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Erythrocyte indices and response to hypoxia-inducible factor prolyl hydroxylase inhibitors in chronic kidney disease patients with renal anemia: a retrospective study

BMC Nephrology volume 25, Article number: 423 (2024) Cite this article

Abstract

Background

Although erythropoiesis-stimulating agents (ESAs) have been the standard treatment for renal anemia, ESA hyporesponsiveness remains a concern. Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are a new class of agents indicated for renal anemia. Several lines of evidence indicate that HIF-PHIs affect erythrocyte indices; nonetheless, their clinical significance remains unclear.

Methods

We retrospectively analyzed data from 233 non-dialysis-dependent chronic kidney disease patients who initiated either ESA (darbepoetin) or HIF-PHI for the treatment of anemia. We analyzed the changes in hemoglobin levels three months after the initiation of anti-anemic treatments, examining their association with changes in erythrocyte indices.

Results

Both ESA and HIF-PHIs significantly increased hemoglobin levels after three months of treatment. In the HIF-PHI group, the increase in hemoglobin levels was positively correlated with the increase in mean corpuscular volume (MCV) levels, a finding that was not observed in the ESA group. In a subgroup analysis based on the mean reference range value for MCV (90.9 fL), a significant difference in the proportion of patients with improved anemia was observed between ESA and HIF-PHIs in patients with lower MCV values. Logistic regression and interaction analyses confirmed that there was a significant interaction between baseline MCV values and the effectiveness of anti-anemic drugs, independently of other covariates.

Conclusions

An increase in hemoglobin levels is associated with an increase in MCV in patients treated with HIF-PHIs. The anti-anemic effects of ESA and HIF-PHIs may be influenced by baseline MCV values. However, long-term consequences need further evaluation.

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Introduction

Renal anemia is one of the most frequent complications in chronic kidney disease (CKD) patients, affecting 40 to 60% of patients with a glomerular filtration rate (GFR) of less than 30 ml/min [1, 2]. Anemia in CKD patients is associated with an increased risk of cardiovascular diseases and the progression of kidney disease [3]. Moreover, renal anemia can decrease exercise capacity in CKD patients, resulting in a reduced quality of life [4, 5]. Therefore, the appropriate management of renal anemia is a key aspect of health care for CKD patients.

The administration of recombinant human erythropoietin and other erythropoiesis-stimulating agents (ESAs) has long been the standard treatment for renal anemia, profoundly improving the control of hemoglobin (Hb) levels in CKD patients. Nonetheless, concerns remain regarding the use of ESAs, such as ESA hyporesponsiveness and the risk of cardiovascular damage at high doses [6, 7]. Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are a new class of agents administered orally and indicated for the treatment of renal anemia [8, 9]. By inhibiting HIF-PH, which targets HIFs for ubiquitination and subsequent degradation, these agents increase HIF abundance and stimulate erythropoiesis in the body. Besides promoting endogenous erythropoietin production, HIF-PHIs are considered to act through multiple mechanisms, including stimulating erythroid differentiation, increasing circulating iron levels by modulating molecules such as ferroportin and hepcidin, and promoting iron uptake in erythrocytes by upregulating the transferrin receptor TfR1 [9, 10]. However, there are currently no clear criteria for determining how to differentiate between the use of ESAs and HIF-PHIs.

Erythrocyte indices are the simple and useful indicators that represent the size and quality of red blood cells, and several lines of evidence indicate that HIF-PHIs affect these indices [11, 12]. For example, it has been shown that HIF-PHIs increase mean corpuscular volume (MCV) and mean corpuscular Hb (MCH) levels in hemodialysis patients, an effect that has not been observed in patients receiving ESAs [13]. However, it is currently uncertain how the changes in erythrocyte indices are associated with the effectiveness of HIF-PHIs in improving anemia in CKD patients. Given that erythrocyte indices deliver information on erythrocyte quality and can reflect multiple factors involved in erythropoiesis, appropriate evaluation of these indices may provide valuable information for guiding the selection between HIF-PHIs and ESAs. In addition, there are studies to suggest that low MCV levels, even within the reference range, are associated with the increased risk of CKD progression [14]. In this retrospective study, we aimed to evaluate whether erythrocyte indices, as well as their changes in response to treatment, are associated with the effectiveness of anti-anemic treatments (ESAs and HIF-PHIs) in CKD patients with renal anemia.

Methods

Patients

The study included non-dialysis-dependent CKD (NDD-CKD) patients who had an eGFR level of < 60 ml/min/1.73 m2 and initiated ESA (darbepoetin) or HIF-PHI for the treatment of anemia at Teikyo University Hospital from April 2021 to June 2023. Among 293 patients that were potentially eligible, those who switched from ESA to HIF-PHIs (n = 59) and who had active bleeding (n = 1) were excluded, and a total of 233 NDD-CKD patients who were ESA-naïve were included in the final analysis. Choice and dose of anti-anemic drugs were at the discretion of each doctor. This study was approved by the Ethics Committee of Teikyo University School of Medicine with a waiver of the requirement for obtaining written informed consent due to its retrospective nature (No. 22-059-3). The current study was conducted in accordance with the principles of the Declaration of Helsinki.

Data collection

Data on demographics (e.g., age, sex, height, weight, life history, and medical history) and clinical values (e.g., hemoglobin (Hb), erythrocyte indices, iron (Fe), ferritin, and CRP) were collected by medical record abstraction. Number of missing values for each variable was reported. The estimated GFR (eGFR) was calculated based on the Japanese Society of Nephrology equation [15]. Data on available clinical values were collected and analyzed before the start of treatment (ESA and HIF-PHIs) and three months after the treatment.

Statistical analysis

Data are summarized as median and interquartile ranges for continuous variables and as absolute numbers and percentages for categorical values. Mann-Whitney U test and Fisher’s exact test were used to compare patient characteristics between ESA and HIF-PHI groups. A paired t-test was used to compare the values between two time points. Correlations between two parameters were analyzed using Spearman’s correlation test. In the subgroup analysis, patients were divided into two groups based on the mean value of the reference range for MCV (reference range, 83.6 to 98.2 fL; mean value, 90.9 fL). The difference in the number of patients with improved anemia (defined as an increase in Hb levels at three months compared to baseline) according to anti-anemic treatment (ESA or HIF-PHIs) was then analyzed using Fisher’s exact test. For sensitivity analysis, we excluded those on iron therapy and re-analyzed the data.

In the logistic regression analysis, patients were divided into four groups based on anti-anemic treatment (ESA or HIF-PHI) and MCV value (either > 90.9 fL or ≤ 90.9 fL), and an improvement in anemia (either Hb levels were increased or not increased at three months compared to the baseline) was used as the outcome. In model 1, age, sex, smoking history, alcohol use, and eGFR levels were included as covariates. In addition, diabetes mellitus and heart disease were included as covariates in model 2. In a separate interaction analysis, MCV value (either > 90.9 fL or ≤ 90.9fL), anti-anemic treatment (ESA or HIF-PHI), and the interaction term between the anti-anemic treatment and MCV values were introduced into the multivariable regression model with the improvement in anemia as the outcome (other covariates were same as model 1 mentioned above). All analyses were performed using JMP version 14.3.0 (SAS institute, USA) and GraphPad Prism software, version 7.05 (GraphPad Software Inc., USA), with two-sided significance set at P < 0.05. Since the study was exploratory rather than confirmatory, no correction for P values was performed.

Results

Patient characteristics

A total of 233 patients were included in the study. The baseline characteristics of the study participants are shown in Table 1. Median age of the participants was 77 [interquartile range (IQR), 68–85] years and 39% were female. Hemoglobin (Hb) level at baseline was 9.7 [9.0-10.3] g/dL, which was similar between HIF-PHI and ESA groups (P = 0.44) (Table 1). Also, there were no significant differences in erythrocyte indices, such as mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC), at the baseline between the two groups. Compared with the ESA group, eGFR was slightly but significantly lower in HIF-PHI group (16.1 [10.4–27.8] ml/min/1.73 m2 in HIF-PHI groups versus 19.9 [14.7–29.4] ml/min/1.73 m2 in ESA group). The proportion of patients with diabetes mellitus (DM) was significantly higher in ESA group, which may be related to the accompanying diabetic retinopathy in these patients. The proportion of heart disease was also higher in ESA group. Other characteristics were overall similar between the two groups, including iron and ferritin levels (Table 1). The anti-anemic drugs used in the study participants are shown in Supplementary Table 1.

Changes in erythrocyte indices in patients receiving ESA and HIF-PHIs

In both groups, Hb levels were significantly increased three months after the treatment compared to the baseline (Fig. 1A). As for erythrocyte indices, we found that MCV significantly increased in HIF-PHI group after treatment, while it remained unchanged in ESA group (Fig. 1B). The increase in MCV by HIF-PHI is consistent with previous studies [13]. MCH and MCHC were not significantly altered by the treatment in our patients (Fig. 1B). To obtain insights into the relationship between changes in MCV levels and the improvement in anemia, we plotted the pre- and post-treatment changes in Hb levels (ΔHb) against ΔMCV. In ESA group, there was no significant relationship between these parameters (Fig. 1C). In contrast, there was a significant positive correlation between ΔHb and ΔMCV in HIF-PHI group (r = 0.24; P = 0.02) (Fig. 1D), indicating that the improvement in anemia was accompanied by the increase in MCV levels in HIF-PHI group but not in ESA group. In HIF-PHI group, the correlation coefficient between ΔHb and ΔMCV was similar in patients receiving daprodustat and in those with other types of HIF-PHIs (data not shown), although the number of patients in the latter group was limited.

Fig. 1
figure 1

Increase in Hb levels positively associates with changes in mean corpuscular volume (MCV) in patients receiving hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) but not in those receiving erythropoiesis-stimulating agents (ESA). (A) Changes in hemoglobin (Hb) concentrations before and after the treatment in patients receiving ESA (left) and HIF-PHIs (right). (B) Changes in MCV, mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC) before and after the treatment in patients receiving ESA (left) and HIF-PHIs (right). (C) Association of changes in Hb levels (ΔHb) with changes in MCV (ΔMCV) before and after the treatment in patients receiving ESA. (D) Association of changes in Hb levels (ΔHb) with changes in MCV (ΔMCV) before and after the treatment in patients receiving HIF-PHIs. Data are expressed as mean ± SD

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Association between baseline MCV levels and the effectiveness of anti-anemic drugs

The above data are consistent with the possibility that ESA and HIF-PHIs have different effects on erythropoiesis and support the diverse actions of HIF-PHIs. To evaluate whether baseline MCV levels have influenced the response to anti-anemic treatment, we divided the study participants into two groups based on the mean value of the reference range for MCV (reference range, 83.6 to 98.2 fL; mean value, 90.9 fL). We then calculated the proportion of patients with improved anemia (defined as the increase in Hb levels 3 months after the initiation of treatment compared to the baseline).

Baseline characteristics of study participants by MCV values are shown in Supplementary Table 2. Hb levels were identical between the two groups (9.7 [9.0-10.3] g/dL in low MCV group versus 9.7 [8.9–10.3] g/dL in high MCV group; P = 0.87). Ferritin and transferrin saturation were not significantly different, although both were numerically lower in the low MCV group. In patients who had higher MCV values (> 90.9 fL) at the baseline, a total of 134 patients out of 174 (77%) showed the improvement in anemia. Similarly, anemia was improved in 42 among 59 patients (71%) in those with lower MCV values (≤ 90.9 fL). When patients were divided according to the anti-anemic treatments, 73% and 82% in higher MCV groups showed the improvement in anemia by ESA and by HIF-PHI, respectively (P = 0.21), (Table 2). However, in lower MCV groups, anemia was improved in 96% of patients by HIF-PHI, while the improvement was observed in 56% by ESA (P < 0.001), suggesting that MCV values at the baseline may have modified the effectiveness of the anti-anemic drugs. When patients were divided according to transferrin saturation levels, an indicator of iron status (either ≤ 20% or > 20%) [16], the response to each treatment (ESA or HIF-PHIs) was overall similar in both low TSAT and high TSAT groups; the difference in P values is likely attributable to the difference in the total numbers of patients in each group (Supplementary Table S3). Similarly, no apparent difference in responses to treatments was observed when patients were divided according to ferritin levels (Supplementary Table S4). To exclude the possibility that the results were confounded by iron therapy, we excluded the patients on iron replacement and performed the analysis. As shown in Table 3, the results were similar and the use of HIF-PHIs was associated with an improvement in anemia in patients with lower MCV values.

Table 1 Characteristics of the study participants
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Table 2 The proportion of patients with increased Hb levels based on the mean of MCV reference value (all patients)
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Table 3 The proportion of patients with increased Hb levels based on the mean of MCV reference value (patients not on iron therapy)
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Interaction between renal anemia treatment and MCV levels

To confirm the interaction between baseline MCV levels and the effects of anti-anemic drugs, we conducted a multivariable analysis using logistic regression, with the improvement in anemia as an outcome measure (see Methods). As shown in Fig. 2A, in those with lower MCV values, the odds ratio for the anemia improvement (increase in Hb levels) by HIF-PHI was 17.3 compared to ESA (P = 0.009). By contrast, in those with higher MCV values, there was no statistical difference in the odds ratio between ESA and HIF-PHI (P = 0.23) (Fig. 2A). Similar results were obtained in model 2 (Fig. 2B). In the interaction analysis, we found that the interaction term between the anti-anemic treatment and MCV values was statistically significant (P = 0.038).

Fig. 2
figure 2

Logistic regression analysis in the study participants based on anti-anemic treatments and baseline MCV values (A and B) Odds ratio for anemia improvement (defined as the increase in Hb levels) in patients receiving ESA and HIF-PHIs based on the mean value (90.9 fL) of MCV reference range. (A) In model 1, age, sex, smoking status, alcohol use, and eGFR were included as the explanatory valuables. (B) In model 2, diabetes and heart diseases were included in addition to the explanatory valuables in model 1

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Discussion

In this study, we found that the improvement in anemia is associated with the increase in MCV levels in HIF-PHIs but not in ESA, and that there was a difference in the proportion of patients with improved anemia between ESA and HIF-PHI in patients with lower MCV values (≤ 90.9 fL). Logistic regression and interaction analyses confirmed that there was a significant interaction between baseline MCV values and the effectiveness of anti-anemic drugs.

In the study participants, we found that Hb levels were significantly increased by 1.1 g/dL at three months in HIF-PHI group. Currently, there are several studies that addressed the effects of HIF-PHIs in NDD-CKD patients [17,18,19,20]. The eGFR levels of study participants in these studies are overall similar to those in the current study (approximately 20 ml/min/1.73m2), and the studies noted increase in Hb levels by 0.5 to 2.0 g/dL 12 to 16 weeks after the initiation of HIF-PHIs. Therefore, the effects on anemia observed in this study were overall similar to those reported in previous studies in NDD-CKD patients. However, the relationship between erythrocyte indices and changes in Hb levels has not been reported previously.

HIF-PHIs increased the MCV levels of erythrocytes, and this increase was positively and significantly correlated with the change in Hb levels. However, this association was not observed in patients receiving ESA. Moreover, our multivariable analysis and the interaction analysis indicated that the improvement in anemia by anti-anemic drugs was influenced by pre-treatment MCV values. Although the reason for the possible interaction remains speculative, one plausible explanation is that a lower MCV value (even within the normal reference range) in a state of anemia may indicate an impaired or inadequate iron uptake by erythrocytes [21], besides iron deficiency in the body. In anemia, particularly in iron deficiency anemia, erythroblasts are known to increase transferrin receptor, which is critical to promote iron delivery to these cells. However, previous studies have suggested that this response is blunted in anemia of chronic disease [22]. Given the evidence that HIF-1 mediates the transcriptional activation of transferrin receptor [23], an insufficient induction of transferrin receptor associated with CKD might have been involved in the interaction with MCV values observed in the study. Alternatively, suppression of hepcidin by HIF-PHI may also play a role [24]. Hepcidin, a polypeptide produced in the liver, promotes cellular retention of iron and limits its utilization by regulating ferroportin [25]. In addition to iron repletion, the induction of hepcidin has been shown to be triggered by inflammatory responses [26, 27], which is shown to be inversely associated with MCV levels in a murine model of CKD [28].

The limitations of this study include its single-center design and retrospective nature, which precludes the ability to draw causal inferences. Because this is a short-term study, the long-term consequences, such as the occurrence of thrombosis and cardiovascular diseases, remain unclear and need further evaluation [29]. It is also important to note that the focus of the study was not on comparing the effects of HIF-PHIs and ESAs, but rather on examining their relationship with MCV. A direct comparison of effects was not possible due to differences in dosage, treatment duration, and other biases, such as prescription bias. Because a considerable number of patients lacked the iron-related parameters, we were not able to perform a detailed analysis on the relationship among MCV, iron status, and the response to treatment. Other limitations include the potential influence of unmeasured confounding factors and modest sample size. Nonetheless, by using patient-level data, the current study reports a previously undescribed observation that the effects of anti-anemic drugs (ESA and HIF-PHIs) might be influenced by the baseline MCV levels. Since MCV is widely used to evaluate the quality of erythrocytes and the underlying cause of anemia, the findings of the current study have clinical relevance. Further studies are necessary to confirm our observation and to determine the molecular basis for the interaction between MCV levels and anti-anemic treatments, as well as the long-term outcomes.

Data availability

The data used in the study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank members of Jinken (Kidney Lab) at Teikyo University for helpful discussions.

Funding

This work was supported by Advanced Comprehensive Research Organization Research Grants from Teikyo University.

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Authors and Affiliations

  1. Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo, 173-8605, Japan

    Kohei Odajima, Shigeyuki Arai, Hitoshi Anzai, Maika Gojo, Shuntaro Taira, Rena Matsui, Yoshihide Fujigaki & Shigeru Shibata

  2. Medical Checkup Center, Inagi Municipal Hospital, Tokyo, Japan

    Ryo Kido

  3. Research Center for Social Systems, Shinshu University, Nagano, Japan

    Ryo Kido

  4. Advanced Comprehensive Research Organization, Teikyo University, Tokyo, Japan

    Shigeru Shibata

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  1. Kohei Odajima
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Contributions

Conceptualization, S.A. and S.S.; investigation, K.O and S.A; resources, H.A., M.G., S.T., and R.M.; data analysis, K.O., S.A., R.K., Y.F., and S.S.; writing- original draft, K.O. and S.S; writing- review and editing, S.S.; supervision, S.A. and S.S. All authors reviewed and approved the manuscript.

Corresponding author

Correspondence to Shigeru Shibata.

Ethics declarations

Ethics approval and consent to participate

This study was approved by the Ethics Committee of Teikyo University School of Medicine with a waiver of the requirement for obtaining written informed consent due to its retrospective nature (No. 22-059-2). The study was conducted in accordance with the principles of the Declaration of Helsinki.

Consent for publication

Not applicable.

Competing interests

S.S. received personal fees and/or research funding from Bayer, Kyowa-Kirin, and Torii.

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Odajima, K., Arai, S., Kido, R. et al. Erythrocyte indices and response to hypoxia-inducible factor prolyl hydroxylase inhibitors in chronic kidney disease patients with renal anemia: a retrospective study. BMC Nephrol 25, 423 (2024). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12882-024-03877-4

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  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12882-024-03877-4

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BMC Nephrology

ISSN: 1471-2369

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