Management of dyslipidemia in pediatric renal transplant recipients

Abstract

Dyslipidemia after kidney transplantation is a common complication that has historically been underappreciated, especially in pediatric recipients. It is also a major modifiable risk factor for cardiovascular disease, a top cause of morbidity and mortality of transplant patients. While most knowledge about post-transplant dyslipidemia has been generated in adults, recommendations and treatment strategies also exist for children and are presented in this review. Awareness of these applicable guidelines and approaches is required, but not sufficient, for the reliable management of dyslipidemia in our patients, and additional needs and opportunities for comprehensive care in this area (e.g., quality improvement) are outlined.

Introduction

Cardiovascular risk in pediatric patients with chronic kidney disease and end-stage renal disease

Risk for cardiovascular disease (CVD) is notably increased in children and adolescents with chronic kidney disease (CKD) and end-stage renal disease (ESRD) requiring renal replacement therapy. Cardiovascular (CV) mortality, specifically, is increased up to 1000-fold for pediatric patients with evolving stages of CKD and ESRD as compared to age-matched peers [1, 2]. Accordingly, the American Heart Association (AHA) has stratified pediatric patients with varying stages of kidney diseases in the highest risk group for the development of CVD and its sequelae, placing them on par with children with diagnoses, such as type 1 diabetes mellitus, homozygous familial hypercholesterolemia, or recipients of orthotopic heart transplants [2]. Children with CKD not only are at risk for developing overt CVD risk factors including hypertension and dyslipidemia; they also frequently exhibit end organ injury, including left ventricular dysfunction and hypertrophy, as well as more subtle indicators of CVD, including endothelial impairment, aortic medial calcification and resultant stiffness, atherosclerosis and—as more recently described [3]—aortic root dilation. Alarmingly, and unlike in adults, serious CVD in children with CKD/ESRD is more often asymptomatic, resulting in sudden cardiac death without more typical signs and symptoms, such as angina or shortness of breath [1].

Pathophysiology for CVD development in adults and children with CKD and ESRD, alike, is multifactorial, with both traditional as well as “non-traditional” or CKD-specific risk factors [4] contributing. Traditional risk factors in pediatric patients include family history, overweight/obesity, tobacco exposure, metabolic syndrome, suboptimal nutrition, dyslipidemia, and hypertension. Non-traditional risk factors are vast and evolving. They include elevated levels of fibroblast growth factor 23 (FGF23), chronic exposure to the uremic milieu and resultant inflammation, chronic fluid overload and frequent related large fluid shifts, altered endothelin/nitric oxide balance, anemia, calcium/phosphate dysregulation, lipoprotein abnormalities, albuminuria, disordered sleep, and longstanding hyperhomocysteinemia.

Kidney transplantation reverses or significantly diminishes both traditional and non-traditional risk factors for CVD—accordingly, normalization of filtering function through transplantation reduces cardiac mortality 10–100-fold [1, 2], with evidence for a cumulative effect of improved CV health over time [5]. Notably, however, and while CVD-related morbidity and mortality are significantly improved, risk for CV-associated adverse events never “normalizes” after transplantation and remains elevated above the pre-CKD baseline [2]. Not surprisingly, CV-related disease is the second leading cause of death behind infections among children and adolescents with kidney transplants [6]. In children and adolescents, longitudinal exposure to CKD/ESRD likely contributes to the pathogenesis of, at least in part, irreversible changes related to CV morbidity and mortality, which persist after and despite kidney transplantation.

Given the general obesity epidemic on the one hand and the known substantial CV morbidity and mortality specifically in kidney transplant recipients on the other [7], it is not surprising that a number of guidelines and scientific statements exist that speak to the detection and management of dyslipidemias both in the general population and also targeted specifically towards patients with kidney transplants. As discussed in detail below, several of these references are even focused primarily on children [2, 8] or at least mention pediatric patients as a distinct population [9]. Nonetheless, and as acknowledged in these references, some limitations continue to exist in our knowledge regarding the appropriateness and the applicability of some of these recommendations to pediatric kidney transplant recipients.

Moreover, a substantial “gap” in the comprehensive management of CV disease, including dyslipidemia, in pediatric kidney transplant recipients has been the reliable implementation of any guideline- and evidence-based strategies in our daily clinical practice. Even if appropriate protocols and clinical pathways exist, ensuring their comprehensive application represents a substantial challenge, both between pediatric kidney transplant centers [10, 11] and within individual programs [12]. The incorporation of established quality improvement-related strategies based on the chronic care model [13, 14], such as population management and pre-visit planning, into the regular clinical care of at-risk patients such as pediatric kidney transplant recipients should therefore be strongly considered to ensure that indicated, guideline-based care is actually delivered to each eligible patient.

Cardiovascular risk in the pediatric renal transplant recipient

In addition to the “carryover” CVD established pre-transplant, i.e., during CKD and—if transplantation did not occur preemptively—on dialysis, there are new risk factors for CVD that patients are exposed to post-transplant. Even though, as mentioned above, transplantation attenuates carryover CVD, transplant recipients therefore continue to face a rather substantial risk for CV morbidity and mortality. The risk factors for CVD that are introduced by kidney transplantation are largely related to the immunosuppression required post-transplant.

Many of these immunosuppressive agents can have both detrimental effects on blood pressure and also drive metabolic derangements that contribute significantly to the development of dyslipidemias following transplantation. Specifically, corticosteroids, calcineurin inhibitors (CNIs), and mammalian target of rapamycin (mTOR) inhibitors have been associated with hyperlipidemia and hypertriglyceridemia in adult and pediatric solid organ transplant recipients. As will be discussed, efforts to minimize the adverse effects of these agents are beneficial, but must be balanced with the need to maintain adequate immunosuppression for graft survival.

Corticosteroids are notorious for the adverse metabolic effects of hypertension, new-onset diabetes after transplant (NODAT) and dyslipidemias, and thus for their contribution to CV morbidity following transplantation. Chronic corticosteroid use is associated with increased activity of free fatty acid synthetase, upregulation of VLDL synthesis, and reduced LDL-receptor expression, resulting in increased total cholesterol, LDL, and triglyceride serum levels [15]. In efforts to minimize these effects, immunosuppressive protocols that feature either complete steroid avoidance, eventual steroid withdrawal, or at least steroid minimization have been developed, but these efforts need to be balanced against any associated increased risk of allograft rejection [16,17,18]. With regards to steroid avoidance, very successful regimens have been described [19], and it has been recommended to stop steroids very soon post-transplant if long-term steroid-free immunosuppression is planned [9]. Moreover, the mid-term use of even rather low-dose steroids in chronic immunosuppression has been shown to be associated with unfavorable CV side effects [17]. That being said, a less rapid path towards steroid elimination (i.e., by about 6 months post-transplant) has also been found to be beneficial and safe not only in single-center [20] but also in very large-scale registry review work [21]. Uncertainty therefore continues to exist regarding the risk-benefit ratio of steroids as part of post-transplant immunosuppression regimens [9], and between-center variability accordingly persists in their use. Moreover, any given program may individualize its use of steroids as part of a given recipient’s immunosuppressive regimen based on risk for (or history of) rejection, underlying disease, growth potential, or CV morbidity.

CNIs (cyclosporine, tacrolimus) negatively impact the metabolic profile of transplant recipients by increasing their risk for hypertension, NODAT, and hyperlipidemia. These effects appear to be dose-dependent and more pronounced with cyclosporine compared to tacrolimus [22]. This—in addition to cyclosporine’s higher incidence of cosmetic side effects and its perhaps somewhat harsher effects on kidney function compared to tacrolimus [23]—may explain why most pediatric kidney transplant programs in the USA currently use tacrolimus as their CNI of choice [24]. Through interference with LDL-receptor binding and lipase enzymatic activity, CNIs have the potential to increase plasma levels of total cholesterol, LDL, and triglycerides [15]. CNI minimization protocols and transition to a CNI-free regimen represent attempts to mitigate these adverse metabolic effects [25], but lipid-lowering therapeutic interventions while preserving some CNI exposure for the best possible protection against rejection should also be considered (see below).

MTOR inhibitors (mTORis, sirolimus, and everolimus) continue to have a role in chronic post-transplant immunosuppression, as their inclusion in recently published immunosuppressive regimens appears to convey non-inferiority to more traditional primarily CNI-based strategies [26]. However, and in addition to likely being associated with a higher risk for the development of donor-specific antibodies (DSAs) compared to CNI-based regimens [27], mTORis do have a substantial propensity to contribute to post-transplant dyslipidemia [28]. Similar to CNIs, this effect appears to be exposure-related, with higher sirolimus trough concentrations associated with a greater risk of dyslipidemia [29, 30]. The mechanisms by which sirolimus increases cholesterol and triglyceride levels are not well understood but believed to be related to impairment of lipase activity and LDL-receptor expression [15]. Reversing the metabolic effects of mTOR inhibitors is best accomplished with dose reduction or withdrawal, although lipid-lowering therapeutic interventions should also be considered (see below).

Specifically, treating these immunosuppressant-associated dyslipidemias with an HMG CoA reductase Inhibitor (i.e., a statin) could actually allow the provision of lipid-lowering strategies that may also have additional, and dyslipidemia-unrelated, effects on chronic immunosuppression. In other words, the pleiotropic effects of statins on cholesterol-related metabolic pathways may target immunologically relevant sites such as lipid rafts [31, 32], thus possibly contributing to a somewhat reduced rejection risk. That said, being on a statin to lower post-transplant cholesterol levels has not been found to be clearly beneficial regarding rejection risk in an adult study [33]. Nonetheless, statin therapy is favored for all adult kidney transplant recipients [4].

As mentioned above, dyslipidemia and resultant atherosclerosis are important risk factors for the development of CVD in children with CKD, on peritoneal and hemodialysis and after kidney transplantation. CKD is associated with unique patterns of dyslipidemia resulting from impaired lipolysis with progressing CKD: normal levels of total cholesterol (TC), but increased low-density lipoproteins (LDLs), triglycerides (TGs), and very low density lipoproteins (VLDLs), as well as decreased high-density lipo-proteins (HDLs), are common in pediatric patients with CKD/ESRD [34]. Uremia itself has been associated with elevated TGs, which may in turn be related to insulin resistance described in uremia and resultant disturbances in lipid metabolism [34, 35]. Interestingly, the transition to hemodialysis does not typically alter the pattern of dyslipidemia; peritoneal dialysis, however, appears to be associated with further increases in TGs and TC [36]. Some of these findings were replicated in children in a recent large European registry study of 386 pediatric and young adult transplant patients, where prevalence of dyslipidemia prior to transplant was very notable at 95% [22]. Moreover, TGs, LDLs, and TCs were all abnormal in 35% of patients, while just TGs were elevated in 82% of patients.

Similar to other CV risk factors, dyslipidemia appears to improve in children after kidney transplantation, but it remains a prevalent threat to long-term CV health. Prevalence of dyslipidemia at 1 year after transplantation improves in both children and adult transplant recipients [22]. Age, body mass index, gender, donor source, and primary renal disease have not reliably been found to be associated with changes in TGs, TCs, or LDLs after transplantation. Estimated glomerular filtration rate and immunosuppressant medication regimens, on the other hand, have been shown to have a strong association with TGs, TCs, and LDLs in both smaller and larger registry studies of pediatric transplant recipients [22, 30, 37].

Monitoring for and diagnosing dyslipidemias post-transplant

Knowledge about a transplant recipient’s history of lipid issues pre-transplant is therefore helpful, but it does not substitute for the careful and ongoing assessment of these patients for dyslipidemia post-transplant and implementing appropriate management if detected. Several different types of dyslipidemias are seen post-transplant [22, 38; Table 1], predominantly hypertriglyceridemia, hypercholesterolemia, and a combination of hypertriglyceridemia and non-HDL-C elevation. It should also be noted that the definition and classification of dyslipidemias vary, some by age and gender (see reference [38] for detailed normal ranges for children and adolescents and reference [22] for a simplified table) as well as CV risk [2, 38, 39, 41]. Moreover, some post-transplant dyslipidemias have specific, identifiable, and treatable causes that should be sought and addressed whenever possible, e.g., nephrotic syndrome, liver disease, hypothyroidism, or diabetes as well as exposure to certain medications, not just immunosuppressants [38, 42].

Table 1 Summary of available guidelines with some applicability to dyslipidemia management in pediatric kidney transplant recipients

Regarding the above-mentioned assessment and management, guidelines and recommendations exist as to how to monitor kidney transplant recipients for dyslipidemias and to classify and manage any detected derangements [2, 4, 8, 9, 38, 39, 41]. For pediatric kidney transplant recipients and the programs taking care of them, synthesizing and reconciling what has been published mostly for adult transplant (or CKD) populations on the one hand, and for children in general on the other, represent key challenges. For example, the persistent paucity of data on statin disposition in children remains a concern [43], and there are discrepant recommendations regarding their use in adolescent kidney transplant recipients with hypercholesterolemia [38, 39; Table 1].

At any rate, dyslipidemia screening in pediatric kidney transplant recipients has been recommended, albeit with some modifications compared to adult patients [9, 39; Table 1]. Whether blood samples used for screening should exclusively be obtained with the patient fasting, which is considered optimal, especially for the determination of low-density lipoprotein cholesterol [LDL-C, 9], could be debated. A normal lipid profile obtained non-fasting is potentially reassuring and could at times be sufficient [2, 38, 41], and there is evidence arguing against the use of LDL-C to identify candidates for statin therapy, at least in adults with CKD [39]. Especially in pediatric centers, who try to minimize needle sticks for their young recipient population and whose patients and families may be traveling substantial distances for clinic visits, fasting bloodwork at such visits may moreover be problematic.

The frequency of dyslipidemia monitoring for any given patient depends on several aspects: patients on an mTORi likely need more frequent testing than patients who are “just” on a CNI with or without steroids, and patients without abnormalities on routine testing need to be monitored less frequently (see Fig. 1 and “Pharmacologic Management of Dyslipidemias in the Pediatric Transplant Recipient” below).

Fig. 1
figure1

Proposed approach to dyslipidemia screening and management in pediatric kidney transplant recipients at least 8 years of age. *Significant changes include changes in a patient’s medical condition (e.g., development of obesity, diabetes, or nephrotic syndrome) or in the patient’s treatment regimen (e.g., adjustments in immunosuppression or new or altered exposure to other medications that can affect lipids). **If there are options to adjust immunosuppression in ways that could improve the lipid profile, they should be considered. Lipid specialists should also be involved as indicated in dyslipidemia management. HDL: high-density lipoprotein, LDL: low-density lipoprotein, TG: triglycerides, TLC: therapeutic lifestyle changes

Management of dyslipidemias

Non-pharmacologic management of dyslipidemias in the pediatric kidney transplant recipient

Factors contributing to post-renal transplant weight gain are increased appetite (in part related to corticosteroid exposure), improved taste sensation with resolution of uremia, liberalization of diet, and low physical activity. Regarding the reduction of modifiable risk factors, therapeutic lifestyle changes (TLCs) are a commonly accepted first-line intervention to reduce elevated lipid levels in pediatric patients. TLCs are accordingly part of the currently available recommendations to improve hyperlipidemia in kidney transplant recipients (Table 1), although details regarding TLCs largely originate from evidence-based nutrition therapy approaches for the general, and not transplant-specific, management of dyslipidemia.

The Academy of Nutrition and Dietetics (AND, https://www.eatright.org) suggests that utilizing a multi-faceted approach to lifestyle changes is most beneficial. This may include education, counseling, and self-management strategies. Other research supports dietary counseling, exercise programs, and/or referral to an obesity clinic to reduce modifiable risk factors contributing to dyslipidemia, including hypertriglyceridemia, hypercholesterolemia, and obesity [11]. It is recommended that medical nutrition therapy (MNT) be provided by a registered dietitian (RD) who is adequately trained on the complexities of TLCs and experienced in nutrition assessments. With intensive pre-transplant RD visits, there have been significant improvements seen in anthropometric and biochemical measurements sustained for at least 1 year [44]. Such improvements, in turn, should contribute to the long-term success of post-transplant lipid management. The KDOQI pediatric clinical nutrition practice guidelines [45] recommend that patients and families should receive intensive nutrition education and counseling to promote a heart-healthy diet and regular physical activity with a goal of 60 min of active play daily to promote the maintenance of healthy weight and decrease CV risk after transplant. In children and families who resist overt dietary modification, healthy food preparation methods should at least be emphasized, including the use of heart-friendly fats such as canola or olive oils and trans-fat-free margarines [45]. Exercise recommendations for children include encouraging time spent in active play (goal ≥ 60 min/day) and limiting screen time (television + computer + video games) to 2 h per day or less [46]. For adolescents and adults, recommendations include moderate physical activity 3 to 4 times weekly (20- to 30-min periods of walking, swimming, and supervised activity within ability), as well as resistance exercise training [38].

As summarized in Table 1 above, the KDIGO lipid management guidelines recommend no pharmacological treatment for patients under the age of 18 years but state that TLCs should be advised for children with CKD (including after transplant) and dyslipidemia. However, dietary modifications should be used judiciously, if at all, in children who are malnourished [39]. KDOQI’s US commentary on these KDIGO lipid management guidelines agrees, although with minor modification given concern for poor growth in children with CKD [40]. The KDOQI US commentary work group suggests that lifestyle changes specifically directed to treat dyslipidemia be reserved for children with HDL-C > 145 mg/dL or LDL-C > 130 mg/dL or for those who are overweight [40].

In contrast, the National Heart, Lung and Blood Institute (NHLBI), endorsed by the American Academy of Pediatrics, suggests broader indications for therapy [8]. The NHLBI suggests that the first-line treatment for dyslipidemia characterized by LDL-C > 130 mg/dL or TG > 100 mg/dL in children under 10 years of age or > 130 mg/dL in older children (in two lipid screenings) should include a trial of diet modification, limiting saturated fat, cholesterol and simple sugars, and advising increased physical activity. If LDL-C is at least 190 mg/dL alone, > 160 mg/dL with one high-risk condition, or > 130 mg/dL with two high-risk conditions at follow-up, initiation of pharmacological treatment (see below) is advised, albeit with limitations for children under 10 years of age. High-risk conditions as defined by NHLBI include high blood pressure treated with antihypertensive medication, BMI above the 97th percentile, smoking, and chronic kidney disease. Very similar recommendations, stratified by degree of risk for premature CVD, have more recently been issued by the American Heart Association [2, Table 1]. Of note, children with “solid-organ transplant vasculopathy” are considered to be at high risk for premature CVD in this statement.

Studies on the role of dietary interventions on metabolic abnormalities and nutrition status after transplantation showed that children who followed a step II AHA diet (≤ 30% total calories from fat, < 7% calories from saturated fat, 10% polyunsaturated fat, < 200 mg/day cholesterol) had 11% and 14% reductions in TG and LDL-C levels, respectively [47]. This work essentially replicated observations made in the adult transplant population [48]. Another study performed primarily to follow the effect of diet on plasma fatty acid levels in 29 children and adolescents, concluded that diets containing protein intakes appropriate for age, a generous carbohydrate intake featuring a low glycemic load, and fat intakes less than 30% of total caloric intake, were reasonable goals of diet therapy after transplantation [49].

Many adult and some pediatric studies show benefits of transitioning to a vegan or plant-based diet: reducing animal intake can lead to reduced total fat, saturated fat, and cholesterol intake, while inherently increasing intake of whole grains and fiber-rich foods, leading to less absorption and conversion to serum cholesterol. Increased intake of soluble fiber also helps increase cholesterol removal through binding of bile acids and cholesterol. The increased soy that likely comes with a plant-based diet may additionally decrease cholesterol synthesis and increase LDL-C oxidation resistance and inhibit thrombus formation due to isoflavin effects, while incorporating monounsaturated fats, nuts, and fruits and vegetables may help decrease inflammation and LDL particle size and also increase LDL-C oxidation resistance [50]. Lastly, intake of legumes may improve the lipid profile by increasing fat excretion via stool output and short chain fatty acid formation in the colon [51]. Increasing specific components of plant-based foods may also help with lowering lipid concentrations. For example, incorporation of plant sterols and stanols at a dose of 2–3 g/day has been shown to significantly lower total cholesterol, LDL-C, and non-HDL-C in both pediatric and adult patients [52, 53]. Addition of plant sterols into the diet reduces cholesterol absorption through binding of cholesterol and bile acids and has shown no serious adverse effects [50, 53].

Data from studies in the general population and the lack of adverse effects make compelling reasons for recommending that exercise, in combination with diet, be encouraged in transplant recipients to prevent and/or aid in the management of dyslipidemia, overweight, and hypertension. There are some concerns regarding varying approaches to MNT given the lack of specific guidelines and recommendations in the literature pertaining to diet. It is notable that studies have shown that specific differences in therapeutic diets do not impact overall acceptability compared to other therapeutic diets [54].

Outside of TLCs, dietary fish oil and omega-3 fatty acid supplementation have shown beneficial effects on lipid levels in CKD and after kidney transplantation. Omega-3 fatty acids are polyunsaturated fatty acids that are mainly obtained from dietary sources such as fatty fish. One study of children with ESRD undergoing chronic hemodialysis that evaluated effects of 1 g/day omega-3 supplementation on serum lipid profile markers demonstrated a significant reduction in total cholesterol albeit with no significant changes in TG, HDL-C, or LDL-C [55]. In post-transplant kidney patients, omega-3 fatty acid supplementation has been shown to significantly decrease total cholesterol and show a trend towards lowering TG levels: Filler et al. found that supplementation of a mean of 16.1 ± 7.4 mg/kg/day docosahexanoic acid (DHA) and 29.2 ± 12 mg/kg/day eicosapentaenoic acid (EPA) was effective in lowering lipids [56].

Pharmacologic management of dyslipidemias in the pediatric transplant recipient

The various possible lipid-altering side effects of our currently used immunosuppressants have been outlined above (see “Cardiovascular risk in the pediatric renal transplant recipient”). Adjustments in a transplant recipient’s immunosuppressive regimen to minimize such side effects can therefore be considered, but need to be weighed against rejection risk. Any such adjustments are typically subject to center practice and may be tied to individual patient risk, both immunological and cardiovascular.

Lipid-lowering pharmacologic therapy should be considered in at-risk children at least 10 years of age who fail to reach lipid and lipoprotein goals despite 6 to 12 months of non-pharmacologic interventions [57]. Earlier initiation for patients as young as 8 years may be warranted for high-risk conditions associated with CVD, such as ESRD or renal transplantation [57, 58]. Evidence for the use of lipid-lowering agents in the pediatric population is primarily found in children with familial hypercholesterolemia (FH), and this experience has been translated into general use recommendations for children and adolescents. To date, however, the available literature lacks long-term follow-up with these agents and experience with non-FH-associated high-risk conditions in children. Common side effects of the different lipid-lowering agents are summarized in Table 2.

Table 2 Common side effects of lipid-lowering agents

HMG CoA reductase inhibitors (statins)

Initial management with HMG-CoA reductase inhibitors (statins) is recommended for pediatric patients based on efficacy and experience in adults and, to some extent, children. Through inhibition of cholesterol synthesis and LDL receptor upregulation, statins primarily target LDL-C, and pediatric studies demonstrate LDL-C reduction in the 20 to 50% range [57]. More modest improvements are seen in HDL-C and TGs.

All available statins are approved for use in pediatric patients meeting criteria for treatment. To promote tolerability and safety, statin therapy should be initiated at the lowest recommended dose and titrated as needed if goals are not achieved within 4 to 12 weeks of treatment [Table 3, 59]. As a general rule, statin doses should be increased by small increments (i.e., 10 to 20 mg) and no earlier than 4 weeks following a prior dosage change. Important adverse effects to monitor with statin use include myopathies and hepatic enzyme elevations. These adverse effects are dose-related and rare with standard dosing. If target LDL-C levels are not achieved with statin therapy after an adequate trial, the addition of a second agent is warranted.

Table 3 HMG-CoA reductase inhibitor (statin) pediatric dosing

Caution should also be exercised when dosing statins with interacting medications. Most statins are metabolized via cytochrome P-450 enzymes (namely CYP3A4 and CYP2C9), predisposing them to many potential drug interactions, including common medications used in post-renal transplant management. The most notable and well-documented interaction exists between cyclosporine and statins. Through inhibition of CYP3A4 and OATP1B1, a hepatocyte transporter, cyclosporine significantly increases the serum concentration of statin agents and thus the risk of statin-induced rhabdomyolysis [39]. If statins are used in the setting of cyclosporine-based immunosuppression, therapy should therefore be initiated at low doses, be titrated cautiously, and not exceed maximum dosage recommendation (Table 2). Of note, this interaction is not as pronounced with the use of tacrolimus and mTOR inhibitors, likely due to an absent or weak inhibitory effect on OATP1B1 and CYP3A4, and standard statin dosing is recommended in this context accordingly [9, 60]. Severity of the interaction varies among drugs within the statin class based on the CYP enzyme involved in metabolism and affinity for that enzyme. Based on these characteristics, the greatest level of interaction is noted with the use of simvastatin, lovastatin and atorvastatin [61].

Cholesterol absorption inhibitor

Ezetimibe, a cholesterol absorption inhibitor, has become widely used as adjunctive therapy with statins in the adult population. As an inhibitor of intestinal cholesterol absorption, this agent interferes with the uptake of dietary cholesterol, creating an additive benefit to statin therapy. A lowering of LDL-C by approximately 20% has been demonstrated in the pediatric population both in combination with a statin and as monotherapy [62,63,64]. These studies have shown an ezetimibe dose of 10 mg daily to be safe, tolerable, and effective in patients aged 10 years and older.

Ezetimibe is generally well tolerated with the most common adverse effects reported as diarrhea and myopathy. Precautions should be exercised in patients with elevated transaminases and hepatic disease concomitantly using statins as there is an increased risk of hepatotoxicity. While dosage adjustments for renal impairment are not recommended, severe renal dysfunction (i.e., a creatinine clearance below 30 mL/min/1.73 m2) may result in increased exposure of ezetimibe [65]).

In general, ezetimibe has few reported drug interactions. However, reports of ezetimibe and cyclosporine used concomitantly in transplant recipients and healthy subjects have shown this combination to result in increased serum ezetimibe concentrations, warranting close monitoring for adverse effects [65, 66].

Bile acid sequestrants

Bile acid sequestrants (cholestyramine, colestipol, colesevelam) are often used in combination with a statin for their additional LDL-C lowering effects, with reports of LDL reductions by as much as 10 to 20% [8, 67]. Bile acid sequestrants have historically been preferred in the pediatric population due to the lack of systemic absorption of these agents and therefore presumed safety. However, their efficacy is dose-dependent, and doses needed to sufficiently reduce LDL-C can create challenges with tolerability and adherence.

As bile acid sequestrant exposure is limited to the gastrointestinal tract, common adverse effects (including bloating, flatulence, constipation, and diarrhea) can be quite bothersome to patients. Reduction of bile salts may also interfere with intestinal lipid absorption, resulting in malabsorption of fat-soluble vitamins.

Bile acid sequestrants also have the potential to interfere with absorption and enterohepatic recirculation of co-administered medications. In the transplant population, this interaction is most notable with mycophenolic acid products. In healthy adult volunteers, co-administration of cholestyramine and mycophenolate mofetil resulted in a 34 to 39% reduction in mycophenolic acid exposure, as estimated by area under the curve [68]. Decreased absorption of cyclosporine and oral corticosteroids when co-administered with bile acid sequestrants has also been reported [69, 70]. These combinations are best avoided, but if clinically necessary the agents should be administrated separately, with medications given 1 h prior to or 4 h after the bile acid sequestrant.

Fibric acid derivatives

Fibric acid derivatives (fenofibrate, gemfibrozil) are used to target high TG levels but have minimal effects on LDL-C. Thus, use in the pediatric population is generally limited to the management of severe hypertriglyceridemia (TG > 400 mg/dL). These agents should be used cautiously in conjunction with statins, as the combination markedly increases the myopathy risk associated with fibric acid derivatives. Moreover, no fibric acid derivative currently has approval for use in pediatrics, and data with this population is lacking. The use of fibrates in adult renal transplant recipients has been accompanied by elevations in serum creatinine, although the mechanism for this effect is unclear [71, 72]. Additionally, these agents have been associated with reduced cyclosporine concentrations when used concomitantly [73].

Nicotinic acid

Nicotinic acid (niacin) lowers triglyceride levels and increases HDL-C in addition to modest effects on LDL-C. Limited safety and efficacy data are available regarding niacin use in children, although in one report, 76% of pediatric patients using this agent experienced adverse effects [74], therefore limiting the use of nicotinic acids in this population.

Omega-3 fatty acids

Omega-3 fatty acids or fish oil, available as EPA and DHA, are commonly used for the management of hypertriglyceridemia in adults. Beneficial, yet modest, changes to the lipid profile with fish oil used as monotherapy or in combination with statins have been demonstrated in the management of post-renal transplant dyslipidemia in adults [75,76,77]. Limited data in children and adolescents show slight improvements in TG levels with fish oil use (1.2–4 g/day) and that use is well tolerated [78, 79].

Newer agents (PCSK9 inhibitors, mipomersen, lomitapide)

Alirocumab and evolocumab are monoclonal antibodies that comprise a new class of lipid-lowering medications. These agents inhibit the serine protease proprotein convertase subtilisin/kexin 9 (PCSK9). They are approved for use in adults as adjuvant therapy in the management of hyperlipidemia to be combined with other lipid-lowering therapy, such as statins and ezetimibe. Approval for pediatric use is currently limited to adolescents (≥ 13 years) with homozygous FH [80, 81]. PCSK9 inhibitor use in adults is associated with significant (50–70%) reductions in LDL-C when combined with statin therapy, and outcomes research demonstrates reduced CVD-related events and associated mortality [61]. Safe and effective use of PCSK9 inhibitors in the transplant population has recently been described in small adult heart transplant cohorts with refractory hyperlipidemia [82]; however, published experience within renal transplantation does not exist at this time. In addition to achieving significant LDL-C reductions, PCSK9 inhibitors are attractive for complex patients as they do not impact CYP450, P-glycoprotein, or OATP pathways and thus have limited potential for drug-drug interactions. While recommendations for use in pediatric renal transplant recipients cannot be made at this time, PCKS9 inhibitors may represent a future alternative therapy for refractory patients.

Mipomersen, an oligonucleotide inhibitor of apo B-100 synthesis, reduces the formation of apo-B, which is a major component of LDL-C and VLDL [83]. This agent is exclusively approved for homozygous FH and within this indication use has demonstrated positive outcomes with LDL-C reduction for both adult and pediatric patients. At this time, efficacy and safety of mipomersen in the solid organ transplant population are unknown [61]. Due to the risk of hepatotoxicity, access to mipomersen is moreover limited to certified providers through a REMS program.

Lomitapide is a microsomal triglyceride transfer protein (MTP) inhibitor that prevents the assembly of apo-B lipoproteins and subsequently reduces concentrations of circulating LDL-C [84]. Similar to mipomersen, this agent is approved only for homozygous FH, and experience with solid organ transplant recipients is limited to patients with a diagnosis of homozygous FH. As well, access is restricted through a REMS program due to risk of hepatoxicity. Additionally, lomitapide relies upon metabolism via CYP3A4 and is an inhibitor of P-glycoprotein, creating the potential for significant drug interactions if combined with immunosuppressive agents also requiring these metabolic and transport pathways.

Outlook and opportunities

Despite the major morbidity and mortality associated with CVD in transplant recipients and the well-recognized contribution of dyslipidemias to the development and worsening of CVD, the reliable and comprehensive provision of CV care for pediatric transplant recipients has unfortunately remained elusive. Wilson et al. [10] describe the high prevalence of metabolic syndrome (and associated left ventricular hypertrophy) in this population at 1 year post-transplant. More recently, Hamdani et al. [85] documented the high incidence of unrecognized and undertreated hypertension in young kidney transplant recipients. Lastly, the high variability and low reliability of CV care for these patients between centers and within a single program have been noted [11, 12]. In the latter context, implementation of quality improvement approaches and utilization of elements of the Chronic Care Model (pre-visit planning, population management) were shown to improve not only the reliability of dyslipidemia screening but also actual serum cholesterol levels in pediatric transplant patients [12].

However, even if programs establish the “infrastructure” to reliably detect and manage dyslipidemias, potential shortcomings, and pitfalls remain: as outlined above, there is a dearth of evidence or even experience regarding the use of lipid-lowering pharmacotherapy in young children with kidney disease [42], and using such therapy in adolescent and young adult patients invariably increases their “pill burden”. Number of medications and frequency of dosing, in turn, are considered potential risk factors for non-adherence, not only after kidney transplantation [86]. This concern, paired with a relative lack of clarity regarding the long-term safety and benefits of initiating lipid-lowering drug therapy at a young age in kidney transplant recipients [39, 40], may be associated with some degree of provider hesitancy and/or leniency regarding dyslipidemia management in this population.

Taking all these aspects into consideration, we propose a simplified approach to lipid management in pediatric kidney transplant recipients at least 8 years old in Fig. 1. Younger patients should be considered very strong candidates for TLCs regardless of laboratory lipid screening because of the almost universal lack of available drug treatment options in this age group. Once pediatric kidney transplant recipients have reached an age at which medical therapy—and especially statin use—could be contemplated, i.e., 8 to 10 years, we propose regular laboratory monitoring and consideration of drug therapy as a management option for detected dyslipidemias. While long-term data on the efficacy and safety of such drug therapy initiated in childhood continue to be lacking [39, 40], we believe that the high risk for CVD associated with kidney transplantation justifies this approach, especially in pediatric recipients whose exposure to this CVD risk over time is expected to be particularly long. On the other hand, drug therapy for dyslipidemias in pediatric kidney transplant recipients should obviously be prescribed and monitored very carefully in view of our limited knowledge regarding possible drug-drug interactions and drug metabolism (especially if there is chronic transplant dysfunction) in this population. Generally, our suggestions are therefore based on the available guidelines as summarized and referenced in Table 1, as well as on pragmatic considerations around logistics and adherence, both with regards to patients and families and with regards to transplant programs and all as mentioned above.

Lastly, and on a more “societal” level, pediatric and young adult kidney transplant recipients could be considered victims of the ongoing obesity epidemic “on steroids”. Systematic measures to enhance physical activity and limit access to unhealthy foods and drinks, e.g., minimizing sugary drink availability in schools, therefore need to be strongly considered and spread to help protect this high-risk population [87].

Key summary points

  1. 1.

    Dyslipidemia is one of the contributors to the high risk for cardiovascular disease in pediatric kidney transplant recipients.

  2. 2.

    While in part a “carry-over” from pre-transplant, this dyslipidemia can be significantly related to several of the immunosuppressive agents used post-transplant, i.e., steroids, cyclosporine, and mTOR inhibitors. Immunosuppressive regimens should therefore be scrutinized regularly regarding their contribution to dyslipidemia and adjusted as indicated.

  3. 3.

    Screening for dyslipidemia in pediatric kidney transplant recipients has been unreliable in many centers. This unreliability is only one of many examples for the current quality gap in the long-term management of this population.

  4. 4.

    Dyslipidemia management in pediatric kidney transplant recipients is in part empiric because of limited available information, especially regarding pharmacotherapy, in this patient population. For older children with kidney transplants, however, existing guidelines and other information can and should be rather readily and consistently applied as dyslipidemias in young transplant recipients contribute to the increased cardiovascular disease “clock’s ticking” especially early in their life.

Multiple choice questions (answers below the references)

  1. 1.

    According to the North American Pediatric Renal Trials and Collaborative Studies 2014 Annual Report, the most common cause of death in pediatric kidney transplant recipients is

    1. a.

      Trauma

    2. b.

      Malignancy

    3. c.

      Cardiovascular disease

    4. d.

      Infection

  2. 2.

    Of the following immunosuppressants, the one with the LEAST potential to contribute to dyslipidemia is

    1. a.

      Mycophenolate

    2. b.

      Prednisone

    3. c.

      Sirolimus

    4. d.

      Cyclosporine

  3. 3.

    According to existing guidelines, pediatric kidney transplant recipients should

    1. a.

      Practice therapeutic lifestyle changes if they have hypertriglyceridemia

    2. b.

      Be treated with a statin as early as 6 years of age if they have hypercholesterolemia

    3. c.

      Discontinue immunosuppression if they have dyslipidemia

    4. d.

      All of the above

  4. 4.

    Many HMG CoA reductase inhibitors (statins) significantly interact with

    1. a.

      Mycophenolate

    2. b.

      Prednisone

    3. c.

      Sirolimus

    4. d.

      Cyclosporine

  5. 5.

    According to existing guidelines, a healthy amount of daily screen time (television + computer + video games) not only for pediatric kidney transplant recipients is no more than

    1. a.

      1 h

    2. b.

      2 h

    3. c.

      3 h

    4. d.

      4 h

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Correspondence to Jens Goebel.

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Bock, M.E., Wall, L., Dobrec, C. et al. Management of dyslipidemia in pediatric renal transplant recipients. Pediatr Nephrol 36, 51–63 (2021). https://doi.org/10.1007/s00467-019-04428-y

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Keywords

  • Dyslipidemia
  • Transplant
  • Pediatric
  • Kidney
  • Cholesterol
  • Triglycerides