KDOQI (Kidney Disease Outcomes Quality Initiative)
NKF KDOQI GUIDELINES

KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease


III. CLINICAL PRACTICE RECOMMENDATIONS FOR ANEMIA IN CHRONIC KIDNEY DISEASE IN CHILDREN

CPR FOR PEDIATRICS 3.2: USING IRON AGENTS

Anemia therapy in patients with CKD requires effective use of iron agents, guided by appropriate testing of iron status. Efficacy of iron therapy appears not to be limited to patients with evidence of iron deficiency. (See Guideline 1.2 for diagnosis of iron deficiency.) Thus, the goals of iron therapy are to avoid storage iron depletion, prevent iron-deficient erythropoiesis, and achieve and maintain target Hb levels.

3.2.1 Frequency of iron status tests: (FULLY APPLICABLE TO CHILDREN)
In the opinion of the Work Group, iron status tests should be performed as follows:

3.2.1.1 Every month during initial ESA treatment.
3.2.1.2 At least every 3 months during stable ESA treatment or in patients with HD-CKD not treated with an ESA.

3.2.2 Interpretation of iron status tests: (FULLY APPLICABLE TO CHILDREN)
In the opinion of the Work Group, results of iron status tests, Hb level, and ESA dose should be interpreted together to guide iron therapy.

3.2.3 Targets of iron therapy: (APPLICABLE TO CHILDREN, BUT NEEDS MODIFICATION)
In the opinion of the Work Group, sufficient iron should be administered to generally maintain the following indices of iron status during ESA treatment:

3.2.3.1 ADULT CPR HD-CKD:
• Serum ferritin > 200 ng/mL, AND
• TSAT > 20%, or CHr > 29 pg/cell.
PEDIATRIC CPR
HD-CKD:
• Serum ferritin > 100 ng/mL; AND
• TSAT > 20%.
3.2.3.2 ND-CKD and PD-CKD:
• Serum ferritin > 100 ng/mL AND
• TSAT > 20%.

3.2.4 Upper level of ferritin: (FULLY APPLICABLE TO CHILDREN)
In the opinion of the Work Group, there is insufficient evidence to recommend routine administration of IV iron if serum ferritin is greater than 500 ng/mL. When ferritin level is greater than 500 ng/mL, decisions regarding IV iron administration should weigh ESA responsiveness, Hb and TSAT level, and the patient’s clinical status.

3.2.5 Route of administration: (FULLY APPLICABLE TO CHILDREN)

3.2.5.1 The preferred route of administration is IV in patients with HD-CKD. (STRONG RECOMMENDATION)
3.2.5.2 In the opinion of the Work Group, the route of iron administration can be either IV or oral in patients with ND-CKD and PD-CKD.

3.2.6 Hypersensitivity reactions: (FULLY APPLICABLE TO CHILDREN)
In the opinion of the Work Group, resuscitative medication and personnel trained to evaluate and resuscitate anaphylaxis should be available whenever a dose of iron dextran is administered.

BACKGROUND

As in adults, the most commonly identified reason for poor responsiveness to ESA therapy in children is iron deficiency.341

The need for iron supplementation in children to maintain iron stores and promote the efficient use of ESAs can be predicted from the knowledge of mean daily blood—hence iron—losses in both those who are predialysis and those on dialysis therapy. Predialysis patients, and likely those on PD therapy, lose on average 6 mL/m2/d of blood, mainly from the GI tract, which translates to a cumulative yearly iron loss and therefore requirement of 0.9 g/1.73 m2.342 This is just more than half of that predicted for pediatric HD patients, for whom the mean GI blood loss is 11 mL/m2/d, and when coupled with the dialyzer losses of 8 mL/m2 per treatment, translates to a yearly cumulative loss of approximately 1.6 g/1.73 m2.342

As in the adult population, several studies have shown that supplementation of iron in children receiving ESA therapy allows a reduction in the ESA dose required per unit of Hb level achieved.343,344 However, constipation and nausea, as well as poor GI iron absorption, often limit effective supplementation with oral iron preparations.166,345,346 These facts and the availability of newer IV iron preparations believed less likely to induce AEs recently led to more studies with IV preparations of iron in children. The majority of these studies examined only patients in CKD stage 5, especially those on HD therapy.304,305,344,347,348

RATIONALE

Frequency of Iron Tests
This guideline is considered applicable to children because there are no special data in the pediatric population and there is no reason for a different recommendation.

Interpretation of Iron Tests
This guideline is considered applicable to children because there are no special data in the pediatric population and there is no reason for a different recommendation.

Targets of Iron Therapy
HD-CKD
Caution must be exercised in applying the targets or normal ranges as outlined in the guideline for adult patients with HD-CKD because the increase in ferritin target from 100 to 200 ng/mL in adult HD patients is based on evidence to suggest that a level of 100 ng/mL underestimates iron deficiency,98,99,151-156 and data from a study in which patients with an average serum ferritin level of 730 ng/mL showed a 40% reduction in ESA dose compared with those with an average ferritin level of 297 ng/mL.108 There is no similar RCT-level evidence for this in children; namely, that achieving a specific ferritin level will produce a consistent decrease in ESA doses required, and there are no adult or pediatric data on the safety of supraphysiological ferritin levels.

One pediatric study in older children on HD therapy suggested that a TSAT less than 20%, but not a ferritin level less than 100 ng/mL, was predictive of iron deficiency.349 However, other pediatric studies in the CKD population have shown that although a normal ferritin level cannot exclude iron deficiency, absolute or functional,348,350 a low ferritin level, less than 60 ng/mL, is a specific predictor of its presence.351

Therefore, we recommend that the current Guidelines be followed in children with the exception that until data are available on the risks and benefits of higher ferritin targets in children, the targets be left at a ferritin level greater than 100 ng/mL and TSAT greater than 20% for patients with HD-CKD, as well as PD-CKD and ND-CKD populations.

With respect to the use of CHr, which has been touted as a valuable screening test for iron deficiency in “normal” children even before the appearance of iron-deficient anemia, the cutoff normal and abnormal values remain unclear and wide. For example, a cutoff value of 26 pg only produced sensitivity and specificity of 70% and 78% for iron deficiency and 83% and 75% for iron deficient anemia in this select group of non-CKD young children, respectively.352

In the pediatric CKD literature, CHr has been examined in a limited fashion in children on HD therapy.304,305 In both studies, an increase from baseline CHr levels was observed in response to oral iron, IV iron dextran, and IV sodium ferric gluconate in patients judged to be both iron replete (oral iron and IV iron dextran)304 and iron-deficient (IV sodium ferric gluconate).305 Unfortunately, cutoff values for use of this marker in the pediatric CKD population are not clear, and this is shown clearly in these 2 studies, in which, in nearly identical patient populations (ie, children on HD therapy), the baseline value for CHr was higher in the group judged as iron deficient based on current DOQI guidelines305 than in those judged iron-replete by those same criteria.304

Therefore, whereas it is clear that CHr may yet have a prognostic or diagnostic role in anemia in children with CKD, further research clearly is needed to understand and define the value of this test in the pediatric CKD population.

ND-CKD and PD-CKD
This guideline is considered applicable to children because there are no special data in the pediatric population and there is no reason for a different recommendation.

Upper Level of Ferritin
This guideline is considered applicable to children because there are no special data in the pediatric population and there is no reason for a different recommendation.

Note: As in the adult guidelines, this refers only to the intentional targeting of a patient’s ferritin level to greater than 500 ng/mL, not to the individual’s achieved or acquired ferritin level, which may be at or greater than this level.

Route of Administration
This guideline is considered applicable to children because there are no special data in the pediatric population and there is no reason for a different recommendation.

Suggestions for iron supplementation in children with CKD vary in terms of dose, as well as type of preparation. Many children in the ND-CKD or PD-CKD populations may benefit from and receive oral iron therapy,325 whereas those on HD therapy are likely to require and most often receive IV agents to allow for sufficient iron stores for ongoing erythropoiesis.325,348,350

Oral Iron
For oral iron therapy, the recommendations are for doses of elemental iron ranging from 2 to 3 mg/kg/d up to 6 mg/kg/d, with a maximum of 150 to 300 mg of elemental iron per day in 2 to 3 divided doses335,336 taken 2 hours before or 1 hour after all calcium-containing binders and food to maximize GI absorption.353 A prospective randomized trial of 35 pediatric patients between 1 and 20 years of age on HD therapy, all iron replete, examined response to oral or IV iron (more details discussed next).304 This study clearly showed a much better response to IV iron in terms of an increased serum ferritin level, but did not show any advantage of IV over oral iron in terms of maintaining iron stores.

Efficacy of IV Iron
To date, the largest randomized prospective study to address this issue is a multicenter, international, double-blind, parallel-group, efficacy and safety study that examined the use of sodium ferric gluconate in anemic children with a mean age of 12.1 ± 2.6 years on HD therapy.305 All patients at the time of enrollment met 1 or both of the current KDOQI targets for iron deficiency while on ESA therapy, ie, a TSAT less than 20% or ferritin level less than 100 ng/mL. Of this group, data from 56 patients were available to assess the efficacy of the 2 dosing regimens chosen: 1.5 versus 3.0 mg/kg administered for 8 sequential HD sessions.

All patients in both dosing arms showed a significant increase in their baseline Hb levels of 0.9 g/dL at 2 weeks; 0.9 g/dL in the 1.5-mg/kg dose and 1.0 g/dL in the 3.0-mg/kg dose arm at 4 weeks from the last dose of IV iron, all P < 0.02. No patient had any change in rHuEPO dose during the iron therapy; however, during the 4-week follow-up period, 5 patients had reductions in rHuEPO dose of 14%, 20%, 50%, 50%, and 67%, all at the 2-week point. Evaluation of all other indices studied (TSAT, ferritin level, and CHr) also showed a significant mean increase from baseline values in both arms, which remained significant at 4 weeks after infusion. However, only ferritin levels showed a significant change between the low-dose and high-dose iron arms, seen at both the 2-week and 4-week time points following the last dose of IV iron. Based on their data, the investigators concluded that IV sodium ferric gluconate was efficacious in both repleting and maintaining iron stores in children on HD up to 4 weeks after infusion.

In a separate and earlier randomized prospective study, the investigators studied 35 pediatric patients between 1 and 20 years of age on HD therapy for their response to oral or IV iron.304 All patients were iron replete, as defined by KDOQI, with a TSAT greater than 20% and ferritin level greater than 100 ng/mL. They were all well dialyzed and randomized to either weekly IV iron dextran, which was dosed by weight and provided as 2 sets of 6 weekly doses with two 2-week breaks to monitor levels, or daily oral iron at a dose of 6 mg/kg/d as outlined in the NKF-KDOQI 2000 Anemia Guidelines for 16 weeks.2 Data showed that only the IV iron dextran produced a significant increase in serum ferritin levels, P = 0.001. Those treated with IV iron dextran also showed a significant decrease in dose of rHuEPO required to maintain target Hb levels, P = 0.046, and an increase in CHr, although this was not statistically different from those seen in the oral iron group. Both the oral and IV preparations maintained all patients in the iron-replete state, as when the study was started. Although there was a significant difference in mean ferritin levels (259.1 compared with 138.5 ng/mL; P = 0.003) and rHuEPO doses (reduction of 33% from baseline; P = 0.046) in the IV iron group during the study, there was no statistically significant difference between the IV versus oral iron arms as a whole. The investigators concluded from this short-term study that IV iron dextran seemed more effective in improving—but no more effective in maintaining—iron stores in pediatric HD patients on ESA therapy compared with oral iron.

Another prospective randomized trial examined the issue of intermittent versus maintenance IV iron in pediatric patients on HD therapy.347 The study group of 20 patients received IV iron dextran targeted to initial ferritin levels and a calculation of the net projected iron stores required to target an Hb level of 11.55 g/dL, whereas the 20 patients in the control group were treated with intermittent courses of 10 weekly doses of IV iron dextran as defined by body weight (repeated as necessary based on the presence of a ferritin level < 100 ng/mL, TSAT < 20%, or Hct < 33%). All patients had basal Hb levels of approximately 8 g/dL and reached 10 g/dL by 3 months in both arms. The study’s end points were ferritin, TSAT, and Hb levels. Success was defined as maintaining an acceptable target range of ferritin between 100 and 800 ng/mL and TSAT of 20% to 50%. The study enrolled both absolute and functionally iron-deficient patients. A large number of patients, 20, were excluded during this study; 13 patients because of iron overload, defined as a ferritin level greater than 800 ng/mL (9 from the control group). Three patients in the control group required a blood transfusion and also were excluded. Using the study’s iron and rHuEPO protocols, there was a significant difference in iron dose required during the study, 6 mg/kg/mo (95% CI, 3.3 to 8.8) in the study group compared with 14.4 mg/kg/mo (95% CI, 12 to 16.8) in the control arm, P < 0.001. The investigators showed that patients in the study arm achieved and maintained a stable Hb value, whereas those treated as controls had a much more variable increase and decrease in Hb values.

Four other nonrandomized trials in children,344,348,350,354 all involving HD patients and 1 including patients with ND-CKD and/or transplant recipients,354 examined the utility of IV iron in maintaining or increasing Hb levels and decreasing the dose of ESA required to do so. Two trials used iron gluconate,350,354 1 trial used iron dextran,348 and 1 trial used iron sucrose344; doses ranged from 1 to 4 mg/kg/wk of the various products as maintenance therapy, and time of therapy varied from 2 to 24 weeks. All 4 trials showed increases in either Hb level or Hct and a decrease in ESA requirements between 5% and 62% per week or per dose of ESA.

A recent meta-analysis on the use of IV iron in pediatric HD patients used pooled data that did not include the 2 most recent trials,304,347 but included the other 4 studies described, as well as a number of abstracts. Meta-analysis showed that in terms of an increase in Hb, Hct, ferritin, and TSAT values and decrease in ESA requirements, there was a positive correlation with IV iron therapy with an effect size that varied from 0.62 (95% CI, 0.11 to 1.13) to 1.86 (95% CI, 1.58 to 2.15) when evaluated using a standardized weighted-mean difference approach.343

Dosing of IV Iron
The use of IV iron preparations and the appropriate dosage of each is a complex topic. It is made more so because one needs an approach to both the immediate repletion of iron stores in a patient who is deficient and a strategy for maintaining an effective level of iron for ongoing erythropoiesis.

The goal of the initial iron therapy is to replenish the body store of functional iron and thus assist in the production of red blood cells and Hb in concert with an ESA. The exact dosing regimens, frequency of IV iron therapy, and appropriate monitoring for effectiveness and safety will be related to the iron preparation chosen.2,305,344,355

Currently published pediatric studies looking at the issue of chronic or maintenance therapy with IV iron have provided 1 to 2 mg/kg/wk of elemental iron and targeted TSATs between 20% and 50% and serum ferritin levels of 100 to 800 ng/mL, based on the prior Anemia Guidelines,2 to decide on further doses and frequency of administration.344,350

It is important to remember that it is possible to have acceptable levels of both TSAT and ferritin and still benefit from IV iron if the patient has so-called functional iron deficiency; therefore, occasionally, after careful assessment of the risk and benefits, a “trial” of IV iron in an anemic patient—even one who appears iron replete—may be indicated.

Use of IV Iron in Patients with ND-CKD and PD-CKD
The issue around the utility and practicality of using IV agents in the non-HD population needs to be addressed in children because it is not uncommon that these patients either show an inability to tolerate or fail to respond to oral replacement of iron stores.

Currently, in pediatrics, the lack of easy IV access hampers the use of the strategies used in the HD population, namely, small, but frequent, dosing. In the non-HD population, much higher single doses of the various IV irons, such as dextran,356-358 sucrose,359,360 or gluconate,361 have been administered at less frequent intervals (eg, monthly) in adults to obtain the benefit of IV therapy while minimizing the inconvenience of both the need for IV starts and hospital monitoring during the therapy. However, this may carry different risks in terms of either acute or chronic toxicities. Currently there is little comparable evidence in children, with only 1 published study reporting a maximum delivered dose of iron sucrose of 200 mg344 and another reporting a maximum dose of 250 mg of iron gluconate.354

Safety of IV Iron
One concern in the use of IV iron in children, especially in an outpatient setting, is the potentially fatal acute AEs.179 All forms of IV iron may be associated with acute AEs, which may include hypotension, anaphylactoid reactions, and a variety of other symptoms. Immune mechanisms with activation of mast cells or release of bioactive partially unbound iron into the circulation resulting in oxidative stress and hypotension (labile or free iron reactions) are both possible mechanisms, and the underlying cause may differ depending on the type of IV iron. Anaphylactoid reactions appear to occur more frequently with iron dextran,173 and labile or free iron reactions, more frequently with nondextran forms of iron.174 (For further discussion, please see the corresponding Adult Guidelines.)

Although very rare in pediatrics, of 28 children enrolled in 2 separate studies involving iron dextran,304,348 1 child had an allergic reaction that necessitated stopping the medication.348 Current evidence would suggest that the risk for life-threatening reactions is greater with IV dextran products than sodium ferric gluconate175 and iron sucrose products.187

Although both iron sucrose and gluconate products seem to have better safety profiles than dextran, side effects—presumably caused by acute iron toxicity during rapid free iron release—also have been described with both of these products.

With respect to sodium ferric gluconate, pediatric safety data from the trial described earlier305 were available in 66 patients administered 8 IV doses. One patient in the group administered 1.5 mg/kg per dose was reported to have isolated episodes of mild nausea, diarrhea, and vomiting, whereas a patient in the 3.0-mg/kg group had an episode of severe anemia ascribed to the drug by the investigator at that site. However, no patient had an allergic or anaphylactic reaction during the immediate treatment; no delayed reactions occurred in the 4 weeks after the last iron dose, and no deaths were reported during the study. Together with data from 2 other trials in which 21 children were administered this product without serious AEs, this observation offers some proof about the safety of sodium ferric gluconate in children.350,354

Iron sucrose safety data are sparse in the pediatric CKD literature, with only 2 studies reported. One was a retrospective study that did not report serious AEs in the 8 patients who had received at least 1 dose of IV iron sucrose as Venofer (American Regent, Shirley, NY).344 Another was a prospective trial that looked at only a small number of patients (n = 14) divided into 3 different treatment groups with various iron regimens and did not specifically report on AEs.362

The issue of iron overload as a “side effect” of IV iron therapy also should be addressed. Iron excess is believed to generate cellular oxidative stress, and iron stored as ferritin can assist in initiating lipid peroxidation of cell membranes.363 In humans, increased ferritin levels have been linked to a variety of conditions, including increased severity of strokes364 and acute renal failure,365 although direct evidence for tissue toxicity related to serum ferritin level is lacking in the CKD population.

In children, a study comparing 2 different dosing strategies of iron dextran showed, by using Kaplan-Meier analysis, a hazard of iron overload (defined by the investigators as a serum ferritin level > 800 ng/mL or TSAT > 50% at any time during the trial) of 20% in the study arm versus 100% in the control arm after 6 months of treatment.347 Patients with functional iron deficiency also were statistically more likely to develop iron overload than those with an absolute iron deficiency, 70% versus 19% P < 0.005. Note: There was no direct or indirect evidence of organ damage offered by the investigators in support of their definition of iron overload.

Finally, the Work Group also was aware of results from a soon-to-be-published prospective multicenter trial of sodium ferric gluconate complex for maintenance iron therapy in iron-replete children on HD therapy and administered rHuEPO (Bradley Warady, personal communication, June 7, 2005). Because results were not yet peer reviewed or published at the time these guidelines were finalized and were not believed to alter the guideline statements, the study is not incorporated in this set of guidelines, but will provide data related to dosing, safety, and efficacy of rHuEPO in the pediatric HD-CKD population.