Evaluation of recombinant human erythropoietin responsiveness by measuring erythrocyte creatine content in haemodialysis patients

Abstract

Background One of the main causes of anaemia in patients with end-stage renal disease is relative deficiency in erythropoietin production. Eythropoiesis stimulating agent (ESA), a potent haematopoietic growth factor, is used to treat anaemia in haemodialysis patients. The effect of ESA is usually assessed by haematological indices such as red blood cell count, haemoglobin concentration and haematocrit, but erythrocyte indices do not provide information of the rapid change in erythropoietic activity. As erythrocyte creatine directly assess erythropoiesis, the aim of this study was to evaluate the effect of ESA in haemodialysis patients by measuring the erythrocyte creatine content. Methods ESA dose was fixed 3 months prior to the enrollment and was maintained throughout the entire study period. Erythrocyte creatine was measured with haematologic indices in 83 haemodialysis patients. Haemoglobin was also measured 3 months after. Results ESA dose (152.4 ± 62.9 vs. 82.2 ± 45.5 units/kg/week, P = 0.0001) and erythrocyte creatine (2.07 ± 0.73 vs. 1.60 ± 0.41 μmol/gHb, p = 0.0003) were significantly higher in 27 patients with haemoglobin <10 g/dL compared to 56 patients with haemoglobin ≥10 g/dL. There was a fair correlation between ESA dose and the concentration of creatine in the erythrocytes (r = 0.55, P < 0.0001). Increase in haemoglobin (>0.1 g/dL) was observed in 37 patients, whereas haemoglobin did not increase in 46 patients. Erythrocyte creatine levels were significantly higher in those patients with an increase in haemoglobin compared to those without (2.04 ± 0.64 vs. 1.52 ± 0.39 μmol/gHb, p < 0.0001). When 8 variables (ESA dose, erythropoietin resistance index, C-reactive protein, intact parathyroid hormone, iron supplementation, presence of anaemia, erythrocyte creatine and reticulocyte) were used in the multivariate logistic analysis, erythrocyte creatine levels emerged as the most important variable associated with increase in haemoglobin (Chi-square = 6.19, P = 0.01). Conclusion Erythrocyte creatine, a useful marker of erythropoietic capacity, is a reliable marker to estimate ameliorative effectiveness of ESA in haemodialysis patients.

Prolyl hydroxylase inhibitor desidustat improves anemia in erythropoietin hyporesponsive state

“…Consistent with this report, we have observed increase in the serum and tissue (liver and spleen) iron in erythropoietin-resistant state indicating an inefficient erythropoiesis despite high erythropoietin and iron in serum. Also, the inefficient hematopoiesis that results in premature destruction of RBCS may also lead to increase in serum iron ( Hasegawa et al., 2021 ). However, when the iron was measured within 24 ​h of the last dose of EPO and turpentine oil, an acute effect of the inflammatory stimuli on hepcidin and iron levels was evident in anemic rats, and it was significantly attenuated by desidustat treatment.…”

Diagnostic accuracy and clinical usefulness of erythrocyte creatine content to predict the improvement of anaemia in patients receiving maintenance haemodialysis

“…Bolus of heparin sodium 1,000 units was intravenously administrated at the start of haemodialysis followed by continuous administration of 500 to 750 units/hour. The dialysate temperature of extracorporeal circulation was strictly maintained at 36-38°C [13,15]. ESA and iron therapy were prescribed in accordance with the Guidelines of Japanese Society for Dialysis therapy [14].…”

“…These indices were calculated as the average of 3 consecutive haemodialysis sessions. One of the following dialysis membranes was used: cellulose FB (Nipro Corporation, Osaka, Japan), polysulfone (PN, Nikkiso Co., Ltd., Tokyo, Japan), polyethersulfone (PES, Nipro Corporation, Osaka, Japan), or polymethylmethacrylate (NF-H, Toray Medical Co., Ltd., Tokyo, Japan) [13,15].…”

“…A weekly ESA dose was administered as a darbepoetin alfa equivalent dose. ESA was converted using the following formula: darbepoetin alfa (µg) = epoetin beta pegol (µg) × 0.8 = epoetin (U) × 200, in accordance with previous reports [13,15]. Post-haemodialysis weight was measured as a body weight.…”

“…Therefore, longitudinal measurement of haemoglobin rather than one point is reported to provide more accurate information in patients receiving maintenance haemodialysis [12]. We previously reported that erythrocyte creatine, a marker of erythropoietic capacity, is reliable to estimate the effectiveness of ESA in haemodialysis patients [13]. However, optimal cut-off point of erythrocyte creatine to predict the improvement of anaemia was not established.…”