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Part 7: Nutrition in PD |
Department of Renal Medicine, University of Queensland at Princess Alexandra Hospital, Brisbane, Queensland, Australia
Correspondence to: D.W. Johnson, Department of Renal Medicine, Level 2, Ambulatory Renal and Transplant Services Building, Princess Alexandra Hospital, Ipswich Road, Woolloongabba, Brisbane, Queensland 4102 Australia. david_johnson{at}health.qld.gov.au
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ABSTRACT |
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 TOP ABSTRACT EFFICACY OF ORAL VERSUS...SAFETYEMERGING IRON THERAPIESCONCLUSIONSREFERENCES |
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Iron supplementation is required in a preponderance of peritoneal
dialysis (PD) patients treated with erythropoietic stimulatory agents (ESAs).
Although many authors and clinical practice guidelines recommend primary oral
iron supplementation in ESA-treated PD patients, numerous studies have clearly
demonstrated that, because of a combination of poor bioavailability of oral
iron, gastrointestinal intolerance, and noncompliance, oral iron
supplementation is insufficient for maintaining a positive iron balance in
these patients over time. Controlled trials have demonstrated that, in
iron-deficient and iron-replete PD patients alike, intravenous (IV) iron
supplementation results in superior iron stores and hemoglobin levels with
fewer side effects than oral iron produces. Careful monitoring of iron stores
in patients receiving IV iron supplementation is important in view of
conflicting epidemiologic links between IV iron loading and infection and
cardiovascular disease. Emerging new iron therapies such as heme iron
polypeptide and ferumoxytol may further enhance the tolerability, efficacy,
and ease of administration of iron in PD patients.
KEY WORDS: Darbepoetin; erythropoietin; ferritin; hemoglobin; iron economics; prospective studies.
The development of erythropoietic stimulatory agents (ESAs), such as recombinant human erythropoietin (EPO) and darbepoetin alpha, has resulted in substantial health benefits for patients with end-stage renal failure (ESRF), including improved quality of life, reduced blood transfusion requirements, decreased left ventricular mass, diminished sleep disturbance, and enhanced exercise capacity (1,2). Unfortunately, a considerable proportion of ESA-treated patients exhibit a suboptimal hematologic response, which in most cases can be attributed to iron deficiency (3,4). According to the European Survey on Anaemia Management 2003 (5), 34% of ESA-treated patients failed to achieve a hemoglobin level of 11 g/dL or more, and 51.6% were assessed as having inadequate iron status, defined as a serum ferritin concentration below 100 µg/L or a transferrin saturation (TSAT) below 20% (or a hypochromic red-cell value of more than 10%), or both. It has therefore become apparent that iron supplementation is required in a preponderance of these patients to ensure an adequate hematologic response to EPO (3).
Numerous studies in hemodialysis populations (6), including a randomized controlled trial (7), have consistently demonstrated that intravenous (IV) iron supplementation is superior to oral iron with respect to enhancing body iron stores, augmenting hemoglobin levels, and reducing EPO requirements. In contrast, the optimal route of iron supplementation in the PD setting has been less well studied. Many authors (8–12) and clinical practice guidelines (13–16) have recommended oral iron supplementation for PD patients in the first instance, mainly because of greater simplicity and convenience, cheaper cost, avoidance of repeated IV cannulation, and generally smaller iron losses in PD patients than in hemodialysis patients. Moreover, several recent studies have raised concerns regarding the safety of regular IV iron supplementation in ESRF populations (17–19). A U.S. survey demonstrated that IV iron supplementation was used in less than 10% of PD patients treated with ESAs (20).
The present paper reviews the pros and cons of oral versus IV iron supplementation in PD.
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EFFICACY OF ORAL VERSUS IV IRON SUPPLEMENTATION IN PD PATIENTS |
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TOPABSTRACTEFFICACY OF ORAL VERSUS...SAFETYEMERGING IRON THERAPIESCONCLUSIONSREFERENCES |
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Oral iron absorption is markedly impaired in PD patients as compared with healthy control subjects (25), and it may be further impaired by concomitant medications such as H2 receptor blockers and phosphate binders. The response to oral iron may be enhanced by large pharmacologic doses (up to 4 tablets daily), although the ensuing rise in serum iron concentration is still less than half that observed in healthy volunteers (26). Effectiveness appears to be no different (3) for the various iron preparations (sulfate, gluconate, fumarate, succinate, polymaltose, polysaccharide complex). According to the Australian Survey of Anaemia Management, oral iron treatment (as compared with IV iron therapy) in 1295 PD patients was associated with significantly lower hemoglobin levels, lower TSAT, lower serum ferritin concentration, and higher prescribed EPO dose (unpublished observations).
Several studies in iron-deficient PD patients (TSAT below 20%, or ferritin concentration below 100 µg/L, or both) have found that IV iron therapy produces a superior hematologic response than oral iron therapy does (27–30). Vychytil and Haag–Weber (28) treated 17 iron-deficient or oral iron–intolerant PD patients with IV iron saccharate monthly over a period of 6 months. They observed significant improvements in hematocrit (to 35.1% ± 0.9% from 32.0% ± 0.8%), iron indices, and ESA responsiveness. The increase in hematocrit correlated well the quantity of IV iron administered.
In 13 PD patients who had failed to reach hematologic targets after at least 3 months of oral iron therapy, Ahsan (29) similarly demonstrated significant improvements in mean hematocrit and percentage TSAT over a 6-month period, despite a reduction in mean EPO dosage, following administration of a single IV infusion of total-dose iron (1000 mg iron dextran). The same investigator (30) subsequently performed a prospective crossover trial that compared IV total-dose iron (1000 mg iron dextran) with oral iron in 11 stable CAPD patients with either a hematocrit of <33% or a TSAT of <30%. The TSAT increased and the EPO dose requirement significantly decreased during the IV phase, while the converse was true during the oral phase.
More recently, Richardson et al. (27) administered an outpatient-based IV iron sucrose regimen to 103 CAPD patients showing evidence of iron deficiency despite high-dose oral iron therapy. The number of patients achieving a hemoglobin target of 11.0 g/dL or more increased from 50% to 75% of the population, with no increase in median EPO requirement. Importantly, the investigators observed that a proactive strategy of treating patients with borderline iron stores produced a greater population benefit than did treating patients with an absolute iron deficiency.
Several lines of evidence also indicate that IV iron therapy is a superior supplementation strategy for iron-replete PD patients. Silverberg and coworkers (31) demonstrated that IV iron infusion (ferrous saccharate 100 mg fortnightly) in 9 iron-replete PD patients over at least 6 months engendered nonsignificant increases in serum hematocrit, ferritin, and percentage TSAT. In a single-center, prospective crossover study comparing oral with every-second-month IV iron supplementation in 28 stable, iron-replete, EPO-treated PD patients over a 12 month period (32), my group demonstrated that hemoglobin concentrations increased significantly during the IV phase (to 114 ± 3 g/L from 108 ± 3 g/L) as compared with each of the oral phases (to 108 ± 3 g/L from 109 ± 3 g/L, and to 107 ± 4 g/L from 114 ± 3, p < 0.05). Similar patterns were seen for both percentage TSAT (to 30.8% ± 3.0% from 23.8% ± 2.3%, to 23.8% ± 2.3% from 24.8% ± 2.1%, and to 26.8% ± 2.1% from 30.8% ± 3.0% respectively, p < 0.05) and ferritin (to 544 ± 103 µg/L from 385 ± 47 µg/L, to 385 ± 47 µg/L from 317 ± 46 µg/L, and to 463 ± 50 µg/L from 544 ± 103 µg/L respectively, p = 0.10). No significant change in the EPO dose requirement was observed during the study, but the monthly cost of IV iron supplementation exceeded that of oral iron therapy by more than a factor of 6.6 (AU$20.30 vs AU$3.05).
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SAFETY |
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TOPABSTRACTEFFICACY OF ORAL VERSUS...SAFETYEMERGING IRON THERAPIESCONCLUSIONSREFERENCES |
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The greater frequency of gastrointestinal intolerance with oral iron often results in poor compliance (3), which may aggravate underlying malnutrition. For example, in a randomized placebo-controlled trial involving 32 consecutive iron-replete dialysis patients, Fishbane et al. observed a 20% decline in normalized protein catabolic rate in patients who received oral ferrous sulfate (33).
Studies of IV iron therapy in PD patients (27,29,30), including the one at my center (32), have reported highly favorable safety profiles. However, IV iron administration may occasionally induce acute "free iron" reactions, characterized by hypotension, dyspnea, arthralgia, myalgia, nausea, vomiting, and abdominal or back pain. These reactions are dose- and rate-dependent and are rarely seen with dosages of 300 mg or less (34,35).
Table 1 outlines maximum doses and infusion rates recommended or published for various IV iron preparations. In my unit, patients receive an infusion of iron polymaltose 500 mg in 100 mL saline at an initial rate of 40 mL/h for the first 15 minutes, then increasing to 120 mL/h if stable blood pressure, pulse, and respiratory rate are observed. (The observations are performed every 5 minutes for the first 15 minutes and every 30 minutes thereafter.) The total infusion time is approximately 1 hour.
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Idiosyncratic anaphylactic reactions may also occur (36,37), but these have been almost exclusively reported in regard to iron dextran (0.7% incidence). The case fatality rate for iron dextran–associated anaphylaxis is reported to be as high as 15.8%. For that reason, test doses are recommended in patients receiving their first exposure to the preparation, and the same recommendation is often extended to other iron preparations. My unit does not perform a test dose for iron polymaltose.
Recent epidemiologic data have linked augmented body iron stores with increased risk for both cardiovascular disease (38) and bacterial infection (3). Certain pathogens, such as staphylococci, require free iron for growth, and several reports have suggested that ferritin levels above the normal range are associated with impaired neutrophil function (39) and infection (40). In a 6-month surveillance study of 998 hemodialysis patients, anemia, but not IV iron therapy, was associated with an increased risk of experiencing at least 1 bacteremic episode (41). Studies of the relationship between IV iron treatment and infections in PD patients have been exceedingly limited. Prakash et al. (42) reported a trend towards higher peritonitis rates in 61 PD patients during the 6 months after IV iron therapy (15 episodes vs 8 episodes respectively in 6 months), although the results were not statistically significant. However, that study had only 36% power at the observed difference in peritonitis frequency.
Recent epidemiologic data have also raised concerns about a possible association between augmented body iron stores and an increased risk of cardiovascular disease (38). Drueke et al. (43) observed significant correlations between annual IV iron dose administered, serum ferritin concentration, serum advanced oxidation protein products, and carotid artery intima media thickness (a marker of early atherosclerosis) in 79 ESRF patients, suggesting a potential role of IV iron therapy and associated augmentation of oxidative stress in the pathogenesis of atherosclerosis in these patients. Subsequently, in a retrospective observational cohort study of 58,058 hemodialysis patients, Kalantar–Zadeh et al. (19) observed that monthly IV iron doses in excess of 400 mg were associated with an increased risk of all-cause and cardiovascular death. Feldman et al. (44) similarly reported a higher mortality rate in ESRF patients prescribed more than 1000 mg iron dextran over a 6-month period, although a subsequent analysis by the same author found no statistically significant association between any level of iron administration and mortality after fitting multivariate models that appropriately accounted for time-varying measures of iron administration, plus other fixed and time-varying measures of morbidity (45). These authors concluded that the previously observed association between iron administration and higher mortality was likely confounded by incomplete representation of iron dosing and morbidity over time.
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EMERGING IRON THERAPIES |
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TOPABSTRACTEFFICACY OF ORAL VERSUS...SAFETYEMERGING IRON THERAPIESCONCLUSIONSREFERENCES |
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Administration of HIP to 14 healthy subjects was associated with fewer side effects and significantly higher bioavailability that had been seen with non-heme iron (48). Hallberg et al. (49) also demonstrated that the absorption of heme iron may be more than 10 times that of iron salts in subjects with serum ferritin levels greater than 400 ng/mL (898 pmol/L).
Recently, Nissenson et al. (50) performed an open-label pre- and post-test trial of HIP (1 tablet three times daily) administered in lieu of IV iron supplementation to 37 ESA-treated hemodialysis patients over a 6-month period. Although 4 of 37 patients (11%) dropped out because of gastrointestinal intolerance (n = 3) or insufficient iron supplementation (n = 1), and 5 patients (14%) were excluded because of unrelated complications or protocol violation, HIP successfully replaced IV therapy in most of the patients, resulting in maintenance of hematocrit targets and iron stores and in significant improvement in EPO efficiency (mean EPO dose divided by hemoglobin level fell to 1023 U·g/dL monthly from 1270 U·g/dL monthly, p = 0.04).
My group is currently undertaking a randomized controlled trial of oral HIP versus oral ferrous sulfate therapy in 60 ESA-treated PD patients [HEMATOCRIT trial (Heme Iron Polypeptide Against Treatment with Oral Controlled Release Iron Tablets)].
Ferumoxytol: Ferumoxytol is a semisynthetic, carbohydrate-coated iron oxide that can be administered by rapid IV injection at rates up to 30 mg/s. A recent phase II clinical trial of rapid IV infusion of ferumoxytol in 21 pre-dialysis and PD patients with hemoglobin and TSAT levels of 12.5 g/dL and 35% (or less) respectively reported significant increases in TSAT level (to 37% ± 22% from 21% ± 10%) at 1 week and hemoglobin level (to 11.4 ± 1.2 g/dL from 10.4 ± 1.3 g/dL) at 6 weeks (51). Non-serious adverse effects—including constipation, chills, tingling, a delayed gastrointestinal viral syndrome, delayed pruritic erythematous rash, and transient pain at the injection site—were reported in 5 of 7 patients.
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CONCLUSIONS |
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TOPABSTRACTEFFICACY OF ORAL VERSUS...SAFETYEMERGING IRON THERAPIESCONCLUSIONSREFERENCES |
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TOPABSTRACTEFFICACY OF ORAL VERSUS...SAFETYEMERGING IRON THERAPIESCONCLUSIONSREFERENCES |
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| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
