12.08.2013 , • • • (60-80 • • • • • ) , ( .) ( ) , • • Am J Kidney Dis 2001;37 (suppl 1): S 182 1 12.08.2013 O2 c Erslev & Beutler. In: Williams’ Hematology. 5th ed. 1995;425-441 O2 Hb - O2 Hb 2 12.08.2013 “ ” Ht Radtke HW . Serum erythropoietin concentration in chronic renal failure: relationship to degree of anemia and excretory renal function. Blood. 1979;54(4):877-884. , , , , . . , Y. Cao Erythropoietin in cancer: a dilemma in risk therapy. Trends in Endocrinology & Metabolism, Volume 24, Issue 4, April 2013, 190-199; Murat O. Arcasoy Non-erythroid effects of erythropoietin Haematologica November 2010 95: 1803-1805 3 12.08.2013 : , , , 0 , , 12 18 20 22 25 K. Kalantar-Zadeh, Intravenous Iron Versus Erythropoiesis-Stimulating Agents: Friends or Foes in Treating Chronic Kidney Disease Anemia? Advances in Chronic Kidney Disease, Volume 16, Issue 2, March 2009, Pages 143-151 < 13 < 12 ( ( , ) ) , 1968 . < 13,5 -13,2 ; < 12,0 70 ) ) KDIGO,2012 ERBP, 2013 Nutritional anaemias. (1968). Report of a WHO scientific group. World Health Organ Tech Rep Ser, 405, 5-37, Robinson, B. E. (2006). Epidemiology of chronic kidney disease and anemia. J Am Med Dir Assoc ; S17-21; Bellizzi, V. Influence of the cyclic variation of hydration status on hemoglobin levels in hemodialysis patients. Am J Kidney Dis PMID: 12200807 S0272-6386(02)00080-X[pii]10.1053/ajkd.2002.34913 , 40(3), 549-555. 4 12.08.2013 , • ( – – • ) Hb 1 32 50% 3–5 3 4 - • 5 (QoL) • 6 1. Astor et al. Arch Intern Med. 2002;162:1401-1408 2. Thorp et al. Dis Manag. 2006;9:115-121 3. McClellan et al. Curr Med Res Opin. 2004;20:1501-1510 3. Locatelli et al. Nephrol Dial Transplant. 2004;19:121-132 4. Silverberg. Nephrol Dial Transplant. 2003;18(Suppl 2):ii7-12 5. Perlman et al. Am J Kidney Dis. 2005; 45:658-666 • • • • • 1 (QoL)2 3 4,5 6 7 1. 4. Eschbach JW . Ann Intern Med1989;111:992-1000; 2. Evans RW , JAMA1990;263:825-830 3. Marsh JT . Kidney Int 1991;39:155-163 Cannella G , Nephrol Dial Transplant 1991;6:31-37 5. Pascual J . Clin Nephrol1991;35:280-287 6. Braumann KM , Nephron1991;58:129-134 7. Veys N . Am J Kidney Dis 1992;19:358-363 5 12.08.2013 KDOQI 11-12 DOQI 11-12 1997 1999 EBPG > 11 2001 2004 EBPG >11 2006 2007 2009 2012 2013 ) Besarab A. What Is So Bad About a Hemoglobin Level of 12 to 13 g/dL for Chronic Kidney Disease Patients Anyway? Advances in Chronic Kidney Disease,16,2,2009,131-142 = 3028 /1,73 < 60 2 1.00 0.95 13,0 0.90 12 12,9 0.85 11 11,9 0.80 0.75 Log-rank test: P=0.0001 0.70 Hb, < 10 10 10,9 0 3 6 9 12 15 18 21 24 27 31 33 37 Levin et al. Nephrol Dial Transplant. 2006;21:370-377 6 12.08.2013 DOPSS: = 4591 1.4 1.29 1.22 1.2 Hb = 0.95 1 (P=0.03) Hb 1 =0.96 (P=0.02) 1.09 1.02 1.00 1.07 1.00 1.0 0.91 0.8 <10 10 10.9 11 11.9 Hb ( 12 <10 10 10.9 11 11.9 12 ) Locatelli et al. Nephrol Dial Transplant. 2004;19:121-132 DOPPS: , , <11 Hb = 7998 , = 0,94 P=0.0001 P<0.0001 P=0.001 P=0.05 Hb 1 , P=0.77 Hb Pisoni et al. Am J Kidney Dis. 2004;44:94-111 7 12.08.2013 US Normal Hematocrit trial: , N=1233 (%) Ht Ht = 1,3 (0,9–1,9; 95% Ht (42%) N=634 ,n ) ) Ht (30%) N=631 221 (34,5%) 185 (29%) 20 (3,2%) 16 (2,5%) Besarab A. et al N Engl J Med 1998; 339: 584-90, FDA CDRAC Briefing Document 2007 CREATE: The Cardiovascular risk reduction by early anemia treatment with epoetin beta Drüeke TB et al. N Engl J Med 2006;355:2071–84 8 12.08.2013 CREATE: ) 100 (%) 90 80 70 60 Hb 13–15 Hb 10,5–11,5 50 40 : 58 vs. 47 =0,78 (0,53–1,14) Log rank test P = 0,20 30 20 10 0 1 2 0 6 12 18 24 30 36 42 48 301 302 279 286 268 272 249 257 207 223 158 177 97 121 56 61 2 2 Drüeke et al. N Engl J Med. 2006;355:2071-2084 CHOIR: Correction of Hemoglobin and Outcomes in Renal Insufficiency Singh AK et al. N Engl J Med 2006;355:2085–98 9 12.08.2013 CHOIR: Hb 13.5 Hb 11,3 , 0.30 3-4 Hb 13.5 Hb 11.3 0.25 0.20 0.15 0.10 : 125 vs. 97 = 1.34 (1.03–1.74) Log rank test P = 0.03 0.05 0.00 1 2 0 3 6 9 12 15 18 21 24 27 30 33 36 39 715 717 654 660 587 594 520 457 539 499 355 397 270 293 176 182 101 107 72 67 55 44 23 23 Singh et al. N Engl J Med. 2006;355:2085-2098 TREAT: Hb 13 II, 2-4 100 (%) 90 80 70 60 50 =1.92 (1.38–2.68) P< 0.001 40 30 20 10 0 0 2012 2026 6 12 1923 1787 1914 1783 18 24 30 36 1581 1575 1247 1262 863 886 590 561 42 341 338 48 141 132 Pfeffer MA et al. N Engl Med 2009;361:2019–32 10 12.08.2013 US NHCT 1 CREATE 2 CHOIR 3 TREAT N=1233 N=605 3-4 N=1432 3-4 N=4038 2-4, 14 48 16 48 42% . (Ht) 30% . Hb 13-15 Hb 10,5-11,5 8 Hb 13-15 Hb 11,3 - . Hb 13 , Ht : , - , : Hb 1 42% . II, (p=0,03) Ht (p=0,001) 1 Besarab A. et al N Engl J Med 1998; 339: 584-90; 2 Drüeke TB et al. N Engl J Med 2006;355:2071–84; 3 Singh AK et al. N Engl J Med 2006;355:2085–98; 4 Pfeffer MA et al. N Engl Med 2009;361:2019–32 Ann Intern Med. 2010;153(1):23-33. doi:10.7326/0003-4819-153-1-201007060-00252 Hb: Hb Hb 11 12.08.2013 KDOQI KDOQI 11 KDOQI 11-12 DOQI 11-12 1997 ( >13 1999 EBPG > 11 2001 2004 EBPG >11 update 11-12 !) 2006 2007 ) 13 ) 2009 EBPG 11-12 13 2012 2013 !) Besarab A. What Is So Bad About a Hemoglobin Level of 12 to 13 g/dL for Chronic Kidney Disease Patients Anyway? Advances in Chronic Kidney Disease,16,2,2009,131-142 , (USRDS) (JSDT) Hb, Hb Iseki K, Kohagura K Anemia as a risk factor for chronic kidney disease. Kidney international. Supplement 2007 ():S4-S9. 12 12.08.2013 KDOQI KDOQI 11 KDOQI 11-12 DOQI 11-12 1997 1999 2001 2004 !) 2006 2007 EBPG >11 EBPG > 11 update 11-12 ( >13 13 ) 2009 2012 ERBP 11-12 ) 13 2013 ) JSDT 10-11 11-12 ( ) Besarab A. What Is So Bad About a Hemoglobin Level of 12 to 13 g/dL for Chronic Kidney Disease Patients Anyway? Advances in Chronic Kidney Disease,16,2,2009,131-142 KDOQI KDOQI 11 1997 ( >13 KDOQI 11-12 DOQI 11-12 1999 EBPG > 11 2001 KDIGO update 11-12 !) 13 : < 10 : < 11,5 ) 13 2004 2006 2007 EBPG >11 2009 ERBP 11-12 ) 13 2012 ) ) 2013 ERBP 10-12 13 JSDT ) 10-11 ( 11-12 ) Besarab A. What Is So Bad About a Hemoglobin Level of 12 to 13 g/dL for Chronic Kidney Disease Patients Anyway? Advances in Chronic Kidney Disease,16,2,2009,131-142 13 12.08.2013 , , Leaf D.E. Kidney International 2009; 75;15-24 • • • • • Leaf D.E. Kidney International 2009; 75;15-24, Besarab A. et al N Engl J Med 1998; 339: 584-90, FDA CDRAC Briefing Document 2007; Khuri F. N Engl J Med 2007; 356:2445-2448 14 12.08.2013 70 Hb ) 100 & < 100 & 100 & < 100 & P Hb ) P 20% 20% < 20% < 20% - 0,2 0,002 - 0,1 0,3 - 0,3 0,001 - 0,4 0,004 - 0,6 <00001 - 0,8 <0,0001 Hsu et al, J Am Soc Nephrol 2002;13:2783-86 Fe • 1-2 Fe 12 300 .– , H. pylori 20 • 300 • Fe ( , 1700 3-4 , Fe – 1200 Fe , .) - • • 1-2 Walter H. Horl, Clinical Aspects of Iron Use in the Anemia of Kidney Disease JASN February 2007;18;2;382-393 B. M. Denker Iron Therapy in Chronic Kidney Disease; Nephrology Rounds, 2005;3;5;1-6 15 12.08.2013 Fe 1-2 Fe Fe (Fe2- Fe ) Fe , • • • • , 12 • • , , , . - , Vaulont S, J Clin Invest 2005,115;2079-2082 : , EBPG 20041 KDOQI 20062 ERBP 20093 • • • 100 100 / • 200-500 • • 200-500 • >100 >200 KDIGO 20124 ERBP 20135 : 1-4) • 5) 500 • < 200 1-4) • < 300 5) • 500 500 : TSAT,% / • • 20% • 1. > 20% • >20% 30% • • TSAT <25% 30% Locatelli F. ,NDT 2004;19:1-47; 2. National Kidney Foundation Am J Kidney Dis 2006;47;S11-145; 3.Locatelli F. NDT 2009;24:348-54; 4.KDIGO Kidney Int Suppl 2012;2:292-298; 5. Locatelli F, NDT 2013doi: 10.1093/ndt/gft033 16 12.08.2013 • ( ) • KDIGO Anemia Work Group Kidney Int Suppl 2012;2;292-8 Hb / , 95% % , 95% Allegra 1990 13,42 -0,90 [0,04; 1,76] Fishbane 1995 14,67 1,53 [0,91; 2,15] MacDougall 1996 12,27 1,45 [0,39; 2,51] Svara 1996 14,97 0,19 [-0,36; 0,74] Warady 2004 14,07 0,24 [-0,55; 0,50] Michael 2007 14,98 0,00 [-0,55; 0,50] Li 2008 15,62 1,99 [1,60; 2,38] 100,00 0,83 [0,09; 1,57] -4 -2 0 2 4 per os Rozen-Zvi B, Am J Kidney Dis 2008;52:897-906 17 12.08.2013 Eugene Goldwasser 14.10.1922 – 17.10.2010 165 32-36000 Fishbane S. Curr Opin Nephrol Hypertens. 2009;18;112-115 18 12.08.2013 ( : ) .) , (CERA) (SEP) : (CERA) . EPO-EPO GM-CSF-EPO Fc-EPO CTNO528 Ala1, Lys 45 ( : ) , ( GATA HCP Lys 52 HIF) : Macdougall I Clin J Am Soc Nephrol 3: 200-207;2008; Jelkmann W. Nephrol Dial Transplant (2007) 22: 2749–2753 – ? – Genentech Nutropin® Abbott Abbokinase® Eli Lilly Humulin® Genzyme Ceredase® Cerezyme® ); AstraZeneca Streptase® ) ) ) ) ) ® Biogen / Roche\ Intron A (IFN- -2b) Serono Eli Lilly Serostim® B 2007 ( Humatrope® EPREX® NeoRecormon® Genentech TNKase® (tenecteplase TNK-tPA) Genentech 2013 - ) 2005 2005, 2006, 2012 ), Actimmune® (IFN- -Ib) Alteplase® (tPA) Chiron Proleukin® (IL-2) Amgen Neupogen® ) NA Epogen®, Procrit® Activase®, ) NA ) Amgen J&J Roche InterMune C ) 2005, 2010 2006, 2012 G-CSF) , , 2015 Schellekens H. Trends Biotechnol 2004;22:406-10. 19 12.08.2013 ” I II (2001 ” - ), ,CERA (2007) ( . , ) » Jelkmann W. Nephrol Dial Transplant (2007) 22: 2749–2753 ) 1 http://gabi-journal.net/news/biosimilars-marketed-in-europe 20 12.08.2013 ? 165 4 , !!! , E. coli , : , : , , , VII , tPA • • • , • • 1) 2) 3) 4) “ ” ” , (3D) : ( , ), , • Crommelin DJA, et al. Int J Pharm 2003;266:3-16. Jelkmann W. Nephrol Dial Transplant (2007) 22: 2749–2753 ( 2 )– , . H. Mellstedt, D. Niederwieser & H. Ludwig. The challenge of biosimilars. Annals of Oncology 19: 411–419, 2008 21 12.08.2013 11 ® ) Combe C, Tredree RL, Schellekens H. Biosimilar epoetins: an analysis based on recently implemented European Medicines Evaluation Agency guidelines on comparability of biopharmaceutical proteins. Pharmacotherapy 2005; 25: 954–962; Schellekens H. Biosimilar therapeutics—what do we need to consider? NDT Plus (2009) 2 [Suppl 1]: i27–i36 ® vs ® ® ®; Dynepo® vs Retacrit®) Retacrit® Dynepro® Brinks V. Quality of original and biosimilar epoetin products Pharm Res (2011) 28:386–393 http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000725/human_med_000675.jsp&murl=menus/medicines/medicines.jsp&mid=WC0b01ac058001d125 22 12.08.2013 ® ) I INJ-5 • 24 ) • ( 3 000 2 500 2 000 1 500 1 000 500 ® (n = 37) ® (n = 0 0 2 4 6 39) 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 , Sörgel et al. BMC Clin Pharmacol 2009; 9: 10 ® ) I INJ-5 • • Hb ( (x106 ) 18 17 16 x106 15 14 13 0 5 10 15 20 25 30 0 ) 5 10 15 20 25 30 ( ) (x109 ) HCT (%) 250 50 48 46 44 42 40 38 36 200 150 x109 % ) 5.8 5.6 5.4 5.2 5.0 4.8 4.6 4.4 4.2 100 50 0 5 10 15 20 25 30 ( ) 0 0 5 10 15 20 25 30 ® (n=37) ( ) ® (n=39) Sörgel et al. BMC Clin Pharmacol 2009; 9: 10 23 12.08.2013 ® III INJ-9 Hb ( ) • Hb 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 ® (n = 207) ® (n = 1 4 8 12 16 20 24 118) 28 Haag-Weber et al. Clin Nephrol 2009; 72: 380-90 III ® INJ-9 18 000 14 16 000 13 14 000 12 12 000 Hb ( ) 15 ) • 10 000 11 8 000 10 6 000 9 4 000 8 2 000 I( 4 ® 8 ) II ®) 0 12 16 20 24 28 32 36 40 44 48 52 56 ® ® Hb Hb ® ® Adapted from Haag-Weber et al. Clin Nephrol 2009; 72: 380-90 24 12.08.2013 : • ( + Hb 10 Hb (>13,0 ) • ) 11,5 • ( ( • vs , ) ; • ?) ? ) Hb? • ? , ? Hb • , , Hb? ? 25 12.08.2013 Eugene Goldwasser 14.10.1922 – 17.10.2010 ! 26