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Anemia and CKD An Update

Anemia and CKD An Update. Prevalence of ESRD has been rising steadily. USRDS ADR, 2008. National Kidney Foundation – Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI) Stages of Chronic Kidney Disease. Anemia Is a Common Complication of CKD.

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Anemia and CKD An Update

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  1. Anemia and CKD An Update

  2. Prevalence of ESRD has been rising steadily USRDS ADR, 2008

  3. National Kidney Foundation – Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI)Stages of Chronic Kidney Disease

  4. Anemia Is a Common Complication of CKD • Anemia often develops early in the course of CKD and worsens as CKD progresses. Percentage of Patients With Anemia (%) N=1658 CKD=chronic kidney disease; Hct=hematocrit. *Anemia defined as at least two Hct values below the gender-specific norm (Hct value <42% for males; Hct value <36% for females) that were at least 30 days apart. Kausz AT, et al. Dis Manage Health Outcomes. 2002;10:505-513.

  5. The Physiological Role of Erythropoietin Decrease in oxygen delivery to the kidneys Peritubular interstitial cells detect low oxygen levels in the blood Pro-erythroblasts in red bone marrow mature more quickly into reticulocytes Peritubular interstitial cells secrete erythropoietin (EPO) into the blood EPO More reticulocytes enter circulating blood Increased oxygen delivery to tissues Return to homeostasis when response brings oxygen delivery to kidneys back to normal Larger number of red blood cells (RBC) in circulation

  6. Major Stages of Erythropoiesis Hematopoietic Stem Cell BFU-E Bone Marrow Erythropoietin Dependent CFU-E Erythroblasts Iron Dependent Reticulocytes Circulation Erythrocytes (RBCs) (Time to maturity = 12 days) Adapted from Bron D, et al. Semin Oncol. 2001;28:1-6.

  7. Retrospective analysis of pre-dialysis patients with CKD Untreated Anemia Is Associated With Increased Hospitalizations Anemia Associated With Decreased Number of Hospital-Free Months Median Number of Hospital-Free Months 25 N=362 21.5 20 P=0.0593 15 13.3 10 5 0 Hb ≤9.5 g/dL Hb >9.5 g/dL CKD=chronic kidney disease; Hb=hemoglobin. Holland DC, et al. Nephrol Dial Transplant. 2000;15:650-658.

  8. What is the optimal Hb target range of CKD patients? • –Rationale for observational trials • –Rationale for randomized controlled trials • –International guidelines and the updated EU-label of ESAs • –Challenges in controlling Hbtarget levels in CKD patients

  9. Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT)

  10. Benefits of Treatment With ESAs • Treatment with ESAs to achieve partial correction of Hb levels is associated with • Improved quality of life1 • Reduced risk for mortality2 • Reduced risk of hospitalization3 ESAs=erythropoietin-stimulating agents; Hb=hemoglobin 1. Eschbach JW, et al. Ann Intern Med. 1989;111:992-1000. 2. Collins AJ, et al. Semin Nephrol. 2000;20:345-349.3. Collins AJ, et al. J Am Soc Nephrol. 2001;12:2465–2473.

  11. Epoetin • Recombinant human erythropoietin; rHuEPO • Forms: epoetin alfa, epoetin beta, epoetin delta*, epoetin omega* • Acts by stimulating the proliferation, survival, and differentiation of erythroid progenitors into reticulocytes1-4 • Approved for either intravenous (IV) or subcutaneous (SC) administration 2 to 3 times per week (often given less frequently in clinical practice)5 • Frequency of administration dictated partly by the short biologic half-life (~6–8 hours following a single IV injection)1-4 * Not available in the US.. 1. Egrie JC, et al. Immunobiology. 1986;172:213-224; 2. Graber SE, et al. Ann Rev Med. 1978;29:51-66; 3. Eschbach JW, et al. N Eng J Med. 1987;316:73-78; 4. Eschbach JW, et al. Ann Intern Med. 1989;111:992-1000.; 5. Papatheofanis FJ, et al. Curr Med Res Opin. 2006;22:837-842.

  12. Darbepoetin alfa • 2 more carbohydrate chains and up to 8 more sialic acid residues than epoetin • This extends the half-life by at least three fold and allows for decreased frequency of administration Egrie JC, et al. Nephrol Dial Transplant. 2001;16 Suppl 3:3-13.Macdougall IC, et al. J Am Soc Nephrol. 1999;10:2392–2395.

  13. C.E.R.A • CERA administered every 3 to 4 weeks is safe and effective for the treatment of anemia associated with CKD • CERA's long duration of action is attributed to the addition of a large polymer chain into the erythropoietin molecule. • The elimination half-life of CERA is approximately 130 hours.

  14. How to Initiate ESA Therapy IV=intravenous; SC=subcutaneous. • Epogen (epoetin alfa) prescribing information, Amgen, Inc, Thousand Oaks, Calif.; 2. Procrit (epoetin alfa) prescribing information, Ortho Biotech Products, L.P., Raritan, New Jersey. 3. Provenzano R, et al. Clin Nephrol. 2005;64:113-123; 4. Provenzano R, et al. Clin Nephrol. 2004;61:392-405. 5. Aranesp (darbopoetin alfa) prescribing information, Amgen, Inc., Thousand Oaks, Calif. 6.Suryani MG, et al. Am J Kidney Dis. 2003;23:106-111; 7. Ling B, et al. Clin Nephrol. 2005;63:327-334. 8.

  15. normocytic anemia Is there increased red cell production? check reticulocyte count increased normal or decreased Is there evidence of: - renal failure anemia of renal failure - endocrine failure anemia of endocrine failure - chronic inflammation anemia of chronic disease Is there evidence of hemolysis? yes no consider bone marrow failure hemolytic anemia recent bleed bone marrow investigation Approach to normocytic anemia

  16. consequences target tissue macrophages retention of iron in macrophages erythropoietin production kidney bone marrow response to erythropoietin Iron Deficiency in CKDPathophysiology of anemia of chronic disease chronic infection, autoimmune disease, malignancy, etc Inflammatory stimulus T-cell & monocyte activation interferon- TNF- IL-1, IL-6, IL-10 Cytokines

  17. Importance of Iron Sufficiency During ESA Initiation 14 12 IV Iron † Oral Iron Hb (g/dL) 10 * No Iron * † † 8 * 6 0 4 8 12 16 Week All 37 patients entered the study iron replete with Hb <8.5 g/d L. <0.05 vs IV iron. *P † <0.005 vs IV iron. P ESA=erythropoietin-stimulating agent; Hb=hemoglobin; IV=intravenous. Adapted from Macdougall IC, et al. Kidney Int. 1996;50:1694-1699.

  18. Avoiding Iron Deficiency • 2006 KDOQI guidelines recommend the following goals of iron therapy during administration of ESAs • For HD patients: • TSAT >20% AND • Serum ferritin concentration >200 ng/mL • For non-HD patients: • TSAT >20% AND • Serum ferritin concentration >100 ng/mL KDOQI=Kidney Disease Outcomes Quality Initiative; ESAs=erythropoietin-stimulating agents; HD=hemodialysis;TSAT=transferrin saturation. National Kidney Foundation. Am J Kidney Dis. 2006;47(suppl 3):S1-S146.

  19. Anemia Summary • Anemia is a common and early complication of CKD • Anemia is associated with an increased risk of morbidity and mortality • Clinical use of ESAs for treatment of anemia requires vigilance regarding Hgb level, complications such as hypertension and resistance to response such as iron deficiency • Increasing Hgb to >12 g/dL in patients with CKD is not recommended

  20. Sorry to confuse you?

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