J Nephrol (2015) 28:321–327
DOI 10.1007/s40620-014-0116-6
ORIGINAL ARTICLE
C reactive protein and long-term risk for chronic kidney disease:
a historical prospective study
Eitan Kugler • Eytan Cohen • Elad Goldberg •
Yuval Nardi • Amos Levi • Irit Krause •
Moshe Garty • Ilan Krause
Received: 30 March 2014 / Accepted: 18 June 2014 / Published online: 1 July 2014
Ó Italian Society of Nephrology 2014
Abstract
Introduction C reactive protein (CRP) is an acute phase
reactant that primarily produced by hepatocytes yet may be
locally expressed in renal tubular cells. We assessed the
association of CRP and the risk for chronic kidney disease
(CKD) development.
Methods Historical prospective cohort study was con-
ducted on subjects attending a screening center in Israel since
the year 2000. Subjects with an estimated GFR (eGFR)
above 60 ml/min/1.73 m2 at baseline were included, and
high sensitive (hs) CRP levels as well as eGFR were recorded
for each visit. Follow up continued for at least 5 years for
each subject until 2013. Risk for CKD at end of follow up
was assessed in relation to mean hs-CRP levels of each
subject. The confounding effects of other predictors of CKD
This work was presented as an abstract in the EFIM––European
Federation of Internal Medicine, Prague, 2013.
E. Kugler
E. Cohen
E. Goldberg
A. Levi
Ilan Krause (&)
Department of Medicine F, Recanati Center, Rabin Medical
Center (Beilinson Hospital), 49100 Petah Tikva, Israel
e-mail: Ilank2@clalit.org.il
E. Cohen
E. Goldberg
Irit Krause
M. Garty
Ilan Krause
Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv,
Israel
Y. Nardi
Faculty of Industrial Engineering and Management,
Technion-Israel Institute of Technology, Haifa, Israel
Irit Krause
The Institute of Pediatrics Nephrology, Schneider Children’s
Medical Center of Israel, Petah Tikva, Israel
M. Garty
Recanati Center for Preventive Medicine, Rabin Medical Center
(Beilinson Hospital), Petah Tikva, Israel
were examined. A logistic regression model treating CRP as
a continuous variable was further applied.
Results Out of 4,345 patients, 42 (1 %) developed CKD
in a mean follow up of 7.6 ± 2 years. Elevated levels of
CRP were associated with greater risk for CKD (crude OR
4.17, 95 % CI 1.46–11.89). The OR for the association of
CRP with CKD when controlling for age and gender was
5.2 (95 % CI 1.7–16.2). When controlling for established
renal risk factors, elevated CRP levels remained signifi-
cantly associated with greater risk for CKD (OR 5.42,
95 % CI 1.76–16.68). When applying logistic regression
models treating CRP as a continuous variable, for patients
with diabetes mellitus (DM), hypertension (HTN) or eGFR
between 60–90 ml\min\1.73 m2, the predictive role of CRP
for CKD was highly significant.
Conclusion Elevated CRP level is an independent risk
factor for CKD development. In patients with DM, HTN or
baseline eGFR between 60–90 ml\min\1.73 m2 its predic-
tive role is enhanced.
Keywords Nephropathy
Estimated glomerular filtration
rate
Early prevention
Inflammatory markers
Introduction
Chronic kidney disease (CKD) is a worldwide public health
problem and the prevalence of end-stage renal disease
(ESRD) is increasing [1]. Rising prevalence may be attrib-
uted to increased number of patients starting renal replace-
ment therapy, or to increased survival of patients with ESRD
[2]. Despite improvement in the quality of dialysis therapy,
ESRD patients continue to experience significant mortality
and morbidity, and a reduced quality of life. Recognition of
earlier stages and risk factors for CKD is important for ESRD
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prevention. Several risk factors influence the progression of
renal function loss, among them diabetes mellitus, hyper-
tension or cardiovascular disease confer the highest risk [3].
Other risk factors such as hyperlipidemia, obesity, metabolic
syndrome and smoking are also to be considered [3].
C-reactive protein (CRP) is an acute phase protein that is
produced predominantly by hepatocytes under the influence
of cytokines such as interleukin (IL)-6 and tumor necrosis
factor-alpha [4]. C reactive protein may also be locally
expressed within renal cortical tubular epithelial cells as
demonstrated by in vitro studies [5]. Although CRP is a
sensitive marker of inflammation, it is not specific. Minor
elevated levels of CRP have been described in various con-
ditions such as obesity, cigarette smoking, diabetes mellitus,
uremia, hypertension, low levels of physical activity, oral
hormone replacement therapy, sleep disturbance, chronic
fatigue, low alcohol consumption, depression or aging [6].
When considered alone or in combination with traditional
cardiovascular risk factors, elevated CRP levels have been
associated with a higher risk of future cardiovascular events
[7–10] possibly because of the association with underline
atherosclerosis, which is a low-grade inflammatory state
[11]. Among apparently healthy individuals, the baseline
level of CRP predicts the long-term risk of a first myocardial
infarction, ischemic stroke, peripheral vascular disease, and
all-cause mortality [8, 12]. Yet, CRP use as a screening tool
in the general population for cardiovascular risk is still
controversial. When considering screening for CKD, the
NKF-K/DOQI guidelines recommend that individuals at
increased risk of developing CKD should undergo testing for
markers of kidney damage (albuminuria), and to estimate the
level of the glomerular filtration rate (eGFR) [1]. Whether to
screen the general population and subjects without known
risk factors is a more complex issue [13, 14]. The United
State Preventive Services Task Force has concluded that
evidence is insufficient to assess benefits and screening of
adults without known risk factors [15]. Biomarkers of
inflammation, including CRP are increased even in early
stages of CKD and have been linked to CKD progression
[16]. Moreover, recent studies show association between
certain CRP polymorphisms and CKD progression [17]. Yet,
longitudinal studies assessing CRP role in predicting long-
term risk for CKD in the general population are lacking [18,
19]. In the current study we sought to evaluate whether CRP
can be used to predict a long term risk for CKD.
Methods
Study population and design
We conducted a historical prospective cohort study on
apparently healthy subjects attending a screening center at
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J Nephrol (2015) 28:321–327
the Rabin Medical Center in Israel. This referral institute
provides regular health assessments for employees of dif-
ferent companies. The population attending the center for
screening includes male and non-pregnant female with an
age range between 20 and 80 years. At each visit, a thor-
ough medical history is taken from each subject and a
complete physical examination along with series of blood
and urine tests, chest X ray, an electrocardiogram, an
exercise stress test and a lung function test is preformed.
The same tests are repeated at each visit including creati-
nine and CRP serum levels. Subjects may return once a
year for repeated investigations despite no apparent change
in their health condition. For the purpose of the present
study, we included all patients who attended the clinic
since the year 2000 and presented with an eGFR of more
than 60 ml/min/1.73 m2. Subjects were followed up for at
least 5 years. Our primary outcome was CKD development
defined as eGFR \60 ml/min/1.73 m2 [20]. High sensitive
(hs) method for measuring CRP was used using the
Beckman coulter AU analyzers. We used in our study
1 mg/l as cutoff for stratification and defined two groups of
hs-CRP as low and high (below and above 1 mg/l
respectively) [11, 21]. Estimated glomerular filtration rate
was the preferred measurement of kidney function in the
current study, and was calculated using the latest CKD-EPI
equation [22]. Creatinine serum levels were assessed on a
Beckman Coulter AU 2700 analyzer. Baseline character-
istics of age, sex, diabetes mellitus (DM), hypertension
(HTN), total cholesterol, HDL cholesterol, current smoker
and body mass index (BMI) were considered as possible
confounders. Diabetes mellitus was defined as any patient
suffering from type 1 or type 2 DM, and being treated with
either diet, oral hypoglycemic agents or insulin. Hyper-
tension was defined as systolic blood pressure above
140 mmHg, the use of antihypertensive medications or a
known previous diagnosis of hypertension. Hypercholes-
terolemia was defined as serum total serum cholesterol
level of [200 mg/dl or a known previous diagnosis of
hypercholesterolemia on medical therapy. Low HDL cho-
lesterol was defined as \40 mg/dl in males and \50 mg/dl
in females. Body mass index was calculated as the ratio
between the weight and the square of the height (kg/m2).
Statistical analysis
All calculations were performed with the R software
environment for statistical computing and graphics, version
2.15.2. All reported P values are two-sided; a P value of
0.05 was considered to indicate statistical significance.
Subject’s baseline characteristics were compared with the
use of Student’s t test or the Chi square test as appropriate.
To calculate the odds ratio for CKD in respect to CRP
groups we conducted a logistic regression analysis
J Nephrol (2015) 28:321–327 323

adjusting for age and gender. Stepwise multiple regression Table 1 Baseline characteristics according to C reactive protein
analysis was performed in order to study the possible groups
confounding effect of various risk factors for CKD. Age, Baseline 0 \ CRP \ 1 mg/l CRP [1 mg/l P value
gender, hypertension, DM, total cholesterol, HDL choles- characteristic (N = 4,235) (N = 110)
terol, BMI and smoking were initially included as covari-
Follow up time 7.6 ± 2 7.2 ± 1.9 0.038
ates. A multivariate model including the confounders age, (years)
hypertension and DM were ultimately selected based on Age (mean, years) 43.5 ± 8.8 42 ± 9.3 NS
Akaike information criterion. To estimate the performance Gender (male, 74.1 63.4 0.018
of Mean CRP value as a binary classifier we plotted a percentage)
receiver operator characteristic (ROC) curve. Binomial Baseline eGFR 100 ± 13.6 103 ± 13.6 0.012
model was used to estimate and plot the ROC curve, as (mean)
implemented with the pROC package for R [23]. Finally, to Diabetes mellitus 2.2 1.8 NS
estimate the cumulative effect of CRP level on risk for (percentage)
CKD in various subgroups of our population we applied Hypertension 4.4 7 NS
(percentage)
additional logistic regression model treating CRP as a
Total cholesterol 199.8 ± 35.8 205.7 ± 38.4 NS
continuous variable with hypertension, mildly reduced
(mg/dl, mean)
renal function at baseline (eGFR 60–90 ml/min/1.73 m2)
HDL cholesterol 49.6 ± 12.5 48.4 ± 13.8 NS
and DM status as covariates. (mg/dl, mean)
BMI (kg/m2, 26.2 ± 4.2 28.9 ± 6.1 \0.001
mean)
Results Smoking 12.4 16.4 NS
(percentage)
Overall, 4,345 subjects fulfilled the inclusion criteria. Mean eGFR estimated glomerular filtration rate in ml/min/1.73 m2, HDL
age was 44.3 ± 8.8 years, and 26 % were women. Base- high-density lipoproteins, BMI body mass index, NS not significant
line characteristics of the two groups of CRP are presented
in Table 1. There were 110 subjects (2.5 %) with a mean
CRP levels higher than 1 mg/l. The group of subjects with Table 2 Odds ratios for chronic kidney disease according to C
elevated CRP had a higher mean baseline eGFR and higher reactive protein groups
mean BMI levels as compared to subjects with lower levels Type of adjustment model 0 \ CRP CRP [1 mg/l
of CRP. Overall, there were more women in the groups of \ 1 mg/la
subjects with elevated CRP levels. The prevalence of other
Crude 1 4.17 (95 % CI 1.46–11.89)
risk factors for CKD as age, DM, HTN, cholesterol level
Age-gender 1 5.2 (95 % CI 1.7–16.2)
and smoking did not differ statistically between the groups.
Multivariable 1 5.42 (95 % CI 1.76–16.68)
During follow up of 32,978 person-years (mean follow up
of 7.6 ± 2 years) 42 patients developed CKD (1 %). CKD The multivariable analysis included the following variables: age
Incidence rate was 5.05 per 1,000 person years in the hypertension and diabetes mellitus
a
elevated CRP group versus 1.18 per 1,000 person years in Used for reference
the normal CRP group. In a logistic regression model,
elevated levels of CRP were associated with greater risk for min/1.73 m2 at presentation (P \ 0.001 for all, Figs. 1, 2, 3
CKD (crude OR 4.17, 95 % CI 1.46–11.89). The OR for respectively). To estimate the performance of Mean CRP
the association of CRP with CKD when controlling for age value as a binary classifier we plotted a receiver operator
and gender simultaneously was 5.2 (95 % CI 1.7–16.2). characteristic (ROC) curve (with age defined as a covari-
Elevated CRP remained significantly associated with CKD ate). The mean area under the curve was 0. 84 (P \ 0.001,
in a third model in which age, hypertension and DM were Fig. 4).
selected as covariates based on the Akaike information
criterion (OR 5.42, 95 % CI 1.76–16.68). Table 2 displays
the odds ratios for CKD according to CRP groups. Discussion
In order to estimate the effect of CRP on CKD in several
subpopulations we plotted a logistic regression model In this longitudinal study on subjects without CKD, high
treating CRP as a continuous variable while controlling for CRP values were significantly associated with greater risk
other predictors. Employing this model, it appears that for CKD during a mean follow up of 7.6 ± 2 years. In a
CRP has an enhanced predicting role for CKD for patients multivariate analysis controlling for traditional risk factors
with DM, HTN or with baseline eGFR between 60–90 ml/ for CKD, CRP remained significantly associated with

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60
60
Baseline eGFR <= 90 mL/min/1.73 m2
Baseline eGFR > 90 mL/min/1.73 m2

50
50
Predicted CKD probability (%)

Predicted CKD probability (%)

Diabetes=no
Diabetes=yes

40
40

30
30

20
20

10
10

0
0

0 1 2 3 4 5 0 1 2 3 4 5
CRP CRP
Effect of baseline eGFR is significant: P<0.001.
Effect of diabetes is significant: P<0.001.
CRP denotes C reactive protein.
CRP denotes C reactive protein.
CKD denotes chronic kidney disease.
CKD denotes chronic kidney disease.
eGFR denotes estimated glomerular filtration rate.

Fig. 1 CKD predicted probability according to CRP and diabetes

Fig. 3 CKD predicted probability according to CRP and baseline
eGFR
40

Hypertension=no
Predicted CKD probability (%)

Hypertension=yes
30
20
10
0

0 1 2 3 4 5
CRP
Fig. 4 Receiver operating characteristic curve (ROC) for the asso-
Effect of hypertension is significant: P<0.001. ciation of C reactive protein and chronic kidney disease
CRP denotes C reactive protein.
CKD denotes chronic kidney disease.

subjects without renal disease or diabetes. In another cross

Fig. 2 CKD predicted
hypertension
increased risk for CKD. For patients with DM, HTN or
with eGFR between 60–90 ml\min\1.73 m2 at baseline, the
predictive role of CRP for CKD was highly significant.
Previous cross sectional studies suggested a possible
association between CRP and decreased kidney function.
Stuveling et al. [18] demonstrated an independent associ-
ation between CRP and diminished filtration rate on
probability according to CRP and
sectional study [19] on elderly subjects (aged [65 years),
increased levels of CRP in individuals with early degree of
renal failure were found in comparison to healthy subjects
and adjustment to baseline characteristics including car-
diovascular disease. CRP levels were in a dose dependent
correlation to the degree of renal insufficiency. Nonethe-
less, from cross sectional data it is difficult to conclude
whether CRP is a primary or a secondary marker for CKD.
Furthermore, decreased renal function may affect the

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inflammatory response. For instance, in animal models, the
serum half-lives of proinflammatory cytokines, tumor
necrosis factor alpha and interleukin-1 levels are greater in
animals with and without renal disease respectively,
probably due to decreased renal clearance of those factors
[24, 25]. In humans, levels of serum CRP, IL-6 and hya-
luronan are inversely correlated with creatinine clearance
[26, 27]. In CKD and especially in ESRD, various under-
lying factors contribute to the chronic inflammatory con-
ditions such as the uremic milieu, oxidative stress, carbonyl
stress, protein energy wasting and enhanced incidence of
infections [28–30]. Therefore, it may be argued that the
elevated levels of CRP previously observed in these cross
sectional studies reflect the increased inflammatory state
affected by the decrease in kidney function, and not nec-
essarily associated with the pathophysiologic processes that
contributed to the kidney disease itself. In order to reveal
whether high levels of CRP are the cause or the effect of
CKD, longitudinal observations are required. The results of
our longitudinal study imply that CRP is independently
associated with increased long-term risk for CKD in
apparently healthy subjects. Several pathophysiological
concepts linking low-grade inflammation and renal disease
have been described. Atherosclerosis is an inflammatory
condition. Data from numerous epidemiologic studies have
shown a significant association between elevated serum or
plasma concentrations of CRP and the prevalence of
underlying atherosclerosis [11]. Atherosclerosis and glo-
merulosclerosis, final common pathways of many types of
kidney injury, have much in common. It has been postu-
lated that mesangial expansion is similar to smooth muscle
cell proliferation in atherosclerosis [31]. Therefore, CRP
may reflect an inflammatory activity of the glomerulo-
sclerotic process. Furthermore, tubulointerstitial infiltration
of macrophages and monocytes causing an inflammatory
cascade is a well recognized feature of kidney injury in
many non-immune conditions such as diabetes, hyperten-
sion, ischemia and proteinuria [32]. In addition, well
known risk factors for decreased kidney function as obes-
ity, smoking, hypertension, diabetes and physical inactivity
may cause low levels of inflammation reflected by elevated
CRP [6, 31, 33]. Finally, as noted earlier, CRP mRNA was
expressed locally in tubular epithelial cells after stimula-
tion with IL-6 using in vitro experiments [5]. Thus, it may
also contribute to elevated serum levels and reflect the
inflammatory response to kidney tissue injury. It should be
emphasized that a low-grade inflammatory state differs
from an acute inflammatory condition. The purpose of the
latter is clearance of necrotic tissue, adaptation, and repair
while the purpose of the former appears to be restoration of
homeostasis [34]. Both of these conditions may result in an
increase of CRP levels. The minor elevation of CRP as
reflected by hs-CRP assays, occurs in many conditions in
325
which there are minor degrees of metabolic malfunction,
such as obesity and insulin resistance, and, in such cir-
cumstances, is not a marker of inflammation as we have
traditionally thought of it. This adaptive response was
suggested to be termed para-inflammation [34]. If tissue
malfunction is present for a sustained period, para-
inflammation can become chronic and in turn, contribute to
further disease progression, in part because of changes in
homoeostatic set points [34]. Taken together, high levels of
hs-CRP demonstrated in our study may reflect a sustained
state of kidney injury and adaption attempts, and not nec-
essarily a pure inflammatory state.
The results of our longitudinal study together with pre-
vious cross sectional studies point to an independent
association between CRP and reduced kidney function [18,
19], as it was previously described for cardiovascular dis-
ease [7–10, 35]. Thus, it may be suggested that CRP might
have a causal role in kidney injury and should not be
regarded merely as a risk marker. CRP causal role was
mainly investigated in association with cardiovascular
disease and atherosclerosis. Earlier observations suggest
that there may be a direct effect. Zwaka et al. [36] have
demonstrated that CRP opsonizes native low density lipo-
protein (LDL), allowing LDL to be taken up by macro-
phages without modification. Furthermore, in an animal
model of increased atherosclerosis, treatment with native
CRP increased aortic plaque area [37]. In addition, CRP
induces adhesion molecule expression and production of
interleukin-6 and monocyte chemo-attractant protein-1
(MCP-1) in human endothelial cells. These effects might
enhance a local inflammatory response within the athero-
sclerotic plaque by recruitment of monocytes and lym-
phocytes [38, 39]. In contrast to these experimental and
clinical observations, other reports have not supported a
direct role of CRP in atherogenesis [40–47]. In a study of
over 50,000 individuals with and without ischemic car-
diovascular disease in whom the levels of high-sensitivity
CRP and genotype for four CRP polymorphisms were
known, none of the genotype combinations were associated
with an increased risk of ischemic cardiovascular disease
[40]. Taken together, the role of CRP as a causal risk factor
in vascular injury has not been established. In our study we
demonstrated a possible additive effect of CRP and
hypertension and diabetes for predicting CKD, but not with
other risk factors that were included in the logistic
regression model (Figs. 1, 2, 3). Stuveling et al. [18] also
observed this effect in a cross sectional study on non-dia-
betic population as presented above. In their study, out of
six risk factors, only hypertension had a joint effect with
CRP for reduced filtration rate Fig. 2.
In our study we estimated the GFR using an equation
while ideally the best way would have been to use an
exogenous filtration marker or a clearance technique.
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However, such methods are invasive and costly and are not
applicable for a large population. Nevertheless, the CKD-
EPI equation has been shown to give the best estimation of
GFR in compression to other formulas while using 125I-io-
thalamate for measurement [48]. Furthermore, additional
studies have demonstrated a lower overall prevalence of
CKD in the general population using the CKD-EPI equations
[49–51]. In addition, CRP values for each subject were cal-
culated as a mean for all visits to the screening center, thus we
could not control for significant changes of CRP values on
day of examination. However, such variations in CRP levels
are extremely exceptional in our cohort, thus the probability
to alter the absolute results is unlikely. Finally, some of the
data is retrospectively analyzed and is prone to bias. Yet, all
subjects included in the study were examined in the same
manner in the clinic, and because the data is collected in a
registered based manner, the risk for information bias
decreases. In addition, the design, large study population and
long follow up time enables us to follow the sequence of
events and evaluate in a more reliable approach the associ-
ation between CRP and CKD development.
In conclusion, elevated serum CRP was found to be an
independent risk factor for future CKD development. CRP
has an enhanced predictive role for CKD in subjects with
DM, HTN or baseline eGFR between 60–90 ml/min/
1.73 m2. Following kidney function and other risk factors
for CKD is essential in those with high CRP levels. Further
prospective studies are needed in order to confirm these
observations and establish cause effect relationship
between CRP and long-term risk for CKD.
Acknowledgments Ilan Krause and Eitan Kugler had full access to
all the data in the study and take responsibility for the integrity of the
data and the accuracy of the data analysis.
Conflict of interest All authors declare no conflict of interest.There
are no funding sources associated with this study.
References
1. National Kidney Foundation (2002) K/DOQI clinical practice
guidelines for chronic kidney disease: evaluation, classification,
and stratification. Am J Kidney Dis Off J Natl Kidney Found 39(2
Suppl 1):S1–266
2. Collins AJ, Foley RN, Herzog C et al (2011) US Renal Data
System 2010 Annual Data Report. Am J Kidney Dis Off J Natl
Kidney Found 57(1 Suppl 1):A8 e1–526
3. As L (2007) Chronic kidney disease as a global public health
problem: approaches and initiatives––a position statement from
kidney disease improving global outcomes. Kidney Int
3(72):247–259
4. Kushner I (1982) The phenomenon of the acute phase response.
Ann NY Acad Sci 389:39–48
5. Jabs WJ, Logering BA, Gerke P et al (2003) The kidney as a
second site of human C-reactive protein formation in vivo. Eur J
Immunol 33(1):152–161
123
J Nephrol (2015) 28:321–327
6. Kushner I, Rzewnicki D, Samols D (2006) What does minor
elevation of C-reactive protein signify? Am J Med 119(2):166
e117–128
7. Kervinen H, Palosuo T, Manninen V, Tenkanen L, Vaarala O,
Manttari M (2001) Joint effects of C-reactive protein and other
risk factors on acute coronary events. Am Heart J
141(4):580–585
8. Ridker PM (2001) High-sensitivity C-reactive protein: potential
adjunct for global risk assessment in the primary prevention of
cardiovascular disease. Circulation 103(13):1813–1818
9. Koenig W, Lowel H, Baumert J, Meisinger C (2004) C-reactive
protein modulates risk prediction based on the Framingham
Score: implications for future risk assessment: results from a
large cohort study in southern Germany. Circulation
109(11):1349–1353
10. Ridker PM, Wilson PW, Grundy SM (2004) Should C-reactive
protein be added to metabolic syndrome and to assessment of
global cardiovascular risk? Circulation 109(23):2818–2825
11. Pearson TA, Mensah GA, Alexander RW et al (2003) Markers of
inflammation and cardiovascular disease: application to clinical
and public health practice: a statement for healthcare profes-
sionals from the Centers for Disease Control and Prevention and
the American Heart Association. Circulation 107(3):499–511
12. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH
(1998) Plasma concentration of C-reactive protein and risk of
developing peripheral vascular disease. Circulation
97(5):425–428
13. van der Velde M, Halbesma N, de Charro FT et al (2009)
Screening for albuminuria identifies individuals at increased renal
risk. J Am Soc Nephrol 20(4):852–862
14. Hoerger TJ, Wittenborn JS, Segel JE et al (2010) A health policy
model of CKD: 2. The cost-effectiveness of microalbuminuria
screening. Am J Kidney Dis Off J Natl Kidney Found
55(3):463–473
15. Moyer VA, Force USPST (2012) Screening for chronic kidney
disease: U.S. Preventive Services Task Force recommendation
statement. Ann Intern Med 157(8):567–570
16. Tonelli M, Sacks F, Pfeffer M et al (2005) Biomarkers of
inflammation and progression of chronic kidney disease. Kidney
Int 68(1):237–245
17. Hung AM, Ikizler TA, Griffin MR et al (2011) CRP polymor-
phisms and chronic kidney disease in the third national health and
nutrition examination survey. BMC Med Genet 12:65
18. Stuveling EM, Hillege HL, Bakker SJ, Gans RO, De Jong PE, De
Zeeuw D (2003) C-reactive protein is associated with renal
function abnormalities in a non- diabetic population. Kidney Int
63(2):654–661
19. Shlipak MG, Fried LF, Crump C et al (2003) Elevations of
inflammatory and procoagulant biomarkers in elderly persons
with renal insufficiency. Circulation 107(1):87–92
20. Levey AS, Coresh J, Balk E et al (2003) National Kidney
Foundation practice guidelines for chronic kidney disease: eval-
uation, classification, and stratification. Ann Intern Med
139(2):137–147
21. Ridker PM (2003) Clinical application of C-reactive protein for
cardiovascular disease detection and prevention. Circulation
107(3):363–369
22. Levey AS, Stevens LA, Schmid CH et al (2009) A new equation
to estimate glomerular filtration rate. Ann Intern Med
150(9):604–612
23. Robin X, Turck N, Hainard A et al (2011) pROC: an open-source
package for R and S? to analyze and compare ROC curves. BMC
Bioinform 12:77
24. Bemelmans MH, Gouma DJ, Buurman WA (1993) Influence of
nephrectomy on tumor necrosis factor clearance in a murine
model. J Immunol 150(5):2007–2017
J Nephrol (2015) 28:321–327
25. Poole S, Bird TA, Selkirk S et al (1990) Fate of injected inter-
leukin 1 in rats: sequestration and degradation in the kidney.
Cytokine 2(6):416–422
26. Panichi V, Migliori M, De Pietro S et al (2001) C reactive protein
in patients with chronic renal diseases. Renal Fail 23(3–4):
551–562
27. Stenvinkel P, Heimburger O, Wang T, Lindholm B, Bergstrom J,
Elinder CG (1999) High serum hyaluronan indicates poor sur-
vival in renal replacement therapy. Am J Kidney Dis Off J Natl
Kidney Found 34(6):1083–1088
28. Spittle MA, Hoenich NA, Handelman GJ, Adhikarla R, Homel P,
Levin NW (2001) Oxidative stress and inflammation in hemod-
ialysis patients. Am J Kidney Dis Off J Natl Kidney Found
38(6):1408–1413
29. Mezzano D, Pais EO, Aranda E et al (2001) Inflammation, not
hyperhomocysteinemia, is related to oxidative stress and hemo-
static and endothelial dysfunction in uremia. Kidney Int
60(5):1844–1850
30. Suliman ME, Heimburger O, Barany P et al (2003) Plasma
pentosidine is associated with inflammation and malnutrition in
end-stage renal disease patients starting on dialysis therapy. J Am
Soc Nephrol JASN 14(6):1614–1622
31. Stuveling EM, Bakker SJ, Hillege HL, de Jong PE, Gans RO, de
Zeeuw D (2005) Biochemical risk markers: a novel area for better
prediction of renal risk? Nephrol Dial Transpl Off Publ Eur Dial
Transplant Assoc Eur Ren Assoc 20(3):497–508
32. Rodriguez-Iturbe B, Pons H, Herrera-Acosta J, Johnson RJ
(2001) Role of immunocompetent cells in nonimmune renal
diseases. Kidney Int 59(5):1626–1640
33. Stengel B, Tarver-Carr ME, Powe NR, Eberhardt MS, Brancati
FL (2003) Lifestyle factors, obesity and the risk of chronic kidney
disease. Epidemiology 14(4):479–487
34. Medzhitov R (2008) Origin and physiological roles of inflam-
mation. Nature 454(7203):428–435
35. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH
(1997) Inflammation, aspirin, and the risk of cardiovascular dis-
ease in apparently healthy men. N Engl J Med 336(14):973–979
36. Zwaka TP, Hombach V, Torzewski J (2001) C-reactive protein-
mediated low density lipoprotein uptake by macrophages:
implications for atherosclerosis. Circulation 103(9):1194–1197
37. Schwedler SB, Amann K, Wernicke K et al (2005) Native
C-reactive protein increases whereas modified C-reactive protein
reduces atherosclerosis in apolipoprotein E-knockout mice. Cir-
culation 112(7):1016–1023
38. Pasceri V, Willerson JT, Yeh ET (2000) Direct proinflammatory
effect of C-reactive protein on human endothelial cells. Circu-
lation 102(18):2165–2168
39. Pasceri V, Cheng JS, Willerson JT, Yeh ET (2001) Modulation of
C-reactive protein-mediated monocyte chemoattractant protein-1
induction in human endothelial cells by anti-atherosclerosis
drugs. Circulation 103(21):2531–2534
327
40. Zacho J, Tybjaerg-Hansen A, Jensen JS, Grande P, Sillesen H,
Nordestgaard BG (2008) Genetically elevated C-reactive protein
and ischemic vascular disease. N Engl J Med 359(18):1897–1908
41. Clapp BR, Hirschfield GM, Storry C et al (2005) Inflammation
and endothelial function: direct vascular effects of human
C-reactive protein on nitric oxide bioavailability. Circulation
111(12):1530–1536
42. Paffen E, Vos HL, Bertina RM (2004) C-reactive protein does not
directly induce tissue factor in human monocytes. Arterioscler
Thromb Vasc Biol 24(5):975–981
43. Taylor KE, Giddings JC, van den Berg CW (2005) C-reactive
protein-induced in vitro endothelial cell activation is an artefact
caused by azide and lipopolysaccharide. Arterioscler Thromb
Vasc Biol 25(6):1225–1230
44. Pepys MB, Hawkins PN, Kahan MC et al (2005) Proinflamma-
tory effects of bacterial recombinant human C-reactive protein
are caused by contamination with bacterial products, not by
C-reactive protein itself. Circ Res 97(11):e97–e103
45. Pai JK, Mukamal KJ, Rexrode KM, Rimm EB (2008) C-reactive
protein (CRP) gene polymorphisms, CRP levels, and risk of
incident coronary heart disease in two nested case-control studies.
PLoS One 3(1):e1395
46. Lawlor DA, Harbord RM, Timpson NJ et al (2008) The associ-
ation of C-reactive protein and CRP genotype with coronary heart
disease: findings from five studies with 4,610 cases amongst
18,637 participants. PLoS One 3(8):e3011
47. Elliott P, Chambers JC, Zhang W et al (2009) Genetic loci
associated with C-reactive protein levels and risk of coronary
heart disease. JAMA J Am Med Assoc 302(1):37–48
48. Michels WM, Grootendorst DC, Verduijn M, Elliott EG, Dekker
FW, Krediet RT (2010) Performance of the Cockcroft-Gault,
MDRD, and new CKD-EPI formulas in relation to GFR, age, and
body size. Clin J Am Soc Nephrol 5(6):1003–1009
49. Matsushita K, Mahmoodi BK, Woodward M et al (2012) Com-
parison of risk prediction using the CKD-EPI equation and the
MDRD study equation for estimated glomerular filtration rate.
JAMA J Am Med Assoc 307(18):1941–1951
50. Matsushita K, Selvin E, Bash LD, Astor BC, Coresh J (2010)
Risk implications of the new CKD Epidemiology Collaboration
(CKD-EPI) equation compared with the MDRD Study equation
for estimated GFR: the Atherosclerosis Risk in Communities
(ARIC) Study. Am J Kidney Dis Off J Natl Kidney Found
55(4):648–659
51. Stevens LA, Li S, Kurella Tamura M et al (2011) Comparison of
the CKD epidemiology collaboration (CKD-EPI) and modifica-
tion of diet in renal disease (MDRD) study equations: risk factors
for and complications of CKD and mortality in the Kidney Early
Evaluation Program (KEEP). Am J Kidney Dis Off J Natl Kidney
Found 57(3 Suppl 2):S9–S16
123