© Borgis - Postępy Nauk Medycznych 4/2011, s. 337-343
*Ryszard Gellert, Tomasz Żelek, Dorota Daniewska, Anna Kajczuk-Kowieska, Danuta Kobus
Suplementacja żelaza drogą dożylną w niedokrwistości nerkowopochodnej u pacjentów dializowanych – krytyczna ocena obecnej praktyki klinicznej w doświadczeniach jednego ośrodka
Intravenous iron supplementation for correcting renal anemia in hemodialysis patients – critical approach to current practices based on single-centre experience
Department of Nephrology, Medical Center for Postgraduate Education, Bielanski Hospital, Warsaw, Poland
Head of Department: prof. dr hab. med. Ryszard Gellert
Streszczenie
Dożylne podawanie prepratów żelaza, procedura z wyboru dla uzupełnienia niedoborów żelaza u pacjentów hemodializowanch, może powodować stres oksydacyjny jeśli ilość podanego „wolnego” żelaza przekroczy zdolność wiązania go przez osoczową transferynę. TSAT rośnie znacząco, i proporcjonalnie do podanej dawki, po dożylnym podaniu żelaza – zarówno cukrzanu, jaki niskocząsteczkowego dekstranu. Przeprowadzone przez nas badanie retrospektywne miało na celu określenie takich maksymalnych dawek każdego z preparatów, które niosą minimalne ryzyko „przesycenia” osoczowej transferyny, oraz zaproponowanie na tej podstawie protokołu bezpiecznego, pod tym względem, podawania żelaza. Dawka 100 mg niskocząsteczkowego dekstranu żelaza okazała się bezpieczna we wszystkich sytuacjach niedoboru żelaza, ale dawki 200 mg dekstranu żelaza i 50 mg cukrzanu żelaza były bezpieczne tylko u pacjentów z dużym jego niedoborem. Na podstawie analizy wyników leczenia zaproponowano protokół wielkości i częstości dawkowania każdego z preparatów żelaza, oparty na aktualnych wynikach TSAT i osoczowej ferrytyny. Przedstawiono także przegląd piśmiennictwa uzasadniający konieczność dożylnej suplementacji żelaza u pacjentów hemodializowanych i unikania powtarzanego przesycania transferryny.
Summary
Intravenous iron, the procedure of choice to replete iron stores in hemodialysis patients can induce oxidative stress if the amount of “free” iron infused exceeds the capability of transferrin to bind it. TSAT increases significantly after both, iron saccharate and LMW-dextran I a dose-dependent manner. The retrospective study was undertaken to evaluate the maximum safe doses of both iv iron formulations and to design a protocol for iron repletion with minimum risko of “oversaturating” plasma transferrin. The 100 mg of LMW iron dextran proved safe in this regard in all patients, but the maximal safe doses in severe iron depletetion were 50 mg and 200 mg for iron saccharate and LMW iron dextran 200 mg , respectively. Based on the observations a protocol for single dose iron amount and dose-interval was proposed. The literature review to support the rationale to avoid transferrin oversaturation with intravenous iron was also presented.
Introduction
In patients on hemodialysis due to the chronic renal failure the yearly loses of iron can exceed 3.0 g, which is 4-10 times more as compared to healthy population (1). The increased iron losses resulting from:
– intrahemodialyser clotting,
– postdialysis bleeding from needle insertion site,
– the incomplete blood return at cessation of the procedure,
– extensive laboratory examinations required to follow and treat hemodialysed patients,
– occult gastrointestinal bleeding,
can add 6-7 mg, or even more, to the physiological daily iron losses of 1-2 mg. The occult blood losses and the need for blood sampling are responsible for the iron deficiency anemia present in 25% of patients commencing chronic dialysis treatment (2).
In healthy individuals the increased iron losses result in increased reabsorption of dietary iron, increased synthesis and release of transferrin, decresed synthesis of hepcidin, and, if anemia ensues, in increased erythropoietin synthesis. All these mechanisms are affected by renal insufficiency.
Advanced chronic renal disease results in inadequately low erythropoietin synthesis and excretion, and the resistance of erythroid progenitor cells to erythropoietin. Hemodialyis corrects these abnormalities in part only.
Iron and erythropoiesis in renal failure patients
Erythropietin is critical for survival of erythroid progenitor cells before they differentiate into proerythroblast. Hypoerythropoietinemia, relative or absolute, causes apoptosis of burst-forming units-erythroid (BFU-E) and colony-forming units-erythroid (CFU-E) (3, 4). At the proerythroblast stage of erythopoiesis the cell becomes erythopietin independent, and starts synthesis of alpha and beta hemogloblin chains. Shortly after, within few hours, large amounts of iron are taken up for hemoglobin synthesis, which is preceded by the presentation of transferrin receptors on the cell surface. The erythroblast iron uptake accelerates for 16 hours, several hours after the commencement of hemoglobin synthesis. In 24-30 hours the iron in-flow stops, and the synthesis of all hemoglobin inside the erythroblast is completed within 2.5 days (5).
The erythroblast inflowing iron is stored initially inside ferritin capsules. The maturation of erthrobalsts is reflected in staining – from the basophilic to polichromatophilic and, finally, to orthochromatophilic erythroblast. As a result, after 5 days and 4 further divisions, each proerythroblast produces 32 reticulocytes, which are released into the bloodstream. The reticulocyte is the first nonnuclear cell of erythroid, and after 24 hours matures to erythrocyte, which stays in blood for the consecutive 120 days, before erythroptosis eliminates it from circulating.
Clearly, adequate and timely availability of erythropoietin and iron to pre-orthochromatophilic erythroblast cells is crucial to prevent renal anemia. The inadequately low levels of endogenous erythropoietin can be easily increased using commercially available erythropiesis stimulating agents (ESA).
The increased iron losses in CKD patients can be hardly replaced by diet for the increased levels of hepcidin in renal failure reduce the duodenal cells’ capability to release dietary iron into the blood stream. Calcium-based phosphate binders given orally to almost every renal patient, with an intention to decrease phosphate reabsorption, compete with iron for the divalent ion transporter on duodenal cells and further decrease dietary iron availability. Additionally, the need in renal patients to decrease dietary phosphate and avoid abundant protein load, often results in diminished delivery of heme iron in meat. All these factors taken together in renal patients – the reduced uptake of dietary iron to the duodenal cells and the inhibition of releasing the reabsorbed iron from duodenal cells into blood contribute to iron depletion.
It is unclear if the hyperhepcidinemia in CKD patients results from abnormal synthesis, decreased degradation by remnant renal tissue, or both. The uremia-related inflammation seems to stimulate hepcidin synthesis, which in turn, like in duodenal cells, limits iron release form ferritin-reach macrophages and reticuloendothelial cells. Thus, even in the iron repleted renal patients, the avaibility of iron for erythropoiesis can be limited (relative or functional iron deficiency), particullarly when ESAs are given.
Absolute and functional iron deficiency in renal patients
The absolute iron deficiency is diagnosed in patients presenting iron-defficient erythropoiesis. Reduced hemoglobin concentration, plasma ferritin and iron concentrations, transferrin saturation, mean erythrocyte hemoglobin content and volume (MCH and MCV), mean reticulocyte hemoglobin content (CHr) and percentage of hypochromic erythrocytes are commonly used to evaluate iron stores and its availability to erythropoiesis. Should hemoglobin concentration increase after the iron have been supplemented in patient with apparently normal erythrocytosis, the functional iron deficiency is diagnosed.
The normal erythropiesis produces erythrocytes and reticulocytes containing more hemoglobin (CHr and MHC, respectively) than 28 pg/cell (normal value 28-32 pg/cell). The percentage of hemoglobin depleted erythrocytes (hypochromic erythrocytes) – %HRBC is lower than 2% in normal population and should be kept< 5% in renal patients. Higher values of %HRBC are suggestive of iron-deficient erythropoiesis. Plasma ferritin, fragments of protein capsules storing intracellular inorganic iron, reflects the amount of iron released from the apoptotic and necrotic cells. Thus, decreased plasma ferritin concentration always indicate absolute iron depletion. The absolute iron deficiency is diagnosed in renal patients after plasma ferritin fell below 225 pmols/l (100 ng/ml) in patients free from dialysis, and below 450 pmol/l (200 ng/ml) in patients on chronic hemodialysis.
The increased ferritin levels can be indicative of iron overload, inflammation (ferritin is a member of acute-phase proteins family), or both. For uremia induces systemic inflammation, ferritin concentrations normal at healthy population, in renal failure can be observed despite severe iron depletion. This is why normal iron status in renal failure can be expected at values higher than in general population, particularly when other acute phase indicators are also high. Even ferritin levels as high as > 1123 pmol/ml (500 ng/ml) cannot warrant iron repletion in renal patients (6).
The basophilic erythroblast takes-up iron from two sources – iron-loaded macropages forming the center of the intramedullary erythroblastic island and from plasma iron transporter – transferrin, which is produced by the liver. Inflammation and malnutrition reduce transfwrrin levels, which makes it as good risk factor for increased mortality as the albumin concentration (7). Anemia increases plasma transferrin concentration. Both, the decreased release of iron from macrophages and the insufficient transferrin-bound iron, result in decreased influx of this ion into erythroblasts 5-7 days prior to reticulocyte formation. If this happens, hypochromic cells appear in circulating blood – hypochromic reticulocytes being indicative of decreased iron delivery 7 days earlier, and hypochromic erythrocytes of iron unavailability 1-119 days prior to examination. Should the reduced iron flux had lasted for longer time period, the percentage of hipochromic erythrocytes would have increased gradually along the decreasing hemoglobin concentration.
The diagnosis of functional iron deficiency can be made only ex juvantibus, i.e. when iron supplementation increases hemoglobin concentration. This happens when the release of iron stores is insufficient to support normal erythropoiesis, and can be reflected, at more advanced stages by low transferrin saturation (TSAT). Levels of TSAT < 20% are suggestive of iron functional depletion, irrespective of ferritin concentration. This has been challenged by the results of DRIVE study – patients presented with apparently repleted iron stores had iron-restricted erythropoiesis reversed after additional iron supplemented intravenously (8, 9). Thus, each renal patient presenting iron-restricted erythorpoiesis (overt anemia, increased percentage of hipochromic reticulocytes and/or erythrocytes, high demand for ESAs) should be offered some form of iron supplementation, irrespective of being on hemodialysis.
Iron supplementation
With no doubt intravenous iron is superior to oral in hemodialysis patients. This is less evident in predialysis and peritoneal dialysis patients. The upper limits of iron-metabolism parameters indicative of stopping the supplementation are not known. Neither the frequency or amount of single dose are internationally agreed upon. This is why every physician and every dialysis unit are advised to design their own strategy reflecting the general giudelines.
The most popular nowadays intravenous iron formulation are:
– Iron saccharate (Venofer),
– Iron gluconate,
– Low molecular dextran iron (CosmoFer).
The clinical use of high molecular weight (HMW) iron dextran is disadvised for the risk of serious anaphylactic reactions is high. The side effects of low molecular weight (LMW) iron dextran are less frequent as compared to HMW iron dextran. These are even less frequent and serious as compared to the observed after saccharate (10, 11) or gluconate base formulations (12). Even so, the test dose of LMW iron is required prior to each infusion, for the patient could carry preformed anti-dextran antibodies (13).
The iv iron is usually well tolerated, unless given at high dose and rate. There are no data the repeated iv iron is harmful as regards to cancer or accelerated atherosclerosis, even if single doses of 100 mg iron sucrose (IS) iv increase plasma TSAT after 210 min to more than 80% (14), and cause proteinuria and albuminuria shortly after the medication was given (15). The effect is thought to result from the presence of highly toxic free iron in the solution infused (16,17).
The free iron and tissue damage
The iv iron formulations contain two forms of iron – the “bound” and the “free” iron. The differences is in size of the particle determine the “free” iron content – the smaller the particle the more “free” iron. The “bound” iron is taken-up by macrophages, and other cells, by pinocytosis. The “free” (“unbound”) iron, if not buffered by transferrin can damage tissue.
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Piśmiennictwo
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