The introduction of erythropoietin (EPO) for treatment of renal anemia in the late 1980's, was a seminal advance in renal failure therapy. In the pre-EPO era, 75 of ESRD patients had hematocrits below 30, and 15-25 were transfusion-dependent <||>. The drug largely abrogated the need for multiple blood transfusions in dialysis patients, thus reducing complications of iron overload, transmission of blood-borne viruses, and alloimmunization with resultant difficulty in cross-matching blood and prospective renal allografts. Treatment with EPO has improved duration and quality of life, and functional capacity of dialysis patients as the debilitating weakness, asthenia and cardiac complications associated with anemia of chronic renal failure were dramatically improved, and in many patients, abolished. Concomitant reductions in hospitalizations and length of hospital stay have also been reported <|[2, 3]|>, and other disorders related to the uremic syndrome endocrine and cognitive dysfunction <|[4, 5]|>, abnormalities of hemostasis <||> have also ameliorated with EPO therapy. In pre-dialysis patients, EPO use may sometimes allow delay in initiation of dialysis treatments through amelioration of the weakness and lethargy which are often prominent components of the uremic syndrome. This delay may garner precious extra time for establishment or maturation of an arteriovenous access.
This paper will address the basics of EPO biology its optimum use in clinical practice in patients on dialysis and with renal transplants and causes of EPO resistance, with particular emphasis on the recognition and treatment of iron deficiency.
THE BIOLOGY OF ERYTHROPOIETIN
EPO is a 34 kiloDalton glycoprotein hormone produced by yet unidentified cells in the peritubular renal interstitium in response to decreased renal tissue oxygen delivery. The liver also produces small amounts of EPO. The recombinant hormone rHuEPO (Amgen, Thousand Oaks, California, USA) in clinical use is produced by inserting the human EPO gene (cloned in 1983 by Lin et al) into the egg of the chinese hamster. EPO works by binding to the few hundred to few thousand of its receptors present on the surface of a relatively late marrow erythroid progenitor cell, the colony forming unit (CFU-E), increasing its proliferation and preventing apoptosis. EPO receptors are not present on early marrow burst forming units (BFUs), and decrease in number on the surface of maturing red blood cells (RBCs) so that reticulocytes and mature RBCs have no receptors. The receptors are also present on megakaryocytes and endothelial cells, and interestingly, are downregulated by interferon gamma. Also present on the surface of erythroid precursors is the transferrin receptor which translocates iron into the proliferating red cell precursor and is shed in a truncated form into the circulation in the presence of iron deficiency (hence increased TIBC) or increased erythropoiesis.
A novel erythropoiesis stimulating protein (NESP) (Amgen, Thousand Oaks, California, USA) bearing 2 extra oligosaccharide chains has been developed for its three times longer half life and 20 fold greater potency <||>, and is currently in phase 3 clinical trials in dialysis patients in Europe and the United States <||>. The long half life of the drug will allow once weekly or every other weekly administration.
ERYTHROPOIETIN USE IN PATIENTS WITH END STAGE RENAL DISEASE
Most hemodialysis patients, and a somewhat lower proportion of patients on PD require therapy with EPO to maintain Hct levels ≥ 30 g/dl. The usual starting dose of EPO is 80-120 U/kg/week in divided doses. The National Kidney Foundation's Dialysis Outcomes and Quality Initiatives study (DOQI) currently recommends a target hemaotcrit of 33-36 and hemoglobin 11-12 g/dl <||>, but there is still active debate regarding the possible beneficial effect of higher target Hcts <||>. In a survey of 4991 in-center hemodialysis patients, Owens et al reported that 94 of patients were receiving EPO at a mean dose of 202.4137.2 U/kg three times weekly <||>. The cost of this therapy is astronomical, with Medicare reimbursement costs for EPO therapy in American dialysis patients totalling approximately $1.5 billion per year <||>. As a result there have been many publications on the topic of optimizing EPO therapy, reducing doses of the drug and aiding cost containment <|[13-15]|>.
After administration of intravenous (IV) EPO, there is intense RBC production for 5-7 hours during which large amounts of iron must be available or mobilizable for red cell production to proceed. The half-life of IV EPO is 8.5 hrs, and though 100 bioavailable by the IV route, a substantive proportion of the drug is probably wasted as the small numbers of EPO receptors on the surface of CFU-s become saturated early. Subcutaneous (SC) EPO is only 10-49 bioavailable, has a longer time to peak effect (18 hrs), and a more prolonged and steady duration of action. SC EPO can therefore be given less frequently and in about 80 of patients, in lower doses than with the IV route <||>. Patient satisfaction with SC EPO however is often low due to the pain of subcutaneous injections in addition to dialysis access cannulation. In patients on PD, EPO may be administered by the intraperitoneal route, but must be instilled into a dry abdomen and left undisturbed for 12 hours to allow adequate absorption. This route would therefore only be possible in patients on nightly cycler assisted peritoneal dialysis.
Hct levels should be followed weekly in patients on EPO, and doses adjusted every two weeks if necessary. When Hct rises above 36 g/dl, it is best to give low maintenance doses of EPO (eg 1000 or 2,000 U) once or twice weekly, rather than stopping the drug, as a saw-tooth pattern of Hct levels will result when Hct levels fall and time is taken for re-stimulation and salvage of erythroid precursors from apoptosis to occur when EPO therapy is restarted.
RESISTANCE TO ERYTHROPOIETIN THERAPY
More than 95 of patients with renal failure respond to EPO within a week of staring therapy. EPO resistance is defined as failure of the Hct to rise despite use of high doses in excess of 400-500 U/kg. The most frequent cause of EPO resistance is iron deficiency, absolute or functional. The United States Renal Data System Morbidity and Mortality study documented that over 50 percent of EPO-treated patients were iron deficient <||>. Other causes of resistance to the drug are listed in <|[Table I]|>.
IRON DEFICIENCY IN PATIENTS ON ERYTHROPOIETIN THERAPY
The overriding importance of iron sufficiency, its accurate recognition and the need for intravenous rather than oral iron supplementation are areas of intense current investigation and debate. About 1 gm of iron is consumed by production of new RBCs during the first month of EPO therapy, and it is estimated that between 0.5-3 gms of iron per year is lost just from dialysis-associated blood losses <||>. Adequate oral replacement of iron is often not possible or successful in dialysis patients for reasons listed in <|[Table II]|> (see next page), hence the need for immediately bioavailable intravenous iron. EPO doses in individual or groups of dialysis patients may be reduced by 32-70 with use of intravenous iron therapy <|[18, 19]|>. Indeed, in new ESRD patients, it is prudent to correct overt iron deficiency before starting EPO therapy, as this alone may suffice to correct anemia initially. Oral iron should be discontinued once an intravenous preparation is started, as intestinal regulation assures that little or no iron is absorbed from the gut once IV iron is administered.
GOALS OF THERAPY WITH INTRAVENOUS IRON
The foremost goal of parenteral iron therapy is correction of anemia due to deficiency of iron, absolute or functional. Accurate diagnosis of iron deficiency based on current laboratory parameters has been controversial, for the two most frequently utilized indices of iron stores the percent saturation of iron or transferrin saturation (reflecting iron in transit from stores to RBC precursors), and serum ferritin (reflecting tissue stores of iron) are both subject to inaccuracies <|[Table III]|> and no single test or combination of tests fully differentiates iron repletion from iron depletion. Despite usual iron parameters in a normal or even elevated range, iron-deficient erythropoiesis may occur because of failure of iron to be released from reticuloendothelial stores (reticuloendothelial blockade), or to reach and be released at the site of RBC synthesis, thus producing a state of functional iron deficiency. Hence there is no clear cut relation between the level of serum ferritin, and iron available for effective erythropoiesis. It is also interesting that serum ferritin is structurally different from tissue ferritin, contains relatively little iron when compared to tissue ferritin, and has no clearly defined physiologic role <||>. Its synthesis in reticuloendothelial cells is dependent on the amount of labile intracellular iron (though as mentioned earlier, there is no obvious relationship between serum ferritin and iron available for effective erythropoiesis), and with a half-life of only 10 minutes, serum levels are primarily dependent upon synthesis.
In summary, the only absolutely accurate way of diagnosing iron deficiency in an anemic dialysis patient is to administer a therapeutic trial of iron and document a rise in the hematocrit.
Newer tests of iron availability have been developed in an effort to more accurately diagnose iron deficiency, these include the percent of hypochromic red cells (levels above 2.5-10 are the earliest indicator of iron deficient erythropoiesis, and a good indicator of functional iron deficiency in the presence of normal or high ferritin levels) <||>; reticulocyte hemoglobin content <||>; soluble transferrin receptor levels <||>; and erythrocyte zinc protoporphyrin (increased levels reflect functional iron deficiency) <||>. Unfortunately these tests are not widely available, the percent hypochromic red cell and reticulocyte hemoglobin content tests require a Technicon H1, H2 or H3 automated cell counter (Bayer Diagnostics, Munchen, Germany).
A recent international task force on the use of parenteral iron in patients with ESRD recommends administration of iron to replete and maintain iron stores in EPO-treated patients such that transferrin saturation be kept between 20-50, and serum ferritin between 100-800 ng/ml <||>. The group was convened to address ongoing concerns regarding possible cardiovascular and infectious complications related to parenteral iron use in dialysis patients. Review of all prior investigations relating to these possible deleterious effects of IV iron were found to be inconsistent and inconclusive. Recommendations by the task force that IV iron be discontinued or reduced when the iron saturation is above 50 or the serum ferritin above 800 ng/ml, are based on best clinical judgement, as no study addressing the risk/benefit profile in patient groups with values above and below these levels exist. A retrospective review of 7,292 adult in-center Medicare hemodialysis patients between October-December 1996, did document however, that in patients receiving equivalent weekly doses of EPO, achieving iron saturations above 20 incrementally resulted in attainment of higher hematocrits (11). It was also recommended that IV iron not be used in patients with active infections, when the iron may theoretically aid microbial proliferation.
Following attainment of target values for iron saturation and ferritin, it is now recommended that low dose maintenance therapy with IV iron continue (eg 50-100 mg/week) to replenish ongoing losses and avoid a saw tooth pattern of iron deficiency with anemia, and iron repletion with anemia correction. Following a course of low dose maintenance IV iron, measurement of iron parameters may be repeated after 1 week <||>, with higher doses (100 mg per week), it is necessary to wait 3-4 weeks to accurately reassess iron parameters.
In anemic (Hct 500 ng/ml, intravenous ascorbic acid in doses of 300 mg three times weekly on dialysis has been tried in attempt to overcome presumed reticuloendothelial blockade <||>. Eighteen of 35 patients treated for 8 weeks had an increase in their Hcts and reticulocyte counts associated with a 24 decrease in EPO dosage.
TYPES OF PARENTERAL IRON PREPARATIONS
Four types of parenteral iron preparations are currently available iron dextran, iron dextrin, iron hydroxysaccharate, and iron sodium gluconate complex in sucrose. The latter compound has recently been approved for use in the USA (Ferrlecit, R & D Laboratories, Inc., Marina del Rey, California, USA) but has been in clinical use in Europe since 1959. The incidence of anaphylactic reactions with iron sodium gluconate is much lower than with iron dextran, and indeed it has been used successfully in some patients with serious allergic reactions to iron dextran <||>.
Similar results are obtained with administering IV iron dextran as a total dose (1 gm) infusion, as with two 500 mg doses or ten 100 mg doses <||>, and the total dose method is potentially more cost effective.
A novel means of replacing iron has been reported ferric pyrophosphate has been added to bicarbonate dialysate concentrate to achieve concentrations in dialysis fluid of between 2-12 microgram/dl <||>. In 10 patients so treated, equivalent effects were seen as with IV iron. This compound may also be able to be added to peritoneal dialysis fluid.
ADVERSE REACTIONS TO INTRAVENOUS IRON
Two main types of adverse reactions to IV iron exist
1. An IgE-mediated anaphylactic reaction occurs in 0.7 of iron dextran-treated patients, and is due to preformed dextran antibodies. This reaction is not seen with other types of IV iron preparations. Some patients receiving IV iron dextran also report arthralgias, myalgias and diarrhoea.
2. A histamine-mediated, dose- and infusion rate-related anaphylactoid or free iron reaction is seen with iron gluconate or hydroxysaccharate, but not with the dextran preparation. It is due to transient overload of the transferrin molecule resulting in free iron in the circulation. Re-challenge with a lower dose of the drug is usually successful.
EPO THERAPY IN RENAL TRANSPLANT RECIPIENTS
In renal transplant recipients with acute or chronic rejection or poor allograft function for any reason, suboptimal EPO production results in EPO-responsive anemia <||>. Some recipients with poor graft function may exhibit EPO resistance related to infections, the inflammatory state associated with ongoing acute rejection, or the uremic milieu. Many of these patients will also exhibit absolute or functional iron deficiency.
In patients with excellent allograft function, pre-transplant anemia resolves by the third post-transplant month. An early transient peak in EPO levels at 1 week (reflecting release of stored EPO from the allograft), is followed by a more prolonged peak at week 4, reflecting EPO production from the functioning allograft <||>. These patients may also develop iron deficiency due to increased erythropoietic demand for iron.
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