Anemia and CKD An Update

Prevalence of ESRD has been rising steadily USRDS ADR, 2008

Kidney Damage with Normal or  GFR Kidney Damage with Mild  GFR National Kidney Foundation – Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI) Stages of Chronic Kidney Disease Stage Description GFR (ml/min/1.73 m2) 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 5 Kidney Failure <15 or Dialysis

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 Anemia Is a Common Complication of CKD Kausz and colleagues published results of a study in 2002, which demonstrates that, as the level of serum creatinine increases, the prevalence of CKD patients defined as anemic increases. In this study, anemia was 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. The results of this study show that anemia often develops early in the course of CKD and worsens as CKD progresses. . Reference Kausz AT, Steinberg EP, Nissenson AR, et al. Prevalence and management of anemia among patients with chronic kidney disease in a health maintenance organization. Dis Manage Health Outcomes. 2002;10:505-513. 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.

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

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.

Untreated Anemia Is Associated With Increased Hospitalizations Anemia Associated With Decreased Number of Hospital-Free Months Median Number of Hospital-Free Months Retrospective analysis of pre-dialysis patients with CKD 25 N=362 21.5 20 P=0.0593 15 13.3 10 Untreated Anemia Is Associated With Increased Hospitalizations In a retrospective analysis of 362 patients with CKD (who were not treated with erythropoietin-stimulating agents), the presence of anemia was independently associated with an increased likelihood of hospitalization. Patients with anemia were hospital free for a median of 13.3 months, compared with a median of 21.5 months for patients with higher Hb levels (P=0.0593). Reference Holland DC, Lam M. Predictors of hospitalization and death among pre-dialysis patients: a retrospective cohort study. Nephrol Dial Transplant. 2000;15:650-658. 5 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.

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

Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT)

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 Benefits of Treatment With Erythropoiesis-Stimulating Agents (ESAs) Treatment with ESAs to achieve partial correction of Hb levels is associated with improved quality of life,1 reduced risk for mortality,2 and reduced risk of hospitalization.3 References 1. Eschbach JW, Abdulhadi MH, Browne JK, et al. Recombinant human erythropoietin in anemic patients with end-stage renal disease. Results of a phase III multicenter clinical trial. Ann Intern Med. 1989;111:992-1000. 2. Collins AJ, Ma JZ, Ebben J. Impact of hematocrit on morbidity and mortality. Semin Nephrol. 2000;20:345-349. 3. 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. 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.

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 Epoetin The first therapeutic agent to be used for the stimulation of erythropoiesis was recombinant human erythropoietin (Epoetin). Recombinant human erythropoietin acts by stimulating the proliferation, survival, and differentiation of erythroid progenitors so that they will survive and enter the circulation as reticulocytes.1-4 Epoetins are approved for either intravenous or subcutaneous administration 2 to 3 times per week; however, in clinical practice they are often given less frequently.5 The frequency of administration is dictated partly by the short biologic half-life of these drugs.1-4 References 1. Egrie JC, Strickland TW, Lane J, et al. Characterization and biological effects of recombinant human erythropoietin. Immunobiology. 1986;172:213-224. 2. Graber SE, Krantz SB. Erythropoietin and the Control of Red Cell Production. Ann Rev Med. 1978;29:51-66. 3. Eschbach JW, Egrie JC, Downing MR, et al. Correction of the Anemia of End-Stage Renal Disease with Recombinant Human Erythropoietin. NEJM. 1987;316:73-78. 4. Eschbach JW, Abdulhadi MH, Browne JK, et al. Recombinant Human Erythropoietin in Anemic Patients with End-Stage Renal Disease. Ann Intern Med. 1989;111:992-1000. 5. Papatheofanis FJ, McKenzie RS, Mody SH, et al. Dosing patterns, hematologic outcomes, and costs of erythropoietic agents in predialysis chronic kidney disease patients with anemia. Curr Med Res Opin. 2006;22:837-842. * 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.

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 Darbepoetin alfa At the turn of this century, darbepoetin alfa became available. Darbepoetin alfa contains two additional N-linked carbohydrate chains and up to 8 more sialic acid residues than epoetin. These modifications extend the half life of the drug by at least three fold and may allow for a decreased frequency of administration. Reference Egrie JC, Browne JK. Development and characterization of novel erythropoiesis stimulating protein (NESP). Nephrol Dial Transplant. 2001;16 Suppl 3:3-13. Macdougall IC, Gray SJ, Elston O, et al. Pharmacokinetics of novel erythropoiesis stimulating protein compared with epoetin alfa in dialysis patients. J Am Soc Nephrol. 1999;10:2392–2395. 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.

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.

How to Initiate ESA Therapy Agent Recommended Dose Clinical Practice Dose Epoetin 50-100 units/kg administered either IV or SC, 3 times per week1,2 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 weekly5 0.75 g/kg administered once every 2 weeks6 [Dose] administered SC once every 4 weeks7 C.E.R.A. 0.6 g/kg administered as a single IV or SC injection once every 2 weeks8   How to Initiate ESA Therapy According to the prescribing information, Epoetin should be initiated at 50-100 units/kg administered either IV or SC, 3 times per week.1,2 In clinical practice, however, . . . According to the prescribing information, darbepoetin alfa should be initiated at 0.45 g/kg, administered as a single IV or SC injection once weekly.5 In clinical practice, however, . . . According to the prescribing information, C.E.R.A. should be initiated at 0.6 g/kg administered as a single IV or SC injection once every 2 weeks8 References Epogen (epoetin alfa) prescribing information, Amgen, Inc, Thousand Oaks, Calif. Procrit (epoetin alfa) prescribing information, Ortho Biotech Products, L.P., Raritan, New Jersey. Provenzano R, Bhaduri S, Singh AK, PROMPT Study Group. Extended epoetin alfa dosing as maintenance treatment for the anemia of chronic kidney disease: the PROMPT study. Clin Nephrol. 2005;64:113-123. Provenzano R, Garcia-Mayol L, Suchinda P, et al. Once-weekly epoetin alfa for treating the anemia of chronic kidney disease. Clin Nephrol. 2004;61:392-405. Aranesp (darbopoetin alfa) prescribing information, Amgen, Inc., Thousand Oaks, Calif. Suryani MG, et al. Am J Kidney Dis. 2003;23:106-111 Ling B, Walczyk M, Agarwal A, Carroll W, Liu W, Brenner R. Darbapoetin alfa administered once monthly maintains hemoglobin concentrations in patients with chronic kidney disease. Clin Nephrol. 2005; 63:327-334. 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.

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

Iron Deficiency in CKD Pathophysiology 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 target tissue macrophages kidney bone marrow retention of iron in macrophages erythropoietin production response to erythropoietin consequences

Importance of Iron Sufficiency During ESA Initiation 14 12 IV Iron † Oral Iron Hb (g/dL) 10 * * No Iron † 8 † * 6 Importance of Iron Sufficiency During ESA Initiation The importance of maintaining sufficient iron stores during the initiation of ESA therapy is made clear by the study by McDougall and colleagues that was published in 1996. Results from this study showed that, over 16 weeks of treatment, patients who received intravenous iron had an increase in hemoglobin levels from approximately 7 g/dL to 12 g/dL. In patients treated with either no iron or with oral iron therapy, a substantial decrease in the effectiveness of ESA treatment was seen, which was related to the development of iron deficiency in a large number of patients. Reference Macdougall IC, Tucker B, Thompson J, et al. A randomized controlled study of iron supplementation in patients treated with erythropoietin. Kidney Int. 1996;50:1694-1699. 4 8 12 16 Week All 37 patients entered the study iron replete with Hb <8.5 g/d L. *P <0.05 vs IV iron. † P <0.005 vs IV iron. ESA=erythropoietin-stimulating agent; Hb=hemoglobin; IV=intravenous. Adapted from Macdougall IC, et al. Kidney Int. 1996;50:1694-1699.

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: Serum ferritin concentration >100 ng/mL Avoiding Iron Deficiency The 2006 KDOQI guidelines recommend specific targets (goals) of iron therapy during administration of ESAs. For hemodialysis (HD) patients, the guidelines recommend iron be administered if transferrin saturation (TSAT) is higher than 20% AND if the serum ferritin concentration higher than 200 ng/mL. For non-HD patients, the guidelines recommend iron be administered if TSAT is higher than 20% AND serum ferritin concentration is higher than 100 ng/mL. Reference National Kidney Foundation. KDOQI clinical practice guidelines and clinical practice recommendations for anemia in chronic kidney disease. 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. National Kidney Foundation. Am J Kidney Dis. 2006;47(suppl 3):S1-S146.

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

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