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Lipid abnormalities in nephrotic syndrome

Lipid abnormalities in nephrotic syndrome
Literature review current through: Aug 2023.
This topic last updated: Apr 18, 2023.

INTRODUCTION — Abnormal lipid metabolism is common in patients with kidney disease. This effect is most prominent in the nephrotic syndrome, where marked elevations in serum cholesterol and triglycerides often occur.

This topic will review the pathogenesis and management of lipid abnormalities in patients with the nephrotic syndrome. The pathogenesis and management of lipid abnormalities in patients with chronic kidney disease and following kidney transplantation are discussed separately:

(See "Lipid management in patients with nondialysis chronic kidney disease".)

(See "Kidney transplantation in adults: Lipid abnormalities after kidney transplantation".)

COMMON LIPID ABNORMALITIES — Patients with the nephrotic syndrome frequently have marked elevations in the plasma levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C), triglycerides, and lipoprotein(a) [1,2]. Total high-density lipoprotein cholesterol (HDL-C) levels are usually normal or reduced in the nephrotic syndrome, and there is often a pronounced decline in the cardioprotective HDL2 fraction. The following studies illustrate the range of findings:

Among 207 adults with nephrotic syndrome due to nondiabetic kidney disease (mean proteinuria 7.2 g/24 hours), the mean total cholesterol concentration was 302 mg/dL (7.8 mmol/L), the mean LDL-C concentration was 208 mg/dL (5.4 mmol/L), and the mean triglyceride concentration was 251 mg/dL (2.8 mmol/L) [3]. The mean HDL-C concentration was 44 mg/dL (1.1 mmol/L).

Another study of 100 patients with the nephrotic syndrome found that the plasma total cholesterol concentration exceeded 200 mg/dL (5.2 mmol/L) in 87 percent, 300 mg/dL (7.8 mmol/L) in 53 percent, and 400 mg/dL (10.3 mmol/L) in 25 percent [4]. Approximately 77 percent of patients had an LDL-C level >130 mg/dL (3.4 mmol/L), and 65 percent had an LDL-C level >160 mg/dL (4.1 mmol/L).

In a study of 57 adults with the nephrotic syndrome, normal kidney function, and no other complicating diseases (such as diabetes), the mean serum triglyceride level was 230 mg/dL (2.6 mmol/L) among males and 223 mg/dL (2.5 mmol/L) among females [5].

Some patients with the nephrotic syndrome may have no lipid abnormalities. As an example, normal serum cholesterol levels in the setting of overt nephrotic syndrome have been reported among nephrotic patients with renal amyloidosis and lupus nephritis [6,7].

The concentration of plasma apolipoproteins in the nephrotic syndrome generally reflects the alterations in lipoprotein metabolism. Thus, there are elevated levels of apolipoprotein B (ApoB), ApoC-II, and ApoE, which are associated with very-low-density lipoprotein cholesterol (VLDL-C) and LDL-C; on the other hand, the levels of the major lipoproteins associated with HDL-C, ApoA-I and -A-II, are usually normal [5]. A strong reduction in glomerular as well as plasma apolipoprotein M (ApoM) levels has been found in patients with glomerular diseases, and plasma ApoM level has been shown to be a predictor of complete remission [8]. A review of the functions of the different apolipoproteins is discussed separately. (See "Lipoprotein classification, metabolism, and role in atherosclerosis".)

PATHOGENESIS

LDL-C and cholesterol metabolism — Patients with the nephrotic syndrome frequently have marked elevations in serum total cholesterol and low-density lipoprotein cholesterol (LDL-C). This is due to a combination of increased biosynthesis and impaired catabolism of lipoproteins containing apolipoprotein B (ApoB) and cholesterol [5,9-12]. Several mechanisms have been shown to contribute to these defects in cholesterol metabolism in patients and experimental animals with the nephrotic syndrome, including the following (figure 1):

Increased 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase activity in the liver of nephrotic animals, resulting in increased cholesterol synthesis [13,14].

Upregulation of the expression and activity of liver acetyl CoA acetyltransferase 2 (ACAT2), which results in enhanced esterification of cholesterol and a reduction in the level of intracellular free cholesterol [10,15]. In experimental models of the nephrotic syndrome, pharmacologic inhibition of ACAT was shown to improve serum lipid levels and ameliorate proteinuria [10].

Decreased hepatic lipase activity and decreased lipoprotein lipase (LPL) activity in the endothelium and peripheral tissues (such as muscle and adipose tissue), which results in impaired clearance of lipoproteins [16-21].

Increased hepatic expression of proprotein convertase subtilisin/kexin type 9 (PCSK9), which promotes degradation of the low-density lipoprotein receptor (LDLR) and leads to acquired LDLR deficiency and, consequently, impaired LDL-C clearance [22,23]. Increased PCSK9 expression in collecting duct cells has also been described in an experimental model of the nephrotic syndrome, and selective deficiency of collecting duct PCSK9 in this model was sufficient to prevent hypercholesterolemia associated with the nephrotic syndrome [24].

Patients with the nephrotic syndrome have been shown to have elevated plasma PCSK9 levels that correlate with the degree of proteinuria and levels of total, non-high-density lipoprotein cholesterol (HDL-C), and LDL-C [25,26]. In one series of nephrotic patients who went into remission, a decrease in plasma cholesterol was accompanied by a reduction in plasma PCSK9 [27].

In addition, plasma lipoprotein(a) levels are markedly elevated in patients with the nephrotic syndrome compared with healthy control patients [3,28]. Both increased hepatic synthesis [29] and decreased catabolism [30] appear to be responsible.

HDL-C metabolism — The nephrotic syndrome results in significant alterations to the structure and function of high-density lipoprotein cholesterol (HDL-C). Patients with the nephrotic syndrome usually have normal to slightly reduced plasma HDL-C levels compared with healthy control patients [31]; the HDL-C to total cholesterol ratio is generally decreased. The maturation of cholesterol ester-poor HDL3 to cholesterol ester-rich HDL2 is also impaired [32,33], which results in impairment of HDL-C mediated reverse cholesterol transport. A number of mechanisms for these HDL-C abnormalities in the nephrotic syndrome have been proposed, including acquired lecithin-cholesterol acyltransferase (LCAT) deficiency, hypoalbuminemia, elevated levels of serum cholesterol ester transfer protein (CETP), and a reduction of hepatic HDL-C docking receptor SR-B1 [1].

Several experimental studies suggest that impaired reverse cholesterol transport in the kidney may contribute to proteinuria and disease progression in a number of glomerular disorders [34,35]. Ongoing phase II trials will determine if newly developed reverse cholesterol transport inducers can improve nephrotic syndrome in patients with primary focal segmental glomerulosclerosis (FSGS; NCT05267262) [36].

Triglyceride metabolism — Patients with the nephrotic syndrome frequently have elevated serum triglyceride, very-low-density lipoprotein (VLDL), and intermediate-density lipoprotein (IDL) levels. Impaired triglyceride metabolism, rather than enhanced synthesis, is primarily responsible for nephrotic hypertriglyceridemia (figure 1) [9,37-39]. The delipidation cascade in which VLDL is converted to IDL and then to LDL-C by LPLs is slowed in the nephrotic syndrome [38]. There is also a trend toward reduced LDLR-mediated clearance of LDL-C and IDL [12,38]. How these changes occur is incompletely understood.

The increase in IDL and VLDL levels in the nephrotic syndrome is primarily due to defective LPL activity and decreased hepatic lipase activity [16]. Decreased LPL activity has been partly attributed to increased glomerular basement membrane permeability and the related loss of LPL activators [40]. The concomitant downregulation of hepatic lipase in the nephrotic syndrome contributes to decreased clearance of IDL and hypertriglyceridemia. This may occur as a consequence of increased circulating angiopoietin-like 4 (ANGPTL4) in response to an elevated ratio of free fatty acids to albumin due to proteinuria [41].

Fatty acid uptake and accumulation of triglycerides in the kidney cortex have been shown to cause glomerular damage in experimental models of nephrotic syndrome [42]. In addition, serum free fatty acid elevation may predict the development of acute kidney injury in nephrotic syndrome [43].

Other mechanisms — The hyperlipidemic response is triggered at least in part by the reduction in plasma oncotic pressure, and the severity of the hyperlipidemia is inversely related to the fall in oncotic pressure [5]. Spontaneous or drug-induced resolution of the nephrotic syndrome reverses the hyperlipidemia [5,44]. (See 'Treatment of nephrotic syndrome' below.)

A low oncotic pressure directly stimulates hepatic ApoB gene transcription [45]. Furthermore, raising the plasma oncotic pressure with albumin or dextran reverses these changes in vitro [45] and produces a rapid reduction in lipid levels in nephrotic patients [46].

The reason why a low oncotic pressure stimulates lipoprotein production by the hepatocyte is not known [45]. This is not a simple compensatory response, since lipoproteins are too large to significantly raise the oncotic pressure toward normal.

CLINICAL IMPLICATIONS — There is a large body of literature implicating hypercholesterolemia as a major risk factor in the pathogenesis of atherosclerotic cardiovascular disease (CVD). Furthermore, lowering high cholesterol levels can decrease the incidence of coronary events by inducing regression and more importantly preventing progression of atherosclerotic lesions. (See "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease" and "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)

Studies to confirm these findings in patients with the nephrotic syndrome are largely lacking and unlikely to be performed. Nevertheless, it seems likely that patients with persistent nephrotic syndrome and hyperlipidemia are at increased risk for atherosclerotic CVD, particularly if other cardiovascular risk factors are present [4,37,47]. In one study that compared 142 nondiabetic adult patients with nephrotic syndrome with matched controls, those with nephrotic syndrome had a higher risk of myocardial infarction (relative risk [RR] 5.5, 95% CI 1.6-18.3) and a nonsignificantly higher risk of coronary death (RR 2.8, 95% CI 0.7-11.3) [47]. Rare cases of myocardial infarction occurring in children with nephrotic syndrome have also been reported [48,49]. Thus, intensive lipid-lowering therapy to prevent CVD may be warranted in patients with chronic nephrotic syndrome who do not achieve disease remission.

Experimental observations in animals with kidney disease and some observations in humans, particularly post-hoc analyses, suggest that hyperlipidemia may also enhance kidney injury due to direct effects on mesangial cells, podocytes, and tubular cells (the so-called "lipid nephrotoxicity hypothesis") [2]. This may constitute an additional rationale for reducing lipid levels in nephrotic patients, although existing data suggest that statin therapy does not reduce the risk of kidney failure events among adults not receiving dialysis [50].

EVALUATION — There are no consensus guidelines on when or how to evaluate for hyperlipidemia in patients with the nephrotic syndrome. We obtain a fasting lipid panel (including total cholesterol, low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein [HDL-C], and triglycerides) in all patients with the nephrotic syndrome at the time of diagnosis. If no lipid abnormalities are detected at the time of diagnosis, we repeat a fasting lipid panel every three months as long as the patient remains nephrotic.

Given that nephrotic syndrome has been associated with an increased risk of atherosclerotic cardiovascular disease (CVD) (see 'Clinical implications' above), all patients with the nephrotic syndrome should undergo atherosclerotic CVD risk assessment similar to the general population. It is important to note that most commonly used CVD risk calculators have not been validated in patients under 40 years of age and do not include nephrotic syndrome as a potential factor in the estimation of risk. Thus, use of CVD risk calculators may not accurately assess CVD risk in patients with the nephrotic syndrome, particularly those who are younger or do not have preexisting CVD risk factors (such as hypertension or diabetes mellitus). The approach to CVD risk assessment in adults and children is discussed separately:

(See "Atherosclerotic cardiovascular disease risk assessment for primary prevention in adults: Our approach", section on 'Our approach to ASCVD risk assessment'.)

(See "Pediatric prevention of adult cardiovascular disease: Promoting a healthy lifestyle and identifying at-risk children", section on 'Routine screening'.)

MANAGEMENT — In patients with the nephrotic syndrome, the management of hyperlipidemia focuses primarily on treatment of the nephrotic syndrome. Lifestyle modifications (including diet, increased physical activity, and weight reduction) and lipid-lowering therapy may be indicated for selected patients, such as those with persistent nephrotic syndrome and hyperlipidemia despite treatment of the underlying kidney disorder. However, evidence to guide the optimal therapy of hyperlipidemia in this patient population is limited.

Treatment of nephrotic syndrome — The primary approach to treating lipid abnormalities associated with the nephrotic syndrome is treatment of the underlying kidney disease responsible for causing the nephrotic syndrome. Such treatments may include immunosuppressive therapy as well as supportive measures, such as treatment with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB). The hyperlipidemia observed in the nephrotic syndrome generally reverses with resolution of the kidney disease. (See 'Pathogenesis' above.)

The reduction in protein excretion with ACE inhibitors or ARBs may be associated with a 10 to 20 percent decline in the plasma levels of total and low-density lipoprotein cholesterol (LDL-C) and lipoprotein(a) [51]. The magnitude of these changes appears to be related to the degree of fall in protein excretion, but they can occur with little or no elevation in the plasma albumin concentration.

Lifestyle modification — All patients with hypercholesterolemia or hypertriglyceridemia associated with the nephrotic syndrome should be counseled on lifestyle modifications, such as a heart-healthy diet, increase in physical activity, smoking cessation, and weight reduction. Although these lifestyle modifications have not been well studied in patients with the nephrotic syndrome, these have been shown to have beneficial effects on preventing cardiovascular morbidity and mortality in the general population. Lifestyle changes are first-line treatment among children with dyslipidemia. (See "Overview of primary prevention of cardiovascular disease", section on 'Rationale' and "Dyslipidemia in children and adolescents: Management", section on 'Heart-healthy lifestyle'.)

It is unclear whether dietary restriction of fats is beneficial to patients with hyperlipidemia associated with the nephrotic syndrome. In a randomized trial of 20 patients with chronic nephrotic syndrome published in 1993, the use of a vegetable soy diet that is low in fat and protein, cholesterol free, and rich in monounsaturated and polyunsaturated fatty acids produced a 25 to 30 percent reduction in lipid levels [52]; however, these favorable effects may have been related to an accompanying reduction in proteinuria.

Pharmacologic therapy

Our approach — All patients with the nephrotic syndrome should receive lipid-lowering therapies for primary or secondary prevention of cardiovascular disease (CVD) as appropriate based upon their assessed CVD risk (using a risk calculator) and estimated glomerular filtration rate (eGFR). Although the use of CVD risk calculators has not been specifically validated in patients with the nephrotic syndrome, we believe it is reasonable to extrapolate their use to most adults with the nephrotic syndrome. However, as previously noted (see 'Evaluation' above), such CVD risk calculators may not accurately assess CVD risk in younger patients with the nephrotic syndrome (age <40 years) or those without preexisting CVD risk factors (such as hypertension or diabetes mellitus). (See "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease" and "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease" and "Lipid management in patients with nondialysis chronic kidney disease".)

In patients with the nephrotic syndrome who do not have an indication for primary or secondary CVD preventive therapies based upon their estimated CVD risk or eGFR, the optimal approach to pharmacologic lipid-lowering therapy is uncertain. There are no existing criteria for a threshold of hyperlipidemia at which pharmacologic therapy should be initiated and no data to guide the optimal timing or goals of pharmacologic therapy. Furthermore, there are no studies demonstrating that lowering lipid levels in patients with the nephrotic syndrome reduces the risk of CVD events. Thus, in the absence of clear evidence supporting its use, pharmacologic lipid-lowering therapy should be considered on a case-by-case basis after weighing the potential benefits and risks of treatment. Our approach, which is based primarily upon our clinical experience, is as follows:

We treat the cause of the nephrotic syndrome first since hyperlipidemia is expected to reverse with resolution of the nephrotic syndrome. (See 'Treatment of nephrotic syndrome' above.)

If the nephrotic syndrome resolves within three to six months, we do not initiate pharmacologic lipid-lowering therapy unless indicated for primary or secondary CVD prevention based upon the patient's CVD risk and eGFR. (See "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease" and "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease" and "Lipid management in patients with nondialysis chronic kidney disease".)

If the nephrotic syndrome does not resolve within three to six months (algorithm 1), we repeat a fasting lipid profile and initiate pharmacologic lipid-lowering therapy with a statin if the LDL-C is >100 mg/dL (2.6 mmol/L) or if indicated for primary or secondary CVD prevention based upon the patient's estimated CVD risk (using a risk calculator) and eGFR. Choice and dosing of statin therapy are discussed below. In rare patients with an LDL-C ≤100 mg/dL (2.6 mmol/L) who have isolated severe hypertriglyceridemia (eg, serum triglycerides >400 mg/dL), we treat with omega-3 fatty acids (such as icosapent ethyl, if available, or fish oil supplements) or a fibrate. (See 'Statin therapy' below and "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease" and "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease" and "Lipid management in patients with nondialysis chronic kidney disease" and "Hypertriglyceridemia in adults: Management", section on 'Marine omega-3 fatty acids'.)

In patients with persistent nephrotic syndrome, we use LDL-C in addition to estimated CVD risk (using a risk calculator) to guide decisions on lipid-lowering therapy since it is unclear that CVD risk can be accurately estimated with risk calculators in such patients (see 'Evaluation' above). However, there is no high-quality evidence to support the use of this (or any other) LDL-C threshold in patients with the nephrotic syndrome; this threshold is similar to that used for non-nephrotic patients without established CVD who are at very high risk for a CVD event.

Our preference for waiting up to three to six months after initiation of treatment of the nephrotic syndrome is an arbitrary threshold, and some clinicians may choose to initiate pharmacologic therapy earlier or later in the course of treatment. We feel that it is reasonable to wait up to six months to start pharmacologic therapy since it is unclear that delaying therapy for up to this amount of time is associated with an increased long-term risk of CVD in this patient population.

Statin therapy — For patients with persistent nephrotic syndrome who are initiated on pharmacologic lipid-lowering therapy (see 'Our approach' above), we suggest treatment with a statin rather than other therapies. Statins are the preferred first-line agents for treatment of hyperlipidemia in patients with the nephrotic syndrome:

Dosing and efficacy – Several different formulations of statin therapy are available. The initial choice of agent is generally based upon potential drug interactions, price, side effects, and patient preference. We usually initiate treatment with a moderate-intensity statin (such as atorvastatin 10 to 20 mg daily or simvastatin 20 to 40 mg daily). (See "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease".)    

In patients with hyperlipidemia associated with nephrotic syndrome, statins can lower the plasma total and LDL-C concentrations by 20 to 45 percent, with a lesser reduction in triglyceride levels [37,53-56]. Lipoprotein(a) levels may also be reduced, especially in patients with high baseline values [57]. However, there are limited data examining statins and CVD end points in nephrotic patients [56].

One report has suggested that statins may be renoprotective [58], an effect possibly mediated by improvements in endothelial function [59], but this finding has not been replicated in other larger studies.

Monitoring and goals of therapy – In patients receiving a statin, a fasting lipid profile should be monitored 4 to 12 weeks after statin initiation or dose adjustment and every 3 to 12 months thereafter to assess response and adherence to therapy.

The optimal LDL-C target in patients with the nephrotic syndrome is not known. We titrate the statin dose to target an LDL-C goal of <100 mg/dL (2.6 mmol/L) in view of the increased CVD risk in patients with the nephrotic syndrome. However, there is no evidence to support this (or any other) LDL-C target in patients with the nephrotic syndrome. If the target LDL-C cannot be achieved with maximally tolerated statin therapy, the use of additional second-line agents may be required. (See 'Second-line agents and other therapies' below.)

Duration of therapy – If the nephrotic syndrome eventually resolves with treatment, statin therapy can be discontinued unless lipid-lowering therapy is indicated for primary or secondary CVD prevention based upon the patient's CVD risk and eGFR. If the patient has persistent albuminuria or their eGFR is <60 mL/min/1.73 m2, we continue therapy indefinitely.

Adverse effects – Statin side effects and intolerance, which vary somewhat among the statins, are discussed in detail separately. (See "Statins: Actions, side effects, and administration".)

Statins should be used with caution in patients who are concomitantly taking cyclosporine. Coadministration of a statin with cyclosporine can increase statin levels and the risk of myotoxicity. Tacrolimus, which does not have a drug interaction with statins, can be used with statins without the need for dose adjustment [60]. (See "Statin muscle-related adverse events", section on 'Concurrent drug therapy'.)

Second-line agents and other therapies — Some patients with persistent nephrotic syndrome who are treated with statin therapy may not be able to tolerate a statin or may not be able to achieve the target LDL-C despite treatment with a maximally tolerated statin. Others may have concomitant hypertriglyceridemia that is not responsive to statin therapy. For such patients, a number of second-line therapies are available, including ezetimibe, proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors, fibrates, bile acid sequestrants, nicotinic acid (niacin), omega-3 fatty acids, and LDL apheresis. The efficacy of these second-line therapies is variable, and use of these agents is often limited by side effects [37,53,61]. Our approach to second-line therapy, which is based upon low-quality evidence and our clinical experience, is as follows:

For patients whose LDL-C is ≥100 mg/dL (2.6 mmol/L) in spite of a maximally tolerated dose of a statin, we suggest adding ezetimibe because of its safety profile and fewer adverse effects. If the target LDL-C still cannot be achieved with a statin plus ezetimibe, a PCSK9 inhibitor or a fibrate is a potential third-line agent. The cost, requirement for injections, and lack of long-term safety data with PCSK9 inhibitors may limit their use.

For patients who are unable to tolerate statin therapy, we suggest either a PCSK9 inhibitor, a fibrate, or a bile acid sequestrant. As stated above, use of a PCSK9 inhibitor may be limited by its cost and requirement for injections. Bile acid sequestrants are considerably less expensive, but their use is frequently limited by their gastrointestinal side effects.

For patients who have persistent and severe hypertriglyceridemia (eg, serum triglycerides >400 mg/dL) in spite of a maximally tolerated dose of a statin, we suggest adding a fibrate.

Evidence for second-line therapies is presented below:

EzetimibeEzetimibe is the most commonly prescribed LDL-C-lowering agent after statins. It has limited vascular and clinical benefits but is frequently used in combination with statins or as an alternative agent in statin-intolerant patients. There are no available data evaluating the use of ezetimibe in patients with the nephrotic syndrome. In experimental models of nephrotic syndrome, ezetimibe was found to improve proteinuria and kidney triglyceride accumulation [42]. (See "Low-density lipoprotein cholesterol lowering with drugs other than statins and PCSK9 inhibitors", section on 'Ezetimibe'.)

PCSK9 inhibitors – PCSK9 inhibitors (eg, evolocumab and alirocumab) may be beneficial for the treatment of hyperlipidemia in patients with nephrotic syndrome who cannot tolerate or are resistant to statin therapy. This potential benefit is based upon studies demonstrating that PCSK9 may be involved in the pathogenesis of nephrotic syndrome-associated hypercholesterolemia. (See 'LDL-C and cholesterol metabolism' above and "PCSK9 inhibitors: Pharmacology, adverse effects, and use".)

In a study of 12 patients with refractory nephrotic syndrome and uncontrolled hypercholesterolemia despite treatment with statins, treatment with a PCSK9 inhibitor decreased LDL-C levels by a mean of 37 percent after four weeks without significant changes in serum albumin levels or proteinuria [62]. Plasma PCSK9 levels were reduced from a mean of 334 ng/mL at baseline to 190 ng/mL at six months after starting treatment (mean relative reduction of 42 percent). While these results are encouraging, additional studies are needed to confirm these findings.

Fibrates – Fibrates, such as gemfibrozil, lower the total cholesterol level by 10 to 30 percent but are associated with an increased risk of myopathy, particularly if given with a statin. Fibrates have a more prominent effect on triglyceride metabolism, lowering the triglyceride concentration by as much as 50 percent. Data describing their efficacy in patients with nephrotic syndrome are limited [56,63,64]. (See "Low-density lipoprotein cholesterol lowering with drugs other than statins and PCSK9 inhibitors", section on 'Fibrates'.)

Bile acid sequestrants – Bile acid sequestrants (colestipol and cholestyramine), in a dose of 15 to 25 grams per day, can lower the total cholesterol level by up to 30 percent when given alone [61] and can produce an additive response when used with a statin [54]. However, the gastrointestinal side effects of these drugs often limit patient adherence. (See "Low-density lipoprotein cholesterol lowering with drugs other than statins and PCSK9 inhibitors", section on 'Bile acid sequestrants'.)

Nicotinic acid (niacin) – Nicotinic acid has only a modest hypolipidemic effect and is associated with a relatively high incidence of side effects such as flushing and headache. Intestinal symptoms have been reported in patients with chronic kidney disease [65]. There are no available data evaluating the use of nicotinic acid in patients with the nephrotic syndrome. (See "Low-density lipoprotein cholesterol lowering with drugs other than statins and PCSK9 inhibitors", section on 'Nicotinic acid (niacin)'.)

Omega-3 fatty acids – Supplementation of omega-3 fatty acids in patients with nephrotic syndrome or nephrotic-range proteinuria may reduce serum triglyceride levels, with mixed effects on LDL-C levels [66,67]. While promising, these results need to be validated in larger studies.

LDL apheresis – LDL apheresis has been used in the treatment of drug-resistant hypercholesterolemia. (See "Treatment of drug-resistant hypercholesterolemia".)

Several uncontrolled studies have reported on the improvement of proteinuria and lipid parameters in adults and children with glucocorticoid-resistant nephrotic syndrome who were treated with LDL apheresis with or without glucocorticoids [68-70]. Possible mechanisms underlying this effect include removal of toxic lipids, removal of autoantibodies and potential permeability factors, reduction of the vasoconstrictive prostanoid and thromboxane A2, and reduction of inflammatory cytokines [70]. In the absence of randomized controlled trials, the role of this expensive therapy in treating nephrotic patients remains uncertain.

SUMMARY AND RECOMMENDATIONS

General principles – Abnormal lipid metabolism is common in patients with kidney disease. This effect is most prominent in the nephrotic syndrome, where marked elevations in the plasma levels of cholesterol, low-density lipoprotein cholesterol (LDL-C), triglycerides, and lipoprotein(a) often occur. Patients with persistent nephrotic syndrome and hyperlipidemia are at increased risk for atherosclerotic cardiovascular disease (CVD), particularly if other cardiovascular risk factors are present. (See 'Introduction' above and 'Clinical implications' above.)

Pathogenesis – The hyperlipidemic response is triggered at least in part by the reduction in plasma oncotic pressure, which stimulates hepatic apolipoprotein B (ApoB) gene transcription. Diminished catabolism may also play a role. Impaired metabolism, rather than enhanced synthesis, is primarily responsible for nephrotic hypertriglyceridemia. Spontaneous or drug-induced resolution of the nephrotic syndrome reverses the hyperlipidemia. (See 'Pathogenesis' above.)

Evaluation – There are no consensus guidelines on when or how to evaluate for hyperlipidemia in patients with the nephrotic syndrome. We obtain a fasting lipid panel (including total cholesterol, LDL-C, high-density lipoprotein [HDL-C], and triglycerides) in all patients with the nephrotic syndrome at the time of diagnosis. All patients with the nephrotic syndrome should be evaluated for hyperlipidemia. (See 'Evaluation' above.)

Management – In patients with the nephrotic syndrome, the management of hyperlipidemia focuses primarily on treatment of the nephrotic syndrome. Lifestyle modifications (including diet, increased physical activity, and weight reduction) and lipid-lowering therapy may be indicated for selected patients, such as those with persistent nephrotic syndrome and hyperlipidemia despite treatment of the underlying kidney disorder. However, evidence to guide the optimal therapy of hyperlipidemia in this patient population is limited. (See 'Treatment of nephrotic syndrome' above and 'Lifestyle modification' above.)

All patients with the nephrotic syndrome should receive lipid-lowering therapies for primary or secondary prevention of CVD as appropriate based upon their assessed CVD risk (using a risk calculator) and estimated glomerular filtration rate (eGFR). (See "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease" and "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease" and "Lipid management in patients with nondialysis chronic kidney disease".)

In patients with the nephrotic syndrome who do not have an indication for primary or secondary CVD preventive therapies based upon their estimated CVD risk or eGFR, the optimal approach to pharmacologic lipid-lowering therapy is uncertain. There are no existing criteria for a threshold of hyperlipidemia at which pharmacologic therapy should be initiated and no data to guide the optimal timing or goals of pharmacologic therapy. Our approach, which is based primarily upon our clinical experience, is as follows:

-We treat the cause of the nephrotic syndrome first since hyperlipidemia is expected to reverse with resolution of the nephrotic syndrome. If the nephrotic syndrome resolves within three to six months, we do not initiate pharmacologic lipid-lowering therapy unless indicated for primary or secondary CVD prevention based upon the patient's CVD risk and eGFR. For patients whose nephrotic syndrome does not resolve within three to six months and who have an LDL-C >100 mg/dL (2.6 mmol/L), we suggest initiating pharmacologic lipid-lowering therapy with a statin, rather than other pharmacologic therapies or no pharmacologic therapy (Grade 2C) (algorithm 1). However, for patients who cannot tolerate a statin, a PCSK9 inhibitor, fibrate, or bile acid sequestrant can be used as an alternative. In rare patients with an LDL-C ≤100 mg/dL (2.6 mmol/L) who have isolated hypertriglyceridemia, we treat with omega-3 fatty acids (such as icosapent ethyl, if available, or fish oil supplements) or a fibrate. (See 'Our approach' above and 'Statin therapy' above.)

-Some patients with persistent nephrotic syndrome who are treated with statin therapy may not be able to tolerate a statin or may not be able to achieve the target LDL-C despite treatment with a maximally tolerated statin. For patients whose LDL-C is ≥100 mg/dL (2.6 mmol/L) in spite of a maximally tolerated dose of a statin, we suggest adding ezetimibe (Grade 2C). If the target LDL-C still cannot be achieved with a statin plus ezetimibe, a PCSK9 inhibitor or fibrate is a potential third-line agent. For patients who have persistent and severe hypertriglyceridemia in spite of a maximally tolerated dose of a statin, we suggest adding a fibrate (Grade 2C). (See 'Second-line agents and other therapies' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Gerald B Appel, MD, who contributed to earlier versions of this topic review.

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Topic 3114 Version 30.0

References

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