the plasma levels of apo B-100 and apo CIII, the latter apo results in the inhibition of plasma LPL (97).

EFFECTS OF POSTTRANSPLANT DYSLIPIDEMIA

Meta-analysis of posttransplant studies revealed that HDL and triglyceride levels are the major predictors of cardiovascular disease than either total or LDL cholesterol levels (40), death with functioning graft remains the most common cause of graft loss due largely to premature cardiovascular death (40,98) on the background of pre-existent cardiovascular disease at the time of undergoing transplantation (6,22).

To what extent dyslipidemia per se contributes to cardiovascular morbidity and mortality in the recipients of solid organ transplants remains poorly understood.

To what extent the results of primary and secondary prevention studies in the general population or at risk population for cardiovascular disease such as those after acute myocardial infarction can be applied to recipients of solid organ transplants remains at best opinion-based.

Due to the lack of large prospective randomized studies using lipid-lowering agents for the primary and secondary prevention of cardiovascular disease in organ transplant recipients, it is difficult to make a strong recommendation for intervention, though one can extrapolate the positive results of those studies in the general population to the organ transplant recipients, as recipients of solid organ transplants are at a higher-risk for cardiovascular disease, and could be designated as a coronary heart disease (CHD) equivalent.

It can also be argued that lipidemia may have a negative impact on the incidence and severity of chronic allograft dysfunction, since the hallmark of chronic allograft dysfunction
is the vascular lesions that are similar to atherosclerosis. Some evidence suggests an association between hyperlipidemia and chronic allograft nephropathy in recipients of kidney transplants (8,38,99). However, it can also be argued that hyperlipidemia in patients with chronic allograft nephropathy could be secondary to decreased GFR and associated varying degrees of proteinuria. Even in patients with mild to moderate degree of renal insufficiency, use of pravastatin has been shown to reduce cardiovascular events in this high-risk population (100).

The Complex Metabolic Syndrome and Vascular Disease

The NCEP-ATP III (see Appendix 18.1) identified that complex metabolic syndrome (MS) is an important risk factor for cardiovascular disease (morbidity and mortality) (101). The definition of the syndrome is based on five different variables; abdominal obesity based on waist circumference, hypertriglyceridemia, low HDL cholesterol, insulin resistance syndrome (fasting glucose greater than 110 mg/dL) and hypertension. The NCEP defined that presence of at least three of the five variables, fulfills the criteria for metabolic syndrome. Affected patients have a 20% mortality risk during 12 years of follow-up (102, 103, 104, 105, 106, 107).

The exact prevalence of complex metabolic syndrome in the posttransplant period is not known at present. However, a recent study from Norway reported that up to 18% developed posttransplant diabetes mellitus and another 31% developed impaired glucose tolerance at 10 weeks after renal transplantation (108). In another study of some 173 recipients of renal transplants, 50% had glucose intolerance (based on the definition of the American Diabetic Association [ADA]) and the cohort with impaired glucose tolerance tests had increased levels of insulin, triglyceride and low levels of HDL. Although waist circumference was not measured, however body mass index was identical in those with or without IGT (24).

Hence it is important to recognize that there could be a high prevalence of different components of the complex metabolic syndrome in the posttransplant period. How it affects the risk of developing cardiovascular disease in recipients of organ transplants needs to be studied. It could be one of the important and indeed treatable factors for the prevention of CVD in the posttransplant period.

TREATMENT TARGETS FOR DYSLIPIDEMIA IN RECIPIENTS OF SOLID ORGAN TRANSPLANTATION

Given the results of recent studies, such as REVERSAL (25) with a goal to lower LDL cholesterol to 79 mg/dL and PROVE IT (26), greater protection was conferred against death or major cardiovascular events in patients whose median LDL cholesterol was 62 mg/dL as compared to 95 mg/dL. In light of these new findings in patients with stable cardiovascular disease and following acute coronary syndrome, respectively, it may be the time to redefine the recommendations of the NCEP ATP III and also the guidelines of the National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative (DOQI) regarding the goal LDL cholesterol levels in recipients of renal transplants.

Based on the recommendations of the clinical practice guidelines committee of the American Society of Transplantation, it is recommended that fasting lipid profile be obtained at least once during the first 6 months and again every year after transplantation. In addition, annual screening should be performed in those with normal lipid profile at baseline evaluation.

Those with abnormal baseline values or those with high risk for cardiovascular disease or events during the follow-up period may need more frequent evaluations as deemed necessary by the treating physician.

It is however, important to recognize that recipients of solid organ transplants may have varying degrees of dyslipidemia at different time intervals after transplantation, depending upon the modifications in the type and doses of different immunosuppressive agents, since modifications in the maintenance immunosuppression is often warranted from time to time.

Based on the available evidence that has accumulated during the past 2 years, it will be a safe practice to consider patients with solid organ transplantation to be at high risk for cardiovascular disease, and the goal should be to achieve an LDL cholesterol level of less than 100 mg/dL and triglyceride goal level of less than 150 mg/dL.

How to Treat Dyslipidemia in Organ Transplant Recipients

Dietary Management

Weight control

Patients are prone to gain weight due to the use of varying doses of corticosteroids in the posttransplant period. This will also lead to increased risk of developing diabetes mellitus (posttransplant diabetes) and will aggravate the lipidemia. Therefore, immediately in the posttransplant period before discharge from the hospital, the patients shall be made cognizant about the risks of weight gain and counseled by the transplant dietitian who can educate the patient about dietary routines in the posttransplant period to avoid excessive weight gain.

In addition, obese patients should be further encouraged to loose weight and all patients should be strongly advised to take regular exercises as tolerated. In diabetic patients, mild to moderate degree of hypertriglyceridemia often responds to improvement in diabetic control to maintain hemoglobin A1C at the target level as recommended by ADA. Even nondiabetic patients with isolated mild to moderate hypertriglyceridemia respond to dietary modification with decreased intake of refined sugars and limiting fat intake to less than 30% of total calories.

The American Heart Association Step 1 cholesterol-lowering diet recommends that fat intake should be less than 30% of total calories and maintenance of a 1:1 ratio of saturated to polyunsaturated fats (11,109). However, dietary therapy alone is effective in less than 20% of patients in achieving the goal LDL in the posttransplant period (110) as has been observed in the general population. Patients treated with dietary intervention should have the lipid profile reexamined in 3 months time to stratify the indication for other treatment strategies.

New Dietary Combinations

Other dietary regimens that have proven to have significant benefit in the prevention of cardiovascular disease in the high-risk general population have been reported recently.

The Lyon Diet Heart Study was a 5-year randomized trial in which post-MI patients were put on a modified Mediterranean Diet—whole-grain bread, fruits, vegetables, beans, and fish; less meat; and an alpha-linolenic acidenriched canola oil margarine. The use of this type of diet was associated with a 60% decrease in mortality and 72% decrease in cardiovascular events, with no change in serum lipids or body weight (111,112).

Another study used the Indo-Mediterranean diet, which is rich in fruits, nuts, vegetables, whole grains, mustard seed oil and other sources of alpha-linolenic acid, and was associated with a markedly lower cardiovascular event rate than the NCEP step 1 diet (113). However, dietary intervention alone was reported to be less effective in patients with kidney disease (114).

Modifications in Maintenance Immunosuppression Therapy

Early Withdrawal or Avoidance of Corticosteroids

Vanrenterghem et al. demonstrated that early cessation of corticosteroids in a treatment regimen consisting of mycophenolate mofetil and CNIs is possible with a significant improvement in specific cardiovascular risk factors, including systolic and diastolic blood pressure, and total cholesterol and triglyceride levels in the group with early cessation of corticosteroids at week 12 posttransplant as compared to those who continued the maintenance steroid therapy without increasing the rate of biopsy-proven acute rejection (115). Birkland et al. reported on the use of antithymocyte globulin induction followed by CsA- and mycophenolate mofetil-based maintenance therapy without the use of corticosteroids in recipients of first and repeat transplants. It showed almost similar graft survival at 1 and 4 years and without increased risk of acute rejection and with avoidance of common steroid side effects (116). Other studies by Kaufman et al. (117) and Cantarovich et al. (118) in recipients of simultaneous kidney and pancreas transplants showed that the use of tacrolimus and mycophenolate mofetil or CsA and mycophenolate mofetil, respectively, was safe and prevented corticosteroid related side effects. Similarly, steroid-free regimens in heart and heart-lung transplant patients have been shown to decrease the magnitude of dyslipidemia with early withdrawal as compared to continuation of steroid therapy (119).

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