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What could contribute additionally to the existing ESA therapy to enhance the patient’s red blood cell production?
Increased doses of EPO
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Iron deficiency and management of anaemia in renal disorders
In chronic kidney disease (CKD), anaemia develops from impaired erythropoiesis, which is often due to lack of erythropoietin (EPO) production. Administration of erythropoiesis-stimulating agents (ESA), such as recombinant human erythropoietin (rHuEPO), is an efficient treatment and has the potential to rectify impaired RBC production fully.
However, insufficient iron availability, caused by an absolute or functional iron deficiency, significantly limits the therapeutic efficiency of rHuEPO . Therefore, the identification of patients who need additional iron supplementation is necessary. Biochemical parameters such as serum ferritin and transferrin saturation were shown to be less accurate in assessing functional iron deficiency under inflammatory conditions . Hence, several clinical practice guidelines propose the parameters percentage of hypochromic red blood cells and the reticulocyte haemoglobin content for the evaluation of iron deficiency and the assessment of iron therapy targets in CKD patients [3, 4].
By now, several studies showed that the parameter reticulocyte haemoglobin equivalent (RET-He) can be used to assess the target of iron supplementation in CKD patients undergoing haemodialysis  and that it is a useful parameter for evaluating the need of iron supplementation during rHuEPO treatment .
Moreover, in end-stage renal disease (ESRD) patients undergoing peritoneal dialysis, a correlation of the parameter Delta-He with the inflammation markers IL-6 and hs-CRP was observed . The study also revealed an association of Delta-He with response to ESA treatment and all-cause mortality risk, suggesting it to be a useful marker for risk assessment and prediction of ESA response in ESRD patients undergoing peritoneal dialysis.
In summary, especially in patients undergoing haemodialysis, the use of RET-He is advantageous and allows the adjustment of iron supplementation and EPO therapy according to a patient’s needs. Besides RET-He, Delta-He is also of great interest as an alternative inflammation marker for the prediction of ESA response and risk assessment in renal disorders.
As a haemodialysis patient, the patient is regularly followed up with a CBC and RET measurement . Reviewing cumulative data over a period of six months, the haemoglobin did not behave as expected. In fact, it showed a declining trend. Also, the RET-He remained low, confirming that newly produced red blood cells contained less haemoglobin.
Upon last evaluation, the patient was anaemic (HGB = 9.5 g/dL or 5.9 mmol/L) and the reticulocyte haemoglobin equivalent (RET-He = 16.2 pg or 1.003 fmol) indicated the presence of hypochromic reticulocytes. For more details on the haematology parameters changing over the course of time, please refer to the table below showing cumulative data on selected red blood cell and reticulocyte parameters.
A treatment with rHuEPO was repeated with an increased dose. Although the reticulocyte absolute count and immature reticulocyte fraction (IRF) increased after this treatment, the RET-He still remained low. The Delta-He value that is usually positive in healthy people, between + 2 pg and + 8 pg , remained negative in this patient throughout the entire observation period due to inflammation. Such ongoing inflammation may cause a poor response to ESA therapy which in turn has been associated with a negative impact on survival in both haemodialysis (HD) and peritoneal dialysis (PD) patients .
Supplemental iron together with the ESA therapy could ensure adequate haemoglobinisation of the new red blood cells.
The table shows cumulative measurement data of selected parameters.
|Parameters / measurement dates||21.06.||26.08.||17.10.||19.11.|
|HGB (g/dL / mmol/L)||11.3 / 7.0||10.6 / 6.6||9.5 / 5.9||10.2 / 6.3|
|RET-He (pg / fmol)||21.9 / 1.362||18.8 / 1.167||16.2 / 1.003||17.3 / 1.074|
|Delta-He (pg / fmol)||- 22.1 / 0.222||- 31.4 / - 0.314||- 43.5 / - 0.435||- 35.1 / 0.351|
 Miwa N et al. (2010): Usefulness of measuring reticulocyte hemoglobin equivalent in the management of haemodialysis patients with iron deficiency. Int. J. Lab. Hematol. 32(2): 248–255.
 Buttarello M et al. (2016): Evaluation of the hypochromic erythrocyte and reticulocyte hemoglobin content provided by the Sysmex XE-5000 analyzer in diagnosis of iron deficiency erythropoiesis. Clin. Chem. Lab. Med. 54(12): 1939–1945.
 Maconi M et al. (2009): Erythrocyte and reticulocyte indices in iron deficiency in chronic kidney disease: Comparison of two methods. Scand. J. Clin. Lab. Invest. 69(3): 365–370.
 Mikhail A et al. (2017): Renal association clinical practice guideline on Anaemia of Chronic Kidney Disease. BMC Nephrol. 18(1): 345.
 Wirawan R et al. (2017): Concordance between Reticulocyte Hemoglobin Equivalent and Reticulocyte Hemoglobin Content in CKD Patients Undergoing Hemodialysis. Acta Med. Indones. 49(1): 34–40.
 Danielson K et al. (2014): Delta-He: A novel marker of inflammation predicting mortality and ESA response in peritoneal dialysis patients. Clin. Kidney J. 7(3): 275–281.
 Tracing iron deficiency – interview with Adjunct Professor Dr Mathias Zimmermann, Head Physician of the Central Department for Laboratory Medicine, German Red Cross hospitals Berlin, Germany. 05 May 2021. https://www.sysmex-europe.com/n/academy/knowledge-centre/expert-voices/haematology/tracing-iron-deficiency-part-1.html