Klotho: a vgzet vagyinkbb a kezdet asszonya?DEOEC Belgygyszati Intzet, I. sz. Belgygyszati Klinika Nephrolgiai Tanszk, DebrecenDr. Mtyus Jnosegyetemi docens

Klotho: a vgzet vagy inkbb a kezdet asszonya?Mtyus Jnos

DNN XVIII. 2012.05.30

VZMoe SM, et al. Kidney Int 2006;69:194553VZ Vesebetegsghez trsul svnyi anyagcsere Zavar (CKD-MBD)VZ: ROD szlesebb rtelmezse

CKD-hez trsul szisztms svnyi s csont anyagcsere zavar, melyet az albbiak kzl egy vagy tbb eltrs jellemez

Laboratoriumi: Ca, P, PTH, vagy D vitamin anyagcsereCsont: turnover, mineralizci, tmeg, linearis nvekeds, szilrdsgSzv-rrendszeri : erek s ms szvetek kalcifikcija, cardilis vltozsokcsonttrs cardiovasc. betegsghallozsSzv-rrendszerivltozsokLaboratriumieltrsekCsont betegsgek(ROD)

Serum iPTH0255075100125150175200100+909980897079606950594049303920291019CrCl (mL/min)iPTH (pg/mL)Serum ionized Ca and P23456100+909980897079606950594049303920291019CrCl (mL/min)Ca and P (mg/dL)CaP CKD-ben a SHPT korn elkezddik s fokozatosan slyosbodikMartinez I et al. Am J Kidney Dis 1997;29:496502Foszftkt, Ca, D-vitamin kezelsben nem rszesl betegek

Bricker: intact nephron hypothesisAm J Med 1960, NEJM 1972Alapbetegsgtl fggetlenl, ahogy a funkcinl nephronok szma cskkenmindegyikk egyre nagyobb rszt vllal a vese sszes kivlaszt funkcijbl ez a nephron adaptci biztostja a beteg tllst.Slatapolsky KI 2011

Klasszikus teria: nephron adaptci kvetkezmnye a secunder hyperparathyreosisGFR+vltozatlan P bevitelse-P se-Ca PTH Ca-P mobilizci , P kivlaszts norm. se-Ca, norm. se-P, magas PTH

P bevitel proporcionlis cskkentsvel a 2HP kivdhet (Slatopolsky KI 1972)

A calcitriol gtolja a PTH gn transzkriptiojt (Silver PNAS 1985, JCI 1986)A calcitriol gtolja a mellkpajzsmirigy prolifercijt (Szab A. Kidney Int. 1989)

A 2HP oka elssorban a calcitriol hinya

Alacsony Ca - alacsony P dita calciumtl s calcitrioltl fggetlenl mrskli a 2HP-t llatkisrletben (Lopez-Hilker Am J Physiol 1990)

A magas phosphat kzvetlenl stimullja a mellkpajzsmirigyet(Slatopolszky JCI 1996, Almaden J Bone Mineral Res 1996, Nielsen NDT 1996)

SHPT progresszija: parathyroid hyperplasiaNormalDiffuseEarlynodularityNodularSingle noduleContinuous functional demandGland volumeSecretorycellsTominaga Y et al. Curr Opin Nephrol Hypertens 1996;5:33641 NormalVery highPTH

13 vvel ezeltti teria: Slatopolszky KI 1999

A calcitriol szintje mr korai veseelgtelensgben cskken, nem a 250HD3 hiny miattLevin et al Kidney Int 2007;71:31-38. n > 1800

Mtyus J.: A foszft anyagcsere szablyozsnak j szerepli. DNN 2000Hypophosphataemival jr onkogn osteomalacia. Orv Hetil 20001985 19 ffi csipfjdalom 1986 patol. fractura? opushypophosphataemis rachitisismtelt intzeti kivizsglsok Bp3x0,5ug calcitriol ellenre P:0,4-0,62x1 indomethacin, bicegve jr

1998 Db nephrol.1,5cm-es gingiva nvedk eltvolitsAznap P szint normalizldik1 v mlva csont BMD normlisphosphatonint termel epulis

Izollt hypophosphataemival jr krkpekJan de BeurJAMA 2005

FGF23FGF csald tagja, 12p13, 251 aminosavTIO-k egy rszben jelen vanADHR-ban mutci akadlyozza az enzimatikus lebontststabil molekula, tarts FGF23 hatsFGF23 mRNS kimutathat: dnten osteocytk, osteoblastok,mj, szv, pajzsmirigy, mellkpajzsmirigyFGF receptorok a szervezetben mindenttFGF23 (-/-) egerek: hyperphosphataemia +generalizlt calcinosis, osteopenia regeds, korai pusztuls

Klotho gn: regedsgtl gnKuro-o Nature 1997Felfedezs 1997: transgenicus egrtrzs,P, Ca, calcitriol, media calcif.regeds, rvid lettartamtransgenicus Klotho overexpresszi 20-30% hosszabb lettartam1014 aminosav; extracellulris rsz: 980 cytoplasmatikus C-term. 11 aminosavExpressio: vese distalis (prox.) tubulus, mellkpajzsmirigyB-glucoronidz, sialidz aktivitsglycoproteinek cukorlnc mdosts?

Klotho (-/-)

Rvid lettartamNvekeds retardciHypogonadismusKorai thymus involuciBr atrophiaArteriosclerosisOsteoporosisPulm. emphysemaLgyrszmeszesedsHyperphosphataemiaHyper D vitaminosisHypercalcaemiaHypoglycaemiaFGF23 (-/-)

Rvid lettartamNvekeds retardciHypogonadismusKorai thymus involuciBr atrophiaArteriosclerosisOsteoporosisPulm. emphysemaLgyrszmeszesedsHyperphosphataemiaHyper D vitaminosisHypercalcaemiaHypoglycaemiaFGF23 > 1000 xKlotho (+/+)Klotho (-/-)

Klotho a FGF23 koreceptoraKlotho rszt vesz az FGF23 jeltovbbtsban?FGF receptorokkal komplexet kpezFGF23 a Klotho/FGFR komplexhez ktdik

Foszft megszorts a fenotpust korriglja (pedig Ca/1,25D!)Kuro-o KI 2011

Kuro-o

A distlis kanyarulatos tubulus Klotho-ja hogy tudja a proximlis tubulus P reabszorcijt befolysolni?ADAM10/17 protez lehastja

Extracellularis trbe szekretldik

(secretlt Klotho inj. phosphaturia)

Paracrin hatsTranscytosis(?) a prox. tubuluson

NaPi2a cukorlncait eltvoltja

NaPi2a mkdse gtldik

P reabszorpci cskken

Hrom feedback hurok szorosan szablyozza a foszftszintet

Calcitriol fokozza a vese Klotho expressiojtTsujikawa Molecular Endocrin 2003

Klotho cskkens a legkorbbi jel?Kuro-o KJIM 2011

Vizelet Klotho korn cskken!

A Klotho koncentrcitl fgg mdon befolysolja a vascularis simaizomsejtek Pi felvtelt (Na-dep. P co-transp. t.III)

Secretlt -Klotho serumszintje mr a korai CKD-ban cskken Shimamura Y Clin Exp Nephrol 2012.03.29.Klotho s eGFR szoros poz. kapcs.Se-Klotho mr CKD2-bensign. kisebb mint CKD1-benSzekretlt -Klotho cskkens a membrn kttt -Klotho cskkenst jelziOka: nephronszm cskkens, RAAS aktivlds?

Az -Klotho rzkeny biomarkere a korai CKD-nak!

AngII KlothoMitani Hypertension 2002Saito FEBS Lett 2003Zou Kidney Blood Press Res 2010Joon NDT 2011

Mechanizmus?Oxydativ stressTACE (ADAM17) upregulls

Se Klotho s se FGF23 negatv korrelcit mutat CKD betegekbenShimamura Y. Clin Exp Neprol 2012

FGF23 s vesefunkcis rtkek(MANET Sopron 2005)A GFR s az FGF23 kapcsolataA szrum kreatinin s FGF23 kapcsolata

Diagram11

50.2

10.1

6.6

41.4

33.7

65

66.7

59.1

11.9

8.9

30.2

118.1

16

6

11.9

127.5

345.7

36.1

26.6

59.7

76.2

381.7

197.7

17.2

39

36.1

gfr

GFR

FGF23

Munka1

NvnemszlHD1idophdtartkorFGF23crgfrccrPCaCa++OCCrosslapsPTHD3

Ujvri Lszl119647/1/054150.2124740.73

Tth Gyula119837/1/05220101114480.63

Makula Iboly219747/1/053110.1371161.2748.9181414.414.5

Szab Lszln219657/1/05406.6761071140.7711.266.53.545

Pti Jzsef119607/1/054541.4731291990.7412.42131.725

Dvid Anett219827/1/052333.712369581.41304763.220

Losonczi Attila119727/1/053365103103561.62.151.187.73751.740

Varga Jzsef119467/1/055966.716342500.632.241.1930.85353.957.5

Zilahi Istvnn219617/1/054459.112062681.072.231.1428.84134.762.5

Fldi Istvnn219527/1/05531835396111.362.191.26141.6111213.447.5

Bodnr Lszln219557/1/055011.9751011150.532.351.27151051.465

Bodnr Zsuzsa219807/1/05250601211680.732.451.2516.82681.472

Tihanics Tams119847/1/05218.997121780.882.421.224812341.8102

Erlichn Jenei Mria219607/1/054530.29685580.942.411.26462122.825

Mszrosn Csod Ildik219617/1/0544118.1681061261.182.25151952.123

Paluska Attila119677/1/05381805785992.232.211.18256146612.240

Deli Jnos119737/1/05321616450170.672.4226.64001.395

Deli Attila119787/1/0527612085311.112.5343941.475

Mricz Tams119807/1/052511.9118890.992.55

Demeter Jzsef119547/1/0551127.599960.782.14

Ss rpd119337/1/0572345.7407121.522.395.37

Pocsai Jnosn219307/1/057536.185791.052.2212.23162.518.3

Kerkgyrt Gyrgy119527/1/055326.6741221210.812.4

Tarnczi Jzsef119667/1/053959.7651340.522.467.9

Gyni Pter119767/1/052976.2581442700.732.34

Varga Hajnalka219557/1/0550381.7119601.482.18

Balogh Gza 2.119767/1/05290199381.222.5560.28281.572.3

Nagy Gbor119387/1/0567197.7244221.182.4319.14138.830

Nagy Lajos119817/1/052417.218544861.362.2917.55313.358.2

Balogh Gza119497/1/05563998940.812.725899585.6

Zubara Lszln219447/1/05611808264170.622.2675.876533.5

Dani Jnos119507/1/055536.1418131.252.1741.671.3

Czak Lajosn219465/19/937/1/05148591872hd02.172.2577.4

Budai Lszln2193612/28/947/1/05128691870hd01.82.1399617141

Urbn Ptern219395/12/947/1/05136661857hd02.072.4225717.730.9

Cseri Imre119591/12/977/1/05103461882hd01.591.640.8663.23.7449.5

Szegedi Csaba119642/1/837/1/0527341954hd01.991.572229.2648.7

Fodor Rza219305/10/957/1/0512475319hd01.821.860.884.4

Juhsz Elemr119613/22/977/1/05101442716hd02.391.960.94326

Lakatos Tibor119514/26/997/1/0575542757hd03.672.511.16110.2

Szab Tibor119617/28/047/1/051144572hd02.082.161.0746.8

Szatmri Zsolt1196911/14/027/1/0532362706hd02.931.650.8

Szab Sndorn2196311/1/997/1/0569422748hd01.811.940.9582.4

Madai Sndorn2193610/22/917/1/05167691915hd02.292.211.0291.2

Sipos Sndor119482/13/917/1/05175572686hd03.572.030.932.4

Fnyi Gbor119405/31/997/1/0574652637hd01.532.151.1637

Szab Imrn219536/24/937/1/05146522729hd02.82.45132.1

Zagarits Kroly1195610/2/967/1/05106491725hd01.652.121.0729.8

Lokodi Attila1197612/4/017/1/0544292754hd03.122.231.0675.2

Juhsz Sndorn219293/19/977/1/05101762801hd01.841.640.777.9

Nagy Lszl119355/12/997/1/0575702710hd01.662.411.2388.4

Takr Jzsef119454/1/937/1/05149602803hd01.832.271.2318.5

Takcs Jnos1194811/20/047/1/057572697hd02.962.050.9916.6

Gajdor Magda219361/18/057/1/05569597hd01.432.061.0520.5

Nagy Miklsn219486/11/847/1/05256572687hd02.232.381.1358.5

Nagy Istvnn219387/23/027/1/0536672690hd02.592.21.0624.1

krs Imrn219555/24/047/1/0513501022hd01.692.111.0314.6

Molnr Jnos119526/15/907/1/05183532772hd03.012.060.9672.3

Ulveczki Menyhrt119378/23/037/1/0523682238hd01.992.161.0723.5

Burai Zoltnn219338/22/017/1/0547722601hd03.561.550.7430.8

Br Mihly1193012/22/017/1/0543752735hd01.92.271.1425.8

Kovcs Balzs119527/17/007/1/0560532628hd02.272.15149.6

Mller Jen119518/31/047/1/0510542701hd03.2720.9432.8

Balogh Imre1196411/10/047/1/058412732hd02.862.061.0224.5

Barcza Lszl119483/23/007/1/0564571633hd01.72.191.0915.5

Papp Barnabs119398/27/027/1/0535661643hd02.042.11.0140.7

Rcz Andrsn219329/8/037/1/0522731307hd01.782.371.1720.7

Kllai Ferenc1194810/5/047/1/05957254hd01.871.750.9396.6

Hodosn Vince119492/3/057/1/055561116hd02.41.790.9125.7

Dinnys Istvnn219572/19/977/1/05102482682hd02.162.441.156.7

Val Jnosn219404/6/057/1/05365331hd01.322.311.16

Fur Ferencn2194011/9/017/1/0544652720hd01.362.371.3237.8

Hetei Gyrgy119622/13/937/1/05151432743hd02.382.291.188.5

Istk Gborn2193211/14/007/1/055673175hd01.482.111.1222.3

Farkas Jnosn219292/8/027/1/0541761200hd01.631.950.9325.4

Szegedi Antaln219423/30/057/1/053632543hd01.812.121.0631.7

Munka2

gfrcrPFGF23

741240.7350.2

116371.2710.1

107760.776.6

129730.7441.4

691231.4133.7

1031031.665

421630.6366.7

621201.0759.1

101750.5311.9

121970.888.9

85960.9430.2

106681.18118.1

501640.6716

851201.116

891180.9911.9

96990.78127.5

124071.52345.7

79851.0536.1

122740.8126.6

134650.5259.7

144580.7376.2

601191.48381.7

222441.18197.7

441851.3617.2

94980.8139

134181.2536.1

Munka2

gfr

GFR

FGF23

Munka3

Diagram13

50.2

10.1

6.6

41.4

33.7

65

66.7

59.1

11.9

8.9

30.2

118.1

16

6

11.9

127.5

345.7

36.1

26.6

59.7

76.2

381.7

197.7

17.2

39

36.1

cr

Kreatinin

FGF23

Munka1

NvnemszlHD1idophdtartkorFGF23crgfrccrPCaCa++OCCrosslapsPTHD3

Ujvri Lszl119647/1/054150.2124740.73

Tth Gyula119837/1/05220101114480.63

Makula Iboly219747/1/053110.1371161.2748.9181414.414.5

Szab Lszln219657/1/05406.6761071140.7711.266.53.545

Pti Jzsef119607/1/054541.4731291990.7412.42131.725

Dvid Anett219827/1/052333.712369581.41304763.220

Losonczi Attila119727/1/053365103103561.62.151.187.73751.740

Varga Jzsef119467/1/055966.716342500.632.241.1930.85353.957.5

Zilahi Istvnn219617/1/054459.112062681.072.231.1428.84134.762.5

Fldi Istvnn219527/1/05531835396111.362.191.26141.6111213.447.5

Bodnr Lszln219557/1/055011.9751011150.532.351.27151051.465

Bodnr Zsuzsa219807/1/05250601211680.732.451.2516.82681.472

Tihanics Tams119847/1/05218.997121780.882.421.224812341.8102

Erlichn Jenei Mria219607/1/054530.29685580.942.411.26462122.825

Mszrosn Csod Ildik219617/1/0544118.1681061261.182.25151952.123

Paluska Attila119677/1/05381805785992.232.211.18256146612.240

Deli Jnos119737/1/05321616450170.672.4226.64001.395

Deli Attila119787/1/0527612085311.112.5343941.475

Mricz Tams119807/1/052511.9118890.992.55

Demeter Jzsef119547/1/0551127.599960.782.14

Ss rpd119337/1/0572345.7407121.522.395.37

Pocsai Jnosn219307/1/057536.185791.052.2212.23162.518.3

Kerkgyrt Gyrgy119527/1/055326.6741221210.812.4

Tarnczi Jzsef119667/1/053959.7651340.522.467.9

Gyni Pter119767/1/052976.2581442700.732.34

Varga Hajnalka219557/1/0550381.7119601.482.18

Balogh Gza 2.119767/1/05290199381.222.5560.28281.572.3

Nagy Gbor119387/1/0567197.7244221.182.4319.14138.830

Nagy Lajos119817/1/052417.218544861.362.2917.55313.358.2

Balogh Gza119497/1/05563998940.812.725899585.6

Zubara Lszln219447/1/05611808264170.622.2675.876533.5

Dani Jnos119507/1/055536.1418131.252.1741.671.3

Czak Lajosn219465/19/937/1/05148591872hd02.172.2577.4

Budai Lszln2193612/28/947/1/05128691870hd01.82.1399617141

Urbn Ptern219395/12/947/1/05136661857hd02.072.4225717.730.9

Cseri Imre119591/12/977/1/05103461882hd01.591.640.8663.23.7449.5

Szegedi Csaba119642/1/837/1/0527341954hd01.991.572229.2648.7

Fodor Rza219305/10/957/1/0512475319hd01.821.860.884.4

Juhsz Elemr119613/22/977/1/05101442716hd02.391.960.94326

Lakatos Tibor119514/26/997/1/0575542757hd03.672.511.16110.2

Szab Tibor119617/28/047/1/051144572hd02.082.161.0746.8

Szatmri Zsolt1196911/14/027/1/0532362706hd02.931.650.8

Szab Sndorn2196311/1/997/1/0569422748hd01.811.940.9582.4

Madai Sndorn2193610/22/917/1/05167691915hd02.292.211.0291.2

Sipos Sndor119482/13/917/1/05175572686hd03.572.030.932.4

Fnyi Gbor119405/31/997/1/0574652637hd01.532.151.1637

Szab Imrn219536/24/937/1/05146522729hd02.82.45132.1

Zagarits Kroly1195610/2/967/1/05106491725hd01.652.121.0729.8

Lokodi Attila1197612/4/017/1/0544292754hd03.122.231.0675.2

Juhsz Sndorn219293/19/977/1/05101762801hd01.841.640.777.9

Nagy Lszl119355/12/997/1/0575702710hd01.662.411.2388.4

Takr Jzsef119454/1/937/1/05149602803hd01.832.271.2318.5

Takcs Jnos1194811/20/047/1/057572697hd02.962.050.9916.6

Gajdor Magda219361/18/057/1/05569597hd01.432.061.0520.5

Nagy Miklsn219486/11/847/1/05256572687hd02.232.381.1358.5

Nagy Istvnn219387/23/027/1/0536672690hd02.592.21.0624.1

krs Imrn219555/24/047/1/0513501022hd01.692.111.0314.6

Molnr Jnos119526/15/907/1/05183532772hd03.012.060.9672.3

Ulveczki Menyhrt119378/23/037/1/0523682238hd01.992.161.0723.5

Burai Zoltnn219338/22/017/1/0547722601hd03.561.550.7430.8

Br Mihly1193012/22/017/1/0543752735hd01.92.271.1425.8

Kovcs Balzs119527/17/007/1/0560532628hd02.272.15149.6

Mller Jen119518/31/047/1/0510542701hd03.2720.9432.8

Balogh Imre1196411/10/047/1/058412732hd02.862.061.0224.5

Barcza Lszl119483/23/007/1/0564571633hd01.72.191.0915.5

Papp Barnabs119398/27/027/1/0535661643hd02.042.11.0140.7

Rcz Andrsn219329/8/037/1/0522731307hd01.782.371.1720.7

Kllai Ferenc1194810/5/047/1/05957254hd01.871.750.9396.6

Hodosn Vince119492/3/057/1/055561116hd02.41.790.9125.7

Dinnys Istvnn219572/19/977/1/05102482682hd02.162.441.156.7

Val Jnosn219404/6/057/1/05365331hd01.322.311.16

Fur Ferencn2194011/9/017/1/0544652720hd01.362.371.3237.8

Hetei Gyrgy119622/13/937/1/05151432743hd02.382.291.188.5

Istk Gborn2193211/14/007/1/055673175hd01.482.111.1222.3

Farkas Jnosn219292/8/027/1/0541761200hd01.631.950.9325.4

Szegedi Antaln219423/30/057/1/053632543hd01.812.121.0631.7

Munka2

gfrcrPFGF23

741240.7350.2

116371.2710.1

107760.776.6

129730.7441.4

691231.4133.7

1031031.665

421630.6366.7

621201.0759.1

101750.5311.9

121970.888.9

85960.9430.2

106681.18118.1

501640.6716

851201.116

891180.9911.9

96990.78127.5

124071.52345.7

79851.0536.1

122740.8126.6

134650.5259.7

144580.7376.2

601191.48381.7

222441.18197.7

441851.3617.2

94980.8139

134181.2536.1

Munka2

gfr

GFR

FGF23

Munka3

cr

Kreatinin

FGF23

Eredmnyek Dializlt betegekA norml vesefunkci mellett mrt rtknl szzszor magasabb FGF23 szintek

Diagram17

1872

1870

1857

1882

954

319

2716

2757

572

2706

2748

1915

2686

2637

2729

1725

2754

2801

2710

2803

2697

597

2687

2690

1022

2772

2238

2601

2735

2628

2701

2732

1633

1643

1307

254

1116

2682

331

2720

2743

175

1200

2543

FGF23

Pi

FGF23

Foszft s FGF23

Munka1

NvnemszlHD1idophdtartkorFGF23crgfrccrPCaCa++OCCrosslapsPTHD3

Ujvri Lszl119647/1/054150.2124740.73

Tth Gyula119837/1/05220101114480.63

Makula Iboly219747/1/053110.1371161.2748.9181414.414.5

Szab Lszln219657/1/05406.6761071140.7711.266.53.545

Pti Jzsef119607/1/054541.4731291990.7412.42131.725

Dvid Anett219827/1/052333.712369581.41304763.220

Losonczi Attila119727/1/053365103103561.62.151.187.73751.740

Varga Jzsef119467/1/055966.716342500.632.241.1930.85353.957.5

Zilahi Istvnn219617/1/054459.112062681.072.231.1428.84134.762.5

Fldi Istvnn219527/1/05531835396111.362.191.26141.6111213.447.5

Bodnr Lszln219557/1/055011.9751011150.532.351.27151051.465

Bodnr Zsuzsa219807/1/05250601211680.732.451.2516.82681.472

Tihanics Tams119847/1/05218.997121780.882.421.224812341.8102

Erlichn Jenei Mria219607/1/054530.29685580.942.411.26462122.825

Mszrosn Csod Ildik219617/1/0544118.1681061261.182.25151952.123

Paluska Attila119677/1/05381805785992.232.211.18256146612.240

Deli Jnos119737/1/05321616450170.672.4226.64001.395

Deli Attila119787/1/0527612085311.112.5343941.475

Mricz Tams119807/1/052511.9118890.992.55

Demeter Jzsef119547/1/0551127.599960.782.14

Ss rpd119337/1/0572345.7407121.522.395.37

Pocsai Jnosn219307/1/057536.185791.052.2212.23162.518.3

Kerkgyrt Gyrgy119527/1/055326.6741221210.812.4

Tarnczi Jzsef119667/1/053959.7651340.522.467.9

Gyni Pter119767/1/052976.2581442700.732.34

Varga Hajnalka219557/1/0550381.7119601.482.18

Balogh Gza 2.119767/1/05290199381.222.5560.28281.572.3

Nagy Gbor119387/1/0567197.7244221.182.4319.14138.830

Nagy Lajos119817/1/052417.218544861.362.2917.55313.358.2

Balogh Gza119497/1/05563998940.812.725899585.6

Zubara Lszln219447/1/05611808264170.622.2675.876533.5

Dani Jnos119507/1/055536.1418131.252.1741.671.3

Czak Lajosn219465/19/937/1/05148591872hd02.172.2577.4

Budai Lszln2193612/28/947/1/05128691870hd01.82.1399617141

Urbn Ptern219395/12/947/1/05136661857hd02.072.4225717.730.9

Cseri Imre119591/12/977/1/05103461882hd01.591.640.8663.23.7449.5

Szegedi Csaba119642/1/837/1/0527341954hd01.991.572229.2648.7

Fodor Rza219305/10/957/1/0512475319hd01.821.860.884.4

Juhsz Elemr119613/22/977/1/05101442716hd02.391.960.94326

Lakatos Tibor119514/26/997/1/0575542757hd03.672.511.16110.2

Szab Tibor119617/28/047/1/051144572hd02.082.161.0746.8

Szatmri Zsolt1196911/14/027/1/0532362706hd02.931.650.8

Szab Sndorn2196311/1/997/1/0569422748hd01.811.940.9582.4

Madai Sndorn2193610/22/917/1/05167691915hd02.292.211.0291.2

Sipos Sndor119482/13/917/1/05175572686hd03.572.030.932.4

Fnyi Gbor119405/31/997/1/0574652637hd01.532.151.1637

Szab Imrn219536/24/937/1/05146522729hd02.82.45132.1

Zagarits Kroly1195610/2/967/1/05106491725hd01.652.121.0729.8

Lokodi Attila1197612/4/017/1/0544292754hd03.122.231.0675.2

Juhsz Sndorn219293/19/977/1/05101762801hd01.841.640.777.9

Nagy Lszl119355/12/997/1/0575702710hd01.662.411.2388.4

Takr Jzsef119454/1/937/1/05149602803hd01.832.271.2318.5

Takcs Jnos1194811/20/047/1/057572697hd02.962.050.9916.6

Gajdor Magda219361/18/057/1/05569597hd01.432.061.0520.5

Nagy Miklsn219486/11/847/1/05256572687hd02.232.381.1358.5

Nagy Istvnn219387/23/027/1/0536672690hd02.592.21.0624.1

krs Imrn219555/24/047/1/0513501022hd01.692.111.0314.6

Molnr Jnos119526/15/907/1/05183532772hd03.012.060.9672.3

Ulveczki Menyhrt119378/23/037/1/0523682238hd01.992.161.0723.5

Burai Zoltnn219338/22/017/1/0547722601hd03.561.550.7430.8

Br Mihly1193012/22/017/1/0543752735hd01.92.271.1425.8

Kovcs Balzs119527/17/007/1/0560532628hd02.272.15149.6

Mller Jen119518/31/047/1/0510542701hd03.2720.9432.8

Balogh Imre1196411/10/047/1/058412732hd02.862.061.0224.5

Barcza Lszl119483/23/007/1/0564571633hd01.72.191.0915.5

Papp Barnabs119398/27/027/1/0535661643hd02.042.11.0140.7

Rcz Andrsn219329/8/037/1/0522731307hd01.782.371.1720.7

Kllai Ferenc1194810/5/047/1/05957254hd01.871.750.9396.6

Hodosn Vince119492/3/057/1/055561116hd02.41.790.9125.7

Dinnys Istvnn219572/19/977/1/05102482682hd02.162.441.156.7

Val Jnosn219404/6/057/1/05365331hd01.322.311.16

Fur Ferencn2194011/9/017/1/0544652720hd01.362.371.3237.8

Hetei Gyrgy119622/13/937/1/05151432743hd02.382.291.188.5

Istk Gborn2193211/14/007/1/055673175hd01.482.111.1222.3

Farkas Jnosn219292/8/027/1/0541761200hd01.631.950.9325.4

Szegedi Antaln219423/30/057/1/053632543hd01.812.121.0631.7

Munka2

gfrcrPFGF23

741240.7350.2

116371.2710.1

107760.776.6

129730.7441.4

691231.4133.7

1031031.665

421630.6366.7

621201.0759.1

101750.5311.9

121970.888.9

85960.9430.2

106681.18118.1

501640.6716

851201.116

891180.9911.9

96990.78127.5

124071.52345.7

79851.0536.1

122740.8126.6

134650.5259.7

144580.7376.2

601191.48381.7

222441.18197.7

441851.3617.2

94980.8139

134181.2536.1

113961.361835

97852.231805

172642.261808

Munka2

gfr

GFR

FGF23

Munka3

cr

Kreatinin

FGF23

FGF23PiCa++

18722.17

18701.8

18572.07

18821.590.86

9541.99

3191.820.88

27162.390.94

27573.671.16

5722.081.07

27062.93

27481.810.95

19152.291.02

26863.570.9

26371.531.16

27292.8

17251.651.07

27543.121.06

28011.840.77

27101.661.23

28031.831.23

26972.960.99

5971.431.05

26872.231.13

26902.591.06

10221.691.03

27723.010.96

22381.991.07

26013.560.74

27351.91.14

26282.271

27013.270.94

27322.861.02

16331.71.09

16432.041.01

13071.781.17

2541.870.93

11162.40.91

26822.161.15

3311.321.16

27201.361.32

27432.381.1

1751.481.12

12001.630.93

25431.811.06

FGF23

Pi

FGF23

Foszft s FGF23

Diagram20

1882

319

2716

2757

572

2748

1915

2686

2637

1725

2754

2801

2710

2803

2697

597

2687

2690

1022

2772

2238

2601

2735

2628

2701

2732

1633

1643

1307

254

1116

2682

331

2720

2743

175

1200

2543

Ca x Pi

FGF23

Ca x Pi s FGF23

Munka1

NvnemszlHD1idophdtartkorFGF23crgfrccrPCaCa++OCCrosslapsPTHD3

Ujvri Lszl119647/1/054150.2124740.73

Tth Gyula119837/1/05220101114480.63

Makula Iboly219747/1/053110.1371161.2748.9181414.414.5

Szab Lszln219657/1/05406.6761071140.7711.266.53.545

Pti Jzsef119607/1/054541.4731291990.7412.42131.725

Dvid Anett219827/1/052333.712369581.41304763.220

Losonczi Attila119727/1/053365103103561.62.151.187.73751.740

Varga Jzsef119467/1/055966.716342500.632.241.1930.85353.957.5

Zilahi Istvnn219617/1/054459.112062681.072.231.1428.84134.762.5

Fldi Istvnn219527/1/05531835396111.362.191.26141.6111213.447.5

Bodnr Lszln219557/1/055011.9751011150.532.351.27151051.465

Bodnr Zsuzsa219807/1/05250601211680.732.451.2516.82681.472

Tihanics Tams119847/1/05218.997121780.882.421.224812341.8102

Erlichn Jenei Mria219607/1/054530.29685580.942.411.26462122.825

Mszrosn Csod Ildik219617/1/0544118.1681061261.182.25151952.123

Paluska Attila119677/1/05381805785992.232.211.18256146612.240

Deli Jnos119737/1/05321616450170.672.4226.64001.395

Deli Attila119787/1/0527612085311.112.5343941.475

Mricz Tams119807/1/052511.9118890.992.55

Demeter Jzsef119547/1/0551127.599960.782.14

Ss rpd119337/1/0572345.7407121.522.395.37

Pocsai Jnosn219307/1/057536.185791.052.2212.23162.518.3

Kerkgyrt Gyrgy119527/1/055326.6741221210.812.4

Tarnczi Jzsef119667/1/053959.7651340.522.467.9

Gyni Pter119767/1/052976.2581442700.732.34

Varga Hajnalka219557/1/0550381.7119601.482.18

Balogh Gza 2.119767/1/05290199381.222.5560.28281.572.3

Nagy Gbor119387/1/0567197.7244221.182.4319.14138.830

Nagy Lajos119817/1/052417.218544861.362.2917.55313.358.2

Balogh Gza119497/1/05563998940.812.725899585.6

Zubara Lszln219447/1/05611808264170.622.2675.876533.5

Dani Jnos119507/1/055536.1418131.252.1741.671.3

Czak Lajosn219465/19/937/1/05148591872hd02.172.2577.4

Budai Lszln2193612/28/947/1/05128691870hd01.82.1399617141

Urbn Ptern219395/12/947/1/05136661857hd02.072.4225717.730.9

Cseri Imre119591/12/977/1/05103461882hd01.591.640.8663.23.7449.5

Szegedi Csaba119642/1/837/1/0527341954hd01.991.572229.2648.7

Fodor Rza219305/10/957/1/0512475319hd01.821.860.884.4

Juhsz Elemr119613/22/977/1/05101442716hd02.391.960.94326

Lakatos Tibor119514/26/997/1/0575542757hd03.672.511.16110.2

Szab Tibor119617/28/047/1/051144572hd02.082.161.0746.8

Szatmri Zsolt1196911/14/027/1/0532362706hd02.931.650.8

Szab Sndorn2196311/1/997/1/0569422748hd01.811.940.9582.4

Madai Sndorn2193610/22/917/1/05167691915hd02.292.211.0291.2

Sipos Sndor119482/13/917/1/05175572686hd03.572.030.932.4

Fnyi Gbor119405/31/997/1/0574652637hd01.532.151.1637

Szab Imrn219536/24/937/1/05146522729hd02.82.45132.1

Zagarits Kroly1195610/2/967/1/05106491725hd01.652.121.0729.8

Lokodi Attila1197612/4/017/1/0544292754hd03.122.231.0675.2

Juhsz Sndorn219293/19/977/1/05101762801hd01.841.640.777.9

Nagy Lszl119355/12/997/1/0575702710hd01.662.411.2388.4

Takr Jzsef119454/1/937/1/05149602803hd01.832.271.2318.5

Takcs Jnos1194811/20/047/1/057572697hd02.962.050.9916.6

Gajdor Magda219361/18/057/1/05569597hd01.432.061.0520.5

Nagy Miklsn219486/11/847/1/05256572687hd02.232.381.1358.5

Nagy Istvnn219387/23/027/1/0536672690hd02.592.21.0624.1

krs Imrn219555/24/047/1/0513501022hd01.692.111.0314.6

Molnr Jnos119526/15/907/1/05183532772hd03.012.060.9672.3

Ulveczki Menyhrt119378/23/037/1/0523682238hd01.992.161.0723.5

Burai Zoltnn219338/22/017/1/0547722601hd03.561.550.7430.8

Br Mihly1193012/22/017/1/0543752735hd01.92.271.1425.8

Kovcs Balzs119527/17/007/1/0560532628hd02.272.15149.6

Mller Jen119518/31/047/1/0510542701hd03.2720.9432.8

Balogh Imre1196411/10/047/1/058412732hd02.862.061.0224.5

Barcza Lszl119483/23/007/1/0564571633hd01.72.191.0915.5

Papp Barnabs119398/27/027/1/0535661643hd02.042.11.0140.7

Rcz Andrsn219329/8/037/1/0522731307hd01.782.371.1720.7

Kllai Ferenc1194810/5/047/1/05957254hd01.871.750.9396.6

Hodosn Vince119492/3/057/1/055561116hd02.41.790.9125.7

Dinnys Istvnn219572/19/977/1/05102482682hd02.162.441.156.7

Val Jnosn219404/6/057/1/05365331hd01.322.311.16

Fur Ferencn2194011/9/017/1/0544652720hd01.362.371.3237.8

Hetei Gyrgy119622/13/937/1/05151432743hd02.382.291.188.5

Istk Gborn2193211/14/007/1/055673175hd01.482.111.1222.3

Farkas Jnosn219292/8/027/1/0541761200hd01.631.950.9325.4

Szegedi Antaln219423/30/057/1/053632543hd01.812.121.0631.7

Munka2

gfrcrPFGF23

741240.7350.2Magas FGF23 nlklMagas FGF23mal

116371.2710.1

107760.776.6

129730.7441.4

691231.4133.7

1031031.665

421630.6366.7

621201.0759.1

101750.5311.9

121970.888.9

85960.9430.2

106681.18118.1

501640.6716

851201.116

891180.9911.9

96990.78127.5

124071.52345.7

79851.0536.1

122740.8126.6

134650.5259.7

144580.7376.2

601191.48381.7

222441.18197.7

441851.3617.2

94980.8139

134181.2536.1

113961.361835

97852.231805

172642.261808

Munka2

gfr

GFR

FGF23

Munka3

cr

Kreatinin

FGF23

GFR

FGF23

Kreatinin

FGF23

FGF23PiCa++CaxPi

18821.590.861.37

3191.820.881.6

27162.390.942.25

27573.671.164.26

5722.081.072.23

27481.810.951.72

19152.291.022.34

26863.570.93.21

26371.531.161.78

17251.651.071.77

27543.121.063.31

28011.840.771.42

27101.661.232.04

28031.831.232.25

26972.960.992.93

5971.431.051.5

26872.231.132.52

26902.591.062.75

10221.691.031.74

27723.010.962.89

22381.991.072.13

26013.560.742.63

27351.91.142.17

26282.2712.27

27013.270.943.07

27322.861.022.92

16331.71.091.85

16432.041.012.06

13071.781.172.08

2541.870.931.74

11162.40.912.18

26822.161.152.48

3311.321.161.53

27201.361.321.8

27432.381.12.62

1751.481.121.66

12001.630.931.52

25431.811.061.92

FGF23

Pi

FGF23

Foszft s FGF23

Ca x Pi

FGF23

Ca x Pi s FGF23

FGF23-PTH interakci vesebetegsgbenKomaba KI 2010FGF23 nem cskkenti a PTH szekrcit hyperplasis mpm-ben

Magas FGF23 hozzjrul a mortalitshoz?Wolf /MucsiJASN 2011

J Clin Invest2011. nov.

A hallozs relatv rizikja a serum phosphat szinttel prhuzamosan n

Block GA: JASN 2004(n=40.538, korriglt rr)

Kuro-o KJIM 2011

Kotho hsges asszony, aki vgigkisri, tovbb fonja letnket, elvesztse esetn gyorsan megregsznk s meghalunk!

Az intakt nephron hypotzis ma is igaz!TeendA circulus viciosus jval hamarabb indul, mint a hyperPA phosphat megszortst korn kell kezdeni (ahogy a se Klotho cskkenni kezd?)Ennek hatsra megmaradt nephronok P tlterhelse FGF23 , 1,25DKlotho expresszio (vese, mpm)FGF23 rzkenysgadott P eltvol. szks. FGF23 mennyisg

***Parathyroid hyperplasia develops in tandem with the progressive decline in renal function. The constantly increasing functional demand on parathyroid glands (mainly as a result of hypocalcaemia) drives cell proliferation. Initially, the parathyroid glands respond by increasing the proportion of secretory (chief) cells within the gland and then by increasing the total number of cells, resulting in diffuse hyperplasia of the gland.1In diffuse hyperplasia, cell growth is polyclonal, but is accompanied by down-regulation of the CaR and VDR.1As CKD progresses to stage 5 (end-stage renal disease [ESRD]), parathyroid hyperplasia evolves even further; monoclonal abnormalities lead to nodular hyperplasia of the glands.2,3 These grossly enlarged parathyroid glands are associated with significantly reduced expression of CaRs and VDRs.4,5Parathyroid glands with nodular hyperplasia therefore become less responsive to serum calcium levels6,7 and resistant to the medical treatment of SHPT.6,81. Tominaga Y et al. Semin Surg Oncol 1997;13:78862. Tominaga Y et al. World J Surg 1996;20:744503. Tominaga Y et al. Clin Nephrol 1995;44 (Suppl 1):S4274. Gogusev J et al. Kidney Int 1997;51:328365. Wang X et al. Chin Med J (Engl) 2001;114:41046. Rodriguez M et al. Kidney Int 2002;80:S155607. Almaden Y et al. J Am Soc Nephrol 1998;9:1845528. Rodriguez M et al. Kidney Int 1999;56:30617