Management of anemia in CKD

Pierre Cochat, MD PhD Professor of Pediatrics

Chair, Pediatrics & Pediatric Surgery Department Head, Center for Rare Renal Diseases Néphrogones

Hospices Civils de Lyon & University Claude-Bernard Lyon 1, Lyon, France

Disclosures

No conflict of interest

Introduction

Anemia in CKD: normochromic and normocytic

One of the most common complications of CKD

Insuficient erythropoietin (EPO) production as GFR decreases below 50 mL/min per 1.73 m2

Dialysis: bleeding/anemia tendency because of Platelet dysfunction

Mechanical hemolysis

Often accompanied by Decreased serum iron levels

Low reticulocyte count

Hb vs. GFR

CKiD study Fadrowski Clin J Am Soc Nephrol 2008

Hb decreases by 1 g/L for every 5 mL/min decrease in eGFR > 58 mL/min per 1.73 m²

3 g/L for every 5 mL/min decrease in eGFR < 58 mL/min per 1.73 m²

But no absolute threshold of GFR associated with anemia

Definition: Hb level

VanDe Voorde Pediatric Nephrology 7th Ed. 2015

Hemoglobin levels for boys and girls of all race/ethnic groups according to age

Hemoglobin values for diagnosis of anemia (KDIGO)

Common causes of anemia in CKD

Erythropoietin deficiency ++

Iron deficiency

Dietary iron deficiency

Gastrointestinal loss, phlebotomy, menses

Poor absorption of enteral iron

Iron depletion from ESA use

Chronic inflammation

Complement activation from dialysis membranes

Systemic inflammation diseases (SLE, etc.)

Surgical procedures

Bone marrow suppression

Inhibitory factors (removed by HD?)

Hyperparathyroidism (bone marrow fibrosis)

Medications (immunosuppressive drugs)

Primary disease (oxalosis)

Increased red cell turnover

Carnitine deficiency

Primary renal disease (HUS)

Malnutrition

Iron deficiency

B12 or folate deficiency

Carnitine deficiency

Aluminum toxicity

Racial differences (-0.6 g/L in African Americans compared to Caucasians)

Assessment of anemia - 1

Complete blood count with RBC indices

Reticulocyte count

Ferritin

Serum iron

Total iron binding capacity

(+serum folate and vitamin B12) KDIGO based on adult data

Normocytic anemia + decreased reticulocyte count

Diagnosis of anemia = increased frequency of Hb monitoring

Assessment of anemia - 2

Decreased WBC/platelet counts – bone marrow depression Transient viral infection

Malignancy

Medication side effect

Autoimmune disorder

Normal/elevated reticulocyte count – Blood loss or hemolysis

MCV (mean corpuscular volume) and RDW (red cell distribution width)

Assessment of anemia - MCV and RDW

Low MCV (microcytosis) Normal MCV High MCV (macrocytosis)

High RDW Iron deficiency Hb S-β thalassemia Hemoglobin H Erythrocyte fragmentation

Early iron deficiency Hemoglobinopathy (SS, SC) Myelofibrosis Sideroblastic anemia

Folate deficiency Vitamin B12 deficiency Immune hemolytic anemia Cold agglutinin

Normal RDW Heterozygous thalassemia Chronic disease

Normal Chronic disease Chronic renal failure Chronic liver disease Hemoglobinopathy (AS, AC) Transfusion Chemotherapy Hemorrhage Chronic myelocytic leukemia Hereditary spherocytosis

Aplastic anemia Preleukemia

Assessment of anemia – Iron status

Ferritin

Measure of iron store

Target ferritin level in the absence of inflammation > 100 mg/L

Low ferritin level: specific predictor of iron deficiency in CKD

Ferritin levels positively correlated to hepcidin levels – lower ability to serve as measure of iron status when elevated

Transferrin saturation (fraction of iron bound to transferrin)

Measure of iron immediately available for Hb synthesis

Therapeutic target > 20% - limited value when low

% of circulating hypochromic red cells: limited value in children

Hepcidin

Hepcidin, a key iron regulatory protein, produced by the liver Affects ferroportin on the cell surface of

Enterocytes: attenuates iron uptake

Macrophages: prevents iron release

from the reticuloendothelial system

Elevated in patients with CKD

Due to

Impaired GFR

Chronic inflammation

Hepcidin causes a « functional iron deficiency »

Higher hepcidin levels are associated with a decreased Hb and an increased risk of incident anemia

Atkinson Pediatr Nephrol 2015

Consequences of anemia

Most symptoms of so-called ‘uremic intoxication’

Increased morbidity and mortality if anemia is still present 1 month after dialysis initiation

Anemia and cardiovascular disease

Leading causes of death in general pediatric population and in children on RRT

Mitsnefes J Am Soc Nephrol 2012

Global management of CKD

Bacchetta 2012

Conventional management of anemia associated with CKD

Historically, blood transfusion leading to sensitization and iron overload

rHuEPO [introduced 1986] has become a standard treatment

ESA: Erythropoietin Stimulating Agents

Goal: Hb level between 110 and 120 g/L Start when Hb > 100 g/L - Increased cardiovascular risk over 130 g/L

Assessment of iron stores: tool for iron supplementation Ferritin levels: should be maintained between 200 and 800 mg/L++

Transferrin saturation: should be maintained between 20 and 50%

Additional noncomittent measures Folate supplementation improve the response to ESA

Blood transfusion limited to patients with symptomatic anemia

Iron supplementation

Iron deficiency= poor intake + increased losses + increased demand associated with the use of ESA

Oral iron therapy (3-5 mg/kg element iron per day)

But frequent malabsoption Food

Concommittent calcium-containing phosphate binders

H2-antagonists

IV iron often required (sodium ferric gluconate, iron sucrose) 15 mg/kg, 1 to 3 times per week

Action of ESA

Stimulation of erythropoiesis

More non-hematopoietic binding sites in younger children

Increase in erythrocytes survival

Increase in MCV as a result of reticulocytosis

Epoietin beta (Eprex, Neorecormon) in children with CKD

Initial dose: SC 100 IU/kg per week (2-3 doses) – Greater doses in children < 5 yrs

Weekly Hb assessment until stabilisation

Adaptation every 4 weeks of ±50% at the beginning

Goal: monthly increase of Hb by 10-20 g/L until reaching target

Not exceeding 720 IU/kg per week

Target Hb: 120 g/L

Chronic phase: injection every week or every other week

Darbopoietin alfa (Aranesp) in children with CKD Modified EPO (1 aminoacid substitution + additional N-glycosylation)

Longer half-life than EPO (22h by IV - 43h by SC)

Children > 1 yr

Initial dose on dialysis: 0.5 μg/kg sc/iv once a week

Before dialysis: 0.75 μg/kg sc every other week

Conversion from rHuEPO: 0.85 μg/kg/wk for every 200 IU/kg/wk EPO

If Hb increase < 1 g/L after 4 weeks, dose +25%

No dose increase less than every 4 weeks

If Hb increase > 2 g/L after 4 weeks, dose -25%

Target Hb= 120 g/L

Weekly Hb measurement until stabilisation

Continuous erythropoiesis receptor activator (CERA) Pegylated form of EPO

Continuous erythropoiesis receptor activator (CERA) Pegylated form of EPO

Roxadustat

Oral hypoxia-inducible factor (prolyl hydroxylase inhibitor) that stimulates erythropoiesis

Transiently and moderately increased endogenous erythropoietin and reduced hepcidin

Adverse events similar to placebo groups

Produces dose-dependent increases in blood Hb

Besarab Nephrol Dial Transplant 2015

Hb level EPO level Hepcidin level

Global improvement under ESA

Together with the correction of anemia:

Appetite

Exercise tolerance

Oxygen consumption

Intelligence testing scores

Quality of life

Left ventricular hypertrophy

Complications from ESA usage

Mostly related to changes in the rate of rise in Hb level

Increased BP (direct effect on Hc + effect of ESA on vessels)

Rarely, antibodies against EPO – pure red cell aplasia

Fall in Hb + low or absent reticulocyte count

Patients with poor response

Initial poor response

Iron depletion (rapid drop in transferrin saturation)

Resistance If target Hb is not reached with > 300 IU/KG/wk epoietin or > 1.5 μg/kg/wk darbopoietin

Poor adherence to ESA

Chronic inflammation/infection

Unusual iron deficiency

Folate, B12, B6 deficiency

Conditions impairing bone marrow (hyperparathyroiditism, oxalosis)

Adjunctive therapies

No evidence: Carnitine, Vitamin C

Questionable: Vitamin D

Can lower hepcidin levels

Anti-inflammatory action

Conclusion

rHuEPO was a revolution

Hb target goals are still debated

Factors contributing to the persistence of anemia are still questionable

Thank you for your attention!