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Anemia Guidelines

Anemia Guidelines. Şehsuvar Ertürk, MD, FASN Ankara University School of Medicine. Across seacoast is motherland I shout from Do you hear me ? Memet , Memet! Nazım Hikmet. Goals of the lecture. To know impact of anemia on clinical outcomes in patients with chronic kidney disease.

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Anemia Guidelines

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  1. Anemia Guidelines Şehsuvar Ertürk, MD, FASN Ankara University School of Medicine

  2. Across seacoast is motherland I shout from Do you hear me? Memet, Memet! Nazım Hikmet

  3. Goals of the lecture • To know impact of anemia on clinical outcomes in patients with chronic kidney disease. • To approach management of anemia of chronic kidney disease in terms of evidence-based medicine.

  4. Plan • Background Epidemiological aspects Pathophysiology Consequences of anemia management • Guidelines/recommendations • Current practice patterns

  5. Bright-1830s “Anemia is a characteristic manifestation of chronic kidney disease”

  6. Prevalence of anemia in CKD Levin A. Kidney Int 61 (Suppl 80):S35-S38, 2002.

  7. Etiology of anemia • Bone marrow depression Relative EPO deficiency/resistance to EPO Inflammatory cytokines Apopitosis / decreased eryhtroid progenitors • Reduced availability of iron Malnutrition Decreased absorption GIS losses (ASA, NSAID) Iatrogenic (repeated blood testing) • Hemodilution (water and sodium retention) Rao M and Pereira BJG. Kidney Int 68:1432-38, 2005 Lewis BS, et al. Nephrol Dial Transplant 20(Suppl 7):vii3-6, 2005

  8. Hemodynamic (Increased Cardiac Output) Systemic arterial dilatation Decreased TPR Reduced afterload Increased stroke volume Decreased blood viscosity Increased venous return Increased preload Symphatetic activation Increased heart rate Non-hemodynamic (Increased O2 extraction) Increased EPO production (?) Increased 2,3-DPG Pathophysiology of anemia Pereira AA and Sarnak MJ. Kidney Int 64(Suppl 87):S32-S39, 2003 Silverberg D. Nephrol Dial Transplant 18(Suppl 2):ii7-12, 2003 Levin A. Kidney Int 61(Suppl 80):S35-S38, 2002

  9. Consequences of anemia Depression Angina LVH Cardiac failure Myopathy Renal disease progression Morbidity Mortality Exercise capacity Coagulation Immune response Cognitive function Sexual function Appetite/Nutrition Growth (in children) Quality of life Gomez JML and Carrera F. Kidney Int 61 (Suppl 80):S39-S43, 2002

  10. Impact of anemia on outcomes General population >1 Million Medicare subjects, Age>67y 1-y mortality Anemia 8% CKD 8% CHF 13% None 4% All 23% Herzog CA, et al. J Card Fail 10:467-72, 2004

  11. Anemia and clinical outcomes CKD (pre-dialysis) • Increased risk for Mortality CVD (LVH, LVD, CHF) Progression of kidney disease

  12. Anemia and clinical outcomes CKD (pre-dialysis) • 246 patients, 12 months follow-up, >20% increase in LVMI OR Hb 0.5 g/dL 1.32 • 853 male patients, Mortality and ESRD Hb<12 g/dL 1.97 Hb<11 g/dL 2.57 Levin A, et al. Am J Kidney Dis 27:347-54, 1996 Kovesdy CP, et al. Kidney Int 69:560-64, 2006

  13. Anemia and clinical outcomes CKD (pre-dialysis) (RENAAL Study) Shahinfar S, et al. Kidney Int 67(Suppl 93):S48-S51, 2005

  14. Anemia and clinical outcomes ESRD Mortality • 432 patients Hb 1 g/dL 14% Foley RN, et al. Am J Kidney Dis 28:53-61, 1996. • 93.087 patients Hb (g/dL) <10 64% Hb (g/dL)12-13 21% Roberts TL, et al. Nephrol Dial Transplant 21:1652-62, 2006.

  15. Anemia and clinical outcomes ESRD 12.733 patients Mortality HR (95% CI) • Whites Hb (g/dL) <10 1.32 (1.16-1.48) • AAs Hb (g/dL) <10 1.50 (1.27-1.76) 10-<11 1.60 (1.37-1.84) Servilla KS, et al. Am J Kidney Dis 54:498-510, 2009.

  16. Anemia and clinical outcomes ESRD • Longer time to target Hb levels HR (95% CI) Hospitalization 1.15 (1.12–1.19) Mortality 1.26 (1.20–1.33) Ishani A, et al. Nephrol Dial Transplant 22:2247-55, 2007. • More months below target Hb levels RR (95% CI) Hospitalization 1.70 (1.63–1.76) Mortality 2.48 (2.28–2.69) Ishani A, et al. Nephrol Dial Transplant 23:1682-89, 2008.

  17. Economic issues Cost difference between anemic and non-anemic patients: CHF 29.511 USD / patient / year CKD 20.529 Cancer 18.418 Ershler WB, et al. Value Health 8:629-38, 2005

  18. Benefits Improved quality of life (QOL) Decrease in LVMI Slowing the progression Decrease in hospitalizations Improved survival Risks Hypertension Thrombosis Increase in mortality Potential benefits/risks of treatment of anemia with ESAs and iron ? ?

  19. Effect of treatmentCKD-predialysis (RCTs) • Increased exercise capacity, QOL Teehan BP, et al. Am J Kidney Dis 18:50-9, 1991. Revicki DA, et al. Am J Kidney Dis 25:548-54, 1995. Ritz E, et al. Am J Kidney Dis 49:194-207, 2007.

  20. Effect of treatmentCKD-predialysis (RCTs) • Decrease in LVMI 101 patients, Hb 11.3 vs. 9.1g/dL Ayus JC, et al. Kidney Int 68:788-95, 2005. • No effect on LVMI 155 patients, Hb 12.1 vs. 10.8 g/dL Roger SD, et al. JASN 15:148-56, 2004. • No effect on LVMI, prevention of new LVH 172 patients, DM Type 1 and 2, Hb 13.5 vs.12.1 g/dL Ritz E, et al. AJKD 49:194-207, 2007.

  21. Effect of treatmentCKD-predialysis (Recent RCTs) CHOIR (Correction of Hemoglobin and Outcomes in Renal Insufficiency) CREATE (Cardiovascular Risk Reduction by Early Anemia Treatment with Epo beta) TREAT(Trial to Reduce Cardiovascular Events with Aranesp Therapy) No cardiovascular or renal benefits or even detrimental outcomes of higher targets. Singh AK, et al. N Engl J Med 355:2085-98, 2006. Drüeke TB, et al. N Engl J Med 355:2071-84, 2006. Pfeffer MA, et al. N Engl J Med 2009 (doi: 10.1056/NEJMoa0907845)

  22. Effect of treatmentESRD-dialysis (RCTs) • Increase in mortality (1.236 pts., Hb 14 vs. 10 g/dL) Besarab A, et al. N Engl J Med 339, 584-90, 1998. • No effect on LVMI, prevention of new LVD (146 pts., Hb 13 vs. 10 g/dL) Foley RN, et al. Kidney Int 58:1325-35, 2000. • No effect on LVMI, improvement in QOL (596 pts., Hb 13.3 vs. 10.9 g/dL) Parfrey PS, et al. J Am Soc Nephrol 16:2180-89, 2005.

  23. Effect of treatment(CKD-predialysis+dialysis) (Metaanalysis) A:Study cohorts with severe anemia at baseline and lower target Hb. B:Study cohorts with moderate anemia at baseline and lower target Hb. Parfrey PS, et al. CJASN 4:755-62, 2009.

  24. High Hb vs. ESA dose Goodkin DA. Semin Dial 22:495-502, 2009.

  25. High Hb vs. ESA dose Regidor DL, et al. JASN 17:1181-91, 2006.

  26. High Hb vs. ESA dose Mortality HR (95% CI) Whites EPO dose (UI/wk) <4,500 0.82 (0.72-0.93) AAs EPO dose (UI/wk) >20,000 1.32 (1.12-1.53) Servilla KS, et al. Am J Kidney Dis 54:498-510, 2009.

  27. High Hb vs. ESA dose Szczech LA, et al. Kidney Int 74:791–98, 2008.

  28. Ağaoğlu Ö. Train, Yenice, 2001

  29. Clinical Practice Guidelines/Recommendations ERBP ERBP EBPG KDOQI Diagnosis/Evaluation/Target Hb/Using ESAs-Iron-Adjuvants/Resistance

  30. Diagnosis of anemia • Hb levels should be measured at least annually in all patients with CKD (regardless of stage or cause). • Diagnosis of anemia should be made if Hb concentrations <13.5 g/dL in adult males. <12.0 g/dL in adult females.

  31. Evaluation of anemia • Hb concentration, white blood cell count and platelet count • Red blood cell indices mean corpuscular volume [MCV] mean corpuscular hemoglobin [MCH] mean corpuscular hemoglobin concentration [MCHC]) • Absolute reticulocyte count • Serum ferritin • Serum TSAT or Content of Hb in reticulocytes (CHr)

  32. Target Hb levels • Hb levels of 11-12 g/dL should be sought, without intentionally exceeding 13 g/dL.

  33. Using ESAs • ESAs should be given to all patients withCKD with Hb levels consistently(i.e.,measured twice at least 2 weeks apart) below 11 g/dL, whereall other causes of anemia have been excluded.

  34. Using ESAs • The initial ESA dose and ESA dose adjustments should be determined by Patient’s Hb level Target Hb level Observed rate of increase in Hb level • The frequency of Hb monitoring in patients treated with ESAs should be at least monthly.

  35. Using ESAs • The objective of initial ESA therapy is a rate of increase in Hb levels of 1-2 g/dL per month. • ESA doses should be decreased by 25%, but not necessarily held, when a downward adjustment of Hb level is needed.

  36. Using ESAs • The route and frequency of ESA administration Non–HD-CKD patients Subcutaneous HD-CKD patients Intravenous Less frequent administration, particularly in non–HD-CKD patients.

  37. Using iron agents • Iron status should be evaluated every month during initial ESA treatment and at least every 3 months during stable ESA treatment or in patients with HD-CKD not treated with an ESA. • Targets levels: TSAT >20% and Serum ferritin >200 ng/mL HD-CKD >100 ng/mL ND-CKD, PD-CKD • Upper limit of ferritin level?

  38. Using iron agents • Route of administration HD-CKD I.V. ND-CKD or PD-CKD I.V. or oral • Hypersensitivity reactions Iron dextran Resuscitative medication and personnel All forms of IV iron (iron dextran, gluconate, and sucrose) may be associated with acute adverse events.

  39. Using adjuvants to ESA • There is insufficient evidence to recommend the use ofvitamin C (ascorbate) and L-carnitine. • Androgens should not be used as an adjuvant to ESAtreatment in the management of anemia in patients with CKD.

  40. Transfusion therapy • No specific Hb concentration justifies or requires transfusion.

  41. Hyporesponse Causes of hyporesponsiveness • Definition A significant increase in the ESA dose requirement to maintain a certain Hb level or a significant decrease in Hb level at a constant ESA dose, A failure to increase the Hb level to >11 g/dL despite an ESA dose equivalent to epoetin > 500 IU/kg/wk. • Causes Persistent iron deficiency Infection/Inflammatory disease/Catheter insertion/ Hypoalbuminemia/Elevated C-reactive protein level Pancytopenia/aplastic anemia/hemolytic anemia Cancer/Chemotherapy/Radiotherapy Acquired immune deficiency syndrome

  42. Antibody-mediated PRCA • Diagnosis Sudden rapid decline in Hb level at the rate of 0.5 to 1.0 g/dL/wk, or requirement of red blood cell transfusions at the rate of approximately 1 to 2 per week; normal platelet and white blood cell counts; and absolute reticulocyte count less than 10,000/L. The definitive diagnosis is dependent upon demonstration of the presence of neutralizing antibodies against erythropoietin. • Management Discontinue the administration of any ESA product Transfusion support Treatment with immunosuppressive approaches • Retreatment with ESAs can be considered if anti-EPO antibodies are not detectable.

  43. Music therapy Sultan Bayezid II Medical School, 17th Century Health Museum, Trakya University, Edirne, Turkey

  44. Are the guidelines useful? Satisfying KDOQI guidelines and mortality risk: (Hematocrit, Serum albumin, Phosphorus, Calcium, PTH, and spKt/V) Frequency, 1% HR (95% CI) 0.11 (0.06-0.19) ------------------------------------------------------------------------------------------------------------ Hematocrit Frequency Mortality (33 to 36%) (%) HR (95% CI) ------------------------------------------------------------------------------------------------ 0 of 3 28.1 1.00 1 of 3 36.5 0.88 (0.82 to 0.94) 2 of 3 25.4 0.81 (0.75 to 0.87) 3 of 3 10.0 0.68 (0.61 to 0.76) ------------------------------------------------------------------------------------------------ Tentori F, et al. JASN 18:2377-84, 2007.

  45. Current practicePredialysis • 24.778 patients, age>67y Claims for anemia testing during 2 years prior to dialysis <50% Kausz AT, et al. J Am Soc Nephrol 16:3092-101, 2005.

  46. Current practiceDOPPS Locatelli F, et al. Am J Kidney Dis 44(Suppl 2):S27-S33, 2004.

  47. Current practiceUSRDS 2006 Foley RN and Collins AJ. JASN 18:2644-48, 2007.

  48. Percentage of monthly rHuEPO claims when Hb>13 g/dL 2.0% to 16.7% Monthly rHuEPO dose 38,687 to 54,299 units Practice vs. Guidelines Differences between the dialysis providers: Collins AJ, et al. Am J Kidney Dis 49:135-42, 2006.

  49. Practice vs. Guidelines Servilla KS, et al. Am J Kidney Dis 54:498-510, 2009.

  50. FDA vs. Guidelines ……The new boxed warning advises physicians to monitor red blood cell levels (hemoglobin) and toadjust the ESA dose to maintainthelowest hemoglobin level needed to avoid the need for blood transfusions. Physicians and patients should carefully weigh the risks of ESAs against transfusion risks. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm108864.htm (Accessed on November 15th, 2009).

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