The results of this study demonstrated the characteristics and patient-reported outcomes according to anaemia and iron deficiency in patients with CKD stage G3b-5 based on the Reach-J CKD cohort study. HRQOL measured using the KDQOL-36 questionnaire, comprising three kidney disease subscale (burden, symptoms, and effects of kidney disease), PCS, and MCS scores, was worsened with anaemia. These scores, except for the PCS scores, were worse in patients with absolute iron deficiency than in those with functional iron deficiency. This study is the first to provide evidence in patients from Asian countries considering the associations of iron deficiency with HRQOL. For international comparisons, the mean MCS score of 49 in this study was similar to that of 47 in patients with CKD G3a-5 in Europe, 49 in the United States, and 44 in China. The mean PCS score of 47 was higher than that of 42 in Europe, 42 in the United States, and 39 in China, although patients with CKD stage G3a were not included in our study [24, 27].

In our study, 12% of the patients with CKD stage G3b-5 had more severe anaemia (Hb levels < 10 g/dL). Compared to the CKDopps countries, its prevalence is similar to 13% in Brazil and the United States [24] and higher than 3% and 7% in France and Germany, respectively [3, 24]. Our study indicated that patients with more severe anaemia were more likely to be female and have diabetes, and have lower eGFR and serum albumin levels, similar to the findings from the CKDopps countries [3, 24]. Regarding the treatment for patients with more severe anaemia, 64% of them in our study were treated with ESA alone, compared to 14–37% in the CKDopps countries. Seventeen percent of these patients were treated with either IV or oral iron, compared to 13%–20% in the CKDopps countries. Fourteen percent of these patients were treated with both ESA and any iron treatment, compared to 13–28% in the CKDopps countries. Japanese patients with more severe anaemia tended to receive more ESA therapy than those overseas [1, 3, 10, 24].

Most studies focusing on iron deficiency in patients with CKD have assessed TSAT and ferritin levels separately [3, 6, 8, 10, 11], and only a few studies have assessed absolute iron deficiency [7, 9]. We demonstrated the differences between absolute and functional iron deficiencies by simultaneously evaluating these two iron deficiency markers. In our study, 12% of the patients had absolute iron deficiency, which was significantly lower than 21% of those in the CKDopps from Brazil, France, Germany, and the United States [11]. Patients with absolute iron deficiency were female, had diabetes, and had cardiovascular comorbidities, similar to those with CKD stage G3a-4 in the United States study [9] and those in the CKDopps countries [11]. Furthermore, patients with functional iron deficiency had lower albumin and Hb levels, higher CRP levels, and non-skin cancer, which is consistent with previous studies showing that functional iron deficiency is associated with chronic inflammation [4, 5]. Regarding the treatments for patients with absolute iron deficiency, 47% of them in our study were treated with ESA alone, compared with 5–13% in the CKDopps countries from Brazil, France, Germany, and the United States. Overall, 37% of these patients were treated with IV or oral iron, compared to 18%–32% in the CKDopps countries, whereas 29% of them were treated with both ESA and any iron therapy, compared to 9–13% in the CKDopps countries. Patients with absolute iron deficiency receive more ESA therapy than those overseas [3]. Many Japanese physicians have prioritised ESA therapy for the subcutaneous formulation because the guidelines for anaemia treatment have highlighted the risks associated with iron overload [1, 2, 10, 15]. Recently, oral hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) have been developed as novel therapeutic options for renal anaemia [5, 14]. Therefore, expanding treatment options may improve defective iron utilisation in patients with CKD.

Similar to those of previous studies, the results of this study showed that the HRQOL was worse with anaemia [24, 27, 28]. All KDQOL-36 scores and MCS and PCS subdomains were worse in patients with anaemia than in those without anaemia. These associations were observed even after accounting for patient characteristics (Fig. 2). The scores for the MCS and PCS subdomains according to Hb levels have varied in previous studies [24, 28]. Our study patients with more severe anaemia (Hb levels < 10 g/dL) had lower scores of ≥ 5 points in emotional role, pain, physical function, and physical role than those without anaemia.

The main finding of our study was the associations of absolute and functional iron deficiencies with HRQOL. Three kidney disease subscales and MCS scores were lower in patients with absolute iron deficiency than in those with functional iron deficiency after accounting for patient characteristics. Despite poor clinical data, patients with functional iron deficiency had slightly higher scores than those with TSAT levels ≥ 20%. This population may have been affected by patients with extreme scores since only 22 patients had functional iron deficiency. We also consider that patients with TSAT levels ≥ 20% had intermediate scores since some patients with iron overload had worse HRQOL due to inflammation or malignancy [4, 11], while others had sufficient iron with better HRQOL. Further studies are required to examine functional iron deficiency and iron overload.

Physical activity, as assessed using the RAPA questionnaire, was associated with Hb levels in patients with CKD stage G3b-5. Patients without anaemia were physically more active than those with anaemia, which is similar to the results of the CKDopps from Brazil and the United States [24]. Patients with functional iron deficiency were more likely to be physically never active than those in the other categories.

Some overseas studies have reported that anaemia treatment improves HRQOL in patients with ND-CKD [29, 30]. Singh et al. reported that ESA treatment improved the KDQOL-36 subdomain scores in patients with ND-CKD with an eGFR of 15–50 mL/min/1.73 m2 in both groups with high and low Hb target levels [29]. A recent study on HIF-PHIs evaluated the HRQOL by assessing only the vitality score in patients with ND-CKD [30]. However, only a few studies have included various underlying diseases and examined all KDQOL-36 scores. Therefore, further studies should evaluate long-term changes in HRQOL using different anaemia treatments, including ESA, iron, and HIF-PHIs, since the REACH-J study is a longitudinal prospective study.

This study had some limitations. Firstly, as expected for self-reported questionnaire surveys that were not assessed by attending physicians, patients who responded to the questionnaires tended to be younger and healthier than those who did not respond. Therefore, HRQOL and physical activity may have been overreported. Secondly, because the KDQOL-36 scores were calculated according to the CKDopps algorithm, some items may be unsuitable for Japanese patients. However, this made conducting international comparisons possible. Finally, we could not consider other comorbidities not shown in Table 1, such as osteoarticular diseases, respiratory diseases, heart failure, and inflammatory diseases, which may contribute to worsening of QOL.