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Anemia management in Hemodialysis

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1 Anemia management in Hemodialysis
Faculty of Medicine 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 Target Hb in HD < 11.5 g/dL, not more than > 13 g/dL intentionally g/dL Start ESA when Hb < 9 g/dL Correct Iron deficiency before start ESA Epoetin alfa and beta can be used as availability Darbepoetin alfa is more convenient for ND-CKD pt

4 Definition Hb concentration < 13.0 g/dl in males
< 12.0 g/dl in females. 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 Mortality/ QOL Anemia in CKD/HD Impact Health budget

6 Infection/ inflammation SI TIBC
Approach anemia in HD Infection/ inflammation SI TIBC eGFR< 60 ml/min/1.73m2 Anemic symptoms Hb Normal: F/U Hb < 13 g/dL Male Hb < 12 g/dL Female Hb < 13 g/dL Male Hb < 12 g/dL Female TSAT=SI/TIBC Anemic work-up: CBC: Rbc indeces/reticulocyte/ serum iron/ TIBC/TSAT/Ferritin/GI bleeding TIBC > 200 mg/dL 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) TSAT < 20% Ferritin < 200 Absolute Iron deficiency TSAT < 20% Ferritin > 200 Functional Iron deficiency 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 TSAT > 20% Ferritin > 200  No IDA IV iron ESA therapy ESA hyporesponsiveness F/U at 4th wks no Hb response ESA hyporesponsiveness

7 Hb levels and cardiovascular comorbidity
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: ASHD: atherosclerotic heart disease CHF: congestive heart failure other cardiovascular diseases, such as arrhythmias or cardiomyopathies

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

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

10 LV geometry changed in high BP and volume overload
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 LV geometry changed in high BP and volume overload

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

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

13 Causes

14 Patient factors Events Service provider Erythropoietin def Infection/Inflammation Service protocol Decrease Rbc survival Hospitalization Protocol adherance Iron def Blood 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 Malnutrition Target iron from K/DIGO DM Drug –induced BM suppression: immunosuppressives 2nd hyperparathyroid Interdialytic weight gain Smoking/ high altitude Vascular access/ temporary catheter problems Ethnicity Dialysis 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 Test for stool occult blood 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.

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

23 Rapid correction of anemia
1. rapid acute hemorrhage without immediate control of bleeding 2. estimated BL > 30–40% of BV (1500–2000 ml) with symptoms of severe BL 3. estimated BL < 25–30% BV without evidence of uncontrolled hemorrhage, if signs of hypovolemia recur despite colloid/crystalloid resuscitation 4. in patients with co-morbid factors, transfusions may be necessary with lesser degrees BL 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
Healthy/stable High-risk patients >65 years and/or with CV or RS disease Hb > 10 g/dL not recommended should be given Hb < 7 g/dl tolerate anemia poorly Hb < 8 g/dl 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 Blood transfusion: High PRA longer waiting time
 be excluded from list lower survival Increased risk of early and late graft loss mean wait-time to transplant USRDS data reported in 2010 Transfused pt > non-transfused pt  2 months the number of HLA molecules contributed by the red cells is comparable to that of leukocytes 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. 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.

26 Erythropoietin stimulating agents

27 Erythropoietin stimulating agents
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

28 Erythropoietin stimulating agents
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 Epoetin alfa and epoetin beta Darbepoetin alfa Peginesatide
Continuous erythropoietin receptor activator: methoxy polyethylene glycol-epoetin beta Peginesatide

31 Darbepoetin alfa structurally different from endogenous erythropoietin
Epoetin alfa and beta = endogenous erythropoietin (immunological/biological) N-linked oligosaccharide Darbepoetin alfa structurally different from endogenous erythropoietin - oligosaccharide chains - amino acid sequence rearranged - larger molecular weight Clinical significance of different molecular structure is unknown 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 DRIVE studies: ESA doses significantly reduced in Ferric Gluconate group at week 12

35 NKF. Am J Kidney Dis 2001;37(1 suppl 1) S 182-238
Maintenance q ½-1 /week 25% q 1-2 /week NKF. Am J Kidney Dis 2001;37(1 suppl 1) S

36 Darbepoietin 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):

37 Darbepoietin 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)
A peptide-based erythropoietin receptor agonist. No structural homology with endogenous EPO no cross react with anti-EPO Ab  apply in PRCA pts once-monthly therapy intravenously or subcutaneously. starting dose: 0.025–0.075 mg/kg. starting dose in PRCA: 0.05 mg/kg. 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;34:1303–1311. 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;35:1201–1208. 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 Alteration of iron balance in CKD
Hb Stability, IV Iron, and ESA: What We Know Suzann VanBuskirk,

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

44 Iron deficiency diagnostic labs

45 IV. iron 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 Additional IV iron should not routinely be administered

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

47 1.Iron dextran 2.Iron gluconate 3.Iron sucrose 4.Ferric Citrate
IV. Iron 1.Iron dextran 2.Iron gluconate 3.Iron sucrose 4.Ferric Citrate

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
D-CKD and ND-CKD treated with ESA Recommend NOT targeting Hgb levels above 13 g/dL. 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 FDA: the New FDA Labeling for ESA
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 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. The New FDA Labeling for ESA—Implications for Patients and Providers B J. Manns, M Tonelli.

53 FDA: the New FDA Labeling for ESA
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. FDA: FDA Drug Safety Communication: Modified Dosing Recommendations to Improve the Safe Use of Erythropoiesis-Stimulating Agents in CKD, 2011. 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.

54 Recent clinical trials comparing in CKD
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. Stroke

55 Persistent low Persistent in target Too low or too high Hb and high variability increase risk of adverse outcome Highest and lowest Hb during 6 month Medicare: all hemodialysis patients who survived the first 6 mo of 2004 low (L; <11 g/dl), intermediate (I; g/dl) high (H; >12.5 g/dl). Ebben JP et al. Clin J Am Soc Nephrol Nov;1(6):

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

57 the TREAT trial 4038 patients Type 2 DN ND-CKD
Darbepoetin alfa vs placebo the TREAT trial Hb 13 g/dL Hb > 9 g/dL Minimal improvement in patient-reported fatigue in the darbepoetin alfa group 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.

58 the TREAT trial 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. . Placebo group: Hb levels increased from a baseline value of 10.4 g/dL to an end-trial value of 11.2 g/dL (median value 10.6 g/dL) making the true definition of a placebo group questionable 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. 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):

59 the United States Normal Hematocrit trial
A cohort of 1233 prevalent CKD 5HD patients with symptomatic heart failure or ischemic heart disease + epoetin alpha 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. 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.

60 Meta-analysis: ESA in CKD
Higher Hb 13 g/dL Lower Hb g/dL 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 Evidence 1. Target Hb in HD & PD  extrapolated from results of trials in CKD patients 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 General Characteristics
จำนวน (คน) % Total 154 Sex male 75 48.7 Age (Median) ปี 60.5 (17-88) DM 54 35

64 กราฟวงกลมแสดงผู้ป่วยที่ได้รับ ESA จำแนกตามประเภท DM

65 General Characteristics
Hb (Mean) g/dl 9.9 Hct (Mean) % 30.3 Duration on ESA 28 mo ± 25.9 (1-122 mo)

66 Take me home Target Hb in HD < 11.5 g/dL, not more than > 13 g/dL intentionally g/dL Start ESA when Hb < 9 g/dL Correct Iron deficiency before start ESA Epoetin alfa and beta can be used as availability Darbepoetin alfa is more convenient for ND-CKD pt


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