Hemoglobin level and erythropoietin response in hemodialysis patients: what can we pay attention to?

Dear editor,

We have read with greatly interest the paper called ‘correlation between ultrafiltration rate and hemoglobin level and erythropoietin response in hemodialysis patients’ by Li et al. [1]. Renal anemia is a prevalent complication in hemodialysis patients, resulting from reduced erythropoietin (EPO) synthesis and EPO resistance. 225 maintenance hemodialysis (MHD) patients were divided into three groups based on the ultrafiltration rate (UFR) (<10 mL/h/kg, 10-13 mL/h/kg, and >13 mL/h/kg) to investigate the association between UFR and hemoglobin levels and EPO response. Multiple linear regression analysis indicated that factors such as male (R = 0.233, p < 0.001), dry weight (R = 0.184, p = 0.006), UFR (R=-0.169, p = 0.011), calcium (R = 0.270, p < 0.001), phosphorus (R = 0.142, p = 0.034), albumin (R = 0.332, p < 0.001), and C-reactive protein (R = -0.195, p = 0.003) levels were associated with hemoglobin levels. Multivariate logistic regression analysis demonstrated that higher UFR (OR=-0.158, 95%CI −1.334∼-0.147, p = 0.015) was linked to lower hemoglobin levels, while male sex (OR = 0.180, 95%CI 0.957-7.378, p = 0.011) and elevated calcium (OR = 0.216, 95%CI 6.789-24.624, p = 0.001) and albumin (OR = 0.179, 95%CI 0.137-1.227, p = 0.014) were associated with higher hemoglobin levels. We would like to emphasize some overlooked details in the article, which caused us some confusion.

Firstly, serum magnesium, which can have important effects on hemoglobin, is a common laboratory result but was overlooked. In the China Health and Nutrition Survey involving 8,511 participants, it was found that elevated magnesium levels were closely related to a reduced risk of anemia [2]. A cross-sectional retrospective study included 213 chronic kidney disease stage 3-5 patients showed that hemoglobin (OR = 0.634, 95%CI 0.505-0.795, p < 0.001) was independently associated with hypomagnesemia by multivariable regression analysis [3]. A total of 307 MHD patients were divided into 3 groups according to serum magnesium concentrations (group A: ≤ 1.05 mmol/L, n = 105; group B: 1.05 ∼ 1.16 mmol/L, n = 99; group C: ≥ 1.16 mmol/L, n = 103). Serum magnesium levels (1.11 ± 0.13 mmol/L) were higher than normal levels (0.75 ∼ 1.02 mmol/L) in MHD patients. A multivariate logistic regression model revealed that magnesium levels was correlated with a high erythropoietin resistance index (ERI) (>11.52 IU/week(g/dL)⁻¹/kg). The OR of a high ERI was found to be 2.57 (95%CI 1.330-4.975, p = 0.005) for group A compared with the OR for group C [4]. In addition to the above, secondary hyperparathyoidism is one of the main causes of EPO resistance in HD patients, the review by Petho et al. [5] showed that a significant negative correlation between serum magnesium and intact parathyroid hormone(PTH) in ESKD patients, as well as oral magnesium supplementation alone in HD patients improved chronic kidney disease-mineral bone disease by modulating serum Ca and PTH metabolism.

Secondly, medications were not considered. A population-based, retrospective, cohort study include of 1080 incident erythropoiesis-stimulating agent (ESA) users (chronic kidney disease: n = 616, cancer: n = 464) showed that iron preparations (OR = 0.3, 95%CI 0.2-0.7, p = 0.002) and angiotensin-converting enzyme inhibitors/angiotensin II-receptor blockers (OR = 0.5, 95%CI 0.3-0.9, p = 0.022) were protective factors against ESA hyporesponsiveness [6]. A nationwide cohort study of 194,698 patients on dialysis in Japan found that the death rate was 13% higher in patients receiving long-acting (darbepoetin alfa or epoetin beta pegol) versus those receiving short-acting (epoetin alfa, epoetin beta, or epoetin kappa) ESAs [7]. While disease severity and comorbidities might partially contribute to ESA hyporesponse, all causes are showed in Figure 1 [8].

Figure 1. Factors associated with ESA hyporespone (from Am J Nephrol, 2021,52(6):450-466. [8]).

Finally, corrected calcium was not activated. The 2019 Chinese chronic kidney disease-mineral and bone disorder diagnosis and treatment guidelines suggest target ranges for serum corrected calcium (2.1 ∼ 2.5 mmol/L), phosphorus (0.87 ∼ 1.45 mmol/L), and PTH (130 ∼ 585pg/mL) for patients undergoing hemodialysis, respectively [9]. When the serum albumin was below 40 g/L, a correction formula for serum calcium was used: corrected calcium (mmol/L) = total serum calcium (mmol/L) + 0.2 × [4-Alb(g/L)/10]. In addition, the paper only mentioned a dialysis frequency of 3 times per week and 4 h per dialysis but did not provide details on specific dialysis anticoagulants (heparin, low-molecular-weight heparin, sodium citrate, argatroban, etc.), dialysis liquid ingredients, dialysate flow, blood flow rate, etc. The specific differences may also impact patient outcomes.

In conclusion, we believe that if the article by Li et al. [1] incorporates the aforementioned details and addresses the inadequacies mentioned in the original text, the research findings may hold greater clinical significance and provide better guidance for clinical practice.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This study was supported by the Fundamental Research Funds for the Central Universities of Northwest Minzu University [grant number 31920230193] and Gansu Science and Technology Plan Project [grant number 23JRRA1631].