Reply

Der-Cherng Tarng and Tung-Po Huang

Division of Nephrology Department of Medicine Taipei Veterans General Hospital and National Yang-Ming University School of Medicine Taipei Taiwan Email: dctarng{at}vghtpe.gov.tw

Sir,

We appreciate the comments by Deira et al. regarding our original article published in the June 2002 issue of Nephrology Dialysis Transplantation [1]. The purpose of our study was to explore the factors determining the circulating soluble transferrin receptor (sTfR) levels in chronic haemodialysis (HD) patients undergoing recombinant human erythropoietin (rHuEPO) treatment. We found that serum EPO, per cent of hypochromic red cells (% HRC) and serum ferritin were three major independent predictors of sTfR levels in our patients, whose rHuEPO doses were maintained constant, i.e. in the steady-state, in response to stable, intermittent erythropoietic stimulation. Cumulative data have already indicated that circulating sTfR levels provide a reliable measure of erythropoiesis in HD patients or pre-dialysis patients with chronic renal failure treated with rHuEPO [24]. The findings of Deira et al. [5] and Chiang et al. [6] have provided an additional piece of information on this. However, information on the specificity of sTfR for detection of iron-deficient erythropoiesis in HD patients is conflicting. Some investigators report that sTfR is a surrogate marker for detecting iron deficiency in HD patients receiving rHuEPO therapy [7,8], but others did not observe this [5,6]. As an elevation in sTfR levels may be caused by enhanced erythropoiesis or tissue iron deficiency, the rHuEPO-enhanced erythropoiesis, which itself raises serum receptor levels, is a major confounder in evaluating the interrelation between sTfR and iron deficiency. If one intends to prove that an increase in sTfR levels is caused by a deficit in iron, then this increase should be accompanied by a decrease in ferritin levels and transferrin saturation (TS), with no increase in haemoglobin or reticulocytes. Vice versa, an increase in receptor levels caused by enhanced erythropoiesis would be accompanied by an increase in haemoglobin and reticulocytes, without changes in serum ferritin and TS.

In the study of Deira et al. [5], increased sTfR concentration paralleled a rise in haemoglobin and reticulocytes is mainly influenced by the administration of rHuEPO in their HD patients as serum ferritin and TS showed no significant changes during the study period. The authors never mentioned the initial and maintenance doses of rHuEPO used in 23 HD patients and, furthermore, any differences in the rHuEPO doses between the two groups of patients with serum ferritin <100 and >100 ng/ml. Although they proposed some reasons for no significant difference in sTfR levels between these two groups for 120 days, we infer that this might be due to the similar erythropoietic stimulation in the two groups of patients treated with the similar rHuEPO doses. Before drawing any conclusions, the authors should re-analyse and compare the rHuEPO doses, changes in haemoglobin and reticulocyte counts between these two groups during the study period. In the study of Chiang et al. [6], increased sTfR levels paralleled a significant rise in haemoglobin and reticulocyte index were observed in 13 HD patients with iron deficiency (three absolute and 10 occult iron deficiency) after 4 weeks of iron therapy. Obviously, the increase in receptor levels is mainly due to enhanced erythropoiesis following ferrotherapy. In spite of the fact that the authors failed to reveal any difference in sTfR levels between iron-deficient (n = 10) and non-iron-deficient (n = 58) patients, we even found that the mean sTfR levels exhibited a left-shift in non-iron-deficient patients with no significant changes in haemoglobin values after ferrotherapy in Figure 1 [6]. Unless the authors can demonstrate that receptor levels did not significantly change after ferrotherapy in non-iron-deficient patients, it is inappropriate to conclude that sTfR cannot reflect iron availability in rHuEPO-treated HD patients. Based on the statements in their letter, however, I do not think that the findings of Deira et al. [5] are consistent with their proposed thesis. We need a prospective, longitudinal study of a large sample size to verify whether sTfR could differentiate iron availability in HD patients receiving rHuEPO therapy by comparing the different parameters of iron status.

Conflict of interest statement. None declared.

References

  1. Tarng D-C, Hung TP. Determinants of circulating soluble transferrin receptor level in chronic haemodialysis patients. Nephrol Dial Transplant 2002; 17: 1063–1069[Abstract/Free Full Text]
  2. Beguin Y, Loo M, R’Zik S et al. Quantitative assessment of erythropoiesis in haemodialysis patients demonstrates gradual expansion of erythroblasts during constant treatment with recombinant human erythropoietin. Br J Haematol 1995; 89: 17–23[ISI][Medline]
  3. Ahluwalia N, Skikne BS, Savin V, Chonko A. Markers of masked iron deficiency and effectiveness of EPO therapy in chronic renal failure. Am J Kidney Dis 1997; 30: 532–541[ISI][Medline]
  4. Mizuguchi T, Minakuchi J, Kawahara K, Kawashima S, Hikawa A, Nomata Y. Serum transferrin receptor level as an index of the response to erythropoietin therapy for anemia in pre-dialysis patients with chronic renal failure. Jpn J Nephrol 1997; 39: 497–502
  5. Lorenzo JD, Rodriguez MM, Martin SS, Romo JM. Assessment of erythropoiesis activity during hemodialysis therapy by soluble transferrin receptor levels and ferrokinetic measurements. Am J Kidney Dis 2001; 37: 550–556[ISI][Medline]
  6. Chiang WC, Tsai TJ, Chen YM, Lin SL, Hsieh BS. Serum soluble transferrin receptor reflects erythropoiesis but not iron availability in erythropoietin-treated chronic hemodialysis patients. Clin Nephrol 2002; 58: 363–369[ISI][Medline]
  7. Tonbul HZ, Kaya H, Selcuk Y et al. The importance of serum transferrin receptor level in the diagnosis of functional iron deficiency due to recombinant human erythropoietin treatment in hemodialysis patients. Int Urol Nephrol 1998; 30: 645–651[Medline]
  8. Daschner M, Mehls O, Schaefer F. Soluble transferrin receptor is correlated with erythropoietin sensitivity in dialysis patients. Clin Nephrol 1999; 52: 246–252[ISI][Medline]




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