Behandlung der renalen Anämie

ZUSAMMENFASSUNG

Anämie stellt, ob als subjektiv empfundene Einschränkung oder als Marker interpretiert, ein signifikanter, prognostischer Parameter in der Entwicklung der CKD dar. Ausgehend von der Isolierung und Herstellung von EPO bzw. ESAs haben Studien gezeigt, dass eine Hb-Anhebung auf bis zu 10 g/dl mit klinischen Vorteilen einhergeht. Allerdings konnte bislang nicht überzeugend nachgewiesen werden, dass eine intensivierte Hb-Anhebung mittels exogener Zufuhr von EPO einen umfassenden Benefit für den Patienten bedeutet. Neuere Entwicklungen versprechen interessante Ansätze, in denen nicht nur die Erythropoese im engeren Sinne stimuliert wird, sondern darüber hinausgehende Mechanismen moduliert werden. Die Activin-Hemmung birgt das Potenzial nicht nur die Anämie, sondern auch den Mineral- und Knochenerkrankungen-Komplex (CKD-MBD) bei Niereninsuffizienz zu verbessern. Die HIF-Prolyl-Hydroxylase-Inhibitoren zeigen auch pleiotrope Wirkungen, die derzeit im Mittelpunkt weiterer Forschungen stehen. Allerdings bieten die konventionellen ESAs einen umfassenden Sicherheitsgrad, an dem die neueren Substanzen gemessen werden dürften. Die Entwicklung eines Blutschlauchsystems für die Hämodialyse stellt einen gänzlich anderen Ansatz dar, um die Anämie zu verbessern. Hier wird nicht eine Stimulierung der Erythropoese, sondern eine unverfängliche Reduzierung einer mechanischen Hämolyse während der Dialyse erreicht.

• Literatur

• 1 Ibrahim HN, Ishani A, Foley RN. et al. Temporal trends in red blood transfusion among US dialysis patients, 1992–2005. Am J Kidney Dis 2008; 52: 1115-1121
• 2 Lawler EV, Bradbury BD, Fonda JR. et al. Transfusion burden among patients with chronic kidney disease and anemia. Clin J Am Soc Nephrol 2010; 5: 667-672
• 3 Fishbane S. Erythropoiesis-stimulating agent treatment with full anemia correction: a new perspective. Kidney Int 2009; 75: 358-365
• 4 Katzung BG. Basic & clinical pharmacology. McGraw-Hill Medical; 10. ed. 2007: 536-538
• 5 Mulcahy L. The erythropoietin receptor. Seminar Oncol 2001; 28 (Suppl. 08) 19-23
• 6 Socolovsky M, Fallon AE, Wang S. et al. Fetal anemia and apoptosis of red cell progenitors in Stat5a-/-5b-/- mice: a direct role for Stat5 in Bcl-X(L) induction. Cell. 1999 98. 181-191
• 7 Wang CQ, Udupa KB, Lipschitz DA. Interferon-gamma exerts its negative regulatory effect primarily on the earliest stages of murine erythroid progenitor cell development. J Cell Physiol 1995; 162: 134-138
• 8 Taniguchi S, Dai CH, Price JO, Krantz SB. Interferon Gamma Downregulates Stem Cell Factor and Erythropoietin Receptors But Not Insulin-Like Growth Factor-I Receptors in Human Erythroid Colony-Forming Cells. Blood 1997; 90: 2244-2252
• 9 Means Jr. RT. Recent developments in the anemia of chronic disease. Curr Hematol Rep 2003; 2: 116-121
• 10 Nissenson AR. Epoetin and cognitive function. Am J Kidney Dis 1992; 20 (Suppl. 01) 21-24
• 11 London GM, Zins B, Pannier B. et al. Vascular changes in hemodialysis patients in response to recombinant human erythropoietin. Kidney Int 1989; 36: 878-882
• 12 Macdougall IC, Lewis NP, Saunders MJ. et al. Long-term cardiorespiratory effects of amelioration of renal anaemia by erythropoietin. Lancet 1990; 335: 489-493
• 13 Collins AJ, Li S, St Peter W. et al Death, hospitalization, and economic associations among incident hemodialysis patients with hematocrit values of 36 to 39 %. J Am Soc Nephrol 2001; 12: 2465-2473
• 14 Canadian Erythropoietin Study Group. Association between recombinant human erythropoietin and quality of life and exercise capacity of patients receiving haemodialysis. BMJ. 1990 300. 573-578
• 15 Parfrey PS, Lauve M, Latremouille-Viau D, Lefebvre P. Erythropoietin therapy and left ventricular mass index in CKD and ESRD patients: a meta-analysis. Clin J Am Soc Nephrol 2009; 4: 755-762
• 16 Parfrey PS, Foley RN, Wittreich BH. et al. Double-blind comparison of full and partial anemia correction in incident hemodialysis patients without symptomatic heart disease. J Am Soc Nephrol 2005; 16: 2180-2189
• 17 Singh AK, Szczech L, Tang KL. et al CHOIR Investigators. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med 2006; 355: 2085-2098
• 18 Drüeke TB, Locatelli F, Clyne N. et al. CREATE Investigators. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med 2006; 355: 2071-2084
• 19 Pfeffer MA, Burdmann EA, Chen CY. et al TREAT Investigators. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med 2009; 361: 2019-2032
• 20 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; 27 339: 584-590
• 21 Coyne DW. The health-related quality of life was not improved by targeting higher hemoglobin in the Normal Hematocrit Trial. idney Int 2012; 82: 235-241
• 22 USRDS. Im Internet: https://www.usrds.org/adr.aspx Stand. 17.05.2017
• 23 FDA. Im Internet: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm260670.htm Stand. 31.09.2011
• 24 G-BA. Im Internet: http://www.g-ba.de/downloads/39-261-1341/2011-06-23_AM-RL-IV_Erythropoese_BAnz.pdf Stand. 12.11.2011
• 25 KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease. Notice. Kidney Int Suppl. 2012; 2: 279-335
• 26 Peter WL, Guo H, Kabadi S. et al Anemia Treatment Pattern Changes in Non-Dialysis-Dependent Chronic Kidney Disease Patients before and after Revised Food and Drug Administration Label and New Anemia Guidelines for Erythropoiesis-Stimulating Agents. ASN. 2016. Chicago (USA): Abstract: FR-PO767
• 27 Chertow GM, Liu J, Monda KL. et al Epoetin Alfa and Outcomes in Dialysis amid Regulatory and Payment Reform. J Am Soc Nephrol 2016; 27: 3129-3138
• 28 Obrador GT, Macdougall IC. Effect of red cell transfusions on future kidney transplantation. Clin J Am Soc Nephrol 2013; 8: 852-860
• 29 Galle JC, Addison J, Suranyi MG. et al Outcomes in patients with chronic kidney disease not on dialysis receiving extended dosing regimens of darbepoetin alfa: long-term results of the EXTEND observational cohort study. Nephrol Dial Transplant 2016; 31: 2073-2085
• 30 Gul A, Schrader R, Miskulin D. et al Dose Requirements, Hospitalization, and Mortality Are Similar with Subcutaneous versus Intravenous Erythropoietin Administration. ASN. 2016 Chicago (USA): Abstract: SA-OR108
• 31 Raje N, Vallet S. Sotatercept, a soluble activin receptor type 2A IgG-Fc fusion protein for the treatment of anemia and bone loss. Curr Opin Mol Ther 2010; 12: 586-597
• 32 Jelkmann W. The ESA scenario gets complex: from biosimilar epoetins to activin traps. Nephrol Dial Transplant 2015; 30: 553-559
• 33 Chen YG, Wang Q, Lin SL. et al Activin signaling and its role in regulation of cell proliferation, apoptosis, and carcinogenesis. Exp Biol Med (Maywood) 2006; 231: 534-544
• 34 Sulyok S, Wankell M, Alzheimer C, Werner S. Activin: an important regulator of wound repair, fibrosis, and neuroprotection. Mol Cell Endocrinol 2004; 15 225: 127-132
• 35 Hruska KA, Seifert M, Sugatani T. Pathophysiology of the chronic kidney disease-mineral bone disorder. Curr Opin Nephrol Hypertens 2015; 24: 303-309
• 36 Ruckle J, Jacobs M, Kramer W, Pearsall AE, Kumar R, Underwood KW, Seehra J, Yang Y, Condon CH, Sherman ML. Single-dose, randomized, double-blind, placebo-controlled study of ACE-011 (ActRIIA-IgG1) in postmenopausal women. J Bone Miner Res 2009; 24: 744-752
• 37 Iancu-Rubin C, Mosoyan G, Wang J. et al Stromal cell-mediated-inhibition of erythropoiesis can be attenuated by Sotatercept (ACE-011), an activin receptor type II ligand trap. Exp Hematol 2013; 41: 155-166
• 38 Finberg KE, Whittlesey RL, Fleming MD, Andrews NC. Down-regulation of Bmp/Smad signaling by Tmprss6 is required for maintenance of systemic iron homeostasis. Blood 2010; 115: 3817-3826
• 39 Clinical Trials. https://www.clinicaltrials.gov/ct2/show/NCT01999582 Stand: 08.02.2017
• 40 Leonhard WN, Kunnen SJ, Plugge AJ. et al Inhibition of Activin Signaling Slows Progression of Polycystic Kidney Disease. J Am Soc Nephrol 2016; 27: 3589-3599
• 41 Prchal JT. Delivery on demand--a new era of gene therapy?. N Engl J Med 2003; 348: 1282-1283
• 42 Holdstock L, Meadowcroft AM, Maier R. et al Four-Week Studies of Oral Hypoxia-Inducible Factor-Prolyl Hydroxylase Inhibitor GSK1278863 for Treatment of Anemia. J Am Soc Nephrol 2016; 27: 1234-1244
• 43 Maxwell PH, Eckardt KU. HIF prolyl hydroxylase inhibitors for the treatment of renal anaemia and beyond. Nat Rev Nephrol 2016; 12: 157-168
• 44 Haase VH, Spinowitz BS, Pergola PE. et al Efficacy and Dose Requirements of Vadadustat Are Independent of Systemic Inflammation and prior Erythropoiesis-Stimulating Agent (ESA) Dose in Patients with Non-Dialysis Dependent Chronic Kidney Disease (NDD-CKD). ASN. 2016. Chicago (USA): Poster Abstract: TH-PO907
• 45 Provenzano R, Besarab A, Wright S. et al Roxadustat (FG-4592) Versus Epoetin Alfa for Anemia in Patients Receiving Maintenance Hemodialysis: A Phase 2, Randomized, 6- to 19-Week, Open-Label, Active-Comparator, Dose-Ranging, Safety and Exploratory Efficacy Study. Am J Kidney Dis 2016; 67: 912-924
• 46 Soni H. Prolyl hydroxylase domain-2 (PHD2) inhibition may be a better therapeutic strategy in renal anemia. Med Hypotheses 2014; 82: 547-550
• 47 Ashby DR, Gale DP, Busbridge M. et al Erythropoietin administration in humans causes a marked and prolonged reduction in circulating hepcidin. Haematologica 2010; 95: 505-508
• 48 Holdstock L, Cizman B, Meadowcroft AM. et al Daprodustat, a HIF-Prolyl-Hydroxylase Inhibitor, Increases and Maintains Hemoglobin over 24 Weeks in Anemic Chronic Kidney Disease Subjects. ASN. 2016. Chicago (USA): Abstract: TH-PO908
• 49 Cobitz AR, Meadowcroft AM, Cizman B. et al Daprodustat, a HIF-Prolyl-Hydroxylase Inhibitor, Maintains Hemoglobin Levels over 24 Weeks in Anemic Hemodialysis Subjects Switching from Recombinant Human Erythropoietin. ASN. 2016. Chicago (USA): Abstract: SA-OR114
• 50 Mokas S, Larivière R, Lamalice L. et al Hypoxia-inducible factor-1 plays a role in phosphate-induced vascular smooth muscle cell calcification. Kidney Int 2016; 90: 598-609
• 51 Szczech L, Hemmerich S, Besarab A. et al Anemia Correction with Roxadustat Improves Health Related Quality of Life (HRQOL) in Chronic Kidney Disease (CKD) Patients. ASN. 2015. San Diego (USA): TH-OR039
• 52 Chen RL, Ogunshola OO, Yeoh KK. et al HIF prolyl hydroxylase inhibition prior to transient focal cerebral ischaemia is neuroprotective in mice. J Neurochem 2014; 131: 177-189
• 53 Clinical Trials. Im Internet: https://clinicaltrials.gov/ct2/show/NCT02879305 Stand: 27.01.2017
• 54 Ratcliffe PJ. Oxygen sensing and hypoxia signalling pathways in animals: the implications of physiology for cancer. J Physiol 2013; 591: 2027-2042
• 55 Macdougall IC, Sousa A, Ryzlewicz T. et al Improving Anemia Therapy in Hemodialysis Patients. ASN. 2016. Chicago (USA): Abstract: SA-PO999