Anemia management in CKD

Salwa Ibrahim, MD FRCP (Edin)Cairo University

4th CKD course, 15-17 May 2016

Agenda

• Mechanism of anemia

• Hemoglobin Target

• KDIGO guidelines

Introduction

• Anemia was first linked to CKD over 170 years ago by Richard Bright

• Caused primarily by erythropoietin deficiency secondary to renal mass loss

• EPO level is inappropriately low relative to the degree of anemia

Prevalence of anemia severity stratified by stage of chronic kidney disease

Erythropoeisis

• Erythropoeitin (EPO) is a glycoprotein hormone secreted (90%) from endothelial cells in proximity to renal tubules

• EPO stimulates stem cells in the bone marrow to RBC production

• Iron essential in latter phase as Hb incorporated into reticulocytes and released into circulation as RBCs– 2/3rds of iron in the body is in Hb

Mechanism of anemia in CKD

• EPO deficiency

• Iron deficiency

• Uremia induced inhibition

• Shortened RBCs survival

• Nutritional deficiency (folate, B12)

Iron deficiency

• CKD patients have increased iron losses, estimated at 1-3 g per year in hemodialysis patients

• Causes include:

1. Chronic bleeding from uremia-associated platelet dysfunction

2. Frequent phlebotomy

3. Blood trapping in dialysis apparatus

4. Impaired dietary iron absorption (anorexia, use of phosphate binders, PPI and H2 blockers)

Functional iron deficiency

• Impaired iron release from body stores (reticuloendothelial cell iron blockade)

• Hepcidin excess accounts for impaired dietary iron absorption and reticuloendothelial cell iron blockade

• Hepcidin produced by the liver binds and induces degradation of iron exporter (ferroportin) on duodenal enterocytes, reticuloendothelial macrophages, and hepatocytes to inhibit iron entry into plasma

Symptoms of anemia

• Fatigue

• Shortness of breath • Diminished quality of life

• Palpitation

Hazards of anemia in CKD

• LVH, CHF

• IHD

• Impaired immune system

• Diminished cognitive functions

• Progression of CKD

Diagnosis of anemia

Use of ESAs to treat anemia in CKD

ESA MAINTENANCE THERAPY

ESA DOSING

ESA ADMINISTRATION

HCT and Mortality in D-CKD

1.33

1.121.00 0.96

1.251.11

1.00 0.97

0

0.2

0.4

0.6

0.8

1

1.2

1.4

<27% 27% to < 30% 30% to < 33% 33% to < 36%

Hct

All-cause deathCardiac-related death

Largest Studies on Target Hgb in D-CKD

1. Normal Hematocrit Study ≈ 1233 pts (1265)• Besareb et al NEJM 1998

Normal Hematocrit Study

P<0.001*

Largest Studies on Target Hgb ND-CKD

1. The CREATE = 603 pts– Drueke et al NEJM 2006

2. The CHOIR study = 1432 pts– Singh et al NEJM 2006

CHOIR1432 patients, 130 centers, US only

Epoetin-alfa

Randomization

High target Hb(13.5 g/dl)

n=715312 completed 36 mo

or withdrew at study termination with no primary event

125 primary event278 Withdrew before

early termination of study

Required RRT (47.1%)Withdrew for Other Reasons (21%)

Low target Hb(11.3 g/dl)

n=717349 completed 36 mo

or withdrew at study termination with no primary event

97 primary event278 Withdrew before

early termination of study

Required RRT (41.0%)Withdrew for Other Reasons (22%)

Median f/u 16 months

Endpoints

Primary Endpoint: Composite event consist of • Death• Myocardial infarction• Stroke• CHF hospitalization (excluding RRT)

Singh et al,New Engl J Med 2006; 355:2085-98

Summary (CHOIR)

• Increased risk with targeting Hb to 13.5 g/dL and achieving 12.6 g/dL (34% P=0.03)

• Strong trends for Death (48% P=0.07) and CHF Hospitalization (41% P=0.07)

• Higher rate of Cardiovascular (23% P=0.03) and All Hospitalization (18% P 0.03)

• No Incremental QOL of benefit with higher Hb

Singh et al,New Engl J Med 2006; 355:2085-98

(10.5 to 11.5 g per deciliter, group 2)

Summary (CREATE)• Increased risk with targeting higher Hb HR=0.78

• Improvement in QOL in both groups

• No benefit in LVH in the Group 1 with higher hemoglobin

TREAT Study 2009 • The risk of stroke doubled in higher HB group

• The risk of cancer also increased with highr hemoglobin level

Phrommintikul et al al, Lancet 2007

ESA available in Egypt

Eprex (Epoeitin alpha)

– IV or SC– 3 x wk– Most HD pts on this– Initial dose 200-3000 units thrice weekly– Half life 4-11 h IV and 19-25 h SC

Recormon (Epoeitin beta)

• IV or SC

Aranesp (Darbepoeitin)

– IV or SC – extra carbohydrate chain, 3 x longer half life, hence can be

given weekly or fortnightly (non-dialysing pts)– Initial dose 25 mcg weekly to 60 mcg twice monthly

• Methoxy polyethylene glycol-epoetin beta is the active ingredient of a drug marketed by Roche under the brand name Mircera

• Mircera is a long-acting erythropoietin receptor activator (CERA) indicated for the treatment of patients with anemia associated with CKD usually given once monthly (150 mcg)

• The drug stimulates erythropoiesis by interacting with the erythropoietin receptor on progenitor cells in the bone marrow

• It has a different receptor binding activity to other ESAs and its reduced affinity for the erythropoietin receptor allows continuous stimulation

• It has an in vivo half-life of around 135 hours as compared to darbapoietin alfa which has a half life of around 21 hours, the half life of which is three times that of the naturally occurring erythropoietin in the body

• Mircera is supplied as a solution in pre-filled syringes for intravenous or subcutaneous administration

Causes of EPO not working

• Iron deficiency ** most common **• B12 & Folate deficiency• Inflammation• ACE inhibitors• Hyperparathyroidism – bone marrow fibrosis• Aluminium toxicity• Inadequate dialysis• Malignancies, including multiple myeloma

New class of ESA

• Hematinide ( synthetic peptide)

• HIF stabilizer (oral agent) used to stabilize HIF to increase the transcription of EPO