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Anemia in Chronic Kidney Disease Dr Abdullah AlHwiesh Associate Professor Consultant Internist/Nephrologist Dammam University AlKhober.

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Presentation on theme: "Anemia in Chronic Kidney Disease Dr Abdullah AlHwiesh Associate Professor Consultant Internist/Nephrologist Dammam University AlKhober."— Presentation transcript:

1 Anemia in Chronic Kidney Disease Dr Abdullah AlHwiesh Associate Professor Consultant Internist/Nephrologist Dammam University AlKhober

2 Outline Impact of anemia in patients (CKD) Impact of anemia in patients (CKD) Prevalence of anemia in CKD Prevalence of anemia in CKD Cardiovascular effects of anemia in CKD Cardiovascular effects of anemia in CKD Target hemoglobin in CKD Target hemoglobin in CKD Erythropoietin stimulating agents (ESAs) available Erythropoietin stimulating agents (ESAs) available New anemia therapies New anemia therapies Summary of clinical practice guidelines Summary of clinical practice guidelines

3 What is anemia? Diagnosis of anemia should be made Diagnosis of anemia should be made and further evaluation if: and further evaluation if: –Hb < 13.5 g/dl in adult males –Hb < 12 g/dl in adult females

4 Impact of anemia in CKD Symptoms Symptoms Diminished quality of life Diminished quality of life Associated with LVH Associated with LVH

5 Impact of anemia in CKD deterioration in cardiac function deterioration in cardiac function decreased cognition and mental acuity. decreased cognition and mental acuity. fatigue, weakness, lethargy, anorexia, and sleep disturbances. fatigue, weakness, lethargy, anorexia, and sleep disturbances.

6 Impact of anemia in CKD increased risk of morbidity and mortality increased risk of hospitalizati mortality in patients with predialysis mortality in patients with predialysis

7 General Population Transplant Dialysis USRDS 2006 General Population Transplant Dialysis

8 AJKD 2002: 39(2)

9 Mortality increases exponentially as GFR declines Go et al NEJM : M Kaiser Permanente patients > <15 Estimated GFR (ml/min/1.73 m 2 ) Number of Events 25,803 11,569 7,802 4,408 1,842 Age Standardized Rate of Death From Any Cause (per 100 person-yr)

10 Adjusted Prevalence of Anemia (NHANES III) N=230,000

11 *NHANES participants aged ≥ 20 y with anemia as defined by WHO criteria: hemoglobin (Hgb) <12 g/dL for women, and Hgb <13 g/dL for men. Anemia Prevalence by CKD Stage Patients With Anemia* (%) NHANES III NHANES CKD Stage

12 based upon over 15,000 participants in the NHANES survey, the prevalence of anemia (Hbg <12 g/dL in men and <11 g/dL in women) based upon over 15,000 participants in the NHANES survey, the prevalence of anemia (Hbg <12 g/dL in men and <11 g/dL in women) 1% GFR 60 ml/min per 1.73 m2 1% GFR 60 ml/min per 1.73 m2 9 percent at an estimated GFR of 30 mL/min per 1.73 m2 9 percent at an estimated GFR of 30 mL/min per 1.73 m2 33 to 67 percent at an estimated GFR of 15 mL/min per 1.73 m2 33 to 67 percent at an estimated GFR of 15 mL/min per 1.73 m2

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14 Anemia is involved in cardiac remodeling Reduced hemoglobin Tissue hypoxia Increased cardiac work Left ventricular hypertrophy Ischemic heart disease Worsening or precipitation of: Congestive heart failure Angina pectoris Myocardial infarction Metivier F, et al. Nephrol Dial Transplant. 2000; 15(suppl 3): 14-18

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19 Early versus late initiation of EPO R,C,T early versus deferred initiation of erythropoietin in nondiabetic predialysis patients with serum creatinine 2 to 6 mg/dL and hemoglobin 9 to 11.6 g/dL. The early treatment arm was immediately started on 50 U/kg/wk of erythropoietin alpha with appropriate titration aiming for hemoglobin of ≥13 g/dL R,C,T early versus deferred initiation of erythropoietin in nondiabetic predialysis patients with serum creatinine 2 to 6 mg/dL and hemoglobin 9 to 11.6 g/dL. The early treatment arm was immediately started on 50 U/kg/wk of erythropoietin alpha with appropriate titration aiming for hemoglobin of ≥13 g/dL Internati onal Society of Nephrology 2006

20 The primary end point doubling of creatinine doubling of creatinine renal replacement renal replacement death death Internati onal Society of Nephrology 2006

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25 Patients With CHF and Anemia (n = 126, 91% CKD) NYHA class = New York Heart Association classification; SOB = shortness of breath. Silverberg et al. Perit Dial Int. 2001;21(suppl 3):S236-S240. Clinical Benefit of Anemia Correction: CHF and CKD ParameterBeforeAfter Hgb (g/dL) Serum creatinine (g/dL) ∆GFR (mL/min/mo) NYHA class (0-4) Fatigue/SOB index (0-10) Hospitalizations Systolic BP (mm Hg) Diastolic BP (mm Hg)7576

26 Prevalence of LVH increases with decreased kidney function Levin et al. Am J Kidney Dis. 1999;34:

27 LVH is present in 74% of patients at initiation of dialysis Foley et al. Kidney Int. 1995; 47:

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30 LVH and anemia of CKD Clear association between anemia and LVH Clear association between anemia and LVH Can correction of anemia of CKD result in LVH regression? Can correction of anemia of CKD result in LVH regression?

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38 When to start ESA treatment Anemia develops early in CKD Anemia develops early in CKD ESA treatment: ESA treatment: –Reduces symptoms –Improves quality of life –May help for LVH –May increase thrombotic risks and BP Decision to initiate treatment based on clinical balancing of risks and benefits Decision to initiate treatment based on clinical balancing of risks and benefits

39 What is the target Hemoglobin?

40 Open label, RCT,130 centers in US, epoetin alfa SC weekly Open label, RCT,130 centers in US, epoetin alfa SC weekly CKD (eGFR ml/min/1.73m2); Hb < 11g/dl CKD (eGFR ml/min/1.73m2); Hb < 11g/dl High Hb target: 13.5 g/dl High Hb target: 13.5 g/dl Low Hb target: 11.3 g/dl Low Hb target: 11.3 g/dl Study terminated early because conditional power poor for showing a benefit of high Hb was <5% Study terminated early because conditional power poor for showing a benefit of high Hb was <5% Choir (Correction of Anemia with Epoetin Alfa in Chronic Kidney Disease)

41 Choir Main results: Main results: –34% increased risk of composite outcome of death, MI, hospitalization for CHF, stroke (p= 0.03) –No significant difference in patients requiring RRT –Similar quality of life measures Singh AK et al. N Engl J Med Nov 16;355(20):

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43 Choir Drop out rate is high High Hb target achieved in few patients

44 Choir Singh AK et al. N Engl J Med Nov 16;355(20):

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52 CREATE Drueke TB, et al. N Engl J Med Nov 16;355(20):

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54 ACORD Open label, RCT, 64 centers in 16 countries, N=170 Open label, RCT, 64 centers in 16 countries, N=170 Epoetin beta SC weekly Epoetin beta SC weekly Creatinine clearance > 30ml/min Creatinine clearance > 30ml/min High Hb target: g/dl High Hb target: g/dl Low Hb target: g/dl after Hb < 10.5 g/dl twice or<10.0 g/dl once Low Hb target: g/dl after Hb < 10.5 g/dl twice or<10.0 g/dl once Ritz E et al. Am J Kidney Dis Feb;49(2):

55 ACORD Main results: Main results: –No significant difference in LVMI –No significant difference in decline in creatinine clearance –Better QOL in high Hb group Ritz E et al. Am J Kidney Dis Feb;49(2):

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59 CRF GFR 20-60ml,Dm and Anaemia placepo Rescue if HB < darpoboitin HB 13g/dl NEJM2009

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61 (hazard ratio 1.05; 95% confidence interval [CI], 0.94 to 1.17; P = 0.41). 632 darbpoitin 602 Placepo Death or cardiovascular event NEJM2009

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63 Death Or ESRD 652 Darbepoetin 618 Palcepo (hazard ratio, 1.06; 95% CI, 0.95 to 1.19; P = 0.29 NEJM 2009

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65 Fatal and non Fatal Strock 101 Darbepoetin53 Placepo (hazard ratio, 1.92; 95% CI, 1.38 to 2.68; P<0.001 NEJM2009

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67 The use of darbepoetin alfa in patients with diabetes, chronic kidney disease, and moderate anemia who were not undergoing dialysis did not reduce the risk of either of the two primary composite outcomes death cardiovascular and was associated with an increased risk of stroke. NEJM 2009

68 KDOQI 2007 update In the opinion of the Work Group, selection of the Hb target and selection of the Hb level at which ESA therapy is initiated in the individual patient should include considerations of potential benefits and potential harms In the opinion of the Work Group, selection of the Hb target and selection of the Hb level at which ESA therapy is initiated in the individual patient should include considerations of potential benefits and potential harms

69 ESA hyporesponsiveness Definition: Definition: –Hb level consistently less than 11 g/dl despite reasonable doses of ESA

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71 ESAs in the treatment of anemia in Chronic Kidney Disease Recombinant version of endogenous human EPO, first ESA approved for tx anemia in CKD (1989) Epoetin alfa Lower binding affinity for EPO receptor, but 3 times longer half life Darbepoetin alfa

72 ESAs in the treatment of anemia in Chronic Kidney Disease First approved chemically synthesized ESA, large molecule, prolonged duration of action CERA

73 ESAs in the treatment of anemia in Chronic Kidney Disease Pegylated synthetic peptide-based ESA, investigational Hematide Transcription factor, stimulates erythropoiesis and iron mobilization, investigational HIF stabilizer

74 Does half-life correlates with response? Half-life,h Agent 4-13 (20% longer in CRF patients) Epoetin alfa 49 (SC) Darbepoetin alfa 130CERA 24Hematide 10.4 HIF stabilizer

75 PEGINESATIDE

76 a peptide could activate the erythropoietin receptor and stimulate erythropoiesis was described first byWrighton et al15 in 1996

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78 mg/kg. given once monthly

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80 HIF STABILIZATION

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82 1- fatal hepatic necrosis 1- fatal hepatic necrosis 2- up regulate VEGF (vascular endothelial growth factor), which may have potential adverse effects on enhancing tumor growth and proliferative diabetic retinopathy. 2- up regulate VEGF (vascular endothelial growth factor), which may have potential adverse effects on enhancing tumor growth and proliferative diabetic retinopathy.

83 Extended dosing Extending dosing of EPO up to every 6 weeks is possible Extending dosing of EPO up to every 6 weeks is possible Darbepoietin and CERA have much longer half-lives Darbepoietin and CERA have much longer half-lives

84 R,O,L,M,16 week 37 Center R,O,L,M,16 week 37 Center 262pt <18 yr old GFR< pt <18 yr old GFR< IU QWK 20,000 Iu Q2WK 20,000 IU Q 4WK IU Q4WK CJASN 2008

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88 CJACN 2008

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91 -0.21,0,44

92 The results of this study demonstrate that epoetin alfa can be initiated Q4W. Although the half-life of epoetin alfa is shorter than other ESAs, it may ultimately be the life span of the red cell that determines the pharmacodynamic effect of these compounds.Therefore, epoetin alfa can provide the flexibility and convenience needed by nondialysis patients with anemia of CKD

93 Intrapatient Hb variability is not due to choice of ESA Multicenter, randomized, double-blind study of 404 patients on HD Nissenson AR et al. ASN 2006

94 CERA and Hb Control in CKD Patients on Dialysis Mean change in Hb levels from baseline over time Lunde NM et al. ASN 2007 (poster presentation)

95 Clinical practice guidelines: target hemoglobin Better quality of life without an increase in adverse reactions are associated with Hgb >11 g/dL compared to values below this level Better quality of life without an increase in adverse reactions are associated with Hgb >11 g/dL compared to values below this level There is also increasing evidence that there is little benefit, and even potential risk, with increased morbidity and mortality, to targeting and maintaining Hgb levels of >13 g/dL in dialysis and predialysis patients There is also increasing evidence that there is little benefit, and even potential risk, with increased morbidity and mortality, to targeting and maintaining Hgb levels of >13 g/dL in dialysis and predialysis patients

96 Clinical practice guidelines The 2007 DOQI update for the hemoglobin target recommends that the selected Hgb target should generally be in the range of 11 to 12 g/dL in all patients with CKD The 2007 DOQI update for the hemoglobin target recommends that the selected Hgb target should generally be in the range of 11 to 12 g/dL in all patients with CKD They also recommend that the Hgb target should not exceed 13 g/dL They also recommend that the Hgb target should not exceed 13 g/dL NKF-K/DOQI Clinical Practice Guidelines for Anemia of Chronic Kidney Disease. Am J Kidney Dis JASN 2007,50: 474

97 Guidelines for management of anemia in CKD Start work up: Start work up: –If Hb < 11g/dl in females –If Hb < 13 g/dl in males and postmenopausal females Hx and lab tests: blood loss, nutrition, adequacy of dialysis, OB, CBC, retc, iron studies, B12, folate, Hb electropheresis Hx and lab tests: blood loss, nutrition, adequacy of dialysis, OB, CBC, retc, iron studies, B12, folate, Hb electropheresis

98 Guidelines for management of anemia in CKD ESA treatment is indicated if Hb <11 g/dl and no other cause of anemia ESA treatment is indicated if Hb <11 g/dl and no other cause of anemia EPO: 150 ug/kg/wk (SC), increase dose if given (IV) EPO: 150 ug/kg/wk (SC), increase dose if given (IV) Darbepoietin: 0.45ug/kg/wk IV or SC, 0.75 ug/kg/2wks in predialysis Darbepoietin: 0.45ug/kg/wk IV or SC, 0.75 ug/kg/2wks in predialysis

99 Guidelines for management of anemia in CKD Adequate response: Hb increases 1 g/dl/month Adequate response: Hb increases 1 g/dl/month Target Hb g/dl Target Hb g/dl Avoid Hb > 13g/dl Avoid Hb > 13g/dl Monitor Hb Monitor Hb

100 Guidelines for management of anemia in CKD Titrate ESA dose: Titrate ESA dose: If Hb decrease < 1 g/dl/month, increase dose by 25-50% If Hb decrease < 1 g/dl/month, increase dose by 25-50% If Hb increases > 2-3 g/dl/month, decrease dose by 25-50% If Hb increases > 2-3 g/dl/month, decrease dose by 25-50% Side effects: worsening of BP control, access thrombosis Side effects: worsening of BP control, access thrombosis

101 ESA hyporesponsiveness: iron deficiency Iron deficiency: Tsat < 20%, S ferritin < 100 Iron deficiency: Tsat < 20%, S ferritin < 100 IV Iron supplement: iron sucrose or gluconate (1000 mg in 10 doses), maintain with 100mg Q 1-2 wks IV Iron supplement: iron sucrose or gluconate (1000 mg in 10 doses), maintain with 100mg Q 1-2 wks Monitor iron stores Monitor iron stores Do not supplement if ferritin> 800 ng/ml and/or Tsat >50% Do not supplement if ferritin> 800 ng/ml and/or Tsat >50%

102 Thank You Thank You

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