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Journal of Physiology andBiochemistryOfficial Journal of the University ofNavarra, Spain ISSN 1138-7548Volume 67Number 3 J Physiol Biochem (2011) 67:437-441DOI 10.1007/s13105-011-0092-4

Paraoxonase-1 and ischemia-modifiedalbumin in patients with end-stage renaldisease

Kazuhiko Kotani, Satoshi Kimura &Alejandro Gugliucci

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MINI REVIEW

Paraoxonase-1 and ischemia-modified albumin in patientswith end-stage renal disease

Kazuhiko Kotani & Satoshi Kimura &

Alejandro Gugliucci

Received: 5 October 2010 /Accepted: 24 March 2011 /Published online: 12 April 2011# University of Navarra 2011

Abstract End-stage renal disease (ESRD) with and/or without treatment by hemodialysis (HD) is associatedwith accelerated atherosclerosis, leading to cardiovas-cular disease (CVD) including acute coronary syn-dromes. Therefore, the regulation of CVD is a crucialissue for ESRD patients. Given the recent reports thatparaoxonase-1 (PON-1) and ischemia-modified albu-min (IMA) could predict CVD-related mortality inESRD, the two recent biomarkers may be useful forpreventive strategies for CVD. This review paperpresents current data on the relationships betweenPON-1, IMA, and ESRD. Many studies have shownthat circulating PON-1 activity is lower in ESRDpatients, and we have shown that its levels increaseafter HD. Although circulating IMA levels can increase

before HD in ESRD patients, there remains to be littledata. Our pilot study has shown a significant inversecorrelation between PON-1 and IMA in ESRD patients.Although the pathogenic link between PON-1 and IMAremains speculative, considering both biomarkers mayprovide new insights into the prevention of CVD inESRD patients.

Keywords Oxidative stress . Oxidation . Renalfailure . Atherosclerosis . Cardiovascular disease

Introduction

End-stage renal disease (ESRD) with and/or withouttreatment on hemodialysis (HD) is associated withaccelerated atherosclerosis, leading to cardiovasculardisease (CVD) including coronary artery disease [9,30]. This constitutes an important medical problem, inview of the mounting prevalence of ESRD as well asthe life span increase of these patients due totreatment [39]. Although classical atherosclerotic riskfactors, such as hypertension and diabetes mellitus,are involved in the increased incidence of atheroscle-rosis seen among ESRD patients, these only partiallyexplain the excess in risk, namely, the precisemechanisms for the pathogenesis of CVD in ESRDpatients is not fully understood [9, 30]. A form ofcomplex dyslipidemia/dyslipoproteinemia consistingof both quantitative and qualitative abnormalities,such as dysfunctional high-density lipoprotein (HDL)

J Physiol Biochem (2011) 67:437–441DOI 10.1007/s13105-011-0092-4

K. Kotani (*)Department of Clinical Laboratory Medicine,Jichi Medical University,3311-1 Yakushiji,Shimotsuke City, Tochigi 329-0498, Japane-mail: kazukotani@jichi.ac.jp

K. Kotani :A. GugliucciGlycation, Oxidation and Disease Laboratory,Touro University—California,Vallejo, CA, USA

S. KimuraDepartment of Laboratory Medicine and Central ClinicalLaboratory, Showa University NorthernYokohama Hospital,Yokohama, Japan

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and increased intermediate density lipoprotein levels,plays a key role in CVD prevalence in ESRD [5, 29,40]. Moreover, increased oxidative stress is a featurein ESRD patients, independently of the other conven-tional atherosclerotic risk factors [19, 41]. In order toprevent CVD in ESRD, it is therefore crucial to betterunderstand the pathophysiology of CVD developmentand to monitor the subjects with biomarkers that aretailored for this population and that may turn to bemore predictive of CVD in ESRD patients.

Recently, prospective studies on CVD outcomes inESRD using the new biomarkers of HDL dysfunctionand/or oxidative stress, paraoxonase-1 (PON-1) andischemia-modified albumin (IMA), have appeared inthe literature. These studies show that serum PON-1activity as well as IMA could predict CVD-relatedmortality in ESRD [15, 33]. The application of thetwo biomarkers may provide new insights into theprevention of CVD among ESRD patients. In thisbrief report, we present the existing current findingson the relationships between PON-1, IMA, andESRD.

Paraoxonase-1 in ESRD

Paraoxonase-1 (PON-1) is an enzyme (calcium-dependent esterase) associated with HDL subfractionsthat contain apo A-I and clusterin, and confersprotection against oxidative damage of various cellsand lipoproteins (i.e., low-density lipoprotein) [11, 21,36]. Its main physiological activity appears to belactonizing/lactonase action on oxidized phospholipidsor homocysteine thiolactone [36]. Changes in HDLsubfractions observed in various diseases under oxida-tive stress conditions can be a cause of reduction ofPON-1 activity [11, 21, 36]. In fact, low levels ofserum PON-1 have been reportedly associated withobesity-related disorders and CVD [1, 4, 22, 34,36]. Interestingly, many studies have shown signif-icantly lower levels of PON-1 (measured by phenyl-acetate and/or paraoxon as substrate in all studies) inESRD patients with and without HD treatmentcompared to controls [6, 7, 10, 12–14, 16–18, 24,26, 27, 31, 32, 35]. These results suggest that ESRDpatients may suffer from chronic oxidative stress and

Fig. 1 Possible interaction between PON-1 and IMA in end-stage renal disease. The figure schematically (and speculativelyin part) summarizes a possible interaction between PON-1 andIMA, described in the text. As seen on the upper part of theillustration, cardiac ischemia (possibly by free radical attack)produces IMA from albumin. Earlier studies have reportedIMA to be a biomarker of cardiac ischemia. Even though there

is no apparent cardiac ischemia, the decreased PON-1 state asobserved in patients with end-stage renal failure may produceIMA via an increase in oxidative stress. A significant inversecorrelation between PON-1 and IMA may partly be explainedin this mechanism, and the two biomarkers may reflectoxidative stress condition levels in end-stage renal failure.LDL: low-density lipoprotein, HDL: high-density lipoprotein

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have less antioxidant capacity, leading to an in-creased incidence of CVD. Of note, we have alsoshown that PON-1 levels in ESRD patients signifi-cantly increase after HD [12, 13].

Ischemia-modified albumin in ESRD

While the amino-terminal end of a circulatingalbumin binds transitional metals such as cobalt,copper and nickel, various changes of circulatingalbumin can occur in the terminal end under certainconditions [2, 3, 25]. When the specific motif (DAKKmotif) in the N-terminus is damaged, this results in areduced binding capacity for transitional metals [2, 3,25]. The effect is related to albumin circulatingthrough ischemic capillary beds as found in CVD,especially in the acute coronary syndromes [2, 3, 25].IMA is thus considered as a CVD-related biomarkerthat is sensitive to cardiac ischemia [25]. Furthermore,the modification of albumin, leading to higher IMAlevels, has also been recently documented in patientswith diabetes mellitus, hyperlipidemia, and metabolicsyndrome [8, 28, 38]. These results suggest that IMAformation may occur not only under acute but alsochronic oxidative stress conditions and also at extracardiac sites [8, 28, 38]. Unfortunately, little informa-tion about circulating IMA in ESRD is presentlyavailable. Recent studies have shown significantlyhigher IMA levels in ESRD patients compared tocontrols and its increased levels after HD [23, 37],while we have not found remarkably increased IMAlevels after HD [13]. Although differences in studypopulations and methodologies including HD proce-dures may partly influence the inconsistencies ofresults, more studies are warranted to resolve thiscontroversy.

The relationship between PON-1 and IMAin ESRD

Despite the great attention paid to the roles of PON-1and IMA as biomarkers for CVD, the actual associationbetween PON-1 and IMA in ESRD has beenunknown. More recently, we have had pilot studydata on this relationship in a small cohort of HDpatients with ESRD [20]. Of note, this study showedthat PON-1 levels were significantly and inversely

correlated with IMA levels in these patients (corre-lation coefficient=−0.522) while such a clear corre-lation was not found in non-ESRD controls [20]. Aninverse correlation between PON-1 and IMA levelsmay partially be explained by the speculation that alow PON-1 activity in these patients producesincreased oxidative stress, leading to IMA formation(Fig. 1). Monitoring serum PON-1 and IMA simulta-neously might thus provide another useful tool for theclinical pathologists as a prognostic biomarker of CVDin ESRD patients.

Conclusions

This article describes the current status of ourknowledge on serum PON-1 and IMA in ESRD.PON-1 activity is lower in ESRD patients and this iscorrected by HD. While some reports show higherIMA levels in ESRD patients and either no changes oran increase after HD, the data are scarce andinconclusive. Especially, PON-1 and IMA have beenrespectively shown to be predictors of CVD-relatedoutcomes in ESRD. Our pilot study shows an inversecorrelation between PON-1 and IMA in ESRDpatients, although the pathologic link between bothbiomarkers remains unclear. To clarify whether thesimultaneous monitoring of serum PON-1 and IMAcan be helpful for the CVD control in ESRD, morestudies with experimental and clinical designs areneeded.

Conflict of interest The authors declared no conflicts ofinterest.

References

1. Aviram M, Rosenblat M (2005) Paraoxonases and cardio-vascular diseases: pharmacological and nutritional influences.Curr Opin Lipidol 16:393–399

2. Bar-Or D, Curtis G, Rao N, Bampos N, Lau E (2001)Characterization of the Co(2+) and Ni(2+) binding amino-acid residues of the N-terminus of human albumin. Aninsight into the mechanism of a new assay for myocardialischemia. Eur J Biochem 268:42–47

3. Bhagavan NV, Lai EM, Rios PA, Yang J et al (2003)Evaluation of human serum albumin cobalt binding assayfor the assessment of myocardial ischemia and myocardialinfarction. Clin Chem 49:581–585

PON-1 and IMA in end-stage renal disease 439

Author's personal copy

4. Bhattacharyya T, Nicholls SJ, Topol EJ, Zhang R et al(2008) Relationship of paraoxonase 1 (PON1) gene poly-morphisms and functional activity with systemic oxidativestress and cardiovascular risk. JAMA 299:1265–1276

5. Cheung AK (2009) Is lipid control necessary inhemodialysis patients? Clin J Am Soc Nephrol 4(Suppl 1):S95–S101

6. Dantoine TF, Debord J, Charmes JP, Merle L et al (1998)Decrease of serum paraoxonase activity in chronic renalfailure. J Am Soc Nephrol 9:2082–2088

7. Dirican M, Akca R, Sarandol E, Dilek K (2004) Serumparaoxonase activity in uremic predialysis and hemodialy-sis patients. J Nephrol 17:813–818

8. Duarte MM, Rocha JB, Moresco RN, Duarte T et al (2009)Association between ischemia-modified albumin, lipids andinflammation biomarkers in patients with hypercholes-terolemia. Clin Biochem 42:666–671

9. Efstratiadis G, Tziomalos K, Mikhailidis DP, AthyrosVG, Hatzitolios A (2008) Atherogenesis in renal patients: amodel of vascular disease? Curr Vasc Pharmacol 6:93–107

10. Ferretti G, Bacchetti T, Masciangelo S, Pallotta G (2008)Lipid peroxidation in hemodialysis patients: effect ofvitamin C supplementation. Clin Biochem 41:381–386

11. Ferretti G, Bacchetti T, Moroni C, Savino S et al (2005)Paraoxonase activity in high-density lipoproteins: a com-parison between healthy and obese females. J ClinEndocrinol Metab 90:1728–1733

12. Gugliucci A, Lunceford N, Kinugasa E, Ogata H, SchulzeJ, Kimura S (2007) Acrolein inactivates paraoxonase 1:changes in free acrolein levels after hemodialysis correlatewith increases in paraoxonase 1 activity in chronic renalfailure patients. Clin Chim Acta 384:105–112

13. Gugliucci A, Mehlhaff K, Kinugasa E, Ogata H et al (2007)Paraoxonase-1 concentrations in end-stage renal diseasepatients increase after hemodialysis: correlation with lowmolecular AGE adduct clearance. Clin Chim Acta377:213–220

14. Hasselwander O, McMaster D, Fogarty DG, Maxwell AP,Nicholls DP, Young IS (1998) Serum paraoxonase andplatelet-activating factor acetylhydrolase in chronic renalfailure. Clin Chem 44:179–181

15. Ikeda Y, Suehiro T, Itahara T, Inui Y et al (2007) Humanserum paraoxonase concentration predicts cardiovascularmortality in hemodialysis patients. Clin Nephrol 67:358–365

16. Itahara T, Suehiro T, Ikeda Y, Inoue M et al (2000) Serumparaoxonase and arylesterase activities in hemodialysispatients. J Atheroscler Thromb 7:152–158

17. Jurek A, Turyna B, Kubit P, Klein A (2006) LDLsusceptibility to oxidation and HDL antioxidant capacityin patients with renal failure. Clin Biochem 39:19–27

18. Juretić D, Tadijanović M, Rekić B, Simeon-Rudolf V et al(2001) Serum paraoxonase activities in hemodialyzeduremic patients: cohort study. Croat Med J 42:146–150

19. Kao MP, Ang DS, Pall A, Struthers AD (2010) Oxidativestress in renal dysfunction: mechanisms, clinical sequelaeand therapeutic options. J Hum Hypertens 24:1–8

20. Kotani K, Kimura S, Kinugasa E, Ogata H, et al. (2010)Relationship between the serum levels of paraoxonase-1and ischemia-modified albumin in subjects with end-stage

renal disease on hemodialysis: a pilot study. J Comp ClinMed (in press)

21. La Du BN, Adkins S, Kuo CL, Lipsig D (1993) Studies onhuman serum paraoxonase/arylesterase. Chem Biol Interact87:25–34

22. Mackness MI, Durrington PN, Mackness B (2004) The roleof paraoxonase 1 activity in cardiovascular disease:potencial for therapeutic intervention. Am J CardiovascDrugs 4:211–217

23. Montagnana M, Lippi G, Tessitore N, Salvagno GL et al(2008) Effect of hemodialysis on traditional and innovativecardiac markers. J Clin Lab Anal 22:59–65

24. Moradi H, Pahl MV, Elahimehr R, Vaziri ND (2009)Impaired antioxidant activity of high-density lipoprotein inchronic kidney disease. Transl Res 153:77–85

25. Pantazopoulos I, Papadimitriou L, Dontas I, Demestiha T,Iakovidou N, Xanthos T (2009) Ischaemia modifiedalbumin in the diagnosis of acute coronary syndromes.Resuscitation 80:306–310

26. Paragh G, Asztalos L, Seres I, Balogh Z et al (1999) Serumparaoxonase activity changes in uremic and kidney-transplanted patients. Nephron 83:126–131

27. Paragh G, Seres I, Balogh Z, Varga Z et al (1998) Theserum paraoxonase activity in patients with chronic renalfailure and hyperlipidemia. Nephron 80:166–170

28. Piwowar A, Knapik-Kordecka M, Warwas M (2008)Ischemia-modified albumin level in type 2 diabetesmellitus—preliminary report. Dis Markers 24:311–317

29. Quaschning T, Krane V, Metzger T, Wanner C (2001)Abnormalities in uremic lipoprotein metabolism and itsimpact on cardiovascular disease. Am J Kidney Dis 38(4Suppl 1):S14–S19

30. Ritz E, Bommer J (2009) Cardiovascular problems onhemodialysis: current deficits and potential improvement.Clin J Am Soc Nephrol 4(Suppl 1):S71–S78

31. Saeed SA, Elsharkawy M, Elsaeed K, Fooda O (2008)Paraoxonase-1 (PON1) activity as a risk factor foratherosclerosis in chronic renal failure patients. HemodialInt 12:471–479

32. Schiavon R, De Fanti E, Giavarina D, Biasioli S,Cavalcanti G, Guidi G (1996) Serum paraoxonase activityis decreased in uremic patients. Clin Chim Acta 247:71–80

33. Sharma R, Gaze DC, Pellerin D, Mehta RL et al (2006)Ischemia-modified albumin predicts mortality in ESRD.Am J Kidney Dis 47:493–502

34. Sharma R, Singh B, Mahajan M (2007) PON1 activity isinversely related to LDL apoB carbonyl content in patientswith coronary artery disease. Kaohsiung J Med Sci 23:225–231

35. Suehiro T, Ikeda Y, Shiinoki T, Inoue M et al (2002) Serumparaoxonase (PON1) concentration in patients undergoinghemodialysis. J Atheroscler Thromb 9:133–138

36. Tavori H, Vaya J, Aviram M (2010) Paraoxonase 1attenuates human plaque atherogenicity: relevance to theenzyme lactonase activity. Adv Exp Med Biol 660:99–111

37. Turedi S, Cinar O, Yavuz I, Mentese A et al (2010)Differences in ischemia-modified albumin levels betweenend stage renal disease patients and the normal population.J Nephrol 23:335–340

38. Valle Gottlieb MG, da Cruz IB, Duarte MM, Moresco RNet al (2010) Associations among metabolic syndrome,

440 K. Kotani et al.

Author's personal copy

ischemia, inflammatory, oxidatives, and lipids biomarkers.J Clin Endocrinol Metab 95:586–591

39. Vassalotti JA, Li S, Chen SC, Collins AJ (2009) Screeningpopulations at increased risk of CKD: the Kidney EarlyEvaluation Program (KEEP) and the public health problem.Am J Kidney Dis 53(3 Suppl 3):S107–S114

40. Vaziri ND (2009) Causes of dysregulation of lipidmetabolism in chronic renal failure. Semin Dial 22:644–651

41. Ward RA, McLeish KR (2003) Oxidant stress in hemodi-alysis patients: what are the determining factors? ArtifOrgans 27:230–236

PON-1 and IMA in end-stage renal disease 441

Author's personal copy