Presentation on theme: "Anemia management in Hemodialysis"— Presentation transcript:
1Anemia management in Hemodialysis Faculty of MedicineAnemia management in HemodialysisChan-on C. MD.
2Content Definition Impact Causes Investigation and monitoring ManagementESA in CKD,PD,HD patients in KKU
3Take me homeTarget Hb in HD < 11.5 g/dL, not more than > 13 g/dL intentionallyg/dLStart ESA when Hb < 9 g/dLCorrect Iron deficiency before start ESAEpoetin alfa and beta can be used as availabilityDarbepoetin alfa is more convenient for ND-CKD pt
4Definition 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 forAnemia in Chronic Kidney Disease. Kidney inter., Suppl. 2012; 2: 279–335.
5Mortality/ QOLAnemia in CKD/HDImpactHealth budget
6Infection/ inflammation SI TIBC Approach anemia in HDInfection/ inflammationSITIBCeGFR< 60 ml/min/1.73m2Anemic symptomsHbNormal: F/UHb < 13 g/dL MaleHb < 12 g/dL FemaleHb < 13 g/dL MaleHb < 12 g/dL FemaleTSAT=SI/TIBCAnemic work-up: CBC: Rbc indeces/reticulocyte/serum iron/ TIBC/TSAT/Ferritin/GI bleedingTIBC > 200 mg/dLModified 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 < 200Absolute Iron deficiencyTSAT < 20%Ferritin > 200Functional Iron deficiencyModified from Intravenous Iron Versus Erythropoiesis-Stimulating Agents: Friends or Foes in TreatingChronic 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: ppTSAT > 20%Ferritin > 200 No IDAIV ironESA therapyESA hyporesponsivenessF/U at 4th wks no Hb response ESA hyporesponsiveness
7Hb levels and cardiovascular comorbidity Impact of anemia in CKD- left ventricular hypertrophy (LVH)- Precipitating factor for congestive heart failure (CHF)- Exacerbation of anginaReductions in- Aerobic capacity- Overall well-being- CognitionErslev AJ. NEJM 1991, 324:ASHD: atherosclerotic heart disease CHF: congestive heart failureother 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
9Kidney function decline, Hb decrease, LVH increase LVH is an independent risk factor for death in patients with ESRDCoresh J. et al. Arch Intern Med. 2001, Levin A. et al. AJKD 1996;27: Levin A. et al. AJKD 1999,
10LV 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 thicknessLV geometry changed in high BP and volume overload
17Rbc 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
18The 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 countAbsolute reticulocyte countSerum ferritin levelSerum transferrin saturation (TSAT)Serum vitamin B12 and folate levelsTest for stool occult bloodKidney Disease: Improving Global Outcomes (KDIGO) Anemia Work Group. KDIGO Clinical Practice Guideline forAnemia in Chronic Kidney Disease. Kidney inter., Suppl. 2012; 2: 279–335.
22In Chronic anemia In Urgent treatment ESA ineffective: hemoglobinopathies/BM failure/ ESA resistanceESA gives risk outweigh benefit: previous or current malignancy, previous strokeIn Urgent treatmentrapid correction of anemia: bleeding/ hemorrhagic shockrapid pre-operative Hb correction
23Rapid 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 BLMurphy MF, Wallington TB, Kelsey P et al. Guidelines for the clinical use of red cell transfusions. Br J Haematol 2001; 113: 24–31.
24Pre-op transfusion in HD Healthy/stableHigh-risk patients>65 years and/orwith CV or RS diseaseHb > 10 g/dL not recommendedshould be given Hb < 7 g/dltolerate anemia poorlyHb < 8 g/dl2 unit PRC transfusion then re-evaluateHb 7-10 g/dL unclearMurphy MF, Wallington TB, Kelsey P et al. Guidelines for the clinical use of red cell transfusions. Br J Haematol 2001; 113: 24–31.
25Blood transfusion: High PRA longer waiting time be excluded from listlower survivalIncreased risk of early and late graft lossmean wait-time to transplant USRDS data reported in 2010 Transfused pt > non-transfused pt 2 monthsthe number of HLA molecules contributed by the red cells is comparable to that of leukocytesBalasubramaniam 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.
27Erythropoietin stimulating agents The response to EPO is dose-dependent, but great variationThe response depends on the route (iv. versus sc.) and the frequency of administration.The response may be limited by many factorsStroke, mortality, and hypertension may complicated
31Darbepoetin alfa structurally different from endogenous erythropoietin Epoetin alfa and beta = endogenous erythropoietin (immunological/biological)N-linked oligosaccharideDarbepoetin alfa structurally different from endogenous erythropoietin- oligosaccharide chains- amino acid sequence rearranged- larger molecular weightClinical significance of different molecular structure is unknownThe terminal half-life of Aranesp® was ~ 3-fold longer than that of Epoetin alfa when administered intravenously.
33Iron repletion before ESA initiation KDOQI. Am J Kidney Dis 2001;37 (suppl):S182-S238
34DRIVE studies: ESA doses significantly reduced in Ferric Gluconate group at week 12
35NKF. Am J Kidney Dis 2001;37(1 suppl 1) S 182-238 Maintenanceq ½-1 /week25%q 1-2 /weekNKF. Am J Kidney Dis 2001;37(1 suppl 1) S
36DarbepoietinKrause 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):
37Darbepoietinde novo q2w darbepoetin alfa is a well tolerated and effective treatment for correcting anaemia in older patients with CKD not receiving dialysis.
39Peginesatide (Hematide) A peptide-based erythropoietin receptor agonist.No structural homology with endogenous EPO no cross react with anti-EPO Ab apply in PRCA ptsonce-monthly therapyintravenously 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.
40ESA 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 marrowHemolysisAluminum toxicityOsteitis fibrosa cysticaKDOQI 2000 Anemia Guidelines Am J Kidney Dis Jan;37(1 Suppl 1):S Kotanko P et al. Semin Dial Sep-Oct;19(5):
45IV. ironPrefer IV route of iron administration in CKD 5HD patients over oral iron with and without concomitantESA treatmentInadequacy of oral iron- Low intestinal absorption of oral iron- Poor patient adherenceAdditional IV iron should not routinely be administered
46Iron targets Individualized depend on pt status If serum ferritin > 500 ng/mlSerum ferritin is not predictive for iron responseTSAT > 25 is not predictive for iron responseKDOQI AJKD 2006
48IV Iron therapyCommon 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
49IV. Iron Disadvantages of IV Iron in CKD Short-term adverse events Iron overloadIncreased risk of infectionIncreased oxidative stressIncreased death risk (?)**Both decreased and increased death risk have been postulated with IV iron administration.Reducing ESA doseImproving ESA hyporesponsivenessMitigating hemoglobin variabilityMitigating risk of thrombocytosisReducing likelihood of blood transfusionCircumventing the need for oral ironsupplementationBeyond anemia effectsTreatment of restless legImproving cognitive functionDecreasing 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
51Current concept: partial correction D-CKD and ND-CKD treated with ESARecommend NOT targeting Hgb levels above 13 g/dL.Trials in predialysis-CKD, suggest thatHb levels near normal range ~ moderate anemiasame in clinical benefit but increased risk of adverse outcomesD-CKD : dialysis dependent CKDND-CKD: non-dialysis dependent CKD
52FDA: the New FDA Labeling for ESA Individualizing therapy for each ptUsing the lowest possible ESA dose requiredto reduce the need for transfusionsThe new labels recommend reducing the ESA dose when Hb > 10 g/dL in ND-CKD andHb > 11 g/dL in D-CKD patientsDoes 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.
53FDA: the New FDA Labeling for ESA For D-CKDInitiate 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.
54Recent clinical trials comparing in CKD the use of ESA targeting low (HB 9 –11.5 g/dL) andnear-normal Hb targets (Hb >13.0 g/dL)no improvements in clinical outcomespotential harm for ESA use targeting near- normal Hb targets.Stroke
55Persistent lowPersistent in targetToo low or too high Hb and high variability increase risk of adverse outcomeHighest and lowest Hb during 6 monthMedicare: all hemodialysis patients who survived the first 6 mo of 2004low (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):
56CKD HD The Normal Hematocrit Cardiac Trial (NHCT) CREATE CHOIR TREAT trialHDThe Normal Hematocrit Cardiac Trial (NHCT)
57the TREAT trial 4038 patients Type 2 DN ND-CKD Darbepoetin alfa vs placebothe TREAT trialHb 13 g/dLHb > 9 g/dLMinimal improvement in patient-reported fatigue in the darbepoetin alfa groupPfeffer 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.
58the TREAT trialDarbepoetin in T2DM + CKD did not reduce the risk of either death or a cardiovascular event or death or a renal eventassociated 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 questionablePfeffer 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):
59the United States Normal Hematocrit trial A cohort of 1233 prevalent CKD 5HD patients with symptomatic heart failure or ischemic heart disease + epoetin alphaMean 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.
60Meta-analysis: ESA in CKD Higher Hb 13 g/dL Lower Hb g/dLin the higher Hb target groupsignificantly 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)
61Evidence1. Target Hb in HD & PD extrapolated from results of trials in CKD patients2. Outcome: target Hb surrogate outcome
62ESA in CKD,PD,HD patients in KKU Setting: CKD clinic, HD unit, PD unitPopulation: PD, HD, CKD patients received ESAtreatmentData collection and analysis: Kridsada Sirichaisit MD.Wilaiporn Wasuthapitak MD.
64กราฟวงกลมแสดงผู้ป่วยที่ได้รับ ESA จำแนกตามประเภท DM
65General Characteristics Hb (Mean) g/dl9.9Hct (Mean) %30.3Duration on ESA28 mo ± 25.9 (1-122 mo)
66Take me homeTarget Hb in HD < 11.5 g/dL, not more than > 13 g/dL intentionallyg/dLStart ESA when Hb < 9 g/dLCorrect Iron deficiency before start ESAEpoetin alfa and beta can be used as availabilityDarbepoetin alfa is more convenient for ND-CKD pt