emerging risk factor

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nature reviews|nephrology volume 5 | DeCemBer 2009 | 677

Division of GeneticEpidemiology,Department of MedicalGenetics, Molecularand ClinicalPharmacology,Innsbruck MedicalUniversity, Innsbruck,

Austria.

Correspondence:Division of GeneticEpidemiology,Department of MedicalGenetics, Molecularand ClinicalPharmacology,Innsbruck MedicalUniversity,Schpfstrasse 41,A6020 Innsbruck,[email protected]

emi isk facts ad maks f cickid disas ssiFlorian Kronenberg

Abstact | Chronic kidney disease (CKD) is a common condition ith an increasing prevalence. A number

of comorbidities are associated ith CKD and prognosis is poor, ith many patients experiencing disease

progression. Recognizing the factors associated ith CKD progression enables highrisk patients to be

identified and given more intensive treatment if necessary. The identification of ne predictive markers might

improve our understanding of the pathogenesis and progression of CKD. This Revie discusses a number

of emerging factors and markers for hich epidemiological evidence from prospective studies indicates

an association ith progression of CKD. The folloing factors and markers are discussed: asymmetric

dimethylarginine, factors involved in calciumphosphate metabolism, adrenomedullin, Atype natriuretic

peptide, Nterminal probrain natriuretic peptide, livertype fatty acid binding protein, kidney injury molecule 1,

neutrophil gelatinaseassociated lipocalin, apolipoprotein AIV, adiponectin and some recently identified

genetic polymorphisms. Additional epidemiological and experimental data are required before these markers

can be broadly used for the prediction of CKD progression and before the risk factors can be considered as

potential drug targets in clinical interventional trials.

Kronenberg, F. Nat. Rev. Nephrol.5, 677689 (2009);doi:10.1038/nrneph.2009.173

Introduction

i 2003, d f h us pp-bd thdn Hh d n ex sy(nHanes iii) pd h h pc fchc kdy d (CKD) h us d pp- 11%.1 wh p bddd hf g f CKD ccdg h n Kdy

Fd Kdy D oc Qy i(nKF-KDoQi) gd, h pc f g 1hgh 5 CKD 3.3%, 3.0%, 4.3%, 0.2% d 0.2%,pcy.1 i ep, h pc f CKD y h h us,2 b h pc hgh a d a.3 Dbgy, h pc fCKD c c, h nHanes d hgh CKD pc cd by 30% b 1990d 2000.4

th cdc f d-g d (esrD) dy b c, h cdc f 100150 p pp p y ep, 300 p pp p y h us d mxc d 400 p

pp p y t.3

my k fcd k f h dp d pg fCKD x (Fg 1) d h dff kdy bc. C f f esrD j cc,pcy gh f h cg pc f CKD.ahgh h pc f esrD y b 0.2%,esrD pg cc f 6.7% f mdcxpd d mdc c cd h esrDcd by 57% b 1999 d 2004.5

th r dc b f gg fcd k f hch pdgc dc fppc d h d xp d h

Cmti itsts

The author, the Journal Editor S. Allison and the CME questionsauthor C. P. Vega declare no competing interests.

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lai bjctivs

Upon completion of this activity, participants should be able to:

1 Specify elements of calciumphosphate metabolism that are

useful in predicting the progression of CKD.

2 Describe the relationship beteen fibroblast groth

factor 23 and CKD.3 Recognize ho novel markers may be used to predict the

progression of CKD.

4 Identify the most discriminatory marker predicting CKD

progression in the Mild to Moderate Kidney Disease study.

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678 | DECEMBER 2009 | voluME 5 www.atu.cm/

h c h CKD pg. t x f h dfyg kf CKD pg. Fy, k ppdc f hch p k f xpcgCKD pg d h cd cqc (fxp, cdc k, cbd, q- f pc hpy, dc qyf f d k f dh). ahgh f

Key points

Chronic kidney disease (CKD) is a highly prevalent health problem ith anincreasing incidence and a strong tendency for progression

Fe studies have searched for emerging risk factors or markers for progressionof CKD

Available studies have identified markers related to nitric oxide synthesis,calciumphosphate metabolism, natriuretic peptides, apolipoprotein AIV,

adiponectin and other parameters

Further epidemiological and experimental studies are required to determinehether these factors are involved in the pathogenesis of CKD progression or

hether they are just markers of the risk for disease progression

Hypothesisfree approaches such as genomeide association studies,

metabolomic studies and other omics technologies ill identify ne risk

factors and markers of CKD progression in elldefined cohorts

b kdy fc y y b,h p h d pdc pc. sp d b h d h c (auC) kdy fc h c pg chcc (roC) y pfd. th fdg gg h h dc- cpby f h p h f

kdy fc , dcg h h p- cd b g p f kdy fc- d cd b d pdc CKD pggd b g f (GFr). thcd f h h fd hdd k gh d b ddgf h phg d pg f CKD, c, y f CKD pg c bxpd f dj f b GFr.

a p, c hh y f h b-k k k k fc f CKDpg. rk k cy d CKD pg b hy dc h pbby

f pg, hy gh b f dgc .rk fc cy ffc d pg d ,hf, g hpc g. of c,pdgc b d cy pcy. sch b y g hyph- h d b p d, d ghy hd h p pg f CKD. Fh pdgcd d xp d dd bf yf h gg k k d fc c b d pdc CKD pg b cdd pdg g cc , d yp ch cc ppc.

Definition of CKD progression

n c d f df x f h pg- f CKD, d h chc f df y f-cd by h ch d b d h df h ppc b pd (tb 1). typcd p g f h GFr p (f xp,dbg f b c d/ hd f pc hpy, pc c f b c , yy hy dc GFr, GFr dc 50% fb, dy kdy p, gf) pc dc f dg (f xp,

g f p, ppc f b p h db). th ck f fy -k h cpg h pgcp f p k fc d k.

Risk factors and markers of CKD progression

th r fc pb k fc d kf CKD pg f hch ppcdy h p z f b 100 ddh b pfd. rh h dcbg d fcc bhd k fc ch g, gd,bd p, kg, bc yd, c

Figure 1 | Risk factors and markers for the initiation and progression of chronickidney disease. Traditional factors involved in the initiation and progression of CKDare discussed elsehere.137 The present Revie discusses emerging risk factorsand markerssuch as ADMA, FGF23, ANP and NTproBNPthat are shon in thebottom panel and require fur ther study. Abbreviations: ADMA, asymmetricdimethylarginine; ANP, Atype natriuretic peptide; apoAIV, apolipoprotein AIV; CKD,chronic kidney disease; ESRD, endstage renal disease; FGF23, fibroblast groth

factor 23; GFR, glomerular filtration rate; PTH, parathyroid hormone; KIM1, kidneyinjury molecule 1; LFABP, livertype fatty acid binding protein; NGAL, neutrophilgelatinaseassociated lipocalin; NTproBNP; Nterminal probrain natriuretic peptide.

Progressionof CKD:

GFR declineand ESRD

CKD

Initiating factors: Age Gender Ethnicity Family history of CKD Diabetes mellitus Metabolic syndrome Hyperltration state High normal urinary albumin excretion Dyslipidemia Nephrotoxins Primary kidney disease Urological disorders Cardiovascular disease

Traditional progressionfactors or markers: African American ethnicity Proteinuria Hypertension High protein intake Obesity Anemia Dyslipidemia Smoking Nephrotoxins Cardiovascular disease

Emerging progressionfactors or markers: ADMA FGF23 Phosphate PTH

Adrenomedullin ANP NT-proBNP L-FABP KIM-1 NGAL ApoA-IV Adiponectin Genetic polymorphisms

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cd, cy gd p ch f d h, gg p dcd (Fg 1). mk h h y bgd c kdy jy (aKi) c-dd, d d d d dcd y bfy.

Asmmtic dimtaii

ayc dhyg (aDma) yccg cd d hb f c xd(no) yh. aDma cp h g f

bdg no yh d d dcdpdc f no (Fg 2). exp d dch dcd c no pdc gh b d pg kdy dg.69

aDma gd f h dgd f hy-d p cg aDma d (Fg 2). i bzd y by dhyg dhy-hyd (DDaH)10 dhy d c-, d y fc f aDma xcdchgd by h kdy. a DDaH d no yh c-czd g dh c d

Table 1 | Prospective observational studies investigating emerging risk factors and markers for CKD progression*

Stud Stud uati ed its Duati f

fw-u

paamts assciatd

wit CKD ssi

paamts swi

assciati wit

CKD ssi

MMKD

study15,25,65,101,111,112177 nondiabetic patientsith primary CKD

Doubling of baseline serumcreatinine and/or renalreplacement therapy (n= 65)

Up to 7 years;median53 months

ADMA, FGF23, Ph, CaPh,PTH, adiponectin (in men),apoAIV, ANP, adrenomedul lin,

NTproBNP (borderline)

Ca

Hanai et al.18 225 patients ith type 2diabetes

Progression of diabeticnephropathy (n= 37)

Median5.2 years

ADMA

EURAGEDIC

casecontrol

study17

397 patients ith type 1diabetes ithnephropathy

Dialysis or kidneytransplantation (n= 70);yearly decline of GFR

Median11.3 years

ADMA

Ravani et al.16 131 nely referredpatients ith stages 25CKD

Dialysis treatment or GFRreduction to half of baseline(n= 29)

Mean27 months

ADMA

Scharz et al.23 985 US male veteransith stages 15 CKD

Doubling of baseline creatinineand/or renal replacementtherapy (n= 258)

Median2.1 years

Ph, CaPh Ca

AASK24,113 1,094 black patientsith hypertensive

nephrosclerosis (GFR2065 ml/min/1.73 m)

Decline in GFR by either 50%or 25 ml/min/1.73 m from

baseline or occurrence ofESRD

Median4 years

Ph CaPh, NTproBNP

Voormolen et al.26 448 patients ithstages 45 CKD and GFR


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b c, d kdy dyfc d c aDma cc.11 th b h fdg f bc d d-g h h kdy h hch aDma d f h cc.12

Cd ch hypch hyp-gyc hb DDaH, hch cdaDma (Fg 2). a h g dc no pdc cd h dcd pf, cd c c, hyp ddh dg, aDma g pk f cdc d.13

aDma kdy d p-

.11,14,15

tgh h h xp dchg aDma b CKD pg fc ,69 f ppc d h fd c b aDma d CKD pg- h (tb 1). th md md KdyD (mmKD) dy, hch fd 177 ph py dbc CKD f p 7 y,hd h ch 0.1 / c aDma cd h 47% c h pbbyf pg f CKD (tb 1), f cc fb c .15 r d c-g fd h hgh aDma cdh cd k f esrD d y g

131 p h CKD.16

a dy 397 p hyp 1 db d dbc phphy hdh aDma hgh h h d c-d h f yy dc GFr d gk f dpg esrD d f-p f11.3 y h aDma b h d.17adj f b b (cdg GFr)kd h c b d bdgfc (P= 0.055). a dy cdg 225 ph yp 2 db (183 h b d42 h cb) fd p 5.2 ypd pg f dbc phphy

dcd g 37 p.18 P h aDma b h d hd 2.7-fd hgh k fd pg h p h aDma b h d. tgh, h d pd gdc h cd aDma cdh pg f CKD.1518

exp d kdy d d-

c c f aDma pg fc fkdy d, ggg h g aDma ghb bfc.19,20 oxp f DDaH gfcydcd aDma d pd h pgf dyfc by hbg h pg fg d pb cp, fb d y p xc. Fh,xp f DDaH ppd h hcdxp f tGF- (hch gh h b c-qc f hypxc cd g f h f g d b cp). s fdg pd d f dbc phphy.21ad f DDaH p hcg c-

y hf ggd p hpcgy f h f CKD. i h cx, g-, dzd, cd b p hCKD f : p cd -p dppd h h k- cd pcbf 3 y.22 idd h cd k- cdxpcd pcd dc aDma , -c bdy f d p, d gfc dy h pg f CKD.

Cap mtabism, vitami D ad FgF23

Dbc ccphph b ffc y cdc bdy d y

p h CKD, b fc h pgf CKD.

Ca, Ph, CaPh product and PTH

ahgh p f ccphph bch cc, phph, ccphph pdcd phyd h (PtH) f h cphy d p p hCKD, y f d h gd hh f h p cd h CKDpg (tb 1).2327 th b d fd cg k f pg h cg ph-ph cc.2327 th d h

cc b hg h phph c- p h CKD h d y q pc hpy gh hp p dkdy fc28 d h phph bd ppg f CKD.29,30

th b d fd cb ccphph pdc d h pg- f CKD.23,25,26 F d hd c c- b cc cc d pg fCKD,23,2527 b d fd c bhgh PtH cc d CKD pg.25,27Fh, pc ch dy xd

Figure 2 | The role of ADMA in the progression of kidney disease. ADMA is mainlymetabolized by the enzyme DDAH. The activity of DDAH is strongly impaired inkidney disease, hich leads to increased ADMA levels. These increased ADMAlevels inhibit NO synthase, thereby resulting in decreased NO levels, hich hasmajor adverse consequences for the kidney and might lead to progression of CKD.Abbreviations: ADMA, asymmetric dimethylarginine; CKD, chronic kidney disease;DDAH, dimethylarginine dimethylaminohydrolase; NO, nitric oxide.

ADMARenally excreted NO synthase

Proteins with ADMA residues L-Arginine

Dimethlyamine + citrulline

80%

20%

LDL cholesterolHomocysteineHyperglycemia

HypertensionSmoking

InammationAging

Renal plasma owRenovascular resistanceBlood pressureEndothelial damageCKD progression

NODDAH

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c c f 186 d 517 pdy dh CKD d db, h d h cdyhypphyd, d fd h dd hcdy hypphyd hd fdcd k f qg dy dg h6-y f-p pd cpd h h hcdy hypphyd.31

ey xp k ggd h phphc h PtH-dpd bfc ffc h pg f d .32 th fdg d by h fc h gy h phy-gc hypphph. a f PtH CKDpg h b ppd by dc xp- cc dc,33 b xp dh h h pg f f gf-cy d by h d f ccc phydcy.34

Vitamin D

i h g pp, D dfccy

cy cd h cd ch hyp,cdc d, db , h fd cc.35 Dp h d fc f

D hh d hgh D h pcd ffc ccphph b,y dy h gd h c b

D d h pg f CKD (tb 1).36 thdy fd 168 cc p y fd CKD cc f g f 48 h. Dgh , 48 p d dy d 78p dd. l f 25-hydxy D dpd pdc f pg esrD dh f dj f g, d GFr

(GFr), h f, d h b. a c f25 / (10 g/) 25-hydxy D cd h 40% dc h hzd fCKD pg.36 igy, 25-hydxy D b pdc f pg esrD dhh 1,25-dhydxy D.

th fdg h ppd by ddc f d. ahgh Dhpy py d b phxc, hbd phxc ffc pbby f D-dcd hypcc p hCKD.37 rc xp dc h cy hh D d g pg

f CKD d.33,38,39

Fibroblast growth factor 23

th mmKD dy hd hgh p fbbgh fc 23 (FGF23) cc b fh g k fc k f CKD pg- (tb 1).25 FGF23 phph hgh b d h yc bc f phph hgh c h h , b dkdy.40,41 i h cc g, d fFGF23 h b h b cd h hyp-phph, 1,25-dhydxy D

d c.42,43 exp df FGF23 pdc dbc ccphph b, d c fh Fgf23 g c hypphphd hgh ccg 1,25-dhydxy D .44,45ud phygc cd, hypphphg dy phph d h c-

f FGF23, g phph d pp- f h pdc f D.46 i hpc f p, h dc fc pd by c FGF23, phph d PtH cc c d gf GFr.25,47 i dcd g f CKD, dbc h gy k y hgh f FGF23.48 H, h cc d cd d hh h cd FGF23 h c f h cd cc d ph-ph h cqc. exp dhd h h c FGF23 pcdd hdc 1,25-dhydxy D cc-

, ggg h FGF23 h p h dp f cdyhypphyd.49th d ppd by f cc dh fd h f FGF23 cd h y g f CKD, bf phphd cc cc hd bc b.50ahgh c hh cd FGF23 c cqc f dbc b d d h CKD, FGF23 xc dc f h cpx dbc fccphph b dcd by CKD, dh g cqc f h dbd b h ccpd by c ccfc-

.5153

of , dy c pbhd 2009 hd h FGF23 pd h pgf kdy d b ggd dyphyby dcg 1-hydxy d hby -g D .54 th h pcd h fh FGF23 gg phy cd b pd phphc phy d 1-hydxy phy,h phphc phy d b d dg g.igy, d pdy CKD ddh cg FGF23 dpdy c-d h f c dx d f c- hypphy.55 i p ccg hdy, cd FGF23 cc d-

pdy cd h cd k f ydg h f y f dy .56

oy ppc b dy hh gd h c b CKD pg- d f FGF23 gh h f hp f ccphph b.25ahgh FGF23, ccphph pdc, ph-ph d PtH pdcd pg f CKD g b (f dj f g, gd,GFr d p), h h p h pdc h FGF23 ddd hpdc d.

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Adicti

adpc j dpcy cy ph p y d p -fy d -hcc pp.57l dpc cd h -c,58,59 by d h f f h bcyd60 d h yp 2 db d

cdc d.6163 a c dyp dd h h d dg f p d p h h py CKDd GFr,64 c b dp-c d pg f CKD d b xpcd.spgy, h, h dpd d hh c b hgh dpc d CKD pg (tb 1).6567 th mmKD dyfd h hgh dpc dpdpdc f d pg b .65 J d cg fd 198 p hyp 1 db d dbc phphy f g f 8 y.66 th 40 p h chd esrD

dg h b pd hd gfcy hghdpc b h h h dd .a dpc b h d cd h 2.7-fd hgh GFr-djd k f esrD h b h d. s bd b-gp f 296 p h yp 1 db dcb f h Fh Dbc nphphysdy.67 adpc gfcy hghg h 83 p h pgd esrDh g h h dd pg. adpc gfcy pdc f pg esrD p h b cb.

a b f hyph f h xpcd fd-

g h b ppd. o gg h hcd dpc cd h chg h gdcp cy ( cc h hh cp y f).68 oh g-g cd h d h h cd dpc CKD f dcd dpc c-c by h kdy69 h c-gyp bc dg f.70igy, xp d f 2009 gg hd p dpc p h CKDgh py cpy h cc dyfc cd h g c d-d.71 rc dpc72,73 pby,

h f dpc dyfc g h dyfc dg f dpc cp- h c-gy c dpcc. s ppc d h fd fd c b dpc d cd-

c c dh, pcy ddh dy h d chc d b-. th ldghf rk d Cdc Hh(luriC) dy, hch fd 2,500 ph hd cy y d b f h 5 y, fd h cd dpc gy cd h -c d cdc

y.74 th mdfc f D r D(mDrD) dy pd fdg p h b GFr f 33 //1.73 .75 Kpet al. pd h hgh dpc pdc- f y p h chc h f,dpdy f h y f h d.76 thd pc h h pg f dp-

c chc d cpy p dh d c dg.77

nuti atias-assciatd icai

nph g-cd pc (nGal) (25 kD) p h xpd bc d d h bd d f xp- hf ch ch xcy. th f nGal cc h h f h d g bf c c cc. nGal h hf b ppd b- dc f c kdy dg hc d GFr k f fc

ph b.78 th f nGal pcfc, d y pdc f aKi f c dd, pc hck, kdy p dcdc gy h b gd xy d hb d h.78,79

D dc h nGal y pdc f aKib f h pg f CKD. o dy fdh y nGal gfcy hgh dd h b phphy h c- d h p h hgh b y nGal hd gfcy hgh k f g d fc h h h .80 ah dy 96 p h g 24 CKD fd

h bh d y nGal dcycd h h pg f CKD df-p f 18.5 h, dpdy f g d GFr b (tb 1).81 a p dy 78 p hCKD hd h b nGal cdgy h chg c (cffc fc r= 0.77) d GFr (r= 0.40) d h c d b g f-p pd f 200 dy p h b nGal .82

t d h dcbd h p f nGal fg h d p f d. o f h hd h p h

phc yd ph hd k-dy d y nGal h dcd p ccf .83 th h dy, p h p cdy d-phc b phphy, hd h ghgh-d b f f gb c-d h dc dc d ynGal 1 h f f, h pp h-fy pp f h .84 i b hh nGal bc fbk qcky gg p p pc .

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liv-t fatt acid bidi ti

Cc d c b -yp fycd bdg p (l-FaBP) d kdy d p. th p xpd px bc d cd xp d hgh h f p h kdy d.85,86 a ghh cg pg h 900 dd

d h g y f l-FaBP ppxy 50% hgh p h db, hyp chc hp h c-.87 a dy gg l-FaBP ph yp 2 db d dff g f ph-phy hd h y l-FaBP cd hh y f dbc phphy.88 s d p h d kdy dyfc gg hy l-FaBP cc cd ph fc d fh.86,89 lgd h g- f-p qd cfh fdg.

Kid iju mcu 1Kdy jy c 1 (Kim-1), b -b c h k fc, dc-b hhy kdy. a phphdy cp,Kim-1 py p pp bycgzg ppc c d dcg h y-.90 Kim-1 xp cd d d py xpd h d fddffd px b d f fbd f.91 t et al. fd h f y Kim-1 gfcy d ph d d dcb hhyc.91 a ppc dy 145 p

cp fd f 4 y d h ddh y Kim-1 cc h cd dhd hd 3.6-fd d 5.1-fd cd k,pcy, f g h gf.92 th ccddpdy f c cc, p dg f h gf d. a p hc y f fp h pc kdy d d h

cb f , d c dhydchhzd dc p hd hh cd Kim-1 cc dcd p- h dc p hgh kdyfc dd chg dg h 6-k bpd.93 whh Kim-1 j bk f

c d chc kdy d hh cyd kdy jy c.

Aiti A-IV

H ppp a-iv (pa-iv) 46 kDgycp h yhzd -cy dg f bp d cpd hfc f c chyc (g pp p-c h p dy pd f h h c h bdy).94 apa-iv h p- ch p, hch d-bd p h CKD.95 apa-iv kdy

d esrD96,97 d k f kdyp h c h gf CKD.98 ihchc d dcbg hcy f pa-iv kdy b cd g f pa-iv h h hpa-iv fd hgh h g d y bbd by px b c.99,100

th mmKD dy fd h hgh pa-iv cd h CKD pg (tb 1). a 10 g/dc b pa-iv ( y cc ph GFr h h g 4590 //1.73 ) cd h ppxy 60% cd kf pg f CKD dg h d bpd f 53 h, dpdy f b GFr,p d h pp p.101

th c f hgh pa-iv cc hCKD pg xpcd g h phygcfc f pa-iv ch pd pd xd pp.102 o ghh cpd h h cd pa-iv

dd h pd kdy fc d hd cd f ch f -g c d h, gh h h xd pp- pa-iv, d d pg f CKD.whh cd pa-iv fc pc f p h d c p h GFr hh pa-iv fy fc c f p c. th hyph gg , pcy h gh f h cf pa-iv h cdc d.103,104H, p h hd dy xpcd h-cc h f h mmKD dy hd pa-iv h h h hcc

cpc ch f GFr.98

natiutic tids

o c y, h c f h h d hkdy bc fc f d h cd- yd cd. H, h ph h fg h c cdy p fkdy fc. a p h py CKD dpcdc yp h h g , bcb h py b h g cch h -y b h h dkdy. th d h d pp f cfcf h cd yd h bcd h fc d phphygc pc, hghy dcd h .105 myk f cdc dyfc pdc fCKD pg. P xp c pp-d ch a-yp c ppd (anP), d-d d B-yp c ppd (BnP). thppd p hyp, dc, d -c ppd h d g cd-

c d h.106108 icd p f anP d dd h b pd dd h cdc d, f cdyfc d h h kdy d.109,110

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add, anP, d N- p-b

c ppd (nt-pBnP) gd h mmKD dy d hgh f ch fd b cd h CKD pg (tb 1).111,112th pcd c fd f d-d: c h p by ddd cd h 2.6-fd cd k fd pg. a c anP by ddd h dbd h k f pg-.112 igy, dpd d gfc c-b f ch p h pdc f CKDpg fd h bh p ddd h Cx g d h .nt-pBnP y f bd gfcc f p-

dcg kdy d pg h mmKD dy.i h afc ac sdy f Kdy D dHyp (aasK), h cdc f dpg cd h cg nt-pBnP ,b h fdg gfc f dj fkdy fc (tb 1).113 a ppc dy 83 p h CKD h cc dc fh f b hd h g nt-pBnP b hgh p h xp-cd pg f CKD h h h dd .114H, dj d f b GFr h dy.

Cmais f aamts i t MMKD stud

m f h d dcd b yzd y f p , kg y p-b cp h . a f h ph g c h ch h, y g Cx g d b pfd hc. rc pg c f GFr, aDma,

FGF23, pa-iv, anP, nt-pBnP d ddf h mmKD dy dc h dd b b dc b p h dh pg f CKD, h b dc-y by h GFr d by hx (Fg 3).P f h dd f ch f h pc b Cx g d djd f g, x, p- d GFr h h dd, FGF23, aDma,anP d pa-iv gfcy cbd h p-dc f CKD pg.15,25,101,111,112 th hd f dpc, b y .65 th pcy cb h pdc f CKD pgd h c f h b h pg-

c py b xpd by c hGFr p.

Genetic factors for progression of CKD

th j dg f g gc fc f -g CKD pg h by, hy hd ccp d d gy chg h d.if hy fd b cd h d, hy f cy d h d q.

Assciati studis usi tic misms

th pcp f c d f gc py-ph h chgd dcy h p f

y. Py, gc d h fc cpx phyp ch cd-

c d, db d kdy d. w k, h, h pyph h k f 2 f h cpx phyp y d ch d gh b f p- chc fdg. G-d c dd -y h h h h gc k f pc c cd h pc gc

f y 1.2 . F xp, b 20g h c by cd hyp 2 db d h y d dd kc f b 1.1 d 1.4 p- b.115

Hg p z dd b ffc cp dfy d-cg gc .idfyg gc pyph h d

c h h j dg, h, hcy ky. th bcccdg h f md dzgc gy cpb h cfdg h cd fdg c b d, g p ch d g hgd pp ffd d f cfdgby pyph kg dqb h hpyph d g c b xcdd116

Figure 3 | Receiver operating curves from the MMKD study for GFR measured by

iohexol, ADMA, FGF23, apoAIV and the natriuretic peptides ANP, NTproBNP andadrenomedullin to predict progression of CKD. Area under the curve values foreach of these parameters are shon as are Pvalues for the addition of each ofthe particular variables to a Cox reference model adjusted for age, sex, proteinuriaand GFR. Adrenomedullin shoed the greatest area under the curve, hichindicates that it had the best ability to discriminate beteen patients ho ouldand ould not experience CKD progression, even superior to the ability of GFRmeasured by iohexol. Data are calculated from a number ofreferences.15,25,101,111,112 Abbreviations: ADMA, asymmetric dimethylarginine;ANP, Atype natriuretic peptide; apoAIV, apolipoprotein AIV; CKD, chronic kidneydisease; FGF23, fibroblast groth factor 23; GFR, glomerular filtration rate;NTproBNP; Nterminal probrain natriuretic peptide.

Parameter AUC Cox model P value

Adrenomedullin 0.873 0.0000003

GFR 0.839 Referencemeasured by iohexol

FGF23 0.815 0.0000084

ADMA 0.811 0.0000058

ANP 0.811 0.0000014

ApoA-IV 0.800 0.012

NT-proBNP 0.751 0.099

Reference line

1.0

0.8

0.6

0.4

0.2

0

0.0 0.2 0.4

Specicity

Sensitivity

0.6 0.8 1.0

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(Fg 4). th md dz ccp ppd c f-p dy h gd hc b dpc d pg- f CKD h euraGeDiC dy.66 adpc cd h pg f yp 1 dbcphphy b c b gcd pyph d pg f CKD

fd. G h y b 8% f h dpc c b xpd by h h dpcg,117 d dpc xp y 10% fCKD pg b, y g b f pd b qd dfy c f h - h CKD pg (Fg 4). if h f, g dy h c f gc d hgh dpc d c fh h CKD pg, cy bgy ggd.

gm-wid assciati studis

th dc f g-d c d

pdd d pf ppch h q fg cd h cpx phyp. th dg hdd f hd f gc c h h g d hhhy cd h h phyp f . ic h hyph-d ppch f cddg d, g-d c d h hj dg h hy hyph f d chf dfy cdd g h kgy bgc p. og h g bf pfd h d, h, g pz qd.

a g-d c dy f pp-

bd ch h f CKD, c-bdGFr d cy-C-bd GFr 19,877, 18,127 d12,266 dd, pcy, h dfd c cd h kdy fc.118 Kg et al.fd h d (UMOD) cd hCKD d h c-bd GFr. Fh,y f d f f h dh ppc- ahc rk C (ariC)dydfd h g g h cd h dcd k f cdCKD (hzd 0.81, 95% Ci 0.720.92, P= 0.001).r h UMOD g k c d d ch f j

hypc phphy, gcyc kdyd, d dy cyc kdy d yp 2.119121i y g h ch h cgc d c p c h g g h fc d-dphyp h pp . oh g d-fd b cd h c-bd GFr hg-d c dy pd by Kget al. h fy b 3 (SHROOM3) ch 4 d pg cd 5-k 1(SPATA5L1) h GATM-SPATA5L1 c ch- 15.118 i dd, cc 1 (STC1)

ch 8 d gc g cdpyph (snP) b h g c f cy- C (CST3) d cy 9 (CST9) ch 20 fd b cd h cy-C-dGFr. lc ch GATM-SPATA5L1 d g h

cy pfy g c (CST3 d CST9)d c d cy yh d d cy fc cpby f CKD GFr.m f h y dfd g d fh fc- chcz d c d hfh kdy-d phyp d h pg- f CKD. oh g c py hgh bcd h CKD CKD pg (f xp,g-i-cg zy, ppp e,hyhydf dc d cpfc 7-k 2122125) dd h g-dgfcc Kg et al.dy.

Kg et al. fd h, gh, h gc c

dfd b cd h GFr d byc xpd b 0.7% f h cf c-d GFr d h h gc cdfd f GFr d by cy xpd b3.2% f h cy-C-bd GFr c.118 Dph hgh hby f GFr, h pcg pg d h fdg f d fh q f hby.126128 thfdg dc h h y dfdgcc x h fc kdy fc d h y h h dfd g gh xph c fh.129 G-d c d

Figure 4 | Application of the concept of Mendelian randomization for identifyingparameters causally related to progression of CKD, using adiponectin as anexample. At conception, hich of the to alleles is inherited from the mother andhich of the to alleles is inherited from the father is determined randomly.Particular genetic variants ithin theADIPOQ gene are associated ith increasedadiponectin levels; these variants explain about 8% of adiponectin concentrationvariance.117 If high concentrations of adiponectin are truly associated ith CKDprogression, the genetic variants associated ith lifelong high adiponectin levelsould be expected to lie more often ithin the group of patients ho experienceCKD progression. As this association is unlikely to be confounded by other factors,a reverse association can be excluded. Very large sample sizes are required todetect an association beteen a particular gene and progression of CKD if only

small fractions (for example, belo 10%) can explain the association beteen thegene and the intermediate phenotype and the association beteen theintermediate phenotype and CKD progression. This concept is discussed in moredetail elsehere.116,138 Abbreviations:ADIPOQ, adiponectin gene; CKD, chronickidney disease. Figure adapted from references 138 and 139 ith kind permissionof Springer Science + Business Media Kronenberg, F. & Heid, I. M. MedizinischeGenetik19, 304308 (2007).

Strongassociation:explains 10%

Weak association:explains 0.8% (0.100.08)

No reverse causation

Strongassociation:explains 8% End phenotype

Progressionof CKD

GeneADIPOQ

Mendelianrandomization

Intermediatephenotype

Plasma adiponectinconcentrations

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d -y h p z ppchg100,000 dd pg d dfy g cd h CKD. F cb d d h h dfc f g cd h

f f py CKD h c-d h pg f CKD. og h zf d f p h py CKD d ppcg CKD pg, dfyg g f

h xdd phyp b chg.

The future

s bchc d gc fc h h hp b k f CKD pg fc d h pc h b dcd.H, h fdg dcd h y pd.v dcpy h h h ffx -c bkg gd (Fg 5). mbc hpdy g fd f g dg b- c fd ch p, , .130mg d phyp ch h c h d h phy f d

d f py cfyg dd hhy dd gh pd d b pyffcd phy h dcy h -gy f h d. a cy k b cb d g pcd f pcd,y b dcy dcy d h dp pg f CKD d b d-fd. th hyph-f ppch h dy bccfy ppd g-d c d dfy g d gc d hdp f cpx d.131,132 By cbgg-d c d h bc,

gp h fd c f c snP h cd h h d h f ky b- h h bdy d c xp p 12% fh bd c f h b.133wh f c b cc d pxy f zyc cy, p 28% f hbd c cd b xpd. th cbd

ppch f bc d g-d cd hd pd gh h phchf d d, h f, h dd cd- f g xp d pc cbdy by p dfc f kfc f CKD d CKD pg. th ybgy ppch gh bg c p-zd hh-c y h cd h fcb f p g dg , chg.

th y bgy ppch, h, y h cb f -c chqb q ch k gh b

h p z qd f ffc c p.i gc pdgy d g-d cd, -y f 10,000 100,000 p y pfd.115,118,126128,134 s b b dd f h y bgy ppch. i dd,ffc ddz f y d pcd b y p. sch ddz dy pcf gypg d qcg d ff dy ddz c .135 ahghcb b dy gp, hch cy h qd p z, ccb f y g, h bc dd pcc hfd f g-d c d.

Conclusions

th gg p cd h CKD pg- b dd fh d hh hy cy d pg f CKD hhhy py pdc h pbby f pg. thp gh fc dhd g f-, dbc b fc kcb kdy fc h d g b fc. s f h p -k k f chc h f, c-fg h pcd ckg b CKD dh d.

th dc p f f h p- b cdd f bd cc hdg f CKD pg. my p hy b gd f d, d d h dffg df f CKD pg- (tb 1). th f d f p gg b ppc hd b dd. whh k f aKi h h f dg f CKD CKDpg c. s p gh b ff h g f hp h fc kdyfc (py gy) d gh

Figure 5 | The systems biology approach for identifying contributors to CKD,progression of CKD, cardiovascular outcomes and responses to drug treatment.

Combining data on genetic variation, transcriptomics, proteomics andmetabolomics, and considering various regulatory and modulatory influences asell as environmental interactions, ill improve our understanding of thepathomechanisms of diseases. Abbreviation: CKD, chronic kidney disease.

Genetic variation

Proteomics

CKDProgression of CKD

Cardiovascular diseaseResponse to drugs

Post-transcriptionaland

post-translationalmodications

Environment(e.g. nutrition,lifestyle, drugs)

Transcriptionalregulation

Epigenetics

MetabolomicsInteractomics

Transcriptomics

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chg g bf hy dfd by c ch chg GFr p.

i h , h f f ch f gpp-bd d ch h Fgh Hsdy, h ariC dy, h Cdc Hh sdyd h rd sdy f dyg phyph b dd.118,123,125 w f

g ppc ch dch h Chcr iffccy Ch (CriC) dy136 d hG Chc Kdy D (GCKD) dyhch fc kdy fc d CKD pg.

Review criteria

A literature search as performed in PubMed using

the search term chronic kidney disease AND

progression. Bibliographies and discussion sections

of the identified articles ere searched for additionalrelevant manuscripts. Papers discussing laboratory

parameters found to predict the progression of chronic

kidney disease ere included hen human studies ere

available that included a prospective observation period.No date restrictions ere placed on the search.

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Ackwdmts

The author ould like to thank all collaborators of theMild to Moderate Kidney Disease (MMKD) study hohave continuously contributed to the investigation. Inparticular, he ould like to thank Dr B. Kollerits for hercontributions to the study. Funding from the

Genomics of Lipidassociated Disorders (GOLD) of theAustrian Genome Research Programme (GENAU),and support from the German Ministry of Educationand Research (BMBF) and the KfH StiftungPrventivmedizin to the German Chronic KidneyDisease (GCKD) study is greatly appreciated.Charles P. Vega, University of Irvine, CA, is the authorof and is solely responsible for the content of thelearning objectives, questions and ansers of theMedscapeCMEaccredited continuing medicaleducation activity associated ith this ar ticle.

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