Management of Anemia in Chronic Kidney Disease

Syakib Bakri

INTRODUCTION • Anemia is frequent complication of CKD. • Prevalence increases with diminishing renal function. • Management changed after introduction of recombinant erythropoietin (rHuEpo) in 1989. • Anemia is one of the modifiable complications of CKD.

Radtke et el, Blood 1979;54:877-884

PATHOGENESIS • Decreased erythropoietin production. • Decreased sensitivity of bone marrow erythroid cell to EPO due to uremic toxins. • Decreased survival of RBC due to uremic toxins. • GIT bleeding. • Iron, folate, B12 deficiency. • Infection, inflammation. • Blood loss during dialysis, routine blood test. • Aluminum toxicity. • Bone marrow fibrosis due to secondary hyperparathyroidism.

Sequence of CVS effect • • • • • •

Low oxygen carrying capacity of RBC. Increased blood volume. Hypoxia induced peripheral vasodilatation. Increased cardiac output. LVH. Impaired cardiac contractility, systolic and diastolic dysfunction. • Myocardial ischemia and CHF.

ERYTHROPOIESIS • Production of EPO is stimulated by hypoxia. • 90% EPO – kidney, 10%-liver. • Other factors necessary for erythropoiesis areA) Normal bone marrow B) Adequate iron, folate , B12.

Normal erythropoiesis

CLINICAL FEATURES • Patient often not severely symptomatic despite degree of anemia. • Tiredness, shortness of breath , palpitation etc. • Morphology –normocytic normochromic . • EPO-LOW.

CLINICAL APPROACH • Do not assume, anemia is caused by CKD only • Exclude other causes of anemia by history taking , clinical examination, lab tests. • Like –inadequate dialysis, poor nutrition, blood loss, infection, inflammation, hemolysis, aluminium toxicity. • Lab tests - CBC, PS, stool for occult blood, iron store, ferritin, transferin saturation, chest x-ray etc. • Other excluded / treated –attributed to CKD.

Causes of anemia other than EPO deficiency should be considered when • the severity of anemia is disproportionate to the impairment of renal function, • there is evidence of iron deficiency, or • there is evidence of leukopenia or thrombocytopenia.

WHEN TO INVESTIGATE AND TREAT ANAEMIA IN CKD • When estimated glomerular filtration rate (eGFR) of less than 60 ml/min/1.73m2 should trigger investigation into whether anaemia is due to CKD.

• Hb level falls to 11 g/dl or less or they develop symptoms attributable to anaemia (such as tiredness, shortness of breath, lethargy and palpitations)

Treatment options Iron. Erythropoietin stimulating agent (ESA). Blood transfusion. Folic acid and vitamin B12.

TREATMENT • With rHuEpo: Important component in managing anemia of CKD. Each available rHuEpo are effective in achieving and maintaining target Hb levels. Aspect of administration may differ between short acting and long acting agents.

Erythropoiesis-stimulating agents (ESAs) Epoetin-α  Same molecular structure as human erythropoietin (recombinant DNA technology).  Binds to and activates erythropoietin receptor.  Administered either SC or IV.

Darbepoetin-α  Molecular structure of human erythropoietin has been modified from 3 N-linked carbohydrate chains to 5 N-linked carbohydrate chains; increased duration of activity. The advantage is less-frequent dosing.  Binds to and activates erythropoietin receptor.

STARTING rHuEPO IN CKD WHY, WHEN, HOW • Why : Improvement in appetite , physical activity. Improvement in quality of life. Improvement in exercise tolerance. Improvement in cardiac performance. Avoidance of blood transfusion and iron overload. Decrease morbidity/mortality

WHY, WHEN, HOW…………….. • When : Patient is symptomatic of anemia. HB < 10 gm%. Has normal iron store. Blood pressure is under control.

WHY, WHEN, HOW…………….. How : dose and frequency Epoetin-alfa or epoetin-beta dosing usually starts at: 20 to 50 IU/kg body weight three times a week. dose and frequency can varied once a good response is achieved. Route of administration: - IV/SC. SC is preferred. adjusted to keep the rate of Hb increase between 1 and 2 g/dl/month In patients with a history of CVD, thrombo-embolism or seizures, or in those with high blood pressure, the initial doses should be in the lower range.

TARGET HB LEVEL • KDOQI GUIDELINE: 11-13 gm%. • FDA: Should not exceed 12 gm%. • HB initially monitored weekly, dose adjustment made every 4 weekly. • Once stable HB achieved, monitor 4 weekly to 3 monthly, or in between any intercurrent illness or symptomatic.

DOSE MODIFICATION • If HB level increases by >1gm%/2wks, then reduce dose of EPO by 25%. • If HB level not increases by >1gm%/mnth, then increase dose of EPO by 25%.

Absolute & functional iron deficiency Absolute iron deficiency

 Depleted body iron stores

– Low serum ferritin (<100ng/ml) or – TSAT <20% – Low hepcidin  Inadequate iron supply to meet

Functional iron deficiency

demand despite normal or abundant iron stores – Normal or high ferritin levels – TSAT <20% – High hepcidin

ESA, erythropoiesis stimulating agent; TSAT, transferrin saturation

Wish JB. Clin J Am Soc Nephrol 2006;1:S4-8

MANAGING IRON STORE • Iron status should be optimised before the initiation and during maintenance treatment with EPO. • Iron status tests initially should be performed every monthly. • Once stable or on HD, 3 monthly . • Results of iron status tests, HB , rHuEPO dose should be interpreted together to guide iron therapy.

Parenteral VS oral iron therapy  Parenteral therapy is the recommended route for all CKD patients.  Most patients with CKD who are receiving erythropoietin therapy require parenteral iron therapy to meet needs (increased requirements, decreased oral absorption).  Oral therapy is limited by poor absorption and non adherence with therapy due to adverse effects.  Consider oral supplemental iron in ND or PD patient without IV access or as maintenance therapy for ND or PD patients.  Oral route is not recommended in HD patients.

Iron Therapy: 



Parenteral:

Oral: 200mg elemental iron per day (= 600 mg Ferrous fumarate,1.8g ferrus gluconate or 1gm ferrous sulphate ).

TARGET IRON THERAPY • Maintain following indices of iron:• sr. ferritin :- 200 to 500ng/ml • TSAT: >20% (unless ferritin is greater than 800 micrograms/l). • Percentage hypochromic red cells less < 6% (unless ferritin is greater than 800 micrograms/l). • Preferred route of administration IV in HD , (oral in PD,or not on dialysis.) • Most patients will require 600–1000 mg of iron , in a single or divided dose depending on the preparation.

MANTAINANCE IRON THEREPY • Once ferritin levels > 200 micrograms/l, and the percentage hypochromic red cells is < 6% or transferrin saturation is > 20%, people with anaemia of CKD who are receiving EPO should be given maintenance iron. • Dose required is 50–60 mg intravenous iron per week.

ADVERSE EVENTS OF rHuEPO • • • • • •

Hypertension, -30%. Hypertensive encephalopathy. Vascular access failure. Increase in pre dialysis CKP,and potassium. Increases risk of stroke in DM type 2. L-Carnitine, vit-c , and androgens should be not be used routinely.

Epo Resistance • An inadequate response to EPO therapy is defined as failure to achieve target Hgb/Hct levels in the presence of adequate iron stores at an intravenous dose of 450 U/kg/week IV or a subcutaneous dose of 300/kg/week within 4–6 months, or failure to subsequently maintain target

Causes for inadequate response to erythropoietin • • • • • • • • • • • • • •

Iron deficiency Infection/inflammation Chronic blood loss Osteitis fibrosa Aluminum toxicity Hemoglobinopathies Folate or vitamin B12 deficiency Multiple myeloma Malnutrition Hemolysis Dialysis-related carnitine deficiency Pure red cell aplasia Drugs: ACE inhibitors Dialysis dose/frequency

Red blood cell transfusion ESA therapy is ineffective (e.g., hemoglobinopathies, bone marrow failure, ESA resistance).  The risks of ESA therapy may outweigh its benefits (e.g., previous or current malignancy, previous stroke). When rapid correction of anemia is required to stabilize the patient’s condition (e.g., acute hemorrhage, unstable coronary artery disease). When rapid pre-operative Hb correction is required. Transfusion should be directed toward reduction of anemia sign and symptoms rather than achieving specific target.

EPREX® Merupakan rekombinan epoetin  dengan 165 glikoprotein asam amino dan berat molekul 30.400 Dalton Eprex® memiliki profil yang mirip dengan epoetin alami yang terdapat di dalam tubuh manusia dan tidak dapat dibedakan dengan pemeriksaan biologi dan imunologi Eprex® merupakan satu-satunya epoetin  yang mendapat persetujuan dari US. FDA Eprex® juga telah mendapatkan persetujuan dari BPOM untuk penggunaan SC dan IV

MP0108

EPREX® terbukti efektif dengan menunjukkan penurunan kebutuhan dosis untuk mencapai dan menjaga kestabilan target hemoglobin yang setara dengan biocopy

Gambar 3. Clinical Efficacy, IV Administration in Renal Patients, Correction phase

Scientific Discussion EMEA 2007–http://www.ema.europa.eu/docs/en_GB/document_library/EPARScientific_Discussion/human/000872/WC500054374.pdf

There’s NO substitute! Stability

Safety

when effectiveness matters Tersedia di:

Predictability

Take home message • Anemia is a significant contributor to mortality and morbidity in CKD. • ESA and iron supplementation forms the core of anemia management and has to be understood in detail. • The data on the upper limit of target Hb is conflicting but there is a trend towards a lower value.

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