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 3.1: USING ESAs

ESAs are critical components in managing the anemia of patients with CKD. Available ESAs are each effective in achieving and maintaining target Hb levels. Aspects of administration may differ between short-acting and long-acting agents.

3.1.1 Frequency of Hb monitoring: (FULLY APPLICABLE TO CHILDREN)

3.1.1.1 In the opinion of the Work Group, the frequency of Hb monitoring in patients treated with ESAs should be at least monthly.

3.1.2 ESA dosing: (FULLY APPLICABLE TO CHILDREN)

3.1.2.1 In the opinion of the Work Group, the initial ESA dose and ESA dose adjustments should be determined by the patient's Hb level, the target Hb level, the observed rate of increase in the Hb level, and clinical circumstances.
3.1.2.2 In the opinion of the Work Group, ESA doses should be decreased, but not necessarily held, when a downward adjustment of Hb level is needed.
3.1.2.3 In the opinion of the Work Group, scheduled ESA doses that have been missed should be replaced at the earliest possible opportunity.
3.1.2.4 In the opinion of the Work Group, ESA administration in ESA-dependent patients should continue during hospitalization.
3.1.2.5 In the opinion of the Work Group, hypertension, vascular access occlusion, inadequate dialysis, history of seizures, or compromised nutritional status are not contraindications to ESA therapy.

3.1.3 Route of administration: (APPLICABLE TO CHILDREN, BUT NEEDS MODIFICATION)

3.1.3.1 ADULT CPR
In the opinion of the Work Group, the route of administration should be determined by the CKD stage, treatment setting, efficacy considerations, and the class of ESA used.
PEDIATRIC CPR
In the opinion of the Work Group, in the pediatric patient, the route of administration should be determined by the CKD stage, treatment setting, efficacy considerations, the class of ESA used, and the anticipated frequency and pain of administration.
3.1.3.2 In the opinion of the Work Group, convenience favors SC administration in non–HD-CKD patients.
3.1.3.3 In the opinion of the Work Group, convenience favors IV administration in patients with HD-CKD.

3.1.4 Frequency of administration: (APPLICABLE TO CHILDREN, BUT NEEDS MODIFICATION)

3.1.4.1 ADULT CPR
In the opinion of the Work Group, frequency of administration should be determined by the CKD stage, treatment setting, efficacy considerations, and class of ESA.
PEDIATRIC CPR
In the opinion of the Work Group, in the pediatric patient, the frequency of administration should be determined by the CKD stage, treatment setting, efficacy considerations, and class of ESA; as well, consideration should be given to the anticipated frequency of, and pain on administration of each agent and their potential effects on the child and family.
3.1.4.2 In the opinion of the Work Group, convenience favors less frequent administration, particularly in non–HD-CKD patients.

RATIONALE

Frequency of Hb Monitoring
This guideline is considered applicable to children because there are some data supporting this assumption and there is no reason for a different recommendation.

There are 2 reasons that may justify closer monitoring of all pediatric patients with 1- to 2-week Hb levels when initiating and/or making significant change to the ESA dose. The first is to ensure that the patient is responding to the current dose. Although not as well described in children as in adult literature, it likely is true that a patient who will reach an intended 1-g/dL increase in Hb level after 1 month of a given ESA/iron regimen will have that increase occur relatively evenly over each of the 4 weeks. In other words, blood work weekly or every 2 weeks will allow the clinician to institute an increase in dosing if a rate of increase of approximately 0.25 g/dL per week is not seen in the early part of the month. (In adults, the rate of increase has been estimated to be 0.3 g/dL per week [0.2 to 0.5 g/dL] on appropriate doses of rHuEPO.324)

Similarly, a child for whom the rate of increase appears rapid, eg, greater than 0.5 g/dL per week, could have the dose adjusted before overshooting at the end of that month of therapy. The greater frequency of monitoring likely is beneficial until the patient has reached a target Hb level and is on a stable dose of ESA. At this point, less frequent monitoring may be indicated, eg, every 4 weeks.

ESA Dosing
In the opinion of the Work Group, this guideline is applicable in children, but needs some modification or adjustment.

Initial Dose and Dose Adjustments
Although there are many dosing guidelines for the use of ESAs in children, it is important to realize that, as in adults,123 there is a large variation in pediatric dosing of these drugs.325 Currently, the most robust evidence for dosing ESA products in children is related to erythropoietin alfa and beta products, with information on darbepoietin alfa dosing just now becoming available.

All clinicians are advised to carefully evaluate the individual patient's particular issues related to their Hb level and likely response before deciding on a particular ESA product, dosing regimen, and frequency of monitoring before the initiation of or changes in ESA and/or iron therapies.

The following section is divided into dialysis versus nondialysis patients and short-acting versus long-acting ESA products.

Dialysis Population (HD and PD)

  1. Short-acting ESAs. Data from the latest NAPRTCS annual report highlight the variation in initial dose reported in children on dialysis therapy, with the younger child consistently receiving more rHuEPO on a per-kilogram-per-week basis.325 The doses referred to next are not derived from RCTs, but rather from registry data and therefore should be interpreted with caution. They represent approximations of the dose required in an average cohort of children and are not represented as recommendations for any specific child. (Note that 93% of these patients were administered erythropoietin alfa as Epogen®; Amgen, Thousand Oaks, CA.)

    This variation in dosing can be seen in relation to:

    a) The dialysis modality, with PD patients initially requiring approximately 225 U/kg/wk compared with nearly 300 U/kg/wk of erythropoietin alfa products to achieve target Hb levels for those on HD therapy.325 Interestingly, this difference in dosing disappears during the first 18 to 30 months of follow-up. It should be noted that the initial dosing difference persisted even when both groups of patients were administered the ESA SC326 and may be caused in part by such factors as blood loss and the use of IV ESAs in HD patients as opposed to SC ESAs in PD or nondialysis patients.319

    b) Age, with patients younger than 1 year requiring an average of 350 U/kg/wk; those 2 to 5 years, approximately 275 U/kg/wk; those 6 to 12 years, 250 U/kg/wk; and finally those older than 12 years needing only slightly more than 200 U/kg/wk at the time of starting ESA therapy.325 One report speculates that this apparently increased “clearance” of erythropoietin in a young child is caused by the presence of nonhematopoietic binding sites for the erythropoietin molecule,327 which—in the fetus or developing child—appears to function as a nonhematopoietic cellular growth factor.328 Because internalization and, potentially, degradation of some of the erythropoietin dose would limit the amount of hormone available for stimulating erythropoiesis, one could explain the need for higher absolute doses to achieve a given marrow response or Hb production. Furthermore, the authors speculate that as the child ages, the number of these sites decreases as development slows, with an attendant decrease in the absolute hematopoietic dose of erythropoietin required.327

    No major differences were noted in relation to either race or sex with respect to initial ESA dose required. There was a general tendency for all doses to decrease over time, presumably on the basis of a lower amount of ESA being required to maintain—as opposed to reach—a given Hb target.

  2. Long-acting ESAs. Currently, there are only 3 published articles329-331 and 1 abstract332 in the peer-reviewed literature related to long-acting ESA products and children with CKD, including those on dialysis therapy. It is expected that there will be other results in due course to assist in guiding the pediatric practitioner in using longer acting ESA agents more effectively.

    The first study evaluated the pharmacokinetic properties of darbepoetin alfa in children with CKD and compared the results with prior studies published in adults.330 They showed that clearance, drug half-life, and bioavailability of darbepoetin alfa, whether administered IV or SC, were similar between pediatric and adult patients. The 1 difference was that absorption of the drug administered SC appeared to be more rapid in pediatric than adult patients.

    The second study described the clinical use of darbepoietin alfa in children.329 The investigators switched 7 long-term HD patients aged 11.5 years (range, 7 to 15.2 years) with a stable Hb level on erythropoietin therapy to darbepoietin IV therapy. Results from this small study suggest that (at least in the pediatric HD population) the conversion dose of erythropoietin alfa to darbepoietin is more likely to be closer to 0.5 µg for every 200 U of erythropoietin alfa, rather than the 1 µg/200 U conversion recommended by the manufacturer. The authors themselves suggest a wide range of doses, 0.25 to 0.75 µg/kg/wk, as being reasonable for the initial switch between therapies.

    The most recent report prospectively looked at the use of darbepoetin alfa in 8 children on PD therapy, 6 children on HD therapy, and 12 children with ND-CKD.331 All patients weighed more than 8 kg and were younger than 18 years. Therapy with ESAs was initiated, if the patient was ESA-naïve, when Hb level was less than 10.0 g/dL, and only patients judged iron-replete, TSAT greater than 20%, were included. The primary outcomes were: (1) the proportion of patients with a mean Hb level greater than 10.0 g/dL between weeks 8 and 12 and then weeks 20 to 28 of the study, and (2) the percentage of all Hb values greater than 10.0 g/dL at each time point.

    The initial dose of darbepoetin alfa was 0.45 µg/kg/wk, administered IV in the HD patients and SC in the PD and ND-CKD patients. Much of the data are presented in aggregate and include both the 26 patients enrolled prospectively and 7 more patients enrolled retrospectively. Statistical analysis by the investigators did not show a difference in terms of drug dose between the beginning and end of the study (P = 0.77), and there was no difference in doses between the HD, PD, and ND-CKD groups (P = 0.62) regardless of their being in the prospective or retrospective arm of the study (P = 0.92 and P = 0.73, respectively).

    Data from 23 patients in the prospective cohort, 18 of whom were available at weeks 20-28 for analysis, showed a statistically significant increase in Hb levels at 8 to 12 weeks of 11.7 ± 1.1 g/dL compared with the baseline of 10.5 ± 1.0 g/dL (P = 0.002), which was still present at week 20 to 28 when Hb level was now 11.4 ± 0.9 g/dL (P = 0.01 compared with baseline). In this group, 96% (CI, 0.90 to 1.0; P = 0.03) compared with baseline at 8 to 12 weeks and 94% (CI, 0.72 to 0.99; P = 0.06) compared with baseline at 20 to 28 weeks had mean Hb values greater than 10.0 g/dL. Similarly, proportions of patients with total Hb values greater than 10.0 g/dL were 94% at 8 to 12 weeks and 90% at 20 to 28 weeks.

    In all ESA-naïve patients (n = 8), the average time to reach the target of 10.0 g/dL from baseline of 9.0 ± 1.4 g/dL was 3.4 weeks, with no patient requiring a higher dose of darbepoetin alfa to achieve this.
    The overall Hb response to darbepoetin alfa was related to the age of the patient, higher values for a given dose being achieved in older patients (P = 0.02).

    Only 1 patient experienced a serious AE that was thought to be possibly related to the darbepoetin alfa. In this case, a girl on home HD therapy was admitted with a worsening of her hypertension; this was at a time when her Hb level was 13.2 g/dL but concurrent with a withdrawal from clonidine some 18 days before the admission. Her blood pressure subsequently was well controlled on fewer medications while remaining on darbepoetin alfa therapy.

Nondialysis Population

  1. Short-acting ESAs. In the ND-CKD population, a number of studies looked at the dose of rHuEPO required to achieve set targets. Currently, there is only 1 published prospective randomized trial that has looked at rHuEPO dosing in children with ND-CKD.319 In this trial, 25 predialysis patients, CKD stages 3 to 5 but not on PD or HD therapy, were randomized to either 150 U/kg/wk (n = 12) or 450 U/kg/wk (n = 13) of rHuEPO administered SC in 3 divided doses. In all 12 of the 150-U/kg/wk patients and 11 of 13 of the 450-U/kg/wk patients, the Hb target of less than 2 SDs less than, but less than the mean for age, was achieved. When at target, the dose was reduced to maintain the target Hb level; on average, this required 143 ± 102 U/kg/wk for the group of responders.

    A nonrandomized open-labeled prospective study took 11 patients aged 0.6 to 17 years with the equivalent of CKD stages 4 and 5 (all predialysis) whose mean Hb level was 7.9 g/dL and treated them with a single dose of 150 U/kg/wk of SC rHuEPO.333 An increase in Hb level greater than 2 g/dL was seen in all 11 patients in a mean of 45 days, range of 14 to 119 days, and subsequently, the patients maintained Hb levels between 11.5 and 13.5 g/dL, with a mean dose of 133 U/kg/wk, range of 75 to 300 U/kg/wk.

    A trial reported on behalf of the Australian and New Zealand Paediatric Nephrology Association also looked at the use of SC ESA in predialysis children.316 Unfortunately, although 10 of the 22 patients were predialysis, their study does not allow the data to be abstracted specifically for this group.

  2. Long-acting ESAs. As discussed in more detail in the preceding section (Long-Acting ESAs in the Dialysis Population), a study showed similar efficacy of darbepoetin alfa in the 15 patients, 12 prospectively enrolled, with ND-CKD treated with a dose of 0.45 µg/kg/wk.331

Rate Of Increase in Hb Levels
A few pediatric studies provide some information on which to base recommendations on the safety and side effects related to the rate of increase in Hb levels.

A prospective trial that examined the safety of rHuEPO therapy in children on HD or PD therapy or predialysis, randomized 44 children (aged 4 months to 21 years) to either low (150 U/kg/wk) or high (450 U/kg/wk) doses of epoetin alfa administered in 3 divided doses.319 Patients were followed up for a total of 12 weeks and targeted for individual Hb levels of between 2 SD less than and the mean value for that child's age. Taking the groups as a whole, there was an average increase of 4.2 ± 2.1 versus 2.4 ± 1.5 g/dL per month in the high-dose versus low-dose groups. Hypertension appeared to be more common, but did not reach statistical significance, for those in the high-dose group compared with the low-dose group, 8 of 21 versus 5 of 23 patients, respectively; chi-squared P = 0.17. The investigators noted that the trend in systolic and diastolic blood pressure was to increase as Hb level increased. No other side effects seemed related to the rate of increase in Hb levels.

Another study randomized 20 anemic children 5 to 16 years of age who were on a stable continuous ambulatory PD regimen for 3 months to examine the effects of low-dose rHuEPO, 50 U/kg/wk (group A), versus high-dose rHuEPO, defined as 50 U/kg 3 times a week (group B).334 Translating their data to Hb values from Hct, those in group A showed a steady increase over 6 months from an Hb level of approximately 6.3 g/dL to 9.9 g/dL compared with the increase seen in group B, for which Hb level went from 6.4 to 10.7 g/dL in only 3 months; an approximately 0.6-g/dL increase per month in group A versus 1.4-g/dL increase per month in group B. Although mean arterial blood pressure increased in both groups during the study (group A, 83 to 87 mm Hg; group B, 85 to 101 mm Hg), it only reached statistical significance in group B, P < 0.05. This was borne out by the need to increase the baseline antihypertensive medications in 8 of the 10 group B patients and initiate these medications in the remaining 2 patients in this group. (Note: rHuEPO therapy was discontinued briefly in 4 patients in group B; 2 patients because of hypertensive encephalopathy; conversely, no patient in group A required an increase in antihypertensive medication or initiation of such therapy during the study.)

If one examines a number of recent pediatric recommendations for the acceptable rate of increase in Hb values, they vary widely. One group recommends a rate of increase between 1 and 2 g/dL per month for all children below the target range.301 Recent guidelines from the European Paediatric Peritoneal Dialysis Working Group recommend an increase of approximately 0.66 g/dL per month as minimally acceptable335 and an increase of more than approximately 2.5 g/dL per month as unacceptable. An often-quoted study recommends, without evidence, that the goal should be an increase in Hb of 1 g/dL per month.336

ESA dosing should be decreased, not held, if Hb level is elevated. In the opinion of the Work Group, this guideline is fully applicable to children.

Missed ESA doses. In the opinion of the Work Group, this guideline is fully applicable to children. ESA dosing during hospitalizations. In the opinion of the Work Group, this guideline is fully applicable to children.

Contraindications to ESA therapy. In the opinion of the Work Group, this guideline is fully applicable to children.

Route of Administration
As in adults, convenience in an outpatient setting favors use of the SC route for delivery of ESAs; with the added realization that even in the face of IV access, a short-acting ESA product will be more efficacious administered SC compared with IV, as confirmed in an observational trial in children.325

As of the 2004 NAPRTCS annual report, 96% of children on PD therapy were administered an ESA by the SC route as opposed to only 14% in the HD population.

However, in children, the psychological impact of frequent and/or painful injections also is important to assess when deciding on a dosing route. Currently, the single-dose preloaded syringes of both epoetin alfa (Eprex®) and darbepoietin alfa available in many parts of the world do not contain benzyl alcohol, which acts as a local anesthetic, in the epoetin alfa multidose vials. This means that injections with the preloaded Eprex® syringes generally are more painful than those from the multidose vials. Similarly, in a Canadian study, 8 of 14 patients with prior experience using epoetin alfa (Eprex®) reported that darbepoetin alfa caused more pain on injection; the remaining 6 patients did not specifically comment about whether they believed Eprex® caused more pain on injection.331

Note: Multidose vials of epoetin alfa should be avoided if at all possible in premature infants and newborns because of a rare, but well-recognized, complication from the use of benzyl alcohol in the preparation of the compound. This excipient has been described to cause numerous serious and potentially fatal reactions, including metabolic acidosis, intraventricular hemorrhage, and neurological problems. Sixteen neonatal deaths were reported that were thought to be caused by benzyl alcohol toxicity, generally described as the so-called “gasping syndrome.”337,338

The issue of dosing epoetin alfa through the intraperitoneal route in children to eliminate injection pain also has been studied by various investigators.339,340 In general, the added costs because of a higher dose required to achieve the same target Hb level, the need for at least 1 dry day dwell (or more) per week to achieve the epoetin alfa absorption required, and the potential for more frequent episodes of peritonitis have lead most centers away from use of this modality routinely. As of the 2004 NAPRTCS report, less than 2% of children on PD therapy currently are administered epoetin alfa through the peritoneal cavity.325 At present, there are no data available on the use of darbepoietin alfa intraperitoneally.

Frequency of Administration
As in the adult population, there is a move toward extending the dosing interval of all ESA products to minimize injections while maintaining efficacy of the product; ie, not having to increase dose significantly more than the gain in time between dosing, to maintain or achieve the target Hb level.

  1. Short-acting ESAs. At present, there is no RCT evidence to show that this strategy is appropriate in children with the current short-acting ESA products on the market. However, data from the 2004 NAPRTCS annual report highlight that 75% to 80% of children on HD therapy will receive short-acting ESA products IV during a standard (3 times per week) HD regimen, whereas a smaller number (15% to 20%) receive it twice a week, and other dosing regimens are uncommon. However, 70% of children on PD therapy generally receive only once-weekly or perhaps twice-weekly injections, with 25% receiving injections thrice weekly, and approximately 5% receiving the drug less than once per week.325

    It also may be reasonable on occasion to consider more frequent SC dosing of the short-acting ESAs, eg, thrice weekly, when the patient's Hb level is well less than the target Hb desired, although the absolute rate of increase should not exceed 2 g/dL per month. Here, the more-frequent dosing ensures that the therapeutic threshold of the hormone is maintained, given its short half-life, and—in concert with adequate iron stores—may assist in achieving a more rapid increase in Hb level.

  2. Long-acting ESAs. Data on the dosing frequency of darbepoietin alfa in pediatric HD patients comes from 7 patients, all of whom were dosed once weekly after HD.329 From a pharmacokinetic study,330 it is clear that extended-dosing regimens with darbepoietin alfa in children should be possible, although currently, few data have been published outlining strategies for dosing frequency.

    In 1 study, to appropriately dose patients at 0.45 µg/kg/wk with the available preloaded darbepoetin alfa syringes, the investigators started 63% of their patients on every 10-, 14-, or 21-day dosing regimens; the remainder were on once-weekly dosing.331 Their results showed no impact of the various dose intervals on the Hb value over time (P = 0.01), but showed that both HD and older patients required more frequent dosing (P < 0.0001 and P = 0.01, respectively), although the dose amount was not different in any group based on age or mode of renal replacement therapy.

    As outlined in CPR 3.1.3.1, the psychological impact of frequent and painful injections also is important to assess when deciding on a dosing frequency in children. Use of less-frequent dosing strategies is, in theory, of benefit by reducing both the absolute number of injections and the pain associated with injections for the child on ESA treatment. However, this may be mitigated by the fact that currently, the only long-acting ESA on the market produces a noticeably increased degree of pain at time of injection for many children compared with some of the short-acting ESA therapies.

    At present, there are no good data from the pediatric ND-CKD population with regard to the dosing frequency of various ESAs.

    Finally, the Work Group also was aware of results from a soon-to-be-published open-label multicenter noninferiority trial examining the use of darbepoetin alfa versus epoetin alfa in the treatment of anemia in children with CKD stages 4 to 5, including patients on HD and PD therapy and the nondialysis CKD population (Bradley Warady, personal communication, June 7, 2005). Because the results were not yet peer reviewed or published at the time the guidelines were finalized and were not blieved to alter the guideline statements, this study is not incorporated in this set of guidelines, but will provide data related to use of darbepoetin alfa in children.