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Analyses of age, gender and other risk factors of erythropoietin resistance in pediatric and adult dialysis cohorts

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Abstract

Previous studies often report lower responses to erythropoietin (EPO) therapy in pediatric patients on chronic dialysis than those of adults. Because of the greater capacity for hematopoiesis in the younger population, these studies may be confounded by poorly identified variables. Thus, we made parallel studies of pediatric and adult cohorts to explore the relationship between age, gender and other risk factors with EPO resistance. Thirty pediatric subjects (aged 8–20 years) and 66 adult subjects (aged 22–85 years) on chronic hemodialysis and EPO were enrolled. After stratification by 50th percentile of EPO response, the best predictive model was identified by backward elimination of the risk factors with the least contribution to the regression. Relationship between age, gender and EPO resistance was examined by analysis of covariance (ANCOVA). The most predictive model of EPO response for the pediatric cohort had, as the major variables, urea clearance × dialysis duration/total body water (Kt/V), urea reduction ratio (URR), intact parathyroid hormone (iPTH), blood loss, normalized protein catabolic rates (nPCR) and indices of malnutrition and inflammation, whereas adults had iron and folate deficiencies as the dominant variables. Although EPO resistance was more common in female subjects than in male subjects, relationship with neither age nor gender was significant. Furthermore, the prescription of a larger (initiating) EPO dose by pediatric physicians compared with adult nephrologists confounded the interaction between age and EPO resistance. In summary EPO resistance in the pediatric dialysis cohort was predicted by nutritional deficits, inflammation, poor dialysis, and hyperparathyroidism, while iron and folate deficits were the major determinants in adults. Although confounded by the pattern of EPO prescription, neither age nor gender was predictive of EPO resistance in the two study groups.

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Acknowledgment

Supported by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Training Grant no. 9-526-3740

Author information

Authors and Affiliations

  1. Division of Pediatric Nephrology, Department of Pediatrics, Children’s Hospital of New Orleans, Louisiana State University Health Science Center, 200 Henry Clay Avenue, New Orleans, LA, 70118, USA

    Oluwatoyin Fatai Bamgbola

  2. Children’s Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, New York, NY, USA

    Fredrick J. Kaskel

  3. Division of Nephrology, Department of Internal Medicine, Montefiore Medical Center/Albert Einstein College of Medicine, New York, NY, USA

    Maria Coco

Authors
  1. Oluwatoyin Fatai Bamgbola
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  2. Fredrick J. Kaskel
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  3. Maria Coco
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Corresponding author

Correspondence to Oluwatoyin Fatai Bamgbola.

Appendix

Appendix

Appendix A. Objective malnutrition inflammation scores

  1. (a)

    Serum albumin: (1) ≥ 4 g/dl = 0, (2) 3.5–3.9 g/dl = 1, (3) 3.0–3.4 g/dl = 2, (4) < 3.0 g/dl = 3

  2. (b)

    Serum transferrin: (1) ≥ 250 mg/dl = 3, (2) 200–249 mg/dl = 2, (3) 150–199 mg/dl = 1, (4) < 150 mg/dl = 0

  3. (c)

    Body mass index: (1) ≥ 20 kg/m2 = 0, (2) 15–19.9 kg/m2 = 1, (3) 16–17.9 kg/m2 = 2, (4) < 16 kg/m2 = 3

  4. (d)

    Dialysis duration (years): (1) 0–1 = 0, (2) 1–3 = 1, (3) 3–5 = 2, (4) > 5 = 3

  5. (e)

    Infection: (1) none = 0, (2) low grade (e.g. line-induced bacteremia, upper respiratory tract infection = 0.5 × no. of events, (3) moderate (e.g. symptomatic line sepsis, pneumonia) = 1.0 × no. of events, (4) severe (infection warranting hospitalization) = 1.5 × no. of events

  6. (f)

    Dialysis adequacy: (1) URR ≥ 80% = 0, (2) 61–79% = 1, (3) 41–60% = 2, (4) < 40% = 3

  7. (g)

    Serum ferritin: (1) 0–500 mg/dl = 0, (2) 501–750 mg/dl = 1, (3) 751–1,000 mg/dl = 2, (4) > 1,001 mg/dl = 3

Appendix B. Clinical and laboratory definitions

EPO resistance index

ERI calculated as EPO dose (international units per kilogram per week) divided by a given value of hemoglobin concentration (grams per deciliter).

Folate deficiency

Because of an overlap in the diagnostic accuracy of the red blood cell (RBC) parameters [e.g. mean corpuscular volume (MCV) and red cell distribution width (RDW) were poorly specific], folate deficiency (FD) was defined as (a) Mean serum folate and/or RBC folate ≤ 2 standard deviation score (b) Mean MCV ≥ 95th percentile for age and gender and/or RDW ≥ 16 and (c) Normal serum vitamin B12.

Iron deficiency

Fe deficiency consists of (a) Mean Fe saturation < 20% (b) Mean serum ferritin < 100 mg/dl and (c) Mean MCV [and/or mean corpuscular hemoglobin (MCH)] < 5th percentile for age and gender.

Malnutrition inflammatory score

The objective malnutrition inflammatory score (OMIS), adapted from the comprehensive MIS [18], is a questionnaire designed to quantify nutritional deficiency and inflammatory burdens. Its components are primary renal disease, dialysis duration, dialysis adequacy, C-reactive protein, total iron binding capacity, serum ferritin, body mass index, serum albumin and transferrin.

Dialysis adequacy

Urea reduction ratio (URR) = pre-dialysis blood urea nitrogen (BUN) − post-dialysis BUN/pre-dialysis BUN

Kt/V was determined by computer analysis (formal urea kinetic modeling) of the variables K, extrapolated from the mass transfer area coefficient (KoA) of the dialyzer, V, estimated total body water, and G, urea generation rate [or normalized protein catabolic rate (nPCR)].

Pubertal status

Post-puberty was defined as (a) Tanner stage (breast and/or pubic hair) ≥ 2, (b) plasma levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) consistent with the stage of puberty (c) and normal plasma free-thyroxine (FT4) and thyroid-stimulating hormone (TSH). Plasma gonadotropins were measured by ultra-sensitive chemiluminometric assay. Tanner I, FSH > 0.65 ng/ml, LH > 0.75 ng/ml; Tanner II, FSH > 2.75 ng/ml, LH > 1.0 ng/ml; Tanner III, FSH > 2.25 ng/ml, LH > 1.0 ng/ml; Tanner IV, FSH > 2.5 ng/ml, LH > 2.5 ng/ml; Tanner V, FSH > 2.5 ng/ml, LH > 2.5 ng/ml.

Infection score

Severity of infection: mild (e.g. line-induced bacteremia, upper respiratory tract infection) = 1, moderate (e.g. symptomatic line sepsis, pneumonia) = 2, and severe (infection warranting hospitalization) = 3.

Grade of surgery

minor (e.g. vascular access placement or revision) = 1, major (e.g. nephrectomy, parathyroidectomy, appendectomy) = 3

Estimated blood loss

Amount of blood collected for all laboratory procedures was measured; blood loss during dialysis (e.g. clotted circuit) was subjectively quantified by experienced dialysis nurses, and surgical blood loss was estimated by the attending surgeons. Blood loss was corrected for blood volume (BV) as EBL/BV. Calculated blood volume = 87 ml/kg for 7–18 years, and 72 ml/kg for > 18 years.

Residual renal function

An estimated minimum daily urine output of 50 ml and 100 ml for study subjects below 10 years of age and above 10 years of age, respectively.

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Bamgbola, O.F., Kaskel, F.J. & Coco, M. Analyses of age, gender and other risk factors of erythropoietin resistance in pediatric and adult dialysis cohorts. Pediatr Nephrol 24, 571–579 (2009). https://doi.org/10.1007/s00467-008-0954-3

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