Anemia Management in Hemodialysis Patients Assoc. Prof. Bancha Satirapoj, MD Division of Nephrology Department of Medicine Phramongkutklao Hospital and College of Medicine
Outline ❖ Physiologic changes and anemic evaluation ❖ Target of hemoglobin in patients with CKD ❖ ESA treatment of anemia in CKD and dialysis ❖ ESA resistance and side effects ❖ Iron treatment in hemodialysis ❖ Novel treatment in anemia of CKD
Diagnosis and evaluation of anemia in CKD Age or gender group Hb below (g/dl) Children 11.0 11.5 6 months to 5 years 12.0 5 to 11 years 12.0 12 to 14 years 13.0 Women > 15 years (non-pregnant) Men > 15 years KDIGO Clinical Practice Guideline for Anemia in CKD Kidney Int. 2012; 2: 279–335.
Higher prevalence of anemia with diabetes mellitus in moderate kidney insufficiency El-Achkar TM, et al. Kidney Int. 2005; 67(4):1483-8.
Higher prevalence of anemia with diabetes mellitus in moderate kidney insufficiency Multivariable logistic regression model evaluating factors associated with anemia El-Achkar TM, et al. Kidney Int. 2005; 67(4):1483-8.
Dialysis patients with Hb<10 g/dL in 2007-2015 Percent of cases 50 43 42.2 44.3 50.3 43.7 41.4 42.5 40 36.8 31.6 30 20 10 0 2007 2008 2009 2010 2011 2012 2013 2014 2015 Chuasuwan A., Lumpaopong A. THAILAND RRT YEAR 2015
Common Causes of Anemia in CKD Fishbane S, et al. Am J Kidney Dis. 2018;71(3):423-435.
Frequency of testing for anemia CKD III CKD patients without CKD patients with CKD IV-V anemia anemia not being CKD 5PD treated with an ESA CKD 5HD Yearly 3 months 6 months 3 months 3 months 3 months 3 months 1 months KDIGO Clinical Practice Guideline for Anemia in CKD Kidney Int. 2012; 2: 279–335.
Adverse Consequences of anemia ❖ Fatigue, dizziness, shortness of breath ❖ Poor quality of life ❖ Increase hospital days ❖ Left ventricular hypertrophy ❖ Increased CV morbidity and mortality
Pathophysiology of the cardiorenal anemia syndrome Besarab A, et al. The Oncologist 2009; 14 (suppl1): 22–33
Pathophysiology of the cardiorenal anemia syndrome Besarab A, et al. The Oncologist 2009; 14 (suppl1): 22–33
Erythropoietin (EPO) and iron are both important in erythropoiesis Besarab A, et al. The Oncologist 2009; 14 (suppl1): 22–33
Cellular basis of erythropoietin deficiency in renal failure EPCs or interstitial cells with EPC potential transdifferentiate into myofibroblasts, which synthesize collagen and losKeoutrhye, iMr.aJb. &iliHtyaatosep, rV.oHd.uNcaet.ERPevO. Nephro 2015: 11, 394–410.
Regulation of HIF degradation by PHDs and hypoxic induction of erythropoietin Koury, M. J. & Haase, V. H. Nat. Rev. Nephro 2015: 11, 394–410. 2OG, 2-oxoglutarate; ARNT, aryl hydrocarbon receptor nuclear translocator; EPO, erythropoietin gene; Fe2+, ferrous iron; HIF, hypoxia-inducible factor; HNF-4, hepatocyte nuclear factor 4; PHD, prolyl-4-hydroxylase domain.
Under normoxia Under hypoxic conditions Fishbane S, et al. Am J Kidney Dis. 2018;71(3):423-435.
All ESAs act on the same target receptor... EPO, Darbepoetin C.E.R.A. EPO-mimetic rHuEPO alfa Peg-rHuEPO peptide Membrane Jak2 Jak2 Jak2 Jak2 Jak2 Jak2 Jak2 Jak2 P PP P Signal Survival, differentiation, proliferation and transduction maturation of RBC progenitors and precursors Gene activation Bunn HF. Cold Spring Harb Perspect Med. 2013; 3:a011619. C.E.R.A., continuous erythropoietin receptor activator; EPO, erythropoietin; Jak, janus kinase; RBC, red blood cell
Erythropoietin (EPO) and iron are both important in erythropoiesis Besarab A, et al. The Oncologist 2009; 14 (suppl1): 22–33
Iron absorption and metabolism is controlled by several proteins Nakhoul G, et al. CLEVELAND CLINIC JOURNAL OF MEDICINE 2016: 613-624.
Investigation of anemia ❖ Complete blood count (CBC) ❖ Absolute reticulocyte count: BM erythropoietic activity ❖ Serum ferritin ❖ Serum transferrin saturation (TSAT) ❖ Serum vitamin B12 and folate levels KDIGO Clinical Practice Guideline for Anemia in CKD Kidney Int. 2012; 2: 279–335.
K/DOQI 2007: IRON status ❖ Serum ferritin ❖ >100 ng/mL among CKD and PD patients ❖ >200 ng/mL among HD patients ❖ TSAT (serum iron/TIBC) >20 % ❖ Percentage of hypochromic cells >10% ❖ Reticulocyte hemoglobin content < 29 pg/cell NKF-K/DOQI: 2007 update. Am J Kidney Dis 2007; 50:474.
Accuracy of serum Ferritin and Transferrin Saturation in Diagnosis of Functional iron deficiency among dialysis patients Tsat (%) Sensitivity (%) Specificity (%) <15 16 88 <18 58 75 <21 81 63 <24 88 44 <27 92 22 <30 96 11 Nissenson, AR. Am J Kidney disease 1997; 30: 907
Accuracy of serum Ferritin and Transferrin Saturation in Diagnosis of Functional iron deficiency among dialysis patients Serum ferritin Sensitivity (%) Specificity (%) (ng/mL) <50 37 75 <100 48 75 <150 71 69 <200 77 37 <300 90 18 <500 100 0 Nissenson, AR. Am J Kidney disease 1997; 30: 907
Recommendations for When to Treat With Iron in CKD ❖ For adult CKD patients with anemia not on iron or ESA therapy we suggest a trial of IV iron or in CKD ND patients alternatively a 1–3 month trial of oral iron therapy if (2C): ❖ An increase in Hb concentration without starting ESA treatment is desired* and ❖ TSAT is <30% and ferritin is <500 ng/mL ❖ Example: ❖ Hb 8.5, TSAT 25% + Ferritin 400 ng/mL ❖ Hb 11.5, TSAT 25% + Ferritin 400 ng/mL KDIGO Clinical Practice Guideline for Anemia in CKD Kidney Int. 2012; 2: 279–335.
Recommendations for When to Treat With Iron in CKD ❖ For adult CKD patients on ESA therapy who are not receiving iron supplementation, we suggest a trial of IV iron or in CKD ND patients alternatively a 1–3 month trial of oral iron therapy) if (2C): ❖ An increase in Hb concentration or a decrease in ESA dose is desired and ❖ TSAT is <30% and ferritin is <500 ng/mL KDIGO Clinical Practice Guideline for Anemia in CKD Kidney Int. 2012; 2: 279–335.
Additional tests ❖ High sensitivity C-reactive protein (CRP) may be indicated if occult inflammation ❖ Level of erythropoietin: not recommend KDIGO Clinical Practice Guideline for Anemia in CKD Kidney Int. 2012; 2: 279–335.
Outline ❖ Physiologic changes and anemic evaluation ❖ Target of hemoglobin in patients with CKD ❖ ESA treatment of anemia in CKD and dialysis ❖ ESA resistance and side effects ❖ Iron treatment in hemodialysis ❖ Novel treatment in anemia of CKD
Probability of death orUS Normalization of hematocrit study Myocardial infarction (%) Normal-Hct group: 42% 60- N=618 50- 40- 30- Low-Hct group; 30% N=615 20- 10- The study was discontinue on 29 months 0- 0 3 6 9 12 15 18 21 24 27 30 Months after randomization One-year and two-year mortality rates were 7 % higher in the normal Hct group than in the low Hct group. Besarab a et al N Engl J Med 1998;339:584-590.
US Normalization of hematocrit study ❖ Thrombosis of vascular access ❖ 39% in intervention vs 29% in control (p=0.01) ❖ Grafts and fistula clotted more often ❖ CHF or ischemic heart disease on hemodialysis ❖ Administration of EPO to raise Hct to 42% is not recommended Besarab a et al N Engl J Med 1998;339:584-590.
CHOIR and CREATE Studies CHOIR CREATE (n=1432) (n=605) Patient Population Stage 3-4 patients with renal anaemia and Stage 3-4 CKD patients with renal not on renal replacement therapy (RRT)† anaemia not on RRT‡ Duration 16 months 48 months Primary Endpoints 700 patients completed trial 476 patients completed trial Composite Composite (sudden death, MI, acute HF, CVA, TIA, (death, MI, HF, stroke) hosp for angina or arrhythmia, PVD complications) Hb Targets Group 1: 13.5 g/dL* Group 2: 11.3 g/dL* Group 1: 13-15 g/dL *Original targets before protocol Group 2: 10.5-11.5 g/dL amendment: Singh et al. N Engl J Med 2006;355:2085–2098 Group 1: 13.0-13.5 g/dL Drüeke et al. N Engl J Med 2006;355:2071–2084 Group 2: 10.5-11.0 g/dL
CHOIR: Increased Risk of Composite Event with Target Hb 13.5 g/dL Stage 3-4 CKD patients Time to the primary composite end point Hb target 13.5 g/dL Hb target 11.3 g/dL Hb 13.5 g/dL 0.30 Probability of 0.25 Hb 11.3 g/dL Composite Event 0.20 Events: 125 vs 97 0.15 HR=1.34 (1.03–1.74) 0.10 Log rank test p=0.03 0.05 0.00 Month 0 3 6 9 12 15 18 21 24 27 30 33 36 39 Target Hb level of 13.5 g/dL is associated with increased risk Singh et al. N Engl J Med 2006;355:2085–2098
CREATE: No Significant Difference in Time to First CV Event CKD patients not on dialysis Time to the primary end point of a first cardiovascular event* Event-free Survival (%) 100 Hb target 13-15 g/dL 90 Hb target 10.5-11.5 g/dL 80 70 Events: 58 vs 47 60 HR=0.78 (0.53–1.14) 50 Log rank test p=0.20 40 30 6 12 18 24 30 36 42 48 2 20 Month 2 10 0 Patients at risk 301 279 268 249 207 158 97 56 0 302 286 272 257 223 177 121 61 Group 1 Group 2 I*n paBtieefonrtescewnistohrinCgKoDf d, aetaarolnypcatoiemntspalet ttheectiomreroefction of anemia does not reduce the risk of CVS events initiation of dialysis Drüeke et al. N Engl J Med 2006;355: 2071–2084
Increased risk of fatal or nonfatal stroke with darbepoetin alfa (HR 1.92, 95% CI 1.38-2.68) Pfeffer MA, et al. N Engl J Med. 2009;361(21):2019.
All cause mortality Stroke events Despite initiating dialysis therapy with a higher hemoglobin level, prior treatment with darbepoetin was not associated with a reduction in mortality, but a higher frequency of stroke was observed Mc Causland FR, et al. Am J Kidney Dis. 2019; 73(3):309-315.
ESA initiation therapy ❖ For adult CKD ND patients with Hb < 10.0 g/dL, ❖ Initiate ESA therapy should be individualized based on the rate of fall of Hb, prior response to iron therapy, the risk of needing a transfusion, the risks related to ESA therapy and the presence of anemic symptoms 2C) ❖ For adult CKD 5D patients ❖ Starting ESA therapy when the hemoglobin is between 9.0–10.0 g/dL (2B) KDIGO Clinical Practice Guideline for Anemia in CKD. Kidney Int. 2012; 2: 279–335.
ESA maintenance therapy ❖ In all patients, we recommend that ESAs not be used to intentionally increase Hb above 13 g/dl (1A) ❖ In general, we suggest that ESAs not be used to maintain Hb concentration above 11.5 g/dl (2C) KDIGO Clinical Practice Guideline for Anemia in CKD. Kidney Int. 2012; 2: 279–335.
Target Hb during ESA treatment is an important determinant of the balance of benefits and risks Prefer Hb levels 10-11.5 g/dL range for patients with CKD Fishbane S, et al. Am J Kidney Dis. 2018;71(3):423-435.
Outline ❖ Physiologic changes and anemic evaluation ❖ Target of hemoglobin in patients with CKD ❖ ESA treatment of anemia in CKD and dialysis ❖ ESA resistance and side effects ❖ Iron treatment in hemodialysis ❖ Novel treatment in anemia of CKD
Erythropoietin(EPO) ❖ Glycoprotein- a hematopoietic growth factor of red blood cells (erythrocytes) in mammals ❖ Cytokine for erythrocyte precursors (hematopoietin or hemopoietin)- produced in the kidney and liver
ESA Therapy ESAs Characteristics Dose Half-life IV Half-life (hour) SC (hour) EPO-alfa EPO-beta Recombinant human EPO 20-50 IU/kg 6-8 19-24 1-3 dose/week Darbepoetin alfa Recombinant human EPO 0.45 mcq/kg every 1 week 24 48-72 with hyperglycosylation 0.75 mcq/kg every 2 weeks Erythropoietin Recombinant human EPO 0.6 mg/kg every 2 weeks 130 130 receptor activator with pegylation 1.2 mg/kg every 4 weeks (CERA) Satirapoj B, Editor. Manual of Dialysis 2018
Lower dose for SC compared with IV within each hemoglobin category by 20%–28% (P<0.001) IV route SC route Wright DG, et al. Clin J Am Soc Nephrol 2015: 10: 1822–1830.
Chuasuwan A., Lumpaopong A. THAILAND RRT YEAR 2015
ESA administration ❖ For CKD 5HD patients and those on hemofiltration or hemodiafiltration therapy, we suggest either intravenous or subcutaneous administration of ESA. (2C) ❖ For CKD ND and CKD 5PD patients, we suggest subcutaneous administration of ESA. (2C) KDIGO Clinical Practice Guideline for Anemia in CKD. Kidney Int. 2012; 2: 279–335.
Type of ESA ❖ We recommend choosing an ESA based on the balance of pharmacodynamics, safety information, clinical outcome data, costs, and availability. (1D) ❖ We suggest using only ESAs that have been approved by an independent regulatory agency. ❖ Specifically for ‘copy’ versions of ESAs, true biosimilar products should be used. (2D) KDIGO Clinical Practice Guideline for Anemia in CKD. Kidney Int. 2012; 2: 279–335.
Cochrane Database of Systematic Reviews 2014, Issue 12. Art. No.: CD010590.
Networks of the treatment efficacy and safety of ESA drugs in the treatment of anaemia in chronic kidney disease Cochrane Database of Systematic Reviews 2014, Issue 12. Art. No.: CD010590.
Forest plots for results from network meta-analyses comparing ESAs versus placebo All cause mortality Odds ratio (95% CI) Odds ratio (95% CI) Epoetin beta Placebo Darbepoetin alfa Methoxy-polyethylene glycol-epoetin beta No treatment Rpoetin alfa Biosimilar ESA Transfusion Epoetin beta Placebo Darbepoetin alfa Methoxy-polyethylene glycol-epoetin beta No treatment Rpoetin alfa Biosimilar ESA Cochrane Database of Systematic Reviews 2014, Issue 12. Art. No.: CD010590.
CREATE: No Significant Difference in Time to First CV Event CKD patients not on dialysis General health and physical function improved significantly in high hemoglobin targets ❖ 603 patients with CKD and mild-to-moderate anemia (Hb, 11.0 to 12.5 g/dL to a target 13.0 to 15.0 d/dL, group 1) or the subnormal range (10.5 to 11.5 g/dL, group 2). Drüeke et al. N Engl J Med 2006;355: 2071–2084
ESA treatment can improve exercise tolerance, reduce symptoms, and have benefits on clinical outcomes in anemic patients with heart failure Kotecha D, et al. Am Heart J 2011;161:822-831.e2.
❖ 27 trials (10,452 patients) ❖ A higher hemoglobin target was associated with increased risks for ❖ Stroke (RR 1.51 [95% CI, 1.03 to 2.21]) ❖ Hypertension (RR, 1.67 [95%CI, 1.31 to 2.12]) ❖ Vascular access thrombosis (RR, 1.33 [95%CI, 1.16 to 1.53]) ❖ No statistically significant differences in the risks for mortality, serious CV events or ESRD Palmer SC, et al. Ann Intern Med. 2010;153:23-33.
Coyne DW, et al. Kidney Int Supplements (2017) 7, 157–163 .
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