Anemia is a common complication of chronic kidney disease (CKD), that is associated with a reduced quality of life (QoL)1 and is a risk factor for morbidity and mortality. Thus, erythropoiesis-stimulating agents (ESAs) are considered as a key therapy in the management of CKD-related anemia,2-4 considerably reducing the need of blood transfusions and improving the QoL of these patients, among other beneficial effects.

The use of ESAs aiming to normalize hemoglobin (Hb) levels (≥13 g/dL), as opposed to the partial correction of anemia (9.0-11.0 g/dL) has been associated with minor improvements in QoL (mainly fatigue),3 but with an increased risk of cardiovascular complications. In this regard, contrary to initial observational studies that suggested positive outcomes associated with higher achieved Hb levels,5,6 subsequent large multicentre randomized controlled trials (RCTs) and related meta-analyses7-10 have demonstrated an association between allocation to higher Hb levels (which is also associated with higher ESA doses) and an increased risk of cardiovascular complications without a benefit on mortality.

Treatment of anemia with ESAs in CKD patients has thus experienced a significant shift from using Hb levels as a surrogate end-point, to a more individualized ESA therapy that takes into consideration Hb targets, required ESA doses, and patients’ comorbidities, as well as a recent recommendation of administering the lowest possible ESA dose required to achieve the target Hb levels.11,12 After the publication of the Trial to Reduce Cardiovascular Events with Aranesp® Therapy (TREAT study),8 the Anemia Working Group of the European Renal Best Practice (ERBP) recommended to maintain Hb levels between 11-12 g/dL, without intentionally exceeding 13 g/dL.13 In this statement, caution was advised when considering Hb targets in diabetic patients, especially those with cardiovascular disease, and in patients with cancer; as well as to consider the dose of ESA required. The Anemia Group of the Spanish Society of Nephrology (S.E.N.) pointed out that ultimately Hb targets should be individualized, taking into account patients’ comorbidities, maximum doses of ESAs and Hb correction speed, as factors to redefine Hb targets.14 Finally, a recent position statement of the ERBP on the management of CKD-related anemia in Europe 12 called for special caution for patients with specific risk factors such as diabetes, cerebrovascular disease or cancer, in which it is advised to target to lower Hb levels (10 g/dL) during ESA therapy.

In view of the current statements on anemia management in CKD patients treated with ESA, it is of paramount relevance to analyze the impact of the experts’ recommendations in routine clinical practice. The main objective of our study was to evaluate whether there has been a change in the perception and attitude of nephrologists in the anemia management with ESAs in anemic CKD patients not on dialysis since the recommendations of the Anemia Working Group of ERBP in 2010 were issued.13

The results of the ACERCA study provide an overview of the clinical practice management of anemia with ESA in CKD patients not on dialysis in Spain following the recommendations of the Anemia Working Group of the ERBP in 2010. In recent years, anemia guidelines have been changing according to the new evidences from the results of randomized controlled trials, Accordingly, Hb targets during ESA therapy have been moving towards more conservative goals and to its individualization, according to the patients’ characteristics.

Our results show that less than 50% of naïve or converted patients maintained Hb levels within the range of 11-12 g/dL and reflect the difficulties associated with achieving and maintaining such a narrow target range in routine clinical practice also in CKD patients not on dialysis.16-18 This aspect has also been confirmed in a recent study which evaluated the percentage of patients who achieved the 2007 European Medicine Agency (EMA) target range (10-12 g/dL), showing that merely one in two patients had an Hb level within this recommended Hb target.19

Around one third of patients, both naïve and converted, had Hb levels below 11 g/dL at the study visit despite being stable on ESA therapy. On the other hand, among naïve patients, 12.8% started ESA treatment with Hb levels above 11 g/dL, while around one forth of patients had Hb levels >12 g/dL, and a small but significant proportion of the overall population (n=35, 8.1%) had Hb >13 g/dL at the study visit. These results call for the need to improve anemia management both increasing the percentage of patients within the target range and avoiding high Hb levels and the potential risks associated. The impact of targeting for higher Hb levels, particularly among CKD patients not on dialysis, has been recently evaluated in a systematic review of 24 RCTs including over 10,000 patients.20 CKD patients treated with ESAs allocated to the high Hb group (13 g/dL) had an increased risk of hypertension, hospitalization and stroke, as compared with patients allocated to the low Hb target (10 g/dL). In addition, a significantly higher risk of mortality (RR 1.18; 95% CI 1.02-1.37) was also observed in the high Hb group. Although the decision of when to start ESA therapy and Hb targets during this treatment in CKD patients remain controversial issues and are continuously revised,12,21 the results of randomized controlled trials and the position statement of the ERBP of 2010 at the time of the study provided enough information for nephrologists to reevaluate, and change accordingly, practice patterns in anemia management in these patients. In this regard, our results indicate that ESA treatment in the clinical setting in Spanish nephrology units seems to be mainly aimed at preventing Hb levels to fall below 11 g/dL.

The ACERCA study also evaluated whether Hb targets under ESA therapy in CKD patients were individualized, considering the presence of some frequent comorbidities, such as diabetes, cardiovascular or cerebrovascular disease, or cancer, as prompted by the ERBP statement. It was thus surprising that in our study, mean Hb levels were similar (or with clinically minimal differences) in CKD patients not on dialysis, independent of the presence or absence of significant comorbidities, suggesting that there might still be some reluctance to individualize Hb targets in patients with signif icant co-morbidities in the clinical practice setting. Otherwise, we cannot rule out that our study did not capture a delayed or a slow but progressive evolution in the perception and attitude of nephrologists towards anemia management, since the study was performed only 6 months after the appearance of the position statement of the ERBP of 2010 and before the publication of the KDIGO recommendations.21

Another relevant result of our study was the finding that in naïve patients, target Hb levels were achieved requiring a monthly dose of C.E.R.A. (1.0μg/kg), which is lower than the recommended in the Summary of Product Characteristics (SPC) (1.2μg/kg). Similarly, in patients converted from other ESA, the switch to C.E.R.A. required lower doses than those recommended in the SPC to maintain Hb levels. Indeed, our data suggest that the C.E.R.A. doses required to achieve or maintain target Hb levels in CKD patients not on dialysis in Spain in clinical practice are relatively low, which is in agreement with two recent cost-minimization analyses conducted in Spanish hospitals22,23 where C.E.R.A. doses required to achieve target Hb levels in non-dialysis CKD patients were also found to be lower than those recommended by the SPC. Relatively low doses of C.E.R.A. were also required in nondialysis CKD patients shifted from darbepoetin alfa in an Italian study,24 and similar results of a beneficial dose conversion for C.E.R.A. has been also found in the MICENAS II study in CKD patients nor on dialysis in Spain.25 These findings of a dose-saving effect observed with the use of longacting ESA, such as C.E.R.A., may have not only economic, but also clinical implications.2,22 In this regard, it must be emphasized that current guidelines indicate that the patient should be prescribed the lowest possible ESA dose to achieve the target Hb.11,26 This is especially relevant in ESA-resistant patients since a recent consensus pointed out that poorly ESAresponsive patients is one of the main challenges in anemia management in CKD.27 These patients, who usually receive higher ESA doses, have a poorer prognosis.11,17,28 Thus, the use of long-acting ESA agents, such as C.E.R.A., is an attractive alternative that may improve safety and cost-effectiveness in this specific subset of patients.

Mean ferritin and TSAT levels were above the minimum targets set by guidelines. In our study, 89.8% of naïve patients and 84.8% of converted patients received iron supplementation. In most patients the oral, as opposed to the intravenous route, was by far the preferred route of iron administration, despite that some studies have shown a higher efficacy of intravenous iron as compared to oral iron in these patients,29-31 the well-established poor gastrointestinal tolerance to oral iron, as well as the reduced intestinal iron absorption in CKD patients,32 that could constrain the efficacy of oral iron supplements and limit the repletion of iron stores. On the other hand, the lack of studies evaluating the longterm safety of intravenous iron, the need to preserve the venous tree for a future vascular accesses, the risk of enhanced oxidative stress, the potential risks of accelerated atherosclerosis, or risk of infections associated with IV iron, together with the need to be administered in the hospital setting, may be barriers to a more liberal use of intravenous iron. The achievement of target levels of ferritin and TSAT might have contributed to the relatively low ESA doses required in our study by allowing an optimization of erythropoiesis, since patients with low TSAT and ferritin levels require higher ESA doses to achieve target Hb levels.22,33

The present study has several limitations including the potential biases inherent to all observational studies. Additionally, our study did not reached the expected sample size, which might have underpowered the statistical analyses conducted. Furthermore, Hb targets have been more recently reevaluated in several guidelines, thus these results may not reflect the current anemia treatment in CKD, but it alerts against a therapeutic inertia, making the results interesting. Finally, in our study the main ESA prescribed was C.E.R.A, both in naïve and in patients that were shifted from another ESA. Although the Nephrology Units involved were selected solely for their interest in participating in the study, and not for the type of ESA prescribed, we cannot extrapolate that the rate of prescription of C.E.R.A in CKD patients not on dialysis at the time of the study in Nephrology Units in Spain was similar

In conclusion, the results of the ACERCA study indicate that anemia management in Spanish nephrology units is mainly aimed at preventing Hb levels below 11 g/dL in the clinical setting. The fact that less than 50% of patients had Hb levels within the recommended target range of 11-12 g/dL, confirms the difficulty to achieve and maintain such a narrow target range also in non-dialysis CKD patients treated with ESA, as recommended by clinical practice guidelines in the real setting, as well as the reluctance to individualize Hb targets according to patients’ comorbidities. In any case, our study shows that there is still room for improving anemia management in ESA-treated CKD patients not on dialysis, particularly regarding patients with a higher risk to develop ESA-related complications.

Ildefonso Varela (Hospital Clínico Virgen de la Victoria, Málaga, Spain); Fernando Vallejo (Hospital Puerto Real, Cádiz, Spain); M Sol García de Vinuesa (Hospital Gregorio Marañón, Madrid, Spain); Carmen Bernis (Hospital La Princesa, Madrid, Spain); Manuel Arias (Hospital Marqués de Valdecilla, Santander, Spain); Antonio Pelegrí (Hospital Universitari Sagrat Cor, Barcelona, Spain); Carmen Vázquez (Complexo Hospitalario Univesitario de Santiago, Santiago de Compostela, Spain); Marisila Molina (Hospital Son Llatzer, Mallorca, Spain); Alba Herreros (Fundació Puigvert, Barcelona); Alfonso Otero (Complexo Hospitalario Universitario de Ourense, Ourense, Spain); M Luisa Méndez (Hospital Universitario Virgen de la Candelaria, Santa Cruz de Tenerife, Spain); José A Herrero (Hospital Clínico San Carlos, Madrid, Spain); Javier Usón (Hospital General Virgen de la Luz, Cuenca, Spain); Joan Fort (Hospital Vall d¿Hebrón, Barcelona, Spain); Xavier Fulladosa (Hospital de Bellvitge, Barcelona, Spain); Enrique Morales (Hospital Universitario 12 de Octubre, Madrid, Spain); Julio Hernández (Hospital La Fe, Valencia, Spain); José R Pons (Hospital General de Castellón, Castellón, Spain); Eduardo Hernández (Hospital Universitario 12 de Octubre, Madrid, Spain); José L Górriz (Hospital Univesitario Dr. Peset; Valencia, Spain).

The ACERCA study was sponsored by the Spanish Society of Nephrology (S.E.N.) with an unrestricted grant from Roche Pharma Spain. AMC declare that has received research support from Amgen, Abbott, Boehringer-Ingelheim and Roche, as well as honoraria for participating in advisory boards from Abbvie, Amgen, Boehringer-Ingelheim, Esteve, Janssen-Cilag, Novartis and Roche. AC has received research support from Amgen and Roche. He has received honoraria for participating in advisory boards from Roche, Amgen, Pfizer, Novartis, Abbott, Astra-Zeneca and received speaker fees from Roche, Amgen, Johnson and Johnson, Bristol Myers Squibb, Novartis, Pfizer, Almirall, Esteve, Astra-Zeneca, Siemens. Others authors declare that they have no competing interests.