Aneemia neeruhaigetel. Aneemia põhjused. Miks on vaja neeruhaigetel ravida aneemiat? Neeruasendusravi haigete diagnoosid (%)
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1 Miks on vaja neeruhaigetel ravida aneemiat? neeruhaigetel Mai Rosenberg TÜ, Sisekliinik ravi eesmärk, tulemused varem: Hb taseme tõstmine Peale EPO kasutuselevõttu vereülekannete vajadus vähenes Elukvaliteedi paranemine - alles praegu uuritakse, millised funktsioonid paranevad - kas toime on lühi- või pikaaegne - neurokognitiivne funktsioon - tööle naasmine VV vatsakese hüpertroofia, k/v haigus GFR languse kiirus hospitaliseerimised vähenenud ravi maksumus suremus muud Millised on aneemia põhjused vanemas eas. põhjused Üldpopulatsioonis: - suure osa moodustab kroonilise neeruhaigusega seoses olev aneemia 18%, - kõik kroonilised haigused kokku ja aneemia esinemine (32%) HD Neeruasendusravi haigete demograafilised näitajad 2002 Keskmine vanus 55,1 M / N 61/ Keskmine vanus 57,0 M / N 77/ Keskmine vanus 59,0 M / N 110 / 86 Neeruasendusravi haigete diagnoosid (%) PD 54,6 30/ 28 57,5 43/ 31 58,0 48 / TX NAR kokku 46,6 52,1 120/94 211/160 45,8 53,4 147/ /194 49,1 57,1 185 / / GN PN DM Hüpert PCKD Amül. Muud
2 põhjused neeruhaigetel EPO defitsiit Raua defitsiit Valgu defitsiit Er-de eluea vähenemine Hemolüüs Verekaotused Trombotsüütide düsfunktsioon Kirurgilised protseduurid Äge või krooniline põletik Tõsine sekundaarne hüperparatüreoidism hüpotüreoidism Folaatide defitsiit käsitlus: ajalugu käsitlus: ajalugu 20 a. tagasi tehtud uuringud: nädalas sai iga dialüüsihaige ~0,5 doosi verd aadrilaskmine pt.-lt pt-le Rh faktori Epoetin Darpoetin ülekanded kirjeldus alfa Looma vere 1901a. Am. Punane Rist ülekanded veregrupid alustas verekogumist Mircera Inimesele A, B ja 0 ja jagamist dok-tud EPO ajalugu Erütropoetiin - EPO 1906 Pariisis: Prof Paul Carnot ja tema assistent DeFlandre pakkusid, et punaliblede produktsiooni reguleerivad hormoonid. Püüdsid suurendada punaliblede arvud eksperimentides jänestega nn. hemotroopse faktoriga, mida nimetasid hemopoetiiniks Eva Bonsdorff and Eeva Jalavisto jätkasid töid ja nimetasid erütropoeesi stimuleeriva agensi erütropoetiiniks (erythropoietin) 1950 a-tel Reissman ja Erslev demonstreerisid, et veres tsirkuleeriv faktor stimuleerib erütrotsüütide produktsiooni Erütropoetiin (EPO) on glükoproteiin hormoon, mis kontrollib erütropoeesi. Luuüdis on EPO tsütokiiniks erütrotsüütide prekursor-rakkudele. EPO bioloogilised funktsioonid: - hormoon, mis reguleerib erütrotsüütide produktsiooni - tähtis osas peaaju vastusel neuronite kahjustusele - EPO on seotud ka haavade paranemise protsessiga Siren AL et al. (2001). "Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress". Proc Natl Acad Sci USA 98: a. - Goldwasser ja Kung alustasid töid EPO puhastamiseks, see õnnestus 9 aastat hiljem 1977a. Erslev A. Humoral regulation of red cell production. Blood Apr;8(4): Erslev A,et al. Erythropoietic stimulation induced by anemic serum. Proc Soc Exp Biol Med Jul;83(3): Jelkmann W (March 2007). "Erythropoietin after a century of research: younger than ever". European journal of haematology 78 (3):
3 Neerud on tihedalt pakitud organid, mis koosnevad veresoontest, tuubulitest ja väikestest filtratsiooni läbiviivatest ühikutest nefronitest. Sündides on igal inimesel kindel arv nefroneid, nende väikese arvu puhul või elu jooksul nefronite kaotuse puhul tekib kõrge vererõhk ja aja jooksul neerupuudulikkus. EPO ajalugu EPO produktsiooni eest vastutavad: 1980 a. viisid Adamson, JW. Eschbach, JC. Egrie, MR. Downing ja JK. Browne läbi kliinilise uuringu Epogeniga (EPO esimene sünteetiline vorm, Amgen). Adamsoni jt töö oli edukas 25 HD haigel kõigil paranesid Hb, Hct Eschbach JW, Egrie JC, Downing MR, Browne JK, Adamson JW (January 1987). "Correction of the anemia of end-stage renal disease with recombinant human erythropoietin. Results of a combined phase I and II clinical trial". N. Engl. J. Med. 316 (2): distaalsete peritubulaar kapillaaride endoteelirakud ja fibroblastid EPO ajalugu 1980 a. viisid Adamson, JW. Eschbach, JC. Egrie, MR. Downing ja JK. Browne läbi kliinilise uuringu Epogeniga (EPO esimene sünteetiline vorm, Amgen). 1985, Lin jt isoleerisid EPO geeni, kirjeldasid seda (bioloogiliselt aktiivne in vitro ja in vivo) ja töötasid välja metoodika tootmiseks. See avastus avas ukse recombinantse erütropoetiini (RhEpo) tööstuslikuks tootmiseks ja haigete aneemia raviks 1989 a. U.S. Food and Drug Administration kiitis heaks Epogeni (Epoetin alfa) kasutuse Eschbach JW, Egrie JC, Downing MR, Browne JK, Adamson JW (January 1987). "Correction of the anemia of end-stage renal disease with recombinant human erythropoietin. Results of a combined phase I and II clinical trial". N. Engl. J. Med. 316 (2): Lin FK, Suggs S, Lin CH, Browne JK, Smalling R, Egrie JC, Chen KK, Fox GM, Martin F, Stabinsky Z (November 1985). "Cloning and expression of the human erythropoietin gene". Proc. Natl. Acad. Sci. U.S.A. 82 (22): Roche Diagnostics Ltd. Penzberg: ajalugu Dr. Hans Ulrich Bergmeyer - biokeemiliste meetodite arendaja Tutzingis Baierimaal 1950 a-tel 1960 a. - esimene teadusdivisjoni juht. Tootma hakati koensüüme, substraate ja metaboliite, mida saadi peamiselt seene fermetatsiooni produktidest koliti Penzbergi Algusaegadel tegeleti peamiselt kliinilises praktikas vajalike diagnostiliste testide ja reagentide väljatöötamisega: - uriini testribad - veresuhkru määramine
4 EPO ajalugu Hiljuti avastati uus erütropoeesi stimuleeriv protein (erythropoiesis-stimulating protein, NESP), mille toime on pikem kui EPO-l Darbepoetin (Aranesp). Macdougall IC (July 2000). "Novel erythropoiesis stimulating protein". Semin. Nephrol. 20 (4): EPO brändid Epoetin (Procrit ( ka Eprex), NeoRecormon) Darbepoetin (Aranesp). Methoxy Polyethylene Glycol-Epoetin Beta (MIRCERA) A Trial of Darbepoetin Alfa in Type 2 Diabetes and Chronic Kidney Disease. Pfeffer MA, Burdmann EA, Chen CY, Cooper ME, de Zeeuw D, Eckardt KU, Feyzi JM, Ivanovich P, Kewalramani R, Levey AS, Lewis EF, McGill JB, McMurray JJ, Parfrey P, Parving HH, Remuzzi G, Singh AK, Solomon SD, Toto R; the TREAT Investigators. N Engl J Med Oct 30. MIRCERA Methoxy polyethylene glycol-epoetin beta (Hoffmann-La Roche) brändi nimi - Mircera. Mircera - pikatoimeline erütropoetiini retseptori aktivaator - erythropoietin receptor activator (CERA), mis on näidustatud kroonilistel neeruhaigetel aneemia raviks. Mircera on esimene keemiliselt modifitseeritud erütropoeesi-stimuleeriv agent (ESA). Mircera on Euroopa Komisjonis kinnitatud sept 2007 ja U.S. Food and Drug Administration Nov 2007 Ravim stimuleerib erütropoeesi luuüdi tüvirakkude EPO retseptorite kaudu Macdougall IC, Eckardt K-U. (2006), "Novel strategies for stimulating erythropoiesis and potential treatments for anaemia", Lancet, 368, p ESA: kasutamine Krooniliste neeruhaigetel aneemia ravi Kasvajate ravis Intensiivravis: Corwin HL, Gettinger A, Fabian TC, May A, Pearl RG, Heard S, An R, Bowers PJ, Burton P, Klausner MA, Corwin MJ (September 2007). "Efficacy and safety of epoetin alfa in critically ill patients". The New England Journal of Medicine 357 (10): EPO doping - kehalise võimekuse suurendamiseks Kroonilise neeruhaige käsitlus Renaalne aneemia: kliinik KNH progresseerumis e ennetamine RAS blokkerid VR kontroll Komplikatsiooni de ennetus Alatoitumus Kaasnevate haigused ja riskitegurid Südamehaigus Vaskulaarhaigus Ettevalmistus NAR-ks NAR meetodi valik Õigeaegne NARks ettevalmistus Väsimus Töövõime langus Südamepuudulikkus Stenokardia Veresuhkru kontroll Valgupiirang Osteodüstroofia Kaltsifikatsioonid Diabeet Düslipideemia Atsidoos Suitsetamine
5 Renaalne aneemia: labor põhiuuringud KNH Hb g/l Hct 33-36% Er (MCV, MCH, MCHC), retikulotsüüdid Fe a/v näitajad: Fe Transferriini saturatsioon <20% Ferritiin <100 ng/ml CRV Renaalne aneemia: Fe Raua toksilised efektid: - Parenhümatoossete elundite infiltratsioon - Risk infektsioonide tekkeks tõuseb - Organite oküdatiivne kahjustus Lisauuringud aneemia dif dgn Vit B12, folaat Lk Hemolüüsi testid (haptoglobiin, LDH, bilirubiin, Coombsi test) Seerumi ja uriini elektroforees Peiteveri väljaheites PTH, alumineemia Luuüdi (näidustuse korral) Südame- ja veresoonkonna haiguse põhjused kroonilisel neeruhaigel komplitseeritud Südame- ja veresoonkonna haigus on kõige levinum surmapõhjus KNP haigetel Suitsetamine Vaskulaarne kaltsifitseerumine Oksüdatiivne stress Düslipideemia Põletik Endoteeli düsfunktsioon Vedeliku Teadmata Insuliini retensioon riski resistentsus tegurid Homotsüsteiin VVH AGE Surevuse risk: - KNP lõpp-staadiumi haigetel on ~16 korda kõrgem võrreldes üldpopulatsiooniga - KNP III-IV staadiumi haigetel on ~11 korda kõrgem võrreldes üldpopulatsiooniga Go AS, jt. N Engl J Med 2004,351(13): Renaalne aneemia: ravi efekt Renaalne aneemia: ravi efekt K/v kasulikud toimed Südame väljutusmahu vähenemine VV hüpertroofia vähenemine Löögimahu alanemine Südame isheemiatõve esinemise vähenemine Mitte-k/v toimed Väsimus Töövõime Koormustaluvuse tõus Vere viskoossuse tõus Kognitiivne toime tõuseb Lipiidiprofiil paraneb Seksuaalne funktsioon paraneb
6 Kardiorenaalne sündroom I tüüp järsk südametegevuse halvenemine (nt. kardiogeenne šokk või SP), mis viib ÄNP tekkele II tüüp krooniline SP (krooniline kongestiivne SP), mis põhjustab progresseeruvat ja permanentset KNH. III tüüp - järsk neerufunktsiooni halvenemine (nt. äge neeruisheemia, glomerulonefriit), mis põhjustab ÄSP (nt. SP, arütmiaid, isheemia). IV tüüp krooniline neeruhaigus (nt. krooniline glomerulaarhaigus), mis seostub kroonilise SP, kardiaalse hüpertroofia ja/või suurenenud südame-veresoonkonna tüsistuste riskiga. V tüüp süsteemne seisund (nt. diabeet, sepsis), mis põhjustab nii südame- kui ka renaalset düsfunktsiooni. Kardiorenaalne sündroom 1951 Odel ja Weissman (textbook) 2004 National Heart, Lung and Blood Institute workgroup 2007 European Society of Cardiology kongressil esines tuntud nefroloog Ronco ja esitas K-R sündroomi definitsiooni Ronco et al 2008 Int Care Medicine Ronco ja Bellomo 2009 Blood Purification Claudio Ronco MD et al 2008 Cardiorenal Syndrome Journal of the American College of Cardiology, Volume 52, Issue 19, Pages
7 Kardiorenaalne sündroom Oluline on individuaalsetel juhtudel eristada, millise subtüübi ja patofüsioloogilise mehhanismiga on tegemist ning sellest juhinduvalt haiget käsitleda Biomarkerid aitavad iseloomustada KRS subtüüpe and juhtida ravi valikut ja ennustada efektiivsust Nt. Troponiin T on paljudel KNP haigetel normist kõrgem ja korrelleerub elulemusega Hickson LJ et al Survival of patients on the kidney transplant wait list: relationship to cardiac troponin T Am J Tranplant 2008: Pavlakis M. Can cardiac troponin T level be used to predict survival of patients awaiting renal transplantation? Nature Clinical Practice Nephrology, March, 2009, Kardiorenaalne sündroom * Soodustavad tegurid - - Kroonilise neeruhaigusega seoses olevad mineraalide ja luu ainevahetuse häired, mis põhjustavad: - Mineraalide laboratoorsed muutused - Luuhaigus - Vaskulaarne kaltsifitseerumine Association between ctnt levels, diabetes and time on dialysis. Y-axis represents the percent of patients in each subgroup with ctnt level >0.01. Patient without DM (N = 412) (hatched bars); patients with DM (N = 232) (black bars). Hickson LJ et al Survival of patients on the kidney transplant wait list: relationship to cardiac troponin T Am J Tranplant 2008: (CKD-MBD: chronic kidney disease-associated mineral and bone disease disorder, Moe S Kidney Int, 2006) * Südame- ja veresoonkonna haigus on kõige levinum surmapõhjus KNH patsientide hulgas
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