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Anemia and CKD An Update Anemia and CKD An Update.

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Presentation on theme: "Anemia and CKD An Update Anemia and CKD An Update."— Presentation transcript:

1 Anemia and CKD An Update 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 StageDescription GFR (ml/min/1.73 m 2 ) 1 Kidney Damage with Normal or  GFR >90 2 Kidney Damage with Mild  GFR 60-89 3 Moderate  GFR 30-59 4 Severe  GFR 15-29 5Kidney Failure <15 or Dialysis

4 *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. Percentage of Patients With Anemia (%) CKD=chronic kidney disease; Hct=hematocrit. N=1658 Anemia Is a Common Complication of CKD Anemia often develops early in the course of CKD and worsens as CKD progresses.

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 More reticulocytes enter circulating blood Larger number of red blood cells (RBC) in circulation Increased oxygen delivery to tissues Return to homeostasis when response brings oxygen delivery to kidneys back to normal EPO Peritubular interstitial cells secrete erythropoietin (EPO) into the blood

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

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


9 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





14 Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT)





19 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. ESAs=erythropoietin-stimulating agents; Hb=hemoglobin Benefits of Treatment With ESAs Treatment with ESAs to achieve partial correction of Hb levels is associated with –Improved quality of life 1 –Reduced risk for mortality 2 –Reduced risk of hospitalization 3



22 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 reticulocytes 1-4 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 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. * Not available in the US.. Epoetin

23 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. 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

24 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.

25 1.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. AgentRecommended DoseClinical Practice Dose Epoetin50-100 units/kg administered either IV or SC, 3 times per week 1,2 In the PROMPT study: 10,000 units (U) administered SC once weekly (QW), 20,000 U every two weeks (Q2W), 30,000 U every three weeks (Q3W) or 40,000 U every four weeks (Q4W) 3 Darbepoetin alpha 0.45  g/kg, administered as a single IV or SC injection once weekly 5 0.75  g/kg administered once every 2 weeks 6 [Dose] administered SC once every 4 weeks 7 C.E.R.A. 0.6  g/kg administered as a single IV or SC injection once every 2 weeks 8 IV=intravenous; SC=subcutaneous. How to Initiate ESA Therapy







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

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

34 Adapted from Macdougall IC, et al. Kidney Int. 1996;50:1694-1699. Week Hb (g/dL) * * * † † † *P <0.05 vs IV iron. † P <0.005 vs IV iron. All 37 patients entered the study iron replete with Hb <8.5 g/dL. 6 8 10 12 14 0481216 IV Iron Oral Iron No Iron ESA=erythropoietin-stimulating agent; Hb=hemoglobin; IV=intravenous. Importance of Iron Sufficiency During ESA Initiation

35 National Kidney Foundation. Am J Kidney Dis. 2006;47(suppl 3):S1-S146. KDOQI=Kidney Disease Outcomes Quality Initiative; ESAs=erythropoietin- stimulating agents; HD=hemodialysis; TSAT=transferrin saturation. 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

36 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

37 Sorry to confuse you? Sorry to confuse you?

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