Kidney International, Vol. 55, Suppl. 69 (1999), pp. S-71–S-78

Iron status and iron supplementation in peritonealdialysis patients

ANDREAS VYCHYTIL and MARIANNE HAAG-WEBER

Department of Medicine III, Division of Nephrology, University Hospital of Vienna, Austria, and Department of Medicine II,Division of Nephrology, St. Elisabeth Hospital, Straubing, Germany

Iron status and iron supplementation in peritoneal dialysis extent of iron loss and therefore a lower incidence ofpatients. Iron deficiency represents an important problem in iron deficiency during peritoneal dialysis treatment mayperitoneal dialysis patients, especially during erythropoietin be one reason for the reported differences [8, 9]. Hockentherapy. A combination of serum ferritin, transferrin saturation,

and Marwah found a mean blood loss into the dialyzerand/or the percentage of hypochromic red cells should be usedof 9 ml per hemodialysis treatment, resulting in a totalto assess iron status in peritoneal dialysis patients. Primarily,

oral iron supplementation should be the preferred therapy. blood loss of 1400 ml per year [10]. Furthermore, bloodHowever, most of the studies using oral substitution in erythro- loss for laboratory investigations was 1.14 to 3.22 liter/poietin-treated peritoneal dialysis patients show a progressive year for center-treated hemodialysis patients, but wasdecline of serum ferritin. Therefore, parenteral iron supple-

only 0.17 liter/year for home-treated hemodialysis pa-mentation is required in part of the patients, and the intrave-nous route should be preferred in these cases. Intravenous iron tients. The reported blood losses correspond to a loss oftherapy is recommended if serum ferritin falls below 100 mg/ elemental iron of up to 830 mg/year in hemodialysisliter and should be stopped if the serum ferritin level is more patients not receiving erythropoietin therapy. Milmanthan 650 mg/liter. The optimal form of intravenous iron supple-

estimated an iatrogenic blood loss of 150 to 200 ml permentation is still unclear. Injections once to three times permonth for hemodialysis patients, as compared with onlyweek restrict the patients’ flexibility, but application of higher

doses in longer intervals may lead to an impairment of neutro- 30 to 60 ml/month for peritoneal dialysis patients [11].phil functions, probably connected to a higher risk of infection. Despite the lesser extent of blood loss, there is muchWe treated 17 stable peritoneal dialysis patients with 100 or evidence from clinical experience that iron deficiency200 mg iron saccharate monthly over a period of six months

also plays a main role in peritoneal dialysis patients. Inand found an increase of transferrin saturation (from 12.1 6 1.6a study published by Blumberg, Marti and Graber, eightto 20.9 6 2.4%, P 5 0.026), serum ferritin (from 100.4 6 32.0 to

372.4 6 54.6 mg/liter, NS) and hematocrit (from 32.0 6 0.8% of 20 continuous ambulatory peritoneal dialysis (CAPD)to 35.1 6 0.9%, P 5 0.099). The required erythropoietin dosage patients receiving neither iron nor erythropoietin supple-could be reduced significantly (from 148.4 6 30.3 to 69.4 6

mentation had diminished bone marrow iron stores [2].19.5 U/kg/week, P 5 0.025). Side effects occurred in 0.9% afterAnother study of non-erythropoietin-treated peritonealapplication of 100 mg and in 5.9% after injection of 200 mg

iron saccharate. The incidence of catheter infections and perito- dialysis patients showed that marrow iron scores werenitis was the same in the period before and after the start of significantly lower in those not receiving iron supplemen-treatment. Further studies are needed to find the most suitable tation as compared with iron-treated patients [12].regime of iron supplementation for peritoneal dialysis patients.

One reason for iron deficiency in peritoneal dialysispatients not receiving erythropoietin may be the im-proved erythropoiesis following initiation of peritonealReports about differences in the degree of renal ane-dialysis treatment. Berry et al demonstrated an improve-mia between hemodialysis and peritoneal dialysis pa-ment of plasma iron clearances and an increased irontients are contradictory. Most of the studies show higheruptake into red blood cells after starting peritoneal dial-hemoglobin/hematocrit levels, a lower transfusion fre-ysis [13]. Saltissi et al showed a significant increase ofquency, and/or lower erythropoietin requirements inserum hemoglobin and red cell mass after initiatingperitoneal dialysis patients compared with hemodialysisCAPD treatment in eight patients not receiving erythro-patients [1–8]. Among several other factors, the lowerpoietin [14]. There also was a progressive decrease inserum ferritin levels, indicating a depletion of bone mar-row iron stores due to increased iron utilization. SimilarKey words: erythropoietin, ferritin, transferrin, hypochromic red cells,

renal anemia. results were found by other authors [15, 16].Blood samples taken for laboratory examinations, 1999 by the International Society of Nephrology

S-71

Vychytil and Haag-Weber: Iron supplementation in PDS-72

menstrual bleeding in females, and occult gastrointesti- the groups, limiting the diagnostic efficiency of these twoparameters [27].nal blood losses may contribute to the occurrence of iron

deficiency in peritoneal dialysis patients. In a study by Although serum ferritin may be an adequate parame-ter for estimating marrow iron stores, limitations for itsMilman, Pedersen and Visfeldt, female peritoneal and

hemodialysis patients with menstruation had signifi- use in peritoneal dialysis patients are similar to those inhemodialysis patients. In peritoneal dialysis patients andcantly lower serum ferritin levels (60 mg/liter vs. 261 mg/

liter) compared with the other patients [17]. Akmal et hemodialysis patients, serum ferritin levels are higherthan those of patients with renal insufficiency not receiv-al detected occult blood in the stool in 7.3% of CAPD

patients, which was comparable to hemodialysis patients ing dialysis or healthy subjects with comparable marrowiron content [17]. Furthermore, it should be considered(6.3%) but much higher than in asymptomatic control

persons (0.8% to 1.3%) [18]. that ferritin levels in patients treated with intravenousiron may be high despite a decreased marrow iron contentErythropoietin treatment causes a substantial increase

of iron demand for erythropoiesis [19–21]. Cheng et al [28]. Serum ferritin levels are also increased in cases ofmalignancy or inflammation [29, 30], for example, duringtreated 10 CAPD patients with subcutaneous erythro-peritonitis, thus limiting its diagnostic efficiency in thesepoietin [22]. Five of them needed iron supplementationincidents [22]. Increased hemoglobin synthesis duringbecause their serum ferritin fell below 200 ng/ml. In aerythropoietin therapy raises the demand of iron, whichstudy by Stevens et al, almost all patients without ironcan exceed the ability of the body iron stores to releaseoverload needed extra iron supplementation duringiron to transferrin. Therefore, a so-called functional ironerythropoietin treatment [23]. Barany et al investigateddeficiency can occur and is also described in erythropoie-45 erythropoietin-treated peritoneal dialysis patients andtin-treated peritoneal dialysis patients [31–33]. Ferritinfound that 91% of these patients needed iron supplemen-levels in patients with functional iron deficiency are nor-tation [24]. The indication for iron therapy was a lowmal or high, but transferrin saturation is always low.or normal serum ferritin. In a multicenter study of 152Because of its limitations and the inability of serum ferri-peritoneal dialysis patients treated with erythropoietin,tin to detect functional iron deficiency, several authors86% needed iron supplementation [25]. In a multicentersuggest measuring transferrin saturation rather than fer-study that Faller et al conducted, the percentage of pa-ritin in order to assess iron demand in erythropoietin-tients who received iron therapy increased from 45% attreated dialysis patients [21, 34–36]. However, transferrinthe beginning of treatment to 93% in the course of thesaturation shows a high day to day and circadian variabil-study [26].ity [37]. Furthermore, transferrin concentrations tend todecline during acute phase reactions and as a consequence

DIAGNOSIS OF IRON DEFICIENCY IN of malnutrition [38]. In a study of 16 hemodialysis, fourPERITONEAL DIALYSIS PATIENTS CAPD, and five predialysis patients, Kalantar-Zadeh et al

A significant correlation between serum ferritin and showed that serum ferritin levels of less than 200 ng/mlstainable marrow iron has been reported for CAPD pa- had a 100% specificity but only a 41% sensitivity for thetients [2], as well as for patients receiving intermittent diagnosis of iron deficiency [39]. Contrary to that, a trans-peritoneal dialysis [17, 27]. In the study by Blumberg et ferrin saturation of less than 20% had a 100% sensitivityal, the geometric mean serum ferritin was 33 ng/ml (range and a 80% specificity, if patients with low serum trans-11 to 62) in patients with diminished bone marrow iron ferrin levels (less than 150 mg/dl) were excluded. Iron

status was defined using bone marrow iron staining [39].content compared with 167 ng/ml (range 96 to 290) inpatients with normal iron stores and 216 ng/ml (range Macdougall et al demonstrated an increase in the pro-

portion of hypochromic red cells in 30 erythropoietin-58 to 1103) in patients with increased iron stores [2].Blumberg et al were unable to detect a correlation be- treated hemodialysis patients and 16 erythropoietin-

treated CAPD patients [32]. There was only a loosetween stainable bone marrow iron and transferrin satura-tion or serum iron levels [2]. In the study by Milman et inverse correlation between serum transferrin saturation

and the percentage of hypochromic red cells. However,al, all peritoneal dialysis and hemodialysis patients withserum ferritin of less than 140 mg/liter showed no or patients with more than 20% hypochromic red cells had

a consistent transferrin saturation of less than 20%. Par-reduced marrow iron, whereas patients with serum ferri-tin levels of more than 145 mg/liter had a normal or enteral iron therapy was followed by a decrease or nor-

malization of the percentage of hypochromic red cells.increased marrow iron content [17]. In contrast toBlumberg et al [2], these authors found that not only Several other reported tests for the assessment of iron

status in dialysis patients (red cell ferritin, free erythro-ferritin but also transferrin and transferrin saturationwere significantly correlated to stainable marrow iron. cyte protoporphyrin, red cell zinc protoporphyrin) lack

widespread validation, especially in peritoneal dialysisHowever, there was a remarkable overlapping between

Vychytil and Haag-Weber: Iron supplementation in PD S-73

patients and more information is needed before these neal dialysis patients [8, 57–60]. Although either the se-rum hemoglobin/hematocrit was increased or erythro-tests can be recommended [40].

Because of the limitations of each parameter, a combi- poietin dosages were reduced in most cases, a decline inserum ferritin levels was detected in all of those studies.nation of serum ferritin levels, transferrin saturation,

and/or the percentage of hypochromic red cells rather In a study of 26 hemodialysis and eight CAPD patients[61], a switch from oral to intravenous iron therapy al-than a single test should be used in order to assess iron

status in dialysis patients [41]. Moreover, repetitive esti- lowed a 27% reduction of erythropoietin dosage afterthree months with stable serum hemoglobin and hemato-mations over time should offer an accurate picture of

the iron status in most patients [38]. The response to crit levels. In a multicenter study conducted by Nissensonet al, 86% of all peritoneal dialysis patients receivederythropoietin treatment is probably one of the most

important factors for diagnosing iron deficiency [42]. oral iron supplements, but 40% needed intravenous irontherapy [25]. In another multicenter study by Barany etal, 23% of the erythropoietin-treated peritoneal dialysis

ROUTE OF IRON ADMINISTRATION INpatients needed intravenous iron supplementation, al-

PERITONEAL DIALYSIS PATIENTSthough almost all (91%) received oral iron therapy [24].

Oral iron therapy Macdougall et al treated 15 CAPD patients with erythro-poietin, all of which received oral iron supplementationSeveral studies in hemodialysis patients showed that

a change from oral to parenteral iron therapy leads to [62]. However, in 12 of the 15 patients, intravenous irontherapy had to be initiated because of a fall of the trans-a marked decrease of the required erythropoietin dosage

or to an improvement of erythropoiesis [21, 38, 43]. ferrin saturation below 20%.In conclusion, most of the studies dealing with oralTherefore, oral iron supplementation alone is insufficient

for these patients. Noncompliance to oral iron supple- iron therapy in erythropoietin-treated peritoneal dialysispatients show either a progressive decline of serum ferri-mentation is described in up to 32% of cases [44], mainly

because of gastrointestinal side effects [45]. Further- tin and/or an increasing number of patients requiringparenteral iron therapy, indicating that oral supplemen-more, reports on hemodialysis patients regarding iron

resorption are controversial, showing both adequate [11, tation is not sufficient for maintaining a positive ironbalance over a longer period of time. Therefore, paren-46–48] or reduced iron resorption [49–51]. In many cases,

iron resorption may be disturbed because of interference teral iron substitution is indicated in a part of the perito-neal dialysis patients.with phosphate binders or H2-blockers [52]. There are

only a few studies concerning intestinal iron absorptionIs intramuscular iron suitable for peritonealin peritoneal dialysis patients. Milman et al measureddialysis patients?iron resorption using whole body counting [11, 12, 53].

The authors found that compared with healthy controls, Some authors prefer administering intramuscular ironto their patients. Suh and Wadhwa treated seven perito-the resorption rate was equal in peritoneal dialysis pa-

tients with histologically reduced bone marrow iron neal dialysis patients with intramuscular iron dextran100 mg weekly or biweekly and reported a significantstores and significantly lower in those patients with nor-

mal bone marrow iron content. There was a significant increase of serum hematocrit and ferritin after fivemonths, whereas the required erythropoietin dosagenegative correlation of iron absorption to serum ferritin

and to bone marrow iron content [11, 53]. Domoto and could be reduced [63]. There were no systemic adverseevents, but in three of the seven patients, local side ef-Martin applied low-dose iron (65 mg elemental iron in

the form of ferrous sulfate, 66 mg elemental iron in the fects occurred (two times pain and once discolorationat the injection site). Intramuscular iron injections areform of ferrous fumarate) to 13 CAPD patients and 12

control subjects [54]. After two hours, there was only a generally not recommended because they are painfuland there is a risk of muscle hematoma [52, 64, 65].significant increase of serum iron levels in the control

subjects. Similar findings were recently observed by Ti- Several other local side effects, such as lipomyodystro-phy [66] and the occurrence of sarcomas at the injectionnawi et al using 150 mg elemental iron as polysaccharide

ferric complex and in the form of ferrous sulfate [55]. site [67], are reported in the literature. Therefore, ifintensification of iron therapy is required, intravenousIn the control subjects, there only was a significant differ-

ence after using ferrous sulfate. administration should be preferred.Most authors suggest primary oral iron supplementa-

Intravenous iron therapytion in peritoneal dialysis patients because it is morepracticable [38, 52, 56]. Indeed, this form of iron therapy The most physiological way of parenteral iron therapy

is the administration of low dosages (10 to 20 mg) ofmay be adequate in patients not receiving erythropoietin[12, 16]. However, several authors also preferred oral intravenous iron given at the end of each hemodialysis

session [68, 69]. Such a regime allows a marked decreaseiron supplementation in erythropoietin-treated perito-

Vychytil and Haag-Weber: Iron supplementation in PDS-74

of the received erythropoietin dosage in hemodialysispatients and is usually well tolerated [70]. However, aprotocol like this is not acceptable for peritoneal dialysispatients. In a recent study of 17 erythropoietin-treatedCAPD patients [33], intravenous application of 100 mgferric saccharate per week in two divided doses (2 3 50mg/week) resulted in a greater increase of hematocritlevels than application of one single dose (1 3 100 mg/week). However, even visits to the center once or twiceweekly to receive intravenous injections are not conve-nient for peritoneal dialysis patients. Moreover, serialintravenous injections are the most expensive method ofiron supplementation in this patient group [71]. Anotherpossibility would be to apply larger amounts of iron inlonger intervals as suggested by several authors [38, 41,56, 64]. In a study by Ahsan, Groff and Waybill, sevenperitoneal dialysis patients were treated with a single1000 mg bolus of iron dextran over five hours [71]. Allpatients received erythropoietin and had oral iron sup-plementation before the study. The authors demon-strated significant increases of serum hematocrit, trans-ferrin saturation, and serum ferritin 12 weeks after theinfusion of iron dextran. Erythropoietin dosage could bereduced, and no side effects were reported. A more re-cent study showed a significantly higher mean hematocritlevel and mean transferrin saturation in patients sixmonths after infusion of a single 1000 mg bolus of irondextran compared with patients receiving oral iron sub-stitution [72]. Intravenous iron treatment resulted in a39% decrease of the erythropoietin treatment dose,whereas erythropoietin requirements increased 57% inpatients with oral iron therapy [72]. Silverberg et al stud-ied the effect of intravenous ferrous saccharate (100 mgelemental iron) given every second week in 64 hemodial-ysis and nine CAPD patients with or without erythropoi-etin therapy [73]. Serum hematocrit, ferritin, and trans-ferrin saturation increased significantly in all patients,and no side effects were reported. However, the numberof peritoneal dialysis patients was too small to allowgeneral recommendations. In another study, the sameauthors treated 33 patients with chronic renal failure notreceiving dialysis (creatinine clearance 10 to 40 ml/min)

Fig. 1. Transferrin saturation (A), serum ferritin (B), serum hematocritwith 10 ml intravenous iron saccharate (200 mg elemen-(C), and erythropoietin dose (D) in 17 peritoneal dialysis patients be-tal iron) monthly over a period of five months [74]. Two fore, three months, and six months after initiation of intravenous iron

thirds of the patients showed an increase of serum hema- saccharate therapy. * P , 0.05 vs. 0 months.tocrit and hemoglobin. Transferrin saturation and ferri-tin increased continuously in the whole group. A compa-rable protocol was used in a study at the University

deficiency. Patients with transferrin saturation of moreHospital of Vienna. We treated 17 stable peritoneal dial-than 20% received 100 mg iron saccharate over a periodysis patients (6 males and 11 females, mean age 53 6of 10 minutes. In case of transferrin saturation of less16.1 years, mean duration of dialysis 14.4 6 10.7 months)than 20%, 200 mg were given. The results are shown inwith intravenous iron saccharate once monthly over aFigure 1. Regression analyses with repeated measure-period of six months. None of the patients had any evi-ments were performed to detect differences betweendence of infection, inflammation, chronic blood loss, he-

matological disorders, malignancy, vitamin B12, or folate beginning and end of the treatment period. During the

Vychytil and Haag-Weber: Iron supplementation in PD S-75

study period, transferrin saturation increased from 12.1 6 occurred in over 50% of cases, but severe adverse reac-tions were rare. Only a few patients underwent abdomi-1.6% (mean 6 sem) to 20.9 6 2.4% (P 5 0.026), serum

ferritin from 100.4 6 32.0 mg/liter to 372.4 6 54.6 mg/ nal surgery because of their pre-existing diseases follow-ing intraperitoneal iron application, and therefore, littleliter (NS) and hematocrit from 32.0 6 0.8% to 35.1 6

0.9% (P 5 0.099), respectively. There was a significant information is available about morphological changes ofthe peritoneal membrane [81]. Iron dextran injected intocorrelation between the amount of iron applied to the

patient and the increase of hematocrit (P 5 0.037). The two-liter dialysis solution bags remained stable at roomtemperature for up to four weeks and at 378C for up torequired erythropoietin dose could be reduced signifi-

cantly from 148.4 6 30.3 U/kg/week to 69.4 6 19.5 U/kg/ 24 hours [82]. Suzuki et al injected dialysate with irondextran into the peritoneal cavity of rats and detectedweek (P 5 0.025). Side effects (vertigo, hypotension,

lumbago, vomiting) developed in 0.9% of the 100 mg a 70% to 80% decrease of the iron concentration in thedialysate during a dwell time of six hours [83]. However,applications and in 5.9% of the 200 mg applications. The

rate of catheter-related infections and peritonitis during serum iron concentrations before and after the intraperi-toneal injection did not differ, probably because of thethe treatment phase (six months) was similar to the pe-

riod before starting intravenous iron therapy (catheter low iron concentration used (2 mg/liter and 10 mg/liter,dialysate fill volume 25 ml). Histologic examination ofinfection rate, 0.06/month during treatment vs. 0.05/

month before treatment; peritonitis rate, 0.01/month the peritoneum showed no iron deposits, inflammatorychanges, or signs of acute toxicity. Park et al appliedduring treatment vs. 0.02/month before treatment, NS).

Only a few adverse events in peritoneal dialysis pa- iron dextran once daily over a period of six months intothe peritoneal cavity of rats [84]. There was a significanttients receiving intravenous iron are reported in the liter-

ature, but the number of patients in most of the studies increase in hematocrit and serum iron levels after sixmonths in two treatment groups (2 mg/liter and 10 mg/is small. Carter, Garris and Ullian described a case of

rusty peritoneal dialysis fluid after application of 1 g iron liter iron dextran intraperitoneally) as compared with acontrol group only receiving a standard 1.5% glucosedextran intravenously to a patient after Staphylococcus

aureus peritonitis receiving rifampicin [75]. Intracellular dialysis solution. Inspection of the peritoneal cavity aftersix months showed adhesions of the peritoneum andtransport of iron dextran through mesothelial cells of

rabbits after intravenous administration of iron dextran fibrosis around the catheter in all cases treated with thehigher dose, but also to a lower extent in cases of thehas been reported [76]. In hemodialysis patients, Peter,

Lambrecht and Macres found no differences in side ef- low-dose group. Peritoneal iron deposits were detectedby Prussian blue staining in both treatment groups. Infects between intravenous push or infusion of iron dex-

tran [77], and the study of Sunder-Plassmann and Horl, the high-dose group, the peritoneal transport rate ofglucose was reduced significantly after six months com-found that the application of iron saccharate in doses of

up to 100 mg was safe in hemodialysis patients [78]. The pared with the baseline value. There was no significantdifference in the peritonitis rate between control andrelative high rate of adverse events in our study was

probably due to an injection of the 200 mg iron saccha- treatment groups [84]. However, a recent study showedno toxic effects on the peritoneal membrane of rats afterrate dose that was administered too fast, as slower admin-

istration in the same patients did not lead to any side intraperitoneal administration of lower concentrations ofiron dextran (0.125 to 0.5 mg/liter) [85]. One case of intra-effects. However, even intravenous administration of 100

mg iron saccharate may induce a significant impairment peritoneal iron dextran treatment in an erythropoietin-treated CAPD patient has been reported [86]. A singleof phagocytosis and intracellular killing of bacteria by

polymorphonuclear leukocytes, which does not improve dose of 500 mg elemental iron in the form of iron dextrancomplex was instilled into the peritoneal cavity duringcompletely after 24 hours (S.I. Patruta, personal commu-

nication). Therefore, further studies will have to investi- an overnight dwell. The authors reported a significantrise of the serum iron level within one day, a significantgate if bolus administration of larger doses of intrave-

nous iron given in longer intervals may be safe. increase of serum ferritin after two weeks, and an in-crease of hemoglobin and hematocrit after four weeks.

Is intraperitoneal iron administration safe for The rise of hemoglobin and hematocrit levels coincidedperitoneal dialysis patients? with improvement of an exit-site infection. No side ef-

fects such as abdominal pain or changes in peritonealIron dextran injected into the peritoneal cavity of ratspenetrates the serosal surface of the small intestine and transport rates were reported [86]. However, before rec-

ommending intraperitoneal iron therapy, further studiesleads to an increase of ferritin in the liver and spleenafter three days [79]. Intraperitoneal iron supplementa- are needed to answer several questions such as the effect

of chronic iron application on local cellular host defensetion was used more than 30 years ago to substitute bloodlosses during operations or to treat iron-deficient patients in the peritoneal cavity. For instance, if there is any

effect, is it dose dependent? Is there an increased riskwithout renal insufficiency [80, 81]. Mild abdominal pain

Vychytil and Haag-Weber: Iron supplementation in PDS-76

Table 1. Summary of the current intravenous iron treatment neutrophil functions in hemodialysis patients exceedingregimes used for peritoneal dialysis patients

ferritin levels of 650 mg/liter, even if the transferrin satu-Reference Preparation Dose ration is less than 20%. Further studies are necessary toVan Wyck et al [64] iron dextran 500 mg single bolus define the most suitable regime of iron supplementation

infusion for peritoneal dialysis patients with the lowest risk ofSchafer and Schafer [38] iron gluconate 300 mg single bolus

side effects.infusionAhsan et al [71, 72] iron dextran 1000 mg single bolus

infusion ACKNOWLEDGMENTSSilverberg et al [73] ferric saccharate 100 mg twice monthlyFishbane and Maesaka [56] iron dextran 1000 mg single bolus The authors thank Ms. Gabriele Wolfl of the Department of Medical

infusion Statistics, University of Vienna, for statistical consultation.Akcicek et al [33] ferric saccharate 2 3 50 mg or 1 3 100

mg/week Reprint requests to Andreas Vychytil, M.D., Department of MedicinePresent study ferric saccharate 100–200 mg monthly III, Division of Nephrology, University Hospital of Vienna, Wahringer

Gurtel 18–20, A-1090 Wien, Austria.

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