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

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Presentation on theme: "Anemia Guidelines Şehsuvar Ertürk, MD, FASN Ankara University School of Medicine."— Presentation transcript:

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

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 O 2 extraction) Increased EPO production (?) Increased 2,3-DPG 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 Pathophysiology of anemia

9 Consequences of anemia Exercise capacity Coagulation Immune response Cognitive function Sexual function Appetite/Nutrition Growth (in children) Quality of life Depression Angina LVH Cardiac failure Myopathy Renal disease progression Morbidity Mortality 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% CHF13% None 4% All23% 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/dL1.97 Hb<11 g/dL2.57 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) <101.32 (1.16-1.48) AAs Hb (g/dL) <101.50 (1.27-1.76) 10-<111.60 (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) Hospitalization1.15 (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) Hospitalization1.70 (1.63–1.76) Mortality2.48 (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: CHF29.511 USD / patient / year CKD 20.529 Cancer 18.418 Ershler WB, et al. Value Health 8:629-38, 2005

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

19 Effect of treatment CKD-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 treatment CKD-predialysis (RCTs) 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. Decrease in LVMI 101 patients, Hb 11.3 vs. 9.1g/dL Ayus JC, et al. Kidney Int 68:788-95, 2005.

21 Effect of treatment CKD-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 treatment ESRD-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 Diagnosis/Evaluation/Target Hb/Using ESAs-Iron-Adjuvants/Resistance EBPG KDOQI

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 with CKD with Hb levels consistently (i.e., measured twice at least 2 weeks apart) below 11 g/dL, where all 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 patientsSubcutaneous HD-CKD patientsIntravenous 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 of vitamin C (ascorbate) and L-carnitine. Androgens should not be used as an adjuvant to ESA treatment in the management of anemia in patients with CKD.

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

41 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 Causes of hyporesponsivenessHyporesponse

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? ------------------------------------------------------------------------------------------------------------ HematocritFrequency 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. 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)

45 Current practice Predialysis 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 practice DOPPS Locatelli F, et al. Am J Kidney Dis 44(Suppl 2):S27-S33, 2004.

47 Current practice USRDS 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 Collins AJ, et al. Am J Kidney Dis 49:135-42, 2006. Differences between the dialysis providers:

49 Not Receiving Epoetin (%) Median Epoetin Dose (U/wk) Overall2.311,270 Hb (g/dL) <10 10-<11 11-<12 12-<13 >13 1.9 0.8 0.6 1.4 21.7 25,122 16,427 10,982 9,162 8,097 Servilla KS, et al. Am J Kidney Dis 54:498-510, 2009. Practice vs. Guidelines

50 FDA vs. Guidelines …… The new boxed warning advises physicians to monitor red blood cell levels (hemoglobin) and to adjust the ESA dose to maintain the lowest 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).

51 Practice vs. FDA Dialysis-Medicare Percentage of patients receiving at least one transfusion (left Y axis), and mean hemoglobin (dark red line, right Y axis) from 1987 through 2006. Coyne DW and Brennan DC. Semin Dial 22:590-91, 2009.

52 Conclusion Anemia is common among patients with chronic kidney disease, and is associated with higher morbidity and mortality rates. Individualized treatment with the use of moderate ESA doses in conjunction with iron therapy to keep hemoglobin between target levels of the currently available guidelines seems to be reasonable.

53 Conclusion Further studies to understand the relationships between target hemoglobin level, ESA dose, and outcomes is essential in designing effective anemia management and reimbursement policies.

54


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