Cardiovascular Pathology

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1 riovsulr Pthology 23 (214) ontnts lists vill t SinDirt riovsulr Pthology Originl Artil High-phosphorus/zin-r it ggrvts hyprtnsion n ri ysuntion in rt mol o th mtoli synrom Yuk Suzuki, Shingo Mitsushim, Ai Kto, Tknori Ymguhi, Shoko Ihihr,, Grut Shool o Rgionl Innovtion Stuis, Mi Univrsity, Tsu , Jpn Dprtmnt o Humn Funtionl Gnomis, Li Sin Rsrh ntr, Mi Univrsity, Tsu , Jpn rtil ino strt Artil history: Riv 4 April 213 Riv in rvis orm 6 Jun 213 Apt 26 Jun 213 Kywors: Mtoli synrom ri ysuntion Hyprtrophy Firosis Antioxint kgroun: ri ysuntion is rport in ptints with th mtoli synrom. W ssss th ts o high-phosphorus n zin-r it on riovsulr systm in spontnously hyprtnsiv rts (SHR)/ NDmr-p (), rt mol o th mtoli synrom. W lso invstigt th ts o N-tyl-Lystin (NA), n ntioxint, on th vlopmnt o ri ysuntion unr suh onitions. Mthos: Ml n ontrol [Wistr Kyoto ()] rts wr ivi into thr groups n ontrol it (P.3% w/w, Zn.2% w/w) or high-phosphorus n zin-r (P 1.2% w/w, Zn.% w/w) it. Th lttr group ws trt with ithr NA (1.5 mg/g pr y) or vhil rom 6 to 18 wks o g (n=6 or 8 or h group). Rsults: High-phospht n zin-r it inrs systoli loo prssur in oth n. Ehoriogrphy show tht high-phospht n zin-r it mrkly ru lt vntriulr systoli n istoli untion in. Histopthologilly, th sm it inu svr myoril irosis in, n this t ws prvnt y NA. Whrs trtmnt with NA prvnt istoli ysuntion inu y th sm it in, it only improv systoli untion ut not istoli untion in. onlusions: High-phospht n zin-r it inu hyprtnsion n ri ysuntion. Ths hngs hmpr th prottiv ts o NA in th mtoli synrom. Summry: Th prsnt stuy show tht onsumption o high-phosphorus n zin-r it inrs th myoril xprssion o onntiv tissu growth tor n ru th xprssion o mtllothionin, whih nhn th vlopmnt o svr ri ysuntion in rts with th mtoli synrom. Th rsults suggst tht th mtoli synrom sms to ggrvt ri ysuntion n hmpr th prottiv ts o ntioxint, NA. 214 Pulish y Elsvir In. 1. Introution Th mtoli synrom is in s lustr o ominl osity, throgni yslipimi (hyprtriglyrimi n hypohigh-nsity lipoprotin holstrolmi, oth ostr plqu uilup in rtril wlls), hyprtnsion, n hyprglymi [1]. Th synrom is n importnt soil onrn us it is ssoit with inrs risk or rtrioslrosis, myoril inrtion, strok, its, n hroni kiny iss [2,3]. Hyprphosphtmi n hypozinmi r linilly sri in som ptints with iti nphropthy n mtoli synrom [4,5]. Furthrmor, it is wll known tht youngr gnrtions tn to tk plnty o pross oo tht oul rsult in vit nutrition suh s zin iiny or phosphorus xss. In ptints with hyprphosphtmi, th onnting phosphorus n lium hstn th progrssion o rnl iss n l to vnmnt o throslroti isss, suh s myoril orrsponing uthor. Tl.: ; x: E-mil rss: sho@gn.mi-u..jp (S. Ihihr). inrtion n strok [6]. On th othr hn, zin iiny is urrntly rogniz to ssoit with vrious isss, suh s hroni urmi, hroni livr iss, hroni rnl iss, n hroni loholism [7]. Hypozinmi improvs th rution in pptit, sns o tst n smll, n immun omptn [8]. Morovr, hypozinmi is ssoit with low rsistn to oxitiv strss [9] n xrts inlmmtory rsponss [1]. Spontnously hyprtnsiv rts/ndmr-p () mnist hyprtnsion (rom SHR) n osity (whih is rlt to nonsns muttion in th lptin rptor gn) [11,12]. xhiit mrk hyprholstrolmi, triglyrimi, hyprglymi, n hyprinsulinmi [13], suggsting tht ths os rts r suitl mol or th mtoli synrom. In th prsnt stuy, w invstigt th ri untion in mtoli synrom n ssss th ts o itry mnipultion o phosphorus n zin (zin-r high-phosphorus it) on ri untion using th s mol o th mtoli synrom. In ition, w xmin th ts o ntioxint N-tyl-L-ystin (NA) on th vlopmnt o ri ysuntion unr suh onitions /$ s ront mttr 214 Pulish y Elsvir In.

2 44 Y. Suzuki t l. / riovsulr Pthology 23 (214) Mthos 2.1. Animl xprimnts At 6 wks o g, ml n Wistr Kyoto () rts wr ivi into thr groups: th ontrol it group (P.3% w/w, Zn.2% w/w, n=6) (); high-phosphorus n zin-r it group (P 1.2%, Zn.% w/w, n=8) (PZ); n th high-phosphorus n zin-r it with NA group (P 1.2%, Zn.% w/w, NA: 1.5 mg/wight/y in rinking wtr, n=8) (PZN). Ths trtmnts ontinu until 18 wks o g. Th nimls wr hous in tmprtur- n light-ontroll nvironmnt t 25 with 12-h light rk yl. oy wight (W), oo intk, n wtr intk wr msur t h wk. Two rts wr kpt in h g, n wtr intk ws msur on wk. Thn, th vrg volum o rinking wtr ws stimt pr rt. s on th volum o wtr n th mount o NA to th wtr, th lult os o NA ws 1.5 mg/kg W/rt. All niml prours wr onut in orn with th guilins or th r n us o lortory nimls pprov y Mi Univrsity Msurmnts o systoli loo prssur, hrt rt, n horiogrphi tst Systoli loo prssur n hrt rt wr msur in onsious rts y th til-u mtho (P-98A, MP-1; Sotron, Tokyo, Jpn) t 18 wks o g. Trnsthori horiogrphy ws prorm with SONOS 55 systm (Philips Mil Systms, othll, WA, USA) s sri prviously [14]. Th rts wr nsthtiz y intrpritonl injtion o pntoritl soium t os o 1-mg/kg W. Wll thiknss n lt vntriulr (LV) n-istoli imtr (LVEDD) wr otin rom th short-xis viw t th lvl o th ppillry musls, n LV rtionl shortning (FS) ws lult. Puls Dopplr trings o th stimt mitrl inlow vloity wr otin in th moii prstrnl long-xis viw [15]. Th pks o th E n A wvs o th mitrl inlow vloity tring wr ror s th vrg o thr ts iohmil tst At 18 wks o g, ll rts wr srii, n loo smpls wr ollt. Plsm ws isolt tr ntriugtion n msurmnts o th onntrtions o triglyri, gluos, n loo ur nitrogn (UN) wr outsour to SRL (Tokyo, Jpn). Th onntrtion o rtinin ws quntii in plsm with Qunti- hrom rtinin Assy Kit (ioassy Systms; Hywr, A, USA) Histologil nlysis Following srii t 18 wks o g, th lt vntril ws isolt n ut into 2-mm-thik slis. Mivntriulr slis wr ix in 1% ormlin, m in prin, stion (thiknss, 4 μm), n stin with hmtoxylin osin solution, to vlut myoril hyprtrophy, n lso with sirius r solution, to vlut th xtnt o irosis. LV myoyt ross-stionl r ws msur on stions o mi-r wll o th lt vntril, s sri prviously [14]. Approximtly 1 lls wr ount pr smpl, n th vrg ws us or nlysis. Th ollgn rtion ws lult s th rtio o th sum o th totl r o intrstitil irosis to th sum o th totl onntiv tissu r plus th myoyt r in th ntir visul il o th stion. Th r o privsulr irosis ws trmin s th rtio o th r o irosis surrouning th vssl wll to th totl vssl r. Approximtly 4 rtril ross stions wr xmin in h hrt. Stions wr lso sujt to immunohistohmistry with rit polylonl ntioy spii or onntiv tissu growth tor (TGF; Am, mrig, UK) n with mous monolonl ntioy spii or mtllothionin (MT; Am) Sttistil nlysis All prmtrs wr xprss s mn±stnr rror (S.E.M.). Sttistil nlyss wr prorm using on-wy nlysis o vrin ollow y Turky-Krmr post-ho nlysis. Th P vlus lss thn.5 wr onsir to sttistilly signiint. 3. Rsults 3.1. W, oo n wtr intk, n plsm iohmil t W ws signiintly highr in 18-wk-ol ontrol rts thn thir ountrprts o (Fig. 1A). W o th PZ group ws signiintly lowr thn tht o th ontrol group o oth n. Thr ws no signiint irn in W twn th PZ n PZN groups o th two rt strins (Fig. 1A).Whrs oo intk to W rtio (oo intk/w rtio) ws signiintly lowr in th PZ group thn in th ontrol, th rtio ws signiintly highr in th PZN group thn in th PZ group o. Thr wr no signiint irns in oo intk/w rtio mong th thr groups o (Tl 1). Th rtio o wtr intk to W (wtr intk/w rtio) ws signiintly lowr in th PZN group thn th ontrol n PZ groups o (Tl 1). Furthrmor, th wtr intk/w rtio ws signiintly grtr in th ontrol group o thn ll groups o. Th wtr intk/w rtio ws signiintly irnt twn th PZ n PZN groups rltiv to th ontrol group o. Plsm triglyri onntrtion ws signiintly highr in thn (Fig. 1). Thr ws no signiint irn in th onntrtion mong th thr groups o h strin. Morovr, thr ws no signiint irn in plsm gluos lvl mong th thr groups (Fig. 1). Th onntrtions o UN in plsm wr highr in thn in (27.9±1.8 vs. 2.9±.5 mg/l). Although th onntrtion o UN ws highr in th PZ n PZN groups thn in th ontrol group o (22.3±.1 n 27.3±1.9, rsptivly, vs. 2.9±.5 mg/l), thr ws no signiint irn mong th thr groups o. Thr ws no signiint irn in plsm rtinin lvl mong th groups (t not shown). W lso stin kiny tissu stions with prioi i-shi stin or light mirosopi nlysis. Thr wr no signiint histopthologil hngs in n (t not shown). Ths inings suggst rly-stg nphropthy t srii, onsistnt with th prvious stuy tht show no rnl histologil hngs in 17-wk-ol SHR/ p s xmin y prioi i-shi stining [16] Systoli loo prssur n horiogrphi inings Systoli loo prssur ws signiintly highr in 18-wk-ol ontrol thn thir ountrprts o (Fig. 1D). Systoli loo prssur ws signiintly highr in th PZ group thn in th ontrol group o oth strins ut signiintly lowr in th PZN group thn th PZ group o only. Thr ws no signiint irn in hrt rt twn ontrol n (334±18 vs. 396± 2/pm, rsptivly). Morovr, thr ws no signiint irn in this prmtr mong th thr groups o h strin. To hrtriz LV istoli untion, w ompr th Dopplr horiogrphi inings o h group. Thr ws no signiint irn in E: mitrl pk vloity o rly illing mong th groups; A: mitrl pk vloity o lt illing ws signiintly lowr, n th E/A rtio ws signiintly highr in th ontrol group o thn in tht o (Tl 1). Th E/A rtio ws signiintly highr in 18-wk-ol PZ rts thn in th ontrol group o oth strins (Tl 1). Th E/A rtio o th PZN group ws signiintly lowr thn tht o th PZ group o, whrs this prmtr ws similr in th PZ n PZN groups o. Furthrmor, LVEDD ws signiintly lowr in 18-wk-ol PZ rts thn in th ontrol group o oth strins. LV n-systoli imtr (LVESD) ws signiintly

3 Y. Suzuki t l. / riovsulr Pthology 23 (214) oy wight (g) A Triglyri (mg/l) PZ PZN PZ PZN PZ PZN PZ PZN Gluos (mg/l) PZ PZN PZ PZN Systoli loo prssur (mmhg) D # PZ PZN PZ PZN Fig. 1. Ets o high-phosphorus/zin-r it n NA on W, plsm iohmil t, n loo prssur. (A) W, plsm lvls o () triglyri n () nonsting gluos, n (D) loo prssur in 18-wk-ol rts. Dt r mn±s.e.m. o six or ight rts pr group. P.5 vrsus ontrol rts; # P.5 vrsus PZ it; P.5 vrsus ontrol rts. lowr in th PZ group thn in th ontrol n signiintly grtr thn in th PZN group o (Tl 1). LV FS ws lso lowr in th PZ group thn in th ontrol n signiintly grtr thn in th PZN group o (Tl 1). Thr wr no signiint irns in LVESD n LV FS mong th thr groups o Myoyt hyprtrophy n ollgn position Light mirosopi nlysis init signiintly lrgr rossstionl r o th ri myoyts in th ontrol groups o thn in thir ountrprts o (Fig. 2A). Th myoyt rossstionl r ws signiintly lrgr in th 18-wk-ol PZ rts o th ontrol groups o oth strins (Fig. 2). This inrs ws mrkly nhn in th PZN group o only. NA tn to ru th mgnitu o this inrs, ut th t ws not signiint in. Th xtnt o privsulr (Fig. 3A) n intrstitil (Fig. 3) irosis ws signiintly mor svr in th PZ group thn in th ontrol ut signiintly milr thn in th PZN group o. Thr wr no signiint irns in ths prmtrs mong th thr groups o (Fig. 3, D). Tl 1 Foo n wtr intk to W rtios n horiogrphi inings in 18-wk-ol rts ontrol PZ PZN ontrol PZ PZN Foo intk/w (g/kg/y) 68.± ± ±.6 # 72.4± ± ±2.3 Wtr intk/w (ml/kg/y) 12.3± ± ±2.8,# 74.6± ± ±1.5, LVEDD (mm) 7.3±.1 6.9±.1 6.5±.1 7.2±.1 6.5±.1 6.2±.1 LVESD (mm) 4.2±.1 4.±.1 3.9±.1 3.8±.1 4.1±.1 3.6±.1 FS (%) 42.8± ± ± ± ±.4 42.±.5 E (m/s) 94.6± ± ± ± ± ±1. A (m/s) 5.9± ± ± ± ± ±1.7 E/A rtio 1.9± ± ±.4 # 1.33± ± ±.4 Dt r mn±s.e.m. o six or ight rts pr group. P.5 vrsus ontrol rts. # P.5 vrsus with PZ it. P.5 vrsus ontrol rts. P.5 vrsus with PZ it.

4 46 Y. Suzuki t l. / riovsulr Pthology 23 (214) A myoyt ross-stionl r (µm 2 ) # PZ PZN PZ PZN Fig. 2. Morphologil nlysis o th lt vntril o 18-wk-ol rts. (A) Light mirogrphs o myoyts in hmtoxylin osin-stin stions o th LV wll in rprsnttiv () ontrol rt; () ontrol rt; () with high-phosphorus n zin-r it; () with high-phosphorus n zin-r it; () with highphosphorus n zin-r it with NA; () with high-phosphorus n zin-r it with NA. Sl rs, 1 μm. () Quntittiv nlysis o th ross-stionl r o myoyts. Dt r mn±s.e.m. o six or ight rts pr group. P.5 vrsus ontrol rts; # P.5 vrsus PZ it; P.5 vrsus ontrol rts Exprssion o TGF n MT Immunohistohmil nlysis init up-rgultion o TGF xprssion in th PZ group ompr with th ontrol o (Fig. 4A). A highr xprssion lvl ws not in th PZN group o. Thr wr no signiint irns in TGF xprssion mong th thr groups o. Immunostining or MT ws osrv in th privsulr sp in th hrt o (Fig. 4). Th xprssion ws lowr in th PZ group thn in th ontrol group n highr in th PZN group. In, low xprssion o MT ws osrv in th thr groups. 4. Disussion W show in th prsnt stuy tht high-phosphorus/zin-r it inu hyprtnsion. This it lso ggrvt istoli ri untion, n trtmnt with th ntioxint, NA, improv ths hngs in. On th othr hn, th sm it ggrvt oth istoli n systoli ri untion in, n NA improv systoli untion ut not th istoli untion in ths spis. Ths hngs in ri untion likly rprsnt th irt ts o hyprphosphtmi n hypozinmi, rthr thn u to rnl ysuntion, sin th lttr ws not osrv in our rts. Sin th xrtion o xss phosphorus is yon th norml rnl mhnisms, hyprphosphtmi is linilly osrv in ptints with vn hroni rnl ilur n ptints on ilysis [17]. In th lttr group, strong rltionship twn high srum phosphorus lvls n ri uss o th hs n rport, spilly ths rsulting rom oronry rtry iss n sun th [18]. Although inrs vsulr liition is rtinly involv s on o th mhnisms [19], high itry phosphorus intk lso ontriuts to ri irosis n rtril wll thikning [2]. Morovr, hyprphosphtmi is ssoit with myoril hyprtrophy in rts with rnl ilur [21].Zin iiny oul lso inu untionl n morphologil hngs uring th ritil prio o rnl vlopmnt n mturtion, ssoit with lvtion o loo prssur n rnl ysuntion [22]. onsistnt with th inings o th ov niml n humn stuis, our rsults show tht high-phosphorus/zin-r it inu hyprtnsion. This it ggrvt only istoli untion in ut oth istoli n systoli untions in, suggsting tht might pron to ri mg us y othr stimuli. Unortuntly, w i not msur plsm lvls o ngiotnsin II n lostron. Howvr, prvious stuis show tht zin-iint it lon inu hyprtnsion ut i not inrs plsm lvls o ngiotnsin II [23] or lostron [24]. Ths osrvtions init tht Zn iiny o not nhn th tivity o th rnin ngiotnsin systm. In prliminry stuy, w trt (n=6) with ithr highphosphorus or zin-r it. Th high-phosphorus it n zin-r it h sprtly inu hyprtnsion (171±5 n 17±2 mmhg, rsptivly). Dopplr horiogrphi inings inlu signiint inrs in th E/A rtio only in with th zin-r it n signiintly rss in LV FS in ithr with highphosphorus it or zin-r it. Howvr, th hngs in th E/A rtio n LV FS wr mor prominnt in with high-phosphorus/ zin-r it thn in ithr with high-phosphorus it or zin-r it lon, suggsting tht th high-phosphorus/zin-r it mrkly ggrvt oth istoli n systoli untions in ompr with h it lon. High-phosphorus/zin-r it inu svr myoril irosis in n this t ws prvnt y NA. Sin zin nhns nognous ntioxint nss, zin-supplmnt it woul tiv in th trtmnt o ri ysuntion. Furthr stuis r n to lriy how th ts o NA ir rom th zin supplmnttion lon. onsumption o rltivly high mounts o pross oo n rsult in norml nutritionl sttus, suh s zin iiny or phosphorus xss. Although hypozinmi n hyprphosphtmi r linilly sri in som ptints with iti nphropthy n mtoli synrom, zin iiny n/or phosphorus xss r lso nountr in othrwis hlthy sujts spilly in thos iniviuls who onsum plnty o pross oo [25,26]. Thror, th prsnt stuy souns wrning on onsumption o high mounts o pross oo n on poor ontrol o plsm phosphorus lvl in ptints with vn hroni rnl ilur n suggsts th tivnss o ntioxints on ri impirmnt unr suh onitions.

5 A Y. Suzuki t l. / riovsulr Pthology 23 (214) D Intrstitil irosis.2.1 Privsulr irosis PZ PZN PZ PZN PZ PZN PZ PZN Fig. 3. Morphologil nlysis o th lt vntril o 18-wk-ol rts. (A n ) Light mirogrphs o stions o th lt vntril stin with sirius r solution in rprsnttiv () ontrol rt; () ontrol rt; () with high-phosphorus n zin-r it; () with high-phosphorus n zin-r it; () with highphosphorus n zin-r it with NA; () with high-phosphorus n zin-r it with NA. Sl rs, 1 μm. Th xtnt o intrstitil () n privsulr (D) irosis. Dt r mn±s.e.m. o six or ight rts pr group. P.5 vrsus ontrol rts; P.5 vrsus ontrol rts; P.5 vrsus with PZ it. ri irosis plys ky rol in ri ysuntion. TGF promots irolst prolirtion n xtrllulr mtrix proution in onntiv tissus [27] n plys n importnt rol in ri A irosis. Sin TGF is mitor o inution o th xtrllulr mtrix protin irontin y vn glyosyltion n prouts [28], this molul sms involv in th vlopmnt o its- Fig. 4. Immunohistohmil nlysis o th lt vntril o 18-wk-ol rts. Immunohistohmil stining or (A) TGF n () MT in () ontrol rt; () ontrol rt; () with high-phosphorus n zin-r it; () with high-phosphorus n zin-r it; () with high-phosphorus n zin-r it with NA, () with high-phosphorus n zin-r it with NA. Sl rs, 1 μm. Arrows init iniltrt immunortiv lls.

6 48 Y. Suzuki t l. / riovsulr Pthology 23 (214) rlt rnl n riovsulr omplitions [29]. In th prsnt stuy, th xprssion o TGF ws highr in with highphosphorus n zin-r it, ompr with. Although thr ws no signiintly irn in plsm lvl o gluos o 18-wkol n, lrly mnist hyprglymi tr pproximtly 24 wks o g [13]. Ths rsults suggst tht th high lvls o TGF in high-phosphorus n zin-r it groups t th prstg o its oul inu hngs in ri xtrllulr mtrix protin in th hrt o. ri irosis ws in s xss umultion o xtrllulr mtrix. Extrllulr mtrix synthsis n stimult y TGF n gr y mtrix mtlloprotinss (MMPs) n ystin prots thpsin milis tht hv n monstrt to ply ritil rols in ri irosis [3,31]. In th prsnt stuy, thr wr no signiint irns in myoril tivitis o MMP-2 n -9, s monstrt y gltin zymogrphy, twn th ontrol group n PZ group in oth strins (t not shown). Ths rsults suggst tht TGF my ky mitor o ri irosis inu y th high-phosphorus/ zin-r it. Zin is ritil lmnt involv in th rgultion o irillr ollgn mtolism n position. A prvious pimiologil stuy monstrt lowr plsm zin onntrtions in ptints with ilt riomyopthy ompr with hlthy sujts [32]. MT is ystin-rih protin tht ins mtls, suh s zin n oppr, n ts s n ntioxint or svnging or qunhing vrious r rils or rtiv oxygn spis [33]. MT hs n rport to signiintly prvnt iti riomyopthy [34], n zin supplmnttion prvnt iti riomyopthy u to n inrs in ri MT xprssion [35]. In th prsnt stuy, highphosphorus/zin-r it inu ri irosis tht ws prvnt y trtmnt with NA in. In prlll, myoril xprssion o MT ws rs y high-phosphorus/zin-r it n signiintly inrs y trtmnt with NA. On th othr hn, th xprssion o MT ws hrly osrv in th hrt o SHR/ p, whih show prominnt ri irosis inu y highphosphorus/zin-r it. This osrvtion is onsistnt with prvious t showing tht MT-positiv lls wr nrly snt in th hrts o ptints with ilt riomyopthy [36]. onsir in onjuntion with th rsults o th ov prvious stuis, our inings suggst tht high-phosphorus/zin-r it sms to ggrvt ri irosis in n tht this t is mit through low xprssion o MT in th myorium. In this rgr, inrs proution o oxygn r rils n inu oxitiv strss, whih is known to involv in th vlopmnt o th mtoli synrom [37]. Prvious stuy monstrt high lvls o oxitiv strss, s wll s nitrtiv strss n inlmmtion, in ompr with ontrol rts [38]. Th prsn o mor pronoun oxitiv strss in thn in oul potntilly xplin th rsistn o to th prottiv ts o NA on impir istoli untion. In onlusion, our stuy monstrt tht high-phosphorus/zinr it inu hyprtnsion n istoli ysuntion in oth strins o rts n systoli ysuntion in only. Our rsults suggst tht ovrxprssion o TGF inu svr irosis n tht low xprssion o MT in th hrt nhn th vlopmnt o svr ri ysuntion in rts with th mtoli synrom. Morovr, mtoli synrom my ggrvt ri ysuntion n lssn th prottiv ts o NA. Aknowlgmnts W thnk Kumi Nko or th srtril support. This work ws support in prt y grnts rom th Jpn Soity or th Promotion o Sin (grnts-in i or Sintii Rsrh # n NEXT Progrm #LS56). Rrns [1] Muto T, Tsuji H, Ars Y, Murs T. lustring o othr mtoli risk tors in sujts with mtoli synrom. Mtolism 21;59: [2] hn J, Muntnr P, Hmm LL, Jons DW, tumn V, Fons V, t l. Th mtoli synrom n hroni kiny iss in U.S. ults. Ann Intrn M 24;14: [3] Gmi AS, Witt J, Howr DE, Erwin PJ, Gmi LA, Somrs VK, t l. Mtoli synrom n risk o inint riovsulr vnts n th: systmti rviw n mt-nlysis o longituinl stuis. J Am oll riol 27;49: [4] Hrusk KA, Mthw S, Dvis MR, Lun RJ. onntions twn vsulr liition n progrssion o hroni kiny iss: thrputi ltrntivs. Kiny Int Suppl 25;1:S [5] Ozt M, Mrgn M, Oktnli, Ayin A, Snisoglu SY, olu E, t l. 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