Advanced Glycation End Product Accumulation and CKD 2014

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Advancedglycationendproductaccumulation:Anewenemytotargetinchronickidneydisease?ARTICLEinCURRENTOPINIONINNEPHROLOGYANDHYPERTENSIONAUGUST2014ImpactFactor:4.24DOI:10.1097/MNH.0000000000000062Source:PubMed

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CURRENTOPINION Advanced glycation end product accumulation: ahronic kidney disease?

e Uribarri b

AGEs) in the progression of chronic diseases andnt. This review summarizes the recent contributions to

intudstudiesum

review is on highlighting the recent studies that advance our current understanding of the mechanismsmediatinabrogate

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Keyworadvance

INTRODUCTION

Advanced glycationbody can form endofrom the environmresults in part frombetween reducing suglipids and proteins, wized as the browning rMaillard [1]. Althoughis part of normal metcentury have characteof excess accumulatinearly every organ system, including diabetes [2],neurodegenerative diseases [3], chrdiseases [4], and rheumatological i

AGbolismintermaldehyis the

Division of Nephrology, Department of Medicine, Stony Brook Universityand bDivision of Nephrology, Department of Medicine, Mount Sinai

87 0389; e-mail: [email protected]

1062-48

REVIEWdes and eventually AGEs. Although diabetesmain cause of chronic kidney disease (CKD)

Curr Opin Nephrol Hypertens 2014, 23:547554

DOI:10.1097/MNH.0000000000000062

21 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins www.co-nephrolhypertens.comrof excess glucose leading to glycolyticediates that increase the pool of reactive

of Med212 9ight Lippincott Williamsult from meta- Nephrology, One Gustave L Levy Place, Box 1243, Mount Sinai Schoolicine, New York, NY 10029, USA. Tel: +1 212 241 1887; fax: +1Es accumulation may also reCorrespondence to Jaime Uribarri, MD, Department of Medicine andonic pulmonaryllnesses [5].

School of Medicine, New York, New York, USAg AGEs-induced CKD progression, as well as novel treatment strategies that have the potential tothis disease process.

bstractnks.lww.com/CONH/A12

dsd glycation end products, chronic kidney disease

end products (AGEs) in thegenously or can be acquiredent. Endogenous formationthe nonenzymatic reactionars and free amino groups ofhich was initially character-eaction by the French chemista limited formation of AGEs

abolism, studies over the pastrized the detrimental effectson of these glycotoxins in

worldwide, the accumulation of AGEs independentof hyperglycemia has been well documented [6

&&

].Additionally, the consumption of a diet rich infoods cooked under dry and high-heat conditionshas been shown to clearly contribute to an increasein the body AGE pool [7,8]. Regardless of whetherthe accumulation of AGEs is from an exogenous orendogenous source, glycotoxins, such as N-carbo-xymethyl-lysine, pentosidine, and methylglyoxal

aAs the prevalence and the incidence of CKD rises in the United States, it is essential to identify therapeuticstrategies that either delay the progression of CKD or improve mortality in this population. The focus of thisnew enemy to target in c

Sandeep K. Mallipattua and Jaim

Purpose of reviewThe critical role of advanced glycation end products (their complications has recently become more apparethe field of AGEs in chronic kidney disease (CKD).

Recent findingsOver the past 3 decades, AGEs have been implicatednephropathy. Although numerous in-vitro and in-vivo saccumulation in tissue injury, few prospective humanprocess ameliorates disease. Nonetheless, recent studcontribute to end-organ injury as a result of AGEs acckidney disease.

Summarys & Wilkins. Unauthorizethe progression of CKD, and specifically diabeticies highlight the detrimental role of AGEsies or clinical trials show that inhibiting thishave focused on the novel mechanisms thatulation, as well as novel targets of therapy ind reproduction of this article is prohibited.

Copyrigh

derivatives,[911].

Potentiexogenousof endoAGEs, andAGEs haveavailable anease are as

(1) Restrict(a) Di

cooking),(b

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KEY POINTS

Independent of hyperglycemia, the tissue accumulationof AGEs cnephropa

Skin autodiagnosticof AGEs,end-organ

Current thconsumptformation

Excess coassociateaccumula

Diagnostics and techniques

548) Inhibition of gastrointestinal absorptionof dietary AGEs (increase dietary content,sevelamer carbonate, AST-120, lysozyme),

) Reduce high-fructose intake.uce endogenous AGEs formation:) Glycemic control,) Probiotics,) Antioxidants [Vitamin E, glutathione(GSH), lipoic acid],

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) (th

) Th) Am) BS) An(A(A

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wwincreasing the breakdown of existingbeen the focus of recent studies. Theti-age strategies in chronic kidney dis-follows:

exogenous sources of AGEs:etary restriction of AGEs (switch fromgh-heat, low-heat, and high-humidity

patiean epredgressdialybilityrecepvatio Lip

/)-2iazoliamiinoT-49giotCEI)/RBs),dralagli

etforglitantoxridoxxane

w.co-ous AGEs, antagonizing tissue effects of tinggenare critical to the progression of CKD

al strategies involving the restriction ofsources of AGEs, reduction in formation

(3) Ib

(4) At

(5) K

Iadvaof AGsis o

EXCPRODAM

RegapatieAGErole

ontributes to the progression of diabeticthy.

fluorescence may serve as a potentialtool for quantifying the tissue accumulationand thereby serve as a surrogate marker ofdamage.

erapeutic targets focus on either limiting theion of exogenous AGEs or inhibiting theof AGEs.

nsumption of high-fructose corn syrup isd with increased serum AGE levels and tissuetion of AGEs.pincott Williams & Wilkins. Unauthorized rep

-isopropylidenehydrazono-4-oxo-idin-5-ylacetanilide (OPB-9195),ne derivatives (Benfotiamine),guanidine,97,ensin-converting-enzyme inhibitorangiotensin receptor blockers

azine,ptinmin,zone,yfylline,amine,extracts,

chronicor perit[14].

Seveterious role of AGEs in contributing to end-organdamagetributetherebyand fuand prFor insreceptor 2 aactivateting to oxirecepto

nephrolhypertens.comroduction of this article is prohibited.Volume 23 Number 6 November 2014has marked antioxidant properties byr 1

dative stress [21]. In contrast, the AGEs se

nd 4 initiates intracellular signaling andveral inflammatory responses, contribu-tance, binding of AGEs to RAGE or toll-like[1419]. The accumulation of AGEs con-s to tissue injury by protein-crosslinking,leading to alteration of protein structure

nction and by activating proinflammatoryooxidative cellular signaling pathways [20].rease breakdown of existing AGEs [alage-um chloride (ALT-711)],E receptor inhibitors [S100A12, pigment-epi-lium derived factor (PEDF), DNA aptamers],ney transplantation.

this review, we discuss recent publishedes in the understanding of the critical roles in patients with CKD, with a special empha-ovel therapeutic targets on the horizon.

SS ADVANCED GLYCATION ENDUCTS CONTRIBUTE TO END-ORGANGE IN CHRONIC KIDNEY DISEASE

less of hyperglycemia, oxidative stress ins with diabetic nephropathy contributes tormation [12

&

]. Miyata et al. [5] described thereactive carbonyl compounds as a contribu-ctor to the formation of AGEs in uremics, independent of hyperglycemia. Althoughation in circulating AGEs is present in ainant number of CKD patients, the pro-n to end-stage renal disease (ESRD) requiringis variable. A potential source of this varia-ay be secondary to polymorphisms in ther for AGE (RAGE), a receptor leading to acti-of inflammatory pathways, and thereby con-g to the progression of CKD [13

&&

]. In aof 174 European patients with stage 3374T/A polymorphism was associated withd plasma levels of interleukin 6 and macro-chemoattractant protein 1 (MCP1) [13

&&

]. Inn, patients whowere carriers of this risk allelecreased albuminuria and worsened renaln by the end of the 84-month follow-up[13

&&

]. The significant role of AGEs in con-g to end-organ damage in patients onrenal replacement therapy, hemodialysis

oneal dialysis was the focus of a recent review

eral reviews have discussed in detail the del-

Copyr ize

regulating AGE/RAGE mediated activation ofnuclear factor kappa-B (NF-kB) [22], epidermalgrowth factor receptor, and extracellular receptorkinase

Theatherosessentigation,[2527lipopro[28], ancentratto oxiadditiotion atIncreasAGE-mrate of across-seinvestiglevelsvelocit[30]. Rcorreladiabetirelationof hype

Theeases,interstiunresoexposuincreasbeta,transglprogreswith elthe auglyoxalprogresby incrtron mdamageated bymembrthe expabrogaproxim

Sevbetweemorbidas a suinvolvisolubleinverseprotein

the authors found that soluble RAGE correlatedstrongly with less LV dysfunction [36]. However,these findings have been contradicted in a small

atrlaC

rve[38ndhe progression of diabetic nephropathy. IntiosE

insasglp

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Advanced glycation end product Mallipattu and Uribarri

1062-482ight Lippincott Williams & Wilkins. Unauthor

[23,24].accumulation of AGEs also accelerates

clerosis via cross-linking of matrix proteinsal to endothelial function, platelet aggre-and abnormal lipoprotein metabolism

]. The oxidative modification of low-densitytein (LDL) plays a vital role in atherosclerosisd CKD patients have a higher serum con-ion of glycated LDL [2], which is more pronedation than nonglycated LDL [29]. Inn, glycated LDL is cleared from the circula-a slower rate than nonglycated LDL [29].ed oxidation and reduced clearance ofodified LDL may contribute to the increasedtherosclerosis observed in CKD patients. In actional study from Poland, the authorsated the relationship between plasma AGEand arterial stiffness (using pulse wavey) in CKD patients with and without diabetesegardless of the cause of CKD, AGE levelsted significantly with arterial stiffness, butc CKD patients demonstrated the strongestship [30], suggesting an additive effectrglycemia.mechanism by which early glomerular dis-

such as diabetic nephropathy, progress totial fibrosis (i.e., advanced CKD) remainslved. Recent in-vitro studies revealed thatre of tubular cells to AGEs results in theed expression of transforming growth factorplasminogen activator inhibitor-1, tissueutaminase, andMCP1 [31]. In addition, fastersion to diabetic nephropathy may correlateevated serum AGE levels [32

&&

]. Specifically,thors showed that serum levels of methyl-derivatives independently predicted a fastersion to diabetic nephropathy, as measuredeased glomerular basement thickness on elec-icroscopy [32

&&

]. Also, AGE-induced tubularin diabetic nephropathy seems to be medi-sodium-glucose cotransporter 2 in the apicalane of proximal tubular cells as inhibitingression of sodium-glucose cotransporter 2

ted AGE-mediated apoptosis of culturedal tubular cells [33].eral studies have highlighted the associationn elevated serum AGEs and cardiovascularity in CKD using left ventricular (LV) massrrogate marker [34]. A cross-sectional study,ng 142 Italian CKD patients, revealed thatRAGE levels, a supposed inhibitor of RAGE,ly correlated with LV mass and C-reactive(CRP) levels [35]. In another recent study,

pedicorrewithobsephy

Ein taddistageof AGForsuchstronESRDExpoendofor Aendo

SAGEintraoxidpoteof AwiththatcorreN-calevelresceserveplasmautointimfuncprogpentmedrevein CitorA pothatAGEmeacatio

LIMADV

SeveminDiet

1 2014 Wolters Kluwer Health | Lippincott Williams & Wilkinsd reproduction of this article is prohibited.

n to the critical role of AGEs in the laterof diabetic nephropathy, the accumulations contributes to the initial endothelial injury.tance, inhibitors to nitric oxide synthase,asymmetric dimethylarginine (ADMA), arey associated with increased AGE levels inatients with endothelial dysfunction [39].re to AGEs increased ADMA levels in culturedelial cells, by inhibiting the enzyme criticalMA degeneration, thereby contributing toelial injury [39].n is another common site, in which excessesult in cross-linking of collagen and initiatellular pathways that result in increasedve stress. A recent review highlights theal use of skin autofluorescence as a markeraccumulation in CKD patients with or

t diabetes [40&

]. Skin biopsies have validatedincrease in skin autofluorescence strongly

tes with an accumulation of pentosidine,xymethyl-lysine, and carboxyethyl lysinen the skin. Interestingly, using skin autofluo-e as a marker of excess AGEs may possiblys a better marker of tissue damage thanAGE levels. For instance, an increase in skinorescence positively correlated with carotidmedial artery thickness and diastolic dys-n, but inversely correlated with endothelialitor function in CKD patients, whereas serumidine only correlated with carotid intima-artery thickness [40

&

]. Recent in-vitro studiesd that AGEs, at the concentrations observedpatients, did not induce endothelial progen-l apoptosis, contrary to previous studies [41].tial hypothesis to explain this discrepancy iscontrast to tissue bound AGEs, circulating

re constantly turning over and serial plasmaements may be required for proper quantifi-of circulating levels.

NG THE EXOGENOUS SOURCES OFNCED GLYCATION END PRODUCTS

studies have examined the beneficial role ofizing the excessive intake of AGEs [4244].AGE intake is easily reduced by changing the

www.co-nephrolhypertens.com 549ic cohort, inwhich plasma AGE levels did notte with a proinflammatory state in patientsKD [37]. This lack of correlation was alsod with serum AGE levels and LV hypertro-].othelial dysfunction is an important factor

Copyrigh d

method of cooking from a high dry-heat applicationto a low heat and high humidity, independent of itsnutrient composition [45,46]. Restricting excessdietary AGE intake protects against a loss of innateimmunity [44] and attenuates diabetic angiopathyand nephropathy [42,43]. Several of these anti-AGEstrategies have been evaluated in recent years(Table 1) [47,48,49

&&

,50].Minimizing the accumulation of exogenous

AGEs in CKD patients can also be accomplishedby inhibiting the absorption of dietary AGEs inthe gut. Although primitive, increasing dietary fibercontent attenuates the increase in AGEs and slowsthe progression of CKD. For instance, consumptionof a high-fiber diet, such as oats, in rats slowed theprogrescurrentSevelambindingto decrsingle-cstudy cwith ca(stage 2AGE lrevealeHbA1cstress iidant mlevels,groupadditioadsorbe50% fro[54

&&

].ents, asremain

MeAGE fofrom thrich inwith thRecentto a hi

increase in serum levels of methylglyoxal deriva-tives, angiotensin II, renin, and blood pressure[55], whereas glutathione levels were signifi-cantly suppressed. Interestingly, in addition to theincreased serum AGE levels, RAGE and NF-kB levelswere specifically increased in aorta of rodents fed thehigh-fructose diet [55]. Furthermore, the formationof AGEs appears to mediate high-fructose diet-induced nonalcoholic fatty liver disease [56]. Withthe increased consumption of beverages rich infructose in the past decade, the role of a high-fruc-tose diet in the accumulation of endogenous AGEscannot be neglected.

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Table product strategies in chronic kidney disease

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Sevelam

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550t Lippincott Williams & Wilkins. Unauthorize

sion of diabetic nephropathy with a con-reduction in RAGE and NF-kB levels [51].er carbonate, a nonabsorbed phosphate-polymer, is frequently used in CKD patients

ease serum phosphate levels [52,53]. A recententer, randomized, open-label crossoverompared the role of sevelamer carbonatelcium carbonate in diabetic CKD patients4) in the accumulation of excess circulatingevels and inflammatory markers. Resultsd a significant reduction in serum AGEs,, and markers of inflammation and oxidativen patients receiving sevelamer [47]. Antiox-arkers, such as AGER1 and SIRT1 mRNAalso markedly improved in the sevelamerindependent of serum phosphate levels. Inn, recent studies reveal that RAGE-based bio-nt devices were effective at lowering AGEs bym serum collected from patients with ESRDHowever, the specificity of these bioadsorb-well as their long-term efficacy and safety,s to be determined.thylglyoxal derivatives, a major precursor ofrmation, are a reactive dicarbonyl formede metabolism of fructose and glucose. A diethigh-fructose corn syrup has been associatede progression of diabetes and hypertension.studies demonstrated that rodents exposedgh-fructose diet for 4 months exhibited an

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1. Recent clinical studies involving anti-advanced glycation end

E strategy Reference Study type

er carbonate [47] Single-center, open-label R

in, pioglitazone [48] Open-label RCT

ransplantation [49&&] Cross-sectional study

er carbonate [50] Multicenter RCT

nced glycation end product; HbA1c, hemoglobin A1c; RCT, randomized contro

www.co-nephrolhypertens.comreproduction of this article is prohibited.

N Primary end-points

20 Serum AGE levels, markers ofoxidative stress and inflammation

66 Serum HbA1c, pentosidine levels

1888 Skin autofluorescence

183 Serum pentosidine levels, coronaryartery calcification score

trial.

Volume 23 Number 6 November 2014NG THE ENDOGENOUS FORMATIONVANCED GLYCATION ENDUCTS IN CHRONIC KIDNEY DISEASE

tion tominimizing the intake of excess AGEs,g the endogenous formation of AGEs is alsoto therapy. As diabetes is a major contributorformation, strict glycemic control can min-he formation of AGEs and has been the focusr reviews [57

&

]. Other therapeutic strategieseen identified in reducing the formation ofnous AGEs, including the use of antioxi-such as vitamin E, GSH, and lipoic acid. In addition, the use of liposoluble thiamineives, such as benfotiamine, has previouslyown to inhibit the formation of AGEs andkidney injury in diabetic murine models. Other agents, such as aminoguanidine, aphile hydrazine group that binds to carbonyland prevents cross-linking, have shown to bee in lowering serum AGEs [61,62], butreactions have also been documented

64]. Similar to aminoguanidine, OPB-9195,olidine derivative, binds to carbonyl groupsevents cross-linking to proteins. Adminis-of OPB-9195 reduced the formation of pen-e and the thickening of the neointimal layermodel of carotid artery injury [65]. Althoughstudies were promising, studies in humansot shown this favorable effect [66,67].

Copyr ize

Angiotensin-converting enzyme inhibitors orangiotensin receptor blockers have shown to reducethe production of reactive carbonyl precursors forAGE fostudiesrevealeDNA ddetachthat hyreducecompodativerecentlreductidismutnephropeptidapromohas beestress [dase-4stressAGE lein diabalso obgliptin,early d

Repincludifyllinedescribtazonein diaba knowto be suat earlymationin CKD

Forthat blattenuaagentsoped toElevateare assstrategiaccumugressiocurrentthat leaglyoxalbeen imdevelopwith Cbetic nlase-I,

derivatives, reduced oxidative stress, and attenuatedglomerular injury and endothelial dysfunction [79].However, further validation will be required before

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rmation [6871]. More recently, in-vitro, involving cultured mouse podocytes,d that exposure to telmisartan attenuatesamage in the podocyte and inhibits cellment [39]. Also, in-vitro studies demonstratedralazine, an antihypertensive agent, canAGE formation by trapping reactive carbonylunds, leading to the modification of oxi-metabolism [72]. Hydralazine was alsoy shown to reduce protein glycation with aon in RAGE, NADPH oxidase, and superoxidease levels [73] in a murine model of diabeticpathy. In addition, inhibiting dipeptidylse-4, an enzyme that degrades incretins thatte insulin release and slow gastric emptying,n shown to reduce AGE-mediated oxidative74]. The use of linagliptin, dipeptidyl pepti-inhibitor, blocks AGE-mediated oxidativein cultured endothelial cells and reducesvels, RAGE expression, and oxidative stressetic rats [74]. A reduction in albuminuria wasserved in the diabetic mice treated with lina-suggesting a potential therapeutic option iniabetic nephropathy [74].urposing of currently used medications,ng metformin, pioglitazone, and pentoxy-to inhibit formation of AGEs, has beened [75]. For instance, metformin and piogli-reduce serum pentosidine levels significantlyetic patients [48]. In addition, pyridoxamine,n AGE inhibitor, was recently demonstratedperior to metformin in inhibiting glycation, intermediate, and late stages of AGE for-[6

&&

]. However, the role of these compoundsremains to be clearly delineated.the past 20 years, animal studies have shownocking RAGE reduced oxidative stress andted endothelial dysfunction [76]. Noveltargeting the RAGE receptor are being devel-treat diabetic vascular complications [77].

d serum levels of the RAGE ligand, S100A12,ociated with mortality [78]. Consequently,es to inhibit S100A12 may reduce thelation of AGEs, as well as curb the pro-n of CKD. Potential therapeutic targets arely being investigated in targeting pathwaysd to degradation of AGEs, such as methyl-derivatives. Methylglyoxal derivatives haveplicated in endothelial dysfunction and thement of vascular complications in patientsKD. Recently, using murine models of dia-ephropathy, the overexpression of glyoxa-which normally catabolizes methylglyoxal

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aluated as a potential clinical therapeutic

use of alternativemedicine in inhibiting theion of AGEs is on the horizon. For instance,e of hexane extracts from the leaves ofnt, Piper auritum, inhibited the formations and limited oxidative stress in cell cultureamurinemodel of diabetic nephropathy [80].ly, the use of quercetin from leaf extracts ofnt, Allium victorialis, inhibited AGEs for-in cultured mouse kidney mesangial cellshe oral administration of 2-dodecyl-6-ycyclohexa-2,5-diene-1,4-dione from thef the plant, Averrhoa carambola, has shownffective in attenuating AGEs formation andsion of kidney disease in diabetic mice [82].studies from Japan revealed that PEDF, aprotease inhibitor, attenuated AGE-inducedsis by suppressing the expression of RAGEDF limited reactive oxygen species genera-activating peroxisome proliferator-activatedr gamma (PPAR-g), a known inhibitor ofatory pathways [83]. However, furtherare required to validate these findings andrmine whether there is a functional and his-al improvement in kidney disease with their

critical role of the microbiome in regulatingcellular processes has been in the forefrontnce in the past few years. Recent studiesthat the accumulation of AGEs in CKD

s may potentially be mediated by the alterediome in these patients [84

&&

]. Specifically,nt with probiotics has shown to reduces of oxidative stress, uremic toxins, andte CKD progression [84

&&

].re recently, the use of high-affinity DNArs, single-stranded molecules that bind withfinity to target proteins, was characterized inc nephropathy [85]. Elevated levels of glo-r RAGE, MCP1, connective tissue growthand type IV collagen are typically observedetic mice, which were blocked after infusionNA aptamers targeting AGEs specifically [85].ition, histological and functional improve-as observed with aptamer use [85]. Althoughing, the effects of nonspecific interactionstamers need to be further investigated.tins do provide benefit to patients with CKDut the mechanism mediating this processs unclear. Recent studies from Japan revealtins may attenuate tubular injury by reduc-levels of RAGE [87]. In AGE-treated cultured

www.co-nephrolhypertens.com 551

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proximal tubular cells, pravastatin inhibited RAGElevels, reactive oxygen species (ROS) generation,and apoptosis in a dose-dependent manner. Thesefinding[87], thwhichby inhibenefic st in patients onchronicpropos

Intation pwith advanced CKD [88]. After kidney transplan-tation,mentsurvivaautoflumarkedplant,[49

&&

]. In this cohort of 66 postkidney transplant,1707 Cautofluthe kidon diabetweeless adv

CONC

RecentAGEs icationsreveal that more novel therapeutic agents are onthe horpotentiWith thworldwisms angressio

Ackno

None.

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There a

REFERREADPapers ofbeen highl& of spe&& of outs

1. Maillarby a m

2. Bucalaplicati

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iyatarmaturemmadridod-pr

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oduoc N

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337ll Dman

hem10. Ahmed

ethyiol

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(Supphilellsponntricviewcatioof m

tingic cragsocphrothoT/An (a

alliptent:52j D

produ380.

hweycatlationghviewlousnicahled thassameo08;

hengd plls.n S

ycatmpl

ai Wppretl A

ai Wuceosp

akitavan38.

assamplerhath Anceitztu91;


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izon. However, we still remain far from theal use of these agents in clinical practice.e burden of a burgeoning CKD populationide, there is a dire need to identify mechan-d therapeutic strategies that halt the pro-n of kidney disease.

wledgements

cts of interest

re no conflicts of interest.

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www.co-nephrolhypertens.comKD, and 115 dialysis patients, mean skinorescence levels were significantly lower inney transplant patients than in the patientslysis. However, the levels were similarn posttransplant patients and patients withanced CKD (stage 3) [49

&&

].

LUSION

published data reaffirm the critical role ofn the progression of CKD and its compli-. In addition, studies from the past year

12.&

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This recomplireviewprevenglycem13.&&

Baasne

The au(374gressio14. M

po25

15. Raorescence showed that tissue AGE levels werely improved in patients postkidney trans-as compared with patients on dialysis

mJ B

11. WMmany factors may contribute to the improve-in cardiovascular morbidity and overalll advantage in these patients. Using skin

8:9. Se

huCdialysis, thereby placing doubt on theed mechanism.comparison to dialysis, kidney transplan-rovides a clear survival advantage to patients

servesassessformati7. Ko

prPrial effect of statins is los were also confirmed with rosuvastatin useereby suggesting that the mechanism bystatins attenuate the progression of CKD isbiting the formation of AGEs. However, this

5. Mfoin

6.&&

Ahpyenreproduction of this article is prohibited.

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xamine in the formation of early, intermediate and advanced glycationoducts. PLoS One 2013; 8:e72128.s demonstrate that regardless of the stage of glycation, pydroxaminea better antiglycating agent than metformin. This is the first study toefficacy of AGE inhibitors at early, intermediate, and late stages of AGE

insky T, He CJ, Mitsuhashi T, et al. Orally absorbed reactive glycationcts (glycotoxins): an environmental risk factor in diabetic nephropathy.

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MU, Thorpe SR, Baynes JW. Identification of N epsilon-carboxy-llysine as a degradation product of fructoselysine in glycated protein.Chem 1986; 261:48894894.Knecht KJ, Brinkmann E, Wells-Knecht MC, et al. New biomarkers ofd reaction damage to proteins. Nephrol Dial Transplant 1996; 11l 5):4147.i NC, Burlina S, Lapolla A. AGEs, rather than hyperglycemia, aresible for microvascular complications in diabetes: a glycoxidation- point of view. Nutr Metab Cardiovasc Dis 2013; 23:913919.article summarizes the critical role of AGEs in inducing microvascularns in diabetes (i.e., nephropathy), independent of hyperglycemia. Theechanisms mediating this process underscores the importance of

AGE formation at the early stage of diabetes, independent of hyper-ontrol.etti I, Norata GD, Sarcina C, et al. 374 T/A RAGE polymorphism isiated with chronic kidney disease progression in subjects affected bycardiovascular disease. PLoS One 2013; 8:e60089.

rs demonstrate that this single nucleotide polymorphism in RAGE) was associated with increased serum MCP-1 levels and CKD pro-

prospective study involving 174 patients for 84 months).attu SK, He JC, Uribarri J. Role of advanced glycation endproducts andial therapeutic interventions in dialysis patients. Semin Dial 2012;9538.S, Choudhury D, Welbourne TC, Levi M. Advanced glycation endcts: a nephrologists perspective. Am J Kidney Dis 2000; 35:365

dler S, Schinzel R, Vaith P, Wanner C. Inflammation and advancedion end products in uremia: simple coexistence, potentiation or causalnship? Kidney Int Suppl 2001; 78:S32S36.R, Barden A, Mori T, Beilin L. Advanced glycation end-products: a. Diabetologia 2001; 44:129146.ova M, Zima T, Tesar V, et al. Advanced glycation end products inl nephrology. Kidney Blood Press Res 2004; 27:1828.nder JM, Franke S, Stein G, Wolf G. Advanced glycation end productse kidney. Am J Physiol Renal Physiol 2005; 289:F645F659.ra H, Uribarri J, Cai W, Striker G. Advanced glycation end productstasis: exogenous oxidants and innate defenses. Ann N Y Acad Sci1126:4652.A, Dong Y, Zhu F, et al. AGE-LDL activates toll like receptor 4 pathway

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ion end-products and their receptor in inflammation and diabetesications. Nat Clin Pract Endocrinol Metab 2008; 4:285293., He JC, Zhu L, et al. Advanced glycation end product (AGE) receptor 1sses cell oxidant stress and activation signaling via EGF receptor. Proccad Sci U S A 2006; 103:1380113806., He JC, Zhu L, et al. AGE-receptor-1 counteracts cellular oxidant stressd by AGEs via negative regulation of p66shc-dependent FKHRL1horylation. Am J Physiol Cell Physiol 2008; 294:C145C152.

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