REVIEWS

Dyslipidaemia in nephrotic syndrome:

mechanisms and treatment
Shipra Agrawal1, Joshua J. Zaritsky2, Alessia Fornoni3 and William E. Smoyer1
Abstract | Nephrotic syndrome is a highly prevalent disease that is associated with high morbidity
despite notable advances in its treatment. Many of the complications of nephrotic syndrome,
including the increased risk of atherosclerosis and thromboembolism, can be linked to
dysregulated lipid metabolism and dyslipidaemia. These abnormalities include elevated plasma
levels of cholesterol, triglycerides and the apolipoprotein B‑containing lipoproteins VLDL and IDL;
decreased lipoprotein lipase activity in the endothelium, muscle and adipose tissues; decreased
hepatic lipase activity; and increased levels of the enzyme PCSK9. In addition, there is an increase
in the plasma levels of immature HDL particles and reduced cholesterol efflux. Studies from the
past few years have markedly improved our understanding of the molecular pathogenesis of
nephrotic syndrome-associated dyslipidaemia, and also heightened our awareness of the
associated exacerbated risks of cardiovascular complications, progressive kidney disease and
thromboembolism. Despite the absence of clear guidelines regarding treatment, various strategies
are being increasingly utilized, including statins, bile acid sequestrants, fibrates, nicotinic acid and
ezetimibe, as well as lipid apheresis, which seem to also induce partial or complete clinical
remission of nephrotic syndrome in a substantial percentage of patients. Future potential
treatments will likely also include inhibition of PCSK9 using recently-developed anti‑PCSK9
monoclonal antibodies and small inhibitory RNAs, as well as targeting newly identified molecular
1
Center for Clinical and regulators of lipid metabolism that are dysregulated in nephrotic syndrome.
Translational Research,
The Research Institute
at Nationwide Children’s
Hospital, and Department of Nephrotic syndrome is one of the most common kidney However, the complications of both the disease and its
Pediatrics, The Ohio State diseases in children and adults, and is characterized by treatment are far-reaching. Major complications include
University, 700 Children’s
massive proteinuria, oedema and hypoalbuminaemia1. infections, acute kidney injury (AKI) and thrombo­
Drive, Columbus,
Ohio 43205, USA. The annual incidence and prevalence of nephrotic syn- embolisms9–12. A 2015 study found that AKI occurred in
2
Division of Pediatric drome in children are 2–7 new cases and 16 cases per ~58% of 336 children admitted to hospital for nephrotic
Nephrology, Department of 100,000 children, respectively, and in adults the yearly syndrome and in ~50% of 615 hospitalized children
Pediatrics, Nemours/Alfred I. incidence is three new cases per 100,000 adults 2–5. It is with nephrotic syndrome12. After infections and AKI,
duPont Hospital for
Children,1600 Rockland
difficult to establish the prevalence of nephrotic syn- thrombo­embolism is also considered to be the most
Road, Wilmington, Delaware drome in adults, as it usually results from an underlying common, major complication of nephrotic syndrome13–16.
19803, USA. disease. Although the majority of children and adults Children with nephrotic syndrome develop thrombo-
3
Katz Family Division of respond to initial treatment with glucocorticoids by embolism at a rate of 2.8%, whereas adults have a much
Nephrology and
entering into clinical remission, a substantial proportion higher rate of 26.7%. Thromboembolism is particularly
Hypertension, Peggy and
Harold Katz Drug Discovery of patients (~20% of children and 50% of adults) either prevalent in patients with membranous nephropathy,
Center, University of Miami present with or subsequently develop clinical steroid affecting as many as 37% of adults and 25% of children14.
Miller School of Medicine, resistance during the course of their disease6,7. Failure Thromboembolism in patients with nephrotic syn-
1580 NW 10th Avenue, to enter clinical remission greatly increases a patient’s drome is thought to be due to increased urinary loss of
Miami, Florida 33133, USA.
risk of various complications. These complications may antithrombotic factors and increased hepatic ­production
Correspondence to W.E.S.
result from persistence of the nephrotic state and/or of prothrombotic factors13,14,16.
william.smoyer@
nationwidechildrens.org from exposure to the relatively toxic alternative therapies Dysregulated lipid metabolism leading to dyslipid­
that are used to induce remission. aemia is an often under-recognized, but nearly uni-
doi:10.1038/nrneph.2017.155
Published online 27 Nov 2017; The primary pathology associated with nephrotic versal, complication of persistent nephrotic syndrome.
corrected online 13 Dec 2017 syndrome is injury to podocytes and the glomeruli1,8. Although elevated serum levels of cholesterol and

NATURE REVIEWS | NEPHROLOGY VOLUME 14 | JANUARY 2018 | 57

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REVIEWS

Key points and in patients with nephrotic syndrome. However, the

efficiency of HDL particles in causing cholesterol efflux
• Prolonged hyperlipidaemia in nephrotic syndrome is a major risk factor for multiple from peripheral tissues has yet to be studied in nephrotic
disease complications, including accelerated atherosclerosis, myocardial infarction, syndrome, but is of interest as cholesterol efflux has
stroke, chronic kidney disease and thrombosis been shown to be impaired in patients with diabetic
• Direct lipid-induced cellular injury to podocytes, mesangial cells and, potentially, nephro­pathy19. In fact, not only the total amount, but
renal tubular cells as a result of dyslipidaemia increasingly seems to have a role in the also the composition and function of lipoproteins are
pathogenesis of nephrotic syndrome
markedly altered in patients with nephrotic syndrome,
• Given the available evidence, we suggest that statins should be the first-line treatment with substantial increases in the levels of ApoA‑I,
for prolonged hyperlipidaemia in patients with nephrotic syndrome, given their
ApoA‑IV, ApoB, ApoC and ApoE, as well as in the ratio
efficacy in the treatment of other diseases and the fact that they are well tolerated
of A
­ poC-III to ApoC‑II18. These changes in serum lipids
• Alternative, less supported treatments include LDL apheresis, cholesterol absorption
and lipoproteins in patients with nephrotic syndrome are
inhibitors, nicotinic acid and bile acid sequestrants; targeting proprotein convertase
subtilisin/kexin type 9 is another potential treatment for hyperlipidaemia in patients
primarily a result of their impaired clearance and, to a
with nephrotic syndrome lesser extent, their altered biosynthesis. In fact, although
• Treatment recommendations in children are limited by a lack of data for both the
nephrotic syndrome can affect LDL synthesis20, the l­ evels
efficacy and the risk of pharmacological interventions of most ApoB-containing lipoproteins are altered owing
to decreased clearance21. Albumin metabolism was
originally thought to be linked to hyperlipid­aemia in
triglycerides have been noted since the early descriptions nephrotic syndrome; however, the link between hepatic
of nephrotic syndrome, the long-term consequences of lipogenesis and albumin synthesis has been challenged
prolonged dyslipidaemia in nephrotic syndrome remain by data from elegant studies suggesting that proteinuria,
relatively poorly understood. Whereas adults with and not albumin synthesis, is linked to hyperlipidaemia
nephrotic syndrome have a markedly increased risk of in nephrotic rats22. The composition of lipoproteins can
both myocardial infarction and coronary death com- also be affected in nephrotic syndrome associated with
pared with that of healthy individuals, very few data are CKD, because the activity of enzymes such as lecithin-­
available regarding these risks in children. Consequently, cholesterol acyltransferase (LCAT) is reduced, whereas
the dyslipidaemia of nephrotic syndrome is probably enzymes such as plasma cholesteryl ester transfer pro-
often under-treated, particularly in children, of whom tein (CETP) are activated, resulting in the production of
very few would have pre-existing hyperlipidaemia immature HDL23.
from other causes. However, hyperlipidaemia has been Severe hypertriglyceridaemia is another important
associated with an increased risk of both accelerated lipid abnormality in patients with nephrotic syndrome,
cardiovascular disease and progressive kidney disease, and recent discoveries have identified angiopoietin-­
and persistent nephrotic syndrome is characteristically related protein 4 (ANGPTL4) and the extent of its
accompanied by moderate to severe dyslipidaemia. sialylation as attractive therapeutic targets for redu­
In this Review, we summarize recent advances in our cing proteinuria and hypertriglyceridaemia in these
understanding of the characteristics, molecular patho- patients24. In addition, the presence of other diseases, as
genesis and consequences of dyslipidaemia in patients well as the use of treatments to reduce proteinuria and
with nephrotic syndrome, as well as the evidence sup- the progression of CKD, might worsen dyslipidaemia
porting current and potential future treatments of in affected patients. The lipid abnormalities observed in
nephrotic syndrome-associated dyslipidaemia. patients with proteinuric disorders who are in the early
stages of CKD are clinically relevant, as they might
Dyslipidaemia in nephrotic syndrome actively contribute to the increased cardiovascular mor-
Characteristics of dyslipidaemia bidity and mortality of these patients, and therefore early
Lipoproteins are the major carriers of lipids in the blood identification and treatment of these lipid abnormalities
and they participate in three major pathways that are is important25.
responsible for the generation and transport of lipids
within the body (TABLE 1) — namely, the exogenous Pathogenesis of dyslipidaemia
pathway, the endogenous pathway and the reverse chol­ Triglycerides, VLDL and fatty acid metabolism. VLDL is
esterol transport pathway (FIG. 1). Lipid and lipoprotein an important vehicle for the delivery of fatty acids to sev-
metabo­lism is altered in nephrotic syndrome, with or eral tissues, primarily muscle and adipose tissue, where
without chronic kidney disease (CKD)17 (FIG. 2). The the fatty acids serve as an energy source (FIG. 1). On arrival
extent of altered lipid metabolism in nephrotic syn- in peripheral tissues, removal of fatty acids from VLDL
drome correlates with the magnitude of proteinuria. by lipoprotein lipase (LPL) results in the formation of
In particular, the plasma concentrations of cholesterol, IDL, which is then cleared from the circulation by LDL
triglycerides and apolipoprotein B (ApoB)-containing receptor-related protein 1 (LRP1)-mediated endocytosis
lipoproteins (including very low-density lipoprotein by hepatocytes. In addition to LRP1, the LDL receptor,
(VLDL), intermediate-­density lipoprotein (IDL) and liver proteoglycans and plasminogen receptor contrib-
Sialylation lipoprotein(a)) are all elevated in nephrotic syndrome. ute to catabolism of lipoprotein(a) and hepatic uptake
Addition of sialic acid groups
onto molecules such as
The concentration of high-density lipoprotein (HDL) of ApoB and ApoA26,27. Furthermore, differences in the
oligosaccharides and cholesterol17 and the content of ApoA‑I and ApoA‑II affinity of ApoE proteins for the receptors responsible for
carbohydrates. apolipoproteins18 are very similar in healthy individuals lipoprotein clearance owing to different APOE genotypes

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Glycocalyx affects lipoprotein(a) catabolism, possibly owing to the development of nephrotic syndrome41. However, the
Layer of glycoproteins and competition between lipoprotein(a) and ApoE for the finding that ApoC‑II may contribute to a new form of
sugar moieties surrounding the same receptors28. The levels of both IDL and VLDL are amyloidosis that primarily affects the kidney in humans
outer surface of the cell increased in patients with nephrotic syndrome, primar- is once more challenging the cause and effect relationship
membrane of some bacteria,
epithelia and other cells.
ily owing to defective LPL activity and decreased hepatic between ApoC‑II and nephrotic syndrome42. A potential
lipase activity21. For decades, the dogma was that LPL, role for ApoA‑V in nephrotic syndrome should also be
which contains positively charged heparin-binding investigated further, as the level of ApoA‑V is higher in
domains, binds to negatively charged heparin sulfate pro- patients with diabetes and ­proteinuria than in patients
teoglycans in the glycocalyx coating of blood vessels29,30. with diabetes without proteinuria43.
However, it is now established that the binding of LPL to
heparan sulfate proteoglycans on endothelial cells occurs Cholesterol metabolism: the role of LDL and HDL.
via endothelium-derived glycosylphosphatidylinositol-­ Both enhanced production and impaired catabolism of
anchored HDL-binding protein 1 (GPIHBP1) 31 . LDL contribute to the increased LDL and cholesterol
Interestingly, GPIHBP1 is downregulated in patients levels observed in patients with nephrotic syndrome. In
with nephrotic syndrome32. Furthermore, the loss of LPL addition, increased expression of proprotein convertase
activators in patients with nephrotic syndrome is associ­ subtilisin/kexin type 9 (PCSK9) results in increased deg-
ated with increased glomerular basement membrane radation of the LDL receptor and decreased LDL uptake
permeability, resulting in hyperlipidaemia33. In addition by the liver44,45. Genetic ablation of podocytes in mice and
to downregulation of LPL activity, nephrotic syndrome treatment of mice with nephrotoxic serum cause hyper-
is also characterized by downregulation of hepatic lipase cholesterolaemia and lead to increased levels of PCSK9
activity, which contributes to decreased clearance of IDL (REFS  45,46). Interestingly, hepatocyte-specific dele-
and hypertriglyceridaemia. Furthermore, upregulation of tion of PCSK9 protects mice from nephrotoxic serum-­
ANGPTL4 levels in nephrotic syndrome, which is driven induced hyperlipidaemia47. Furthermore, the elevated
primarily by circulating free fatty acids34, may inactivate plasma ­levels of both cholesterol and PCSK9 detected
LPL by converting active LPL dimers into inactive mono­ in patients with active nephrotic syndrome have been
mers35 or by acting as a reversible noncompetitive inhib- reported to return to normal levels upon remission of
itor of LPL36. The reduced plasma clearance of VLDL disease47. Hypercholesterolaemia and increased LDL
in nephrotic syndrome may be linked to suppression ­levels occur in conjunction with upregulation of the
of VLDL receptor expression, as was described in a rat expression and activity of liver acetyl-CoA acetyltrans-
model of nephrotic syndrome37. Fatty acid metabolism is ferase 2 (ACAT2), which results in enhanced esteri-
also altered in nephrotic syndrome, as there is increased fication of cholesterol and a reduction in the level of
expression of key enzymes involved in fatty acid biosynth­ intracellular free cholesterol48. Cholesterol synthesis via
esis, including acetyl-CoA carboxylase and fatty acid syn- 3‑hydroxy-3‑­methylglutaryl-CoA (HMG-CoA) reduc-
thase, and downregulation of fatty acid catabolism in the tase is also increased in experi­mental models of nephrotic
liver38. Triglyceride-rich, ApoB-containing lipo­proteins, syndrome49. Evidence also suggests that LDL oxidation
such as VLDL, may have atherogenic properties and in nephrotic syndrome might be augmented by lipo­
increase the risk of coronary events independently of protein(a)50, the level of which is increased in nephrotic
LDL39. The levels of ApoC‑II and ApoC-III are elevated syndrome 51. Accumulation of oxidized LDL, IDL
in patients with nephrotic syndrome40, although they and chylomicron remnants stimulates monocytes and
return to normal within 4 weeks after normalization of macro­phages to release proinflammatory cytokines
the levels of urinary protein, suggesting that the elevated and chemokines and accelerates inflammation52, which
ApoC‑II and ApoC-III levels are unlikely to contribute to may in turn promote the progression of CKD.

Table 1 | Classes of lipoproteins

Lipoprotein Composition Apolipoproteins and enzymes Function in normal physiology
High-density • Apolipoproteins (45%) • ApoA‑I, ApoA‑II, ApoC‑II, Reverse cholesterol transport
lipoprotein (HDL) • Cholesterol (25%) ApoC-III, ApoE, ApoL-I from tissues to the liver
• Triglycerides (30%) • CETP, LCAT
Low-density • Apolipoproteins (25%) ApoB‑100 Major cholesterol carrier
lipoprotein (LDL) • Cholesterol (45%)
• Triglycerides (30%)
Intermediate-density Mostly triglycerides ApoB‑100 Intermediate between LDL and
lipoprotein (IDL) and some cholesterol VLDL
Very low-density Mostly triglycerides ApoB‑100, ApoC‑II, ApoC-III, Major triglyceride carrier
lipoprotein (VLDL) ApoE
Chylomicrons • Apolipoproteins (2%) ApoB‑48, ApoC‑II, ApoC-III, Transport of dietary (exogenous)
• Cholesterol (3%) ApoE triglycerides to the systemic
• Triglycerides (93%) circulation and to adipose tissue
and the liver
ApoA‑I, apolipoprotein A‑I; CETP, cholesteryl ester transfer protein; LCAT, lecithin-cholesterol acyltransferase.

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Exogenous pathway

Endocrine system
Dietary for steroid hormone
fat synthesis
Chylomicrons
Intestine

Blood
vessel
Muscle, adipose
and other tissues
Fatty
LPL acids LPL
Bile acids
and Extrahepatic
Remnant tissue
cholesterol cholesterol
Reverse cholesterol HDL
transport pathway
LDLR

LDL Cholesterol
Hepatic LPL
lipase

Dietary
IDL
cholesterol LPL
Liver
VLDL
Apolipoproteins
LPL Triglycerides

Muscle, adipose Fatty Cholesterol

LPL acids
and other tissues

Endogenous pathway

Figure 1 | The major pathways of lipid metabolism. Lipoproteins are the major carriers of lipids Nature Reviews
in the | Nephrology
circulation and
they participate in three major pathways that are responsible for the generation and transport of lipids within the body.
The two major forms of circulating lipid in the body, triglycerides and cholesterol, are packaged with apolipoproteins and
phospholipids to form lipoproteins. The major forms of lipoproteins are chylomicrons, very low-density lipoprotein (VLDL),
intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL) and high-density lipoprotein (HDL), and they differ in
their size, density, composition and functions (detailed in TABLE 1). In the exogenous pathway, dietary lipids, which consist
mainly of triglycerides (95%) and some phospholipids, free fatty acids and cholesterol, are packaged into chylomicrons by
intestinal mucosal cells. These chylomicrons enter the lymphatic system and then the circulation, where triglycerides are
released as free fatty acids by lipoprotein lipase (LPL) activity on the capillary endothelium. These free fatty acids are taken
up by the muscle, adipose and other peripheral tissues, whereas the remnants of chylomicrons are cleared by the liver. In
the endogenous pathway, the liver produces VLDL, which interacts with LPL in the circulation to form IDL, with the release
of triglyceride and free fatty acids. IDL is rapidly removed by the liver via the interaction of its apolipoprotein E component
with LDL receptor (LDLR). Furthermore, IDL forms LDL upon removal of triglyceride by hepatic lipase. LDL, which is very
high in cholesterol content, is in turn removed from the circulation by binding to LDLR in the liver and in extrahepatic
tissues. HDL is an anti-atherogenic lipoprotein or ‘good cholesterol’, as it captures the cholesterol from peripheral tissues
or other lipoproteins and transports it back to liver by the third pathway, which is termed reverse cholesterol transport.

Patients with nephrotic syndrome can present with properties55,56, and protects against endothelial dys-
variable levels of HDL cholesterol, although the ratio function by binding to scavenger receptor B1 to acti-
of HDL cholesterol to total cho­lesterol is frequently vate endothelial nitric oxide synthase57. In nephrotic
decreased53. HDL is the main lipoprotein involved syndrome, in addition to a change in the HDL
in cholesterol efflux from peripheral organs, as well ­cholesterol:total cho­lesterol ratio, the maturation of chol­
as in the delivery of cholesterol to hepatocytes to be esterol ester-poor HDL3 to cholesterol ester-rich HDL2
converted into bile acids (FIG. 1). The principal role of is often impaired58, suggesting impaired reverse choles-
HDL is to promote cholesterol efflux, primarily via the terol transport could be a key component of nephrotic
membrane-­associated transporters ATP-binding cassette syndrome and contribute to its associated vascular com-
subfamily A member 1 (ABCA1) and ATP-binding cas- plications. Although extensively reviewed elsewhere59,
sette subfamily G member 1 (ABCG1)54. In addition new experimental studies suggest that improvement
to the induction of reverse cholesterol transport, HDL in cholesterol efflux via ABCA1 is also associated with
also has antioxidant activities and anti-inflammatory improved proteinuria and renal failure in experimental

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Muscle, adipose ↓ Cholesterol

and other tissues efflux via ABCA1
↓ Uptake

↓ LPL activity ↑ Immature HDL

↑ Triglycerides
Blood
vessel
↓ Clearance ↑ ANGPTL4 levels
and sialylation

↑ Acetyl-CoA carboxylase
↑ Fatty acid synthase ↑ Fatty acids
↓ Fatty acid catabolism ↑ Lipoprotein(a)

↑ IDL
↑ VLDL
↓ Lipase activity
↓ LDLR ↑ ApoA-I
Liver ↑ ApoA-IV
↑ ApoB
↑ LDL ↑ ApoC
↑ PCSK9 ↑ LDL ↑ ApoE
↑ ACAT2 ↑ Cholesterol ↑ ApoC-III/ApoC-II
↑ HMG-CoA

↓ LDL uptake

Lipid nephrotoxicity
Complications
• Atherosclerosis
• Cardiovascular disease
• Thromboembolism

Figure 2 | Pathophysiology of dyslipidaemia in nephrotic syndrome. Alterations of lipid and lipoprotein metabolism
in nephrotic syndrome result in ‘lipid nephrotoxicity’ and other complications, such as atherosclerosis, cardiovascular
Nature Reviews | Nephrology
disease and thromboembolism. The major lipoproteins, including intermediate-density lipoprotein (IDL), very low-
density lipoprotein (VLDL) and low-density lipoprotein (LDL), and cholesterol are increased in the plasma of patients
with nephrotic syndrome, owing mainly to impaired clearance and, to a lesser extent, increased biosynthesis. Impaired
clearance is a direct result of decreased hepatic lipase activity and decreased lipoprotein lipase (LPL) activity in the
endothelium and peripheral tissues, such as muscle and adipose. In addition, hepatic levels of proprotein convertase
subtilisin/kexin type 9 (PCSK9) are increased in patients with nephrotic syndrome; PCSK9 degrades the LDL receptor
(LDLR), and is thus a major therapeutic target for lipid lowering. Furthermore, the composition and function of the
lipoproteins are also altered, with substantial increases in the plasma levels of apolipoprotein A‑I (ApoA‑I), ApoA‑IV, ApoB,
ApoC and ApoE, and in the ApoC-III/ApoC‑II ratio. The level of immature HDL in the plasma is also increased, resulting in
reduced cholesterol efflux, which occurs mainly via ATP-binding cassette subfamily A member 1 (ABCA1), in peripheral
organs, including in podocytes. Another major lipid abnormality in nephrotic syndrome is hypertriglyceridaemia, as well
as increased production and sialylation of ANGPTL4, which is driven primarily by increased circulating free fatty acids.
ANGPTL4 in turn suppresses LPL activity by either preventing its dimerization or by inhibiting its activity noncompetitively.
Hypercholesterolaemia and increased LDL levels occur in conjunction with 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. Cholesterol synthesis via 3‑hydroxy-3‑methylglutaryl-CoA (HMG-CoA) reductase is
also increased in experimental models of nephrotic syndrome. Evidence also exists that LDL oxidation in nephrotic
syndrome may be augmented by lipoprotein(a), the level of which is also increased in patients with nephrotic syndrome.
Accumulation of oxidized LDL, IDL and chylomicron remnants stimulates monocytes and macrophages to release
proinflammatory cytokines and chemokines, and accelerates inflammation, which may in turn promote the progression
of chronic kidney disease.

models of focal segmental glomerulosclerosis60. Of note, to kidney disease (FIG. 3). Similar to atherosclerosis,
this last study challenges the long-held idea that impaired the effect of dyslipidaemia on decreased kidney func-
HDL function is a consequence, rather than a cause, of tion was first advocated as the ‘lipid nephrotoxicity’
proteinuria in nephrotic syndrome. hypothesis by Moorhead et al. in 1982 (REF. 33). In fact,
minimal change disease was also originally defined as
Lipoid nephrosis and foamy podocytes. Although ‘lipoid nephrosis’, based on the presence of foamy cells
the association between altered lipid metabolism and in kidney biopsy samples61, although the identity of these
protein­uria has been extensively studied, it remains cells (infiltrating macrophages or resident glomeru-
unclear whether dyslipidaemia actually contributes lar cells) has never been established. In addition, data

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Elevated lipids and lipoprotein levels Impaired cholesterol efflux

general population, elevated plasma concentrations of
HDL cholesterol are associated with atheroprotective
properties63–65, although raising the plasma HDL choles-
terol concentration does not necessarily reduce cardio­
Altered sphingolipid Fatty acid oxidation
metabolism and impaired uptake vascular risk66,67. However, the effects of HDL quantity
and function were not discriminated in these studies.
In addition, genetic variants associated with a higher
HDL cholesterol concentration are not associated with
a reduced risk of cardiovascular disease68. The failure to
Kidney observe cardiovascular protection in multiple trials with
inhibitors of cholesteryl ester transfer protein (CETP)
Lipid nephrotoxicity
should not discourage additional research in the field,
as CETP inhibitors were developed to raise HDL levels,
and not to increase the functionality of HDL. However,
a clinical trial (NCT01841684)69 showed that the CETP
Glomerular injury Tubulointerstitial injury inhibitor anacetrapib met its primary end point of redu­
↑ Proteinuria ↑ Proteinuria
↑ Albumin uptake ↑ Inflammatory cytokines cing cardiovascular events in patients at risk of cardiac
↑ Podocyte injury ↑ Immunoglobulins events who were already receiving a statin, compared
↑ Inflammatory cytokines with placebo70. Further research is also necessary to
↑ Mesangial cell proliferation
Altered insulin signalling determine if agents capable of increasing cholesterol
efflux, such as HDL mimetic peptides or recombinant
ApoA‑I, might represent novel therapeutic strategies to
treat patients with proteinuric kidney diseases and the
Progressive kidney disease
atherosclerosis associated with these diseases. The fact
Figure 3 | Mechanisms and consequences of lipid nephrotoxicity. The direct
Nature Reviews effects
| Nephrology
that LCAT deficiency in fish eye disease results in a renal
of dyslipidaemia on decreased kidney function are referred to as ‘lipid nephrotoxicity’, lipidosis that is associated with nephrotic range protein-
although the role of altered lipid metabolism in the molecular pathophysiology of uria strongly suggests that the elevated ratio of plasma
nephrotic syndrome is not well understood. During dyslipidaemia, triglyceride- unesterified cholesterol:total cholesterol observed in
rich lipoproteins, such as very low-density lipoprotein (VLDL) and intermediate-density LCAT deficiency might contribute to the development
lipoprotein (IDL) as well as oxidized LDL, are taken up by mesangial cells, leading to the of proteinuria71. Lipoprotein X, an abnormal cholesterol-­
production of cytotoxic agents, cytokines and reactive oxygen species, which further rich particle, might also contribute to renal disease in
damage the glomerular epithelial and endothelial cells, resulting in sclerosis. patients with LCAT deficiency72. Although more subtle
Furthermore, levels of free fatty acids are increased in patients with nephrotic syndrome,
than LCAT deficiency, the phenotype of patients with
which have been reported to have toxic effects in the kidney, especially in glomeruli
ABCA1 deficiency (Tangier disease) is also characterized
and podocytes, but also in the tubulointerstitium. Free fatty acids bound to albumin
cause podocyte damage by enhancing macropinocytosis and activating G protein- by early atherosclerosis, very low HDL levels and mild
coupled receptor (GPCR) signalling, leading to disruption of the podocyte actin proteinuria with foamy podocytes in kidney biopsy sam-
cytoskeleton and podocyte morphology. In addition, these albumin-bound free fatty ples73. Therefore, novel therapeutic strategies aimed at
acids cause loss of podocyte viability and increased production of several cytokines. reducing the acquired LCAT defect could potentially be
Moreover, free cholesterol-mediated injury is another pathway of cellular injury in effective in both reversing dyslipidaemia and slowing
podocytes, and involves the ATP-binding cassette sub-family A member 1 (ABCA1) disease progression in patients with CKD.
cholesterol transporter. Furthermore, the role of free fatty acids, and saturated fatty Finally, the finding that a mutation in the enzyme
acids in particular, is well-documented in causing damage to proximal tubule cells sphingosine 1 phosphate lyase causes nephrotic syn-
and tubulointerstitial injury.
drome74, together with the observation that enzymes
involved in sphingolipid metabolism, such as acid
from studies in experimental models of focal segmental sphingomyelinase-­like phosphodiesterase 3b (SMPDL3b),
glomerulo­sclerosis support the concept that lipid infil- might serve as modulators of lipid raft-dependent signal-
tration and accumulation in primary glomerular cells ling75 and might cause proteinuria, raises the important
might ­contribute to the pathogenesis of proteinuria60. question of the potential role of sphingolipid modulators
It is important to consider the evidence suggesting in causing podocyte injury in nephrotic syndrome.
that altered lipid metabolism might have a pathophysio­ An important consideration in the treatment of
logic role in nephrotic syndrome. In fact, LDL apheresis nephrotic syndrome is that many of the treatments
has been reported to be an effective measure to reduce themselves contribute to abnormal lipid metabolism.
Tangier disease proteinuria and podocyte loss or excretion in patients Data on the efficacy of glucocorticoids for the treatment
A rare inherited disorder
with refractory nephrotic syndrome62, suggesting that of dyslipidaemia are inconclusive — some observational
characterized by significantly
reduced levels of HDL in the renal cholesterol uptake via LDL and/or inflammatory data in adults suggest that glucocorticoids have only a
blood. responses to oxidized LDL might contribute to the devel- minimal effect on serum lipid levels76, whereas several
opment of proteinuria. With regard to reverse cholesterol cross-sectional studies in patients with systemic lupus
Lipid raft transport, the notion that impaired cholesterol efflux erythematosus demonstrated that administration of high
A subdomain of the plasma
membrane that contain high
and/or production of a non-functioning HDL is a cause, doses of corticosteroids (>10 mg per day) is associated
concentrations of cholesterol rather than a consequence, of proteinuria remains to be with elevated LDL and triglyceride levels77,78; however,
and glycosphingolipids. established, but is the subject of intense research. In the the interpretation of these studies is complicated by the

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fact that many of the patients also had renal involve- Lipid nephrotoxicity
ment. Glucocorticoids also increase VLDL levels directly The lipid nephrotoxicity hypothesis was proposed
(via increased hepatic production) and indirectly (via more than three decades ago, and proposes that hyper­
increased peripheral insulin resistance)79. Furthermore, lipidaemia, in addition to proteinuria and hypo­albumin­
inhibition of calcineurin activity using immunosuppres- aemia, lead to adverse and injurious effects in kidneys
sive drugs can lead to hypercholesterolaemia, and this and may cause glomerulosclerosis33,84. This hypothesis
effect is more prominent with ciclosporin treatment than is supported by a number of observations, leading to
with tacrolimus treatment80,81. the theory that the renal toxicity of filtered albumin is
dependent on its lipid moiety85,86. Cholesterol and lipo-
Clinical consequences of dyslipidaemia protein uptake are essential for the development, survival
There are numerous clinical consequences of dyslipid­ and growth of mammalian cells. In fact, in podocytes,
aemia in general, and in patients with nephrotic syn- lipid rafts contain many elements that are essential for
drome in particular (FIG.  2; TABLE  2). Dyslipidaemia the normal spatial organization and regulation of the slit
can result in acceleration of atherosclerosis, as well as diaphragm87. Excess accumulation of cellular cholesterol
an increased risk of myocardial infarction or cerebro- and lipids might, however, adversely affect cellular func-
vascular accident (stroke). Furthermore, dyslipidaemia tion and lead to toxicity and injury in podocytes as well
in nephrotic syndrome might have a causative role in as other cell types. In addition, during hyperlipidaemia,
the established increased risk of thrombosis associated specific anatomical features of the glomeruli and renal
with this disease. Dyslipidaemia is one of the dominant interstitium probably make these the preferred locations
risk factors associated with atherothrombotic disorders. for lipid deposition in the kidney84.
Atherosclerosis is usually accompanied by hyperreactive
platelets that increase the risk of thrombosis, which is Mesangial cell proliferation. Within the kidney, the
further exacerbated by dyslipidaemia82. Furthermore, mesangial cells and the extracellular matrix within
the products of LDL oxidation enhance platelet activa- the glomerulus are most accessible to plasma lipo­
tion and thrombus formation83. Dyslipidaemia during proteins such as LDL, as they are not separated from the
nephrotic syndrome is also clearly associated with an capillary wall by an intervening basement membrane.
increased risk of nephrotoxicity, which can manifest as Under normal conditions, mesangial cells take up LDL
progressive kidney disease33,82. This progressive kidney via a specific LDL receptor, and LDL is metabolized in a
disease might result from the development of glomeru- regulated manner. However, during hyperlipidaemia or
losclerosis, owing to podocyte injury and/or mesangial extracellular matrix expansion, excess LDL is trapped
cell proliferation, as well as from proximal tubular cell in the extracellular matrix, where it is subject to oxi-
injury (FIG. 3). dation, especially under conditions of mesangial cell
Of note, the presence of CKD, which often develops stress, such as inflammatory, mechanical or ischaemic
and/or progresses in patients with refractory nephrotic injury88,89. The oxidized LDL is taken up by receptors
syndrome, further increases the risk of many of the on mesangial cells, leading to the production of prosta-
complications, including dyslipidaemia (TABLE 2), as glandin E2 and other cytotoxic agents, such as tumour
­discussed below. necrosis factor (TNF), which further damage glomerular
epithelial and endothelial cells, leading to sclerosis88,89.
In addition to LDL and oxidized LDL, triglyceride-rich
Table 2 | Consequences of dyslipidaemia in nephrotic syndrome or CKD
lipoproteins such as VLDL and IDL are also taken up
Complications associated Estimates of individual and additive risk for by mesangial cells, leading to their proliferation and the
with dyslipidaemia in complications occurring in different disease states release of several cytokines, such as IL‑6, platelet derived
nephrotic syndrome growth factor (PDGF) and transforming growth factor‑β
Nephrotic CKD Nephrotic syndrome
syndrome and CKD (TGFβ)89. In addition, the uptake of lipoproteins by both
Cardiovascular disease mesangial and endothelial cells is increased in the pres-
Atherosclerosis ++ + +++
ence of lipoprotein lipase, which is localized to the glo-
merulus90,91. Furthermore, increased lipid accumulation
Myocardial infarction ++ + +++ owing to experimentally induced inflammatory stress
Cerebrovascular accident ++ + +++ results in the production of reactive oxygen species
(stroke) and increased expression of endoplasmic reticulum
Progressive kidney disease (ER) stress m­ arkers, both in the kidneys in vivo and in
Glomerulosclerosis ++ + +++ ­mesangial cells in vitro92.
• Mesangial cell proliferation + + +
Podocyte injury. The podocyte is the primary target of
• Podocyte injury + + ++ cellular injury in nephrotic syndrome8, both in minimal
Tubulointerstitial disease ++ + +++ change disease and in focal segmental glomerulosclero-
• Proximal tubular cell injury + + ++ sis, and podocyte loss and hypertrophy have a crucial
role in the progression to end-stage renal disease. Lipids
Other
and the proteins that regulate lipids have a direct role in
Thromboembolism ++ + ++ podocyte biology and pathophysiology via several dif-
±, minimal risk; +, low risk; ++, moderate risk; +++, high risk; CKD, chronic kidney disease. ferent mechanisms, some of which we highlight here.

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Variants of APOL1, which encodes an important compo- Tubulointerstitial disease. Nephrotic syndrome is associ­
nent of HDL and is expressed by podocytes, are widely ated with the development of renal tubular cell injury,
associated with focal segmental glomerulosclerosis and and acute interstitial nephritis has been demonstrated
podocytopathies93–95. Furthermore, antibodies directed in animal models of nephrotic syndrome105,106. This
against secretory phospholipase A2 receptor (PLA2R), tubulointerstitial injury in nephrotic syndrome is char-
which is also expressed by podocytes, have been detected acterized by the infiltration of macrophages and T lym-
in many patients with membranous nephropathy96,97. phocytes into the tubulointerstitial space105. Of note, fatty
In addition, decreased expression of SMPDL3b has been acids bound to albumin might be the main contributors
observed in podocytes exposed to the sera of patients to tubulointerstitial injury in a protein-overload model
with recurrent focal segmental glomerulosclerosis75,98. of proteinuria85. Furthermore, several studies have
Several different free fatty acids bound to albumin reported lipotoxic effects of saturated fatty acids in prox-
have been shown to increase podocyte injury, by stim- imal tubular cell injury107–110 and stearoyl-CoA desaturase
ulating enhanced macropinocytosis by podocytes via (SCD), an enzyme involved in free fatty acid metabo-
lipid-binding G‑protein-coupled receptors (GPCRs)99,100. lism, mediates the desaturation of saturated fatty acids
GPCR signalling leads to the triggering of the Gβ/Gγ and reduces the formation of lipid droplets and their
subunits and their dissociation, which in turn activate lipotoxicity to cultured proximal tubule cells107. In addi-
the RHO GTPases RAC1 and CDC42, leading to dis- tion, the renin–angiotensin system plays an important
ruption of the actin cytoskeleton and dramatic changes part in mediating ER stress in proximal tubule cells by
in podocyte morphology. Furthermore, compared to saturated fatty acids108. Another study has demonstrated
mice fed control chow, those fed a high-fat diet develop that the peroxisome proliferator-activated receptor‑α
elevated levels of free fatty acids and an increased sus- (PPARα) agonist fenofibrate protects proximal tubule
ceptibility to adriamycin-induced proteinuria, which cells by inhibiting fatty acid toxicity mediated by nuclear
underscores the effect of free fatty acids on podocyte ­factor‑κB (NF‑κB)109. Furthermore, circulating fatty acids
function99,100. In addition, exposure of podocytes to bound to albumin can change the redox environment in
albumin and its associated factors, such as fatty acids, the tubules, thus inducing a peroxide-mediated, redox-­
has been shown to induce cell death, disruption of the sensitive apoptosis in tubular cells110. Thus, these findings
cytoskeleton and injurious molecular responses, such as collectively provide evidence supporting a substantial
increased production of cyclooxygenase 2 (COX2) and role for direct lipid-induced cellular injury to both renal
several cytokines101. However, these injury responses are tubular cells and podocytes resulting from dyslipidaemia
attenuated when podocytes are instead exposed to fatty in nephrotic syndrome.
acid-free albumin. Of note, the role of arachidonic acid
in causing podocyte injury is highlighted by its ability Importance of dyslipidaemia treatment
to increase COX2 production when conjugated to fatty Lipid abnormalities in the general population are associ­
acid-free albumin. The marked reduction in protein­ ated with a reduction in kidney function. In addition, a
uria in a protein-overload model of renal injury in rats strong relationship exists between hypercholesterol­aemia
when the administered albumin was devoid of free fatty and the risk of coronary artery disease, and multiple clin-
acids and other associated factors further demonstrates ical trials have shown that a reduction in cholesterol or
the in vivo relevance of albumin-bound fatty acids and LDL in high-risk patients is associated with statistically
other associated factors101. In particular, palmitic acid and clinically significant reductions in cardiovascular
induces ER stress, apoptosis and necrosis in podocytes mortality111,112. Hyperlipidaemia is also known to esca-
in a dose-dependent manner, which is enhanced by fatty late the progression of glomerular injury, in part owing
acid oxidation102,103. Furthermore, the lipotoxic effects to accelerated atherosclerosis in the renal vascular sys-
of palmitic acid accelerate glomerular disease through tem (TABLE 2). Consistent with accelerated atherosclero-
inflammation, oxidative stress and derangements of sis, patients with CKD have an increased prevalence of
the actin cytoskeleton and decrease in the expression hyperlipidaemia and an increased risk of cardiovascular
of the NPHS1 gene, which encodes the slit diaphragm disease. Similarly, adults with nephrotic syndrome are
protein nephrin, in podocytes104. In addition, stimula- at increased risk of myocardial infarction (relative risk
tion of podocytes with TNF results in free cholesterol-­ (RR) 5.5) and coronary death (RR 2.8), compared to that
mediated cell injury in a nuclear factor of activated of the general population113–118. By contrast, although
T cells cytoplasmic 1 (NFATc1)-dependent manner60. myocardial infarction is extremely rare in children, a few
Furthermore, this cholesterol-mediated injury is also case studies have reported myocardial infarctions in chil-
dependent on ABCA1, which, as mentioned earlier, dren with nephrotic syndrome119,120. Given the high mor-
is a transporter responsible for cholesterol efflux from bidity associated with dyslipid­aemia and the severity of
podocytes60. Together, these findings support a role for the dyslipidaemia that occurs in patients with nephrotic
direct lipid-induced podocyte injury in the patho­genesis syndrome, a clear need exists to prioritize aggressive
of nephrotic syndrome resulting from dyslipidaemia. treatment of dyslipidaemia in patients with chronic
In light of these results, future therapeutic interventions forms of nephrotic syndrome who do not enter remis-
to reduce the effects of hyperlipidaemia in nephrotic sion. Below, we detail the available evidence for the effi-
syndrome should not only include interventions to lower cacy of various treatments for dyslipid­aemia in nephrotic
lipid levels and prevent lipid oxidation, but also those to syndrome in both adults and children, as well as future
reduce lipid uptake by glomerular cells. directions for treatment (TABLE 3).

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Table 3 | Clinical trials and studies of dyslipidaemia treatments in patients with nephrotic syndrome
Treatment Action Outcomes Limitations Refs or trials
Conservative • ↓ Cholesterol • ↓ Hyperlipidaemia Implementation and 121–123
lifestyle changes • ↓ Apolipoproteins • ↓ Proteinuria patient compliance
(diet, weight, (small reduction)
exercise) • ↓ Triglycerides
Statins • ↓ HMG-CoA • ↓ LDL Limited number 125–131,139*,140*,
• ↓ Cholesterol of studies NCT00004466*
• ↓ Triglycerides (REF. 157),
• ­­↑ HDL NCT01845428
• Few adverse effects (REF. 158)
• Improved cardiovascular
outcome in CKD
Bile acid • ↓ Enterohepatic bile • ↓ LDL • ­Gastrointestinal 133
sequestrants acid circulation adverse effects
• Less effective than
statins
Fibrates • ↑ Lipoprotein lipase • ↓ Triglycerides Meta-analysis found 112,134,135
activity • ↓ LDL a lack of support for
• ↓ Cholesterol fibrate efficacy
LDL-apheresis • ↓ LDL • Complete or partial Requires central 141*,142–144,
• ↓ Cholesterol remission of nephrotic venous access NCT02235857*
• ↓ Triglycerides syndrome (REF. 154)
• ↑ Response to • Few adverse effects
immunosuppressants
• Anti‑PCSK9 • Inactivation of PCSK9 • ↓ LDL Very expensive 44‡,
antibodies • Degradation of PCSK9 NCT03004001
• PCSK9 RNA mRNA (REF. 149),
interference • ↑ Hepatic LDLR NCT02314442‡
(REF. 146)
*Studies or trials with paediatric patients. ‡Not in nephrotic syndrome setting. CKD, chronic kidney disease; HDL, high-density
lipoprotein; HMG-CoA, 3‑hydroxy-3‑methyl-glutaryl-coenzyme A; LDL, low-density lipoprotein; LDLR, LDL receptor; PCSK9,
proprotein convertase subtilisin/kexin type 9.

Treatment of dyslipidaemia recommendations have never been formally studied in

Lifestyle changes to treat dyslipidaemia patients with nephrotic syndrome and are based largely
Unfortunately, little evidence exists to guide the optimal on studies of healthy individuals. Dietary supplements,
treatment of dyslipidaemia in patients with nephrotic such as fish oils (discussed above) and policosanol, have
syndrome. Typically, the initial recommended treatment been poorly studied in patients with nephrotic syn-
includes lifestyle changes that focus on diet, which is drome. Data supporting the best-studied supplement,
based on a study of 20 adult patients with long-­standing omega‑3 fatty acids, in patients with nephrotic syndrome
severe proteinuria121. Compared with their values on the have shown a small decrease in serum triglycerides, with
baseline diet, a soya-based vegetarian diet low in both mixed effects on LDL levels123. Another study examin-
fat and protein resulted in reductions in serum levels ing omega‑3 fatty acid supplementation in patients with
of cholesterol and apolipoprotein, but not in triglycer- nephrotic syndrome demonstrated a decrease in post-
ide levels, in these patients. Interestingly, proteinuria prandial chylomicrons124. Although promising, these
also decreased on the soya-based vegetarian diet. In results are based on studies with a small number of
a follow‑up trial, 20 patients consumed either a soya- patients and with limited follow‑up.
based diet or soya-based diet that included fish oil, for
2 months, followed by a crossover to the other treatment Pharmacological treatment of dyslipidaemia
group122. The introduction of the soya-based diet again Statins. Statins are the most common pharmacologi-
resulted in a decrease in hyperlipidaemia as well as pro- cal intervention to treat dyslipidaemia in patients with
teinuria, without any measurable effect of fish oil sup- nephrotic syndrome. The mechanism of action of stat-
plementation. Despite the promising results from these ins has been well characterized; statins competitively
trials, these results have not been replicated, and there is inhibit HMG-CoA reductase, reducing hepatic pro-
some question of whether the decrease in serum lipids in duction of cholesterol, which in turn leads to increased
patients who consumed the soya-based vegetarian diet uptake of LDL cholesterol from the blood. However, it
was the result of the lower dietary protein or the lower is important to note that this class of drugs has been
lipid intake. studied most extensively in patients with other dis-
Other lifestyle changes to combat hyperlipid­ eases, with several large randomized controlled trials
aemia include weight loss in patients who are over- showing compelling reductions in the incidence of
weight, and increased aerobic exercise. However, these ­cardiovascular disease112.

NATURE REVIEWS | NEPHROLOGY VOLUME 14 | JANUARY 2018 | 65

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The use of statins for the treatment of patients with treatment with gemfibrozil showed a small reduction
nephrotic syndrome has been less well-studied. Early in cholesterol and LDL levels, and a marked reduction in
studies found significant reductions in the serum levels triglyceride levels, in 11 patients with nephrotic syn-
of total cholesterol and LDL cholesterol, with lesser effects drome134. Another small study of 12 paediatric patients
on the levels of triglycerides and apolipo­proteins125,126. with nephrotic syndrome who were randomly assigned to
Pilot trials of atorvastatin treatment in children with receive either gemfibrozil or placebo also showed lower-
nephrotic syndrome and pravastatin treatment in adults ing of serum cholesterol, LDL and triglyceride levels with
with nephrotic syndrome have been undertaken, but gemfibrozil treatment135. However, a meta-analysis did not
the results of these trials are not yet available (TABLE 3). support the findings of that study131.
However, a meta-analysis that included four randomized Nicotinic acid (also known as niacin) and ezetimibe
controlled trials comparing statin versus placebo versus are two additional agents that are used to treat hyperlipid­
no treatment showed limited effectiveness of statins in aemia. Nicotonic acid inhibits diacylglycerol acyltrans-
reducing dyslipidaemia127–131. Only one of these trials ferase 2 in the liver, resulting in reduced triglyceride
showed a significant increase in HDL levels after statin synthesis136, which in turn leads to decreased secretion
treatment127, and no differences were seen in total serum of VLDL and LDL. In addition, nicotinic acid stimulates
cholesterol, LDL or triglyceride levels. Fortunately, as hepatic ApoA‑I production, leading to increased HDL
noted in other studies, statins seem to be very well toler- levels. Ezetimibe has a unique mechanism of action —
ated in patients with nephrotic syndrome and have a low it decreases enteric cholesterol absorption, resulting in
adverse effect profile. Unfortunately, however, very few markedly lower LDL cholesterol137. Ezetimibe is often
data have described the effects of statins on cardiovascular a last-line agent for treatment of hyperlipidaemia in
end points. Although statin treatment improved cardio­ patients who are intolerant to statins, due to its limited
vascular outcomes among patients with CKD who were vascular and clinical benefits138. However, neither nico­
not undergoing dialysis132, there are no studies ­showing a tinic acid nor ezetimibe have been studied in patients with
similar benefit in patients with nephrotic syndrome. nephrotic syndrome.

Second-line agents. In addition to statins, second-line Pharmacological treatments in children. In comparison

agents that have been studied for the treatment of dys- to adults, the data describing the treatment of dyslipid­
lipidaemia in nephrotic syndrome include bile acid aemia in paediatric patients with nephrotic syndrome
sequestrants, fibrates, nicotinic acid and ezetimibe. Bile are very limited. In fact, this dearth of data, together
acid sequestrants, such as colestipol and cholestyramine, with the lack of FDA approval for use of lipid-­lowering
work by blocking the normal enterohepatic circulation agents in paediatric patients and a lack of long-term
of bile acids by preventing their enteral reabsorption. safety data, have led to a lower utilization of lipid-­
This inhibition in turn causes the upregulation of sev- lowering agents in children with chronic nephrotic
eral hepatic enzymes responsible for bile acid synthesis. syndrome compared to adults. Most studies of paedi-
The end result is increased liver cholesterol catabolism atric patients have focused on statin therapy, with the
and a compensatory increase in LDL absorption from exception of the above-described study of gemfibrozil135.
the blood. Studies of bile acid sequestrants in the treat- One 12‑month prospective, uncontrolled study of seven
ment of patients with other diseases have shown an paediatric patients with nephrotic syndrome compared
approximately 25% reduction in serum levels of LDL the use of dietary interventions before, or in combina-
cholesterol, with occasional increases in levels of triglyc- tion with, simvastatin treatment139. This study reported
erides112. One study of colestipol treatment found a 30% a 30% reduction in cholesterol and a 36% reduction in
decrease in serum levels of LDL cholesterol in patients triglyceride levels from combination treatment. Another
with nephrotic syndrome133. Another small crossover prospective, uncontrolled study of 12 paediatric patients
trial of 10 patients with nephrotic syndrome compared with nephrotic syndrome who were treated with either
treatment with cholestyramine versus simvastatin, and lovastatin or simvastatin found decreases in cholesterol,
found a decrease in LDL cholesterol levels of 19% versus LDL and triglyceride levels after 12 months of treatment
39%, respectively125. Unfortunately, the bile sequestrants with either statin140.
have a high rate of gastrointestinal adverse effects, which
often limits their use. Lipid apheresis. Lipid apheresis is a novel treatment for
Fibrates, such as gemfibrozil, clofibrate and fenofibrate, dyslipidaemia in patients with nephrotic syndrome and
are another class of agents that are used as a second-line is a well-established extracorporeal technique that is used
therapy for treatment of dyslipidaemia in patients with to treat patients with homozygous familial hypercholes-
nephrotic syndrome. Their mechanism of action is to terolaemia. A study utilizing lipid apheresis in combina-
increase LPL activity, which decreases triglyceride syn- tion with prednisone in children with treatment-resistant
thesis and lowers serum triglyceride levels by 30–50%. nephrotic syndrome found reductions in both cholesterol
Fibrates have a much more modest effect on serum LDL and triglyceride levels141, similar to previous reports using
levels than that induced by other agents, with typical lipid apheresis in adults142. However, the outcomes of
reductions of approximately 10%112. Unfortunately, data this combination treatment in children with nephrotic
Lipid apheresis
A non-surgical therapy and a
describing the effectiveness of fibrates in patients with syndrome were notable in that the majority of patients
form of apheresis that removes nephrotic syndrome are rather limited. A randomized, went into either complete or partial remission of their
LDL from a patient’s blood. double-blind, placebo-controlled trial with a 6‑week nephrotic syndrome141 — five of 11 patients (45%) went

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into complete remission, and two of 11 patients (18%) inhibitor in combination with a statin, is ­ongoing
went into partial remission. Remarkably, all of the (NCT03004001 (REF. 149); TABLE 3). Interestingly, suc-
patients that responded to therapy remained in remis- cessful treatment of a patient with refractory nephrotic
sion at 10 year follow‑up. The mechanism by which lipid syndrome using a PCSK9 inhibitor has also been
apheresis leads to remission remains unclear, but pos- reported for the first time150. A practical obstacle in
sible explanations include direct effects associated with utilizing these agents is their tremendous cost, which is
improved dyslipidaemia, the removal of pathogenic vas- estimated at US$14,000 per patient per year151.
cular permeability factors and/or enhancement of the Acetyl-CoA acetyltransferase (ACAT) inhibitors are
response to immunosuppressants62. One potential but another novel class of agents for the treatment of dys-
unexplored hypothesis is that lipid apheresis, by lower- lipidaemia. Studies using low-dose therapy with ACAT
ing the level of free fatty acids, could reduce or prevent inhibitors in animal models of nephrotic syndrome
podocyte damage and reduce proteinuria99. suggest that these inhibitors are also able to reduce
The prospective multicentre POLARIS trial in protein­uria while improving dyslipidaemia152. However,
Japan assessed the efficacy of lipid apheresis for treat- enthusiasm for these agents has been tempered by a
ing dyslipid­aemia and inducing remission in patients large randomized controlled trial of avasimibe, which
with nephrotic syndrome. Initial results demonstrated did not demonstrate a favourable outcome in slowing
nearly 50% reductions in both total cholesterol and coronary atherosclerosis153.
LDL cholesterol levels during treatment143. A follow‑up The high cost and the need in most cases for central
paper144 demonstrated complete remission in 25% of venous access might limit the potential adoption of lipid
the 44 patients enrolled in the study, and reported that apheresis. One system of lipid apheresis, the Liposorber
an additional 23% of patients had partial remission LA‑15 (Kaneka), is being utilized in a prospective study
(defined as <1 g of urinary protein per day). Furthermore, for the treatment of focal segmental glomerulosclerosis
a case report demonstrated the induction of remission in children (NCT02235857 (REF. 154)). This study is a
by lipid apheresis in an adult with rituximab-resistant post-approval trial mandated by the FDA after the LA‑15
nephrotic syndrome145. system received a humanitarian device exemption for
the treatment of paediatric patients with drug-resistant
Future treatment directions focal segmental glomerulosclerosis.
PCSK9 has a vital role in the regulation of cholesterol Despite the potential benefit of treating dyslipid­aemia,
homeostasis and has thus gained considerable attention it is important to note that no agreed criteria exist for
in the context of lipid-lowering strategies44. Furthermore, a threshold of dyslipidaemia at which treatment should
PCSK9 levels are elevated in patients with nephrotic syn- be initiated for patients with nephrotic syndrome. The
drome, and are directly correlated with protein­uria45–47. Kidney Disease: Improving Global Outcomes guidelines
Of interest, remission in patients with nephrotic syn- for management of glomerular disease state “treatment
drome correlated with decreases in plasma levels of both of hyperlipidemia in patients with glomerular disease
cholesterol and PCSK9 (REF. 47). Inhibitors of PCSK9, in should usually follow the guidelines that apply to those
the form of monoclonal antibodies targeting PCSK9, at high risk for the development of cardiovascular dis-
have been developed as a new class of drug to treat dys- ease.” (REF. 155). No definitive data are available about
lipidaemia, and have been shown to markedly lower LDL when an intervention should take place. Instead, the
cholesterol levels when provided either as a monotherapy potential benefits and risks of intervention or treatment
or in combination with statins44,45. PCSK9 promotes deg- of dyslipidaemia need to be considered on a case‑by‑case
radation of the LDL receptor in the liver, resulting in ele- basis. Most nephrologists would consider the institution
vated LDL levels in the blood. However, the mono­clonal of lipid-lowering interventions in patients who remain
anti‑PCSK9 antibodies bind to and inactivate PCSK9, overtly nephrotic for several months. Interestingly,
resulting in an increase in the level of LDL receptors one small study of 40 adult patients who had relapsing
on the surface of liver cells, thus promoting LDL uptake nephrotic syndrome as children showed that the occur-
by the liver and its metabolism, which ultimately results rence of cardiovascular disease in this cohort was simi­
in decreased LDL levels in the blood. A small inhibitory lar to that of the general population, suggesting that
RNA (siRNA) inhibitor of PCSK9 has also been tested in relapsing nephrotic syndrome during childhood does
a phase I trial to lower LDL cholesterol in healthy individ- not portend an increased risk of cardiovascular disease
uals (NCT02314442 (REF. 146)). The early results indicate as an adult156. As discussed above, although dietary inter­
that treatment with this siRNA had no serious adverse ventions do not carry much risk, they also do not seem
events, and induced significant reductions in the levels to be very effective in treating dyslipidaemia in patients
of PCSK9 and LDL cholesterol147. with nephrotic syndrome. Statins have shown good
Given their efficacy in treating dyslipidaemia and the efficacy in the treatment of other disease states, and are
potential link between an acquired LDL receptor defi- generally well tolerated in patients with nephrotic syn-
ciency and the pathogenesis of nephrotic syndrome148, drome, but few, reliable outcome data exist for this patient
future trials to explore the use of PCSK9 inhibitors in popu­lation. Finally, although it is tempting to extrapo-
treating dyslipidaemia in patients with nephrotic syn- late findings from adults to children, it is important to
drome are warranted. One such trial in adult patients note that very few data exist regarding the efficacy or,
with nephrotic syndrome, comparing the hypolipid­ perhaps more importantly, the risks of pharmacological
aemic effects of statin monotherapy to those of a PCSK9 ­intervention among children with nephrotic syndrome.

NATURE REVIEWS | NEPHROLOGY VOLUME 14 | JANUARY 2018 | 67

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Conclusions including the origin of hypertriglyceridaemia and

The dyslipidaemia that accompanies nephrotic syn- direct injury of podocytes, we still do not fully under-
drome unfortunately remains one of the least under- stand its molecular pathogenesis. In addition, many of
stood yet most severe complications of nephrotic the standard therapies for dyslipidaemia have not yet
syndrome. Dyslipidaemia probably plays a part in been studied in well-controlled trials of patients with
the increased rate of atherosclerosis in patients with nephrotic syndrome. This lack of clinical trials contrib-
nephrotic syndrome, which in turn increases the risks utes to delays in the adoption of many newer therapies,
of multiple cardiovascular morbidities, including stroke, including PCSK9 inhibitors, which, despite their cost,
myocardial infarction and thrombosis. More impor- seem to be quite effective in other patient populations.
tantly, dyslipidaemia itself causes renal injury, which, Furthermore, many of these novel therapies, such as lipid
if not interrupted, contributes to progressive CKD and, apheresis using the Liposorber LA‑15, if shown to be
ultimately, the development of end-stage renal disease in successful, could also enhance our understanding of the
some patients. Despite improved understanding of how molecular pathogenesis of d­ yslipidaemia in patients with
nephrotic syndrome leads to altered lipid metabolism, nephrotic syndrome.

1. Greenbaum, L. A., Benndorf, R. & Smoyer, W. E. lipoproteins in experimental nephrosis. J. Clin. Invest. 38. Zhou, Y. et al. Expression profiling of hepatic genes
Childhood nephrotic syndrome — current and future 74, 1375–1383 (1984). associated with lipid metabolism in nephrotic rats.
therapies. Nat. Rev. Nephrol. 8, 445–458 (2012). 22. Davies, R. W., Staprans, I., Hutchison, F. N. & Am. J. Physiol. Renal Physiol. 295, F662–F671
2. Hull, R. P. & Goldsmith, D. J. Nephrotic syndrome Kaysen, G. A. Proteinuria, not altered albumin (2008).
in adults. BMJ 336, 1185–1189 (2008). metabolism, affects hyperlipidemia in the nephrotic 39. O’Donnell, M. P. Mechanisms and clinical importance
3. Clark, A. G. & Barratt, T. M. in Pediatric Nephrology rat. J. Clin. Invest. 86, 600–605 (1990). of hypertriglyceridemia in the nephrotic syndrome.
(eds Barratt, T. M., Avner, E. D. & Harmon, W. E.) 23. Vaziri, N. D. Dyslipidemia of chronic renal failure: Kidney Int. 59, 380–382 (2001).
731–747 (Lippincott Williams & Wilkins, 1998). the nature, mechanisms, and potential consequences. 40. Kashyap, M. L. et al. Apolipoprotein CII and
4. McEnery, P. T. & Strife, C. F. Nephrotic syndrome in Am. J. Physiol. Renal Physiol. 290, F262–F272 lipoprotein lipase in human nephrotic syndrome.
childhood. Management and treatment in patients (2006). Atherosclerosis 35, 29–40 (1980).
with minimal change disease, mesangial proliferation, 24. Mace, C. & Chugh, S. S. Nephrotic syndrome: 41. Ohta, T. & Matsuda, I. Lipid and apolipoprotein levels
or focal glomerulosclerosis. Pediatr. Clin. North Am. components, connections, and angiopoietin-like in patients with nephrotic syndrome. Clin. Chim. Acta
89, 875–894 (1982). 4‑related therapeutics. J. Am. Soc. Nephrol. 25, 117, 133–143 (1981).
5. Nash, M. A., Edelmann, C. M. J., Bernstein, J. & 2393–2398 (2014). 42. Nasr, S. H. et al. Novel type of renal amyloidosis
Barnett, H. L. in Pediatric Kidney Disease (ed. 25. Keith, D. S., Nichols, G. A., Gullion, C. M., Brown, J. B. derived from apolipoprotein-CII. J. Am. Soc. Nephrol.
Edelmann, C. M. J.) 1247–1266 (Little, 1992). & Smith, D. H. Longitudinal follow‑up and outcomes 28, 439–445 (2017).
6. Ponticelli, C. et al. Can prolonged treatment among a population with chronic kidney disease in a 43. Tentolouris, N. et al. High postprandial
improve the prognosis in adults with focal segmental large managed care organization. Arch. Intern. Med. triglyceridemia in patients with type 2 diabetes
glomerulosclerosis? Am. J. Kidney Dis 34, 618–625 164, 659–663 (2004). and microalbuminuria. J. Lipid Res. 48, 218–225
(1999). 26. Yeang, C., Gordts, P. L. & Tsimikas, S. Novel (2007).
7. MacHardy, N. et al. Management patterns of lipoprotein(a) catabolism pathway via apolipoprotein(a) 44. Di Bartolo, B., Scherer, D. J., Brown, A., Psaltis, P. J.
childhood-onset nephrotic syndrome. Pediatr. Nephrol. recycling: Adding the plasminogen receptor PlgRKT to & Nicholls, S. J. PCSK9 inhibitors in hyperlipidemia:
24, 2193–2201 (2009). the list. Circ. Res. 120, 1050–1052 (2017). current status and clinical outlook. BioDrugs 31,
8. Ding, W. Y. & Saleem, M. A. Current concepts of the 27. Sharma, M., Redpath, G. M., Williams, M. J. & 167–174 (2017).
podocyte in nephrotic syndrome. Kidney Res. Clin. McCormick, S. P. Recycling of apolipoprotein(a) after 45. Morris, A. W. Nephrotic syndrome: PCSK9: a target
Pract. 31, 87–93 (2012). PlgRKT-mediated endocytosis of lipoprotein(a). for hypercholesterolaemia in nephrotic syndrome.
9. Harris, R. C. & Ismail, N. Extrarenal complications Circ. Res. 120, 1091–1102 (2017). Nat. Rev. Nephrol. 12, 510 (2016).
of the nephrotic syndrome. Am. J. Kidney Dis 23, 28. Moriarty, P. M., Varvel, S. A., Gordts, P. L., 46. Pavlakou, P., Liberopoulos, E., Dounousi, E. &
477–497 (1994). McConnell, J. P. & Tsimikas, S. Lipoprotein(a) mass Elisaf, M. PCSK9 in chronic kidney disease. Int. Urol.
10. Cameron, J. S. The nephrotic syndrome and its levels increase significantly according to APOE Nephrol. 49, 1015–1024 (2017).
complications. Am. J. Kidney Dis 10, 157–171 genotype: an analysis of 431 239 patients. 47. Haas, M. E. et al. The role of proprotein convertase
(1987). Arterioscler. Thromb. Vasc. Biol. 37, 580–588 subtilisin/kexin type 9 in nephrotic syndrome-
11. Llach, F. Hypercoagulability, renal vein thrombosis, (2017). associated hypercholesterolemia. Circulation 134,
and other thrombotic complications of nephrotic 29. Merkel, M., Eckel, R. H. & Goldberg, I. J. Lipoprotein 61–72 (2016).
syndrome. Kidney Int. 28, 429–439 (1985). lipase: genetics, lipid uptake, and regulation. 48. Warwick, G. L. et al. Low-density lipoprotein
12. Rheault, M. N. et al. AKI in children hospitalized with J. Lipid Res. 43, 1997–2006 (2002). metabolism in the nephrotic syndrome. Metabolism
nephrotic syndrome. Clin. J. Am. Soc. Nephrol. 10, 30. Allan, C. M. et al. Mobility of “HSPG-bound” LPL 39, 187–192 (1990).
2110–2118 (2015). explains how LPL is able to reach GPIHBP1 on 49. Vaziri, N. D. & Liang, K. H. Hepatic HMG-CoA
13. Al‑Azzawi, H. F., Obi, O. C., Safi, J. & Song, M. capillaries. J. Lipid Res. 58, 216–225 (2017). reductase gene expression during the course of
Nephrotic syndrome-induced thromboembolism in 31. Davies, B. S. et al. GPIHBP1 is responsible for the puromycin-induced nephrosis. Kidney Int. 48,
adults. Int. J. Crit. Illn. Inj. Sci. 6, 85–88 (2016). entry of lipoprotein lipase into capillaries. Cell Metab. 1979–1985 (1995).
14. Kerlin, B. A., Ayoob, R. & Smoyer, W. E. Epidemiology 12, 42–52 (2010). 50. Tsimikas, S. et al. Oxidized phospholipids, Lp(a)
and pathophysiology of nephrotic syndrome- 32. Vaziri, N. D., Yuan, J., Ni, Z., Nicholas, S. B. & lipoprotein, and coronary artery disease. N. Engl.
associated thromboembolic disease. Clin. J. Am. Soc. Norris, K. C. Lipoprotein lipase deficiency in chronic J. Med. 353, 46–57 (2005).
Nephrol. 7, 513–520 (2012). kidney disease is accompanied by down-regulation of 51. Wanner, C. et al. Elevated plasma lipoprotein(a) in
15. Kerlin, B. A., Haworth, K. & Smoyer, W. E. Venous endothelial GPIHBP1 expression. Clin. Exp. Nephrol. patients with the nephrotic syndrome. Ann. Intern.
thromboembolism in pediatric nephrotic syndrome. 16, 238–243 (2012). Med. 119, 263–269 (1993).
Pediatr. Nephrol. 29, 989–997 (2014). 33. Moorhead, J. F., Chan, M. K., El‑Nahas, M. & 52. Glass, C. K. & Witztum, J. L. Atherosclerosis: the road
16. Loscalzo, J. Venous thrombosis in the nephrotic Varghese, Z. Lipid nephrotoxicity in chronic ahead. Cell 104, 503–516 (2001).
syndrome. N. Engl. J. Med. 368, 956–958 (2013). progressive glomerular and tubulo-interstitial disease. 53. Gherardi, E., Rota, E., Calandra, S., Genova, R. &
17. Vaziri, N. D. Disorders of lipid metabolism in nephrotic Lancet 2, 1309–1311 (1982). Tamborino, A. Relationship among the concentrations
syndrome: mechanisms and consequences. Kidney Int. 34. Clement, L. C. et al. Circulating angiopoietin-like 4 of serum lipoproteins and changes in their chemical
90, 41–52 (2016). links proteinuria with hypertriglyceridemia in composition in patients with untreated nephrotic
18. Joven, J. et al. Abnormalities of lipoprotein nephrotic syndrome. Nat. Med. 20, 37–46 (2014). syndrome. Eur. J. Clin. Invest. 7, 563–570 (1977).
metabolism in patients with the nephrotic syndrome. 35. Sukonina, V., Lookene, A., Olivecrona, T. & 54. Yvan-Charvet, L., Wang, N. & Tall, A. R. Role of HDL,
N. Engl. J. Med. 323, 579–584 (1990). Olivecrona, G. Angiopoietin-like protein 4 converts ABCA1, and ABCG1 transporters in cholesterol efflux
19. Zhou, H., Tan, K. C., Shiu, S. W. & Wong, Y. Cellular lipoprotein lipase to inactive monomers and and immune responses. Arterioscler. Thromb. Vasc.
cholesterol efflux to serum is impaired in diabetic modulates lipase activity in adipose tissue. Proc. Natl Biol. 30, 139–143 (2010).
nephropathy. Diabetes Metab. Res. Rev. 24, 617–623 Acad. Sci. USA 103, 17450–17455 (2006). 55. Birjmohun, R. S. et al. High-density lipoprotein
(2008). 36. Lafferty, M. J., Bradford, K. C., Erie, D. A. & attenuates inflammation and coagulation response on
20. de Sain-van der Velden, M. G. et al. Increased VLDL Neher, S. B. Angiopoietin-like protein 4 inhibition of endotoxin challenge in humans. Arterioscler. Thromb.
in nephrotic patients results from a decreased lipoprotein lipase: evidence for reversible complex Vasc. Biol. 27, 1153–1158 (2007).
catabolism while increased LDL results from increased formation. J. Biol. Chem. 288, 28524–28534 (2013). 56. Murphy, A. J. et al. High-density lipoprotein reduces
synthesis. Kidney Int. 53, 994–1001 (1998). 37. Liang, K. & Vaziri, N. D. Acquired VLDL receptor the human monocyte inflammatory response.
21. Garber, D. W., Gottlieb, B. A., Marsh, J. B. & deficiency in experimental nephrosis. Kidney Int. 51, Arterioscler. Thromb. Vasc. Biol. 28, 2071–2077
Sparks, C. E. Catabolism of very low density 1761–1765 (1997). (2008).

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 REVIEWS

57. Yuhanna, I. S. et al. High-density lipoprotein binding 84. Gyebi, L., Soltani, Z. & Reisin, E. Lipid nephrotoxicity: 110. Ruggiero, C. et al. Albumin-bound fatty acids but not
to scavenger receptor‑BI activates endothelial new concept for an old disease. Curr. Hypertens. Rep. albumin itself alter redox balance in tubular epithelial
nitric oxide synthase. Nat. Med. 7, 853–857 14, 177–181 (2012). cells and induce a peroxide-mediated redox-sensitive
(2001). 85. Thomas, M. E., Harris, K. P., Walls, J., Furness, P. N. & apoptosis. Am. J. Physiol. Renal Physiol. 306,
58. Muls, E., Rosseneu, M., Daneels, R., Schurgers, M. & Brunskill, N. J. Fatty acids exacerbate tubulointerstitial F896–F906 (2014).
Boelaert, J. Lipoprotein distribution and composition injury in protein-overload proteinuria. Am. J. Physiol. 111. Sacks, F. M. et al. The effect of pravastatin on coronary
in the human nephrotic syndrome. Atherosclerosis 54, Renal Physiol. 283, F640–F647 (2002). events after myocardial infarction in patients with
225–237 (1985). 86. Kamijo, A. et al. Urinary free fatty acids bound to average cholesterol levels. N. Engl. J. Med. 335,
59. Vaziri, N. D. HDL abnormalities in nephrotic syndrome albumin aggravate tubulointerstitial damage. 1001–1009 (1996).
and chronic kidney disease. Nat. Rev. Nephrol. 12, Kidney Int. 62, 1628–1637 (2002). 112. Reiner, Z. et al. ESC/EAS Guidelines for the
37–47 (2016). 87. Schermer, B. & Benzing, T. Lipid-protein interactions management of dyslipidaemias: the Task Force for
60. Pedigo, C. E. et al. Local TNF causes NFATc1- along the slit diaphragm of podocytes. J. Am. Soc. the management of dyslipidaemias of the European
dependent cholesterol-mediated podocyte injury. Nephrol. 20, 473–478 (2009). Society of Cardiology (ESC) and the European
J. Clin. Invest. 126, 3336–3350 (2016). 88. Schlondorff, D. Cellular mechanisms of lipid injury in Atherosclerosis Society (EAS). Eur. Heart J. 32,
61. Jao, W., Lewy, P., Norris, S. H., Pollak, V. E. & the glomerulus. Am. J. Kidney Dis. 22, 72–82 (1993). 1769–1818 (2011).
Pirani, C. L. Lipoid nephrosis: a reassessment. 89. Nishida, Y., Oda, H. & Yorioka, N. Effect of lipoproteins 113. Bagga, A., Sharma, A. & Srivastava, R. N. Inefficacy of
Perspect. Nephrol. Hypertens. 1, 183–198 (1973). on mesangial cell proliferation. Kidney Int. Suppl. 71, pefloxacin in steroid-responsive nephrotic syndrome.
62. Muso, E. Beneficial effect of LDL-apheresis in S51–S53 (1999). Pediatr. Nephrol. 9, 793–794 (1995).
refractory nephrotic syndrome. Clin. Exp. Nephrol. 18, 90. Stevenson, F. T., Shearer, G. C. & Atkinson, D. N. 114. Keane, W. F. Lipids and the kidney. Kidney Int. 46,
286–290 (2014). Lipoprotein-stimulated mesangial cell proliferation 910–920 (1994).
63. Gordon, T., Castelli, W. P., Hjortland, M. C., and gene expression are regulated by lipoprotein 115. Culleton, B. F. et al. Cardiovascular disease and
Kannel, W. B. & Dawber, T. R. High density lipoprotein lipase. Kidney Int. 59, 2062–2068 (2001). mortality in a community-based cohort with mild
as a protective factor against coronary heart disease: 91. Shearer, G. C. et al. Hypoalbuminemia and proteinuria renal insufficiency. Kidney Int. 56, 2214–2219
the Framingham study. Am. J. Med. 62, 707–714 contribute separately to reduced lipoprotein (1999).
(1977). catabolism in the nephrotic syndrome. Kidney Int. 59, 116. Falk, R. J. in Acute Renal Failure: A Companion to
64. Rye, K. A. & Barter, P. J. Cardioprotective functions 179–189 (2001).
 Brenner & Rector’s The Kidney (eds Molitoris, B. A.
of HDLs. J. Lipid Res. 55, 168–179 (2014z). 92. Zhong, S. et al. Inflammatory stress exacerbated & Finn, W.) (Saunders, 2001).
65. Boden, W. E. et al. Niacin in patients with low HDL mesangial foam cell formation and renal injury via 117. Kasiske, B. L. Hyperlipidemia in patients with chronic
cholesterol levels receiving intensive statin therapy. disrupting cellular cholesterol homeostasis. renal disease. Am. J. Kidney Dis. 32, S142–S156
N. Engl. J. Med. 365, 2255–2267 (2011). Inflammation 38, 959–971 (2015). (1998).
66. Barter, P. J. et al. Effects of torcetrapib in patients at 93. Kopp, J. B. et al. APOL1 genetic variants in focal 118. Ordonez, J. D., Hiatt, R. A., Killebrew, E. J. &
high risk for coronary events. N. Engl. J. Med. 357, segmental glomerulosclerosis and HIV-associated Fireman, B. H. The increased risk of coronary heart
2109–2122 (2007). nephropathy. J. Am. Soc. Nephrol. 22, 2129–2137 disease associated with nephrotic syndrome. Kidney
67. Brunzell, J. D., Zambon, A. & Deeb, S. S. The effect of (2011). Int. 44, 638–642 (1993).
hepatic lipase on coronary artery disease in humans is 94. Genovese, G. et al. Association of trypanolytic ApoL1 119. Suryawanshi, S. P., Das, B. & Patnaik, A. N.
influenced by the underlying lipoprotein phenotype. variants with kidney disease in African Americans. Myocardial infarction in children: two interesting
Biochim. Biophys. Acta 1821, 365–372 (2012). Science 329, 841–845 (2010). cases. Ann. Pediatr. Cardiol. 4, 81–83 (2011).
68. Voight, B. F. et al. Plasma HDL cholesterol and risk of 95. Freedman, B. I. et al. The apolipoprotein L1 (APOL1) 120. Silva, J. M. et al. Premature acute myocardial
myocardial infarction: a mendelian randomisation gene and nondiabetic nephropathy in African infarction in a child with nephrotic syndrome.
study. Lancet 380, 572–580 (2012). Americans. J. Am. Soc. Nephrol. 21, 1422–1426 Pediatr. Nephrol. 17, 169–172 (2002).
69. US National Library of Medicine. ClinicalTrials.gov (2010). 121. D’Amico, G. et al. Effect of vegetarian soy diet on
https://clinicaltrials.gov/ct2/show/NCT01841684 96. Debiec, H. & Ronco, P. PLA2R autoantibodies and hyperlipidaemia in nephrotic syndrome. Lancet 339,
(2015). PLA2R glomerular deposits in membranous 1131–1134 (1992).
70. Brooks, M. REVEAL: CETP inhibitor anacetrapib nephropathy. N. Engl. J. Med. 364, 689–690 (2011). 122. Gentile, M. G. et al. Treatment of proteinuric patients
meets primary end point. Medscape Nephrology 97. Beck, L. H. Jr et al. M‑Type phospholipase A2 receptor with a vegetarian soy diet and fish oil. Clin. Nephrol.
http://www.medscape.com/viewarticle/882173 as target antigen in idiopathic membranous 40, 315–320 (1993).
(2017). nephropathy. N. Engl. J. Med. 361, 11–21 (2009). 123. Bell, S., Cooney, J., Packard, C. J., Caslake, M. J. &
71. Faraggiana, T. & Churg, J. Renal lipidoses: a review. 98. Fornoni, A., Merscher, S. & Kopp, J. B. Lipid biology Deighan, C. J. The effect of omega‑3 fatty acids on the
Hum. Pathol. 18, 661–679 (1987). of the podocyte — new perspectives offer new atherogenic lipoprotein phenotype in patients with
72. Ossoli, A. et al. Lipoprotein X causes renal disease in opportunities. Nat. Rev. Nephrol. 10, 379–388 nephrotic range proteinuria. Clin. Nephrol. 77,
LCAT deficiency. PLoS ONE 11, e0150083 (2016). (2014). 445–453 (2012).
73. Ferrans, V. J. & Fredrickson, D. S. The pathology of 99. Chung, J. J. et al. Albumin-associated free fatty acids 124. Hall, A. V. et al. Omega‑3 fatty acid supplementation
Tangier disease. A light and electron microscopic induce macropinocytosis in podocytes. J. Clin. Invest. in primary nephrotic syndrome: effects on plasma
study. Am. J. Pathol. 78, 101–158 (1975). 125, 2307–2316 (2015). lipids and coagulopathy. J. Am. Soc. Nephrol. 3,
74. Lovric, S. et al. Mutations in sphingosine-1‑phosphate 100. Allison, S. J. Free fatty acid-induced macropinocytosis 1321–1329 (1992).
lyase cause nephrosis with ichthyosis and adrenal in podocytes. Nat. Rev. Nephrol. 11, 386 (2015). 125. Rabelink, A. J., Hene, R. J., Erkelens, D. W., Joles, J. A.
insufficiency. J. Clin. Invest. 127, 912–928 (2017). 101. Agrawal, S., Guess, A. J., Chanley, M. A. & & Koomans, H. A. Effects of simvastatin and
75. Fornoni, A. et al. Rituximab targets podocytes in Smoyer, W. E. Albumin-induced podocyte injury and cholestyramine on lipoprotein profile in
recurrent focal segmental glomerulosclerosis. protection are associated with regulation of COX‑2. hyperlipidaemia of nephrotic syndrome. Lancet 2,
Sci. Transl Med. 3, 85ra46 (2011). Kidney Int. 86, 1150–1160 (2014). 1335–1338 (1988).
76. Choi, H. K. & Seeger, J. D. Glucocorticoid use and 102. Sieber, J. et al. Regulation of podocyte survival and 126. Thomas, M. E. et al. Simvastatin therapy for
serum lipid levels in US adults: the Third National endoplasmic reticulum stress by fatty acids. Am. hypercholesterolemic patients with nephrotic
Health and Nutrition Examination Survey. Arthritis J. Physiol. Renal Physiol. 299, F821–F829 (2010). syndrome or significant proteinuria. Kidney Int. 44,
Rheum. 53, 528–535 (2005). 103. Kampe, K., Sieber, J., Orellana, J. M., Mundel, P. & 1124–1129 (1993).
77. Leong, K. H., Koh, E. T., Feng, P. H. & Boey, M. L. Lipid Jehle, A. W. Susceptibility of podocytes to palmitic acid 127. M., S. et al. Evaluation of effects of lovastatin on
profiles in patients with systemic lupus erythematosus. is regulated by fatty acid oxidation and inversely hyercholesterolaemia and renl functions in nephrotic
J. Rheumatol 21, 1264–1267 (1994). depends on acetyl-CoA carboxylases 1 and 2. Am. syndrome. Indian Acad. Clin. Med. 5, 143–146
78. MacGregor, A. J. et al. Fasting lipids and J. Physiol. Renal Physiol. 306, F401–F409 (2014). (2004).
anticardiolipin antibodies as risk factors for vascular 104. Martinez-Garcia, C. et al. Renal lipotoxicity-associated 128. Gheith, O. A. et al. Impact of treatment of dyslipidemia
disease in systemic lupus erythematosus. Ann. Rheum. inflammation and insulin resistance affects actin on renal function, fat deposits and scarring in patients
Dis. 51, 152–155 (1992). cytoskeleton organization in podocytes. PLoS ONE 10, with persistent nephrotic syndrome. Nephron 91,
79. Macfarlane, D. P., Forbes, S. & Walker, B. R. e0142291 (2015). 612–619 (2002).
Glucocorticoids and fatty acid metabolism in humans: 105. Eddy, A. A. & Michael, A. F. Acute tubulointerstitial 129. Gheith, O., Sheashaa, H., Abdelsalam, M., Shoeir, Z. &
fuelling fat redistribution in the metabolic syndrome. nephritis associated with aminonucleoside nephrosis. Sobh, M. Efficacy and safety of Monascus purpureus
J. Endocrinol. 197, 189–204 (2008). Kidney Int. 33, 14–23 (1988). Went rice in subjects with secondary hyperlipidemia.
80. Vincenti, F., Jensik, S. C., Filo, R. S., Miller, J. & 106. Eddy, A. A., McCulloch, L., Liu, E. & Adams, J. Clin. Exp. Nephrol. 12, 189–194 (2008).
Pirsch, J. A long-term comparison of tacrolimus A relationship between proteinuria and acute 130. Olbricht, C. J., Wanner, C., Thiery, J. & Basten, A.
(FK506) and cyclosporine in kidney transplantation: tubulointerstitial disease in rats with experimental Simvastatin in nephrotic syndrome. Kidney Int. Suppl.
evidence for improved allograft survival at five years. nephrotic syndrome. Am. J. Pathol. 138, 1111–1123 71, S113–S116 (1999).
Transplantation 73, 775–782 (2002). (1991). 131. Kong, X. et al. Lipid-lowering agents for nephrotic
81. Mayer, A. D. et al. Multicenter randomized trial 107. Iwai, T. et al. Stearoyl-CoA desaturase‑1 protects cells syndrome. Cochrane Database Syst. Rev. 12,
comparing tacrolimus (FK506) and cyclosporine in the against lipotoxicity-mediated apoptosis in proximal CD005425 (2013).
prevention of renal allograft rejection: a report of the tubular cells. Int. J. Mol. Sci. 17, E1868 (2016). 132. Baigent, C. et al. The effects of lowering LDL
European Tacrolimus Multicenter Renal Study Group. 108. Li, C. et al. Intrarenal renin-angiotensin system cholesterol with simvastatin plus ezetimibe in patients
Transplantation 64, 436–443 (1997). mediates fatty acid-induced ER stress in the kidney. with chronic kidney disease (Study of Heart and Renal
82. Jackson, S. P. & Calkin, A. C. The clot thickens — Am. J. Physiol. Renal Physiol. 310, F351–F363 (2016). Protection): a randomised placebo-controlled trial.
oxidized lipids and thrombosis. Nat. Med. 13, 109. Zuo, N., Zheng, X., Liu, H. & Ma, X. Fenofibrate, a Lancet 377, 2181–2192 (2011).
1015–1016 (2007). PPARα agonist, protect proximal tubular cells from 133. Valeri, A., Gelfand, J., Blum, C. & Appel, G. B.
83. Podrez, E. A. et al. Platelet CD36 links hyperlipidemia, albumin-bound fatty acids induced apoptosis via the Treatment of the hyperlipidemia of the nephrotic
oxidant stress and a prothrombotic phenotype. activation of NF‑kB. Int. J. Clin. Exp. Pathol. 8, syndrome: a controlled trial. Am. J. Kidney Dis. 8,
Nat. Med. 13, 1086–1095 (2007). 10653–10661 (2015). 388–396 (1986).

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REVIEWS

134. Groggel, G. C., Cheung, A. K., Ellis-Benigni, K. 144. Muso, E. et al. A prospective observational survey on human atherosclerotic lesions. Circulation 110,
& Wilson, D. E. Treatment of nephrotic the long-term effect of LDL apheresis on drug- 3372–3377 (2004).
hyperlipoproteinemia with gemfibrozil. Kidney Int. 36, resistant nephrotic syndrome. Nephron Extra 5, 154. US National Library of Medicine. ClinicalTrials.gov
266–271 (1989). 58–66 (2015). https://clinicaltrials.gov/ct2/show/NCT02235857
135. Buyukcelik, M. et al. The effects of gemfibrozil on 145. Suzuki, H., Tsukamoto, T. & Muso, E. Rituximab- (2016).
hyperlipidemia in children with persistent nephrotic resistant nephrotic syndrome with successful induction 155. [No authors listed.] Chapter 2: General principles in
syndrome. Turk. J. Pediatr. 44, 40–44 (2002). of remission by low-density lipoprotein apheresis. the management of glomerular disease. Kidney Int.
136. Kamanna, V. S. & Kashyap, M. L. Mechanism of action Ther. Apher. Dial. 21, 295–296 (2017). Suppl. 2, 156–162 (2012).
of niacin. Am. J. Cardiol. 101, 20B–26B (2008). 146. US National Library of Medicine. ClinicalTrials.gov 156. Lechner, B. L., Bockenhauer, D., Iragorri, S.,
137. Phan, B. A., Dayspring, T. D. & Toth, P. P. Ezetimibe https://clinicaltrials.gov/ct2/show/NCT02314442 Kennedy, T. L. & Siegel, N. J. The risk of cardiovascular
therapy: mechanism of action and clinical update. (2015). disease in adults who have had childhood nephrotic
Vasc. Health Risk Manag. 8, 415–427 (2012). 147. Fitzgerald, K. et al. A highly durable RNAi therapeutic syndrome. Pediatr. Nephrol. 19, 744–748 (2004).
138. Kastelein, J. J. et al. Simvastatin with or without inhibitor of PCSK9. N. Engl. J. Med. 376, 41–51 157. US National Library of Medicine. ClinicalTrials.gov
ezetimibe in familial hypercholesterolemia. N. Engl. (2017). https://clinicaltrials.gov/ct2/show/NCT00004466
J. Med. 358, 1431–1443 (2008). 148. Liu, S. & Vaziri, N. D. Role of PCSK9 and IDOL in the (2017).
139. Coleman, J. E. & Watson, A. R. Hyperlipidaemia, diet pathogenesis of acquired LDL receptor deficiency 158. US National Library of Medicine. ClinicalTrials.gov
and simvastatin therapy in steroid-resistant nephrotic and hypercholesterolemia in nephrotic syndrome. https://clinicaltrials.gov/ct2/show/NCT01845428
syndrome of childhood. Pediatr. Nephrol. 10, 171–174 Nephrol. Dial. Transplant. 29, 538–543 (2014). (2017).
(1996). 149. US National Library of Medicine. ClinicalTrials.gov
140. Sanjad, S. A., al‑Abbad, A. & al‑Shorafa, S. https://clinicaltrials.gov/ct2/show/NCT03004001 Acknowledgements
Management of hyperlipidemia in children with (2017). The authors acknowledge the expert assistance of L. Feurer
refractory nephrotic syndrome: the effect of statin 150. Awanami, Y. et al. Successful treatment of a patient (Center for Clinical and Translational Research, The Research
therapy. J. Pediatr. 130, 470–474 (1997). with refractory nephrotic syndrome with PCSK9 Institute at Nationwide Childrens Hospital, Columbus,
141. Hattori, M. et al. A combined low-density lipoprotein inhibitors: a case report. BMC Nephrol. 18, 221 Ohio,USA) in creating initial drafts of the figures in this
apheresis and prednisone therapy for steroid- (2017). manuscript.
resistant primary focal segmental glomerulosclerosis 151. Kazi, D. S. et al. Cost-effectiveness of PCSK9 inhibitor
in children. Am. J. Kidney Dis. 42, 1121–1130 therapy in patients with heterozygous familial Author contributions
(2003). hypercholesterolemia or atherosclerotic cardiovascular All authors contributed to researching data for the article,
142. Muso, E. et al. Low density lipoprotein apheresis disease. JAMA 316, 743–753 (2016). and writing, reviewing and editing the article before
therapy for steroid-resistant nephrotic syndrome. 152. Vaziri, N. D. & Liang, K. H. Acyl-coenzyme submission.
Kansai-FGS-Apheresis Treatment (K‑FLAT) Study A:cholesterol acyltransferase inhibition ameliorates
Group. Kidney Int. Suppl. 71, S122–S125 (1999). proteinuria, hyperlipidemia, lecithin-cholesterol Competing interests statement
143. Muso, E. et al. Immediate therapeutic efficacy of acyltransferase, SRB‑1, and low-denisty lipoprotein The authors declare that they have no competing interests.
low-density lipoprotein apheresis for drug-resistant receptor deficiencies in nephrotic syndrome.
nephrotic syndrome: evidence from the short-term Circulation 110, 419–425 (2004). Publisher’s note
results from the POLARIS Study. Clin. Exp. Nephrol. 153. Tardif, J. C. et al. Effects of the acyl coenzyme A: Springer Nature remains neutral with regard to jurisdictional
19, 379–386 (2015). cholesterol acyltransferase inhibitor avasimibe on claims in published maps and institutional affiliations.

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