Renal Anemia: The Basics Meredith Atkinson, M.D., M.H.S. Associate Professor of Pediatrics Johns Hopkins School of Medicine 16 March 2019 No Disclosures Learning Objectives At the end of this session the listener will be able to: Describe the etiology, epidemiology and adverse associations of the anemia of CKD in children Define anemia and initiate a work-up Describe indications for and approach to iron supplementation Understand the formulations, risks, and benefits of erythropoiesis stimulating agent (ESA) use and dosing schemes Recognize emerging anemia therapies 3 1
Described in 1839..by far the most remarkable character of the blood in the advanced stage of Bright s disease is a gradual and rapid reduction of its colouring no other natural disease comes as close to hemorrhage for impoverishing the red particles of the blood. Fishbane, Spinowitz. Update on Anemia in ESRD and Earlier Stages of CKD: Core Curriculum 2018. AJKD 71(3):423-435. 4 Etiology of Anemia of CKD Erythropoietin dysregulation and deficiency 5 Erythropoietin 2
Figure 5 Cellular basis of erythropoietin deficiency in renal failure Koury, M. J. & Haase, V. H. (2015) Anaemia in kidney disease: harnessing hypoxia responses for therapy Nat. Rev. Nephrol. doi:10.1038/nrneph.2015.82 Figure 2 Normoxia: HIF-α is hydroxylated, degraded Hypoxia: HIF-α translocates to nucleus, binds HIFβ, activates hypoxia response element, EPO transcribed American Journal of Kidney Diseases 2018 71, 423-435DOI: (10.1053/j.ajkd.2017.09.026) Copyright 2017 National Kidney Foundation, Inc. Terms and Conditions Erythropoiesis Stimulating Agents (ESA) 9 3
Erythropoietin Etiology of Anemia of CKD Erythropoietin dysregulation and deficiency Iron deficiency Inflammation-associated iron restriction ESA-Resistant Anemia 11 Decreased GFR = Decreased Hepcidin Excretion IL-6 Adapted from Malyszko et al. Hepcidin in anemia and inflammation in chronic kidney disease. Kidney Blood Press Res. 2007:30(1):15-30. 4
Decreased GFR = Decreased Hepcidin Excretion IL-6 Adapted from Malyszko et al. Hepcidin in anemia and inflammation in chronic kidney disease. Kidney Blood Press Res. 2007:30(1):15-30. Zaritsky et al. Hepcidin and Ferroportin Fe Hepcidin Hepcidin Fe macrophage enterocyte (Donovan et al, 2005; Nemeth et al, 2004) Hepcidin and Ferroportin Decreased Fe recycling Decreased dietary uptake (Donovan et al, 2005; Nemeth et al, 2004) 5
Epidemiology of Anemia in CKD/ESRD Atkinson, et. al. Pediatr Nephrol (2010) 25:1699-1709 16 Hemoglobin versus GFR in children with chronic kidney disease (CKD): Linear threshold model (solid line) and nonparametric smoothing model (dashed line) describing relationship of hemoglobin concentration and GFR in 340 pediatric patients with CKD. Jeffrey J. Fadrowski et al. CJASN 2008;3:457-462 2008 by American Society of Nephrology Etiology of Anemia of CKD Erythropoietin deficiency Iron deficiency Inflammation-associated iron restriction Hyperparathyroidism Uremic toxins /Oxidative stress Other nutritional deficiencies 18 6
Adverse Associations of Anemia Anemia in CKD has been associated with a wide variety of adverse effects/outcomes including: Hospitalization and mortality Decreased quality of life Increased risk for cardiovascular disease and CKD progression Transfusions and allo-sensitization 19 http://www.kdigo.org/clinical_practice_guidelines/pdf/kdigo-anemia%20gl.pdf 20 Definition and Evaluation of Anemia CBC including red blood cell indices, WBC differential, and platelets Absolute reticulocyte count Serum ferritin Serum transferrin saturation, iron % hypochromic red blood cells Reticulocyte hemoglobin content Serum B 12 and folate KDIGO Clinical Practice Guidelines for Anemia in Chronic Kidney Disease. Kidney International 2(4):2012 21 7
Definition and Evaluation of Anemia CBC including red blood cell indices, WBC differential, and platelets Absolute reticulocyte count Serum ferritin Serum transferrin saturation, iron % hypochromic red blood cells Reticulocyte hemoglobin content Serum B 12 and folate Hemoglobin electrophoresis Screen for hemolysis Screen for blood loss KDIGO Clinical Practice Guidelines for Anemia in Chronic Kidney Disease. Kidney International 2(4):2012 22 Iron Deficiency (ID) Correction of ID reduces severity of anemia of CKD Untreated ID is a frequent cause of ESA hypo-responsiveness Risk factors include: Blood loss Inflammation Poor absorption of enteral iron 23 Markers of Iron Availability Ferritin (serum) Intracellular iron-storage protein by inflammation, iron overload Transferrin saturation (TSAT) Transferrin binds to iron in plasma Transports to bone marrow 24 8
KDIGO Iron Targets Iron supplementation to maintain Ferritin > 100 ng/ml TSAT > 20% Ferritin has limitations as a marker of accessible stored iron Hepcidin-mediated iron blockade 25 KDIGO Iron Targets Iron supplementation to maintain Ferritin > 100 ng/ml TSAT > 20% Ferritin has limitations as a marker of accessible stored iron Hepcidin-mediated iron blockade Low ferritin = iron deficiency High ferritin does not rule out iron blockade 26 KDIGO Iron Targets No routine iron supplementation for Ferritin > 500 TSAT > 30% 27 9
Hb grouped by concomitant serum ferritin levels. Dagmara Borzych-Duzalka et al. JASN 2013;24:665-676 2013 by American Society of Nephrology Iron Supplementation: Route Oral/Enteral Pros: inexpensive, available, few adverse effects Cons: poorly absorbed, adherence Dosing: 2-6 mg/kg/day elemental iron Intravenous 29 Iron Supplementation: Route Oral/Enteral Pros: inexpensive, available, few adverse effects Cons: poorly absorbed, adherence IV 30 10
IV Iron: Safety Charytan et al. Considerations and Challenges in Defining Optimal Iron Utilization in Hemodialysis. J Am Soc Nephrol 26:1238-1247:2015 31 IV Iron: Safety Charytan et al. Considerations and Challenges in Defining Optimal Iron Utilization in Hemodialysis. J Am Soc Nephrol 26:1238-1247:2015 32 IV Iron: Safety KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease. Kidney International 2(4): August 2012 Iron is essential for bacterial growth May impair host immune response by decreasing PMN and T-cell function 33 11
Children not on an ESA and not on HD, treat with oral iron unless intolerant or target Hgb is not reached within 3 months On ESA and not on HD trial of oral iron Offer IV iron to children on HD 34 ESA THERAPY 35 ESA Initiation ESA initiation for hemoglobin 9-10 g/dl (90-100 g/l) *Children: maintain hemoglobin 11-12 g/dl (110-120 g/l) 36 KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease. Kidney International 2(4): August 2012 12
Physicians and their patients with chronic kidney disease should weigh the possible benefits of using ESAs to decrease the need for red blood cell transfusions against the increased risks for serious adverse cardiovascular events. For each patient, individualize dosing and use the lowest dose of ESA sufficient to reduce the need for transfusion. Volume 339, Number 9, 1998 For patients with the anemia of chronic kidney disease NOT on dialysis Consider starting ESA treatment only when the hemoglobin level is less than 10 g/dl and when certain other considerations apply If the hemoglobin level exceeds 10 g/dl, reduce or interrupt the dose of ESA. For patients with the anemia of chronic kidney disease on dialysis Initiate ESA treatment when the hemoglobin level is less than 10 g/dl. If the hemoglobin level approaches or exceeds 11 g/dl, reduce or interrupt the dose of ESA. Volume 355, Number 20, 2006 WARNING: ESAs INCREASE THE RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMBOLISM, THROMBOSIS OF VASCULAR ACCESS AND TUMOR PROGRESSION OR RECURRENCE See full prescribing information for complete boxed warning. 37 Amaral et al. Association of Mortality and Hospitalization with Achievement of Adult Hemoglobin targets in Adolescents Maintained on Hemodialysis. JASN 17: 2878-2885, 2006 680 HD patient Increased mortality with lower hemoglobin 38 Dahlinghaus et al. Hemoglobin level and risk of hospitalization and mortality in children on peritoneal dialysis. Pediatric Nephrology 29: 2387-2394, 2014 Subjects with hemoglobin > 11 g/dl (110 g/l) were less likely to be hospitalized and had no difference in mortality risk Hemoglobin > 12 vs. 11-12 g/dl not associated with increased risk What is the optimal hemoglobin level for pediatric CKD patients? 39 13
Types of ESA Epoetin alfa/beta Dosed 1-3 times weekly Longer half-life when given subcutaneously (19-24 hrs) than IV (6-8 hrs) Darbepoetin alfa Given SC weekly or every 2 weeks Efficacy 40 Darbepoietin two additional sialic-acidcontaining carbohydrates result in extended in vivo biologic activity 41 RCT Darbepoetin alfa associated with higher pain perception Buffer ph more physiologic in epogen 42 14
Types of ESA Continuous EPO receptor activators (CERA) Methoxy polyethylene glycol-epoetin beta (Mircera Hoffman-La Roche) SC or IV administration Approved for clinical use in 2007 43 Integration of a large methoxy polyethylene glycol polymer chain Extended half-life of up to 130 hours 44 45 15
ESA: ADVERSE ASSOCIATIONS 46 Borzych-Duzalka et al. 47 No association between Hgb > 12 and increased risk for cardiovascular morbidity in children Children with Hgb > 12 had lower frequency or no difference in number of cardiac visits, lower all-cause mortality, and lower all-cause hospitalizations Rheault et al. Hemoglobin of 12 g/dl and above is not associated with increased cardiovascular morbidity in children on hemodialysis. Kidney International 2017;91:177-182. 48 16
ESA Dosing Goal rate of hemoglobin increase: 1-2 g/dl/month Epoetin alfa or beta 20-50 IU/kg/dose three times weekly IV or SC Darbepoetin alfa 0.45 µg/kg SC or IV weekly 0.75 µg/kg SC or IV every 2 weeks 49 Darbepoetin alfa can be safely administered either weekly or q 2 weeks in ESA-naïve pediatric pts to achieve Hgb targets of 10-12. Warady et al. De novo weekly and biweekly darbepoetin alfa dosing in pediatric patients with chronic kidney disease. Pediatric Nephrology. 2018;33:125-137. 50 ESA Dosing 275-350 units/kg/week in infantskoshy et al. Anemia in children with CKD. Ped Neph 23: 2008 200-250 units/kg/week in older childrenkoshy et al. Anemia in children with CKD. Ped Neph 23: 2008 Children and adolescents on HD may require higher absolute doses than adults despite lower body weightbamgbola et al. Analyses of age, gender, and other risk factors for Epo resistance. Ped Neph 24:2009 Increased drug clearance with growth? 51 17
ESA Dosing Make dose adjustments after 4 weeks of therapy No more often than q 2 weeks When a decrease in hemoglobin is necessary, decrease dose rather than hold therapy Long-acting ESAs lower starting dose and less frequent adjustments 52 ESA Dosing CERA Approved with initial starting dose of 0.6 mcg/kg IV or SC every 2 weeks Subsequent monthly dosing Conversion dosing for children 5-17 yrs 4 µg every 4 weeks for each 125 IU epoetin alfa/beta or 0.55 µg darbepoetin 53 Regional variation of anemia control. Dagmara Borzych-Duzalka et al. JASN 2013;24:665-676 2013 by American Society of Nephrology 18
ESA Hypo-Responsiveness 56 KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease. Kidney International 2(4): August 2012 Transfusion Balance risks and benefits to patient HLA sensitization 57 KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease. Kidney International 2(4): August 2012 19
Emerging Anemia Therapies HIF prolyl hydroxylase inhibitors Stabilize HIF Stimulate endogenous EPO synthesis Decrease hepcidin Hepcidin modulators Iron supplementation Ferric citrate as a phosphate binder Soluble ferric pyrophosphate 58 Summary Impaired EPO production and iron-restricted erythropoiesis are primary causes of anemia, and are the mechanisms targeted by current therapies Ongoing therapeutic challenges include Identifying optimal hemoglobin levels in children Limitations of ferritin to identify patients with ironrestriction who may benefit from additional iron supplementation Safety and efficacy of escalating ESA dose for resistant anemia 59 The chief post-natal site of erythropoietin production is: 1. Liver 2. Tubular epithelial cell 3. Bone marrow 4. Peritubular interstitial cell 5. All of the above 60 20
Thank you for your attention! 61 IV Iron: Safety Ferritin 500-1200 ng/ml TSAT < 25% 62 Limitations of Ferritin 304 children Ferritin > 100 ng/ml, serum iron < 50 µg/dl, and lower GFR were most strongly associated with lower hemoglobin percentile TSAT > 20% was associated with only a modest increase in hemoglobin percentile 63 21
Types of ESA Epoetin alfa/beta Dosed 1-3 times weekly Longer half-life when given subcutaneously (19-24 hrs) than IV (6-8 hrs) Darbepoetin alfa Given weekly or every 2 weeks Efficacy Warady et al. Darbepoetin alfa for the treatment of anemia in pediatric patients with chronic kidney disease. Pediatric Nephrology. 21:1144-1152. 2006 64 USRDS data 22,820 HD patients IV iron within 14 days of hospitalization for bacterial infection 11% received additional IV iron after admission No increased risk for 30- day or 1-year mortality, longer LOS, readmission or death within 30 days 65 Diagnosing ID 66 22
Diagnosing ID TSAT and serum ferritin have only limited sensitivity and specificity in patients with CKD for prediction of bone marrow iron stores and erythropoietic response to iron supplementation We do not recommend routine use of iron supplementation in patients with TSAT > 30% or serum ferritin > 500 mg/ml Ferritin levels need to be interpreted with caution 67 Higher hepcidin levels associated with Decreased hemoglobin Increased risk for incident anemia over time 68 69 23
Cano et al. Continuous EPO receptor activator therapy of anemia in children under peritoneal dialysis SC CERA dosed once every 2 weeks in 16 children on PD Target Hgb reached by month 3, no adverse effects 70 Lestz et al. Association of higher erythropoiesis stimulating agent dose and mortality in children on dialysis. Pediatric Nephrology 29: 2820-2829, 2014 71 Pure Red Cell Aplasia Sudden onset of severe, transfusiondependent anemia after at least 8 weeks of therapy Rare: 0.5 cases/10,000 pt years Neutralizing antibodies to ESA and endogenous EPO Rare with IV administration Treatment: stop ESA 72 24