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



Although relative resistance to the effect of ESAs is a common problem in managing the anemia of CKD and is the subject of intense interest, the bulk of available information suggests that—in the absence of iron deficiency—there are few readily reversible factors that contribute to ESA hyporesponsiveness.

3.5.1 Hyporesponse to ESA and iron therapy: (FULLY APPLICABLE TO CHILDREN)
In the opinion of the Work Group, the patient with anemia and CKD should undergo evaluation for specific causes of hyporesponse whenever the Hb level is inappropriately low for the ESA dose administered. Such conditions include, but are not limited to:

In the opinion of the Work Group, evaluation for antibody-mediated PRCA should be undertaken when a patient receiving ESA therapy for more than 4 weeks develops each of the following:


Hyporesponsiveness to ESA and Iron
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.

Definition of Hyporesponsiveness
The principles outlined in the adult guideline should be kept in mind when assessing a child who appears to have hyporesponsiveness to ESA therapy; however, the indications as outlined in Guideline 3.5.1 may not be directly applicable to children because there are no published data from which we can confidently define an excessive epoetin dose to maintain a given Hb target.

In terms of the mean ESA dose required, it is clear from the NAPRTCS 2004 annual report that in all children, the average dose never appears to exceed approximately 350 U/kg/wk, even in the youngest children and even during up to 30 months of follow-up.325 What is not clear is what the upper limit of this dose is in children who seem to respond with an increase in Hb level; hence, it is not currently feasible to set an upper limit dose that, if exceeded in a child whose Hb level is persistently less than 11.0 g/dL, should trigger a consideration for the presence of hyporesponsiveness, although the target in children younger than 5 years would intuitively be greater than that set in the adult guidelines.

Potentially Treatable Disorders
In terms of the factors outlined in the adult guideline as being associated with persistent failure to achieve target Hb levels, these are relevant to children as well, and in a retrospective review of 23 patients on HD therapy for more than 6 months, it was shown that there appeared to be a relationship between the need for high doses of rHuEPO (defined as > 450 U/kg/wk) in patients who were younger, weighed less, had greater parathyroid hormone levels, and had more episodes of bacteremia (all P < 0.03).341 An unexpected finding in this study, relating a high serum ferritin level to an increased risk for hyporesponsiveness, likely (as suggested by the investigators) was related to the presence of inflammation in patients with more frequent episodes of bacteremia.

Evaluation for Diagnosing and Treating Antibody-Mediated PRCA
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.

A brief review of pediatric PRCA cases is presented next.

A study reviewed all 191 confirmed cases of PRCA up until April 2004, including 3 pediatric patients; an 11-year-old boy from the United States, a 17-year-old girl from Brazil, and a 19-year-old boy from France.278 Two of these patients, the 11- and 17-year-olds, received only 1 ESA, epoetin alfa (Procrit®; Ortho Biotech Products, LP, Bridgewater, NJ and Eprex®; Ortho Biotech Products, LP, Bridgewater, NJ, respectively) before developing PRCA. The 19-year-old received both epoetin alfa and epoeten beta, Eprex® and Neorecormon® (F. Hoffmann-La Roche, Ltd, Basel, Switzerland). The 11- and 19-year old patients developed PRCA after 18 months of exposure to an ESA, whereas the 17-year-old developed it 7 months after first exposure to an ESA. The latter subsequently died of cardiac arrest 20 months after the original diagnosis; no data about any form of therapy are available. There are no outcome or therapy data available for the 19-year-old patient; however, the 11-year-old received a renal transplant and subsequently “recovered” from PRCA.

Obviously, these numbers are very small and, for practical purposes, suggest a very low risk for PRCA in children compared with the risk inherent in being anemic or requiring repeated blood transfusions. However, it should be recognized that this problem can occur in children and should be part of the differential for a child with a low reticulocyte anemia in the presence of a decreasing Hb level and preserved white blood cell and platelet lines that fail to respond to increased iron and/or ESA therapy.