Nrneph 2010 157

Download as pdf or txt
Download as pdf or txt
You are on page 1of 10

REVIEwS

Atherosclerosis in chronic kidney disease:


the role of macrophages
Valentina Kon, MacRae F. Linton and Sergio Fazio
Abstract | Patients with chronic kidney disease (CKD) are at increased risk of atherosclerotic cardiovascular
disease and loss of renal parenchyma accelerates atherosclerosis in animal models. Macrophages are
central to atherogenesis because they regulate cholesterol traffic and inflammation in the arterial wall. CKD
influences macrophage behavior at multiple levels, rendering them proatherogenic. Even at normal creatinine
levels, macrophages from uninephrectomized Apoe–/– mice are enriched in cholesterol owing to downregulation
of cholesterol transporter ATP‑binding cassette subfamily A member 1 levels and activation of nuclear
factor κB, which leads to impaired cholesterol efflux. Interestingly, treatment with an angiotensin‑II‑receptor
blocker (ARB) improves these effects. Moreover, atherosclerotic aortas from Apoe–/– mice transplanted into
renal‑ablated normocholesterolemic recipients show plaque progression and increased macrophage content
instead of the substantial regression seen in recipient mice with intact kidneys. ARBs reduce atherosclerosis
development in mice with partial renal ablation. These results, combined with the clinical benefits of
angiotensin‑converting‑enzyme (ACE) inhibitors and ARBs in patients with CKD, suggest an important role
for the angiotensin system in the enhanced susceptibility to atherosclerosis seen across the spectrum of
CKD. The role of macrophages could explain why these therapies may be effective in end‑stage renal disease,
one of the few conditions in which statins show no clinical benefit.
Kon, V. et al. Nat. Rev. Nephrol. 7, 45–54 (2011); published online 23 November 2010; doi:10.1038/nrneph.2010.157

Introduction
more than 50% of deaths in patients with chronic kidney subsequent diapedesis into the intima.7 Chemokines
disease (CKD) on dialysis are attributable to cardio­ (chemotactic cytokines) and their receptors have been
vascular disease.1 even modest renal dysfunction, includ­ implicated in the migration of monocytes and t cells into
ing isolated albuminuria, results in a dramatic increase the arterial intima.8 the critical role for macrophages
in the risk of cardiovascular disease.2–5 the relationship in the development of atherosclerosis is illustrated by the
between decreasing renal function and increasing rates observation that osteopetrotic mice, which lack macro­
of cardiovascular disease and mortality is due to multiple phage colony­stimulating factor, have low numbers
mechanisms, including abnormal myocardial remodel­ of macrophages in their atherosclerotic lesions and a
ing, ventricular hypertrophy, arrhythmia and cardiac small lesion area, even in the presence of severe hyper­
arrest; the influence of these factors depends on the lipidemia.9 macrophages also have a central role in innate
level of CKD. Compared with the prevalence of athero­ immunity.10 the interaction between antigen­presenting
sclerotic disease in individuals with intact kidney func­ dendritic cells and t cells activates the adaptive immune
tion, however, atherosclerotic disease is over­represented response and defines the inflammatory processes of early
across the entire spectrum of patients with CKD. atherogenesis. ligation of CD40 on activated t cells leads
macrophages have critical roles in all stages of athero­ to enhanced production of t helper (tH) 1 cell cytokines,
sclerotic lesion formation and mounting experimental including interferon γ,11 which is proatherogenic.12 this
evidence implicates their importance in the vascular tH1 cytokine cascade is counterbalanced by the presence
complications of renal disease. of antiatherogenic tH2 cytokines, including interleukin Department of
macrophages contribute to all stages of atherosclerosis (il)­10.13 this review focuses on the mechanisms of Pediatrics (V. Kon),
through their role in inflammation and lipid homeostasis.6 CKD­induced atherosclerosis, with particular empha­ Department of
Medicine (M. F. linton,
retention of atherogenic lipoproteins in the arterial sis on the role of macrophages, as demonstrated by S. Fazio), Vanderbilt
intima prompts the production of leukocyte chemo­ experimental studies and data from clinical studies. University Medical
Center, 383 Preston
attractant molecules. these molecules activate receptors Research Building,
on rolling monocytes, which leads to their initial adhe­ Macrophages and atherosclerosis 2220 Pierce Avenue,
sion mediated by selectins, followed by their integrin­ the accumulation of macrophages laden with chole­ Nashville, TN
37332‑6300, USA.
dependent adhesion to the endothelium and their sterol ester in the arterial intima is the hallmark of fatty
streak formation in humans and experimental models. Correspondence to:
S. Fazio
Competing interests macrophages internalize atherogenic lipoproteins (such sergio.fazio@
The authors declare no competing interests. as oxidized lDl) via scavenger receptors, including vanderbilt.edu

nature reviews | nephrology volume 7 | JanuarY 2011 | 45


© 2010 Macmillan Publishers Limited. All rights reserved
reViewS

Key points is strongly antiatherogenic.21,22 macrophages and/or den­


■ Even subtle chronic kidney disease (CKD) increases the risk of cardiovascular
dritic cells are also capable of leaving the atherosclerotic
events in humans and worsens atherosclerosis in experimental models plaque, thus promoting regression of atherosclerosis
■ CKD‑associated inflammatory and oxidant stress promotes the infiltration and
in murine models. Gene expression profiles of regress­
trapping of circulating monocytes in the arterial intima ing atherosclerotic plaques have linked CC­chemokine
■ CKD promotes the formation of foam cells by downregulating cholesterol efflux
receptor (CCr) 7 with dendritic cell emigration, and
through activation of nuclear factor κB and repression of cholesterol transporter antibody­blocking experiments in Apoe–/– mice have
ATP‑binding cassette subfamily A member 1 confirmed that CCr7 causes macrophage emigration
■ CKD modifies lipoproteins and makes them more susceptible to scavenging by and plaque regression.23
macrophages and less capable of acting as acceptors of cellular cholesterol macrophages also influence atherogenesis through
■ Systemic and macrophage angiotensin II actions contribute to the enhanced their susceptibility to death. endoplasmic reticulum
susceptibility of patients with CKD to atherosclerosis stress is a major inducer of macrophage apoptosis24,25
■ Treatment with antagonists and inhibitors of angiotensin II might be of
and, whereas macrophage apoptosis in the early stages
particular value in the prevention of cardiovascular disease in patients of atherogenesis might result in reduced lesion cell­
with CKD ularity, 26 apoptosis in advanced lesions expands the
necrotic core owing to impaired phagocytosis of apop­
totic bodies.27 In vitro and in vivo experiments from our
CKD laboratory revealed a critical cooperative role for lDl
Vascular adhesion molecules
e.g. VCAM1, ICAM1, selectins
Monocyte receptor­related protein 1 and apoe in a functional axis
infiltration
Chemoattractants that regulates efferocytosis of apoptotic macrophages in
e.g. CCL2, MCSF Macrophage Macrophage atherosclerotic lesions.28
Macrophage migration trapping egress

CKD modulates macrophage function


Modification of extracellular matrix
(oxidation, glycosylation) Macrophage infiltration
Lipoprotein retention anatomical and radiological analyses document that
Cholesterol content of the
macrophage membrane
CKD dramatically accelerates growth of atherosclerotic
Vascular
intima Disruption of cellular cytoskeleton lesions.29–32 atherosclerotic plaques of patients with CKD
are more complex than those of individuals with normal
renal function, and have features that suggest greater
Disrupted CCR7 pathway instability. these features include increased lipid content,
widespread necrosis, disruption of the extracellular
Figure 1 | Potential pathways by which CKD modulates the accumulation of arterial matrix, and enhanced inflammation. 30 macrophages,
macrophages. CKD potentiates macrophage infiltration into the vessel wall by the largest cell contingent of the atheroma, are involved
increasing the expression of vascular adhesion molecules (VCAM1, ICAM1 and in all of these processes.
selectins) and chemoattractants (CCL2 and MCSF). CKD modifies extracellular experimental studies in atherosclerosis­prone Apoe–/–
matrix components of the vasculature (for example, the oxidation or glycation of mice reveal that a reduction in the renal parenchyma,
glycoproteins, collagen, and elastin), thereby increasing lipoprotein retention and ranging from uninephrectomy to subtotal renal ablation,
the migratory capacity of macrophages. CKD impairment of macrophage egress
significantly expands macrophage­positive areas within
from the vessel wall might involve disruption of the CCR7 pathway. Abbreviations:
CCL2, CC‑chemokine ligand 2; CCR7, CC‑chemokine receptor 7; CKD, chronic
the intima (Figure 1).33–35 Peritoneal macrophages har­
kidney disease; ICAM1, intercellular adhesion molecule 1; MCSF, macrophage vested from uninephrectomized Apoe–/– mice show 50%
colony‑stimulating factor; VCAM1, vascular cell adhesion molecule 1. greater migratory activity in response to chemoattraction
with CC­chemokine ligand (CCl) 2 (also known as
monocyte chemoattractant protein 1) than macrophages
CD36 14 and class a scavenger receptors (sr­a). 15,16 obtained from Apoe –/– mice with intact kidneys. 35
native lipoprotein receptors, such as the lDl receptor­ experimental renal ablation activates numerous vascular
related protein 1,17 are also expressed by macrophages chemotactic cytokines and chemokine receptors, includ­
and contribute to atherogenesis. Cholesterol entry ing vascular cell adhesion molecule 1 (vCam1), inter­
into macrophages is counterbalanced by the efflux of cellular cell adhesion molecule 1 (iCam1), e­selectin,
free cholesterol into acceptor particles (such as HDl).18 Free il­6, tumor necrosis factor and CCl2, to promote macro­
cholesterol efflux is mediated by active transporters, such phage adhesion to the endothelium and transmigration
as atP­binding cassette subfamily a member 1 (aBCa1), into the subendothelial space.36–38 increased vascular
atP­binding cassette subfamily G member 1 (aBCG1) expression of some of these factors precedes both the
and scavenger receptor class B member i (sr­Bi), or by elevation in their plasma levels and the development of
passive diffusion.19 an in vitro study of isolated mouse arterial plaques in renal­ablated Apoe–/– mice, findings
macrophages demonstrated that abca1 mediates the that support a role for early macrophage recruitment into
efflux of free cholesterol and phospholipids to both apo­ the vessel wall in renal­injury­induced atherogenesis.34
lipoprotein a­1 (apoa1) and apolipoprotein e (apoe).20 Plasma levels of adhesion molecules and markers of
apoe is abundantly expressed by macrophages in athero­ inflammation and oxidation are increased in patients
sclerotic lesions, 21 might represent the physiological with CKD and correlate with the degree of renal impair­
acceptor of cholesterol in atherosclerotic plaques,20 and ment. 39–43 indeed, high plasma levels of iCam1 and

46 | JANUARY 2011 | volUme 7 www.nature.com/nrneph


© 2010 Macmillan Publishers Limited. All rights reserved
reViewS

vCam1 are strong independent predictors of poor oxidative stress in patients with mild to moderate CKD
outcome in patients with CKD.43 uremic serum increases and patients with esrD on hemodialysis,64–66 no large
the expression and shedding of adhesion molecules by clinical trials have been conducted to evaluate the effi­
vascular endothelial cells.44 the coronary plaques of cacy of such interventions on the risk of cardiovascular
patients with CKD (particularly calcified plaques) have events or death in these populations. indeed, large­scale,
increased expression of the inflammatory markers long­term follow­up studies of vitamin e supplementa­
CD40–CD154 and of C­reactive protein. 45 notably, tion in individuals with normal renal function have been
peripheral leukocytes of patients with CKD have greater disappointing.67,68 nonetheless, CKD increases oxidative
responses to inflammatory and oxidative stimuli than stress, thus creating an optimal set up for antioxidant
those of healthy controls.46–48 even without stimulation, therapies to target macrophage infiltration and function.
circulating granulocytes and monocytes of patients on However, currently available antioxidant therapies might
dialysis produce elevated levels of superoxide and hydro­ not be sufficiently effective to influence the complexi­
gen peroxide, and have greater expression of CD11b/ ties that underlie the increased mortality rates in patients
CD18 integrins than those of healthy individuals. 47 with CKD.
in addition, monocytes from patients with end­stage
renal disease (esrD) have suppressed levels of anti­ Macrophage egress
inflammatory cytokines and seem to be more susceptible in addition to increased cellular infiltration, the vascular
to macrophage transformation than cells from normal accumulation of macrophages in CKD might be caused
controls. 46 such observations support the idea that by their increased survival or decreased egress from
CKD increases systemic inflammation, vascular micro­ the vascular wall (Figure 1). transplantation of athero­
inflammation and macrophage priming, all of which can sclerotic aorta from hyperlipidemic Apoe–/– mice into
amplify the expression of cytokines by macrophages and normolipemic wild­type mice results in plaque regres­
their recruitment into the subendothelial space. sion and the loss of foam cells into the local lymphatic
a major contributor to heightened inflammation is the system and circulation.23,69,70 substantial foam­cell exit
enhanced oxidative stress that develops early in CKD, is observed within 3 days of transplantation. the resolu­
persists as renal function declines, and is not improved tion of the atheroma under these conditions also includes
by dialysis treatment. 47–52 urea, at disease­ relevant abatement in areas of necrosis, extracellular accumulation
concentrations, stimulates the generation of reactive of cholesterol, and fibrosis.71 in a 2010 study, renal abla­
oxygen species in vitro and in vivo.53 Factors that promote tion has been shown to inhibit macrophage emigration
oxidative stress in the setting of CKD include naDPH out of the vessel wall.72 transplantation of atheromatous
oxidase, uncoupled endothelial nitric oxide synthase and aortic segments from Apoe–/– mice into normolipemic
myeloperoxidase.49,54,55 myeloperoxidase is a predictor of mice after renal ablation did not cause plaque regres­
cardiovascular disease risk and is abundantly expressed sion as seen after transplantation of atheromatous aortic
by neutrophils and macrophages within athero­ segments from Apoe–/– mice into normolipemic recipient
sclerotic lesions in patients with CKD.56,57 Compared mice with intact kidneys. on the contrary, the plaques of
with healthy controls, leukocyte lysate from patients with renal­ablated normolipemic recipients actually expanded
CKD has increased myeloperoxidase activity, which is and contained more macrophages than those of recipi­
not improved by dialysis.46 a single nucleotide poly­ ents with intact kidneys. the increased macrophage
morphism in the promoter region of the myeloperoxidase content was not linked to changes in cellular survival and
gene has been associated with reduced expression of macrophages within the plaques of renal­ablated mice
myeloperoxidase and linked to reduced prevalence showed downregulation of serum response factor target
of cardiovascular disease in patients with CKD and genes and upregulation of the migration factor CCr7. in
esrD. 58,59 treatments that decrease oxidative stress view of the dynamic nature of the atherosclerotic plaque,
and inflammation, such as N­acetylcysteine or neutraliz­ impaired plaque regression and decreased macrophage
ing antibodies against the receptor for advanced glycation emigration in the setting of renal damage might contrib­
end products, significantly reduce experimental athero­ ute not only to accelerated atherosclerosis, but also to
sclerosis caused by renal dysfunction.60,61 moreover, and the lack of vascular benefits from treatments that lower
in contrast with results in the general population, anti­ plasma lipids in advanced CKD.
oxidative therapy substantially reduces cardiovascular
morbidity in patients with CKD. 62,63 For example, Macrophage trapping
N­acetylcysteine has been shown to decrease concen­ CKD­induced changes within the local vascular milieu
trations of oxidized lDl cholesterol by 76% and the and modulation of macrophage function may cause sub­
composite end points of nonfatal myocardial infarction, endothelial trapping of macrophages (Figure 1). CKD
cardiovascular death, revascularization and ischemic increases the oxidation and glycosylation of matrix mol­
stroke by 40% in patients with stage 5 CKD.62,63 in these ecules including proteoglycans, collagen, and elastin.73,74
same small studies, antioxidant therapy with vitamin e modifications of extracellular matrix promote lipoprotein
reduced the rate of cardiovascular end points by >50% retention and oxidation and lead to increased cholesterol
and the rate of myocardial infarction by 70% in patients accumulation by the macrophage, resulting in increased
on hemodialysis.62,63 although antioxidant therapies cholesterol content in the cellular membrane, which
decrease levels of electronegative lDl and biomarkers of causes stiffness and impaired cellular mobility.75,76

nature reviews | nephrology volume 7 | JanuarY 2011 | 47


© 2010 Macmillan Publishers Limited. All rights reserved
reViewS

than monocytes from patients with CKD who are not


on dialysis or individuals without renal disease. 77,78
increased expression of sr­a has also been documented
in macrophages from patients on hemodialysis. 83,87,88
mLDL (including oxidized and carbamylated LDL), uremic serum enhanced sr­a expression and activity in
CKD
VLDL, chylomicron, chylomicron remnants, IDL + the human monocytic cell line u937.83,87,88 such changes
+
predict increased lipid uptake, inflammation, migration
+ and trapping of macrophages.75,76,79–81 once upregulated,
macrophages do not downregulate scavenger receptors
Retained metabolites or alter the influx of cholesterol by this pathway and
Oxidative stress
Inflammatory cytokines prevention of foam­cell formation becomes critically
CD36 dependent on lipid efflux.
SR-A Cholesterol efflux involves the mobilization of excess
+ – lipids from intracellular pools to the plasma membrane
SR-BI
as well as the transfer of excess lipids to external chole­
Cell
ABCG1 sterol acceptors.89,90 a 2009 experimental study showed

NFκB that even subtle renal perturbation resulting from uni­
ABCA1
PPAR LXR/RXR
nephrectomy disrupted the mobilization of macrophage
+
cholesterol and potentiated foam­cell formation. indeed,
macrophages from uninephrectomized Apoe –/– mice
APOAI HDL
show a massive accumulation of cellular cholesterol that
Figure 2 | Potential mechanisms by which CKD modulates macrophage lipid is independent of plasma cholesterol levels.91 these find­
handling. CKD promotes the modification (oxidation, carbamylation) of lipids and ings complement clinical observations demonstrating
lipoproteins as well as the upregulation of scavenger receptors (CD36 and SR‑A), that the development of atherosclerotic complications in
leading to increased macrophage lipid uptake and foam‑cell formation. CKD also CKD does not necessarily follow plasma lipid levels and
dysregulates lipid efflux, by downregulating the expression of the ABCA1 emphasize the importance of altered local dynamics in
transporter (but not ABCG1 or SR‑BI) via upregulated NFκB activity. Retained
macrophage lipid handling under conditions of impaired
metabolites, oxidative stress and inflammatory cytokines prevailing in CKD are
likely key modulators of these macrophage receptors and transporters.
renal function.
Abbreviations: ABCA1, ATP‑binding cassette subfamily A member 1; ABCG1, ATP‑ the key pathways for the movement of cholesterol
binding cassette subfamily G member 1; APOAI, apolipoprotein A‑I; CKD, chronic out of macrophages involve an energy­dependent efflux
kidney disease; HDL, high‑density lipoprotein; IDL, intermediate‑density lipoprotein; that involves the cholesterol transporters aBCa1 and
LXR/RXR, liver X receptor and retinoid X receptor heterodimer; mLDL, modified low‑ aBCG1, and the scavenger receptor sr­Bi, which is
density lipoprotein; NFκB, nuclear factor κB; PPAR, peroxisome proliferator‑ driven by the cholesterol gradient (Figure 2). using the
activated receptor; SR‑A, scavenger receptor class A member 1; SRBI, scavenger Apoe–/– mouse model, we showed that uninephrectomy
receptor class B member I; VLDL, very‑low‑density lipoprotein.
downregulates the expression of both macrophage
Abca1 and the protein it encodes, but does not have
macrophage migration and trapping are also affected signifi cant effects on abcg1 or sr­b1 expression. 91
by the scavenger receptor CD36, which is upregulated notably, the repression of abca1 in macrophages of uni­
in monocytes of patients with CKD and uremia.77,78 one nephrectomized mice occurred despite very high levels
study showed that CD36­mediated uptake of oxidized of cellular cholesterol, the physiological stimulus that
lDl induced actin polymerization and cell spreading via increases cholesterol efflux via membrane transporters.
activation of focal adhesion kinase and inactivation of src interestingly, uremic plasma downregulates levels of
homology 2­containing phosphotyrosine phosphatase, aBCa1 in cultured human coronary artery endothelial
which inhibited cellular migration.79 other investiga­ cells.92 Downregulation of aBCa1 expression in experi­
tors, however, have reported that upregulation of CD36 mental and human CKD might be caused by activation
actually enhances macrophage migration. 80,81 since of the nuclear factor κB (nFκB) signaling pathway.93–95 in
CD36 regulates several specific intracellular signaling support of this hypothesis, we showed that specific antag­
pathways related not only to cellular migration but also onism of nFκB activation pathways in macrophages of
to inflammation and cholesterol efflux, CD36 activation uninephrectomized Apoe–/– mice restored abca1 levels.91
might induce several diverse functions depending on the modulation of atP­binding cassette transporters has also
activating trigger in each particular biological setting.82 been reported for other chronic diseases, particularly
diabetes mellitus, in which metabolic factors including
CKD and macrophage lipid homeostasis reactive carbonyls and free fatty acids impair abca1­
macrophage foam­cell formation results from an dependent cholesterol export by destabilizing abca1.96,97
imbalance between lipoprotein uptake and cholesterol these metabolites are also elevated in patients with
efflux (Figure 2). scavenger receptors are upregulated CKD. 98 these findings indicate that repression of
in macrophages from patients with CKD as well as in aBCa1 owing to renal dysfunction might contribute to
tissues such as the aorta and kidneys of animals with the impaired clearance of excess cholesterol from arterial
renal injury.77,78,83–86 monocytes from patients on hemo­ macrophages and suggest a potential target for interven­
dialysis or peritoneal dialysis have higher levels of CD36 tion in CKD­induced atherosclerosis. of note, treatment

48 | JANUARY 2011 | volUme 7 www.nature.com/nrneph


© 2010 Macmillan Publishers Limited. All rights reserved
reViewS

with human aPoai did not reduce the atherosclerotic activity, which is not altered by dialysis. 85,112,115–118
burden of nephrectomized Apoe–/– mice.99 However, this Furthermore, HDl from patients on hemodialysis does
intervention did lessen the lipid and collagen content not protect lDl from oxidation,118 whereas the addi­
of the atherosclerotic plaques and increased the area tion of an aPoai mimetic peptide to lDl obtained
occupied by smooth muscle cells—changes that could from patients on dialysis reduces its capacity to increase
be indicative of plaque stabilization.99 monocyte chemotactic activity in cultured endothelial
in addition to modulating cholesterol homeostasis, cells.118 taken together, these observations suggest that
aBCa1 has major anti­inflammatory and antiapoptotic severe CKD influences the composition and function of
functions.90 macrophages from abca1­deficient mice lDl and HDl, as well as macrophage gene expression, to
have increased toll­like receptor (tlr) signaling, which cause perturbations that are not necessarily targeted by
enhances their inflammatory response to lipopoly­ current lipid­lowering interventions. whether extreme
saccharide and other tlr ligands.100,101 upregulation reductions in lDl level have cardiovascular benefits in
of tlr2 and tlr4 has been reported in monocytes of patients with esrD remains unknown, but the answer
dialysis patients with systemic inflammation,102 whereas to this question might come from studying the direct
expression of these receptors was reportedly decreased in cellular effects of statin therapy. statins suppress chole­
dialysis patients with low levels of C­reactive protein.103 sterol synthesis and reduce intracellular concentrations
aBCa1 also directly suppresses lipopolysaccharide­ of oxysterols and isoprenoids, intermediaries that influ­
induced inflammatory cytokine production by macro­ ence nuclear receptors and G proteins to modulate sig­
phages through a pathway that involves signal transducer naling pathways and gene expression. the effect of statins
and activator of transcription 3 and is independent of on these pathways is influenced by cholesterol content
cholesterol export.96 in view of the chronic systemic and and by cellular activation and differentiation.119–125 For
vascular inflammation that prevails in CKD, repressed example, the downregulation of aBCa1 level induced by
aBCa1 function in macrophages might be especially statins is more pronounced with increased macrophage
detrimental through suppression of lipid export and differentiation and less pronounced with increased
activation of the inflammatory response. cholesterol loading of the cell.119 it is therefore possible
that the activated macrophages of patients with advanced
CKD and lipoproteins CKD do not respond normally to statin stimulation
CKD influences lipoproteins that are involved in macro­ owing to their abnormal content and distribution of
phage function. CKD generates both atherogenic lDl and cellular lipids.
dysfunctional HDl particles. Plasma levels of modified
and oxidized lDl, which correlate with cardiovascular CKD activation of angiotensin II
event rates in the general population,104 are elevated at CKD activates the renin–angiotensin system (ras),
all stages of CKD.105 myeloperoxidase­generated reactive which leads to heightening of its principal effec­
nitrogen species facilitate lipid peroxidation and protein tor peptide, angiotensin ii, and ultimately modula­
nitration, which enables lDl to be avidly taken up by tion of macrophage function. antagonism of the ras
CD36.55,106 Furthermore, the catalysis of lDl carbamyla­ by angiotensin­converting­enzyme (aCe) inhibitors
tion by myeloperoxidase reduces the affinity of lDl for or angiotensin­ii­receptor blockers (arBs) is the corner­
the lDl receptor and increases its affinity for scavenger stone of treatment of progressive renal failure. 126,127
receptors.55,107 such findings suggest that CKD might be angiotensin ii is also a major driving force in athero­
associated with modifications in the composition and sclerosis. numerous epidemiological studies document
function of lDl that promotes atherosclerosis, but is not fewer cardiovascular events and increased survival in
affected by lipid­lowering therapy.108,109 individuals treated with antagonists or inhibitors of
CKD also affects HDl levels and function. low levels angiotensin ii.128,129 notably, these benefits are indepen­
of HDl cholesterol are a powerful negative risk factor dent of hemodynamic effects and underscore a more
for cardiovascular disease, prevail at all stages of CKD direct role for angiotensin ii in cardiovascular and
and, as in the general population, are associated with renal diseases. the levels, duration, and localization of
increased mortality.110 experimental and clinical studies angiotensin ii activation that are necessary to activate
demonstrate that several factors contribute to the low these disease pathways are unknown. activated angio­
level of HDl in CKD, including reduced levels of aPoai, tensin ii in CKD can potentiate macrophage infiltration
enriched levels of serum amyloid a, and decreased of the arterial intima in every stage of atherogenesis.
lecithin–cholesterol acyltransferase function. 84,85,110–112 experimentally, a sustained increase in circulating
CKD also impairs HDl maturation, which can pro­ levels of angiotensin ii through exogenous infusion
foundly compromise many of its protective functions. causes recruitment of macrophages along with vascular
For example, under normal conditions HDl fractions inflammation, lesional neovascularization, hemorrhage
contain antioxidant enzymes such as paraxonase and and elastolysis in hyperlipidemic mice and rabbits.130–135
glutathione peroxidase.113,114 However, the accumulation in clinical settings, short­term elevations in angio­
of advanced glycation end products and acrolein in CKD tensin ii activity, such as hypotension, volume depletion,
reduces the levels of these enzymes, compromising HDl and cardiac ischemia, might have delayed consequences
function. indeed, HDl from patients with esrD has on atherosclerosis. we examined whether transient
markedly reduced antioxidant and anti­inflammatory elevations in levels of angiotensin ii can affect future

nature reviews | nephrology volume 7 | JanuarY 2011 | 49


© 2010 Macmillan Publishers Limited. All rights reserved
reViewS

plaque development, and found that athero sclerosis inhibition of the action of angiotensin ii with aCe
was dramati cally increased in Apoe­knockout mice inhibitors or arBs reduces the risk of cardiovascular
3 months after a 2­week infusion of a nonhypertensive events in individuals with normal renal function.
dose of angiotensin ii.130 as the amplification of athero­ experimental findings suggest similar benefits in patients
sclerosis did not occur during angiotensin ii infusion, with CKD. we showed that atherosclerosis after uni­
these results confirm that angiotensin ii activates mecha­ nephrectomy in Apoe–/– mice is dramatically lessened by
nisms that promote and amplify atherogenic processes. antagonism of angiotensin ii with losartan but not with
indeed, angiotensin ii exposure caused an immediate the nonspecific antihypertensive agent, hydralazine.35 the
increase in the vascular messenger rna expression of reduction in the atherosclerotic burden with losartan
several chemoattractants (including CCl2 and its recep­ treatment was accompanied by changes in plaque com­
tor CCr2) and a subsequent accumulation of macro­ position that included fewer macrophages. moreover,
phages in the aorta of angiotensin­ii­infused mice.130 in vitro macrophage migration was reduced by arB
interestingly, our ex vivo study found that macrophages treatment. these effects on macrophage infiltration were
harvested from angiotensin­ii­infused mice had sub­ accompanied by the preservation of extracellular matrix
stantially increased migration across the cell mem­ components, especially elastin, and decreased levels of the
brane in response to CCl2 chemotaxis.136 moreover, proteolytic enzyme, cathepsin s. none of these benefits
angiotensin ii amplifies atherosclerosis and increases were observed in hydralazine­treated mice.
macrophage content in the aorta of mice carrying Apoe–/– as discussed above, a reduction in renal mass by
macrophages.136 Conversely, inhibition of angiotensin ii uninephrectomy decreases cholesterol efflux in macro­
reduces macrophage infiltration and promotes compo­ phages via repression of the macrophage aBCa1
sitional changes such as increased collagen content that transporter.91 In vivo treatment with an arB restored
might stabilize the atherosclerotic plaque.137,138 macrophage abca1 expression in the macrophages of
the modulation of macrophage­specific functions by uninephrectomized Apoe–/– mice. these results comple­
angiotensin ii is supported by observations that mono­ ment previous in vivo and in vitro findings demon­
cytes and macrophages express all components of the strating that exogenous angiotensin ii downregulates
ras, including type­1 (at1) and type­2 (at2) angio­ aBCa1.150,151 Furthermore, incubation of human and
tensin ii receptors.139–141 In vitro, angiotensin ii increases mouse macrophages with arBs, especially, telmisartan,
the macrophage­mediated modification and uptake of increased cholesterol efflux via a peroxisome proliferator­
lDl, cholesterol synthesis in macrophages, differentiation activated receptor γ­dependent pathway, which caused
of monocytes to macrophages, activation of macrophage­ an upregulation of aBCa1 level.150–153 taken together,
generated oxidative stress, and levels of proinflammatory these observations suggest a pivotal importance of
cytokines.142 monocytes from patients with hypertension angiotensin ii–aBCa1 interaction for cholesterol
have high numbers of at1 receptor in dimer form, which homeostasis in macrophages in the setting of renal dys­
correlates with increased angiotensin­ii­dependent function, which provides a basis for possible modulation
adhesion to endothelial cells.143,144 of excess risk of cardiovascular disease in patients with
the functional importance of the macrophage at1 CKD. interestingly, in vivo treatment of Apoe–/– mice
receptor in modulating atherosclerosis in vivo is illustrated with the arB losartan substantially attenuated upregula­
by studies using chimeric mice in which the at1 recep­ tion of nFκB subfamily proteins rela and p50, suggest­
tor (atgr1) is either ablated or expressed exclusively in ing a potential key regulatory step in this pathway in
hematopoietic cells.145–148 transplantation of bone marrow cholesterol efflux.91 arB treatment was also found to
from Atgr1­knockout mice into atherosclerosis­prone have suppressive effects on nFκB in other tissues.95,154
mice lacking either apoe or the lDl receptor did not CKD­induced activation of angiotensin ii can
markedly alter their atherosclerotic lesions.145,147 infusion also derange lipoprotein composition and function.
of angiotensin ii increased atherosclerosis and macro­ angiotensin ii promotes lDl oxidation and impairs
phage infiltration in Apoe–/– mice that had received bone maturation of HDl, whereas inhibition of angiotensin ii
marrow from Atgr1+/+ mice but not in Apoe–/– mice that action has opposite effects. 138,142,153–156 indeed, aCe
had received bone marrow from Atgr1­knockout mice. inhibitors substantially reduced lipid myeloperoxidase­
likewise, reconstitution of Ldlr­knockout mice with bone mediated oxidation of lDl,157 oxidized­lDl­mediated
marrow from Atgr1+/+ mice or Atgr1­knockout mice pro­ transformation of cultured macrophages into foam
duced the same results.145,147 By contrast, Atgr1­knockout cells,158 and levels of oxidized lipoproteins in the serum
mice reconstituted with bone marrow from Atgr+/+ mice and arteries of hypercholesterolemic rabbits and mice.159
had increased atherosclerosis and decreased collagen although experimental findings suggest that antagonism
content after exposure to angiotensin ii, consistent with of angiotensin ii might benefit patients with CKD, clini­
the phenotype of a more unstable lesion. these findings cal studies remain sparse. Post hoc analysis of aCe
suggest that in an angiotensin­ii­heightened state, such inhibitor treatment in patients with mild to moderate
as CKD, the macrophage at1 receptor is responsible for renal impairment found an increased reduction in risk of
acceleration and destabilization of plaques.35 in this way, cardiovascular events in these individuals than in those
increased expression of aCe by circulating monocytes without compromised renal function.2,160 However, an
correlates with cardiovascular events and mortality in inclusive evaluation of studies of aCe inhibitor or arB
patients on hemodialysis.149 treatment on cardiovascular outcomes in patients with

50 | JANUARY 2011 | volUme 7 www.nature.com/nrneph


© 2010 Macmillan Publishers Limited. All rights reserved
reViewS

CKD, including esrD, did not allow a clear and defini­ of the ras and are responsive to treatment with
tive interpretation of the findings. some studies did not agents that reduce vascular exposure to angiotensin ii.
find a benefit of angiotensin ii inhibition,161–163 while interventions that modulate macrophage behavior via
many others, including a large meta­analysis,164 report antagonism of angiotensin might produce vascular
that patients with advanced CKD treated with aCe benefits across the spectrum of CKD.
inhibitors or arBs have fewer cardiovascular events and
reduced mortality.165–171 Review criteria

Conclusions Original articles, review articles and abstracts for this


Review were obtained by searching PubMed and MEDLINE
CKD affects macrophage function both directly and
for full‑length articles in English published up until 2010
indirectly. Direct effects include upregulation of scav­ using the search terms: “atherosclerosis”, “plaque”,
enger receptors, decreased cholesterol efflux via activa­ “myocardial infarction”, “cardiovascular disease”, “CVD”,
tion of nFκB and repression of aBCa1. indirect effects “vascular calcification”, “intima–media thickness”
include the modification of lipoproteins that renders “apolipoprotein E”, “statin”, “chronic kidney disease”,
these particles more susceptible to scavenging by macro­ “CKD”, “kidney”, “renal”, “uninephrectomy”, “dialysis”,
phages and inflammatory and oxidative insults to the “macrophage”, “monocyte”, “foam cell”, “cholesterol”,
endothelium that cause increased recruitment, trapping “lipid”, “lipid metabolism”, “LDL”, “HDL”, “cholesterol
efflux”, “scavenger receptor”,“CD36”, “ABCA1”, ”ABCG1”,
and decreased egress of arterial macrophages. many of
“ApoAI”, “NFκB”, “PPAR” and “angiotensin”.
these macrophage changes are linked to the activation

1. Foley, R. N., Parfrey, P. S. & Sarnak, M. J. Clinical 13. Pinderski, L. J. et al. Overexpression of and phagocytic efficiency. Arterioscler. Thromb.
epidemiology of cardiovascular disease in interleukin‑10 by activated T lymphocytes Vasc. Biol. 25, 2255–2264 (2005).
chronic renal disease. Am. J. Kidney Dis. inhibits atherosclerosis in LDL receptor‑deficient 25. Erbay, E. et al. Reducing endoplasmic reticulum
32 (Suppl.), S112–S119 (1998). mice by altering lymphocyte and macrophage stress through a macrophage lipid chaperone
2. Mann, J. F., Gerstein, H. C., Pogue, J., Bosch, J. phenotypes. Circ. Res. 90, 1064–1071 (2002). alleviates atherosclerosis. Nat. Med. 15,
& Yusuf, S. Renal insufficiency as a predictor of 14. Endemann, G. et al. CD36 is a receptor for 1383–1391 (2009).
cardiovascular outcomes and the impact of oxidized low density lipoprotein. J. Biol. Chem. 26. Babaev, V. R. et al. Macrophage EP4 deficiency
ramipril: the HOPE randomized trial. Ann. Intern. 268, 11811–11816 (1993). increases apoptosis and suppresses early
Med. 134, 629–636 (2001). 15. Kodama, T. et al. Type I macrophage scavenger atherosclerosis. Cell. Metab. 8, 492–501
3. Muntner, P., He, J., Hamm, L., Loria, C. & receptor contains α‑helical and collagen‑like (2008).
whelton, P. K. Renal insufficiency and coiled coils. Nature 343, 531–535 (1990). 27. Tabas, I. Macrophage death and defective
subsequent death resulting from cardiovascular 16. Babaev, V. R. et al. Reduced atherosclerotic inflammation resolution in atherosclerosis. Nat.
disease in the United States. J. Am. Soc. Nephrol. lesions in mice deficient for total or macrophage‑ Rev. Immunol. 10, 36–46 (2010).
13, 745–753 (2002). specific expression of scavenger receptor‑A. 28. Yancey, P. G. et al. Macrophage LRP‑1 controls
4. Go, A. S., Chertow, G. M., Fan, D., Arterioscler. Thromb. Vasc. Biol. 20, 2593–2599 plaque cellularity by regulating efferocytosis and
McCulloch, C. E. & Hsu, C. Y. Chronic kidney (2000). Akt activation. Arterioscler. Thromb. Vasc. Biol. 30,
disease and the risks of death, cardiovascular 17. Overton, C. D., Yancey, P. G., Major, A. S., 787–795 (2010).
events, and hospitalization. N. Engl. J. Med. 351, Linton, M. F. & Fazio, S. Deletion of macrophage 29. Amann, K. Media calcification and intima
1296–1305 (2004). LDL receptor‑related protein increases calcification are distinct entities in chronic
5. Hillege, H. L. et al. Urinary albumin excretion atherogenesis in the mouse. Circ. Res. 100, kidney disease. Clin. J. Am. Soc. Nephrol. 3,
predicts cardiovascular and noncardiovascular 670–677 (2007). 1599–1605 (2008).
mortality in general population. Circulation 106, 18. Yancey, P. G. et al. Importance of different 30. Miyagi, M. et al. Impact of renal function on
1777–1782 (2002). pathways of cellular cholesterol efflux. coronary plaque composition. Nephrol. Dial.
6. Glass, C. K. & witztum, J. L. Atherosclerosis: Arterioscler. Thromb. Vasc. Biol. 23, 712–719 Transplant. 25, 175–181 (2010).
the road ahead. Cell 104, 503–516 (2001). (2003). 31. Nicholls, S. J. et al. Comparison of coronary
7. Huo, Y. & Ley, K. Adhesion molecules and 19. Cuchel, M. & Rader, D. J. Macrophage reverse atherosclerotic volume in patients with
atherogenesis. Acta Physiol. Scand. 173, 35–43 cholesterol transport: key to the regression of glomerular filtration rates ≤60 versus >60 ml/
(2001). atherosclerosis? Circulation 113, 2548–2555 min/1.73 m2: a meta‑analysis of intravascular
8. Peters, w. & Charo, I. F. Involvement of (2006). ultrasound studies. Am. J. Cardiol. 99, 813–816
chemokine receptor 2 and its ligand, monocyte 20. Yancey, P. G., Yu, H., Linton, M. F. & Fazio, S. (2007).
chemoattractant protein‑1, in the development A pathway‑dependent on ApoE, ApoAI, and 32. Rigatto, C. et al. Atheroma progression in chronic
of atherosclerosis: lessons from knockout mice. ABCA1 determines formation of buoyant high‑ kidney disease. Clin. J. Am. Soc. Nephrol. 4,
Curr. Opin. Lipidol. 12, 175–180 (2001). density lipoprotein by macrophage foam cells. 291–298 (2009).
9. Smith, J. D. et al. Decreased atherosclerosis in Arterioscler. Thromb. Vasc. Biol. 27, 1123–1131 33. Bro, S. et al. Chronic renal failure accelerates
mice deficient in both macrophage colony‑ (2007). atherogenesis in apolipoprotein E‑deficient mice.
stimulating factor (op) and apolipoprotein E. 21. Linton, M. F., Atkinson, J. B. & Fazio, S. J. Am. Soc. Nephrol. 14, 2466–2474 (2003).
Proc. Natl Acad. Sci. USA 92, 8264–8268 (1995). Prevention of atherosclerosis in apolipoprotein 34. Bro, S., Moeller, F., Andersen, C. B., Olgaard, K. &
10. Michelsen, K. S. et al. Lack of Toll‑like receptor 4 E‑deficient mice by bone marrow transplantation. Nielsen, L. B. Increased expression of adhesion
or myeloid differentiation factor 88 reduces Science 267, 1034–1037 (1995). molecules in uremic atherosclerosis in
atherosclerosis and alters plaque phenotype in 22. Fazio, S. et al. Increased atherosclerosis in mice apolipoprotein‑E‑deficient mice. J. Am. Soc.
mice deficient in apolipoprotein E. Proc. Natl reconstituted with apolipoprotein E null Nephrol. 15, 1495–1503 (2004).
Acad. Sci. USA 101, 10679–10684 (2004). macrophages. Proc. Natl Acad. Sci. USA 94, 35. Suganuma, E. et al. Antiatherogenic effects of
11. Mach, F. et al. Functional CD40 ligand is 4647–4652 (1997). angiotensin receptor antagonism in mild renal
expressed on human vascular endothelial cells, 23. Trogan, E. et al. Gene expression changes in dysfunction. J. Am. Soc. Nephrol. 17, 433–441
smooth muscle cells, and macrophages: foam cells and the role of chemokine receptor (2006).
implications for CD40–CD40 ligand signaling in CCR7 during atherosclerosis regression in ApoE‑ 36. Bro, S., Binder, C. J., witztum, J. L., Olgaard, K. &
atherosclerosis. Proc. Natl Acad. Sci. USA 94, deficient mice. Proc. Natl Acad. Sci. USA 103, Nielsen, L. B. Inhibition of the renin–angiotensin
1931–1936 (1997). 3781–3786 (2006). system abolishes the proatherogenic effect of
12. Gupta, S. et al. IFN‑gamma potentiates 24. Tabas, I. Consequences and therapeutic uremia in apolipoprotein E‑deficient mice.
atherosclerosis in ApoE knock‑out mice. J. Clin. implications of macrophage apoptosis in Arterioscler. Thromb. Vasc. Biol. 27, 1080–1086
Invest. 99, 2752–2761 (1997). atherosclerosis: the importance of lesion stage (2007).

nature reviews | nephrology volume 7 | JanuarY 2011 | 51


© 2010 Macmillan Publishers Limited. All rights reserved
reViewS

37. Buzello, M. et al. The apolipoprotein E knockout 54. Touyz, R. M., Yao, G., Quinn, M. T., Pagano, P. J. & 70. williams, K. J., Feig, J. E. & Fisher, E. A. Rapid
mouse: a model documenting accelerated Schiffrin, E. L. p47phox associates with the regression of atherosclerosis: insights from the
atherogenesis in uremia. J. Am. Soc. Nephrol. 14, cytoskeleton through cortactin in human clinical and experimental literature. Nat. Clin.
311–316 (2003). vascular smooth muscle cells: role in NAD(P)H Pract. Cardiovasc. Med. 5, 91–102 (2008).
38. Massy, Z. A. et al. Uremia accelerates both oxidase regulation by angiotensin II. Arterioscler. 71. Trogan, E. et al. Serial studies of mouse
atherosclerosis and arterial calcification in Thromb. Vasc. Biol. 25, 512–518 (2005). atherosclerosis by in vivo magnetic resonance
apolipoprotein E knockout mice. J. Am. Soc. 55. wang, Z. et al. Protein carbamylation links imaging detect lesion regression after correction
Nephrol. 16, 109–116 (2005). inflammation, smoking, uremia and of dyslipidemia. Arterioscler. Thromb. Vasc. Biol.
39. Carrero, J. J., Yilmaz, M. I., Lindholm, B. & atherogenesis. Nat. Med. 13, 1176–1184 24, 1714–1719 (2004).
Stenvinkel, P. Cytokine dysregulation in chronic (2007). 72. Ponda, M. P., Barash, I., Feig, J. E., Fisher, E. A. &
kidney disease: how can we treat it? Blood Purif. 56. Düzgünçinar, O. et al. Plasma myeloperoxidase Skolnik, E. Y. Moderate kidney disease inhibits
26, 291–299 (2008). is related to the severity of coronary artery atherosclerosis regression. Atherosclerosis 210,
40. Honda, H. et al. Serum albumin, C‑reactive disease. Acta Cardiol. 63, 147–152 (2008). 57–62 (2010).
protein, interleukin 6, and fetuin a as predictors 57. Meuwese, M. C. et al. Serum myeloperoxidase 73. Osada, S. et al. Alterations in proteoglycan
of malnutrition, cardiovascular disease, and levels are associated with the future risk of components and histopathology of the
mortality in patients with ESRD. Am. J. Kidney Dis. coronary artery disease in apparently healthy peritoneum in uraemic and peritoneal dialysis
47, 139–148 (2006). individuals: the EPIC–Norfolk Prospective (PD) patients. Nephrol. Dial. Transplant. 24,
41. Pachaly, M. A. et al. Interleukin‑6 is a better Population Study. J. Am. Coll. Cardiol. 50, 3504–3512 (2009).
predictor of mortality as compared to C‑reactive 159–165 (2007). 74. Yamamoto, Y. et al. Possible involvement of
protein, homocysteine, pentosidine and 58. Grahl, D. A. et al. Associations between the increased glycoxidation and lipid peroxidation of
advanced oxidation protein products in CYBA 242C/T and the MPO –463G/A elastin in atherogenesis in haemodialysis
hemodialysis patients. Blood Purif. 26, 204–210 polymorphisms, oxidative stress and patients. Nephrol. Dial. Transplant. 17, 630–636
(2008). cardiovascular disease in chronic kidney (2002).
42. Stinghen, A. E. et al. Increased plasma and disease patients. Blood Purif. 25, 210–218 75. Nagao, T., Qin, C., Grosheva, I., Maxfield, F. R. &
endothelial cell expression of chemokines and (2007). Pierini, L. M. Elevated cholesterol levels in the
adhesion molecules in chronic kidney disease. 59. Pecoits‑Filho, R. et al. A functional variant of the plasma membranes of macrophages inhibit
Nephron Clin. Pract. 111, c117–c126 (2009). myeloperoxidase gene is associated with migration by disrupting RhoA regulation.
43. Suliman, M. E., Qureshi, A. R., Heimbürger, O., cardiovascular disease in end‑stage renal Arterioscler. Thromb. Vasc. Biol. 27, 1596–1602
Lindholm, B. & Stenvinkel, P. Soluble adhesion disease patients. Kidney Int. Suppl. 84, (2007).
molecules in end‑stage renal disease: S172–S176 (2003). 76. Zerbinatti, C. V. & Gore, R. w. Uptake of modified
a predictor of outcome. Nephrol. Dial. Transplant. 60. Bro, S. Cardiovascular effects of uremia in low‑density lipoproteins alters actin distribution
21, 1603–1610 (2006). apolipoprotein E‑deficient mice. Dan. Med. Bull. and locomotor forces in macrophages. Am. J.
44. Serradell, M. et al. Uremic medium causes 56, 177–192 (2009). Physiol. Cell. Physiol. 284, C555–C561 (2003).
expression, redistribution and shedding of 61. Ivanovski, O. et al. The antioxidant 77. Chmielewski, M. et al. Expression of scavenger
adhesion molecules in cultured endothelial cells. N‑acetylcysteine prevents accelerated receptor CD36 in chronic renal failure patients.
Haematologica 87, 1053–1061 (2002). atherosclerosis in uremic apolipoprotein E Artif. Organs 29, 608–614 (2005).
45. Campean, V. et al. CD40–CD154 expression in knockout mice. Kidney Int. 67, 2288–2294 78. wu, C. C. et al. Aberrant activation of the TNF‑α
calcified and non‑calcified coronary lesions of (2005). system and production of Fas and scavenger
patients with chronic renal failure. 62. Boaz, M. et al. Secondary prevention with receptors on monocytes in patients with end‑
Atherosclerosis 190, 156–166 (2007). antioxidants of cardiovascular disease in stage renal disease. Artif. Organs 29, 701–707
46. Sela, S. et al. Primed peripheral endstage renal disease (SPACE): (2005).
polymorphonuclear leukocyte: a culprit randomised placebo‑controlled trial. Lancet 79. Park, Y. M., Febbraio, M. & Silverstein, R. L.
underlying chronic low‑grade inflammation and 356, 1213–1218 (2000). CD36 modulates migration of mouse and human
systemic oxidative stress in chronic kidney 63. Tepel, M., van der Giet, M., Statz, M., macrophages in response to oxidized LDL and
disease. J. Am. Soc. Nephrol. 16, 2431–2438 Jankowski, J. & Zidek, w. The antioxidant may contribute to macrophage trapping in the
(2005). acetylcysteine reduces cardiovascular events in arterial intima. J. Clin. Invest. 119, 136–145
47. Yoon, J. w., Pahl, M. V. & Vaziri, N. D. patients with end‑stage renal failure: (2009).
Spontaneous leukocyte activation and oxygen‑ a randomized, controlled trial. Circulation 107, 80. Harb, D. et al. The role of the scavenger receptor
free radical generation in end‑stage renal 992–995 (2003). CD36 in regulating mononuclear phagocyte
disease. Kidney Int. 71, 167–172 (2007). 64. Himmelfarb, J. et al. Gamma‑tocopherol and trafficking to atherosclerotic lesions and
48. Pahl, M. V., Vaziri, N. D., Yuan, J. & Adler, S. G. docosahexaenoic acid decrease inflammation in vascular inflammation. Cardiovasc. Res. 83,
Upregulation of monocyte/macrophage HGFIN dialysis patients. J. Ren. Nutr. 17, 296–304 42–51 (2009).
(Gpnmb/Osteoactivin) expression in end‑stage (2007). 81. Kuchibhotla, S. et al. Absence of CD36 protects
renal disease. Clin. J. Am. Soc. Nephrol. 5, 56–61 65. Nanayakkara, P. w. et al. Randomized placebo‑ against atherosclerosis in ApoE knock‑out mice
(2010). controlled trial assessing a treatment strategy with no additional protection provided by
49. Himmelfarb, J., Stenvinkel, P., Ikizler, T. A. & consisting of pravastatin, vitamin E, and absence of scavenger receptor A I/II. Cardiovasc.
Hakim, R. M. The elephant in uremia: oxidant homocysteine lowering on plasma asymmetric Res. 78, 185–196 (2008).
stress as a unifying concept of cardiovascular dimethylarginine concentration in mild to 82. Marleau, S. et al. EP 80317, a ligand of the
disease in uremia. Kidney Int. 62, 1524–1538 moderate CKD. Am. J. Kidney Dis. 53, 41–50 CD36 scavenger receptor, protects
(2002). (2009). apolipoprotein E‑deficient mice from developing
50. Kaysen, G. A. & Eiserich, J. P. The role of oxidative 66. Mafra, D. et al. Alpha‑tocopherol atherosclerotic lesions. FASEB J. 19,
stress‑altered lipoprotein structure and function supplementation decreases electronegative 1869–1871 (2005).
and microinflammation on cardiovascular risk in low‑density lipoprotein concentration [LDL(‑)] in 83. Ando, M., Lundkvist, I., Bergström, J. &
patients with minor renal dysfunction. J. Am. Soc. haemodialysis patients. Nephrol. Dial. Lindholm, B. Enhanced scavenger receptor
Nephrol. 15, 538–548 (2004). Transplant. 24, 1587–1592 (2009). expression in monocyte‑macrophages in dialysis
51. Oberg, B. P. et al. Increased prevalence of oxidant 67. Lee, I. M. et al. Vitamin E in the primary patients. Kidney Int. 49, 773–780 (1996).
stress and inflammation in patients with prevention of cardiovascular disease and 84. Kim, H. J., Moradi, H., Yuan, J., Norris, K. &
moderate to severe chronic kidney disease. cancer: the women’s Health Study: Vaziri, N. D. Renal mass reduction results in
Kidney Int. 65, 1009–1016 (2004). a randomized controlled trial. JAMA 294, 56–65 accumulation of lipids and dysregulation of lipid
52. Pupim, L. B., Himmelfarb, J., McMonagle, E., (2005). regulatory proteins in the remnant kidney. Am. J.
Shyr, Y. & Ikizler, T. A. Influence of initiation of 68. Sesso, H. D. et al. Vitamins E and C in the Physiol. Renal Physiol. 296, F1297–F1306
maintenance hemodialysis on biomarkers of prevention of cardiovascular disease in men: (2009).
inflammation and oxidative stress. Kidney Int. the Physicians’ Health Study II randomized 85. Moradi, H., Yuan, J., Ni, Z., Norris, K. &
65, 2371–2379 (2004). controlled trial. JAMA 300, 2123–2133 (2008). Vaziri, N. D. Reverse cholesterol transport
53. D’Apolito, M. et al. Urea‑induced ROS generation 69. Llodrá, J. et al. Emigration of monocyte‑derived pathway in experimental chronic renal failure.
causes insulin resistance in mice with chronic cells from atherosclerotic lesions characterizes Am. J. Nephrol. 30, 147–154 (2009).
renal failure. J. Clin. Invest. 120, 203–213 regressive, but not progressive, plaques. Proc. 86. Zager, R. A., Johnson, A. C., Hanson, S. Y. &
(2010). Natl Acad. Sci. USA 101, 11779–11784 (2004). Shah, V. O. Acute tubular injury causes

52 | JANUARY 2011 | volUme 7 www.nature.com/nrneph


© 2010 Macmillan Publishers Limited. All rights reserved
reViewS

dysregulation of cellular cholesterol transport 104. Tsimikas, S. et al. Oxidized phospholipids, Lp(a) 120. Shoji, T. et al. Advanced atherosclerosis in
proteins. Am. J. Pathol. 163, 313–320 (2003). lipoprotein, and coronary artery disease. N. Engl. predialysis patients with chronic renal failure.
87. Ando, M., Gafvels, M., Bergström, J., J. Med. 353, 46–57 (2005). Kidney Int. 61, 2187–2192 (2002).
Lindholm, B. & Lundkvist, I. Uremic serum 105. Liu, J. & Rosner, M. H. Lipid abnormalities 121. Sone, H. et al. Statins downregulate
enhances scavenger receptor expression and associated with end‑stage renal disease. Semin. ATP‑binding‑cassette transporter A1 gene
activity in the human monocytic cell line U937. Dial. 19, 32–40 (2006). expression in macrophages. Biochem. Biophys.
Kidney Int. 51, 785–792 (1997). 106. Podrez, E. A. et al. Macrophage scavenger Res. Commun. 316, 790–794 (2004).
88. Konishi, Y. et al. Enhanced gene expression of receptor CD36 is the major receptor for LDL 122. Tamehiro, N. et al. Sterol regulatory element‑
scavenger receptor in peripheral blood modified by monocyte‑generated reactive binding protein‑2‑ and liver X receptor‑driven dual
monocytes from patients on cuprophane nitrogen species. J. Clin. Invest. 105, promoter regulation of hepatic ABC transporter
haemodialysis. Nephrol. Dial. Transplant. 12, 1095–1108 (2000). A1 gene expression: mechanism underlying the
1167–1172 (1997). 107. Hörkkö, S., Huttunen, K., Kervinen, K. & unique response to cellular cholesterol status.
89. wang, X. & Rader, D. J. Molecular regulation of Kesäniemi, Y. A. Decreased clearance of J. Biol. Chem. 282, 21090–21099 (2007).
macrophage reverse cholesterol transport. Curr. uraemic and mildly carbamylated low‑density 123. Argmann, C. A. et al. Regulation of macrophage
Opin. Cardiol. 22, 368–372 (2007). lipoprotein. Eur. J. Clin. Invest. 24, 105–113 cholesterol efflux through hydroxymethylglutaryl‑
90. Yvan‑Charvet, L., wang, N. & Tall, A. R. Role of (1994). CoA reductase inhibition: a role for RhoA in
HDL, ABCA1, and ABCG1 transporters in 108. Fellström, B. C. et al. Rosuvastatin and ABCA1‑mediated cholesterol efflux. J. Biol. Chem.
cholesterol efflux and immune responses. cardiovascular events in patients undergoing 280, 22212–22221 (2005).
Arterioscler. Thromb. Vasc. Biol. 30, 139–143 hemodialysis. N. Engl. J. Med. 360, 1395–1407 124. Becker, L. et al. A macrophage sterol‑responsive
(2010). (2009). network linked to atherogenesis. Cell. Metab. 11,
91. Zuo, Y. et al. Renal dysfunction potentiates foam 109. wanner, C. et al. Atorvastatin in patients with 125–135 (2010).
cell formation by repressing ABCA1. Arterioscler. type 2 diabetes mellitus undergoing 125. Qiu, G. & Hill, J. S. Atorvastatin inhibits ABCA1
Thromb. Vasc. Biol. 29, 1277–1282 (2009). hemodialysis. N. Engl. J. Med. 353, 238–248 expression and cholesterol efflux in THP‑1
92. Cardinal, H., Raymond, M. A., Hebert, M. J. & (2005). macrophages by an LXR‑dependent pathway.
Madore, F. Uraemic plasma decreases the 110. Tsimihodimos, V., Dounousi, E. & J. Cardiovasc. Pharmacol. 51, 388–395 (2008).
expression of ABCA1, ABCG1 and cell‑cycle Siamopoulos, K. C. Dyslipidemia in chronic 126. Lewis, E. J., Hunsicker, L. G., Bain, R. P. &
genes in human coronary arterial endothelial kidney disease: an approach to pathogenesis Rohde, R. D. The effect of angiotensin‑
cells. Nephrol. Dial. Transplant. 22, 409–416 and treatment. Am. J. Nephrol. 28, 958–973 converting‑enzyme inhibition on diabetic
(2007). (2008). nephropathy. The Collaborative Study Group.
93. Baranova, I. et al. Lipopolysaccharide down 111. Mekki, K., Bouchenak, M., Remaoun, M. & N. Engl. J. Med. 329, 1456–1462 (1993).
regulates both scavenger receptor B1 and ATP Belleville, J. L. Effect of long‑term hemodialysis 127. Maschio, G. et al. Effect of the
binding cassette transporter A1 in RAw cells. on plasma lecithin: cholesterol acyltransferase angiotensin‑converting‑enzyme inhibitor
Infect. Immun. 70, 2995–3003 (2002). activity and the amounts and compositions of benazepril on the progression of chronic renal
94. Chen, M., Li, w., wang, N., Zhu, Y. & wang, X. HDL2 and HDL3 in hemodialysis‑treated insufficiency. The Angiotensin‑Converting‑Enzyme
ROS and NF‑κB but not LXR mediate IL‑1β patients with chronic renal failure: a 9‑year Inhibition in Progressive Renal Insufficiency
signaling for the downregulation of ATP‑binding longitudinal study. Med. Sci. Monit. 10, Study Group. N. Engl. J. Med. 334, 939–945
cassette transporter A1. Am. J. Physiol. Cell. CR439–CR446 (2004). (1996).
Physiol. 292, C1493–C1501 (2007). 112. Moradi, H., Pahl, M. V., Elahimehr, R. & 128. Baker, w. L. et al. Systematic review:
95. Ferreira, V. et al. Macrophage‑specific inhibition Vaziri, N. D. Impaired antioxidant activity of high‑ comparative effectiveness of angiotensin‑
of NF‑κB activation reduces foam‑cell formation. density lipoprotein in chronic kidney disease. converting enzyme inhibitors or angiotensin
Atherosclerosis 192, 283–290 (2007). Transl. Res. 153, 77–85 (2009). II‑receptor blockers for ischemic heart disease.
96. Tang, C., Kanter, J. E., Bornfeldt, K. E., 113. Gugliucci, A. et al. Acrolein inactivates Ann. Intern. Med. 151, 861–871 (2009).
Leboeuf, R. C. & Oram, J. F. Diabetes reduces paraoxonase 1: changes in free acrolein levels 129. Yusuf, S. et al. Effects of an
the cholesterol exporter ABCA1 in mouse after hemodialysis correlate with increases in angiotensin‑converting‑enzyme inhibitor, ramipril,
macrophages and kidneys. J. Lipid Res. 51, paraoxonase 1 activity in chronic renal failure on cardiovascular events in high‑risk patients.
1719–1728 (2010). patients. Clin. Chim. Acta 384, 105–112 (2007). The Heart Outcomes Prevention Evaluation
97. wang, Y., Kurdi‑Haidar, B. & Oram, J. F. LXR‑ 114. Gugliucci, A. et al. Paraoxonase‑1 concentrations Study Investigators. N. Engl. J. Med. 342,
mediated activation of macrophage stearoyl‑CoA in end‑stage renal disease patients increase 145–153 (2000).
desaturase generates unsaturated fatty acids after hemodialysis: correlation with low 130. Ayabe, N. et al. Transiently heightened
that destabilize ABCA1. J. Lipid Res. 45, molecular AGE adduct clearance. Clin. Chim. Acta angiotensin II has distinct effects on
972–980 (2004). 377, 213–220 (2007). atherosclerosis and aneurysm formation in
98. Bohlender, J. M., Franke, S., Stein, G. & wolf, G. 115. Jurek, A., Turyna, B., Kubit, P. & Klein, A. LDL hyperlipidemic mice. Atherosclerosis 184,
Advanced glycation end products and the kidney. susceptibility to oxidation and HDL antioxidant 312–321 (2006).
Am. J. Physiol. Renal Physiol. 289, F645–F659 capacity in patients with renal failure. Clin. 131. da Cunha, V. et al. Angiotensin II induces
(2005). Biochem. 39, 19–27 (2006). histomorphologic features of unstable plaque in
99. Pedersen, T. X. et al. Effect of treatment with 116. Kalantar‑Zadeh, K., Kopple, J. D., a murine model of accelerated atherosclerosis.
human apolipoprotein A‑I on atherosclerosis in Kamranpour, N., Fogelman, A. M. & Navab, M. J. Vasc. Surg. 44, 364–371 (2006).
uremic apolipoprotein‑E deficient mice. HDL‑inflammatory index correlates with poor 132. da Cunha, V. et al. Enalapril attenuates
Atherosclerosis 202, 372–381 (2009). outcome in hemodialysis patients. Kidney Int. angiotensin II‑induced atherosclerosis and
100. Francone, O. L. et al. Increased cholesterol 72, 1149–1156 (2007). vascular inflammation. Atherosclerosis 178,
deposition, expression of scavenger receptors, 117. Kronenberg, F., Ikewaki, K., Schaefer, J. R., 9–17 (2005).
and response to chemotactic factors in Abca1‑ Konig, P. & Dieplinger, H. Kinetic studies of 133. Daugherty, A., Manning, M. w. & Cassis, L. A.
deficient macrophages. Arterioscler. Thromb. atherogenic lipoproteins in hemodialysis Angiotensin II promotes atherosclerotic lesions
Vasc. Biol. 25, 1198–1205 (2005). patients: do they tell us more about their and aneurysms in apolipoprotein E‑deficient
101. Zhu, X. et al. Increased cellular free cholesterol pathology? Semin. Dial. 20, 554–560 (2007). mice. J. Clin. Invest. 105, 1605–1612 (2000).
in macrophage‑specific Abca1 knock‑out mice 118. Vaziri, N. D., Moradi, H., Pahl, M. V., 134. Sasaki, T. et al. AT1 blockade attenuates
enhances pro‑inflammatory response of Fogelman, A. M. & Navab, M. In vitro stimulation atherosclerotic plaque destabilization
macrophages. J. Biol. Chem. 283, 22930–22941 of HDL anti‑inflammatory activity and inhibition accompanied by the suppression of cathepsin S
(2008). of LDL pro‑inflammatory activity in the plasma of activity in apoE‑deficient mice. Atherosclerosis
102. Gollapudi, P., Yoon, J. w., Gollapudi, S., Pahl, M. V. patients with end‑stage renal disease by an 210, 430–437 (2010).
& Vaziri, N. D. Leukocyte toll‑like receptor apoA‑1 mimetic peptide. Kidney Int. 76, 135. Xu, H. X. et al. Decreased infiltration of
expression in end‑stage kidney disease. Am. J. 437–444 (2009). macrophages and inhibited activation of nuclear
Nephrol. 31, 247–254 (2010). 119. wong, J., Quinn, C. M., Gelissen, I. C., Jessup, w. factor‑kappa B in blood vessels: a possible
103. Kuroki, Y. et al. A study of innate immunity in & Brown, A. J. The effect of statins on ABCA1 mechanism for the anti‑atherogenic effects of
patients with end‑stage renal disease: special and ABCG1 expression in human macrophages losartan. Acta Cardiol. 62, 607–613 (2007).
reference to toll‑like receptor‑2 and ‑4 expression is influenced by cellular cholesterol levels and 136. Nobuhiko, A. et al. Angiotensin II amplifies
in peripheral blood monocytes of hemodialysis extent of differentiation. Atherosclerosis 196, macrophage‑driven atherosclerosis. Arterioscler.
patients. Int. J. Mol. Med. 19, 783–790 (2007). 180–189 (2008). Thromb. Vasc. Biol. 24, 2143–2148 (2004).

nature reviews | nephrology volume 7 | JanuarY 2011 | 53


© 2010 Macmillan Publishers Limited. All rights reserved
reViewS

137. Blessing, E. et al. Anti‑atherosclerotic properties 150. Nakaya, K. et al. Telmisartan enhances randomized, controlled study. Ann. Intern. Med.
of telmisartan in advanced atherosclerotic cholesterol efflux from THP‑1 macrophages by 139, 105–112 (2003).
lesions in apolipoprotein E deficient mice. activating PPARγ. J. Atheroscler. Thromb. 14, 162. Zannad, F. et al. Prevention of cardiovascular
Atherosclerosis 199, 295–303 (2008). 133–141 (2007). events in end‑stage renal disease: results of a
138. Takahashi, M. et al. Angiotensin II and tumor 151. Takata, Y. et al. Transcriptional repression of ATP‑ randomized trial of fosinopril and implications for
necrosis factor‑α synergistically promote binding cassette transporter A1 gene in future studies. Kidney Int. 70, 1318–1324
monocyte chemoattractant protein‑1 expression: macrophages: a novel atherosclerotic effect of (2006).
roles of NF‑κB, p38, and reactive oxygen angiotensin II. Circ. Res. 97, e88–e96 (2005). 163. Akbari, A. et al. Angiotensin‑converting enzyme
species. Am. J. Physiol. Heart Circ. Physiol. 294, 152. wang, Y. et al. Angiotensin II increases the inhibitors and angiotensin receptor blockers in
H2879–H2888 (2008). cholesterol content of foam cells via down‑ peritoneal dialysis: systematic review and meta‑
139. Daugherty, A., Rateri, D. L., Lu, H., Inagami, T. & regulating the expression of ATP‑binding analysis of randomized controlled trials. Perit.
Cassis, L. A. Hypercholesterolemia stimulates cassette transporter A1. Biochem. Biophys. Res. Dial. Int. 29, 554–561 (2009).
angiotensin peptide synthesis and contributes Commun. 353, 650–654 (2007). 164. Balamuthusamy, S. et al. Renin angiotensin
to atherosclerosis through the AT1A receptor. 153. Takaya, T. et al. Angiotensin II type 1 receptor system blockade and cardiovascular outcomes
Circulation 110, 3849–3857 (2004). blocker telmisartan suppresses superoxide in patients with chronic kidney disease and
140. Okamura, A. et al. Upregulation of renin– production and reduces atherosclerotic lesion proteinuria: a meta‑analysis. Am. Heart J. 155,
angiotensin system during differentiation of formation in apolipoprotein E‑deficient mice. 791–805 (2008).
monocytes to macrophages. J. Hypertens. 17, Atherosclerosis 186, 402–410 (2006). 165. Berger, A. K., Duval, S. & Krumholz, H. M. Aspirin,
537–545 (1999). 154. Yoshiyama, M. et al. Angiotensin blockade beta‑blocker, and angiotensin‑converting enzyme
141. Sales, V. L. et al. Angiotensin type 2 receptor is inhibits increased JNKs, AP‑1 and NF‑κB DNA‑ inhibitor therapy in patients with end‑stage renal
expressed in murine atherosclerotic lesions and binding activities in myocardial infarcted rats. disease and an acute myocardial infarction.
modulates lesion evolution. Circulation 112, J. Mol. Cell. Cardiol. 33, 799–810 (2001). J. Am. Coll. Cardiol. 42, 201–208 (2003).
3328–3336 (2005). 155. Calkin, A. C. et al. The HMG‑CoA reductase 166. Efrati, S. et al. ACE inhibitors and survival of
142. Montecucco, F., Pende, A. & Mach, F. The renin– inhibitor rosuvastatin and the angiotensin hemodialysis patients. Am. J. Kidney Dis. 40,
angiotensin system modulates inflammatory receptor antagonist candesartan attenuate 1023–1029 (2002).
processes in atherosclerosis: evidence from atherosclerosis in an apolipoprotein E‑deficient 167. Fang, w., Oreopoulos, D. G. & Bargman, J. M.
basic research and clinical studies. Mediators mouse model of diabetes via effects on Use of ACE inhibitors or angiotensin receptor
Inflamm. doi:10.1155/2009/752406. advanced glycation, oxidative stress and blockers and survival in patients on peritoneal
143. AbdAlla, S., Lother, H., Langer, A., el Faramawy, Y. inflammation. Diabetologia 51, 1731–1740 dialysis. Nephrol. Dial. Transplant. 23,
& Quitterer, U. Factor XIIIA transglutaminase (2008). 3704–3710 (2008).
crosslinks AT1 receptor dimers of monocytes at 156. Koh, K. K., Han, S. H., Oh, P. C., Shin, E. K. & 168. Hou, F. F. et al. Efficacy and safety of benazepril
the onset of atherosclerosis. Cell 119, 343–354 Quon, M. J. Combination therapy for treatment or for advanced chronic renal insufficiency. N. Engl.
(2004). prevention of atherosclerosis: focus on the lipid– J. Med. 354, 131–140 (2006).
144. Dörffel, Y. et al. Preactivated monocytes from RAAS interaction. Atherosclerosis 209, 307–313 169. McCullough, P. A., Sandberg, K. R., Yee, J. &
hypertensive patients as a factor for (2010). Hudson, M. P. Mortality benefit of angiotensin‑
atherosclerosis? Atherosclerosis 157, 151–160 157. Van Antwerpen, P. et al. Captopril inhibits the converting enzyme inhibitors after cardiac events
(2001). oxidative modification of apolipoprotein B‑100 in patients with end‑stage renal disease. J. Renin
145. Cassis, L. A., Rateri, D. L., Lu, H. & Daugherty, A. caused by myeloperoxydase in a comparative Angiotensin Aldosterone Syst. 3, 188–191
Bone marrow transplantation reveals that in vitro assay of angiotensin converting enzyme (2002).
recipient AT1a receptors are required to initiate inhibitors. Eur. J. Pharmacol. 537, 31–36 (2006). 170. Suzuki, H. et al. Effect of angiotensin receptor
angiotensin II‑induced atherosclerosis and 158. Kojima, C., Ino, J., Ishii, H., Nitta, K. & blockers on cardiovascular events in patients
aneurysms. Arterioscler. Thromb. Vasc. Biol. 27, Yoshida, M. MMP‑9 inhibition by ACE inhibitor undergoing hemodialysis: an open‑label
380–386 (2007). reduces oxidized LDL‑mediated foam‑cell randomized controlled trial. Am. J. Kidney Dis. 52,
146. Fukuda, D., Sata, M., Ishizaka, N. & Nagai, R. formation. J. Atheroscler. Thromb. 17, 97–105 501–506 (2008).
Critical role of bone marrow angiotensin II type 1 (2010). 171. Takahashi, A. et al. Candesartan, an angiotensin II
receptor in the pathogenesis of atherosclerosis 159. de Nigris, F. et al. Chronic treatment with type‑1 receptor blocker, reduces cardiovascular
in apolipoprotein E deficient mice. Arterioscler. sulfhydryl angiotensin‑converting enzyme events in patients on chronic haemodialysis—a
Thromb. Vasc. Biol. 28, 90–96 (2008). inhibitors reduce susceptibility of plasma LDL to randomized study. Nephrol. Dial. Transplant. 21,
147. Lu, H. et al. Renin inhibition reduces in vitro oxidation, formation of oxidation‑specific 2507–2512 (2006).
hypercholesterolemia‑induced atherosclerosis in epitopes in the arterial wall, and atherogenesis
mice. J. Clin. Invest. 118, 984–993 (2008). in apolipoprotein E knockout mice. Int. J. Cardiol. Acknowledgments
148. Tsubakimoto, Y. et al. Bone marrow angiotensin 81, 107–115 (2001). The authors’ work described in this Review was
AT1 receptor regulates differentiation of 160. Tokmakova, M. P. et al. Chronic kidney disease, supported in part by grants from NIH HL087061
monocyte lineage progenitors from cardiovascular risk, and response to (V. Kon) and DK044757 (V. Kon and S. Fazio),
hematopoietic stem cells. Arterioscler. Thromb. angiotensin‑converting enzyme inhibition after HL086988 and HL065405 (M. F. Linton), HL65709
Vasc. Biol. 29, 1529–1536 (2009). myocardial infarction: the Survival And and HL57986 (S. Fazio), and the Lipid, Lipoprotein
149. Ulrich, C., Heine, G. H., Seibert, E., Fliser, D. & Ventricular Enlargement (SAVE) study. Circulation and Atherosclerosis Core of the Vanderbilt Mouse
Girndt, M. Circulating monocyte subpopulations 110, 3667–3673 (2004). Metabolic Phenotyping Center (NIH DK59637‑01).
with high expression of angiotensin‑converting 161. Li, P. K., Chow, K. M., wong, T. Y., Leung, C. B. &
enzyme predict mortality in patients with end‑ Szeto, C. C. Effects of an angiotensin‑converting Author contributions
stage renal disease. Nephrol. Dial. Transplant. enzyme inhibitor on residual renal function in V. Kon, M. F. Linton and S. Fazio contributed equally to
25, 2265–2272 (2010). patients receiving peritoneal dialysis. A all aspects of this manuscript.

54 | JANUARY 2011 | volUme 7 www.nature.com/nrneph


© 2010 Macmillan Publishers Limited. All rights reserved

You might also like