Inflamation Markers in Chronic Kidney Disease

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Advances in Peritoneal Dialysis, Vol. 27, 2011

Inammation Markers,

Chronic Kidney Disease,

and Renal ReplacementTherapy

Chronic kidney disease (CKD) is associated with a

proinammatory state and an excess of cardiovascular

risk. In this work, we describe changes in inamma-

tory markersC-reactive protein (CRP), pentraxin 3

(PTX3), serum component of amyloid A (SAA), and

procalcitonin (PCT)in CKD patients compared with

a control group of subjects with a normal estimated

glomerular ltration rate (eGFR). Blood samples

were obtained from 69 healthy individuals (GP) and

70 end-stage CKD patients25 not yet on dialysis,

22 on peritoneal dialysis (PD), and 23 on hemodi-

alysis (HD). These were the results [median (95%

condence interval)] for the GP, CKD, PD, and HD

groups respectively:

CRP: 1.40 mg/L (1.19 2.11 mg/L), 6.50 mg/L

(3.57 8.32 mg/L), 7.60 mg/L (2.19 22.10 mg/L),

9.60 mg/L (6.62 16.38 mg/L)

SAA: 3.10 mg/L (2.90 3.53 mg/L), 7.11 mg/L

(3.81 15.40 mg/L), 9.69 mg/L (5.07 29.47 mg/L),

15.90 mg/L (6.80 37.48 mg/L)

PCT: 0.03 ng/mL (0.02 0.03 ng/mL), 0.12 ng/mL

(0.09 0.16 ng/mL), 0.32 ng/mL (0.20 0.46 ng/

mL), 0.79 ng/mL (0.45 0.99 ng/mL)

PTX3: 0.54 ng/mL (0.33 0.62 ng/mL), 0.71 ng/

mL (0.32 1.50 ng/mL), 1.52 ng/mL (0.65

2.13 ng/mL), 1.67 ng/mL (1.05 2.27 ng/mL)

Compared with levels in the GP group, levels of

SAA and CRP (systemic response) were signicantly

higher in CKD patients on and not on dialysis. Levels

of PTX3 were higher only in dialyzed patients, signi-

cantly so in those on HD (greatly different from the

CRP levels). These differing levels might be related

to a local reaction caused by an invasive intervention

(PD or HD). As eGFR declines and with the start of

renal replacement therapy, PCT increases. Levels of

PCT could potentially cause confusion when these

patients are being evaluated for the presence of infec-

tion, and may also demonstrate some microvascular

implications of dialysis therapy.

Key words

Inammation markers, cardiovascular risk, chronic

kidney disease, proinammatory state, renal replace-

ment therapy

Introduction

More and more studies show that the immune system

actively participates in the development of vascular

disease. The early stages of atherosclerosis are char-

acterized by inltration of inammatory cells into the

vascular wall, with the involvement of innate immu-

nity factors (1,2). For that reason, the research effort

to elucidate the mechanisms behind these relationships

and their consequences is growing.

Among the components involved in the innate

immune inflammatory process are found short

pentraxins such as C-reactive protein (CRP) and long

pentraxins such as pentraxin 3 (PTX3). Some other

peptides not structurally related to pentraxinssuch

as serum component of amyloid A (SAA) andprocalcitonin (PCT)may also be involved in

inflammatory states. The systemic acute-phase

reactant CRP is released in the liver after induction

by interleukin 6. The main functions of PTX3 are

closely related to those of CRP, but the PTX3 protein

is produced at a locoregional level by many kind of

cells (endothelial dendritic cells, smooth muscle cells,

broblasts, neutrophils, monocytes, and macrophages,

and also kidney proximal tubular epithelial and

mesangial cells) (35). Synthesis and release of

PTX3 is orchestrated by inammatory stimuli such as

Bernardo A. LavnGmez,1 Rosa PalomarFontanet,2

Mara GagoFraile,2 Jos A. QuintanarLartundo,2

Estefana GmezPalomo,1Domingo GonzlezLamuo,3Mara T. GarcaUnzueta,2Manuel A. AriasRodrguez,2

Juan A. GmezGerique1

From: Departments of 1Clinical Biochemistry (Dyslipidemia

and Vascular Risk Unit), 2Nephrology, and 3Pediatrics,

University Hospital Marqus de Valdecilla, IFIMAV,

University of Cantabria, Santander, Spain.


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34 LavnGmezet al.

interleukin 1, tumor necrosis factor , oxidized low-

density lipoprotein cholesterol, and micro-organisms

(6,7). Another systemic acute-phase reactant, SAA,

is synthesized and released by the liver (8,9).

Procalcitonin is a marker of bacterial infection induced

in extra-thyroid tissues (kidney, liver, pancreas, brain)by tumor necrosis factor (10,11); but PCT may also

be involved in microvascular inammatory processes.

Some studies of the biocompatibility of hemodialysis

(HD) membranes in HD patients having no acute or

chronic infection have shown a decline in PTC levels

as membranes and lters that are more biocompatible

are used (12).

The pathologic condition of chronic kidney dis-

ease (CKD) is associated with a relatively unexplained

excess of cardiovascular risk (13,14). For that reason,

a study of the impact of these inammatory and innateimmune factors is needed (15). The aim of the pres-

ent work was therefore to describe changes in these

emerging markers of innate immune and inammatory

response (CRP, PTX3, SAA, PCT) in CKD patients

on and not on renal replacement therapy [RRT, peri-

toneal dialysis (PD) or HD] compared with a control

group of subjects with a normal estimated glomerular

ltration rate (eGFR).

Methods

We obtained serum and EDTA plasma from 69 healthy

subjects in the general population (GP) and 70 CKD

patients, including 25 in stages IV and V CKD not on

dialysis, 22 on PD, and 23 on HD. In the HD group, the

samples were taken before a HD session (all patients

had been using biocompatible membranes in the im-

mediate past). All of the subjects were associated with

the Nephrology Department of University Hospital

Marqus de Valdecilla, and none had an infection at

the time of the blood draw. Samples of EDTA plasma

were available only from approximately 15 patientsin each group.

In all subjects, these renal function and inam-

matory serum markers were quantied: serum creati-

nine (sCr) by the Jaffe method on a Dimension RXL

analyzer (Siemens Healthcare, Mannheim, Germany);

standardized CRP, SAA, and cystatin C (CysC) by

immunonephelometry (CardioPhase High Sensitiv-

ity C-Reactive Protein and N Latex SAA and Cys-

tatin C kits) on a Behring Nephelometer II (Siemens

Healthcare); serum PCT by immunoassay (Brahms

PCT-sensitive Kryptor assay: Brahms, Hennigsdorf,

Germany); and plasma PTX3 by ELISA (Human Pen-

traxin3/TSG-14 ELISA System: Perseus Proteomics,

Tokyo, Japan).

The statistical treatment of data (MannWhitney

U-test, with signicance set atp< 0.050) was carried

out using the MedCalc software application (Med-Calc, Ghent, Belgium). The levels of all inammatory

markers have a nonparametric distribution, and so

results are expressed as medians with 95% condence

intervals (CIs).

Results

Table I shows the resulting data.

Serum creatinine and CysC were determined to

evaluate the eGFR and evolving renal insufciency

of the subjects.

Compared with the GP group, all CKD patients(on and not on RRT) had higher levels of serum

CRP (taking 3 mg/L as the lower reference limit for

long-term inammation). Although CRP tended to

increase with eGFR decline, the increase was sig-

nicant only between the GP group and the CKD

groups (p< 0.050).

Serum levels of SAA (upper reference limit:

6.40 mg/L) changed in a manner similar to that of

the CRP levels. Levels of SAA were elevated in

CKD patients and not signicantly altered by HD or

PD therapy.

Compared with the GP group and with each

other, all CKD groups showed differences in PCT

levels. This biomarker increased signicantly with

eGFR decline.

Plasma PTX3 (upper reference limit: 1.18 ng/mL)

was higher in the RRT groups than in the GP group.

Levels were also different between the patients on HD

and those not yet on RRT, but levels in those not yet

on RRT were not very different from those in the CP

group (Figure 1).

Discussion and conclusions

In the present study, serum CRP was increased in

CKD patients, and although it trended slightly higher

with RRT, that trend was nonsignicant. Severe CKD

therefore seems to bring on a low-level inamma-

tory state.

Plasma PTX3 increased only in end-stage CKD

patients on HD (greatly different from the CRP levels).

These differing levels might be related to a systemic

proinammatory state caused by CKD, followed by


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Inammation and Dialysis 35

FIGURE1 Number of times (n) that each determination exceeded the upper reference limit (URL). The URLs are, for C-reactive protein

(CRP), 10.00 mg/L (acute inammation); for pentraxin-3 (PTX3), 1.18 ng/mL; for serum component of amyloid A (SAA), 6.40 mg/L;

and for procalcitonin (PCT), 0.200 ng/mL (local infection). GP = general population; CKD = chronic kidney disease; PD = peritoneal

dialysis; HD = hemodialysis.

TABLEI Features of the general, chronic kidney disease (CKD), peritoneal dialysis, and hemodialysis populationsa

Parameter Population

General CKD Peritoneal dialysis Hemodialysis

Patients (n) 69 25 22 23sCr (mg/dL) 0.910.04 3.950.46 7.461.06 8.150.82

CysC (mg/L) 0.810.05 3.160.28 5.340.69 5.560.50

CRP (mg/L) 1.40 (1.19 to 2.11) 6.50 (3.57 to 8.32)b 7.60 (2.19 to 22.10)b 9.60 (6.62 to 16.38)b

SAA (mg/L) 3.10 (2.90 to 3.53) 7.11 (3.81 to 15.40)b 9.69 (5.07 to 29.47)b 15.90 (6.80 to 37.48)b

PCT (ng/mL) 0.03 (0.02 to 0.03) 0.12 (0.09 to 0.16)b,d,e 0.32 (0.20 to 0.46)b,c,e 0.79 (0.45 to 0.99)b,c,d

PTX3 (ng/mL)f 0.54 (0.33 to 0.62) 0.71 (0.32 to 1.50)e 1.52 (0.65 to 2.13)b 1.67 (1.05 to 2.27)b,c

(n=20) (n=15) (n=15) (n=23)

a Data shown as mean standard deviation, or median (95% condence interval) for variables with a non-normal distribution.b p< 0.050 compared with the general population.c p< 0.050 compared with the CKD population.d p< 0.050 compared with the PD population.

e p< 0.050 compared with the hemodialysis population.f Sample sizes are different because of difculties in collecting another EDTA tube.

sCr = serum creatinine; CycC = cystatin-C; CRP = C-reactive protein; SAA = serum component of amyloid A; PCT = procalcitonin;

PTX3 = pentraxin 3.


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36 LavnGmezet al.

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a local (microvascular) reaction (release of PTX3) in

the case of invasive intervention (HD) (12).

Similarly, we observed that levels of serum SAA,

an acute-phase reactant with a structure different

from the pentraxins, changed in the same way that

the levels of C-reactive protein did (systemic inam-matory response).

Of particular relevance was the progressive in-

crease in serum PCT as eGFR declined. The increase

in PCT was especially marked in the PD and HD

groups (invasive RRTs) and could potentially cause

confusion when such patients are being evaluated for

the presence of infection. Those levels may also dem-

onstrate certain microvascular implications of RRT.

We observed that PTX3 and PCT increased in

parallel in patients on RRT. These increases might be

a result of local stimulation of peritoneum by dialy-sis uids and of blood polymorphonuclear cells by

dialysis membranes.

Recent reports have provided evidence for the

efcacy and safety of the combination of ezetimibe

and simvastatin for lowering low-density lipoprotein

cholesterol among a wide range of patients with

CKD not on RRT, but not among CKD patients on

RRT (16,17).

Taken together, these data showing elevations in

innate immune and inammatory markers suggest

that, because of the decline in eGFR, CKD patients are

in a proinammatory state that should be intensively

treated to prevent undesirable cardiovascular events.

In the case of CKD patients on RRT, the traditional

therapy (statins) is insufcient to handle the exces-

sive proinammatory state because of the chronic

proinammatory stimuli induced locally by RRT. We

therefore think that conventional therapy should be

combined with new therapies to combat the inam-

matory state and lower the cardiovascular risk in CKD

patients on RRT.

Acknowledgments

We thank all staff of the Nephrology and Biochemistry

laboratories for their assistance with data collection

and management.

Disclosures

The authors have no nancial conicts of interest to

declare. BAL is a researcher whose work is supported

by IFIMAV (Instituto de Formacin e Investigacin

Marqus de Valdecilla) grant no. BFR 03/09.
http://www.ppmx.com/en/corporate/news/20070918PR_E..htmlhttp://www.ppmx.com/en/corporate/news/20070918PR_E..html


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Inammation and Dialysis 37

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(USRDS). 2010 Annual data report: atlas of chronic

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lism and activity in chronic kidney disease. Nat Rev

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16 SHARP Collaborative Group. Study of Heart and

Renal Protection (SHARP): randomized trial to

assess the effects of lowering low-density lipoprotein

cholesterol among 9,438 patients with chronic kidney

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17 Canadian Heart Research Centre (CHRC),

SHARP Collaborative Group. Results: question

and answers about the SHARP trial (web page).Toronto, ON: CHRC; n.d. [Available online at:

www.chrc.net/LDLINCKD/results.html; cited June

27, 2011]

Corresponding author:

Bernardo A. LavnGmez, MD, HU Marqus de

Valdecilla, Avda. de Valdecilla s/n, Santander 39008

Cantabria, Spain.

E-mail:

[email protected]
http://www.chrc.net/LDLINCKD/results.htmlmailto:[email protected]:[email protected]://www.chrc.net/LDLINCKD/results.html

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