Blackwell Publishing AsiaMelbourne, AustraliaNEPNephrology1320-53582005 Asian Pacific Society of Nephrology20051113641Original ArticleInflammation in ESRDP Stenvinkel

NEPHROLOGY 2006; 11, 36–41 doi:10.1111/j.1440-1797.2006.00541.x

Review Article

Inflammation in end-stage renal disease: The hidden enemy

PETER STENVINKEL

Division of Renal Medicine, Department of Clinical Science, Intervention and Technology, Karolinska University
Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden

SUMMARY: Cardiovascular disease (CVD) remains the major cause of morbidity and mortality in end-stage
renal disease (ESRD) patients. As traditional risk factors cannot alone explain the unacceptable high prevalence
and incidence of CVD in this high-risk population, inflammation (interrelated to insulin resistance, oxidative stress,
wasting and endothelial dysfunction) has been suggested to be a significant contributor. Indeed, several different
inflammatory biomarkers, such as high sensitivity C-reactive protein (hs-CRP), have been shown to indepen-
dently predict mortality in ESRD patients. As CRP is so strongly associated with vascular disease it has been sug-
gested that this hepatic-derived protein is not only a marker, but also a mediator, of vascular disease. Although
in vitro data from studies on endothelial cells, monocytes-macrophages and smooth muscle cells support a direct
role for CRP in atherogenesis, data from studies performed in vivo have been controversial. The causes of the
highly prevalent state of inflammation in ESRD are multiple, including inflammatory signals associated with the
dialysis procedure, decreased renal function, volume overload, comorbidity and intercurrent clinical events. As
the prevalence of inflammation varies considerably between continents and races, dietary and/or genetic factors
may have an impact on inflammation in ESRD. Elevated CRP in dialysis patients could be evaluated at three dif-
ferent levels: (i) national/regional level; (ii) dialysis unit level; and (iii) individual patient level.

KEY WORDS: cardiovascular disease, C-reactive protein, dialysis, inflammation, interleukin-6.

RISK FACTOR FOR VASCULAR DISEASE IN non-traditional risk factors are of relevance in moderate
KIDNEY DISEASE CKD,4 studies in both haemodialysis (HD)5 and peritoneal
dialysis (PD)6 patients suggest that novel (i.e. non-
The lifespan of end-stage renal disease (ESRD) patients is traditional) risk factors are far more prevalent in this pop-
reduced, and cardiovascular disease (CVD) accounts for ulation than in the general population. However, as novel
premature death in more than 50% of dialysis patients in risk factors and traditional risk factors do not operate in sep-
Europe and North America.1 In fact, even subtle kidney dys- arate rigid compartments, a solid distinction between tradi-
function should be considered a medical condition predis- tional and novel risk factors may not be easy to perform.7
posing to increased cardiovascular risk.2 Despite recent Among several novel risk factors, such as oxidative stress
improvements in dialysis technology, the majority of main- and hyperhomocysteinaemia, persistent inflammation (usu-
tenance dialysis patients die within a 5-year period: a sur- ally recognised by elevated serum levels of C-reactive
vival rate worse than that of the majority of patients with protein (CRP)), has attracted much interest. Although the
cancer disease. By extrapolating data from the general pop- association between CRP and vascular disease has been
ulation, nephrologists have mostly focused on conventional recognised for several decades,8 the concept of microinflam-
risk factors, such as hypertension, diabetes mellitus and dys- mation is at present a hot topic in renal literature.
lipidaemia. Indeed, in elderly persons with mild–moderate
chronic kidney disease (CKD) traditional risk factors seems
DOES CRP PROMOTE VASCULAR DISEASE?
to be the major contributor to cardiovascular mortality.3 On
the other hand, whereas data from the Atherosclerosis Risk While CRP was thought initially to be only a marker of
in Communities (ARIC) suggests that both traditional and inflammation and atherosclerosis, several groups have sug-
gested that CRP may also be a direct mediator of vascular
Correspondence: Associate Professor Peter Stenvinkel, Department disease.9,10 However, as any inflammatory stimuli that would
of Renal Medicine K56, Karolinska Institutet, Karolinska University
prompt the release of pro-atherogenic cytokines (e.g. inter-
Hospital at Huddinge, 141 86 Stockholm, Sweden.
Email: peter.stenvinkel@ki.se
leukin-1, IL-6 and tumour necrosis factor α) would also
Accepted for publication 6 November 2005. stimulate hepatic CRP production, it has been argued that
© 2006 The Author the association between vascular damage and CRP may be
Journal compilation © 2006 Asian Pacific Society of Nephrology indirect and that inflammatory mediators other than CRP
Inflammation in ESRD
are the main culprits.11 As CRP is associated with a number
of other cardiovascular risk factors, such as insulin resis-
tance, oxidative stress, endothelial dysfunction and vascular
calcification,11 this may also support the concept of an indi-
rect association between elevated CRP and vascular disease.
As recent data from Zoccali et al.12 show that low circulat-
ing free triiodothyronine (fT3) levels frequently are
observed in HD patients, this may be yet another reason
why inflammation is linked to heart disease. On the other
hand, as CRP is present in almost all atherosclerotic
plaques, binds to modified low density lipoprotein (LDL)
and activates the classical complement pathway, CRP may
also act as a mediator of vascular disease.9 Indeed, abundant
in vitro data have emerged showing that CRP have pro-
inflammatory and pro-thrombotic effects in vitro.13,14 More-
over, human CRP has been shown to contribute to ischemic
tissue damage in both the brain and heart of adult rats.15
Other documented effects of CRP include inhibition of
endothelial progenitor cell differentiation and function16
and upregulation of angiotensin type-1 receptors.17 How-
ever, as pointed out by Pepys,8 most of the published studies
have used commercially purchased CRP and few studies
report any controls to establish whether or not results
obtained are attributable to CRP itself or a bacterial con-
tamination. Indeed, despite the numerous reports of poten-
tial pro-atherogenic properties of CRP in vitro, the evidence
that CRP promote atherosclerosis in vivo is controversial.
Whereas one study in apoE-deficient mice showed that
human transgene expression caused accelerated aortic
atherosclerosis18 another study showed that human trans-
genic CRP is not pro-atherogenic in apoE-deficient mice.19
Because work on drugs that specifically inhibit CRP effects
is currently in progress, CRP blocking drugs may in future
enable definite direct determination of whether or not CRP
has pro-atherogenic properties.8
INFLAMMATION IS A COMMON FEATURE THAT
PREDICTS OUTCOME IN CKD
Evidence suggest that persistent inflammation (and oxida-
tive stress) starts early in the process of failing kidney
function.3 Indeed, several recent studies3,20–22 have reported
that kidney disease is associated with low-grade elevation
of CRP even among patients with moderate renal impair-
ment (Fig. 1). Primed peripheral polymorphonuclear leu-
kocytes seem to be a key mediator of low-grade
inflammation and oxidative stress in mild CKD.23 Because
inflammatory and pro-thrombotic markers predict change
in kidney function,24 interventions that reduce inflamma-
tion have been suggested to confer not only cardiovascular
but also renal benefits. In ESRD patients, elevated median
CRP levels have been documented both close to the start
of dialysis25 and in patients receiving dialysis.26 Taken
together, as chronic inflammation is such a common phe-
nomenon in European27 and North-American28 CKD pop-
ulations, its role as an atherosclerotic mediator and
prognostic indicator has been an area of much recent
interest in nephrology.
© 2006 The Author
Journal compilation © 2006 Asian Pacific Society of Nephrology
37
8
Ducloux et al.26 240 PD
Stenvinkel et al. 228 HD (unpublished data)
Median CRP (mg/L)
6
Stenvinkel et al.25 304 ESRD
Shlipak et al.3
4
1249 CKD
Landray et al.20
334 CKD
2 Sarnak et al.21
559 CKD
Tonelli et al.22
687 CKD
0
0 10 20 30 40 50 60
GFR (mL/min)
Fig. 1 Relation between median C-reactive protein (CRP)
and glomerular filtration rate (GFR). Data are taken from some
recently published (and unpublished) data from cohorts of
chronic kidney disease patients with different degrees of renal
impairment.
Numerous studies have shown that elevated CRP pre-
dicts both all-cause and cardiovascular mortality in CKD29
as well as ESRD patients treated with HD30–32 or PD.26
Moreover, persistent, rather than occasional, inflammation
predicts death in dialysis patients33 and elevated CRP con-
centrations observed after a HD session is associated with
both cardiac hypertrophy34 and a higher mortality risk.35 In
PD patients, an elevated CRP was shown to be an indepen-
dent predictor of non-fatal myocardial infarction36 and
increased incidence of CVD.26 Also, other inflammatory
markers, such as IL-637–39 and fibrinogen,40 have been shown
to predict mortality in this population. Actually, Panichi
et al.39 have demonstrated that IL-6 has a stronger predic-
tive value than CRP in a group of HD-patients. Their data
are corroborated by my own recent findings showing that
out of four putative biochemical risk markers (CRP, IL-6, S-
albumin and fetuin-A) IL-6 may be the most reliable pre-
dictor of CVD and mortality in ESRD.41
EVALUATION OF ELEVATED CRP
When elevated CRP should be evaluated in a dialysis
patient it could be done at three different levels: (i) a
national/regional level; (ii) the dialysis unit level; and (iii)
the individual patient level (Table 1). The reason for eval-
uating CRP at a national/regional level is the markedly dif-
ferent prevalence of elevated CRP when comparing dialysis
patients of Caucasian and Asian origin. Indeed, the preva-
lence of elevated CRP is markedly lower in Asian dialysis
patients compared to Caucasian patients dialysed in Europe/
North-America.42 The lower prevalence of inflammation in
Asian patients could be one important factor accounting for
the striking differences in cardiovascular mortality that
have been observed in dialysis patients from the USA,
Europe and Japan, even after adjustment for standard risk
factors.43 As Asian dialysis patients treated in the USA also
have a markedly lower adjusted relative risk than Cauca-
sians,44 it could be speculated that factors other than dialysis
38
Table 1 Evaluation of elevated C-reactive protein in haemo-
dialysis or peritoneal dialysis patients at different levels
Level I. National/regional
• Cultural habits;
• Dietary differences, such as the intake of:
soy
fish
fibres
antioxidants (e.g. berries, fruits, nuts)
• Genetic factors (single nucleotide polymorphisms).
Level IIA. Haemodialysis unit
• Bio-incompatible membranes;
• High flux dialysis;
• Daily dialysis;
• Impure dialysate;
• Type of access (central venous catheter, AV-fistula or graft);
• Biofilm.
Level IIB. Peritoneal dialysis unit
• Bio-incompatible PD solutions;
• Peritonitis and/or exit site infection rate;
• Impurity of PD solutions.
Level III. Individual patient
• Intercurrent clinical events, such as:
infections (eg. bacterial infection, Chlamydia pneumoniae)
major surgery
malignancy
peripheral vascular disease
silent ischemic cardiac ischemia
arthritis
vasculitis
congestive heart failure
peridontal disease
• Low residual renal function;
• Volume overload;
• Failed kidney transplant;
• Increased truncal fat mass;
• Depression.
treatment characteristics (such as diet and genetic factors)
play a role. Thus, it could be speculated that cultural habits
and/or different dietary habits between the continents may
explain differences in disease susceptibility, vascular mor-
bidity and mortality. As the traditional Asian diet is similar
to the Mediterranean diet it is of interest that both fish45 and
a Mediterranean diet rich in vegetables, fruits and nuts46
seems to protect against cardiovascular disease in the gen-
eral population. In accordance, one study in dialysis patients
reported that regular fish consumption was associated with a
50% lower risk of death during the observation period.47
Soybeans (a unique source of the anti-inflammatory phy-
toestrogen genistein), may be yet another component of the
Asian diet that has an anti-inflammatory potential.48
Finally, as gene polymorphisms are associated with the pro-
duction of inflammatory mediators, genetic variance may
explain a large part of ethnic and racial differences among
dialysis patients from different parts of the world.49
As there are inflammatory signals associated with the
dialysis procedure, the second level of elevated CRP to eval-
P Stenvinkel
No. patients
0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150
CRP (mg/L)
Fig. 2 Hypothetical distribution curves of C-reactive protein
(CRP) in a haemodialysis unit with poor water quality or a high
prevalence of dialysis access infections. ( ), Typical distri-
bution of CRP in a haemodialysis (HD) unit; ( ), hypothet-
ical distribution of CRP in a HD unit with poor water quality;
( ), hypothetical distribution of CRP in a HD unit with
access problems.
uate should be the dialysis unit level. Much important infor-
mation can be gained by calculating and plotting yearly
distribution curves of CRP in the HD unit, especially if
national/regional CRP distribution curves are available for
comparison (Fig. 2). If the distribution curve of the unit is
shifted to the right with a higher proportion of dialysis
patients having mild–moderately elevated CRP levels, this
could indicate that something in the dialysis practice pat-
tern needs evaluation. Indeed, several in vivo studies suggest
that membrane differences may induce inflammatory pro-
cesses and, following HD with regenerated cellulose, gene
expression of IL-1 takes place in peripheral blood mononu-
clear cells.50 In a randomised study, Schindler et al.51 dem-
onstrated lower CRP levels in HD patients treated with
polyamide compared to those treated with cuprophane or
polycarbonate. In accordance, Memoli et al.52 showed that a
significant relationship exists between membrane bio-
incompatibility and circulating levels of CRP, IL-6 and S-
albumin. It has also been proposed that not only the type of
membrane but also its flux, extent of convective transport
and frequency of dialysis may influence inflammation.53 In a
recent prospective controlled study, Ayus et al.54 showed
that short, daily HD (6 sessions/week of 3 h each) was asso-
ciated with a reduction in not only left ventricular hyper-
trophy but also inflammatory mediators compared to those
that received conventional HD (3 sessions/week of 4 h
each). As cytokine-inducing substances in dialysis fluid may
penetrate intact dialyser membranes and induce cytokine
production in the patient’s blood, impure dialysate may be
yet another cause of inflammation.55 Schindler et al.56 have
shown that small bacterial DNA fragments in dialysis fluid
can pass through dialyser membranes. In accordance, Sitter
et al.57 showed that a switch from conventional to online-
produced ultrapure dialysate resulted in lower bacterial
© 2006 The Author
Journal compilation © 2006 Asian Pacific Society of Nephrology
Inflammation in ESRD
contamination with a significant decrease in blood levels of
CRP and IL-6. Likewise, Shiffl et al.58 showed that changing
from conventional to ultrapure dialysate reduced the levels
of IL-6 and CRP and improved nutritional status. Small
studies have demonstrated that ultrapure dialysate may also
slow the loss of residual renal function59 and lower cardio-
vascular morbidity60 in HD patients. Biofilm formation has
also been speculated to be a cause of inflammation in this
patient group.61 Clearly, vascular access management may
also affect the prevalence of inflammation at the dialysis
unit. Both clotted access grafts62 and catheter infections63
may be significant contributors to the inflammatory process
in HD patients. As native fistulas are more commonly used
in Japan than in the USA (where the usage of tunnelled
catheters and grafts are more common) this may be one rea-
son why inflammation is more common in North-American
dialysis units, Taken together, when CRP distribution
curves showing a higher number of patients with markedly
elevated CRP levels the management of dialysis accesses
need evaluation (Fig. 2). It should be emphasised that in PD
patients some specific causes of inflammation related to dial-
ysis practice patterns (i.e. bio-incompatibility of PD solu-
tions, impurity of PD solutions, peritonitis and exit site
infections) may also exist.64
The last, and obviously most important, level to evaluate
in elevated CRP is at the individual patient level. Not sur-
prisingly, intercurrent clinical events may be the most
important factor predicting CRP alterations in dialysis
patients.65 Evidence suggest that subclinical chronic infec-
tions with Chlamydia pneumoniae, Helicobacter pylori66–68 and
peridontitis69 also contribute to inflammation in this patient
group. Obesity is another factor that may contribute to a
state of subclinical inflammation and truncal (i.e. visceral)
fat mass is significantly associated to circulating IL-6 levels
in ESRD patients.70 In accordance, a recent report by van
Ree et al.71 demonstrates that abdominal obesity is also an
important determinant of CRP in renal transplant recipi-
ents. Moreover, as studies suggest that a reduction of kidney
function per se may be associated with an inflammatory
response in both mild72 and advanced73 kidney failure, dif-
ferences in residual renal function may also contribute to
‘uraemic inflammation’. As the failing heart produces large
quantities of pro-inflammatory cytokines,74 volume overload
and/or congestive heart failure may link inflammation to
reduced residual renal function. Indeed, strong interrela-
tions between inflammation, residual renal function and
cardiac hypertrophy are found in PD patients.75 Depression
is associated with increased mortality in HD patients.76 As
depression has been associated with heightened expression
of inflammatory markers in other patients,77 it could be
speculated that psychosocial disease may also be related to
inflammation in this patient group. Finally, the possibility of
a failed kidney transplants as a cause of inflammation should
be kept in mind.78 Although there are multiple (both dial-
ysis-related and non-dialysis-related) factors that may cause
an inflammatory response in dialysis patients, it should be
emphasised that a large proportion of dialysis patients have
normal, or even low, CRP levels. In Stockholm, Sweden
approximately 20–25% of both incident ESRD patients
© 2006 The Author
Journal compilation © 2006 Asian Pacific Society of Nephrology
39
100
Cumulative frequency (%)
80
60
40
20
0
0 2 4 6 8 10 12 14 16 18 20
CRP (mg/L)
Fig. 3 The cumulative frequency of elevated C-reactive pro-
tein (CRP) in 304 incident end-stage renal disease patients
starting dialysis therapy and 231 prevalent haemodialysis
patients treated in Stockholm, Sweden. The grey area
represents the proportion of patients with CRP levels <2 mg/L.
( ), Incident dialysis patients (n = 304); ( ), prevalent hae-
modialysis patients (n = 231).
starting dialysis treatment and prevalent (median vintage
time 29 months) HD patients have a CRP level <2 mg/L as
shown in Figure 3 (Stenvinkel et al., pers. comm., 2005).
Although lower age, less comorbidity and higher residual
renal function may be one of the major reasons for low CRP
levels in uninflamed dialysis patients it could be hypothe-
sised that genetic variations may also contribute.49
CONCLUSION
In summary, elevated circulating concentrations of CRP are
a common phenomenon in ESRD patients. The prevalence
and magnitude of inflammation increases as renal function
declines. However, as not all ESRD patients show signs of
inflammation, this suggests that genetic factors play an
important role in the propensity of inflammation in this
patient group. Elevated CRP in dialysis patients should be
evaluated at three different levels: (i) a national/regional
level; (ii) a dialysis unit level; and (iii) the individual
patient level. Although the clinical usefulness of regular
CRP monitoring has not yet been fully validated, a careful
search for infectious processes, correction of volume status
as well as the use of biocompatible dialysis membranes and
ultrapure water can be recommended.
ACKNOWLEDGEMENTS
This study was supported by the Söderbergs Foundation and
Vetenskapsrådet.
REFERENCES
1. Foley RN, Parfrey PS, Sarnak MJ. Clinical epidemiology of car-
diovascular disease in chronic renal failure. Am. J. Kidney Dis.
1998; 32 (Suppl. 5): S112–19.
40
2. Vanholder R, Massy Z, Argiles A, Spasovski G, Verbeke F, Lam-
iere N. Chronic kidney disease as cause of cardiovascular morbid-
ity and mortality. Nephrol. Dial. Transpl. 2005; 20: 1048–56.
3. Shlipak MG, Fried LF, Cushman M et al. Cardiovascular mortality
risk in chronic kidney disease: Comparison of traditional and
novel risk factors. JAMA 2005; 293: 1737–45.
4. Muntner PHJ, Astor BC, Folsom AR, Coresh J. Traditional and
nontraditional risk factors predict coronary heart disease in
chronic kidney disease: Results from the atherosclerosis risk in
communities study. J. Am. Soc. Nephrol. 2005; 16: 529–38.
5. Cheung AK, Sarnak MJ, Yan G et al. Atherosclerotic cardiovas-
cular disease risks in chronic hemodialysis patients. Kidney Int.
2000; 58: 353–62.
6. Zoccali C, Enia G, Tripepi G, Panuccio V, Mallamaci F. Clinical
epidemiology of major nontradtional risk factors in peritoneal dial-
ysis patients. Perit. Dial. Int. 2005; 25 (Suppl. 3): S84–7.
7. Beddhu S, Kimmel PL, Ramkumar N, Cheung AK. Associations of
metabolic syndrome with inflammation in CKD: Results from the
third national health and nutrition examination survey
(NHANES III). Am. J. Kidney Dis. 2005; 46: 577–86.
8. Pepys MB. CRP or not CRP? That is the question. Arterioscler.
Thromb. Vasc. Biol. 2005; 25: 1091–4.
9. Yeh ETH. CRP as a mediator of disease. Circulation 2004; 109
(Suppl. II): II–11–14.
10. Li J-J, Fang C-H. C-reactive protein is not only an inflammatory
marker but also a direct cause of cardiovascular disease. Med.
Hypotheses 2004; 62: 499–506.
11. Stenvinkel P, Ketteler M, Johnson RJ et al. Interleukin-10, IL-6
and TNF-a: Important factors in the altered cytokine network of
end-stage renal disease – the good, the bad and the ugly. Kidney
Int. 2005; 67: 1216–33.
12. Zoccali C, Tripepi G, Cutrupi S, Pizzini P, Mallamaci F. Low tri-
iodothyronine: A new facet of inflammation in end-stage renal
disease. J. Am. Soc. Nephrol. 2005; 16: 2789–95.
13. Pasceri V, Cheng JS, Willerson JT, Yeh ET, Chang JW.
Modulation of C-reactive protein-mediated monocyte che-
moattractant protein-1 induction in human endothelial cells by
anti-atherosclerosis drugs. Circulation 2001; 103: 2531–4.
14. Pasceri V, Willerson JT, Yeh ET. Direct proinflammatory effect of
C-reactive protein on human endothelial cells. Circulation 2000;
102: 2165–8.
15. Gill R, Kemp JA, Sabin C, Pepys MB. Human C-reactive protein
increases cerebral infarct size after middle cerebral artery occlusion
in adult rats. J. Cereb. Blood Flow Metab. 2004; 24: 1214–18.
16. Verma S, Kuliszewski MA, Li SH et al. C-reactive protein atten-
uates endothelial progenitor cell survival, differentiation, and
function: Further evidence of a mechanistic link between C-
reactive protein and cardiovascular disease. Circulation 2004; 109:
2058–67.
17. Wang CH, Li SH, Weisel RD et al. C-reactive protein upregulates
angiotensin type 1 receptors in vascular smooth muscle. Circula-
tion 2003; 107: 1783–90.
18. Paul A, Kerry WS, Li L et al. C-reactive protein accelerates the
progression of atherosclerosis in apolipoprotein E-deficient mice.
Circulation 2004; 109: 647–55.
19. Hirschfield GM, Gallimore JR, Kahan MC et al. Transgenic
human C-reactive protein is not proatherogenic in apolipoprotein
E-deficient mice. Proc. Natl Acad. Sci. USA 2005; 102: 8309–14.
20. Landray MJ, Wheeler DC, Lip GY et al. Inflammation, endothelial
dysfunction, and platelet activation in patients with chronic kid-
ney disease: The chronic renal impairment in Birmingham
(CRIB) study. Am. J. Kidney Dis. 2004; 43: 244–53.
21. Sarnak MJ, Poindexter A, Wang SR et al. Serum C-reactive
protein and leptin as predictors of kidney disease in the modifi-
P Stenvinkel
cation of diet in renal disease study. Kidney Int. 2002; 62: 2208–
15.
22. Tonelli M, Sacks F, Pfeffer M et al. Biomarkers of inflammation
and progression of chronic kidney disease. Kidney Int. 2005; 68:
237–45.
23. 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 kid-
ney disease. J. Am. Soc. Nephrol. 2005; 16: 2431–8.
24. Fried L, Solomon C, Shlipak M et al. Inflammatory and prothrom-
botic markers and the progression of renal disease in elderly indi-
viduals. J. Am. Soc. Nephrol. 2004; 15: 3184–91.
25. Stenvinkel P, Heimbürger O, Paultre F et al. Strong association
between malnutrition, inflammation, and atherosclerosis in
chronic renal failure. Kidney Int. 1999; 55: 1899–911.
26. Ducloux D, Bresson-Vautrin C, Kribs M, Abdelfatah A, Chalopin
J-M. C-reactive protein and cardiovascular disease in peritoneal
dialysis patients. Kidney Int. 2002; 62: 1417–22.
27. Stenvinkel P, Wanner C, Metzger T et al. Inflammation and out-
come in end-stage renal failure: Does female gender constitute a
survival advantage? Kidney Int. 2002; 62: 1791–8.
28. Menon V, Wang X, Greene T et al. Relationship between C-
reactive protein, albumin, and cardiovascular disease in patients
with chronic kidney disease. Am. J. Kidney Dis. 2003; 42: 44–52.
29. Menon V, Greene T, Wang X et al. C-reactive protein and albu-
min as predictors of all-cause and cardiovascular mortality in
chronic kidney disease. Kidney Int. 2005; 68: 766–72.
30. Yeun JY, Levine RA, Mantadilok V, Kaysen GA. C-reactive pro-
tein predicts all-cause and cardiovascular mortality in hemodialy-
sis patients. Am. J. Kidney Dis. 2000; 35: 469–76.
31. Zimmermann J, Herrlinger S, Pruy A, Metzger T, Wanner C.
Inflammation enhances cardiovascular risk and mortality in hemo-
dialysis patients. Kidney Int. 1999; 55: 648–58.
32. Iseki K, Tozawa M, Yoshi S, Fukiyama K. Serum C-reactive (CRP)
and risk of death in chronic dialysis patients. Nephrol. Dial.
Transpl. 1999; 14: 1956–60.
33. Nascimento MM, Pecoits-Filho R, Qureshi AR et al. The prog-
nostic influence of fluctuating levels of C-reactive protein in Bra-
zilian hemodialysis patients: A prospective study. Nephrol. Dial.
Transpl. 2004; 19: 2803–9.
34. Park CW, Shin YS, Kim CM et al. Increased C-reactive protein
following hemodialysis predicts cardiac hypertrophy in chronic
hemodialysis patients. Am. J. Kidney Dis. 2002; 40: 1230–39.
35. Korevaar JC, van Manen JG, Dekker FD, de Waart DR, Boescho-
ten EW, Krediet RT. Effect of an increase in CRP level during a
hemodialysis session on mortality. J. Am. Soc. Nephrol. 2004; 15:
2916–22.
36. Herzig KA, Purdie DM, Chang W et al. Is C-reactive protein a use-
ful predictor of outcome in peritoneal dialysis patients? J. Am. Soc.
Nephrol. 2001; 12: 814–21.
37. Bologa RM, Levine DM, Parker TS et al. Interleukin-6 predicts
hypoalbuminemia, hypocholesterolemia, and mortality in hemo-
dialysis patients. Am. J. Kidney Dis. 1998; 32: 107–14.
38. Pecoits-Filho R, Barany B, Lindholm B, Heimbürger O, Sten-
vinkel P. Interleukin-6 and its receptor is an independent predic-
tor of mortality in patients starting dialysis treatment. Nephrol.
Dial. Transpl. 2002; 17: 1684–8.
39. Panichi V, Maggiore U, Taccola D et al. Interleukin-6 is a stronger
predictor of total and cardiovascular mortality than C-reactive
protein in haemodialysis patients. Nephrol. Dial. Transpl. 2004; 19:
1154–60.
40. Zoccali C, Mallamaci F, Tripepi G et al. Fibrinogen, mortality and
incident cardiovascular complications in end-stage renal failure. J.
Intern. Med. 2003; 254: 132–9.
© 2006 The Author
Journal compilation © 2006 Asian Pacific Society of Nephrology
Inflammation in ESRD
41. Honda H, Qureshi AR, Heimbürger O et al. Serum albumin, C-
reactive protein, interleukin-6 and fetuin-A as predictors of mal-
nutrition, cardiovascular disease and mortality in patients with
end-stage renal disease. Am. J. Kidney Dis. 2006; 47: 139–48.
42. Nascimento MM, Pecoits-Filho R, Lindholm B, Riella MC, Sten-
vinkel P. Inflammation, malnutrition and atherosclerosis in end-
stage renal disease: A global perspective. Blood Purif. 2002; 20:
454–8.
43. Uhlig K, Levey AS, Sarnak MJ. Traditional risk factors in individ-
uals with chronic kidney disease. Semin. Dial. 2003; 16: 118–27.
44. Wong JS, Port FK, Hulbert-Shearon TE et al. Survival advantage
in Asian American end-stage renal disease patients. Kidney Int.
1999; 55: 2515–23.
45. Kris-Etherton PM, Harris WS, Appel LJ. Fish consumption,
omega-3 fatty acids and cardiovascular disease. Circulation 2002;
106: 2747–57.
46. de Lorgeril M, Salen P, Martin JL, Monjaud I, Delaye J, Mamelle
N. Mediterranean diet, traditional risk factors, and the rate of car-
diovascular complications after myocardial infarction. final report
of the Lyon Diet Heart Study. Circulation 1999; 99: 779–85.
47. Kutner NG, Clow PW, Zhang R, Aviles X. Association of fish
intake and survival in a cohort of incident dialysis patients. Am. J.
Kidney Dis. 2002; 39: 1018–24.
48. Stenvinkel P, Lindholm B, Heimbürger O. Novel approaches in
an integrated therapy of inflammatory-associated wasting in end-
stage renal disease. Semin. Dial. 2004; 17: 505–15.
49. Nordfors L, Lindholm B, Stenvinkel P. End-stage renal disease –
not an equal opportunity disease: The role of genetic polymor-
phisms. J. Int. Med. 2005; 258: 1–12.
50. Schindler R, Linnenweber S, Schulze M et al. Gene expression of
interleukin-1 beta during hemodialysis. Kidney Int. 1993; 43: 712–
21.
51. Schindler R, Boenisch O, Fischer C, Frei U. Effect of the hemo-
dialysis membrane on the inflammatory reaction in vivo. Clin.
Nephrol. 2000; 53: 452–9.
52. Memoli B, Minutolo R, Bisesti V et al. Changes of serum albumin
and C-reactive protein are related to changes of interleukin-6
release by peripheral blood mononuclear cells in hemodialysis
patients treated with different membranes. Am. J. Kidney Dis.
2002; 39: 266–73.
53. Shindler R. Causes and therapy of microinflammation in renal fail-
ure. Nephrol. Dial. Transpl. 2004; 19 (Suppl. 5): v34–40.
54. Ayus JC, Mizani MR, Achinger SG, Thadhani R, Go AS, Lee
SK. Effects of short daily versus conventional hemodialysis on
left ventricular hypertrophy and inflammatory markers: A pro-
spective, controlled study. J. Am. Soc. Nephrol. 2005; 16: 2778–
88.
55. Lonnemann G. When good water goes bad: How it happens, clin-
ical consequences and possible solutions. Blood Purif. 2004; 22:
124–9.
56. Schindler R, Beck W, Deppisch R et al. Short bacterial DNA frag-
ments: Detection in dialysate and induction of cytokines. J. Am.
Soc. Nephrol. 2004; 15: 3207–14.
57. Sitter T, Bergner A, Schiffl H. Dialysate related cytokine induc-
tion and response to recombinant human erythropoietin in hae-
modialysis patients. Nephrol. Dial. Transpl. 2000; 15: 1207–11.
58. Schiffl H, Lang SM, Stratakis D, Fisher R. Effects of ultrapure dial-
ysis fluid on nutritional status and inflammatory parameters. Neph-
rol. Dial. Transpl. 2001; 16: 1863–9.
59. Schiffl H, Lang SM, Fischer R. Ultrapure dialysis fluid slows loss of
residual renal function in new dialysis patients. Nephrol. Dial.
Transpl. 2004; 17: 1814–18.
© 2006 The Author
Journal compilation © 2006 Asian Pacific Society of Nephrology
41
60. Lederer SR, Schiffl H. Ultrapure dialysis fluid lowers the cardio-
vascular morbidity in patients on maintenance hemodialysis by
reducing continuous microinflammation. Nephron 2002; 91: 452–
5.
61. Capelli G, Tetta C, Canaud B. Is biofilm a cause of silent chronic
inflammation in haemodialysis patients? A fascinating working
hypothesis. Nephrol. Dial. Transpl. 2005; 20: 266–70.
62. Ayus JC, Sheikh-Hamad D. Silent infection in clotted hemodial-
ysis access grafts. J. Am. Soc. Nephrol. 1998; 9: 1314–21.
63. Allon M, Depner TA, Radeva M et al. Impact of dialysis dose and
membrane on infection-related hospitalization and death: Results
of the HEMO study. J. Am. Soc. Nephrol. 2003; 14: 1863–70.
64. Pecoits-Filho R, Stenvinkel P, Wang AY, Heimburger O, Lind-
holm B. Chronic inflammation in peritoneal dialysis. the search
for the holy grail? Perit. Dial. Int. 2004; 24: 327–39.
65. van Tellingen A, Grooteman MPC, Schoorl M et al. Intercurrent
clinical events are predicitive of plasma C-reactive protein levels
in hemodialysis patients. Kidney Int. 2002; 62: 632–8.
66. Stenvinkel P, Heimbürger O, Jogestrand T. Elevated interleukin-
6 predicts progressive carotid atherosclerosis in dialysis patients:
Association to Chlamydia pneumoniae seropositivity. Am. J. Kidney
Dis. 2002; 39: 274–82.
67. Haubitz M, Brunkhorst R. C-reactive protein and chronic Chlamy-
dia pneumonia infection – long term predictors of cardiovascular
disease survival in patients on peritoneal dialysis. Nephrol. Dial.
Transpl. 2001; 16: 809–15.
68. Sezer S, Ibis A, Ozdemir BH et al. Association of Helicobacter
pylori infection with nutritional status in hemodialysis patients.
Transplant. Proc. 2004; 36: 47–9.
69. Craig RG, Spittle MA, Levin NM. Importance of peridontal dis-
ease in the kidney patient. Blood Purif. 2002; 20: 113–19.
70. Axelsson J, Qureshi AR, Suliman ME et al. Truncal fat mass as a
contributor to inflammation in end-stage renal disease. Am. J.
Clin. Nutr. 2004; 80: 1222–9.
71. van Ree RM, de Vries APJ, Oterdoom LH et al. Abdominal obesity
and smoking are important determinants of C-reactive protein in
renal transplant recipients. Nephrol. Dial. Transpl. 2005; 20: 2524–
31.
72. Shlipak MG, Fried LF, Crump C et al. Elevations of inflammatory
and procoagulant biomarkers in elderly persons with renal insuffi-
ciency. Circulation 2003; 107: 87–92.
73. Pecoits-Filho R, Heimbürger O, Bárány P et al. Associations
between circulating inflammatory markers and residual renal func-
tion in CRF patients. Am. J. Kidney Dis. 2003; 41: 1212–18.
74. Feldman AM, Combes A, Wagner D et al. The role of tumor
necrosis factor in the pathophysiology of heart failure. J. Am. Coll.
Cardiol. 2000; 35: 537–44.
75. Wang AY, Wang M, Woo J et al. Inflammation, residual kidney
function, and cardiac hypertrophy are interrelated and combine
adversely to enhance mortality and cardiovascular death risk of
peritoneal dialysis patients. J. Am. Soc. Nephrol. 2004; 15: 2186–
94.
76. Kimmel PL, Peterson RA, Weihs KL et al. Multiple measurements
of depression predict mortality in a longitudinal study of chronic
hemodialysis outpatients. Kidney Int. 2000; 57: 2093–8.
77. Miller GE, Stetler CA, Carney RM, Freedland KE, Banks WA.
Clinical depression and inflammatory markers for coronary heart
disease. Circulation 2002; 90: 1279–83.
78. Lopez-Gomez JM, Perez-Flores I, Jofre R et al. Presence of a failed
kidney transplant in patients who are on hemodialysis is associated
with chronic inflammatory state and erythropoietin resistance.
J. Am. Soc. Nephrol. 2004; 15: 2494–501.