Anemia is one of the most common complications in chronic kidney disease (CKD), being more prevalent as the disease progresses.1 The causes of anemia associated with CKD are diverse. Classically, an inadequate production of endogenous erythropoietin was recognized as the main cause. However, in recent years other contributing factors have been recognized, such as decreased bone marrow erythropoietic response, absolute or functional iron deficiency and shortened red blood cell lifespan, among others.2,3 Anemia in CKD leads to reduced quality of life, increased risk of cardiovascular disease and progression to end-stage CKD, increased hospitalization and mortality rates, as well as cognitive impairment.4–7

CKD has an overall prevalence that is ranging between 11 and 13%, with the majority of patients at stage 3.8,9 In Spain, the EPIRCE (2010)10,11 and ENRICA (2018)12 studies have evaluated this prevalence, denoting its increase over time in our country.

With respect to anemia, although there are studies in Spain that analyze its prevalence in CKD, there are limitations in the available data. These publications are old or are limited to a specific population of patients.13–17 The MERENA study (2011) estimated this comorbidity in CKD stages 3 and 4 (43.7% and 58.1%, respectively).14 The NADIR study (2013) analyzed the incidence of anemia in patients with CKD stage3 (35% in 36 months).13,15 Shortly thereafter, the MICENAS study (2014) evaluated the prevalence of anemia (58.5%) and its clinical management in patients with CKD stages 3–5.16 In 2017, Guerrero et al.17 estimated the prevalence in patients with CKD stage 3a-5 and older than 90 years at 35.7%.

In this context, iron therapy and erythropoiesis-stimulating agents (ESA) have been widely used, especially in combination, for the treatment of renal anemia.1 However, the use of iron for the treatment of renal anemia is not optimal, as iron parameters are not adequately corrected.18 Furthermore, the literature on epidemiology and treatment of anemia in Spain is not recent and it is limited.10–17 The aim of the present study was to evaluate the prevalence and incidence of anemia in CKD, as well as to characterize the subpopulation with anemia and its management in real clinical practice in Spain.

This population-based study analyzed the prevalence and incidence of anemia, as well as its treatment, in the Spanish population. In the RIKAS study, the prevalence of ND-CKD stages 3–5 was somewhat lower than in previous studies, although similar in number and distribution to that of the EPIRCE study.12

Other studies analyzed the prevalence of anemia in CKD in Spain. However, these studies are not recent or focus only on certain subgroups of patients. In addition, the definition of anemia is not consistent among the different studies, or it is not specified, and most of them analyze patients attended in outpatient nephrology clinics, unlike this population-based study. Thus, in the MICENAS study, the prevalence of anemia in ND-CKD stage 3–5 patients in Catalonia was 58.5%.16 In general, as the disease progressed, mean hemoglobin levels decreased and ESA use was increased. However, there was no change in the prescription of Iron according to stage. In this study, more than half of the patients were able to correct their anemia with iron supplementation combined with moderate doses of ESA. In the MERENA multicenter observational study of patients with ND-CKD stages 3 and 4, 43.7% and 58.1%, respectively, were anemic,14 of which 16% and 34.1% of the patients received ESA treatment, respectively. Guerrero et al.17 conducted a prospective study in a center in Huesca in 288 patients over 90 years of age, obtaining a prevalence of anemia of 35.7% in stages 3a-5. The results regarding the prevalence of anemia in CKD patients in our study were consistent with previous studies in Spain, although its prevalence was somewhat lower. In this context, it is important to highlight the population base of our study. At international level, this prevalence was higher than that found in the population-based study by Stauffer and Fan,21 based on data from the National Health and Nutrition Examination Survey (NHANES) of the United States, and it was similar to that recently published using the Swedish registry of renal patients.22 Overall, prevalence increased with CKD stage in ND-CKD patients, as shown in previous studies. Anemia was more prevalent among men than women, consistent with previous studies. The demographic data of the RIKAS study population is also consistent with previous analyses. In addition, the most common comorbidities were hypertension, dyslipidemia, diabetes mellitus, and cardiovascular disease.

Regarding data on the incidence of renal anemia in Spain, the single study in the literature is the NADIR study, which evaluated the incidence of anemia in patients with ND-CKD stage 3 in a prospective analysis over 3 years.13,15 During the first year of the study, up to 12.4% of subjects were diagnosed with anemia. Over the 3 year follow-up, half of the patients progressed to stages 4–5, and about 35% were diagnosed with anemia (mostly of renal origin). A significant association was found between the development of anemia and baseline hemoglobin levels, eGFR, and the sex of the patients. In addition, the development of anemia was associated with a more rapid progression of the disease and a higher risk of having a major cardiovascular event. This incidence was slightly higher than the one found in our study for that subgroup of patients (∼7 to 10%). However, our study analyzed the incidence of anemia and ESA treatment in all groups of ND-CKD (3a-5) and D-CKD, and it is a population-based study and not of patients followed in nephrology outpatient clinics. Up to ∼8% and ∼61% of the ND-CKD and D-CKD population initiated ESA treatment during the study period.

An interesting finding of the present study was that anemic patients with ND-CKD had a higher prevalence of inflammation than those without anemia (∼18% vs. ∼10%). Among them, ESA-treated patients were the cohort with the highest prevalence of inflammation (∼29%). Although this could be due, in part, to a worse renal function in anemic patients (treated or not with ESA), as the prevalence of anemia and ESA treatment increased with more advanced stages of the disease. In addition, in the subgroup of patients with D-CKD, all subgroups showed a high prevalence of inflammation (approximately 50%). These values are lower than the reported in the Swedish study on ND-CKD subgroup, but similar to the D-CKD group.22 Inflammation has been associated with a hyporesponsiveness to ESA and the consequent need for higher doses of ESA.22,23

Regarding treatment, the KDIGO guidelines recommend iron supplementation if the TSAT is < 30% and serum ferritin < 500 ng/mL.24 However, the European Renal Best Practice (ERBP) guideline recommends supplementation if there is absolute iron deficiency (TSAT < 20% and ferritin < 100 ng/mL in ND-CKD).25 There is also a recommendation to start iron treatment if there is a desire to increase Hb levels without ESA and ferritin levels are < 200 μ g/l (ferritin < 300 μ g/l if patient is in dialysis) and TSAT < 25% or reduce ESA doses if ferritin < 300 μ g/l and TSAT < 30%.26,27 In our study the mean ferritin and TSAT values were lower than recommended in the guidelines, suggesting an underutilization of iron therapy in this anemic population with CKD in both non-dialysis and dialysis. Consequently, there is an opportunity for improvement to optimize the management of renal anemia.

In order to treat anemia, iron was given to 74.7% of anemic patients with ND-CKD (69.4% oral and 5.2% intravenous) and 81.9% of anemic patients with D-CKD (13% oral and 68.9% intravenous) and 33.8% of anemic patients with ND-CKD and 88.9% of anemic patients with D-CKD received ESA. It should be noted that it is not known whether the patients could have received intravenous iron for causes other than renal anemia, such as heart failure. Nevertheless, the data collected was the use of intravenous iron in patients with anemia associated with CKD, so it seems reasonable that it was used mainly for the correction of anemia. As in previous studies, patients with ND-CKD mostly received oral iron, as advised by the ERBP or National Institute for Health and Care Excellence (NICE) guidelines.25,28 However, there is no data available on dose or compliance, but analyzing the mean ferritin and TSAT levels achieved, patients would probably benefit from a greater use of intravenous Iron, despite its greater use in stages 4 and 5. Iron therapy was similarly across all stages of ND-CKD, in line with what was observed in previous studies.16,22 Several clinical studies and a meta-analysis in patients with ND-CKD have shown that intravenous Iron is safe, and more effective and faster than oral iron in achieving the increase Hb levels and the reduction of ESA doses.29 In dialysis patients, especially on HD, most received intravenous iron, as advised by guidelines.

ESA use increased with the severity of the disease, as did the requirement for higher doses, as shown in Fig. 1. The ERI was lower in ND-CKD patients, and tended to increase with the disease severity, being higher in hemodialysis patients (Table 5). These data is similar to the obtained in the Swedish study by Evans et al.22

Hemoglobin variability is common in this population, especially in those treated with ESA, and in some, but not all studies, it has been associated with worse quality of life, increase in hospitalizations, morbidities and mortality.3 In the present study, a minority of anemic patients with CKD successfully maintained target Hb levels in the 10−12 g/dl range during the follow-up. Among the different subgroups, HD patients had the highest rates of variability, a fact that coincides with a Spanish retrospective study in dialysis patients.30

On the other hand, the need for transfusions was relatively high in our study (especially in D-CKD), despite the fact that the guidelines recommend a restrictive use of transfusions.24 Although the reasons are unknown, presumably the patients could have received transfusions for reasons other than anemia associated with CKD. In this regard, a higher rate of hospitalizations was observed according to the severity of renal dysfunction and was higher in patients on dialysis. In general, the more acute events requiring hospitalization, the higher the risk of transfusions. In this context, it should be remembered that transfusions should be avoided due to the intrinsic risks, especially in patients who are candidates for renal transplantation.

The absence of randomization is an intrinsic limitation of the design, as it produces a selection bias in observational studies, and also allows to describe associations but we cannot infer acausal relationship. In addition, treatment was assessed on the basis of prescriptions, with no information available about adherence. Patients could be participating in a clinical trial and, therefore, the treatment pattern would not be a true reflection of normal patterns, although it is not expected to significantly influence the results. In addition, the database from the different geographic areas of Spain are not distinguishable. The number of transfusions was high in ND-CKD stage 5 and D-CKD patients; however, the database does not capture the reasons for transfusions, which might not be directly related to CKD.

Among the strengths of the study is the large sample used, which is representative of the Spanish population. In addition, currently, data have been used to calculate prevalence and incidence, in a scenario in which previous publications did not capture the reality of the pathology. Another relevant point is that it has been analyzed the anemia associated with ND-CKD (3a-5) and D-CKD instead of focusing on a single subgroup of patients, thus providing a global view of the disease and its progression. Also, It is important to add that our study adds the treatments that patients are following, which allows us to analyze the real clinical practice in Spain.

The RIKAS study provides a recent epidemiological assessment of anemia in ND-CKD (stages 3a-5) and D-CKD (HD, PD) in Spain during 2015−2017. The prevalence of anemia and that of inflammation vary according to the disease severity. Finally, although anemic patients receive oral or intravenous iron therapy, associated or not with ESA, in the long term these treatments are insufficient to achieve the optimal values of iron parameters recommended by the guidelines. Consequently, there is a broad room for improvement in optimizing treatment in patients with anemia associated with CKD.

This study was approved by the Ethics Committee of the Consorci Sanitari de Terrassa.

This study was sponsored by Astellas Pharma Inc. Medical writing support was provided by Sonia Romero Perez, PhD, of Meisys-Mediación Científica S.L., funded by Astellas Pharma S.A. Permission for this acknowledgement was obtained and has been included in the final version of the manuscript.

Aleix Cases reports receiving a grant, consulting and speaking fees from Vifor Pharma, speaking and consulting fees from Astellas, AstraZeneca and Novo Nordisk; consulting fees from GSK and Otsuka and speaking fees from Amgen and Bayer. Elena González de Antona Sánchez and Giovanna Cadeddu are employees of Astellas Pharma S.A. Maria Mata Lorenzo is an employee of Astellas Pharma Europe Ltd.