* *,** * ** (Erythropoiesis stimulating agent, ESA) (erythropoietin, ) darbepoetin CERA ESA ESA ( 70 ml/min 50 ml/min) 50% 12 g/dl 75% [1] Eschbach 1970 112 2 201 02-28757518 02-28757841 E-mail:wctseng@vghtpe.gov.tw ; dctarng@vghtpe.gov.tw Lin 1985 [2] Eschbach [3] 90% (fibroblast-like interstitial cell)[4] 10% exons introns 193 27 C arginine 165 N-linked O-linked 30,400D [5] Epoetin epoetin alfa beta 97 20 3 165
N-linked O-linked 14epoetin beta ( 1) 80 120 U/kg/week ( ) 120 180 U/kg/week ( ) 6000 U [6] 1 2 g/dl/mo 2 3 g/dl/mo Darbepoietin epoetin alfa N-linked darbepoetin alfa 22 37000Da 1 2 1 Macdougall darbepoetin epoetin alfa (23.3 8.5 ) darbepoetin 48.8 0.45 µg/kg/week 0.75 µg/kg/2weeks 1µg darbepoetin 200U epoetin CERA (Continuous erythropoiesis receptor activator; CERA) epoetin beta methoxypolyethylene glycol polymer 130 phase III CERA (0.6 µg/kg) darbepoetin (0.45 µg/kg) [7] CERA ( ) epoetin CERA epoetin [8]CERA hypoxia-inducible factor (HIF) HIF HIF-2α hypoxia responsive element (HRE) GATA-2 NF-κB [9] (R)R STAT5 R Ras/MAP kinase PI3-kinase/Akt Akt Bad Bcl-X L hematopoietic cell phosphatase BFU-E CFU-E R CFU-E 1. (Pharmacokinetics) [1] mean S.E.M ( ) Epoetin alfa 6.8 0.6 19.4 2.5 Epoetin beta 8.8 0.5 24.2 2.6 Darbepoetin alfa 25.3 2.2 48.8 5.2 CERA 134 19 139 20 166 97 20 3
1000 R CFU-E [1] 1998 Besarab epoetin (42%) (30%) 1.3 (0.9 1.9) Kt/V [10] CREATE (13 15 g/dl) (10.5 11.5 g/dl) [11] CHOIR (13.5 g/dl)(11.3 g/dl) [12] ACCORD (13 15 g/dl) (10.5 11.5 g/dl) [13] 11 12 g/dl13 g/dl 450 300 B12 (ferritin) 200 ng/ml 100 ng/ml 500 ng/ml (HO-1) PI3 kinase/akt HO-1 superoxide dismutase catalase glutathione peroxidase [14] NK-κB NMDA NO [15] 4-hydroxy-2- nonenal malondialdehyde Bcl-2 Bcl-X L bax bak [16] Gouva [17] ACCORD CREATE CHOIR [11-13] R 97 20 3 167
BEST epoetin alfa 12 14 g/dl (70% 76%) ENHANCE epoetin beta 14.5 15 g/dl ( 1.39) -CAN-20 12 14 g/dl ( 1.84) 2007 [18] (PRCA) 20 30% ( 10 mmhg) ADMA NO endothelin norepinephrine PRCA 2 1.6 0.02 1998 1998 2004 200 Eprex (epoetin alfa) Eprex Tween-80 Eprex prednisolone (1 mg/kg/day) 50% cyclophosphamdie (50 100 mg/day) 87% cyclosporine (100 200 mg/day) IVIg plasmapheresis rituximab Hematide R Hematide 14 60 0.025 0.05 mg/kg Hematide 2. (PRCA) ( 10 10 9 /L) (transferrin saturation) ( 5% erythroblasts) 2 ( 10 ) 168 97 20 3
PRCA [19] Prolyl Hydroxylase (HIF ) HIF HIF-α prolyl hydroxylase asparaginyl hydroxylase 2-oxoglutarate 2-oxoglutarate HIFHIF HIF prolyl hydroxylase [19] GATA GATA-2 mrna GATA-2 GATA-2 CFU-E [19] Hemopoietic cell phosphatase Hemopoietic cell phosphatase (HCP) HCP [19] R Receptor recycling P P P P HCP P P Proliferation Ras/MAP Pl3K/Akt Anti-apoptosis NFkB STAT5 SOCS/CIS 1. Ras/MAPK PI3K/Akt NF- B STAT5 HCP ( [20]) 97 20 3 169
1. Tarng DC: Cardiorenal anemia syndrome in chronic kidney disease. J Chin Med Assoc 2007; 70: 424-9. 2. Lin FK, Suggs S, Lin CH, et al: Cloning and expression of the human erythropoietin gene. Proc Natl Acad Sci U S A 1985; 82: 7580-4. 3. Eschbach JW, Egrie JC, Downing MR, Browne JK, Adamson JW: 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 1987; 316: 73-8. 4. Maxwell PH, Ferguson DJ, Nicholls LG, Johnson MH, Ratcliffe PJ: The interstitial response to renal injury: fibroblast-like cells show phenotypic changes and have reduced potential for erythropoietin gene expression. Kidney Int 1997; 52: 715-24. 5. Egrie JC, Browne JK: Development and characterization of novel erythropoiesis stimulating protein (NESP). Nephrol Dial Transplant 2001; 16 Suppl 3: 3-13. 6. KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease: Am J Kidney Dis 2006; 47: S11-145. 7. Macdougall IC, Walker R, Provenzano R, et al: C.E.R.A. corrects anemia in patients with chronic kidney disease not on dialysis: results of a randomized clinical trial. Clin J Am Soc Nephrol 2008; 3: 337-47. 8. Levin NW, Fishbane S, Canedo FV, et al: Intravenous methoxy polyethylene glycol-epoetin beta for haemoglobin control in patients with chronic kidney disease who are on dialysis: a randomised non-inferiority trial (MAXIMA). Lancet 2007; 370: 1415-21. 9. Nangaku M, Eckardt KU: Pathogenesis of renal anemia. Semin Nephrol 2006; 26: 261-8. 10. Besarab A, Bolton WK, Browne JK, et al: The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med 1998; 339: 584-90. 11. Drueke TB, Locatelli F, Clyne N, et al: Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med 2006; 355: 2071-84. 12. Singh AK, Szczech L, Tang KL, et al: Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med 2006; 355: 2085-98. 13. Ritz E, Laville M, Bilous RW, et al: Target level for hemoglobin correction in patients with diabetes and CKD: primary results of the Anemia Correction in Diabetes (ACORD) Study. Am J Kidney Dis 2007; 49: 194-207. 14. Katavetin P, Tungsanga K, Eiam-Ong S, Nangaku M: Antioxidative effects of erythropoietin. Kidney Int Suppl 2007: 10-5. 15. Digicaylioglu M, Lipton SA: Erythropoietin-mediated neuroprotection involves cross-talk between Jak2 and NFkappaB signalling cascades. Nature 2001; 412: 641-7. 16. Anagnostou A, Lee ES, Kessimian N, Levinson R, Steiner M: Erythropoietin has a mitogenic and positive chemotactic effect on endothelial cells. Proc Natl Acad Sci U S A 1990; 87: 5978-82. 17. Gouva C, Nikolopoulos P, Ioannidis JP, Siamopoulos KC: Treating anemia early in renal failure patients slows the decline of renal function: a randomized controlled trial. Kidney Int 2004; 66: 753-60. 18. Rizzo JD, Somerfield MR, Hagerty KL, et al: Use of epoetin and darbepoetin in patients with cancer: 2007 American Society of Clinical Oncology/American Society of Hematology clinical practice guideline update. J Clin Oncol 2008; 26: 132-49. 19. Macdougall IC. Novel erythropoiesis-stimulating agents: a new era in anemia management. Clin J Am Soc Nephrol 2008; 3: 200-7. 20. van der Putten K, Braam B, Jie KE, Gaillard CA: Mechanisms of Disease: erythropoietin resistance in patients with both heart and kidney failure. Nat Clin Pract Nephrol 2008; 4: 47-57. 170 97 20 3