Dyslipidemia in Chronic Kidney Disease

CKD and LDL-C

Even though low-density lipoprotein cholesterol (LDL-C) levels correlate significantly with cardiovascular risk in the general population, the composition and structure are more important predictors of adverse outcomes in the case of CKD (shown in Fig. 1). First and foremost, oxidation of LDL-C on the basis of inflammation and increased oxidative stress in the context of CKD may account for its greater atherogenic potential despite lower levels [7]. Moreover, higher levels of electronegative LDL-C due to the increase of its L5 subfraction in CKD could result in increased inflammatory burden and, therefore, accelerated atherosclerosis as it enhances the differentiation of monocytes to pro-inflammatory M1 macrophages via action on the lectin-like oxidized LDL receptor-1 as well as NLRP3 inflammasome activation [8^, 9]. Moving on, small dense LDL-C particles merit specific attention due to their easier oxidation and ability to penetrate the arterial wall [10]. A recent meta-analysis displayed a relationship between these molecules and coronary artery disease [11] while their levels could be indicative of future cardiovascular events in CKD [12^, 13].

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The Role of HDL-C

High-density lipoprotein cholesterol (HDL-C) is a molecule known for its cardioprotective effect. Under physiologic conditions, HDL is an important mediator of endothelial function since it activates endothelial nitric oxide synthase leading to an increase in NO levels while also counteracting the production of reactive oxygen species [14^, 15]. Furthermore, it is believed to possess anti-inflammatory and antithrombotic properties [16^, 17]. In the setting of CKD, the beneficial actions of HDL-C are largely lost. To begin with, paraoxonase 1 appears to be an important determinant since its low levels have been linked with enhanced HDL oxidation, while in its absence, the concentration of malondialdehydes may accentuate phosphorylation of endothelial nitric oxide synthase and thus constrain NO availability [18^, 19]. Other mechanisms have also been suggested, such as the reduced ApoA-1 and lecithin-cholesteryl acyltransferase production, the upregulation of acetyl-CoA acetyltransferase-1, the oxidation of HDL constituents, and the impaired reverse cholesterol transport [20]. Ultimately, the resulting endothelial dysfunction, inflammation, and oxidative stress could be responsible for the association between HDL and increased mortality in CKD [21]. Another interesting concept was presented by Florens et al. [22] who showed that CKD-induced carbonylation of HDL was responsible for impaired platelet aggregation, further contributing to the etiology of increased cardiovascular events in the CKD population.

Hypertriglyceridemia in CKD

Elevated serum triglycerides represent the most frequent abnormality in the lipid profile of CKD patients. The main mechanism involved is their hindered catabolism due to the hypoactive hepatic triglyceride lipase. In addition, an increased amount of lipase inhibitors, namely, apoC-III, in the setting of uremia may also play a role in decreased lipoprotein lipase-dependent triglyceride-rich lipoprotein catabolism [23]. Importantly, triglyceride-rich lipoproteins were recently proven to be important risk factors for cardiovascular outcomes in CKD patients, highlighting a potential novel therapeutic target [24].

Lipoprotein(a)

The effect of Lp(a) on inflammation, atherosclerosis, and thrombosis has been well established in the past years, with the formation of a definite bond between its levels and adverse cardiovascular events [25^-27]. Concerning its structure, it consists of Apo-B linked with apolipoprotein(a), encrypted by the LPA gene whose expression is primarily mediated by the liver and secondarily by the kidneys [27]. Furthermore, Lp(a) clearance mainly depends on kidney function, thus resulting in higher levels as glomerular filtration rate deteriorates, especially in those with large apolipoprotein(a) isoforms [28^, 29]. It was recently suggested that elevated Lp(a) was an independent risk factor for the incidence of myocardial infarction and death in CKD patients [26]. Interestingly, statin prescription in high-risk populations could account for the increased Lp(a) concentration with potential mechanisms involving higher LPA mRNA expression and proprotein convertase subtilisin/kexin type 9 (PCSK9) levels following statin use [30].

Gut Microbiota and Lipid Metabolism

In CKD patients, a dysbiotic intestinal environment has been noted in a recent study [31]. With regard to dyslipidemia, several intestinal bacteria were shown to be able to produce bile acids from the intestinal bile salt pool leading to hepatic and systemic lipid adjustments via action on the nuclear or G protein-coupled receptors [32]. Moreover, lack of specific bacteria involved in the fermentation of nondigestible carbohydrates could result in loss of beneficial metabolites, namely, short-chain fatty acids, which are significant regulators of lipid metabolism [33]. Trimethylamine N-oxide (TMAO), a product of gut microbiome-related metabolism of choline and L-carnitine, has also been associated with pro-atherosclerotic effects via modulation of reverse cholesterol transport, cholesterol metabolism, and bile acid composition [34^-36].

Dietary Considerations

Essential dietary modifications are the initial step toward the management of dyslipidemia in CKD. Mediterranean diet has been extensively studied, providing evidence of ameliorated lipid profiles in CKD patients as well as post-kidney transplantation [37^, 38]. Moreover, the benefits of a low-protein diet on cholesterol levels and kidney function were recently reported in patients with advanced CKD [39]. A high-fiber diet was also met with favorable outcomes in the means of improved quality of life and lipid profile within 6 weeks of initiation [40]. Recently, resveratrol supplementation was shown to dose-dependently improve kidney function and lipid metabolism via autophagy modulation in an experimental model of diabetic nephropathy [41].

Statins-Ezetimibe

Statin therapy has been the main focus of published international guidelines through the years (Table 1), and CKD frequently consists of an indication for statin prescription. The most recent international guidelines on the management of dyslipidemias recommend treatment with a statin up until stage 5 CKD [42^-44], despite the limited benefit observed in this subgroup of patients.

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The major clinical trials demonstrated important reductions in adverse cardiovascular outcomes following statin therapy in nondialysis-dependent CKD [45^, 46]. However, the effect appears to be variable, mainly depending on the degree of kidney dysfunction (shown in Fig. 2). Even though meta-analytic data display significant reductions in cardiovascular outcomes of patients with CKD, they have also stressed the declining benefit of statin treatment with worsening renal function [47^-49]. Regarding a possible effect of statin therapy on CKD progression, this has not been proven since they did not result in slower CKD progression despite reduction of proteinuria according to the published meta-analyses [48^, 50]. Last but not least, statins appear to be beneficial in subjects with autosomal dominant polycystic kidney disease if started early in the disease course, owing to their pleiotropic mechanism of action [51]. As far as the side effects of statin therapy are concerned, no significant differences have been noted compared to placebo in major trials [52].

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Ezetimibe, acting on the small intestine to inhibit cholesterol absorption thus increasing circulating cholesterol uptake by hepatocytes, is an important add-on treatment in CKD patients also. In a recently reported meta-analysis, the combination of ezetimibe with statins led to a greater reduction of all-cause mortality and adverse cardiovascular outcomes paired with improvement in cholesterol and triglyceride levels compared to statin monotherapy [49].

As far as patients on dialysis are concerned, inconsistent benefit has been reported following statin treatment. Even though the current guidelines recommend against the initiation of statins in patients on dialysis owing to the negative results of the 4D and AURORA trials [43], it appears that some subgroups are met with significant benefits, such as dialysis patients with atherosclerotic cardiovascular disease or significant hypercholesterolemia [53]. Continuing long-term statin therapy after dialysis initiation is another topic of interest, with the recent study of Streja et al. [54] reporting favorable outcomes in the continuation group.

Regarding patients on peritoneal dialysis, even though statins can potently and effectively lower cholesterol levels [55], only a small proportion of SHARP trial participants were in this dialysis method and did not gain any cardiovascular benefit [56]. Data from a retrospective cohort study using propensity score matching in peritoneal dialysis patients demonstrated reduced all-cause mortality in statin-treated arms [57].

Triglyceride-Lowering Therapy

Increased triglycerides have been linked with cardiovascular morbidity and mortality, making fibrates a presumably important agent in patients with CKD, characterized by hypertriglyceridemia. Their mechanism of action involves stimulation of peroxisome proliferator-activated receptor alpha (PPARα) which is associated with triglyceride homeostasis while possessing anti-inflammatory and antithrombotic properties.

A meta-analysis conducted in 2012 reported a lower risk of cardiovascular events and mortality in fibrate users with mild-to-moderate CKD [58]. In a recently reported cohort study of patients with advanced CKD, a cardiovascular risk reduction was reported in the fenofibrate treatment arm while also protecting against incident renal function worsening [59]. Potential nephroprotective mechanisms involve attenuated oxidative stress, inflammation, and apoptosis [60]. Pemafibrate has been in the spotlight due to its ability to selectively, potently, and safely interact with PPARα compared to other fibrates (Table 2). Experimental evidence has shown beneficial lipid alterations and attenuated inflammatory response, collectively halting atherosclerosis progression [72^, 73]. Moreover, it provides renal protection via reduction of oxidative stress and lipid deposition [74], undergoes primarily hepatic excretion, and has no significant interaction with statins. Pemafibrate demonstrated a significant triglyceride-lowering effect with a good safety profile in CKD and hemodialysis patients. Another point that merits special notice is the higher drop of triglyceride-rich lipoproteins and small dense LDL-C in those with the most impaired renal function [61].

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PPARγ agonists are another important drug category with beneficial effects on dyslipidemia and adverse outcomes. Specifically, treatment with pioglitazone has been associated with a lower incidence of hard endpoints in individuals with DM and advanced CKD [62^, 63]. It should also be noted that recent trials have unveiled novel antifibrotic mechanisms of pioglitazone which could affect the progression of CKD [75].

Regarding ω3-polyunsaturated fatty acids, eicosapentaenoic acid (EPA) exerts unique cardioprotective properties, namely, via the interactions in membranes and lipoproteins, oxylipin production, free fatty acid receptor-4 signaling, and stimulation of PPAR [76]. Two recently completed trials demonstrated significant benefits of high-dose EPA on adverse cardiovascular events and atherosclerosis in high-risk patients with hypertriglyceridemia under statin therapy [77^, 78]. Importantly, the REDUCE-IT trial recruited patients with CKD in whom the benefits remained unaffected. However, the STRENGTH trial reported contradictory findings, making the use of these agents uncertain with regard to cardiovascular benefits, since guideline recommendations were reported before this study [79]. Interestingly, EPA is also implicated in the prevention of palmitate-induced lipotoxicity and subsequent renal proximal tubule injury while also protects against renal fibrosis, thus halting CKD evolution [80^, 81].

PCSK9 Inhibitors

Involved in the degradation of the LDL receptor, PCSK9 inhibition has revolutionized the treatment of dyslipidemia. The randomized controlled trials provided robust evidence on their potency in reducing adverse cardiovascular events [82], being also efficacious in participants with mild-to-moderate renal dysfunction (Table 2) [64^, 66]. Unfortunately, none of those trials enrolled patients with severe or dialysis-dependent CKD which creates inevitable gaps in evidence. However, a recent study evaluating evolocumab’s pharmacologic properties demonstrated no significant differences in its exposure while maintaining the LDL-lowering properties across severe kidney impairment (eGFR 15–29 mL/min/1.73 m²) and dialysis-dependent CKD [65]. An analysis of inclisiran studies including patients with CKD (eGFR ≥30 mL/min/1.73 m²) was also performed, reporting similar efficacy and safety to patients with normal kidney function [67].

Emerging Therapeutic Strategies

Dyslipidemia in Renal Transplant Recipients

The presence of dyslipidemia is common after renal transplantation owing to the mechanism of action of immunosuppressive agents (shown in online suppl. Fig. 1; see http://www.karger.com/doi/10.1159/000518456) [85]. Statin therapy with caution on potential drug-drug interactions due to metabolism in CYP3A4 is indicated, while the addition of ezetimibe is reasonable in cases of intolerance or insufficient response [43]. Interestingly, pretransplantation high-intensity statin treatment was met with a survival benefit after transplantation [86].

Nephrotic Syndrome-Related Dyslipidemia

Uncontrolled and prolonged dyslipidemia in the setting of nephrotic syndrome is an important determinant of CKD due to podocyte injury and mesangial cell proliferation as well as cardiovascular disease development. Increased cholesterol levels in patients with nephrotic syndrome result from multiple mechanisms including the diminished lipoprotein lipase and hepatic lipase activity and the increased PCSK9 levels [87]. Pharmacologic management is largely dependent on statin treatment even though data are limited and inconclusive. LDL apheresis, PCSK9 inhibition, and hepatic angiopoietin-like protein 3 inhibition via RNA interference are alternative approaches that deserve further investigation before adoption in clinical practice.