Optimal Use of Epoetin-α in the Anaemia of Chronic Renal Failure

Optimal Use of Epoetin-α in theAnaemia of Chronic Renal FailureOnyekachi Ifudu

Renal Disease Division, Department of Medicine, State University of New York, Health ScienceCenter at Brooklyn, Brooklyn, New York, USA

ContentsAbstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1751. Aetiology of Anaemia in Chronic Renal Failure (CRF) . . . . . . . . . . . . . . . . . . . . . . . . . . 1762. Clinical Features of Anaemia in CRF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176

2.1 Managing Anaemia in CRF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1763. Persons with CRF Prior to Initiation of Dialysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1774. Persons with End-Stage Renal Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177

4.1 Haemodialysis Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1784.2 Continuous Ambulatory Peritoneal Dialysis Patients . . . . . . . . . . . . . . . . . . . . . . . . 1784.3 Kidney Transplant Recipients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178

5. Predictors of Response to Epoetin-α . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1785.1 Impaired Utilisation of Iron/Iron Deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1795.2 Inadequate Dialysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1805.3 Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1805.4 Residual Renal Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1815.5 Bone Marrow Fibrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181

6. Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1817. Cost Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1818. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182

Abstract Anaemia, a major feature of chronic renal failure, is responsible for a signif-icant proportion of the multisystemic disabling symptoms in patients with chronicrenal failure (CRF). Anaemia correction with recombinant human erythropoietin(epoetin-α) often leads to significant amelioration of these symptoms.

Starting dose should be 50 U/kg of bodyweight given subcutaneously or intra-venously 1, 2 or 3 times a week. The subcutaneous route is more effective, re-sulting in use of less epoetin-α and subsequent cost-saving. Adverse effects ofepoetin-α tend to be more severe and more likely following intravenous admin-istration.

Once the target haematocrit is achieved, the epoetin-α dose should be reducedby 50 to 80%, but should not be stopped, since an abrupt fall in haematocrit mayensue if epoetin-α is completely discontinued. There is an emerging consensusthat it is deleterious, and not necessary, to allow patients to become severelyanaemic before starting epoetin-α. Thus, the current trend is to start epoetin-αonce the haematocrit is 30 to 35%. On the other hand, what the target haematocrit

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should be is controversial. The threshold haematocrit beyond which the risks ofanaemia correction outweigh the benefits in patients with CRF is not established.Studies that assessed quality of life outcomes as well as clinical experience inEurope clearly demonstrate better outcomes without adverse effects in patientswith a haematocrit between 36 to 40%, compared to those with haematocrit of30%.

Prior to starting epoetin-α in any patient with CRF, a methodological evalutionshould be performed to exclude other major causes of anaemia and to identifyany comorbid conditions that may impair response to epoetin-α. Response toepoetin-α may be impaired by loss of residual renal function in patients withprogressive CRF or kidney transplant recipients. Other major factors that impairresponse to epoetin-α include impaired utilisation of iron, absolute iron def-iciency, inadequate dialysis, infection and bone marrow fibrosis.

1. Aetiology of Anaemia in ChronicRenal Failure (CRF)

Anaemia in chronic renal failure (CRF) resultsmainly from diminished erythropoietin productionfrom failing kidneys.[1] In healthy individuals, 90%of erythropoietin is produced in the kidney and10% is produced in the liver. Anaemia becomesapparent when the glomerular filtration rate fallsbelow 30 to 40% of normal. Endogenous erythro-poietin, a 30 400 dalton glycoprotein with 165amino acids, is produced by endothelial cells liningthe renal peritubular capillaries in response to tissuehypoxia. In the bone marrow it stimulates theprimitive stem cell burst-forming units and colony-forming units, preventing programmed cell deathand increasing production of mature erythrocytes.

Other causes of anaemia in CRF include bloodloss (from the gut and dialysis blood lines) result-ing from the bleeding tendency in uraemia, shorten-ed red blood cell survival due to haemolysis andsuppression of erythropoiesis by retained uraemictoxins.[1]

2. Clinical Features of Anaemia in CRF

Anaemia is a major source of morbidity in CRFand plays a key role in generating excess cardio-vascular mortality in these patients.[1] Other feat-ures of anaemia in CRF include anorexia, weak-ness, diminished mental acuity, poor exercisetolerance and decreased sexual function.[1-4] Anae-

mia associated with CRF is usually normocytic andnormochromic, and the reticulocyte count is oftenlow. In patients with advanced CRF about to startdialysis, haematocrit is usually about 22 to 24%.[5]

If anaemia is more severe or has unusual features,then nonrenal causes of anaemia must be excluded.

2.1 Managing Anaemia in CRF

Prior to the availability of epoetin-α (recombinanthuman erythropoietin), the mainstays of anaemia

Table I. Benefits of treatment with epoetin-α

Benefit Comment

Anaemia correction Dramatic amelioration of symptoms ofanaemia; improves cardiovascular andhaemodynamic abnormalities ofuraemia; improves functional status andcognitive function

Reduces needand/or frequency ofblood transfusions

Curtails risk of viral hepatitis and AIDS;less HLA sensitization improvesoutcomes in kidney transplantation

Improved hormonemetabolism

Improved sexual function and fertility;improved carbohydrate and cortisolmetabolism

Lipid lowering effect Reduced triglyceride and cholesterollevels may modulate risk ofcardiovascular disease

Relief of pruritus Not uniformly observed

Reduction in maculaoedema

In patients with diabetes mellitus

Improveshaemostatic defect

Decreased risk of uraemic bleeding;improves platelet function and raisesplatelet count; no evidence that ahypercoagulable state results

HLA = human leucocyte antigen.

176 Ifudu

© Adis International Limited. All rights reserved. BioDrugs 1999 Mar; 11 (3)

therapy in end-stage renal failure were largely in-effective androgen injections and blood trans-fusions. The latter carried significant risks of viralhepatitis infection, iron overload and sensitisationto human leucocyte antigens (HLA) which madekidney transplantation less successful. Epoetin-α,which was introduced into clinical practice in1987, expands red cell mass, often resulting in adramatic improvement in symptoms associatedwith anaemia. Other beneficial effects of epoetin-αtreatment are listed in table I.

Prior to starting epoetin-α in any patient withCRF, a methodical evaluation should be performedto exclude other major causes of anaemia and ident-ify any comorbid conditions that may impair re-sponse to the drug (table II).

Initiation of epoetin-α treatment should also bepreceded by review of the peripheral blood smearto confirm normocytic normochromic anaemia,serial stool haemoccult testing to exclude gastro-intestinal blood loss, and assessment of the body ironstores (table II). Adequate iron stores are necessaryfor a maximal response to epoetin-α. However, al-though in CRF each of the commonly measuredindices of iron availability is imperfect, a trans-ferrin saturation >20% appears to be an acceptableindication that the patient is iron replete. Ferritinis an acute phase reactant and its level varies overa wide range in may patients with CRF. Thus, it haslimited utility in this setting as determinant of bodyiron store.

3. Persons with CRF Prior to Initiation of Dialysis

In CRF [pre-dialysis and end-stage renal disease(ESRD)], the exact level of haematocrit at whichepoetin-α therapy should be initiated has been in-fluenced predominantly by economic rather thanclinical factors. The only large scale study that ex-amined the relationship between haematocrit andmortality in patients with CRF receiving haemo-dialysis showed that mortality began to increasesignificantly with haematocrit less than 30%.[6]

Therefore, it was recommended that epoetin-α bestarted in patients with progressive CRF once the

haematocrit was below 30%. However, epoetin-αmay be started in persons with comorbid illnesses,such as ischaemic heart disease, when the haema-tocrit is still greater than 30%.

The starting dose should be epoetin-α 50 U/kgbodyweight subcutaneously twice weekly. In pa-tients with more severe anaemia (haematocrit≤24%), the same dose may be given thrice weekly,but it must be recognised that an undesired rapidrise in haematocrit may follow thrice weekly ad-ministration. Moreover, severe anaemia (haema-tocrit ≤24%) may indicate incipient uraemia andthe need to commence renal replacement therapy(that is, dialysis or kidney transplantation).[5]

While iron deficiency contributes to anaemiain some patients with progressive renal failure, itsincidence and magnitude has not been extensivelycharacterised.[7-9] It has been speculated that ratherthan frank ‘iron deficiency’, many patients withCRF may indeed have impaired ability to useiron.[10-12]

4. Persons with End-Stage Renal Failure

Epoetin-α is indicated for anaemia correction inpatients with ESRD treated by maintenancehaemodialysis or peritoneal dialysis if theirhaematocrit is less than 36%. Epoetin-α may alsobe used in the small percentage of kidney trans-plant recipients with unexplained persistent anae-mia (haematocrit ≤30%) or anaemia associatedwith chronic allograft rejection. The thresholdhaematocrit at which epoetin-α therapy should bestarted may vary on the basis of local practice, pre-sence of comorbid illnesses and/or third party re-imbursement policies. There is no strong scientific

Table II. Requisite patient evaluation before using epoetin-α (re-combinant human erythropoietin) in chronic renal failure

Detailed history and physical examination; identify history ofanaemia prior to renal failure, haemoglobinopathy, malignancy,chronic infections, known vitamin deficiencies, hypersplenismand blood loss

Review peripheral blood smear; uraemic anaemia is usuallynormocytic and normochromic

Haemoccult stool testing

Baseline assessment of body iron status (transferrin saturation)

Epoetin-α in the Anaemia of CRF 177


data to support any specific value of haematocritsignalling the need for epoetin-α therapy.

Current practice is to start with epoetin-α ≤50U/kg bodyweight once, twice or thrice weekly de-pending on the severity of the anaemia. Althoughadministration of the total weekly dose at one timeor in 3 weekly doses has not made any differencein the outcome of achieving target haematocrit, onetime administration may be cost effective.[13,14]

Epoetin-α may be given either intravenously orsubcutaneously. The subcutaneous route is moreefficacious, resulting in use of less epoetin-α andsubstantial cost-savings.[13,14] Once the target haema-tocrit of 36% or greater is achieved, the epoetin-αdose should be reduced by 50 to 80%, but shouldnot be stopped, since an abrupt fall in haematocritmay ensue if epoetin-α is suddenly discontin-ued.[13,14]

4.1 Haemodialysis Patients

Most haemodialysis patients receive epoetin-αthrice weekly to coincide with their dialysis schedule.Although the manufacturers have asserted thatthere is no removal of epoetin-α by haemodialysis,it is prudent to give the drug postdialysis as thestudies that have examined epoetin-α clearanceduring dialysis did not evaluate all commerciallyavailable dialysers, and as dialyser technology im-proves with enhanced permeability, some epoetin-αmay be removed.

4.2 Continuous Ambulatory PeritonealDialysis Patients

Prior to the emergence of epoetin-α, patients oncontinuous ambulatory peritoneal dialysis (CAPD)had been shown to have less severe anaemia thanthose treated with haemodialysis.[15,16] This hadbeen attributed in part to less blood loss, higherendogenous erythropoietin levels and better clear-ance of ‘middle-molecule’ uraemic inhibitors oferythropoiesis.[17,18] A switch from maintenancehaemodialysis to CAPD has increased haematocritwithout a concomitant increase in endogenouserythropoietin levels, suggesting an extraction bydialysis of an inhibitor of erythropoiesis.[16]

However, CAPD patients are more likely to re-ceive epoetin-α subcutaneously and this, in addi-tion to their less severe baseline anaemia, maypartly explain the contention that they respondbetter to epoetin-α than their counterparts onhaemodialysis.

Epoetin-α may be given via the intraperitonealroute because CAPD removes only about 2 to 3%of an administered dose of epoetin-α. However,intraperitoneal administration has been discourageddue to poor bioavailability of the drug comparedwith either the subcutaneous or intravenous routesof administration.[19,20]

4.3 Kidney Transplant Recipients

Persistent anaemia (haematocrit ≤30%) in kid-ney transplant recipients may be associated withdelayed graft function, acute or chronic allograftrejection, iron deficiency or blood loss.[21-25] Further-more, endogenous erythropoietin production maybe diminished in some kidney transplant recipientsdespite normal allograft function.[22] In addition,for unknown reasons, anaemia has persisted insome kidney transplant recipients with normal endo-genous erythropoietin levels and normal allograftfunction.[22]

Epoetin-α is effective in correcting anaemia inkidney transplant recipients.[21-24] The accompany-ing rise in haematocrit does not appear to eitherprolong the period of delayed graft function oraccelerate loss of renal function among those kid-ney transplant recipients with chronic allograftdysfunction.[21,24]

5. Predictors of Response to Epoetin-α

Like most drugs, the response to epoetin-α isdose-dependent, but at any specific dose (i.e., 50U/kg bodyweight) the response may vary amongpatients depending on a number of factors. Responsealso depends on the route of administration, thesubcutaneous route being the most efficacious andthe intraperitoneal route being the least efficacious.

Clinical experience has indicated that intravenousor subcutaneous epoetin-α 50 U/kg bodyweightthrice weekly is an adequate starting dose in most

178 Ifudu


patients with CRF. This dose should result in a risein haematocrit to 30% or greater within 16 weeks.Therefore, if anaemia persists despite epoetin-αtherapy, the appropriate response is not to increasethe dose, but rather, a methodical exclusion of fac-tors that may impair response to epoetin-α (tableIII).

In patients with ESRD receiving epoetin-α, aninsufficient epoetin-α dose is almost never thedominant factor explaining persistent anaemia.The major factors that impair response to epoetin-α include impaired utilisation of iron/iron de-ficiency, inadequate dialysis and infection.

5.1 Impaired Utilisation of Iron/Iron Deficiency

Adequate body iron stores are necessary tomaximise response to epoetin-α. Parenteral ironinjections have been vigorously advocated for an-aemia correction in CRF either as monotherapy orin combination with epoetin-α.[10,26,27] When admin-istered in combination with epoetin-α, parenteral ironinjections enable an adequate response to epoetin-α

to be achieved, and consequently, epoetin-α re-quirements may decline, resulting in substantialcost-savings.[26,27]

However, while the metabolism of iron is some-what understood in patients with normal renalfunction, much remains to be clarified about ironmetabolism in CRF. First, the commonly measuredindices of iron availability (transferrin saturation,ferritin and total iron binding capacity) may notcorrectly reflect body iron stores in patients withCRF.[28-30] Thus, short of performing a bone marrowbiopsy, making the diagnosis of iron deficiencyanaemia is difficult in patients with CRF.[28-30]

Second, in patients with normal renal functionand severe iron deficiency anaemia, oral iron ab-sorption may increase up to 50-fold to support a 2to 3 times increase in the rate of erythropoiesis,assuming that the marrow can respond nor-mally.[31] The small intestinal regulation of ironplaces a ceiling on how much iron can be orallyadministered, irrespective of the intensity of irondeficiency anaemia.[31]

In patients with CRF receiving epoetin-α, keyquestions regarding iron metabolism remain un-answered including: (i) what is the magnitude of in-crease in oral iron absorption in the face of presumediron deficiency and revved up erythropoiesis stim-ulated by exogenous bolus injections of epoetin-α?(ii) since ESRD may be a chronic or persistantacute phase state,[12] is the release of iron frommacrophages to the marrow for erythropoiesismuch slower than in individuals with normal renalfunction as suggested by Beamish et al.?[12] (iii) isoral iron absorption increased in CRF but then lim-ited by the ceiling imposed by small intestin-al reg-ulation?

There have been conflicting reports as to theextent of oral iron absorption in patients with CRFreceiving epoetin-α. Goch et al.,[32] in a single-centrestudy, showed that uraemic patients with iron de-ficiency absorbed significantly less oral iron thandid those with normal renal function and iron de-ficiency.

In patients with normal renal function andpresumed iron deficiency anaemia, a rise in haema-

Table III. Factors that may impair response to epoetin-αa (recom-binant human erythropoietin)

Impaired utilisation of iron in the presence of adequate iron stores

Absolute iron deficiency

Inadequate dialysis

Infections/inflammation

Gastrointestinal blood loss

Bone marrow fibrosis [myelofibrosis/secondaryhyperparathyroidism/aluminium (aluminum) toxicity]

Malignancy

Excessive blood collection for laboratory tests

Haemoglobinopathy

Vitamin B12 deficiency

Folic acid deficiency

Antibodies to epoetin-αLoss of residual renal function in patients with progressivechronic renal failure

Acute or chronic rejection in kidney transplant recipients

Failed kidney transplant returning to dialysis

Treatment with ACE inhibitors

a Impaired response is defined as haematocrit <30% after treat-ment with epoetin-α 50 U/kg bodyweight thrice weekly for≥16 weeks.



tocrit after iron therapy is considered proof of thecorrectness of the diagnosis of iron deficiency.[31]

However, based on available evidence,[33-35] it isdoubtful whether this thesis is true in patients withCRF. Both human[34,36] and animal studies[35] haveshown that haematocrit may go up with intravenousiron administration even in the absence of anaemiaor iron deficiency. On the other hand, failure torespond with a rise in haematocrit following ironadministration may not necessarily exclude irondeficiency in patients with CRF.[10]

Release of iron from macrophages to marrowfor erythropoiesis slows down considerably afterthe third week following a bolus dose of parenteraliron. Consequently, repeat infusions of iron dex-tran may raise the haematocrit in individuals withadequate iron stores. This fact is instructive for theuse of intravenous iron in epoetin–α-treated patientswith renal failure where an increase in haematocritafter iron dextran infusion has been widely adver-tised as confirmation of iron deficiency. These con-cerns are pertinent because of the numerous shortterm and long term adverse effects of parenteraliron. A recent study of intravenous iron dextran usein patients with ESRD observed that the incidenceof short term adverse effects was 4.7%.[27]

The most dangerous systemic reaction to irondextran is anaphylactic shock, which may lead toacute myocardial infarction or death.[37] Anaphylac-tic reaction is infrequent, occurring in less than 1%of patients. It is not dose-dependent and may occurfollowing the administration of only a few drops ofdiluted iron dextran solution and may occur after anegative test dose. Iron dextran should only be ad-ministered in a setting in which anaphylaxis can bequickly detected and treated.

Increased iron levels in the serum following irondextran infusion induces proliferation of bacteria,impairs the immune system and results in splenicand hepatic deposition of iron.[38-40] This may beparticularly relevant in patients with ESRD whoseimmune function is already compromised. In fact,Collins et al.,[40] in their recent study of 33 120haemodialysis patients, found a 35% higher risk ofdeath due to infection among those who had received

intravenous iron for 4 to 6 months compared withthose who had received iron for 1 to 3 months dur-ing the period of observation. There was no statis-tically significant difference between the 2 groupswith regards to all-cause mortality.

Furthermore, epidemiological studies in nonrenalfailure patients have suggested a higher risk of cancerand coronary heart disease in patients with largeriron stores compared to those with lower ironstores.[41,42] In addition, unfortunately, iron dextransequestered within macrophages in the marrow orelsewhere may initiate signals that impair gastro-intestinal absorption of iron,[43] setting up a viciouscycle that results in even more parenteral iron use.

In short, while we continue to use intravenousiron in patients with CRF, it must be recognisedthat most of the studies supporting the use of intra-venous iron did not consider many of the majorpotential problems. Effort must be focused on iden-tifying and eliminating the obstacles (if any) thatlimit oral iron absorption in patients with CRF receiv-ing epoetin-α.

5.2 Inadequate Dialysis

Inadequate dialysis, as reflected by either low se-rum albumin concentration, low urea reduction ratioor low Kt/V (dialysis dose), is associated with a poorresponse to epoetin-α in patients with CRF treatedwith either haemodialysis[44-46] or CAPD.[47,48]

However, increased dialysis dose in underdialysedepoetin–a-treated patients with low haematocrits hasresulted in an increase in their haematocrit.[46]

5.3 Infection

Infections, possibly via the release of interleukin-6,impair erythropoiesis[49] and additionally suppressproduction of endogenous erythropoietin. How-ever, the magnitude of this variable among patientswith CRF is unquantified and the effect of viralinfections appears to be less severe than what hasbeen observed following bacterial infections.[45,50,51]

In fact, patients with CRF and AIDS do respondwell to epoetin-α if they have enough iron storesand are adequately dialysed.[45] In addition, patientswith hepatitis B viral infections respond well to

180 Ifudu


epoetin-α, although elevated endogenous serumerythropoietin levels may be partly responsible fortheir good haematocrits.[50]

On the other hand, bacterial infections in epoetin–α-treated patients with CRF are associated with anabrupt fall in haematocrit which cannot be explainedsolely by bone marrow suppression.[51] This abruptdecline in haematocrit has been attributed to acutehaemolysis.[51]

5.4 Residual Renal Function

In kidney transplant recipients with chronic allo-graft rejection treated with epoetin-α for anaemia,there is an inverse correlation between epoetin-αdose and creatinine clearance.[21] Also, in patientswith CRF not yet on dialysis, response to epoetin-αappears to depend on the amount of residual renalfailure, but this has not been confirmed in a protocolstudy.

5.5 Bone Marrow Fibrosis

Bone marrow fibrosis associated with second-ary hyperparathyroidism is the most difficult todocument cause of resistance to epoetin-α in CRF.This is because it entails the performance of a bonemarrow biopsy – an invasive and painful procedure.Haematocrit does not correlate significantly withserum parathyroid hormone levels,[52,53] and thusthere is no reliable marker to identify those patientswith severe osteodystrophy that should receive abone marrow biopsy to confirm fibrosis. In practice,bone marrow biopsy is often a last resort in theevaluation of resistance to epoetin-α.

6. Adverse Effects

New onset hypertension or exacerbation ofpre-existent hypertension has been described inup to 30% of patients initiating epoetin-α ther-apy.[54-56] The precise mechanism for the hyper-tension is unknown, but may be multifactorialand dose-dependent.[54,55] Suggested mechanismsfor epoetin–α-associated hypertension include in-creased peripheral vascular resistance secondary toincreased whole blood viscosity and failure of an

elevated cardiac output to decease in response toincreased haematocrit. In addition, a pressor effectby epoetin-α on vascular smooth muscle has beenpostulated either directly or indirectly via local activa-tion of the renin-angiotensin system or through re-lease of endothelin-1.

Seizures, described in approximately 2.5% ofpatients in some of the clinical trials of epoetin-α,have not been a major problem in clinical practice.While the relationship between hypertension, sei-zures and rate of rise in haematocrit is uncertain, itwould be prudent to limit the rise in haematocrit to4 points or less in any 2 week period.

An influenza-like syndrome, responsive to anti-inflammatory drugs, has been observed in about5% of patients receiving epoetin-α but is unusualin patients treated with subcutaneous administra-tion. Up to 15% of patients may have headache.

Epoetin-α therapy increases the platelet count,and heparin requirements may need to be increasedto avoid clotting of the dialyser.[57] There is no otherevidence that a hypercoagulable state results;[58] theincidence of vascular access thrombosis has notincreased in patients receiving epoetin-α.[58-60]

An emerging consequence of epoetin-α use in pre-dialysis CRF is that amelioration of anaemia-associated debilitation has resulted in delayed in-itiation of dialytic therapy – in the absence of majorsymptoms, some patients whose other laboratorydata suggest the need for renal replacement therapyare refusing the offer to start dialysis. The longterm outcome of this subset of patients is unknown.The persistence of a ‘uraemic’ state despite a normalhaematocrit may be detrimental to their long termwellbeing.

7. Cost Issues

The annual cost of epoetin-α in the US for a70kg haemodialysis patient receiving intravenousepoetin-α 50 U/kg bodyweight thrice weekly isabout US$5460 (1995). Because of decreased re-quirements, the cost may be reduced by as muchas 50% if such a patient is switched to subcutane-ous administration of epoetin-α.[13] It is estimatedthat if 50 000 haemodialysis patients were switched



from intravenous to subcutaneous epoetin-α therapy,$164 million could be saved annually without com-promising patient wellbeing. Inadequate responseto epoetin-α often prompts an inappropriate in-crease in dose or precludes a timely reduction inepoetin-α dose. Consequently, it costs more to treatanaemia in patients with poor response to epoetin-α either due to iron deficiency or inadequate dial-ysis.[61]

8. Conclusions

The established potential of epoetin-α to expandred cell mass and improve the haematocrit in patientswith CRF is not in doubt. However, recent multi-centre studies show that a large proportion of patientswith CRF treated with epoetin-α were unable toraise their haematocrit to the same levels docu-mented in the original clinical trials of epoetin-α.It is imperative that, to maximise outcomes in theuse of epoetin-α and avoid wasteful spending ofhealthcare resources, clinicians must search for andcorrect any factors that limit the abilty of patientsto achieve the target haematocrit. Because impairedutilisation of iron is a major problem in patientswith CRF receiving epoetin-α, future researchneeds to focus on identifying factors that modulatethe release of iron from macrophages and exploringways to improve the relase of iron from macro-phages to the marrow for erythropoiesis.

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Correspondence and reprints: Dr Onyekachi Ifudu, RenalDisease Division, Box 52, Department of Medicine, SUNYHealth Science Center at Brooklyn, 450 Clarkson Avenue,Brooklyn, New York, 11203-2098, USA.E-mail: [email protected]



Optimal Use of Epoetin-α in the Anaemia of Chronic Renal Failure

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