Dyslipidemia Following Kidney Transplantation: Diagnosis and Treatment Stéphanie Badiou, PhD, PharmD, Jean-Paul Cristol, MD, PhD, and Georges Mourad, MD

Corresponding author Georges Mourad, MD Department of Nephrology and Transplantation, University of Montpellier, Hôpital Lapeyronie, 371 Avenue du Doyen Gaston Giraud, 34295 Montpellier 05, France. E-mail: [email protected] Current Diabetes Reports 2009, 9:305–311 Current Medicine Group LLC ISSN 1534-4827 Copyright © 2009 by Current Medicine Group LLC

Lipid abnormalities are a common complication of kidney transplantation, occurring in up to 60% of patients. In fact, impairment of lipid metabolism is often present before renal transplantation due to the uremic state. After transplantation and recovery of renal function, lipid disturbances usually persist but show a different profi le due to the various effects of immunosuppressive drugs on lipid metabolism. Actually, steroids, calcineurin inhibitors, and mammalian target of rapamycin inhibitors usually lead to quantitative and qualitative abnormalities of very low-density, low-density, and high-density lipoproteins. As cardiovascular diseases remain the leading cause of death in renal transplant recipients, management of dyslipidemia and other traditional risk factors, such as smoking, arterial hypertension, diabetes mellitus, and obesity, is of great importance to prevent cardiovascular complications and chronic allograft dysfunction. This review addresses the causes of dyslipidemia, the role of immunosuppressive drugs, and current recommendations to manage lipid disorders in renal transplant recipients.

survival. In addition, it has been suggested that dyslipidemia could be associated with lower allograft survival [2]. High levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), non–high-density lipoprotein cholesterol (non–HDL-C), and triglycerides (TG) occur in up to 60% of RTR (Table 1). This hyperlipidemia is associated with qualitative lipoprotein modifications such as LDL enrichment in TG, which are then reduced in size to form small dense LDL (sdLDL) [3,4]. Serum lipid profi le of RTR is mainly the result of pretransplantation dyslipidemia, concomitant presence of glucose intolerance or diabetes mellitus, and the effect of immunosuppressive drugs on lipid metabolism. Calcineurin inhibitors (CNI), including cyclosporine (CsA) and tacrolimus, are a cornerstone of immunosuppressive regimens, which are currently associated with antiproliferative drugs such as mycophenolate mofetil, sodium mycophenolate, and azathioprine. Mammalian target of rapamycin (mTOR) inhibitors (eg, sirolimus and everolimus) are preferentially given as an alternative to CNI in RTR with cancer or allograft dysfunction. The addition of steroids was a usual practice but steroid-free protocols are now gaining in popularity [5,6]. Dyslipidemia is a common adverse effect of these drugs, requiring early diagnosis and specifi c management in order to reduce CV risk. Management of dyslipidemia should be included in a global strategy taking into account other traditional CV risk factors, such as smoking, hypertension, diabetes, and obesity.

Causes of Posttransplant Dyslipidemia Introduction Kidney transplantation improves the outcome of transplant recipients, but long-term use of immunosuppressive drugs leads to atherogenic complications in part through impairment of lipid metabolism. In fact, cardiovascular (CV) disease is now the leading cause of death in renal transplant recipients (RTR) [1], and better management of CV risk factors could result in improvement in patient

Immunosuppressive drugs are not the only culprit in posttransplant dyslipidemia. Pretransplant dyslipidemia is a significant risk factor for posttransplant dyslipidemia. In addition, similar to the general population, the role of familial predisposition, age, and obesity is well established. The usual comorbidities often present after renal transplantation, such as reduced renal function, proteinuria, and diabetes, may also be involved. Other drugs such as diuretics and β-blockers may also play a role.

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Table 1. Prevalence of dyslipidemia after kidney transplantation Lipid parameter

Level

Occurrence, %

Total cholesterol

> 200 mg/dL

50–60

LDL-C

> 130 mg/dL

50–60

Triglycerides

> 1.5 g/L

40–50

Lipoprotein(a)

> 300 mg/L

25

HDL-C

< 40 mg/dL

25–35

Non–HDL-C

> 160 mg/dL

40–50

HDL-C—high-density lipoprotein cholesterol; LDL-C—low-density lipoprotein cholesterol. (From Mourad, unpublished data.)

Table 2. Effect of immunosuppressive drugs on lipid parameters Drug

TC

LDL-C

HDL-C

TG

Cyclosporine

↑↑

↑↑

↓

↑↑

Tacrolimus

↑

↑

↓

↑

Sirolimus

↑↑

↑↑

↓

↑↑↑

Everolimus

↑↑

↑↑

↓

↑↑↑

–

–

–

–

Mycophenolate mofetil Azathioprine

–

–

–

–

Prednisone

↑

↑

↑

↑

Deflazacort

↑

↑

↑↑

↑

HDL-C—high-density lipoprotein cholesterol; LDL-C—low-density lipoprotein cholesterol; TC—total cholesterol; TG—triglcyeride.

Role of Immunosuppressive Drugs CNI and lipid metabolism CsA treatment is associated with a dose-dependent impairment of lipid metabolism characterized by elevation of TC, LDL-C, non–HDL-C, TG, apolipoprotein (apo) B, and apoC-III (Table 2) [7,8]. Because it is metabolized by the cytochrome P450 pathway, CsA interferes with sterol 27hydroxylase (CYP27A1) activity [9]. In vitro, CsA acts as a noncompetitive inhibitor of CYP27A1, causing reduced 27hydroxycholesterol formation. As 27-hydroxycholesterol drives bile acid production, its reduction slows bile acid formation, which is one method of cholesterol catabolism. In addition, 27-hydroxycholesterol is a potent inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the limiting step of cholesterol synthesis. Besides hypercholesterolemia, CsA induces hypertriglyceridemia, mainly through inhibition of lipoprotein lipase activity [10]. In contrast to CsA, tacrolimus is associated with less incidence of de novo hypercholesterolemia and similar incidence of de novo hypertriglyceridemia [7]. Despite higher levels than in hemodialysis patients, RTR treated with CNI have low HDL-C levels, which worsens their atherogenic risk [11]. A decrease in HDL-C is frequently associated with hypertriglyceridemia as a result of HDL metabolism change in the presence of very low-density lipoprotein

(VLDL) accumulation, as usually reported in insulin-resistant states and metabolic syndrome (MS). Increased activity of the cholesterol ester transfer protein in association with decreased lipoprotein lipase activity, as observed in vitro with CsA [10], could be a contributing factor in accelerating HDL catabolism. Switching from CsA to tacrolimus in RTR can result in a decrease of LDL-C and TG levels but no change in HDL-C levels [12,13]. In addition to impaired HDL metabolism, VLDL accumulation leads to TG enrichment of LDL [3], which is then reduced in size to become sdLDL (Fig. 1). Only a few studies have explored LDL size in RTR. One study reported sdLDL (defined as LDL < 25.5 nm in diameter) in approximately 30% of patients receiving either CsA or tacrolimus in association with azathioprine and prednisolone [4]. In this study, the decrease in LDL size was highly correlated with increased non–HDL-C levels, which could be used as a marker of sdLDL presence. Low HDL-C, hypertriglyceridemia, and presence of sdLDL are the characteristic cluster of MS. MS is observed in around 20% of RTR and appears significantly associated with lower graft survival [14,15]. Beyond induced dyslipidemia, patients receiving tacrolimus have a higher risk of new-onset diabetes [16], especially if they have high TG levels before transplantation [17]. The specific metabolic complications of CNI, in relation to the glucose and lipid status, should be taken into account in the choice of each individual treatment before transplantation.

mTOR inhibitors and lipid metabolism Use of sirolimus or everolimus has a favorable effect on renal function and provides similar graft survival rates as CNI [18–20]. However, patients treated with mTOR inhibitors have impaired lipid metabolism (Table 2) and required more use of lipid-lowering agents compared with those receiving CNI [21,22]. Sirolimus is associated with dosedependent hypercholesterolemia that could be related in part to a competitive inhibition of CYP27A1 [23]. As does CsA, sirolimus reduces the levels of 27-hydroxycholesterol in vitro [9]. In addition, sirolimus inhibits the transcription of the LDL receptor gene in hepatic cells, leading to decreased LDL clearance [24]. Hypertriglyceridemia is also a key feature of treatment with mTOR inhibitors [21]. It appears in sirolimus-treated patients as a result of increased VLDL synthesis [23] and decreased lipoprotein lipase activity (Fig. 1) [10]. The influence of mTOR inhibitors on CV risk needs to be assessed, taking into account all the pleiotropic effects of sirolimus and everolimus. Indeed, animal studies highlighted a paradox, as the atheroprotective effects of mTOR inhibitors are observed despite the presence of significant hyperlipidemia [25].

Purine synthesis inhibitors and lipid metabolism The antiproliferative agents mycophenolate mofetil, mycophenolate sodium, and azathioprine have little involvement in lipid disorders (Table 2). When comparing the two mycophenolic acid–containing drugs, no difference in lipid levels is observed [8].

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Figure 1. In vitro effects of immunosuppressive drugs on lipid metabolism. Decreased activity of lipoprotein lipase (LpL) leads to very low-density lipoprotein (VLDL) accumulation and thus hypertriglyceridemia. The cholesterol ester transfer protein (CETP) then transfers triglyceride from VLDL into low-density lipoprotein (LDL) in exchange for esterified cholesterol (dashed arrows). These triglyceride-rich LDL are then hydrolyzed by hepatic lipase (HL) to form small dense LDL (sdLDL), which have low affinity for the apolipoprotein (Apo) B/E receptor. CsA— cyclosporine; HDL—high-density lipoprotein; IDL—intermediate-density lipoprotein.

Corticosteroids and lipid metabolism Increases in TC and HDL-C are frequently observed with steroid treatment (Table 2); an increase in TC is mainly due to stimulation of HMG-CoA reductase, the limiting step in cholesterol synthesis [26]. Interestingly, in a pediatric population, deflazacort was associated with a greater increase in HDL-C than was prednisolone [27]. Steroid treatment is also associated with increased VLDL synthesis and a decrease in lipoprotein lipase activity, leading to hypertriglyceridemia (Fig. 1) [26]. These findings were reported in relatively older protocols that used higher steroid doses than current protocols. More recent studies have reported similar TC and lower TG levels in RTR with early steroid withdrawal (day 7) or steroid avoidance compared with standard (ie, low-dose) steroid therapy [28••,29]. Interestingly, steroid avoidance and early withdrawal of steroids were associated with a significant decrease of new-onset diabetes, MS, and CV events [29].

Diagnosis of Posttransplant Dyslipidemia According to the National Kidney Foundation (NKF) Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines [30], the fasting lipid profile including TC, HDLC, calculated LDL-C, and TG should be determined in all RTR 3 months after transplantation and at least annually thereafter. Checking for lipid levels is also required 3 months after a change in immunosuppressive or hypolipemiant treatment or the occurrence of any conditions known to cause dyslipidemias. Non–HDL-C, a reflection of all apoB100–containing atherogenic lipoproteins, is calculated as TC minus HDL-C. Measurement of lipoprotein(a) and apoA-I and apoB concentrations is usually not required in routine clinical practice. RTR should be considered as having chronic kidney disease, so they are in the highest CV risk category (corresponding to coronary heart disease) [31]. According to the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP)-III criteria, dyslipidemia in RTR is diagnosed if one of the following is found: TC greater than

200 mg/dL (5.18 mmol/L), LDL-C greater than 100 mg/dL (2.59 mmol/L), TG greater than 150 mg/dL (1.7 mmol/L), or HDL-C less than 40 mg/dL (1.03 mmol/L) [32].

Management of Posttransplant Dyslipidemia Although no large randomized trials have assessed the effect of dyslipidemia on long-term clinical outcome of RTR, preliminary studies highlighted the potential involvement of dyslipidemia in increased CV mortality and decreased allograft survival [2]. From extrapolation of the relationship between dyslipidemia and CV diseases in the general population, correction of dyslipidemia should be important in trying to curb CV mortality in RTR. Specific guidelines for dyslipidemia management in RTR have been available since 2004. They have always considered RTR in the highest risk category [30]. Strategies to obtain a reduction of lipid levels include therapeutic life change (TLC), lipid-lowering drugs, and potential modification of the immunosuppressive regimen. TLC includes a reduction of saturated fats (< 7% of total calories) and cholesterol intake (< 200 mg/d), consideration of dietary option such as plant stanols/sterols, increase of dietary fibers, weight control, and moderate daily physical activity (3–4 times per week, 20–30 minute periods of activity) [30].

LDL-C levels According to the NKF K/DOQI guidelines, LDL-C less than 100 mg/dL (2.59 mmol/L) remains the fi rst goal in all RTR unless TG levels are higher than 500 mg/dL (5.65 mmol/L) [30]. LDL-C: 100–129 mg/dL If LDL-C ranges from 100 to 129 mg/dL, TLC is the first step. A diet should be proposed in patients without evidence of malnutrition, and the assistance of a dietitian with experience in RTR care is often necessary. Interventional studies in RTR showed beneficial effects of diet on TC

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and LDL-C levels without change in HDL-C [33]. It was reported that 1 year of TLC, including diet (total fat < 30% of total calories, saturated fatty acids < 10%, cholesterol < 300 mg) and physical activity (30 min/d, 5 d/wk) initiated during the first year after renal transplantation, provides a significant decrease in TC (25%) at 12 months compared with baseline levels [34]. After 3 months of TLC, if LDL-C remains between 100 and 129 mg/dL, a statin should be added to the TLC in the absence of liver disease. LDL-C ≥ 130 mg/dL TLC and statin therapy should be initiated simultaneously. The use of statins is recommended mainly on the basis of beneficial results obtained in the general population, as there is only one randomized study with valid results assessing the effects of statins on clinical outcome of RTR. In the Assessment of Lescol in Renal Transplantation (ALERT) study, only the secondary end points (cardiac death, definite myocardial infarction, and the combined end point of cardiac death or nonfatal myocardial infarction) were significantly reduced by fluvastatin (40 mg/d for 5 years), whereas the primary end point (total cardiac adverse major events including cardiac death, nonfatal myocardial infarction, coronary artery bypass surgery, or percutaneous coronary intervention) were not significantly different compared with the placebo group [35]. In the 2-year extension study of ALERT, fluvastatin (80 mg/d) treatment was associated with a significant reduction in cardiac death or definite nonfatal myocardial infarction when compared with placebo, with no significant effect on the total mortality or graft loss [36]. Although encouraging, these results demonstrate a lower efficacy of statins in RTR than in the general population, so additional trials in RTR are needed. The result on the mortality contrasted with observational studies reporting beneficial effect of statin use on RTR survival [37,38•]. Beyond CV protection, statins were expected to improve graft survival [2], but this effect was not confirmed in the ALERT study. Statins should always be used at the lowest doses that achieve the LDL-C goal in order to minimize the risk of myopathy. Statins should be discontinued in case of elevation of creatine phosphokinase greater than 10 times the upper limit of normal. According to the NCEP ATP-III recommendations, a reduced dose (50% compared with the general population) is suggested in RTR, taking into account the alteration of statin metabolism by immunosuppressive drugs, especially CsA [39]. Although interaction between tacrolimus and statins is not proven [40], the NKF K/DOQI guidelines recommend considering that tacrolimus could increase statin blood levels [30]. For patients who have undergone TLC and optimal statin treatment and who still have persistent LDL-C ≥ 100 mg/dL, a combination with a bile acid sequestrant should be considered if TG are less than 400 mg/dL (4.52 mmol/L). Because there are few data available on the interaction between bile acid sequestrant agents and immunosuppressive drugs, the expected benefit should be

carefully assessed. The cautious approach is to avoid the administration of the bile acid sequestrant from 1 hour before to 4 hours after the dose of a CNI, especially CsA, and to regularly monitor blood levels of CNI [30]. For patients with persistent LDL-C ≥ 100 mg/dL who cannot receive a bile acid sequestrant (TG ≥ 400 mg/dL or intolerance), nicotinic acid could be considered in combination with a statin; however, there are no data available on the safety and efficacity of this combination in RTR. Ezetimibe could also be an alternative option; however, the NKF K/DOQI guidelines underline the lack of data and recommend waiting for the demonstration of safety and efficacy of the statin–ezetimibe combination in RTR. More recently, a pilot study reported a beneficial effect of ezetimibe added to lovastatin in RTR with TC greater than 200 mg/dL [41]; however, additional studies are needed to determine the rationale of treating these patients with a statin–ezetimibe combination. If lipid-lowering therapy fails to achieve LDL-C less than 100 mg/dL, modification of the immunosuppressive therapy could be an alternative option. However, the risk of acute rejection or under-immunosuppression should always be taken into account and carefully weighed before changing immunosuppressive medications. After minimizing drug dosages, the main strategies are the switch from mTOR inhibitors or CsA to tacrolimus or purine synthesis inhibitors, allowing a significant reduction of LDL-C and/or TG [12,13,42••].

TG levels TG > 500 mg/dL According to the NKF K/DOQI guidelines, TG greater than 500 mg/dL (5.65 mmol/L) should be treated before LDL-C in order to prevent pancreatitis. TLC is the fi rstline treatment. This should include diet, weight loss, increased physical activity, abstinence from alcohol, and, if present, treatment of hyperglycemia. If TLC fails to reduce TG to less than 500 mg/dL, modification of immunosuppressive regimen or introduction of TG-lowering drugs such as fibrate or niacin should be considered. However, there are few data on the safety and efficacy of fibrate or niacin in RTR. Fibrate-induced creatinine increase may be observed; several mechanisms could be involved, including enhanced metabolic production of creatinine or a toxic effect on the proximal tubule [43]. TG: 200–499 mg/dL TG ≥ 200 mg/dL (2.26 mmol/L) with non–HDL-C greater than 130 mg/dL should be managed as detailed in the following text to reach the non–HDL-C goal.

Non–HDL-C levels For patients with optimal LDL-C, a second target of non–HDL-C less than 130 mg/dL (3.36 mmol/L) is defi ned for RTR with TG from 200 to 499 mg/dL (this is in agreement with the NCEP ATP-III recommendations for high-risk patients in the general population,

Dyslipidemia Following Kidney Transplantation: Diagnosis and Treatment

including those with MS). As VLDL-C should not exceed 30 mg/dL, the non–HDL-C goal is defi ned as LDL-C goal plus 30 mg/dL. Therefore, a target of 130 mg/dL (3.36 mmol/L) should be applied for all RTR with TG levels between 200 and 499 mg/dL (2.26–5.64 mmol/L). The NKF K/DOQI working group recommend statin therapy for managing non–HDL-C. Although fibrate therapy would be fi rst-line treatment in the general population, there is no randomized study to evaluate the safety of fibrate in RTR. Therefore, the cautious approach is to treat RTR with non–HDL-C greater than 130 mg/dL and TG from 200 to 499 mg/dL using statins rather than fibrates. Nicotinic acid could be used as an alternative approach to fibrate for patients with high TG, but there are also few data on this therapeutic approach in RTR. Particular attention should be given to reduction of alcohol consumption and treatment of hyperglycemia in those patients in order to reach the therapeutic goal. Interestingly, non–HDL-C, which is a reflection of the VLDL mass that is classically increased in MS, is inversely correlated with LDL size in RTR [4], as in other populations [44,45]. Taking into consideration the association between sdLDL and coronary heart disease [46], the role of sdLDL could be underestimated in RTR with or without MS. It was reported that a decrease of non–HDL-C, in contrast to a decrease of LDL-C, is associated with a favorable effect on LDL size in a nontransplant hyperlipidemic population [47]. In agreement with the mechanism of sdLDL formation, no change in the proportion of sdLDL is observed in RTR despite significant improvement of LDL-C levels after switching from CsA to tacrolimus or introduction of statins [48]. In view of the predictive power of non–HDL-C in CV mortality [49] and the association between non–HDL-C and coronary calcifications in nontransplant patients [50•], reaching the non–HDL-C goal could be expected to reduce CV complications in RTR. Nevertheless, prospective randomized trials are needed to confirm this hypothesis.

HDL-C levels As in the general population, HDL-C is inversely associated with CV mortality in RTR. In addition, HDL-C in the general population is inversely correlated with coronary calcification scores [50•], suggesting a major role of HDL in prevention of vascular calcifications. The NCEP ATP-III guidelines defi ned an HDL-C less than 40 mg/ dL as an additional risk factor, whereas HDL-C greater than 60 mg/dL is considered protective. Low HDL-C, which is associated with high TG and high non–HDLC (as observed in MS), should be corrected to reach the non–HDL-C goal of less than 130 mg/dL. RTR with isolated HDL less than 40 mg/dL (1.03 mmol/L) should be managed with TLC only, as there is no evidence of clinical benefit with pharmacologic treatment. In the general population, moderate physical activity three to five times per week, equivalent to a caloric expenditure of 1200 to 1600 kcal/wk, is associated with a significant increase in HDL-C.

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Conclusions Dyslipidemia, a common complication of kidney transplantation, should usually be treated by TLC and statins in order to reach goal levels of LDL-C and non–HDL-C. Management of dyslipidemia would help to curb the high CV mortality observed in these patients. However, as maintaining an effective immunosuppressive therapy is the first requirement and as these drugs promote or worsen lipid disorders and/or complicate their effective management, more than half of RTR still do not achieve their LDL and non–HDL-C goals. Large interventional randomized studies are needed to analyze the efficacy and safety of lipid-lowering strategies and drug combinations and their impact on the long-term clinical outcome in this specific population.

Disclosure Dr. Mourad has received honoraria for conferences from Novartis, Roche, and Amgen. Dr. Cristol has received honoraria for conferences from Beckman, Olympus, and Siemens. No other potential confl icts of interest relevant to this article were reported.

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