Effect of protein intake on erythropoiesis during erythropoietin treatment of anemia of prematurity

doi:10.1016/S0022-3476(96)70362-1

The Journal of Pediatrics

Volume 128, Issue 4, April 1996, Pages 512-517

https://doi.org/10.1016/S0022-3476(96)70362-1 Get rights and content

Abstract

OBJECTIVE: To examine the effect of protein intake on the erythropoietic response of very low birth weight infants to treatment with recombinant human erythropoietin (rHuEPO). STUDY DESIGN: Twenty very low birth weight infants were enrolled in the study and 19 completed the 6 weeks of study. Weekly absolute reticulocyte counts, protein intakes, and growth, as well as selected markers of protein metabolism-prealbumin, albumin, and transferrin-were analyzed. Iron stores were estimated for each infant to exclude iron deficiency as a cause of anemia. The relationship between protein intake and absolute reticulocyte count was evaluated with a linear breakpoint analysis to account for any plateau in the relationship at higher protein intakes. RESULTS: Adequate iron stores were present in all infants, and transferrin concentrations correlated with measured total iron-binding capacity (r = 0.95, p = 0.0001). In the rHuEPO-treated infants, absolute reticulocyte count was significantly associated with protein intake up to 3.1 gm/kg per day and extending to 3.5 gm/kg per day (p = 0.041 to 0.032); beyond this point there was no longer any effect. Moreover, in comparison with the infants who received placebo, the rHuEPO-treated infants had a better daily percent weight gain for a protein intake up to 3.5 gm/kg per day (p = 0.016). CONCLUSIONS: In VLBW infants treated with rHuEPO, higher protein intake up to 3.1 to 3.5 gm/kg per day improved the erythropoietic response, and protein utilization for growth was improved. During treatment with rHuEPO, infants who receive adequate protein to achieve satisfactory growth also receive sufficient protein for erythropoiesis. (J PEDIATR 1996;128:512-7)

Section snippets

METHODS

This study was approved by the Food and Drug Administration (investigational new drug No. 4117) and the Presbyterian/St. Luke's Medical Center institutional review board as part of the United States multicenter, double-blind, placebo-controlled trial of rHuEPO treatment of anemia of prematurity.⁶ Parental consent was obtained.

RESULTS

The infants in the two study groups were comparable at birth (placebo group versus rHuEPO treatment group, mean ± SD): birth weight 889 ± 249 gm versus 845±155 gm, gestational age 26.4 ± 1.5 weeks versus 25.7 ± 1.6 weeks, and at entry: age 16.3 ± 9.2 days versus 15.6 ± 8.9 days, weight 950 ± 198 gm versus 864 ± 183 gm, and ventilation needs (4 of 10 in placebo group versus 6 of 10 in treatment group). In both groups of infants, dexamethasone was used only at the time of extubation. The study

DISCUSSION

We found that treatment with rHuEPO did not adversely affect growth in VLBW infants and that the erythropoietic response to rHuEPO improved with increased protein intake. The necessity for protein for erythropoiesis in our analysis was focused on erythroid proliferation and differentiation because erythropoietin was provided exogenously. These observations suggest that in preterm infants protein is additionally and separately important for erythroid formation.

Weight gain per gram per kilogram

Acknowledgements

We thank Kim Dohren for expertise with graphics and T. Heaberlin, P. Dillon, S. Aschfort, and R. Zatopek for technical assistance with data collection and drug administration. We thank Barbara Quissell, MD, Peter Honeyfield, MD, Delphine Eichorst, MD, Bruce Reddix, MD, Jeffrey B. Hanson, MD, and the nurses in the neonatal intensive care unit for their support in conducting this study and for their care of the study infants.

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Citation Excerpt :
Effects of nutrition on EPO responsiveness in nonuremic patients have also been reported. Brown et al42 showed that in premature infants with profound anemia who were treated with EPO, higher protein intake improved both erythropoietic response and protein utilization to achieve satisfactory growth. PEM is a common phenomenon in dialysis patients and a well-established risk factor for poor outcome, including risk of cardiovascular disease and death, in these individuals.43,44
Elements of malnutrition-inflammation complex syndrome (MICS) may blunt the responsiveness of anemia of end-stage renal disease (ESRD) to recombinant human erythropoietin (EPO).
The authors examined cross-sectional associations between the required dose of EPO within a 13-week interval as prescribed by practicing nephrologists who were blind to the study and several laboratory values known to be related to nutrition and/or inflammation, as well as the malnutrition-inflammation score (MIS), which is a fully quantitative assessment tool based on the subjective global assessment of nutrition.
A total of 339 maintenance hemodialysis (MHD) outpatients, including 181 men, who were aged 54.7 ± 14.5 years (mean ± SD), who had undergone dialysis for 36.3 ± 33.2 months, were selected randomly from 7 DaVita dialysis units in Los Angeles South/East Bay area. The average weekly dose of administered recombinant human EPO within a 13-week interval was 217 ± 187 U/kg. Patients were receiving intravenous iron supplementation (iron gluconate or dextran) averaging 39.5 ± 47.5 mg/wk. The MIS and serum concentrations of high-sensitivity C-reactive protein, interleukin 6 (IL-6), tumor necrosis factor-α, and lactate dehydrogenase had positive correlation with required EPO dose and EPO responsiveness index (EPO divided by hemoglobin), whereas serum total iron binding capacity (TIBC), prealbumin and total cholesterol, as well as blood lymphocyte count had statistically significant but negative correlations with indices of refractory anemia. Most correlations remained significant even after multivariate adjustment for case-mix and anemia factors and other relevant covariates. Similar associations were noticed across EPO per body weight tertiles via analysis of variance and after estimating odds ratio for higher versus lower tertile via logistic regression after same case-mix adjustment.
The existence of elements of MICS as indicated by a high MIS and increased levels of proinflammatory cytokines such as IL-6 as well as decreased nutritional values such as low serum concentrations of total cholesterol, prealbumin, and TIBC correlates with EPO hyporesponsiveness in MHD patients.
Alterations in body weight, breaking strength, and wound healing in Wistar rats treated pre- and postoperatively with erythropoietin or granulocyte macrophage-colony stimulating factor: Evidence of a previously unknown anabolic effect of erythropoietin?
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Several growth factors, such as growth hormone and insulin-like growth factor-1, have been used to reverse the high rate of catabolism observed either after an operation or during serious illness. We conducted a pilot study in Wistar rats in an attempt to assess whether regulatory peptides widely used in clinical practice, such as erythropoietin (EPO) and granulocyte macrophage colony-stimulating factor (GM-CSF), alone or in combination, might influence the metabolism after surgery. Forty animals were randomly allocated into four groups (one control group and three experimental groups; 10 animals per group). The rats in the control group received isotonic NaCl; the rats in one experimental group received recombinant human EPO (rHuEPO) at a dose of 500 IU/kg (EPO group) and those in another received recombinant GM-CSF at a dose of 20 μg/kg (GM-CSF group); in the fourth group, each animal received the two drugs in combination (EPO/GM-CSF group). In all groups, rats were given the drug(s) or NaCl daily for 15 days before the operation and for 7 days after the operation until they were killed. We estimated the body weight (g) and the hematocrit (%) on the first day of the experiment (baseline values) and on the seventh day after the operation, and we estimated the rate of healing and the breaking strength of the intestinal anastomosis on the day the rats were killed. At the end of the study we found that the body weight (median 250 g, minimum 230 g, maximum 270 g) and the levels of hematocrit (median 64%, minimum 60%, maximum 65%) were significantly increased in the EPO group (P <.001 and P <.005, respectively) as compared with the baseline values (median 217.5 g, minimum 200 g, maximum 250 g; median 51.5%, minimum 45%, maximum 55%, respectively). A similar significant increase in body weight (median 230 g; minimum 200 g; maximum 250 g) and hematocrit (median 64%; minimum 59%; maximum 67%) was found at the end of the study in the EPO/GM-CSF group (P =.01 and P <.005, respectively) as compared with the baseline values (median 210 g; minimum 200 g; maximum 250 g; median 50%, minimum 48%, maximum 54%, respectively). The breaking strength (in newtons [N]) statistically differed in the four groups (Kruskal-Wallis, P =.0008). A comparison between groups showed that the breaking strength had been significantly increased in the animals in the EPO group (median 2.18 N, minimum 1.98 N, maximum 2.44 N) as compared with those in the control group (median 1.66 N, minimum 1.33 N, maximum 1.87 N; P =.004), GM-CSF group (median 1.73 N, minimum 1.25 N, maximum 2.07 N; P <.005), and EPO/GM-CSF group (median 1.71 N, minimum 1.37 N, maximum 1.91 N; P =.0005). In conclusion, this study demonstrated that the administration of rHuEPO appears to have a beneficial positive effect on the body weight, hematocrit, and healing rate and the breaking strength of large bowel anastomoses in rats. These observations provide evidence of an as-yet-unknown anabolic effect of EPO, and they may expand its usual applications. However, more studies are needed to confirm our findings and furthermore to define the optimal dose and timing of EPO administration. (J Lab Clin Med 1999;133:253-9)
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^☆: From the Departments of Pediatrics and Research and Development, Presbyterian/St. Luke's Medical Center, Denver, Colorado

^☆☆: Supported by R. W. Johnson Pharmaceutical Research Institute (Raritan, N.J.), and Presbyterian/St. Luke's Community Foundation (Denver, Colo.), grant No. 9014.

^★: Reprint requests: Mark S. Brown, MD, 1601 East 19th Ave., Suite 5300, Denver, CO 80218.

^★★: 0022-3476/96/$5.00 + 0 9/20/71133

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Effect of protein intake on erythropoiesis during erythropoietin treatment of anemia of prematurity☆,☆☆,★,★★

Abstract

Section snippets

METHODS

RESULTS

DISCUSSION

Acknowledgements

J Nutr

Blood

Blood

J Pediatr

J Pediatr

J Pediatr

Anal Biochem

Blood

J Pediatr

J Pediatr

Haemoglobin concentration depends on protein intake in small preterm infants fed human milk

Arch Dis Child

Erythropoietin, protein, and iron supplementation and the prevention of anaemia of prematurity

Arch Dis Child

Recombinant human erythropoietin stimulates erythropoiesis and reduces erythrocyte transfusions in very low birth weight preterm infants

Pediatrics

Iron requirements of the premature infant