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Pharmacological Research 57 (2008) 93–99

Anti-inflammatory effects of combined treatment with acetylsalicylic acid and atorvastatin in haemodialysis patients

affected by Normal Weight Obese syndrome

Laura Di Renzo a,b, Annalisa Noce c, Sandro De Angelis d, Natascia Miani c,Nicola Di Daniele e, Carmela Tozzo c, Antonino De Lorenzo a,b,∗

a Department of Neuroscience, Division of Human Nutrition, University of Tor Vergata, Via Montpellier 1, I-00133 Rome, Italyb I.N.Di.M., National Institute for Mediterranean Diet and Nutrigenomic, Reggio Calabria, Italy

c Nephrology and Dialysis Service, University Hospital “Tor Vergata”, Rome, Italyd Specialization School of Nephrology, University of “Tor Vergata”, Rome, Italy

e Internal Medicine Departement, University Hospital “Tor Vergata”, Rome, Italy

Accepted 28 November 2007

bstract

Low-grade inflammation is a common feature of chronic kidney disease (CKD) and persistent systemic inflammation is thought to be a strongredictor of cardiovascular events. Inflammation plays a role in determining the serum albumin levels in haemodialysis patients (HD) independentlyf the nutritional status. Increased cardiovascular mortality in CKD has been associated with the increased incidence of obesity in uremic patients.ngenbleek suggested a prognostic inflammation and nutritional index (PINI), based on serum albumin, pre-albumin, C-reactive protein, and �1cid glycoprotein, to identify and to follow up acutely ill patients at risk of major complications. The aims of the present study were: to verifyhe incidence of Normal Weight Obese (NWO) syndrome; to evaluate by PINI the effect of 8 weeks acetyl salicylic (100 mg/die) and atorvastatin10 mg/die) combined treatment on chronic inflammation in 52 selected HD patients. Laboratory evaluation, anthropometric and body compositioneasurements were detected. At baseline the 56.25% of non-obese, the 84.21% of pre-obese-obese, and the 41.17% of NWO women showed PINI

alues >1 (normal status PINI < 1). After the pharmacological treatment, high significant (P < 0.001) reduction in lipid profile, an elevated increase

f HDL levels, and a significant reduction of inflammatory markers were obtained. Firstly, our results showed that ASA and atorvastatin combinedreatment was effective in reducing inflammatory status in HD patients independently of body composition: at the end of the study only 7.49% ofhe patients exhibited PINI > 1. Further studies will be necessary to understand the causes of inflammation in non-responder patients.

2008 Elsevier Ltd. All rights reserved.

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eywords: PINI; Inflammation; Body composition; NWO syndrome; ESRD; D

. Introduction

In a cross-sectional analysis of the haemodialysis (HEMO)tudy, the prevalence of cardiovascular disease in dialysisatients far exceeded that in the general population and could not

e readily explained by conventional cardiovascular risk factors1]. Approximately it has been evaluated that dialysis patientsave a tenfold increased risk of cardiovascular death compared

∗ Corresponding author at: Department of Neuroscience, Division of Humanutrition, University of Tor Vergata, Via Montpellier 1, I-00133 Rome, Italy;

.N.Di.M., National Institute for Mediterranean Diet and Nutrigenomic, Reggioalabria, Italy. Tel.: +39 0672596415; fax: +39 0672596415.

E-mail address: delorenzo@med.uniroma2.it (A. De Lorenzo).

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043-6618/$ – see front matter © 2008 Elsevier Ltd. All rights reserved.oi:10.1016/j.phrs.2007.11.005

ith the general population, adjusted for age, gender, race, andiabetes [2,3]. Among traditional risk factors, chronic inflamma-ion, commonly observed in haemodialysis (HD) patients, haseen correlated to CVD and malnutrition by several pathogeneticechanisms [4]. Moreover, the increased incidence of obesity in

remic patients (due to ameliorated nutritional intakes and lifetyle changes) was associated with increased CVD morbiditynd mortality in chronic kidney disease (CKD) [5,6,7].

Obesity represents an expansion of the adipose tissue mass,dynamic endocrine organ [8], that is an important source of

arious adipokine, that contributes to a pro-inflammatory milieu9], and insulin resistance [10]. The obese state is characterizedy what has been called low-grade systemic inflammation. Inact, inflammatory markers, such as C-reactive protein (CRP),

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nd other pro-inflammatory cytokines are increased in obesendividuals compared with lean subjects, although not to theame extent observed in classic inflammatory condition.

Recently De Lorenzo et al. identified in the general pop-lation the so-called normal weight obese (NWO) syndrome11]. The NWO subjects show low body mass index (BMI),ut high fat mass percentage (FM%), high level of high-densityipoprotein cholesterol (HDL-C) and elevated total cholesterolTC)/HDL-C ratio, that increased the risk to develop CVD.urthermore, an early inflammatory status characterized theyndrome [12]. Therefore, it may be necessary to verify the inci-ence of NWO syndrome in HD patients. In addition, to improveurvival of HD patients, preventive and therapeutic strategieshat may contribute to reduce the prevalence of obesity, NWOyndrome and CVD, are necessary. Interestingly, lipid-loweringith simvastatins has been found to slow the progression of

enal disease in patients with nephrotic syndrome, just as wasbserved Lovastatin employment exerts favourable effects on thevolution of diabetic nephropathy [13]. Furthermore, a signifi-ant reduction in serum creatinine and uric acid concentrationas observed in patients with peripheral arterial disease treatedith atorvastatin (20 mg/day) [14].In order to identify and follow up acutely ill patients at risk of

ajor complications a prognostic inflammation and nutritionalndex (PINI), based on the levels of serum albumin, pre-albumin,RP and alpha-1 acid glycoprotein (�1-AGP) was developed

15,16].Thus, the aims of our study were:

as first to verify the incidence of NWO syndrome in HDpatients;second to evaluate the potential utility of a prognosticinflammation and nutritional index (PINI) assessment in HDpatients, as it has never been assessed in this class of patientsandfinally to determine through PINI monitoring if inflamma-tory status could be differently affected in relation to bodycomposition by short-term (8 weeks) ASA (100 mg/day) andatorvastatin (10 mg/day) combined treatment.

. Patients and methods

.1. Patients

Adult asymptomatic patients who had been stable on thrice-eekly HD for at least 3 months and who had a permanent access

arterio-venous fistula) capable of delivering a blood flow ratef at least 250 ml/min were eligible for inclusion in the study.

This study included 52 end-stage renal diseases (ESRD)symptomatic chronic adult HD patients (mean time of.02 ± 6.80 years), 25 men and 27 women (aged 50 ± 11.41ears), randomly selected from 121 Caucasian Italian sub-ects, recruited from Renal Unit of Policlinico Tor Vergata,

n Rome. The causes of renal failure included the following:hronic glomerulonephritis (16.3%), pyelonephritis and intersti-ial nephritis (7.5%), polycystic kidney disease (6.9%), diabeticephropathy (15.8%), nephroangiosclerosis (26%), other dis-

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al Research 57 (2008) 93–99

ases or unknown cause (27.5%). As for dialysis procedures,9 patients were treated with conventional haemodialysis withicarbonate containing dialysis fluids and non-Cuprophan lowux dialysis membranes, while 23 patients were undergo-

ng hemodiafiltration techniques (respectively: 6 patients onemodiafiltration, 4 patients on acetate free biofiltration (AFB),3 patients on HFR-ON LINE). Only first-use dialysers weresed; bicarbonate dialysate was used with a dialysate flow of00 ml/min. The dialysis session lasted three to four hours,epending on the individual prescription of the patient. Theialytic adequacy was evaluated by KT/V: mean values were.3. All patients had arterio-venous fistulas. The dialysis ses-ion lasted three to four hours, depending on the individualrescription of the patient.

The subjects were classified as pre-obese-obese according tohe WHO Technical Report [17]. None of patients had a shortife expectancy because of a metastatic malignancy or terminalIV disease.The study received ethics committee approval and informed

onsent was obtained from all patients before their enrolment inhe study.

Exclusion criteria. Patients with familiar hypercholes-erolemia, diabetes mellitus, poorly controlled hypertension andhose receiving lipid-lowering treatment before the study.

Pharmacological treatment. All patients were started on ASA100 mg/day) and atorvastatin (10 mg/day) for 8 weeks.

Baseline characteristics of the patients are shown inables 2–4.

.2. Anthropometric measurements

After a 12-h overnight fast, all subjects underwent anthropo-etrical evaluation. Anthropometric parameters were measured

or all participants according to standard methods: body weight,eight, hip and waist circumferences [18]. Subjects werenstructed to take off their clothes and shoes before performingll the measurements. Body weight (kg) was measured to theearest 0.1 kg, using a balance scale (Invernizzi, Rome, Italy).eight (cm) was measured using a stadiometry to the nearest.1 cm (Invernizzi, Rome, Italy). The circumferences (waist andip) were measured with a flexible steel metric tape to the near-st 0.5 cm. The abdominal circumference was defined as theorizontal distance around the abdomen at the umbilicus. Hipircumference was measured as the horizontal distance betweenhe two superior iliac bones.

The body mass index (BMI) was calculated using the for-ula:

MI = body weight (kg)

height (m2).

.3. Dual X-ray absorptiometry (DXA)

Body composition was determined by means of Dual-Xbsorptiometry (DXA) (Lunar model DPX-IQ Lunar Corp.,adison) fan beam scanner, according to the previously

escribed procedure [19,20]. The subjects were instructed

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pbody mass index (BMI)): (1) 16 non-obese subjects (controlgroup), with BMI ≤ 25 kg/m2 (normal range18–25 kg/m2), andFM% ≤ 30%; 56.25% of them exhibited PINI values >1, and43.75% of them PINI values <1; (2) 19 pre-obese-obese patients

Table 1Baseline patients characteristics

Patients characteristics

No. of patients 52Age median, years (range) 50 (41–68)Gender (M, W) (25, 27)BMI, (kg/m2) (S.D.) 24.6 (±5.1)Systolic BP, mm Hg (S.D.) 148 (±16)Diastolic BP, mm HG (S.D.) 86 (±8)No. of current smokers (%) 18 (34.6%)No. of ex-smokers (%) 34 (65.4%)

L. Di Renzo et al. / Pharmaco

ot to exercise within 24 h from the test. The subjects wereiven complete instructions on the testing procedure. Theyore a standard cotton t-shirt, shorts and socks. They laidrone on the DXA, without moving for 20 min while theXA scan recorded their results. The coefficient of variation

CV% = 100S.D./mean) intra- and inter-subjects ranged from% to 5%. Radiation exposure was <8 SV Radiation exposureas <8 SV.The NWO group was distinguished from non-obese women

n the basis of their FM distribution using DXA, namely theM percentage (FM%) classification criterion. The expectednd reference values for FM% in NWO women were 30.1–48.311,12].

.4. Biochemical analysis

Early morning blood samples were taken from each individ-al for biochemical screening tests after a 12-h overnight fast.ll materials were immediately placed on ice. The plasma wasbtained by centrifugation at 1600 × g for 10 min at 4 ◦C. Forlbumin, pre-albumin, and �1-acid glycoprotein, a highly puri-ed antiserum produced by rabbit immunization was used. For

he determination of the C-reactive protein, a highly sensitiveethod based on polystyrene particle coated with monoclonal

ntibodies specific to human CRP was used (CardioPhase hs-RP). Albumin, pre-albumin, �1-acid glycoprotein, and plasmaigh-sensitivity C-reactive protein (hs-CRP) levels were mea-ured by the nephelometric method (BN IITM Nephelometer,ADE-BEHRING-Marburg GmbH), with reagents provided by

he same company.The lipid profile, included plasma total cholesterol (TC),

igh-density lipoprotein–cholesterol (HDL–chol), low-densityipoprotein–cholesterol (LDL–chol), and triglyceride (TG)oncentrations, was determined through standard enzymatic col-rimetric techniques (Roche Modular P800, Roche Diagnostics,ndianapolis, IN, USA), according to the manufacturer’s proce-ures, with reagents provided by the same company. All theseipid markers were useful predictors of vascular risk. After 8eeks of atorvastatin and ASA treatment, an identical assess-ent was carried out.Analyses were carried out by the accredited Clinical Chemi-

al Laboratories of the “Tor Vergata” Polyclinic (PTV) of Rome,taly.

.5. Prognostic inflammatory and nutritional index

The prognostic inflammatory and nutritional index was calcu-ated by PROTIS Program (DADE-BEHRING-Marburg GmbH)nd it was defined as:

INI = CRP (mg/L) × �-1 acid glycoprotein (g/L)

Albumin (g/L) × Pre-albumin (g/L)

PINI values are the following: <1 normal status, 1–10

arginal malnutrition, 11–20 moderate malnutrition, >20 severealnutrition.We divided the subjects in two groups, according their PINI

alues: (1) with PINI < 1; (2) with PINI > 1. As PINI was never

N

VMB

l Research 57 (2008) 93–99 95

easured in NWO and obese HD patients, the expected PINIalues were in the range of 0.85–21.5.

.6. Statistical analysis

Data are presented as group means ± standard deviationsS.D.). A Tukey’s test was used to assess the significance amonghe three groups, while the nonparametric Mann–Whitney testas used when comparing two groups. A Pearson’s simple cor-

elation was used to study the association between two variables.he minimal level of significance was fixed at P ≤ 0.05 for all

he procedures. The statistical analysis was carried out by meansf the Instat—GraphPad Software, SanDiego, CA, USA andersion number 4.03, 2005.

. Results

All patients completed the study and remained on a regimenf 10 mg/day of atorvastatin and 100 mg/day of ASA at the end ofhe study. Descriptive characteristics of the selected HD patientsre listed in Table 1.

As shown in Table 2, the 52 HD subjects were subdi-ided according PINI values and hemodialytic techniques: 29f the patients were undergoing diffusive standard hemodial-ses (SHD) versus a total of 23 convective hemodialfiltrationsHDF). 14 of the SHD patients showed a PINI values >1. Instead,nly 1 patient undergoing haemofiltration with reinfusion (ofltrafiltrate) (HFR – ON LINE) and only 1 patient undergoingDF have a PINI value >1; 3 patients on undergoing acetate freeiofiltration (AFB) showed a PINI value >1.

In Fig. 1A are reported PINI values in the selected patientsefore pharmacological treatment. The patients were classifieds non-obese and NWO on the basis of their body fat massercentage (FM%) and or as pre-obese-obese according to theHO Technical Report [17].We identified three groups of subjects through body com-

osition assessment (dual X-ray absorptiometry (DXA) and

o. of patients taking anti-hypertensives (%) 44 (84.6%)

alues are expressed as mean (S.D.) unless otherwise stated.= men, W = women, BMI = body mass index, S.D. = standard deviation,

P = blood pressure.

96 L. Di Renzo et al. / Pharmacological Research 57 (2008) 93–99

Table 2PINI values in 52 ESRD patients according to different dialysis procedures

Standard hemodialysis Acetate-free biofiltration Hemodia-filtration HFR-on-line Total and (%)

PINI < 1 15 1 5 13 34 (65.38%)PINI > 1 14 3 1 0 18 (34.62%)

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INI = Prognostic Inflammation and Nutritional Index; HFR-on-line = haemofil

ith BMI ≥ 25 kg/m2 and FM% ≥ 30%; 15.79% of them hadINI values <1, while the 84.21% of pre-obese-obese the showedINI values >1. (3) 17 NWO women with BMI ≤ 25 kg/m2, andM% ≥ 30%; 41.17% of them had PINI values >1; 58.83% of

hem had PINI values <1.After 8 weeks of drugs therapy, all non-obese patients showed

he PINI values <1; 89.47% of pre-obese-obese HD patients had

he PINI values <1; 88.24% of NWO women showed the indexalues <1 (Fig. 1B).

The correlation between the anthropometric parameters andhe blood markers of inflammation (CRP and �1-AGP) and nutri-

ig. 1. (A) Relationship between PINI values and body composition parametersn three groups: non-obese (BMI < 25, FM% < 30), pre-obese-obese (BMI > 25,M% > 30), NWO (BMI < 25, FM% > 30), at baseline time. (B) Relationshipetween PINI values and body composition parameters in three groups: Non-bese (BMI < 25, FM% < 30), pre-obese-obese (BMI > 25, FM% > 30), NWOBMI < 25, FM% > 30), after 8 weeks of drugs theraphy with ASA and atorvas-atin.

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ion (albumin and pre-albumin) are reported in Table 3. In HDon-obese subjects, a significant positive correlation (P < 0.05*)as observed between weight to hip ratio and �1-AGP, between

ean body mass and pre-albumin (P < 0.001**) and betweeneight to hip ratio and CRP (P < 0.001). As expected in HDre-obese-obese subjects the correlation between BMI pre-nd post-dialysis weight and pre-albumin was high signifi-antly positive (P < 0.001**). Interestingly, we found in HDatients, affected by NWO syndrome, high significant positiveorrelations (P < 0.001**) between FM% and blood markersf inflammation, CRP and �1-AGP and no significant cor-elation between body composition parameters and nutritionarkers.In Table 4 are presented the changes in lipid profile (TC,

DL, LDL, TG, LDL/HDL) after the pharmacological treat-ent. There was also a significant increase in HDL cholesterol

evels (P < 0.001**).The baseline and post-treatment values of nutritional (albu-

in and pre-albumin) and inflammatory (CRP and �1-AGP)roteins had a similar trend in the three groups. Pre-obese-bese patients had the highest blood levels of the inflammatoryattern. In the NWO women the inflammatory proteins levelsere in an intermediate position between non-obese and pre-bese-obese blood concentrations. After ASA and atorvastatinreatment, a significant reduction of only inflammatory markersere obtained in all patients (Table 5).

. Discussion

The mortality rate of dialysis patients remains unacceptablyigh and cardiovascular disease is the leading cause of mortal-ty accounting for more than 50% of deaths in end-stage renalisease.

Increasing circulating levels of inflammatory markers, suchs C-reactive protein and pro-inflammatory cytokines have beenescribed in CKD patients with or without ongoing dialysisreatment [21]. The prevalence of inflammation was dependingn multiple factors, such as residual renal function, environmen-al and genetic differences, dialysis therapy [22]. Furthermore,here are intimate links among albumin and pro-inflammatoryroteins as well as fat and muscle tissue in HD patients23,24,25]. Co-occurrence of diabetes and hypertension seemso have a probable effect on the development of kidney diseasen obese individuals. In addition, research has established that

ncreased BMI leads to glomerular hyperfiltration, which mayndependently lead to renal disease [26]. After renal disease haseen established, the impact of BMI may be obscured by otherathologic processes, including malnutrition, and inflammation.

L. Di Renzo et al. / Pharmacological Research 57 (2008) 93–99 97

Table 3Pearson correlations were performed to examine the relation between the blood markers of inflammation and nutrition and body composition parameters in the threegroups (NWO, controls, pre-obese-obese women)

Non-obese (n = 16) NWO (n = 17) Pre-Ob-Ob. (n = 19)

A Pre-A �1-AGP CRP PINI A Pre-A �1-AGP CRP PINI A Pre-A �1-AGP CRP PINI

Lean (kg)R 0.70* 0.56** 0.32 0.25 0.06 0.51 0.45 −0.39 −0.03 0.04 0.65 0.75* 0.04 −0.44 −0.53P NS NS NS NS NS NS NS NS NS NS NS NS

FM (kg)R 0.30 −0.28 0.18 0.24 0.15 0.14 0.25 0.24 0.46 0.42 0.42 0.63 0.38 0.24 0.02P NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS

FM%R 0.26 −0.33 0.13 0.22 −0.19 −0.34** −0.17 0.73** 0.68** 0.56 −0.08 0.14 0.47 0.45 −0.42P NS NS NS NS NS NS NS NS NS NS NS NS

Weight–preD (kg)R 0.62** 0.29 0.32 0.32 −0.13 0.37 0.40 −0.00 −0.12 0.13 0.61 0.74* 0.12 −0.22 −0.35P NS NS NS NS NS NS NS NS NS NS NS NS NS

Weight -postD (kg)R 0.61* 0.26 0.29 0.32 −0.11 0.43 0.42 −0.15 0.25 0.19 0.59 0.78* 0.18 −0.21 −0.35P NS NS NS NS NS NS NS NS NS NS NS NS NS

BMI (kg/m2)R 0.75* 0.29 0.29 0.36 −0.14 0.35 0.26 0.26 0.55 0.35 0.40 0.71** 0.29 0.08 −0.12P NS NS NS NS NS NS NS NS NS NS NS NS NS

Waist (cm)R −0.07 −081* 0.18 0.36 0.43 0.54 0.26 −0.16 0.26 0.19 0.32 0.50 0.06 0.14 −0.06P NS NS NS NS NS NS NS NS NS NS NS NS NS NS

Hip (cm)R −0.35 −0.62** 0.66* 0.68* 0.78 0.32 0.22 0.22 0.51 0.38 0.67 0.76* 0.23 −0.01 −0.36P NS NS NS NS NS NS NS NS NS NS NS

W/HR −0.41 −0.08 0.71* 0.60** 0.66* 0.22 0.15 0.29 0.47 0.35 0.45 0.31 0.24 −0.25 −0.37P NS NS NS NS NS NS NS NS NS NS NS NS

NWO = normal weight obese; non-obese = control; pre-Ob-Ob. = Pre-obese-obese; LEAN = lean body mass; BMI = body mass index; weight-postD = weight postd odyW P = ali .001.

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ialysis; weight-preD = weight pre-dialysis; FM = fat body mass; FM% = fat b/H = ratio waist to hip; A = albumin (g/L); pre-A = pre-albumin (g/L); �1-AG

nflammation and nutrition index. NS = not significant value; *P < 0.05; **P < 0

he strong association between obesity and the risk for end-

tage renal disease (ESRD) reported is a valuable addition to theist of risk factors for these patients [27]. This finding providesn important insight in determining the significance of BMI inhe development of renal disease, and subsequent renal replace-

able 4hanges in lipid profile either anti-inflammatory pre-treatment or post-treatment

Pre-treatment Post-treatment P value

C (mmol/L) 7.4 (±1.5) 3.9 (±0.6) <0.001**DL (mmol/L) 1.1 (±0.1) 1.6 (±0.6) <0.001**DL (mmol/L) 4.5 (±0.9) 2.4 (±0.7) <0.001**G (mmol/L) 2.5 (±1.0) 1.6 (±0.8) <0.001**DL/HDL 3.4 (±1.3) 2.6 (±0.7) <0.001**

C = total cholesterol, HDL = high-density lipoprotein cholesterol, LDL = low-ensity lipoprotein cholesterol, and TG = triglyceride levels. Results arexpressed as mean ± S.D., NS = not significant value; *P < 0.05; **P < 0.001.

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mass percentage; waist = circumference of waist; hip = circumference of hip;pha-1 glycoprotein (g/L); CRP = C-reactive protein (mg/L); PINI = prognostic

ent therapy, a relationship that is both complex and not yetully understood [28,29].

In the present study we subdivided our population accord-ng to body fat and BMI three classes of patients (non-obese,re-obese-obese, Normal Weight Obese). For the first time, byody composition assessment, we identified NWO women inD patients, with a frequency of 32.69%. In our previous report

30,31,32], we described the Normal Weight Obese (NWO) syn-rome, that characterises the subjects with a normal body weightnd BMI (<25 kg/m2), high fat mass percentage (FM% > 30),nd increased CVD risk compared to normal subjects. Due to theigh values of plasma circulating levels of cytokines and CRP, anarly inflammatory status characterized the syndrome [12,32].

s prognostic inflammation nutritional index (PINI) has nevereen adopted in HD patients, never in NWO subjects, we utilisedhe potential usefulness of this simple scoring system in our pop-lation, as tool to verify the efficacy of the anti-inflammatory

98 L. Di Renzo et al. / Pharmacological Research 57 (2008) 93–99

Table 5Changes of nutritional and inflammatory proteins either pre-treatment or post-treatment in the three groups

Normal (non-obese) (16) NWO (17) Pre-obese-obese (19)

Pre-treatment Post-treatment Pre-treatment Post-treatment Pre-treatment Post-treatment

CRP (mg/L) 18.50 ± 8.7 0.70 ± 1.2 21.31 ± 10.82 3.1 ± 2.5 24.15 ± 13.18 3.80 ± 2.90P <0.05* <0.05* <0.05*�1-AG(g/L) 1.18 ± 0.12 0.60 ± 0.24 1.48 ± 0.21 0.75 ± 0.21 1.45 ± 0.28 0.88 ± 0.41P <0.05* <0.05* <0.05*Albumin(g/L) 39.4 ± 4.3 40.2 ± 3.9 37.2 ± 2.19 4.2 ± 3.81 39.17 ± 4.18 42 ± 4.71P NS NS NSP 4 ± 0.P

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re-albumin(g/L) 0.32 ± 0.06 0.34 ± 0.04 0.3NS

RP = C-reactive protein,�1-AGP = �1-acid glycoprotein, NWO = Normal Weig

reatment. From our present data, we identified the 43.75% ofon-obese subjects, with normal PINI values (PINI < 1), whereashe 84.21% of pre-obese-obese showed a PINI values >1. In thistudy, we identified HD patients affected by NWO syndrome,ith both normal PINI values (38.83%), than with pathologi-

al PINI values (41.17%). In particular, according to previousesults [12,30], we observed that the higher PINI values wereelated to inflammation proteins plasma levels. In fact, highignificant positive correlation between body fat mass percent-ge and blood markers of inflammation, CRP and �1-AGP, wasbserved. Whereas, no significant correlation was observed withutrition markers. This finding supports the hypothesis that adi-ose tissue, as endocrine organ, is responsible of inflammationtatus, increasing the risk obesity related diseases, such as CVD.

Risk factor modification and cardiovascular benefits withhe use of cardio-protective medications such as angiotensin-onverting enzyme inhibitors (ACEIs), beta-adrenergic antag-nists (beta-blockers), acetyl salicylic acid (ASA) and-hydroxy-3-methylglutaryl coenzyme A reductase inhibitorsstatins) has been shown to reduce mortality in the generalopulation, and recently new therapeutic protocols have beenssessed for HD patients [33,34]. In particular, statins pre-cription is associated with reduced mortality in HD patients,roviding additional support for the value of statin therapyn this patient group. Statins may improve renal function byestoring endothelium dependent nitric oxide (NO) production,hich could improve renal blood flow by exerting its vasodilator

ction [35]. Statins can ameliorate both structural and functionalhanges in the glomeruli, and they exert an anti-inflammatoryction, for example lowering the CRP circulating level, a markerf inflammation and vascular risk. Furthermore, simvastatin maylso inhibit renal mesangial proliferation, beyond hypocholes-erolemic effects [36]. ASA and beta-blockers were associated inrials of cardioprotective therapy after acute myocardial infarc-ion in patients with chronic kidney disease [37].

This study originally assessed the effects of a short time8 weeks) therapy protocols with association between atorvas-atin (10 mg/die) and ASA (100 mg/die) on HD patients with orithout NWO syndrome. We observed a significant reduction

P < 0.001) of total and LDL cholesterol with the associationf these two drugs, suggesting that this therapy can inhibit theevelopment or progression of atherosclerosis in HD patientss in the general population. No relation was found with body

R

08 0.29 ± 0.08 0.39 ± 0.07 0.38 ± 0.13NS NS

ese. NS = not significant value; *P < 0.05; **P < 0.001.

omposition, and this observation suggests the relative greatermportance of risk factors specific of kidney disease in this classf patients. Moreover, the results suggest that ASA and atorvas-atin combined treatment was effective in reducing inflammatorytatus in our population: at the end of the study only 7.69% ofhe patients exhibited PINI values in the pathologic range ver-us 61.53% at the baseline. It is possible that the anti-oxidantroperties of atorvastatin added to the effect of ASA, in dialysisatients decreased the levels of oxidative stress that has beenypothesized to effect non-cardiac functions such as immuneesponses to infection.

The limit of the present study was the small sample. Fur-her analysis will be necessary to fully understand the causes ofnflammation in non-responder patients.

cknowledgments

Antonino De Lorenzo is responsible author for the conceptionnd the design of the experiments. Laura Di Renzo, Carmelaozzo, Annalisa Noce, Sandro De Angelis, Natashia Miani, andicola Di Daniele are responsible authors for the conduct of

he experiments, the data interpretation and the writing of theanuscript. Mario Bigioni is gratefully acknowledged for the

upport in statistical analyses.Biochemical analyses were assessed at the Laboratory

edicine, University Hospital “Tor Vergata” Rome, Italy. Wehank M. Dessi’ for assistance in the clinical study.

This work was performed with the support of PROTISrogram for specific plasma protein profiles, supplied by DADE-EHRING-Marburg GmbH. The skilful technical assistance ofiuseppe Bruschetti, Riccardo D’Amico and Roberto Codignoli

s gratefully acknowledged.The authors do not have any financial or personal interests in

ny organization sponsoring the research at the time the researchas done.This study was supported by grants from Ministero Politiche

gricole e Forestali: (1) SABIO, D.M. 908001 May 26, 2004nd (2) PACB, D.M. 91567 Dic 29, 2004.

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