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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 therapies03/20/2019 3

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• “..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.

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Described in 1839

Fishbane, Spinowitz. Update on Anemia in ESRD and Earlier Stages of CKD: Core Curriculum 2018. AJKD 71(3):423-435.

Etiology of Anemia of CKD

• Erythropoietin dysregulation and deficiency

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Erythropoietin

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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 therapyNat. Rev. Nephrol. doi:10.1038/nrneph.2015.82

Figure 2

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

Normoxia: HIF-α is hydroxylated, degraded

Hypoxia: HIF-αtranslocates to nucleus, binds HIF-β, activates hypoxia response element, EPO transcribed

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Erythropoiesis Stimulating Agents (ESA)

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Erythropoietin

Etiology of Anemia of CKD

• Erythropoietin dysregulation and deficiency

• Iron deficiency

• Inflammation-associated iron restriction

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ESA-Resistant Anemia

IL-6

Decreased GFR =Decreased HepcidinExcretion

Adapted from Malyszko et al. Hepcidin in anemia and inflammation in chronic kidney disease. Kidney Blood Press Res. 2007:30(1):15-30.

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IL-6

Decreased GFR =Decreased HepcidinExcretion

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

macrophage enterocyte

Fe

Fe

Hepcidin Hepcidin

(Donovan et al, 2005; Nemeth et al, 2004)

Decreased Ferecycling

Decreased dietary uptake

Hepcidin and Ferroportin

(Donovan et al, 2005; Nemeth et al, 2004)

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Epidemiology of Anemia in CKD/ESRD

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Atkinson, et. al. Pediatr Nephrol(2010) 25:1699-1709

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

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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

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http://www.kdigo.org/clinical_practice_guidelines/pdf/KDIGO-Anemia%20GL.pdf

Definition and Evaluation of Anemia

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KDIGO Clinical Practice Guidelines for Anemia in Chronic Kidney Disease. Kidney International 2(4):2012

• 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 B12 and folate

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Definition and Evaluation of Anemia

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KDIGO Clinical Practice Guidelines for Anemia in Chronic Kidney Disease. Kidney International 2(4):2012

• 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 B12 and folate• Hemoglobin electrophoresis• Screen for hemolysis• Screen for blood loss

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 iron03/20/2019 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

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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

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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 blockade03/20/2019 26

KDIGO Iron Targets

• No routine iron supplementation for– Ferritin > 500

– TSAT > 30%

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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

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Iron Supplementation: Route

• Oral/Enteral– Pros: inexpensive, available, few adverse

effects

– Cons: poorly absorbed, adherence

• IV

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IV Iron: Safety

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Charytan et al. Considerations and Challenges in Defining Optimal Iron Utilization in Hemodialysis. J Am Soc Nephrol 26:1238-1247:2015

IV Iron: Safety

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Charytan et al. Considerations and Challenges in Defining Optimal Iron Utilization in Hemodialysis. J Am Soc Nephrol 26:1238-1247:2015

IV Iron: Safety

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• Iron is essential for bacterial growth

• May impair host immune response by decreasing PMN and T-cell function

KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease. Kidney International 2(4): August 2012

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• 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

ESA THERAPY

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ESA Initiation

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KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease. Kidney International 2(4): August 2012

• ESA initiation for hemoglobin 9-10 g/dl (90-100 g/l)

• *Children: maintain hemoglobin 11-12 g/dl (110-120 g/l)

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Volume 339, Number 9, 1998

Volume 355, Number 20, 2006

• 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.

• 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.

“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.

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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

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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?

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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

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• Darbepoietin – two additional sialic-acid-containing carbohydrates result in extended in vivo biologic activity

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• RCT• Darbepoetin alfa associated with higher pain perception• Buffer pH – more physiologic in epogen

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Types of ESA

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• Continuous EPO receptor activators (CERA)

– Methoxy polyethylene glycol-epoetinbeta (Mircera® Hoffman-La Roche)

• SC or IV administration

• Approved for clinical use in 2007

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• Integration of a large methoxy polyethylene glycol polymer chain • Extended half-life of up to 130 hours

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ESA: ADVERSE ASSOCIATIONS

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03/20/2019 47Borzych-Duzalka et al.

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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.

• 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

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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 weeks03/20/2019 49

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Warady et al. De novo weekly and biweekly darbepoetin alfa dosing in pediatric patients with chronic kidney disease. Pediatric Nephrology. 2018;33:125-137.

• Darbepoetin alfa can be safely administered either weekly or q 2 weeks in ESA-naïve pediatric pts to achieve Hgb targets of 10-12.

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? 03/20/2019 51

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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

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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

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Regional variation of anemia control.

Dagmara Borzych-Duzalka et al. JASN 2013;24:665-676

©2013 by American Society of Nephrology

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ESA Hypo-Responsiveness

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KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease. Kidney International 2(4): August 2012

Transfusion

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KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease. Kidney International 2(4): August 2012

• Balance risks and benefits to patient• HLA sensitization

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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 pyrophosphate03/20/2019 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 iron-restriction who may benefit from additional iron supplementation

– Safety and efficacy of escalating ESA dose for resistant anemia

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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

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Thank you for your attention!

IV Iron: Safety

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• Ferritin 500-1200 ng/ml• TSAT < 25%

Limitations of Ferritin

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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

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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

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Warady et al. Darbepoetin alfa for the treatment of anemia in pediatric patients with chronic kidney disease. Pediatric Nephrology. 21:1144-1152. 2006

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• 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

Diagnosing ID

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Diagnosing ID

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“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”

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• Higher hepcidin levels associated with • Decreased hemoglobin• Increased risk for incident anemia

over time

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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

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Lestz et al. Association of higher erythropoiesis stimulating agent dose and mortality in children on dialysis. Pediatric Nephrology 29: 2820-2829, 2014

Pure Red Cell Aplasia

• Sudden onset of severe, transfusion-dependent 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 ESA03/20/2019 72