review
org
Oxidative stress and inflammation, a link between
chronic kidney disease and cardiovascular disease
Victoria Cachofeiro1, Marian Goicochea2, Soledad Garcı́a de Vinuesa2, Pilar Oubiña1, Vicente Lahera1
and José Luño2
1
Departement of Physiology, School of Medicine, Universidad Complutense, Madrid, Spain and 2Department of Nephrology, Hospital
General Universitario Gregorio Marañon, Madrid, Spain
Patients with chronic kidney disease (CKD) show a high
cardiovascular morbidity and mortality. This seems to be
consequence of the cardiovascular risk factor clustering in
CKD patients. Non traditional risk factors such as oxidative
stress and inflammation are also far more prevalent in this
population than in normal subjects. Renal disease is
associated with a graded increase in oxidative stress markers
even in early CKD. This could be consequence of an increase
in reactive oxygen species as well as a decrease in
antioxidant defence. This oxidative stress can accelerate renal
injury progression. Inflammatory markers such as C reactive
protein and cytokines increase with renal function
deterioration suggesting that CKD is a low-grade
inflammatory process. In fact, inflammation facilitates renal
function deterioration. Several factors can be involved in
triggering the inflammatory process including oxidative
stress. Statin administration is accompanied by risk reduction
in all major vascular events in patients with CKD that are
considered high-risk patients. These beneficial effects seem
to be consequence of not only their hypolipidemic effect but
especially their pleitropic actions that involve modulation of
oxidative stress and inflammation.
Kidney International (2008) 74 (Suppl 111), S4–S9; doi:10.1038/ki.2008.516
KEYWORDS: chronic kidney disease; dyslipemia; inflammation; oxidative
stress; statin
Correspondence: Victoria Cachofeiro, Departamento de Fisiologı´a, Facultad
de Medicina, Universidad Complutense, Madrid 28040, Spain.
E-mail: vcara@med.ucm.es
S4
http://www.kidney-international.
& 2008 International Society of Nephrology
THE LINK BETWEEN CARDIOVASCULAR DISEASE AND
CHRONIC KIDNEY DISEASE: ATHEROSCLEROTIC PROCESS
Cardiovascular disease is the leading cause of worldwide
mortality not only in the general population but also in
individuals with chronic kidney disease (CKD).1,2 This
increased cardiovascular morbidity and mortality is
presented across the whole renal dysfunction spectrum even
in patients with moderate renal insufficiency (glomerular
filtration rate (GFR) o60 ml/min per 1.73 m2). In fact, most
patients with CKD (stage 3–4) die of cardiovascular causes
rather than progress to end-stage renal disease in which
cardiovascular mortality is 15–30% times higher than the
age-adjusted control groups.3 This high risk of cardiovascular
disease seems to be the consequence of a higher prevalence of
risk factors in patients with CKD than in the general
population.1,3,4 In fact, an inverse correlation has been
reported between the presence of risk factors and the
glomerular filtration rate.3 This explains why the Seventh
Report of the Joint National Committee on Prevention,
Detection, Evaluation, and Treatment of High Blood Pressure
and the National Kidney Foundation considered both CKD
to have the same risk level as coronary disease and patients to
be high-risk patients.5,6
Atherosclerosis is a diffuse arterial disease triggered in
response to various insults such as dyslipemia, which is very
prevalent in CKD patients, and is the main cause of
cardiovascular disease.4,7 This is mainly characterized both
by low levels of high-density lipoproteins and increased
plasma triglycerides because of the accumulation of very
low-density lipoprotein (LDL) and intermediate-density
lipoproteins.7 Oxidative stress, endothelial dysfunction, and
inflammation represent a key triad serving as the foundation
for the development and progression of atherosclerosis.8–10
An increase in oxidative stress favors endothelial dysfunction
by reducing nitric oxide availability and subsequent beneficial
effects on vascular function.11 In these conditions, vascular
permeability changes and allows for the entrance of LDL
cholesterol into the intima, where it is oxidized and
transformed into a highly atherogenic molecule that initiates
an inflammatory process in the vessel.9,10 This results in the
Kidney International (2008) 74 (Suppl 111), S4–S9
V Cachofeiro et al.: Oxidative stress and inflammation in chronic kidney disease
expression of leukocyte adhesion molecules and subsequent
binding of circulating inflammatory cells and their migration
into the subendothelial space. Monocytes are transformed
into foam cells by taking up oxidized LDL and forming
a fatty streak, the earliest structural change in the
atherosclerotic process.10 As lesions progress, smooth muscle
cells migrate from the media to the intima where they
proliferate and produce extracellular matrix such as collagen
and elastin in response to different growth factors. This leads
to the formation of a fibrous cap that encloses and defines the
morphology of the atherosclerotic lesion while protecting it
from circulating blood.12 Plaque rupture is triggered by acute
inflammatory processes that favor the release of modulators
of extracellular matrix from macrophages and other inflam-
matory cells and subsequent cap weakening.13 Once the
plaque ruptures, contact between the procoagulant lipid core
and blood is accommodated, thus leading to thrombus
formation associated with clinical outcomes such as stroke
and myocardial infarction.13,14
OXIDATIVE STRESS STATUS AND RENAL FUNCTION
DETERIORATION
Oxidative stress can be considered an imbalance in the
reactive oxygen species (ROS) production/degradation ratio.
Under normal conditions, ROS (which include various
compounds such as superoxide anions, hydrogen peroxide,
and hydroxyl radical) are produced in mammalian cells
during energy production in mitochondria by reducing
oxygen during aerobic respiration.15 In addition, a variety of
enzymatic and nonenzymatic sources of ROS exist in vascular
vessels as well as different tissues, among which can be
included nicotinamide dinucleotide (phosphate) (NAD(P)H
oxidase enzyme complex, xanthine oxidase, lipoxygenases,
and cyclooxygenases.16 An uncoupling of nitric oxide
synthase (the enzyme involved in nitric oxide production)
owing to the reduction of its cofactor, BH4, can also
contribute to ROS production.17 ROS levels are maintained
at a normal range by scavenging through various enzyme
activities such as superoxide dismutase, catalase, glutathione
peroxidase, and other components (which constitute en-
dogenous antioxidant defenses) such as reduced glutathione,
transition metal ions, and ascorbic acid.18 ROS are part of the
organism’s unspecified defense system. However, excessive
ROS levels can produce cellular damage by interacting with
biomolecules (proteins, lipids, and nucleic acids) and thus
have negative effects on tissue function and structure. As
such, they are implicated in different pathological situations
including a variety of renal diseases.19
Renal dysfunction is frequently associated with oxidative
stress, as levels of different markers including plasma F2-
isoprostanes, advanced oxidation protein products, and
malonyldialdehyde are increased in patients with varying
degrees of renal function, including patients with end-stage
renal failure.20–22 In addition, high levels of oxidized LDL
have been reported.7,23 This increase in oxidized LDL can
favor the atherosclerotic process and seems not to be the
Kidney International (2008) 74 (Suppl 111), S4–S9
review
consequence of higher susceptibility to oxidation of circulat-
ing LDL particles from renal patients, as they showed
sensitivity to copper-induced oxidation similar to those
obtained from matched controls.23 It appears that ROS
increase in a graded manner as renal function deteriorates, as
different studies have reported inverse correlations between
different markers of oxidative stress and glomerular filtration
rate.20,24 In addition, graded increases in oxidative stress have
been reported with increasingly longer durations of dialysis
therapy,22 thus suggesting that oxidative stress could accel-
erate renal injury progression by inducing cytotoxicity. In
agreement with this is the observation that plasma malonyl-
dialdehyde values are accompanied by increases in renal
malonyldialdehyde levels in rats with renal mass reduction,
suggesting that plasma ROS levels could reflect local ROS
production in kidneys.25 The presence of other pro-oxidant
states such as diabetes mellitus, dyslipemia, hypertension,
and aging,7,16,26 commonly present in the CKD population,3
or even intravenous iron administration for correcting
anemia can further aggravate oxidative stress status asso-
ciated with uremia.27
Oxidative stress in uremia might be the consequence of
higher ROS production. This affirmation is based on the fact
that increases in NAD(P)H oxidase activity or expression has
been reported in patients and models with renal insuffi-
ciency28,29 even in early CKD.28 In addition, the presence of
p22phox subunit gene polymorphism ( þ 242 C/T) of
NAD(P)H oxidase is associated with oxidative stress in
patients with CKD,30 with individuals having CC genotype
presenting with higher oxidative stress status. This poly-
morphism has also been associated with complications such
as dialysis requirement and death in patients with acute renal
failure.31 Whether impaired antioxidant defense becoming
overwhelmed by ROS production participates in oxidative
stress in uremic patients is unclear, as a variety of results have
been reported.19–21 In a recent study, we aimed to evaluate
oxidative stress status in patients with CKD (age: 66.2±13.6
years) stages 2–4 with glomerular filtration rate in the range
of 15–90 ml/min. As expected, patients with CKD showed
higher plasma lipid hydroperoxide and oxidized LDL levels
than control subjects, which implies altered oxidative stress
status (Figure 1). However, no differences are observed in
the plasma total antioxidant capacity (TAC) as compared
with patients with normal function (Figure 1). Similarly,
Karamouzis et al.21 have found that TAC levels remain stable
with renal function loss in spite of a gradual isoprostanoid
increase. TAC level reduction, in fact, was observed only in
patients with end-stage renal failure.21 However, level
reductions in plasma or intracellular antioxidant factors such
as superoxide dismutase, catalase, glutathione peroxidase,
reduced intracellular glutathione, and plasma thiol19,20,27
have been reported in patients with CKD. This apparent
discrepancy can be explained by the fact that TAC quantifies
levels of aqueous and lipid soluble antioxidant activities such
as vitamins (E and C), proteins, lipid, glutathione, and uric
acid. Therefore, the uric acid increases produced in uremic
S5
review
20
*
LPO (µM)
§
10
0 0
CT CKD CKD+ATV
150 * §
ox-LDL (IU)
75
0
CT CKD CKD+ATV
3
TAC (nM)
1 5
0
CT CKD CKD+ATV
Figure 1 | Bars represent plasma levels of lipid hydroperoxide
(LPO, upper panel), oxidized low-density lipoprotein
cholesterol (ox-LDL, middle panel), and total antioxidant
capacity (TAC, lower panel) in subjects with normal renal
function (CT) or patients with chronic kidney disease
(CKD, stages 2–4) at baseline or after 6 months (CDK-ATV)
with atorvastatin treatment (20 mg/day). Data are
average±s.d. *Po0.001 vs CT; yPo0.05 vs CDK.
states could compensate for potential decreases in other
antioxidant defense factors, such as vitamins, because of the
malnutrition that these patients face.32
CHRONIC KIDNEY DISEASE: AN INFLAMMATORY STATE
Inflammatory response is not only a local process but it can
also be reflected systemically, as it is accompanied by
increases in inflammatory markers including acute phase
proteins, cytokines, and adhesion molecules. Evaluation of
these markers has been suggested as a useful tool from a
clinical point of view. In recent years, the role of some of
these markers, such as C-reactive protein (CRP), IL-6, serum
ameloid type A, TNF-a, adhesion molecules, and CD 40
ligand, has been evaluated regarding their prognostic value in
normal patients as well as patients with cardiovascular
disease. Numerous studies have reported an association
between renal impairment and different mediators and
markers of inflammation including CRP, IL-6, TNF-a, and
fibrinogen, even among patients with moderate renal
impairment, suggesting that CKD is a low-grade inflamma-
tory process33–36 with peripheral polymorphonuclear leuko-
cyte and CD14 þ /CD16 þ cells being key mediators in this
process.37,38 In fact, persistent inflammation may also be a
risk factor per se for progression of CKD, as inflammatory
markers are predictors of kidney function deterioration.39
This could be a consequence of inflammatory mediators such
S6
V Cachofeiro et al.: Oxidative stress and inflammation in chronic kidney disease
8
* 7,1
CRP (mg/l)
6
4 4,1
3,2
2 2,5
1,5
1
CT CKD
3
IL-1β (pg/ml)
2
1
0
CT CKD
10
*
TNF-α (pg/ml)
0
CT CKD
Figure 2 | Line segments and bar represent plasma levels of
C-reactive protein (CRP upper panel), interleukin 1b (IL-1b,
middle panel), and tumor necrosis factor-a (TNF-a, lower
panel) in subjects with normal renal function (CT) or patients
with chronic kidney disease (CKD, stages 2–4). Data are
average±s.d. or median (25th–75th percentile, in the case of CRP).
*Po0.001 vs CT.
as TNF-a or IL-6 being able to act as toxins participating in
uremia complications.40 In addition, CRP formed locally in
the renal inflammatory process41 reduces nitric oxide
production, stimulates endothelin-1 formation, and induces
some of the steps involved in the atherosclerosis process
(monocyte recruitment and foam cell formation).42
Moreover, it has been shown that elevated CRP, IL-6, and
fibrinogen are independent predictors of cardiovascular
outcomes in patients with CKD,36 as already reported, not
only in patients with stable and unstable angina, but also in
apparently healthy patients.42 It is thus possible that
inflammation could promote both renal deterioration
(triggering endothelial dysfunction, atherosclerosis, and
glomerular injury) and cardiovascular mortality.
Although precise mechanisms that contribute to the high
prevalence of inflammation in CKD are not well established,
ROS have been proposed as potential contributors to
inflammation when renal function declines.
Inflammation is a redox-sensitive mechanism, as oxidative
stress is able to activate transcriptor factors such as NF-kB,
which regulates inflammatory mediator gene expression.43
NF-kB is a dimer factor maintained inactivated in the
cytoplasm by binding to inhibitory proteins (members of
I-kB family). Their phosphorylation, posterior ubiquitina-
tion, and proteolysis result in the release and translocation of
NF-kB to the nucleus and consequent activation of specific
Kidney International (2008) 74 (Suppl 111), S4–S9
V Cachofeiro et al.: Oxidative stress and inflammation in chronic kidney disease
genes. Some of these steps, such as phospholyration and
degradation of I-kB system, seem to be affected by oxidative
stress as the presence of antioxidants prevents NF-kB
activation by ROS.43,44 Similarly, reduced glutathione deple-
tion facilitates its activation.44 To explore this aspect, we have
evaluated inflammatory markers as well as markers of
oxidative stress in a group of patients (age: 67.2.0±13.8
years) with CKD stages 2–4 (eGFR: 42.8±24.9 ml/min). As
expected, renal dysfunction was accompanied by higher levels
of lipid hydroperoxide and oxidized LDL as compared with
subjects with normal function. In addition, we have observed
higher CRP, TNF-a, and IL-1b levels in uremic patients
than in age-matched subjects with normal renal function
(Figure 2). A correlation was also found between oxidized
LDL and CRP (r2 ¼ 0.47; Po0.046), supporting the
inflammation oxidative stress link. Autonomic dysfunction,
malnutrition, volume overload, and genetic factors have been
implicated in this inflammation process.36
STATINS AND CHRONIC KIDNEY DISEASE
Primary (The West of Scotland Coronary Prevention Study,
Air Force/Texas Coronary Atherosclerosis Prevention Study)
and secondary (The Scandinavian Simvastatin Survival
Study, The Cholesterol and Recurrent Events Study, The
Long-term Intervention with Pravastatin in Ischaemic
Disease Trial, Pravastatin Pooling Project, The Heart Protec-
tion Study) prevention trials with statins have shown that
reducing lipid concentrations is accompanied by a reduction
in risk of all major vascular events. Although the number of
studies evaluating the effect of statins in patients with
renal failure has been limited, post hoc analysis of large
trials such as The Anglo Scandinavian Cardiac Outcomes
Trial, The Cholesterol and Recurrent Events Study, and
Pravastatin Pooling Project have suggested that statins reduce
cardiovascular outcomes in patients with impaired renal
function (mainly stages 2 and 3), and that this benefit
increases as renal function declines.45 A similar observation
has also been made in the Assessment of LEscol in Renal
Transplantation Trial in patients who received renal
transplants and where fluvastatin administration reduced
the risk of a first major adverse cardiac event.46 However, this
benefit seems to be limited in hemodialysis patients. In the
prospective 4D study that included patients with type 2
diabetes on hemodialysis for o2 years, atorvastatin for 4
years was not able to improve cardiovascular outcomes
(cardiac death, fatal myocardial infarction, stroke) despite an
important LDL cholesterol decrease (42%).47 The reasons for
this unexpected failure are unclear but might derive from
complex pathophysiological mechanisms involved in end-
stage renal disease.
Statins reduce cholesterol synthesis by inhibiting
3-hydroxy-3-methyl-glutaryl-CoA reductase, which is also
involved in isoprenoid compound formations such as
farnesylpyrophosphate and geranylgeranylpyrophosphate
(both involved in post-transcriptional protein modifica-
tions). Isoprenylation blockade has been implicated in
Kidney International (2008) 74 (Suppl 111), S4–S9
review
statin pleitropic effects, which are involved in modulation/
prevention of endothelial dysfunction, inflammatory
process, and oxidative stress. Furthermore, experimental
studies have indicated that statins may reduce renal injury
associated with hypertension.48 These lipid-independent
effects have been shown by numerous studies in patients
with normal renal function. However, there is little informa-
tion regarding the antioxidant and anti-inflammatory effects
of statins in patients with CKD. Therefore, we aimed to
evaluate the effect of atorvastatin (20 mg/day for 6 months)
on markers of inflammation and oxidative stress in patients
with CKD (stages 2–4, 44 patients), estimated glomerular
filtration rate (42.8±24.9 ml/min), serum total levels
(229.4±24.7 mg 100 ml), and LDL cholesterol levels
(147.1±20.2 mg 100 ml). The reduction in total (22%) and
LDL (32%) cholesterol levels induced by atorvastatin
administration was accompanied by reduction (40%) in
plasma levels of CRP.35 Similar CRP level decreases have been
reported with other statins in dialysis and nondialysis CKD
patients.49,50 This reduction was also observed with other
inflammatory markers such as IL 1-b (38%) and TNF-a
(26%),35 and it seems to be independent of concomitant
treatment (83% were taking renin–angiotensin system block-
ers) as patients kept their pharmacologic schedule during the
study. Changes in CRP and cholesterol levels during the study
were not correlated, suggesting that the effect of atorvastatin
on inflammatory markers in CKD patients seems to be
independent of its lipid-lowering action. This is a patient of
intense discussion as both favorable and unfavorable data on
this dependency have been reported in dyslipemic patients
with normal renal function.51–53 Inflammatory marker
reduction was accompanied by oxidative stress amelioration
as suggested by lipid hydroperoxide and oxidized LDL level
reductions (Figure 1), supporting the inflammatory-oxida-
tive stress link. A similar reduction in other oxidative stress
markers (8 hydroxy-2-deoxyguanosine) has been observed
with lovastatin (20 mg/day for 6 months) in HD patients.
This suggests that statins exert antioxidant action in patients
with differing degrees of renal impairment, as has already
been reported in patients with normal renal function. This
improvement seems to be a consequence of ROS synthesis
reduction by preventing NAD(P)H oxidase activation48
rather than by increasing antioxidant defense because no
changes in TAC were observed. However, lovastatin was also
able to improve TAC in HD patients in whom it had earlier
been reduced.54 Therefore, the data suggest that statins can
improve the oxidative stress in CKD acting on the ROS
production/degradation ratio.
In summary, cardiovascular morbid-mortality is higher in
CKD patients than in the general population. This is partially
explained by the high cardiovascular risk factor clustering
that these patients exhibit. Dyslipemia, oxidative stress, and
inflammation, all of which favor the atherosclerotic process
(the main cause of cardiovascular disease), outline a
common scenario in renal impairment. Therefore, drugs
such as statins exert not only hypolipidemic effects but also
S7
review V Cachofeiro et al.: Oxidative stress and inflammation in chronic kidney disease
lipid-independent actions, which in turn involve oxidative
stress/inflammation modulation, and have a potential benefit
in CKD.
DISCLOSURE
José Luño has received lecture fees from Boehringer and Pfizer.
Soledad Garcı́a de Vinuesa has received grant support from Pfizer.
The remaining authors have declared no financial interests.
REFERENCES
1. Berl T, Henrich W. Kidney-heart interactions: epidemiology, pathogenesis,
and treatment. Clin J Am Soc Nephrol 2006; 1: 8–18.
2. Fried LF, Shlipak MG, Crump C et al. Renal insufficiency as a predictor of
cardiovascular outcomes and mortality an elderly individuals. J Am Coll
Cardiol 2003; 41: 1364–1372.
3. Sarnak MJ, Levey AS, Schoolwerth AC et al. Kidney disease as a risk factor
for development of cardiovascular disease: a statement from the
American Heart Association Councils on Kidney in Cardiovascular Disease,
High Blood Pressure Research, Clinical Cardiology, and Epidemiology and
Prevention. Hypertension 2003; 42: 1050–1065.
4. Schiffrin EL, Lipman ML, Mann JFE. Chronic kidney disease. Effects on the
cardiovascular system. Circulation 2007; 116: 85–97.
5. Chobanian AV, Barkris GL, Black HR et al. Seventh Report of the Joint
National Committee on Prevention, Detection, Evaluation, and Treatment
of High Blood Pressure. Hypertension 2003; 42: 1206–1252.
6. Mitka M. Guidelines offer ‘roadmap’ for chronic kidney disease. JAMA
2002; 287: 973.
7. Diepeveen SH, Wetzels JF, Bilo HJ et al. Cholesterol in end-stage renal
disease: the good, the bad or the ugly? Neth J Med 2008; 66: 53–61.
8. Heitzer T, Schlinzig T, Krohn K et al. Endothelial dysfunction, oxidative
stress, and risk of cardiovascular events in patients with coronary artery
disease. Circulation 2001; 104: 2673–2678.
9. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease.
N Engl J Med 2005; 352: 1685–1695.
10. Libby P. Inflammation in atherosclerosis. Nature 2002; 420: 868–874.
11. Münzel T, Just H, Harrison DG. The physiology and pathophysiology of
the nitric oxide/superoxide system. In: Born GVR, Schwartz CJ (eds).
Vascular Endothelium: Physiology, Pathology and Therapeutic Options.
Schattauer: Stuttgart, 1997, pp 205–220.
12. Newby AC, Zaltsman AB. Fibrous cap formation or destruction: the critical
importance of vascular smooth muscle cell proliferation, migration and
matrix formation. Cardiovasc Res 1999; 41: 345–360.
13. Rodriguez JA, Orbe J, Paramo JA. Metalloproteases, vascular remodeling,
and atherothrombotic syndromes. Rev Esp Cardiol 2007; 60: 959–967.
14. Davies MJ. The pathophysiology of acute coronary syndromes. Heart
2000; 83: 361–366.
15. Pieczenik SR, Neustadt J. Mitochondrial dysfunction and molecular
pathways of disease. Exp Mol Pathol 2007; 83: 84–92.
16. Portaluppi F, Boari B, Manfredini R. Oxidative stress in essential
hypertension. Curr Pharm Des 2004; 10: 1695–1698.
17. Andrew PJ, Mayer B. Enzymatic function of nitric oxide synthases.
Cardiovasc Res 1999; 43: 521–531.
18. Blokhina O, Virolainen E, Fagerstedt KV. Antioxidants, oxidative damage
and oxygen deprivation stress: a review. Ann Bot (Lond) 2003; 91:
179–194.
19. Dobashi K, Ghosh B, Orak JK et al. Kidney ischemia-reperfusion:
modulation of antioxidant defenses. Mol Cell Biochem 2000; 205: 1–11.
20. Dounousi E, Papavasiliou E, Makedou A et al. Oxidative stress is
progressively enhanced with advancing stages of CKD. Am J Kidney Dis
2006; 48: 752–760.
21. Karamouzis I, Sarafidis PA, Karamouzis M et al. Increase in oxidative stress
but not in antioxidant capacity with advancing stages of chronic kidney
disease. Am J Nephrol 2008; 28: 397–404.
22. Ferretti G, Bacchetti T, Masciangelo S et al. Lipid peroxidation in
hemodialysis patients: effect of vitamin C supplementation. Clin Biochem
2008; 41: 381–386.
23. Westhuyzen J, Saltissi D, Healy H. Oxidation of low density lipoprotein in
hemodyalisis patients: effect of dialysis and comparison with matched
controls. Atherosclerosis 1997; 129: 199–205.
24. Terawaki K, Yoshimura K, Hasegawa T et al. Oxidative stress is enhanced
in correlation with renal dysfunction: examination with the redox state of
albumin. Kidney Int 2004; 66: 1989–1993.
S8
25. Quiroz Y, Ferrebuz A, Romero F et al. Melatonin ameliorates oxidative
stress, inflammation, proteinuria, and progression of renal damage in rats
with renal mass reduction. Am J Physiol Renal Physiol 2008; 294:
F336–F444.
26. Haffner SM. Clinical relevance of the oxidative stress concept. Metabolism
2000; 49(Suppl 1): 30–34.
27. Lahera V, Goicoechea M, de Vinuesa SG et al. Oxidative stress in uremia:
the role of anemia correction. J Am Soc Nephrol 2006; 17(Suppl 3):
S174–S177.
28. Fortuño A, Beloqui O, San José G et al. Increased phagocytic nicotinamide
adenine dinucleotide phosphate oxidase-dependent superoxide
production in patients with early chronic kidney disease. Kidney Int Suppl
2005; 99: S71–S75.
29. Castilla P, Dávalos A, Teruel JL et al. Comparative effects of dietary
supplementation with red grape juice and vitamin E on production of
superoxide by circulating neutrophil NADPH oxidase in hemodialysis
patients. Am J Clin Nutr 2008; 87: 1053–1061.
30. Grahl DA, Axelsson J, Nordfors L et al. Associations between the CYBA
242C/T and the MPO -463G/A polymorphisms, oxidative stress and
cardiovascular disease in chronic kidney disease patients. Blood Purif
2007; 25: 210–218.
31. Perianayagam MC, Liangos O, Kolyada AY et al. NADPH oxidase p22phox
and catalase gene variants are associated with biomarkers of oxidative
stress and adverse outcomes in acute renal failure. J Am Soc Nephrol
2007; 18: 255–263.
32. Rambod M, Kovesdy CP, Kalantar-Zadeh K. Malnutrition-inflammation
score for risk stratification of patients with CKD: is it the promised gold
standard? Nat Clin Pract Nephrol 2008; 4: 354–355.
33. Landray MJ, Wheeler DC, Lip GY et al. Inflammation, endothelial
dysfunction, and platelet activation in patients with chronic kidney
disease: the chronic renal impairment in Birmingham (CRIB) study. Am J
Kidney Dis 2004; 43: 244–253.
34. Garcı́a de Vinuesa MS, Goicoechea M, Kanter J et al. Insulin resistance,
inflammatory biomarkers and adipokines in patients with chronic kidenay
disease: efects of angiotensin II blockade. J Am Soc Nephrol 2006; 17(12
Suppl 3): S206–S212.
35. Goicoechea M, Garcı́a de Vinuesa MS, Lahera V et al. Effects of
atorvastatin on inflammatory and fibrinolytic parameters in patients with
chronic kidney disease. J Am Soc Nephrol 2006; 17(12 Suppl 3):
S231–S235.
36. Stenvinkel P. New insights on inflammation in chronic kidney
disease-genetic and non-genetic factors. Nephrol Ther 2006; 2: 111–119.
37. Merino A, Nogueras S, Buendı́a P et al. Microinflammation and
endothelial damage in hemodialysis. Contrib Nephrol 2008; 161:
83–88.
38. Sela S, Shurtz-Swirski R, Cohen-Mazor M et al. Primed peripheral
polymorphonuclear leukocyte: a culprit underlying chronic low-grade
inflammation and systemic oxidative stress in chronic kidney disease.
J Am Soc Nephrol 2005; 16: 2431–2438.
39. Fried L, Solomon C, Shlipak M et al. Inflammatory and prothrombotic
markers and the progression of renal disease in elderly individuals. J Am
Soc Nephrol 2004; 15: 3184–3191.
40. Vanholder R, De Smet R, Glorieux G et al. Review on uremic toxins:
classification, concentration, and interindividual variability. Kidney Int
2003; 63: 1934–1943.
41. Jabs WJ, Lögering BA, Gerke P et al. The kidney as a second site of
human C-reactive protein formation in vivo. Eur J Immunol 2003; 33:
152–161.
42. Labarrere CA, Zaloga GP. C-reactive protein: from innocent bystander to
pivotal mediator of atherosclerosis. Am J Med 2004; 117: 499–507.
43. Li N, Karin M. Is NF-kB the sensor of oxidative stress? FASEB J 1999; 13:
1137–1143.
44. Schreck R, Rieber P, Beauerle PA. Reactive oxygen intermediates as
apparently widely used messengers in the activation of NF-kappa B
transcription factor and HIV-1. EMBO J 1991; 10: 2247–2252.
45. Baber U, Toto RD, de Lemos JA. Statins and cardiovascular risk reduction
in patients with chronic kidney disease and end-stage renal failure.
Am Heart J 2007; 153: 471–477.
46. Holdaas H, Fellström B, Cole E et al. Long-term cardiac outcomes in renal
transplant recipients receiving fluvastatin: the ALERT extension study. Am
J Transplant 2005; 5: 2929–2936.
47. Wanner C, Krane V. Lessons learnt from the 4D trial. Nephrol Ther 2006; 2: 3–7.
48. Zhou MS, Schulman IH, Jaimes EA et al. Renoprotection by statins is
linked to a decrease in renal oxidative stress, TGFb and fibronectin with
concomitant increase in nitric oxide bioavailability. Am J Physiol Renal
Physiol 2008; 295: F53–F59.
Kidney International (2008) 74 (Suppl 111), S4–S9
V Cachofeiro et al.: Oxidative stress and inflammation in chronic kidney disease
49. Panichi V, Paoletti S, Mantuano E et al. In vivo and in vitro effects of
simvastatin on inflammatory markers in pre-dialysis patients. Nephrol Dial
Transplant 2006; 21: 337–344.
50. Di Renzo L, Noce A, De Angelis S et al. Anti-inflammatory effects of
combined treatment with acetyl salicylic acid and atorvastatin in
haemodialysis patients affected by Normal Weight Obese syndrome.
Pharmacol Res 2008; 57: 93–99.
51. Albert MA, Danielson E, Rifai N et al. Effect of statin therapy on
C-reactive protein levels: the pravastatin inflammation/CRP
evaluation (PRINCE): a randomized trial and cohort study. JAMA 2001;
286: 64–70.
Kidney International (2008) 74 (Suppl 111), S4–S9
review
52. Kinlay S. Low-density lipoprotein-dependent and -independent effects
of cholesterol-lowering therapies on C-reactive protein: a meta-analysis.
J Am Coll Cardiol 2007; 49: 2003–2009.
53. Alvarez-Sala LA, Cachofeiro V, Masana L et al. Effects of fluvastatin extended-
release (80 mg) alone and in combination with ezetimibe (10 mg) on low-
density lipoprotein cholesterol and inflammatory parameters in patients
with primary hypercholesterolemia: a 12-week, multicenter, randomized,
open-label, parallel-group study. Clin Ther 2008; 30: 84–97.
54. Mastalerz-Migas A, Reksa D, Pokorski M et al. Comparison of a statin vs
hypolipemic diet on the oxidant status in hemodialyzed patients with chronic
renal failure. J Physiol Pharmacol 2007; 58(Suppl 5, Part 1): 363–370.
S9