Erythropoietin resistant anemia R 4 Introduction Anemia Men

Erythropoietin resistant anemia R 4 김효식

Introduction • Anemia – Men : Hb < 13. 0 g/dl – Women : Hb < 12. 0 g/dl • Nearly 90% of patients with a glomerular filtration rate (GFR) of less than 25– 30 ml/min have anemia Reduces quality of life and contributes to symptoms of advanced renal failure • Epoetin 50~100 IU/kg three times weekly • Darbepoetin alfa 0. 45 mcg/kg once weekly

Definition • 1. Significant decrease in Hb level at a constant ESA dose • 2. Significant increase in the ESA dose requirement to preserve a certain Hb level • 3. Failure to raise the Hb level to greater than 11 g/dl despite an ESA dose equivalent to erythropoietin greater than 500 IU/kg/week • Erythropoietin resistance index(ERI) : r. Hu EPO/kg/week divided by Hb level in g • ERI value > 0. 02 g/kg/week/g Hb Resistance to ESA

Etiology

Etiology

Etiology

Management

Management • Dialysis Strategies – High-flux dialysis • Controversial – Ultrapure dialysate( bacterial count<100 CFU/m. L, maximum endotoxin concentration<0. 03 EU/m. L) • Molina et al. 107 HD patients were evaluated for 12 months Use of ultrapure dialysate significantly decreases the ESA resistance index, while Hb levels remained within the established margins with a 34% reduction in the weekly dose of darbepoetin – Hemodiafiltration (HDF) with on-line endogenous reinfusion • Ballabeni et al. HDF for 6 months, an increase in hematocrit and reduction in ESA dosage was observed

Management • Ascorbic Acid (Vitamin C) Parenteral vitamin C improves the release of iron from iron storage deposits, and promotes an enhancement of soluble transferrin receptors and TSAT – A recent review suggested that HD patients with poor response to EPO can be initiated on a 2 - to 6 -month trial of 100 mg i. v. vitamin C administration at the end of the HD session three times a week titrated up to a dose of 300 or 500 mg i. v. three times a week for another 2– 6 months – • Vitamin E • L –Carnitine – Vitamin E has reduced CRP and monocyte IL-6 levels – Cruz et al. 12 months on VECMs(vitamin E-coated membranes), a significant increase in Hb levels and a decrease in r. Hu. EPO dosage were seen – Patients who have been on dialysis therapy for at least 3 months, have a plasma free carnitine level less than 40 umol/L, and have erythropoietinresistant anemia

Management • Statins – Antiproliferative, anticoagulant, immuno suppressive, anti-inflammatory, antioxidant, and cytoprotective effects – Sirken et al. the statin group, EPO requirements were decreased by 25% – There is clearly a need for randomized control trials to precisely define the utility of statins in ESA resistance. • Oxpentifylline – Oxpentifylline (pentoxifylline) has important anti-inflammatory properties (via inhibition of phosphodiesterase) that are anti-apoptotic, anti-oxidant, anti-TNF and anti-IFN actions • • Cooper et al. oral oxpentifylline (400 mg daily) for 4 months to 16 ESRD patients with EPO-resistant anemia 12 patients who completed the study, mean Hb concentration increased from 95 8 9 to 117 8 10 g/l (p = 0. 0001) Johnson et al. multicenter study to determine whether oxpentifylline represents a safe and effective strategy for treating erythropoiesis stimulating agent resistance in CKD Not yet been completed

Management • New Therapeutic Options – Growth arrest specific gene 6 (Gas 6) product • Murine erythroblasts released Gas 6 in response to erythropoietin and Gas 6 enhanced EPO receptor signaling – Juzen-taiho-to (TJ-48) • Japanese Herbal extracts 12 weeks of 7. 5 g/day treatment is effective – Growth hormone (GH), Insulin-like growth factor-1 (IGF-1) • Potent stimulants of erythroid progenitors, and both hormones stimulate the release of erythropoietin • Zinc supplementation

Case • • Patient ID : 001438704 Sex/Age : M/69 • Chief Complaint : Dyspnea onset : 20 day • Past Hx. – 1995년 DM: Lantus 18 IU – 2005년 HTN: Losartan 50 mg, Nifedipine 33 mg DM Nephropathy Duodenal ulcer, H. pylori, Small bowel ulcer – 2010년 Gout – 2011년8월 PD catheter insertion – 2011년9월 CAPD 시작: Pyridoxime, Sevelarmer – 2012년10월 CAPD peritonitis 로 입원치료 – 2013년7월 Anemia로 입원치료 – 2014년 Bursitis, Hip: Sekaron(Afloqualone), Ultracet

• Anemia study – – – – PB morphology : Normocytic normochromic Iron profile : Iron 50 UIBC 157 TIBC 207 Ferritin 2369. 91 Haptoglobin : 251 Erythropoietin : 42. 0 Vitamin B 12 : 2000 이상 Bone marrow, biopsy: Normocellular marrow (about 30% cellularity) with polymorphous cellular populations, and adequate megakaryocytes. No reticulin myelofibrosis. Intact-PTH : 232. 73 • 2014/7/16 GFS : ultra short barrett esophagus, Intestinal metaplasia, Duodenal polypoid lesion • 2014/7/16 CFS : Colon polyp, TC 1, s/p CPP, Hemorrhoids with hypertrophic anal papilla, No evidence of bleeding focus or stigma

Date 15/03/09 15/02/02 14/12/29 14/11/27 14/10/23 14/09/18 14/08/21 14/07/24 14/07/14 14/06/05 Hg 6. 3 7. 6 8. 5 8. 3 10. 8 11. 4 10. 4 6. 6 11. 0 EPO NESP 120 mcg Mircera 200 mcg Mircera 50 mcg Mircera 120 mcg Mircera 200 mcg 2 pint(3/13 ) BUN/Cr 75. 4/13. 71 CRP 7. 22 2 pint(7/15) 96. 6/13. 09 105. 6/12. 7 9 89. 7/11. 71 56. 7/13. 13 67. 7/13. 30 57. 0/11. 89 57. 4/13. 24 67. 8/13. 13 0. 3 72. 0/15. 22

Reference • 1. Erythropoiesis Stimulatory Agent-Resistant Anemia in Dialysis Patients: Review of Causes and Management • 2. Soluble Erythropoietin Receptor Contributes to Erythropoietin Resistance in End-Stage Renal Disease • 3. Erythropoietin resistance: the role of inflammation and proinflammatory cytokines • 4. Carbamylation of Serum Albumin and Erythropoietin Resistance in End Stage Kidney Disease • 5. KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease