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Anemia management in Hemodialysis Chan-on C. MD..

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Presentation on theme: "Anemia management in Hemodialysis Chan-on C. MD.."— Presentation transcript:

1 Anemia management in Hemodialysis Chan-on C. MD.

2 Content Definition Impact Causes Investigation and monitoring Management ESA in CKD,PD,HD patients in KKU

3 Take me home  Start ESA when Hb < 9 g/dL  Target Hb in HD 13 g/dL intentionally  Correct Iron deficiency before start ESA g/dL  Epoetin alfa and beta can be used as availability  Darbepoetin alfa is more convenient for ND-CKD pt

4 Definition Kidney Disease: Improving Global Outcomes (KDIGO) Anemia Work Group. KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease. Kidney inter., Suppl. 2012; 2: 279–335.

5 Impact Health budget Anemia in CKD/HD

6 Approach anemia in HD Modified from National Kidney Foundation. K/DOQI Clinical Practice Guidelines for Anemia of Chronic Kidney Disease, Am J Kidney Dis 37:S182-S238, 2001 (suppl 1) eGFR< 60 ml/min/1.73m2 Anemic symptoms Hb < 13 g/dL Male Hb < 12 g/dL Female Hb Anemic work-up: CBC: Rbc indeces/reticulocyte/ serum iron/ TIBC/TSAT/Ferritin /GI bleeding TSAT < 20% Ferritin < 200 Absolute Iron deficiency TSAT < 20% Ferritin > 200 Functional Iron deficiency TSAT > 20% Ferritin > 200  No IDA F/U at 4th wks no Hb response  ESA hyporesponsiveness Normal: F/U ESA therapy IV iron ESA hyporespon siveness TIBC > 200 mg/dL Modified from Intravenous Iron Versus Erythropoiesis- Stimulating Agents: Friends or Foes in Treating Chronic Kidney Disease Anemia? Kamyar Kalantar- Zadeh, Elani Streja, Jessica E. Miller, and Allen R. Nissenson. Advances in Chronic Kidney Disease, Vol 16, No 2 (March), 2009: pp Modified from Intravenous Iron Versus Erythropoiesis- Stimulating Agents: Friends or Foes in Treating Chronic Kidney Disease Anemia? Kamyar Kalantar- Zadeh, Elani Streja, Jessica E. Miller, and Allen R. Nissenson. Advances in Chronic Kidney Disease, Vol 16, No 2 (March), 2009: pp Hb < 13 g/dL Male Hb < 12 g/dL Female TSAT=SI/TIBC Infection/ inflammation SI TIBC Infection/ inflammation SI TIBC

7 Impact of anemia in CKD - left ventricular hypertrophy (LVH) - Precipitating factor for congestive heart failure (CHF) - Exacerbation of angina Reductions in - Aerobic capacity - Overall well-being - Cognition Erslev AJ. NEJM 1991, 324: Impact of anemia in CKD - left ventricular hypertrophy (LVH) - Precipitating factor for congestive heart failure (CHF) - Exacerbation of angina Reductions in - Aerobic capacity - Overall well-being - Cognition Erslev AJ. NEJM 1991, 324: Hb levels and cardiovascular comorbidity ASHD: atherosclerotic heart disease CHF: congestive heart failure other cardiovascular diseases, such as arrhythmias or cardiomyopathies

8 Prevalence of Anemia: KKU RRT unit > 50 % of pts Hb > 10 g/dL

9 LVH is an independent risk factor for death in patients with ESRD Kidney function decline, Hb decrease, LVH increase Coresh J. et al. Arch Intern Med. 2001, Levin A. et al. AJKD 1996;27: Levin A. et al. AJKD 1999,

10 LVMI: left ventricular mass index; RV, right ventricle; LV, left ventricle; LVH, left ventricular hypertrophy; d, left ventricular chamber diameter; e, left ventricular wall thickness LVMI: left ventricular mass index; RV, right ventricle; LV, left ventricle; LVH, left ventricular hypertrophy; d, left ventricular chamber diameter; e, left ventricular wall thickness

11 Non-hemodynamic factors Uremia Sympathetic tone Renin angiotensin system Hyperparathyroidism Chronic inflammation? Genetic predisposition Pressure overload -arterial hypertension Volume overload -hypervolemia -fistula flow -anemia (RWT relative wall thickness = MWT/EDD) LV end-diastolic diameter (EDD), LV mean wall thickness (MWT Concentric LVH RWT > 0.45 RWT< 0.45 Eccentric LVH/ LV dilatation Increase events of -myocardial ischemia -heart failure -arrhythmia Left ventricle Hemodynamic factors Hemodynamic factor

12 The relationship between the risk of Mortality and Hct in HD patients

13 Causes

14 Patient factorsEventsService provider Erythropoietin defInfection/InflammationService protocol Decrease Rbc survivalHospitalizationProtocol adherance Iron defBlood loss(acute/chronic)Frequency of sample drawn Vitamin def (Folic/ Vitamin B) Blood loss from procedures/ samples Target Hb from K/DIGO Comorbidity Malignancy/HIV/HCV/ Autoimmune MalnutritionTarget iron from K/DIGO DMDrug –induced BM suppression: immunosuppressives 2 nd hyperparathyroidInterdialytic weight gain Smoking/ high altitudeVascular access/ temporary catheter problems EthnicityDialysis mode

15 Management Diagnosis Therapeutic options blood transfusion ESA Iron administration Monitoring

16 Investigation & monitoring

17 Rbc needs EPO and Iron in maturation Kamyar Kalantar-Zadeh, Elani Streja, Jessica E. Miller, and Allen R. Nissenson. Intravenous Iron Versus Erythropoiesis-Stimulating Agents: Friends or Foes in Treating Chronic Kidney Disease Anemia? Advances in Chronic Kidney Disease, Vol 16, No 2 (March), 2009: pp

18 The tests in initial evaluation of the anemia Complete blood count (CBC), which should include Hb concentration, red cell indices, white blood cell count and differential, and platelet count Absolute reticulocyte count Serum ferritin level Serum transferrin saturation (TSAT) Serum vitamin B12 and folate levels Kidney Disease: Improving Global Outcomes (KDIGO) Anemia Work Group. KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease. Kidney inter., Suppl. 2012; 2: 279–335. Test for stool occult blood

19 Iron deficiency diagnostic labs

20 Therapeutic options

21 Pack red cell transfusion transfusion-transmitted infection immunologic sensitization iron overload syndromes volume overload transfusion reactions.

22 In Urgent treatment  rapid correction of anemia: bleeding/ hemorrhagic shock  rapid pre-operative Hb correction In Chronic anemia  ESA ineffective: hemoglobinopathies/BM failure/ ESA resistance  ESA gives risk outweigh benefit: previous or current malignancy, previous stroke  ESA ineffective: hemoglobinopathies/BM failure/ ESA resistance  ESA gives risk outweigh benefit: previous or current malignancy, previous stroke

23 Rapid correction of anemia Murphy MF, Wallington TB, Kelsey P et al. Guidelines for the clinical use of red cell transfusions. Br J Haematol 2001; 113: 24–31.

24 Pre-op transfusion in HD Hb > 10 g/dL not recommended should be given Hb < 7 g/dl Healthy/stable High-risk patients >65 years and/or with CV or RS disease Hb < 8 g/dl tolerate anemia poorly 2 unit PRC transfusion then re- evaluate Hb 7-10 g/dL  unclear Murphy MF, Wallington TB, Kelsey P et al. Guidelines for the clinical use of red cell transfusions. Br J Haematol 2001; 113: 24–31.

25 the number of HLA molecules contributed by the red cells is comparable to that of leukocytes Blood transfusion: High PRA  longer waiting time  be excluded from list lower survival Increased risk of early and late graft loss Terasaki PI, Ozawa M. Predicting kidney graft failure by HLA antibodies: a prospective trial. Am J Transplant 2004; 4: 438–443. Terasaki PI, Ozawa M. Predictive value of HLA antibodies and serum creatinine in chronic rejection: results of a 2-year prospective trial.Transplantation 2005; 80: 1194–1197. Terasaki PI, Ozawa M. Predicting kidney graft failure by HLA antibodies: a prospective trial. Am J Transplant 2004; 4: 438–443. Terasaki PI, Ozawa M. Predictive value of HLA antibodies and serum creatinine in chronic rejection: results of a 2-year prospective trial.Transplantation 2005; 80: 1194–1197. Balasubramaniam GS, Morris M, Gupta A et al. Allosensitization rate of male patients awaiting first kidney grafts after leuko-depleted blood transfusion. Transplantation 2012; 93: 418–422.

26 Erythropoietin stimulating agents

27 The response to EPO is dose-dependent, but great variation The response depends on the route (iv. versus sc.) and the frequency of administration. The response may be limited by many factors Stroke, mortality, and hypertension may complicated Erythropoietin stimulating agents

28  Improve cardiac morphology  Increase survival  Reduced hospitalization  Improve QOL/well-being  Improve energy/work capacity

29 Erythropoietin stimulating agents Stroke Vascular access loss Hypertension

30 Epoetin alfa and epoetin beta Darbepoetin alfa Continuous erythropoietin receptor activator: methoxy polyethylene glycol-epoetin beta Peginesatide

31 Darbepoetin alfa structurally different from endogenous erythropoietin - oligosaccharide chains - amino acid sequence rearranged - larger molecular weight Clinical significance of different molecular structure is unknown Epoetin alfa and beta = endogenous erythropoietin (immunological/biological) N-linked oligosaccharide The terminal half-life of Aranesp® was ~ 3-fold longer than that of Epoetin alfa when administered intravenously.

32 ESA dosing consideration

33 Iron repletion before ESA initiation KDOQI. Am J Kidney Dis 2001;37 (suppl):S182-S238

34

35 Maintenance NKF. Am J Kidney Dis 2001;37(1 suppl 1) S % q ½-1 /week q 1-2 /week

36 Krause MW, Raja R, Agarwal A, Silver MR, Scarlata D, Sciarra A, Kewalramani R. Every-other-week darbepoetin alfa in the correction and maintenance of haemoglobin levels in elderly patients with chronic kidney disease: post hoc subanalysis of data from two clinical trials. Drugs Aging. 2009;26(8): Darbepoietin

37 de novo q2w darbepoetin alfa is a well tolerated and effective treatment for correcting anaemia in older patients with CKD not receiving dialysis.

38 Continuous erythropoietin receptor activator: methoxy polyethylene glycol- epoetin beta

39 Peginesatide (Hematide)  once-monthly therapy  intravenously or subcutaneously.  starting dose: 0.025–0.075 mg/kg.  starting dose in PRCA: 0.05 mg/kg. A peptide-based erythropoietin receptor agonist. No structural homology with endogenous EPO  no cross react with anti-EPO Ab  apply in PRCA pts 1.Fan Q, Leuther KK, Holmes CP, et al. Preclinical evaluation of Hematide, a novel erythropoiesis stimulating agent, for the treatment of anemia. Exp Hematol. 2006;34:1303– Woodburn KW, Fan Q, Winslow S, et al. Hematide is immunologically distinct from erythropoietin and corrects anemia induced by antierythropoietin antibodies in a rat pure red cell aplasia model. Exp Hematol. 2007;35:1201– Macdougall IC, Rossert J, Casadevall N, et al. A peptidebased erythropoietin-receptor agonist for pure red-cell aplasia. N Engl J Med. 2009;361:1848– Fan Q, Leuther KK, Holmes CP, et al. Preclinical evaluation of Hematide, a novel erythropoiesis stimulating agent, for the treatment of anemia. Exp Hematol. 2006;34:1303– Woodburn KW, Fan Q, Winslow S, et al. Hematide is immunologically distinct from erythropoietin and corrects anemia induced by antierythropoietin antibodies in a rat pure red cell aplasia model. Exp Hematol. 2007;35:1201– Macdougall IC, Rossert J, Casadevall N, et al. A peptidebased erythropoietin-receptor agonist for pure red-cell aplasia. N Engl J Med. 2009;361:1848–1855.

40 ESA hyporesponsiveness Causes of ESA hyporesponsiveness - Iron content and availability - inflammation - nutritional status - specific nutrients availability: folic B - delivered dialysis dose - parathyroid function - demographic eg. race gender age - functioning bone marrow Hemolysis Aluminum toxicity Osteitis fibrosa cystica KDOQI 2000 Anemia Guidelines Am J Kidney Dis Jan;37(1 Suppl 1):S Kotanko P et al. Semin Dial Sep-Oct;19(5):

41 Iron therapy

42 Hb Stability, IV Iron, and ESA: What We Know Suzann VanBuskirk, Alteration of iron balance in CKD

43 TSAT < 20% Ferritin > 200 Functional Iron deficiency or RE blockade TSAT < 20% Ferritin > 200 Functional Iron deficiency or RE blockade

44 Iron deficiency diagnostic labs

45 IV. iron  Additional IV iron should not routinely be administered  Prefer IV route of iron administration in CKD 5HD patients over oral iron with and without concomitant ESA treatment Inadequacy of oral iron - Low intestinal absorption of oral iron - Poor patient adherence

46 Iron targets KDOQI AJKD 2006 If serum ferritin > 500 ng/ml Individualized depend on pt status Serum ferritin is not predictive for iron response TSAT > 25 is not predictive for iron response

47 IV. Iron

48 IV Iron therapy Common approach IV iron treatment in CKD 5HD patients: (1) periodic iron repletion, consisting of a series of IV iron doses administered episodically to replenish iron stores (2) maintenance treatment, smaller doses at regular intervals to maintain iron status in specific limits

49 IV. Iron Disadvantages of IV Iron in CKD Short-term adverse events Iron overload Increased risk of infection Increased oxidative stress Increased death risk (?)* *Both decreased and increased death risk have been postulated with IV iron administration. Reducing ESA dose Improving ESA hyporesponsiveness Mitigating hemoglobin variability Mitigating risk of thrombocytosis Reducing likelihood of blood transfusion Circumventing the need for oral iron supplementation Beyond anemia effects Treatment of restless leg Improving cognitive function Decreasing death risk (?)* Kamyar Kalantar-Zadeh, Elani Streja, Jessica E. Miller, and Allen R. Nissenson. Intravenous Iron Versus Erythropoiesis-Stimulating Agents: Friends or Foes in Treating Chronic Kidney Disease Anemia? Advances in Chronic Kidney Disease, Vol 16, No 2 (March), 2009: pp

50 Target

51 Current concept: partial correction Trials in predialysis-CKD, suggest that Hb levels near normal range ~ moderate anemia same in clinical benefit but increased risk of adverse outcomes D-CKD : dialysis dependent CKD ND-CKD: non-dialysis dependent CKD

52 Individualizing therapy for each pt Using the lowest possible ESA dose required to reduce the need for transfusions The new labels recommend reducing the ESA dose when Hb > 10 g/dL in ND-CKD and Hb > 11 g/dL in D-CKD patients The New FDA Labeling for ESA—Implications for Patients and Providers B J. Manns, M Tonelli. Does not seem to be factually correct, because trials found higher risks in patients randomized to near-normal hemoglobin targets (i.e., >130 g/L and not >110 g/L). Information from clinical trials is not available to inform the selection of a hemoglobin target between 11.5 and 13 g/L.

53 For D-CKD Initiate ESA when Hb <10 g/dl. If the Hb level > 11 g/dl, reduce or interrupt the dose of ESA. When initiating or adjusting therapy, monitor Hb levels at least q1wk until stable, then at least q1mo. If pts do not respond adequately over a 12-wk escalation period, increase ESA dose further  unlikely to improve response  may increase risks. The New FDA Labeling for ESA—Implications for Patients and Providers. B J. Manns, M Tonelli. Clin J Am Soc Nephrol February; 7(2): 348–353. FDA: FDA Drug Safety Communication: Modified Dosing Recommendations to Improve the Safe Use of Erythropoiesis-Stimulating Agents in CKD, 2011.

54 Recent clinical trials comparing in CKD Stroke the use of ESA targeting low (HB 9 –11.5 g/dL) and near-normal Hb targets (Hb >13.0 g/dL)  no improvements in clinical outcomes  potential harm for ESA use targeting near- normal Hb targets. the use of ESA targeting low (HB 9 –11.5 g/dL) and near-normal Hb targets (Hb >13.0 g/dL)  no improvements in clinical outcomes  potential harm for ESA use targeting near- normal Hb targets.

55 low (L; 12.5 g/dl). Medicare: all hemodialysis patients who survived the first 6 mo of 2004 Highest and lowest Hb during 6 month Persistent in target Persistent low Too low or too high Hb and high variability increase risk of adverse outcome Ebben JP et al. Clin J Am Soc Nephrol Nov;1(6):

56 CREATE CHOIR TREAT trial The Normal Hematocrit Cardiac Trial (NHCT)

57 the TREAT trial Pfeffer MA, Burdmann EA, Chen CY, Cooper ME, de Zeeuw D, Eckardt KU, et al; TREAT Investigators. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med Nov 19;361(21): doi: /NEJMoa Epub 2009 Oct patients Type 2 DN ND-CKD Darbepoetin alfa vs placebo 4038 patients Type 2 DN ND-CKD Darbepoetin alfa vs placebo Hb 13 g/dL Hb > 9 g/dL Minimal improvement in patient-reported fatigue in the darbepoetin alfa group

58 the TREAT trial Francesco Locatelli, et al and On behalf of the Anaemia Working Group of ERBP. Target haemoglobin to aim for with erythropoiesis-stimulating agents: a position statement by ERBP following publication of the Trial to Reduce Cardiovascular Events with Aranesp ® Therapy (TREAT) Study Nephrol. Dial. Transplant.(2010) 25 (9): Pfeffer MA, Burdmann EA, Chen CY, Cooper ME, de Zeeuw D, Eckardt KU, et al; TREAT Investigators. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med Nov 19;361(21): doi: /NEJMoa Epub 2009 Oct 30.  Darbepoetin in T2DM + CKD did not reduce the risk of either death or a cardiovascular event or death or a renal event  associated with an increased risk of stroke.

59 the United States Normal Hematocrit trial Besarab A, Bolton WK, Browne JK et al. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med 1998; 339: 584–590. Mean 42+/- 3% Mean 30 +/- 3% a target hematocrit value of 42% in this patient with cardiac disease who are undergoing hemodialysis cannot be recommended.

60 Meta-analysis: ESA in CKD in the higher Hb target group  significantly higher risk of all-cause mortality (RR 1·17, 95% CI 1·01—1·35; p=0·031)  VA thrombosis (1·34, 1·16—1·54; p=0·0001)  significantly higher risk of poorly controlled BP (1·27, 1·08—1·50; p=0·004)

61 1. Target Hb in HD & PD  extrapolated from results of trials in CKD patients Evidence 2. Outcome: target Hb  surrogate outcome

62 ESA in CKD,PD,HD patients in KKU Setting: CKD clinic, HD unit, PD unit Population: PD, HD, CKD patients received ESA treatment Data collection and analysis: Kridsada Sirichaisit MD. Wilaiporn Wasuthapitak MD.

63 จำนวน ( คน ) % Total154 Sex male Age (Median) ปี 60.5 (17-88) DM5435

64

65 Hb (Mean) g/dl9.9 Hct (Mean) %30.3 Duration on ESA28 mo ± 25.9 (1-122 mo)

66 Take me home  Start ESA when Hb < 9 g/dL  Target Hb in HD 13 g/dL intentionally  Correct Iron deficiency before start ESA g/dL  Epoetin alfa and beta can be used as availability  Darbepoetin alfa is more convenient for ND-CKD pt


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