Management of anemia in CKD

Transcription

1 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

2 No conflict of interest Disclosures

3 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 m 2 Dialysis: bleeding/anemia tendency because of Platelet dysfunction Mechanical hemolysis Often accompanied by Decreased serum iron levels Low reticulocyte count

4 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

5 Definition: Hb level Hemoglobin levels for boys and girls of all race/ethnic groups according to age Hemoglobin values for diagnosis of anemia (KDIGO) VanDe Voorde Pediatric Nephrology 7th Ed. 2015

6 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)

7 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

8 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)

9 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

10 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

11 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

12 Consequences of anemia Most symptoms of so-called uremic intoxication Increased morbidity and mortality if anemia is still present 1 month after dialysis initiation

13 Anemia and cardiovascular disease Leading causes of death in general pediatric population and in children on RRT Mitsnefes J Am Soc Nephrol 2012

14 Global management of CKD Bacchetta 2012

15 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

16 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

17 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

18 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 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

19 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

20 Continuous erythropoiesis receptor activator (CERA) Pegylated form of EPO

21 Continuous erythropoiesis receptor activator (CERA) Pegylated form of EPO

22 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 Hb level EPO level Hepcidin level Besarab Nephrol Dial Transplant 2015

23 Global improvement under ESA Together with the correction of anemia: Appetite Exercise tolerance Oxygen consumption Intelligence testing scores Quality of life Left ventricular hypertrophy

24 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

25 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)

26 Adjunctive therapies No evidence: Carnitine, Vitamin C Questionable: Vitamin D Can lower hepcidin levels Anti-inflammatory action

27 Conclusion rhuepo was a revolution Hb target goals are still debated Factors contributing to the persistence of anemia are still questionable

28 Thank you for your attention!