Version May 2024
INTRODUCTION — The pathogenesis of posttransplant atherosclerotic cardiovascular disease (ASCVD) most likely involves traditional and nontraditional risk factors. Although lipid abnormalities and ASCVD are common complications of kidney transplantation, a causal association of dyslipidemias with cardiovascular risk has not been proven in this patient population.
However, extrapolation from general population studies and some data in kidney transplant patients support the view that the assessment and treatment of dyslipidemias should be part of routine post–kidney transplantation care. Since immunosuppressive medications often cause secondary dyslipidemias, medication regimens should be individualized to minimize the competing risks of rejection and ASCVD.
Due to the high incidence of atherosclerotic disease events in the kidney transplant population, we and several national groups believe that patients with kidney transplants should be considered to be in the highest ASCVD risk group with respect to risk factor management [1]. Kidney transplantation should therefore be considered a coronary heart disease equivalent risk. The prevalence of and ability to modify dyslipidemias therefore render lipid modification a potentially important intervention for improving outcomes after kidney transplantation.
This topic will review the causes and management of lipid abnormalities in an attempt to lower cardiovascular risk in kidney transplant recipients.
PREVALENCE — Dyslipidemia is defined by elevated plasma total cholesterol, elevated low-density lipoprotein cholesterol (LDL-C), elevated triglycerides, and/or low high-density lipoprotein cholesterol (HDL-C), all factors that may contribute to the development of atherosclerosis. Dyslipidemia is a frequent complication prior to and after kidney transplantation, even when allograft function is normal or near normal.
Increases in total cholesterol and LDL-C levels are the most common abnormalities, with elevated triglyceride levels also frequently noted [1]:
●Historically, single- and multicenter reports have estimated that by one year posttransplantation, 80 to 90 percent of adult recipients have total cholesterol levels >200 mg/dL (5.2 mmol/L) and 90 to 97 percent have LDL-C levels >100 mg/dL (2.6 mmol/L) [2,3]. Mean reported triglyceride level values ranged from 160 to 200 mg/dL (1.8 to 2.26 mmol/L) [1]. A high prevalence of dyslipidemia, especially hypertriglyceridemia, has also been identified among pediatric transplant recipients [4].
●In a multicenter, prospective, cohort study of 935 kidney transplant recipients, 45 percent of patients had LDL-C levels >100 mg/dL, and mean triglyceride levels were 142 mg/dL at six months posttransplantation [5]. These patterns likely reflect lower target levels in contemporary maintenance immunosuppression regimens, as well as concomitant statin treatment in 41 percent.
●HDL-C levels <40 mg/dL have been estimated in 14 to 48 percent of transplant recipients at one year or later posttransplantation [1]. In one small study of longitudinal trends in lipid levels before and after kidney transplantation, transplantation was associated with an increase in HDL-C levels, but the benefit was dependent upon maintenance of allograft function [6].
CAUSES OF DYSLIPIDEMIA
Immunosuppressive agents — Immunosuppressive agents, particularly glucocorticoids, calcineurin inhibitors (CNIs), and mammalian (mechanistic) target of rapamycin (mTOR) inhibitors, have well-known dose-related effects on serum lipid levels:
●Glucocorticoids – Glucocorticoids alter lipoprotein metabolism to cause dyslipidemia, particularly elevated cholesterol levels, via multiple indirect pathways. These include hyperinsulinemia-mediated stimulation of hepatic very-low-density lipoprotein (VLDL) synthesis and downregulation of low-density lipoprotein cholesterol (LDL-C) receptors, possibly via adrenocorticotropic hormone (ACTH) suppression [7]. (See "Major adverse effects of systemic glucocorticoids".)
Data from clinical trials demonstrate that glucocorticoid withdrawal may lower total cholesterol and, possibly, triglyceride levels [8-11]. However, these benefits must be considered in the context of higher acute rejection risk, as well as a possible increased risk of allograft loss and recurrent glomerulonephritis [8,9,12]. In addition, glucocorticoid elimination may not yield a net benefit in the overall lipid profile, since it may depress protective high-density lipoprotein cholesterol (HDL-C) levels to the same extent as total cholesterol [13]; as a result, the HDL-C to total cholesterol ratio remains unchanged [13]. Nonetheless, reducing glucocorticoids may have other cardioprotective benefits, including improved blood pressure and glucose tolerance.
●Calcineurin inhibitors – Cyclosporine can directly cause posttransplant hypercholesterolemia, an effect that is independent of concurrent glucocorticoid use [14]. The impact of cyclosporine upon lipid levels appears dose dependent as trough blood levels of the agent correlate with elevations in total and LDL-C concentrations and with reductions in HDL-C levels [15,16].
By comparison, lipid profiles appear to be more favorable among patients receiving tacrolimus, rather than cyclosporine, from the time of transplantation [17-19]. Converting from cyclosporine to tacrolimus may provide significant benefits in serum lipid levels. In a multicenter trial, 124 patients at least one year posttransplantation were randomly assigned to the continuation of cyclosporine at target trough levels of 50 to 200 ng/mL versus conversion to tacrolimus at target trough levels of 5 to 8 ng/mL [20]. After six months, participants in the tacrolimus group experienced significant mean reductions in LDL-C and triglycerides of 134 to 120 mg/dL (3.48 to 3.11 mmol/L) and 186 to 152 mg/dL (2.11 to 1.72 mmol/L), respectively. In addition, tacrolimus-related LDL-C reductions were confined to patients not using statins, the administration of which was not regulated. Several smaller, randomized trials have also shown consistent reductions in total cholesterol and LDL-C after the conversion from cyclosporine to tacrolimus among stable patients [21,22].
●mTOR inhibitors – mTOR inhibitors (sirolimus and everolimus) are frequently associated with dyslipidemias posttransplantation, particularly hypertriglyceridemia. The mechanism of action includes blocking insulin-stimulated lipoprotein lipase [23]. This is also supported by the finding of fractional reductions in the catabolism of apoB100-containing lipoproteins in kidney transplant recipients with sirolimus-related hypertriglyceridemia [24].
Data from clinical trials comparing sirolimus with cyclosporine or tacrolimus as part of a triple-drug immunosuppression regimen reveal the time course and degree of dyslipidemia that may occur in association with sirolimus [25-27]. In these studies, patients receiving sirolimus, compared with those on a CNI, had higher levels of triglycerides, LDL-C, and total cholesterol in the first few months posttransplantation, but these differences decreased at later timepoints. Sirolimus-treated patients were also more likely to be on lipid-lowering drugs.
Other causes — Other secondary causes in this patient population may include the nephrotic syndrome, hypothyroidism, diabetes mellitus, excessive alcohol intake, obesity, and chronic liver disease. Genetic predisposition and low daily exercise also contribute to dyslipidemia.
MONITORING — For all transplant recipients, we measure an initial fasting lipid panel (including total cholesterol, low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], and triglycerides) before initiation of statin therapy (see 'Our approach' below), followed by a second measurement 4 to 12 weeks later to assess adherence and then by repeat measurements every 3 to 12 months, as clinically indicated. This is consistent with the 2013 American College of Cardiology (ACC)/American Heart Association (AHA) Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults [28].
The 2013 Kidney Disease: Improving Global Outcomes (KDIGO) guideline suggests evaluation of all patients who have newly identified chronic kidney disease (CKD; including those treated with transplantation) with a lipid profile including total cholesterol, LDL-C, HDL-C, and triglycerides but suggest that follow-up is not required for the majority of patients, since the indication for treatment is the higher cardiovascular risk, rather than LDL-C concentration [29].
The ACC/AHA guideline on treatment of blood cholesterol to reduce atherosclerotic cardiovascular disease (ASCVD) also concluded that initiation of statin therapy for patients without kidney disease should be based on clinical indications rather than lipid levels [28]. However, the ACC/AHA guideline suggests that measurement of fasting lipid levels and percentage reductions in LDL-C are reasonable for assessing the response to therapy and adherence. (See 'Our approach' below and 'Rationale for our approach' below.)
TREATMENT
Management of LDL-C to reduce cardiovascular risk — Overall, the management of low-density lipoprotein cholesterol (LDL-C) to reduce cardiovascular risk is similar in kidney transplant recipients and in nontransplant patients with chronic kidney disease (CKD). Our approach depends upon whether the patient has established atherosclerotic cardiovascular disease (ASCVD; secondary prevention) or does not have established ASCVD (primary prevention). (See 'Patients with established ASCVD (secondary prevention)' below and 'Patients without established ASCVD (primary prevention)' below.)
Patients with established ASCVD (secondary prevention) — Kidney transplant recipients with established atherosclerotic cardiovascular disease (ASCVD; prior history of coronary, cerebrovascular, or peripheral arterial disease) should receive maximally tolerated statin therapy, similar to nontransplant patients with established ASCVD.
The treatment of such patients, including goal LDL-C and monitoring, is presented separately. (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease", section on 'Our approach'.)
Patients without established ASCVD (primary prevention)
Our approach — Statin therapy is appropriate for adult kidney transplant recipients age >40 years without established atherosclerotic cardiovascular disease (ASCVD) if their estimated 10-year ASCVD risk is >10 percent (calculator 1). This approach is similar to the management of LDL-C for primary prevention in the general population. (See "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease".)
For all other adult kidney transplant recipients age >30 years without established ASCVD, we suggest statin therapy. For adult kidney transplant recipients age 18 to 29 years without established ASCVD, the decision to treat with statin therapy should be individualized, considering patient preferences and a relatively small expected ASCVD reduction over 10 years versus the risks of polypharmacy and drug toxicity. (See 'Rationale for our approach' below.)
●Initial dose – In patients receiving a statin, we initiate statin therapy with lower doses than the doses suggested by Kidney Disease: Improving Global Outcomes (KDIGO) to prevent possible side effects, such as one of the following regimens:
•Fluvastatin 40 mg daily
•Atorvastatin 10 mg daily
•Rosuvastatin 5 mg daily
•Pravastatin 20 mg daily
•Simvastatin 20 mg daily
●Target dose – For transplant recipients who are not on cyclosporine, doses may be increased, if the patient does not report side effects, in order to achieve the following final target doses: fluvastatin 80 mg daily, atorvastatin 20 mg daily, rosuvastatin 10 mg daily, pravastatin 40 mg daily, or simvastatin 40 mg daily. These regimens have been shown to be beneficial in the CKD population in clinical trials.
For transplant recipients who are receiving cyclosporine, special caution is warranted. Cyclosporine inhibits the hepatic metabolism of many statins, resulting in higher blood levels. Thus, for patients who are on cyclosporine, we suggest continuing to use the lower doses listed above (ie, fluvastatin 40 mg daily, atorvastatin 10 mg daily, rosuvastatin 5 mg daily, pravastatin 20 mg daily, and simvastatin 20 mg daily). Roughly similar doses have been used in randomized clinical trials of statin therapy among kidney transplant recipients, which included patients on cyclosporine-based regimens, although most of these trials were of relatively short duration [30].
●Alternatives to statins – For transplant recipients who do not tolerate statins, we suggest the use of ezetimibe as a second choice. A statin/ezetimibe combination is also a reasonable option if the target statin dose is not tolerated due to side effects. These recommendations are based largely on extrapolation from the demonstration of efficacy among patients with CKD and, in our experience, the absence of significant observed toxicity [31,32].
Data supporting the use of proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors (evolocumab, alirocumab) or bempedoic acid are lacking in kidney transplant recipients. In our clinical experience, however, such agents can be effective for patients who do not tolerate statins, and their pharmacokinetic profile does not suggest risk of significant interactions with immunosuppressive therapy. In the absence of data in the kidney transplant population, cautious use of these agents may be reasonable.
●Monitoring on therapy – We do not target a specific LDL-C goal. However, we monitor lipids annually and encourage treatment adherence as necessary based upon total cholesterol and LDL-C levels. (See 'Rationale for our approach' below and 'Monitoring' above.)
In the general population, studies that have demonstrated better outcomes with lipid-lowering therapy have used statins rather than other lipid-lowering therapies. In addition, among heart transplant patients, statins are associated with significant mortality benefits. (See "Heart transplantation: Hyperlipidemia after transplantation" and "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)
By comparison, there are no definitive data of statin-related improvement in ASCVD outcomes in patients with kidney transplants, although there is suggestive evidence of benefits [33-35]:
●Assessment of LEscol in Renal Transplantation (ALERT) is the only randomized, controlled trial on the effect of dyslipidemia management on ASCVD outcomes after kidney transplantation [34]. In this study, 2101 kidney transplant recipients with total cholesterol levels between 154 and 347 mg/dL (4 to 9 mmol/L) were randomly assigned to fluvastatin 40 mg or placebo. After a mean of 5.1 years, the statin group achieved a 32 percent lower mean LDL-C level compared with the placebo group (average difference of 38 mg/dL [1.0 mmol/L]). There was a nonsignificant trend with active therapy toward a reduction in the primary composite outcome of cardiac death, nonfatal myocardial infarction, or coronary interventions (relative risk [RR] 0.83, 95% CI 0.64-1.06). In addition, significantly fewer cardiac deaths or nonfatal myocardial infarction, a secondary outcome, were observed with fluvastatin (70 versus 104, RR 0.65, 95% CI 0.48-0.88) [36]. The ALERT trial did not enroll participants <30 years of age.
Significant long-term benefits in the primary composite outcome with statin therapy were observed in an extension of the ALERT study, in which all patients initially enrolled were offered fluvastatin for an additional two years [35]. At a mean total follow-up of 6.7 years, the group initially randomly assigned to active therapy, compared with the original placebo group, had a significantly lower risk of the primary cardiac composite outcome (hazard ratio [HR] 0.79, 95% CI 0.63-0.99). However, there was no significant difference in overall mortality or in the rate of allograft loss.
●A 2012 meta-analysis that included 3297 transplant recipients showed an uncertain impact of statin use versus placebo or no treatment on overall mortality (RR 1.05, 95% CI 0.84-1.31) but a possible reduction in cardiovascular mortality (RR 0.68, 95% CI 0.45-1.02) [37]. However, the number of events was low.
●A 2014 Cochrane meta-analysis of 22 studies including 3465 kidney transplant recipients compared statins with placebo or no treatment (17 studies, 3282 participants) or another statin (5 studies, 183 participants) [38]. There were trends toward a benefit of statins in terms of cardiovascular mortality (4 studies, 2322 participants; RR 0.68, 95% CI 0.45-1.01), major cardiovascular events (1 study, 2102 participants; RR 0.84, 95% CI 0.66-1.06), and fatal or nonfatal myocardial infarction (1 study, 2102 participants; RR 0.70, 95% CI 0.48-1.01). Statins were not associated with lower all-cause mortality (6 studies, 2760 participants; RR 1.08, 95% CI 0.63-1.83) or stroke (1 study, 2102 participants; RR 1.18, 95% CI 0.85-1.63).
Additional trials have shown that statin therapy improves lipid profiles in kidney transplant recipients. The average range in reductions in lipid levels was 18 to 33 percent for total cholesterol, 20 to 42 percent for LDL-C, and 0 to 23 percent for triglycerides, while average increases in high-density lipoprotein cholesterol (HDL-C) were 0 to 13 percent [39-47].
Data evaluating the use of ezetimibe in the transplant population are limited [48-51]. A prospective study of 18 kidney transplant recipients with uncontrolled cholesterol levels, despite statin therapy, found that the combination of ezetimibe plus statin therapy significantly lowered LDL-C levels [50]; ezetimibe therapy was stopped in two patients because of nausea and muscle pain without elevations in creatine kinase (CK) levels.
Rationale for our approach — A paradigm shift has emerged with regard to the role of using lipid levels to guide the initiation and titration of statins for ASCVD risk reduction in both the general population and among patients with CKD, including transplant recipients. The 2013 American College of Cardiology (ACC)/American Heart Association (AHA) guideline identified four major groups of patients for whom there was robust evidence of benefit of statin therapy to reduce ASCVD risk, which outweighed the risk of adverse events [52]. These groups were defined as individuals with clinical ASCVD, individuals with primary elevations of LDL-C >190 mg/dL, patients with diabetes aged 40 to 75 years with LDL-C 70 to 189 mg/dL and without clinical ASCVD, or individuals without clinical ASCVD or diabetes with LDL-C 70 to 189 mg/dL and estimated 10-year ASCVD risk >7.5 percent.
The traditional "treat-to-goal" paradigm was replaced with use of clinical criteria as the indication for therapy. This was based on the rationale that, among these groups in the general population (ie, without kidney disease), randomized, controlled trials have demonstrated reductions in ASCVD events with use of the maximum-tolerated statin therapy in specific groups.
Furthermore, there is concern that use of LDL-C targets may result in undertreatment with statin therapy or overtreatment with nonstatin drugs that have not been shown to reduce ASCVD events in randomized, controlled trials. However, while randomized, controlled trial evidence to support lipid levels as treatment targets was not identified, measurement of fasting lipid levels and percentage reductions in LDL-C were deemed reasonable for assessing the response to therapy and adherence, with "high-intensity" therapy defined as an average LDL-C reduction >50 percent from the untreated baseline, "moderate-intensity" therapy defined as LDL-C reductions of 30 to <50 percent from the untreated baseline, and "low-intensity" therapy defined as an average <30 percent reduction in LDL-C. The ACC/AHA guideline advises measurement of an initial fasting lipid panel before initiation of statin therapy, followed by a second measurement 4 to 12 weeks later to assess adherence and then by repeat measurements every 3 to 12 months, as clinically indicated.
The ACC/AHA guideline concluded that there was insufficient randomized, controlled trial evidence for guiding clinical recommendations for some groups, including solid organ transplant recipients and individuals <40 years of age with low estimated 10-year ASCVD risk but high lifetime ASCVD. Thus, clinical judgment weighing potential benefits, adverse effects, drug-drug interactions, and patient preferences were advised for these groups. A pilot qualitative study of kidney transplant recipients' perspectives on cardiovascular disease and related risk factors found that, in contrast with patients' concerns centered on immunosuppression and preserving allograft function, participants did not identify preventing hyperlipidemia as a posttransplantation-care priority [53]. This finding may suggest a need for education to engage patients in complying with lipid-lowering therapies when treatment is prescribed.
Considering the same evidence from the transplant population summarized above (see 'Our approach' above), the KDIGO Clinical Practice Guideline for Lipid Management in Chronic Kidney Disease recommended treatment with statins in all adult kidney transplant recipients but noted that supporting evidence was considered weak, since there was only a single, large, randomized, controlled trial in this population, the ALERT trial cited above, which showed a trend toward reduction in the ASCVD endpoint but, as noted, failed to reach statistical significance in the primary trial. Although this recommendation was not stratified by demographic or clinical factors, the risk of ASCVD is age dependent, and the ALERT trial did not enroll participants <30 years of age. Thus, inclusion of adult kidney transplant recipients age 18 to 29 years in this KDIGO recommendation is opinion based. A 2020 position paper of the Italian Society of Nephrology similarly endorses statins as the cornerstone of dyslipidemia therapy in transplant recipients [54].
Management of hypertriglyceridemia — Some kidney transplant recipients have very high triglyceride levels due primarily to the consequences of immunosuppressive medications. (See 'Immunosuppressive agents' above.)
The overall approach to the management of hypertriglyceridemia among kidney transplant recipients is similar to that for the general population (see "Hypertriglyceridemia in adults: Management", section on 'Treatment goals'). All patients should participate in nonpharmacologic lifestyle interventions such as dietary modification, weight reduction if overweight, increased physical activity, and reduced alcohol intake [29]. However, diets should be used judiciously, if at all, in patients with protein-energy malnutrition. In addition, because kidney transplant recipients frequently have other nutritional concerns, dietary modification requires consultation with a dietitian experienced in the care of these patients. Alternatives to medications known to aggravate lipid levels should also be considered. (See "Hypertriglyceridemia in adults: Management", section on 'General measures'.)
If pharmacologic therapy is indicated, ezetimibe, omega-3 fatty acids (eg, icosapent ethyl), and nicotinic acid (niacin) can be used, although data supporting their efficacy in kidney transplant recipients are limited [31,48,49,55,56]. We avoid fibrates (such as gemfibrozil), given the potential toxicity associated with these agents, particularly fibrate-related myositis and rhabdomyolysis. Associations of fibrate therapy with 30 to 40 percent elevations in serum creatinine concentrations have also been noted in retrospective studies among patients with baseline kidney function impairment and/or solid organ transplants [57,58]. While such changes are often reversible and their relation to true alterations of glomerular filtration rate is unclear, such elevations may complicate the assessment of other conditions such as acute rejection. A unique nephrotoxicity attributed to fibrates has also been described. (See 'Drug interactions and adverse effects' below.)
Management of immunosuppression — Agents used for maintenance immunosuppression in transplant recipients are a common cause of dyslipidemia. (See 'Immunosuppressive agents' above.)
Balancing the efficacy and side effects of immunosuppressive therapy, acute rejection risk, risks of other complications including ASCVD, and related treatment options is complex. Given that allograft failure is the principal risk to a patient's health, dyslipidemia may be tolerated, even if it is related to immunosuppressive therapy and cannot be optimally treated. Thus, if the perceived risks of dyslipidemia are less than the risk of alternative immunosuppression associated with decreased adverse lipid effect, immunosuppressive therapy should take precedence over dyslipidemic therapy. In general, we are inclined to replace cyclosporine with tacrolimus, discontinue sirolimus if dyslipidemia occurs, and continue low-dose prednisone at 5 mg per day.
Drug interactions and adverse effects
●Drug interactions – Several of the statins, including simvastatin, atorvastatin, and lovastatin, are metabolized by the hepatic cytochrome P450 3A4 (CYP3A4) enzyme system. This enzyme system is also responsible for the metabolism of cyclosporine, tacrolimus, and sirolimus.
Despite the shared metabolic pathway, it is the level of the statins that tends to be most affected (raised) with concurrent therapy with both classes of agents and not that of the immunosuppressive agents. Cyclosporine increases blood levels of essentially all statins investigated, regardless of the pathway of statin metabolism. This can be associated with significant myopathy, including rhabdomyolysis, although myopathy is rare with pravastatin. (See "Statin muscle-related adverse events".)
The clearances of pravastatin, fluvastatin, and rosuvastatin do not rely upon CYP3A4, but increased levels of all these drugs have been reported with coadministration of cyclosporine in kidney and/or heart transplant recipients. In pharmacokinetic studies limited to patients with kidney transplants, statin levels increased 3- to 20-fold, and elevations appeared greatest for lovastatin [1].
Although interactions between cyclosporine and statins are well described, limited data are available on potential interactions between tacrolimus and statins. A pharmacokinetics study examined atorvastatin levels in 13 healthy volunteers after four days of statin treatment and short (12-hour) concomitant exposure to cyclosporine or tacrolimus [59]. Systemic exposure to atorvastatin and its metabolites was increased when atorvastatin was administered with cyclosporine but not when administered with tacrolimus. In a small study of 24 tacrolimus-treated kidney transplant recipients, the addition of atorvastatin, simvastatin, pravastatin, or fluvastatin did not change tacrolimus pharmacokinetics or CK levels, although the effect of tacrolimus use on statin levels was not studied [60].
●Adverse effects – Statins have been associated with certain adverse effects, such as adverse muscle events and hepatic dysfunction. (See "Statins: Actions, side effects, and administration", section on 'Side effects' and "Statin muscle-related adverse events".)
The randomized, controlled trials of statin use (low to moderate doses) among kidney transplant recipients on cyclosporine-based immunosuppression for the reduction of ASCVD risk surrogates or events or for the prevention of acute allograft rejection have reported some adverse events or safety markers, although some variability in ascertaining such events were noted [34,39-45,61-65]. The ALERT study, the largest of these trials, found no difference in the frequencies of total or types of adverse events among patients treated with fluvastatin compared with placebo, including no difference in rates of infections and malignancies [34].
The risk of fibrate-related myositis and rhabdomyolysis is higher in patients with CKD. The safety of combining fibrates with statins has not been well studied in patients with CKD and should be avoided pending more clinical information. (See "Statin muscle-related adverse events", section on 'Concurrent drug therapy'.)
A unique nephrotoxicity attributed to fibrates has also been described. Acute kidney injury (AKI) due to biopsy-verified proximal tubule dysfunction was reported in three kidney transplant recipients treated with fenofibrate [66]. Kidney function impairment was not thought to be due to sirolimus or cyclosporine, as serum levels of these agents were in the therapeutic range and resolved with discontinuation of fenofibrate. Additional case reports and case series have described fenofibrate-associated increases in serum creatinine levels in a variety of patient populations, with a suggestion that the risk may be higher in patients with CKD [67].
SUMMARY AND RECOMMENDATIONS
●General principles – Although lipid abnormalities are common complications of kidney transplantation, a causal association of dyslipidemias with cardiovascular risk has not been proven in this population. However, due to the high incidence of atherosclerotic disease events in the kidney transplant population, we and several national groups consider kidney transplantation to be a coronary heart disease equivalent risk. Thus, the assessment and treatment of dyslipidemias in kidney transplant patients should be part of routine posttransplantation care. (See 'Introduction' above.)
●Causes of dyslipidemia – Immunosuppressive medications, particularly glucocorticoids, calcineurin inhibitors (CNIs; cyclosporine more than tacrolimus), and mammalian (mechanistic) target of rapamycin (mTOR) inhibitors, frequently cause secondary dyslipidemias. Regimens should therefore be individualized to minimize competing risks of rejection and atherosclerotic cardiovascular disease (ASCVD). (See 'Causes of dyslipidemia' above and 'Management of immunosuppression' above.)
●Monitoring – For all transplant recipients, we measure an initial fasting lipid panel (including total cholesterol, low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], and triglycerides) before initiation of statin therapy, followed by a second measurement 4 to 12 weeks later to assess adherence and then by repeat measurements every 3 to 12 months, as clinically indicated. (See 'Monitoring' above.)
●Management of LDL-C to reduce cardiovascular risk – Overall, the management of LDL-C to reduce cardiovascular risk is similar in kidney transplant recipients and in nontransplant patients with chronic kidney disease (CKD). Our approach depends upon whether the patient has established ASCVD (secondary prevention) or does not have established ASCVD (primary prevention):
•Secondary prevention – Kidney transplant recipients with established ASCVD (prior history of coronary, cerebrovascular, or peripheral arterial disease) should receive maximally tolerated statin therapy, similar to nontransplant patients with established ASCVD. (See 'Patients with established ASCVD (secondary prevention)' above.)
•Primary prevention – Statin therapy is appropriate for adult kidney transplant recipients age >40 years without established ASCVD if their estimated 10-year ASCVD risk is >10 percent. This approach is similar to the management of LDL-C for primary prevention in the general population. (See "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease".)
For all other adult kidney transplant recipients age >30 years without established ASCVD, we suggest statin therapy (Grade 2C). For adult kidney transplant recipients age 18 to 29 years without established ASCVD, we engage in shared decision-making about statin therapy. (See 'Patients without established ASCVD (primary prevention)' above and "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease".)
●Management of hypertriglyceridemia – The overall approach to the management of hypertriglyceridemia among kidney transplant recipients is similar to that for the general population. All patients should participate in nonpharmacologic lifestyle interventions such as dietary modification, weight reduction if overweight, increased physical activity, and reduced alcohol intake. If pharmacologic therapy is indicated, we avoid fibrates, given the potential toxicity associated with these agents. (See "Hypertriglyceridemia in adults: Management", section on 'Treatment goals' and 'Management of hypertriglyceridemia' above.)
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