Erythropoietin for anemia of CRF

Introduction Kidney - primary site of erythropoietin production in adult - interstitial fibroblasts : major source of renal erythropoietin synthesis - release of erythropoietin is regulated via feedback mechanisms involving tissue oxygenation - transcription of the erythropoietin gene : regulated by hypoxia induced factor (HIF)

Anemia of CRF - normocytic, normochromic due to EPO production↓ Anemia due to renal dysfunction - developes when GFR <30mL/min - cardiac function, cognition, mental acuity ↓, fatigue, weakness, lethargy, anorexia, sleep disturbance - high cardiovascular mortality Hgb decrease 1g/dL -> LVH risk 6% ↑

Correction of anemia with EPO agents - quality of life, increased energy levels - greater capacity for work and exercise - restored sexual activity - reduce depression and fatigue - some improvement in LVH - slow progression to ESRD - correction abnormal PLT function

Use for anemia of ESRD(HD) The use of EPO - In the USA, 90 % of chronic dialyzed pts receive EPO The response to EPO - dose dependent, but varies among pts - dependent on the route and frequency of administration - may be limited by low iron stores, bone marrow fibrosis, inflammation, inadequate dialysis

<Indication of EPO> - indicated for use in CRF pts who have Hb <11g/dL - extensive evaluation to help exclude cause of anemia other than EPO deficiency

<Iron issue> Iron status evaluation before EPO use Iron supplements should be given first in pts with evidence of absolute iron deficiency (serm ferritin <100 ng/dL, transferrin saturation <20%) Ongoing EPO administration -> adequate iron stores must be continually maintained

<Hemoglobin versus hematocrit> Hematocrit alone is not the optimal method for assessing the response to EPO -> Use of Hb rather than hematocrit value Target hemoglobin level - 11-12 g/dL

<Dose> Starting dose of EPO for HD pts - 50-100 U/kg IV or SC three times weekly Adequate response - within three months - required dose : 50-300 U/kg (interpatient variability) Starting dose 100 U/kg : 50 U/kg - 90% : 70% attain target Hb IV therapy - approximately 30% more EPO than with S.C route

<Recommendation> SC > IV Initial subcutaneous dose for adult pts - 80-120 U/kg per week (6000U/week) given in 2-3 doses If Hb increase rate : < 0.3-0.5 g/dL per week - dose increase of 25% after 4 weeks If once target is reached -> smaller changes in the EPO dose

If Hct increase >8% or Hb increase > 2.5-3g/dL/mon - EPO dose should be reduced by 10-25% - some clinicians recommend holding EPO for short time EPO administration initiation or dose change - Hb should be measured once per week Hb of pts with stable Hb levels and EPO dose - Hb can be assessed every 2-4 weeks

<Side effects> HTN and its related problems Headache (15%) influenza like syndrome (5%) Pure red cell aplasia - associated with neutralizing anti-EPO antibody

<Resistance to EPO> Requirement of excessive doses during initiation of Tx Inability to achieve or maintain target Hb levels despite the large dose in the iron replete patient Excessive dose - 300 U/kg/week SC EPO

<Cause of resistance to EPO> Absolute iron deficiency Bone disease due to secondary hyperparathyroidism Occult malignancy Chronic inflammation Accumulation of AL in bone Malnutrition Pure red cell aplasia Adequacy of dialysis ACE inhibitor

Use in predialysis pts Anemia is common feature in many pts with CKD who do not yet require dialysis Large number of pts with CKD are not receiving EPO Only 32.4 % pts receive EPO prior to start of dialysis <Annual Data Report 2003,42> Dose : 80-120 U/kg/week 2-3 dose Currently commonly give once per week

Use in PD pts Some difference in PD pts versus in HD pts - Hgb level are relatively better preserved in PD pts, - less blood loss - S.C administration is preferred - Dargbepoetin alfa is appropriate - Intraperitoneal administration : not recommend

Darbepoetin alfa for the management of anemia in CRF Epoetin alfa (recombinant human erythropoietin : rHuEPO-Epogen or Procrit) Darbepoetin alfa (Aranesp) - binds to the EPO receptor, same mechanism of intracellular signaling as rHuEPO - three fold longer half life (25.3 versus 8.5 hrs) and greater biological activity - fewer needle sticks, decrease nursing time, better pts compliance, improve control of anemia

<Efficacy in rHuEPO-naïve pts> Darbepoetin alfa once weekly (initial 0.45 ug/kg, or 60 ug) - achieve target Hgb in 93-97% in 5-7weeks <Efficacy following switch from rHuEPO to Darbepoetin alfa> A study - 522 dialysis pts over 52 weeks - 95% of pts switched from rHuEPO to darbepoetin alfa : maintained their target Hgb with similar safety profiled <Kidney Int 2002:62>

<Long term efficacy and extended dosing interval> Long term preliminary studies (up to 36 weeks) - darbepoetin alfa administered once weekly or once every two weeks can effectively maintain Hb levels Some pts – once monthly dose of darbepoetin alfa <Safety and side effect profile> Infection, HTN, myalgia, headache - not considered to be attributable to darbepoetin alfa

<Recommendation> Whether to use rHuEpo or darbopoetin alfa ? Predialysis CKD pts and PD pts - are likely to benefit the most from the longer duration of action of darbepoetin alfa Pts on already on Epogen or Procrit - decision to switch should consider pts and staff convinience, compliance, availability and cost

<Starting dose> rHuEPO naive pts - 0.45 ug/kg once weekly Pts with CRF who are not dialysis dependent - once every other week at dose of 60 ug Pts stabilized on rHuEPO - equivalent dose of darbepoetin alfa based on simple dose conversion chart - range from 200:1 to 900:1 - 2-3 times weekly -> once weekly, once weekly -> once every two weeks

Future directions Gene therapy - Uremic mice in which myoblast transfer of human EPO gene -> led to persistent secretion of human EPO J Clin Invest 1995 Epo mimetics - agonist of the EPO receptor Science 1996