What do we learn about the “ Anemia Module ” of the French language Peritoneal Dialysis ? Interest and Results

Contexte : l’anémie est fréquente chez les patients insuffisants rénaux chroniques (IRC), dès que le débit de filtration glomérulaire devient inférieur à 30 ml/min. Les patients atteints d’IRC ont fréquemment un déficit en fer. C’est la raison pour laquelle une réserve en fer adaptée est essentielle pour atteindre le bénéfice thérapeutique optimal des agents stimulant l’érythropoïèse (ASE). De nombreux groupes s’accordent à considérer que l’anémie des patients en dialyse péritonéale (DP) est moins importante que celle des sujets en hémodialyse (HD) et que les pratiques thérapeutiques pour la prise en charge de l’anémie diffèrent fortement entre DP et HD. Méthodes : analyse du module Anémie du registre RDPLF au cours de la période 2010-2017. Résultats : 568 patients ayant participé au module Anémie au cours de la période de suivi 2010-2017, ont été analysées. L’âge médian est de 71 ans, avec 42% de femmes, et la médiane de l’ancienneté en DP est de 13 mois, 40,5% sont diabétiques, 74% sont sous ASE, 23% sous fer oral et seulement 11% reçoivent du fer injectable. Sur le plan du bilan biologique, on constate qu’en moyenne le taux d’hémoglobine est proche de 12 g/dl et la médiane de la protéine C-réactive (CRP) est de 5 mg/l. Sur le plan du bilan martial, la ferritine après avoir atteint un taux moyen de 270 μg/l en 2013, s’est stabilisée à 200 μg/l en 2017. La saturation de la transferrine a toujours oscillé entre 23% et 25% de 2010 à 2017. Conclusion: les résultats du module Anémie apparaissent en accord avec les valeurs cibles des recommandations européennes de l’ERA-EDTA (ERBP 2013) et mettent en évidence une faible utilisation de fer intraveineux en DP (en seconde intention). Le Bulletin de la Dialyse à Domicile


INTRODUCTION
The development of erythropoiesis-stimulating agents (ESA) has resulted in benefits for patients with chronic kidney disease (CKD) including: significant improvement in quality of life, reduced blood transfusions and HLA sensitization, decreased left ventricular mass, a decrease in sleep disorders, and an increase in physical capacity [1,2]. Unfortunately, a considerable proportion of patients treated with ESA have a suboptimal hematologic response. A European survey on the management of dialysis anemia in 2003 showed that 66% of patients had a hemoglobin level of 11 g / dl or more, and only 48% had a suitable martial status defined by ferritin greater than 100 μg / ml, transferrin saturation greater than 20% or hypochromic red blood cells less than 10% [3]. These results suggested that adequate iron supplementation is required to provide patients with an appropriate hematologic response to ESAs. However, recent publications warn against excessive prescription of intravenous (IV) iron as sometimes practiced in France and Europe and more often in the United States [4][5][6]. These practices have led the National Agency of Safety of Medicines and Health Products (ANSM) to the publication of a newsletter for the attention of prescribers [7] and epidemiologists in the group Dialysis Outcomes and Practice Patterns Study (DOPPS) recently showed that there was a relationship between very high doses of IV iron (greater than 300 mg / month) and mortality in HD [8]. This excessive use of injectable iron in hemodialysis may also lead to hepatic iron overload, which has been demonstrated by the quantitative magnetic resonance imaging (MRI) method from 2011 onwards as shown in various publications both in France and abroad [9][10][11].
We present here exclusively the data of management and therapeutic practices of the Anemia module (Metropolitan France) from 2010 to 2017 among 568 patients treated with PD.

METHODS
We analyzed raw data from the French-language Peritoneal Dialysis Registry (RDPLF) from the Anemia module comprising 568 patients reported from 2010 to 2017. One of the hypotheses of this work was that martial supplementation practices differed significantly between HD and DP.

Data collection
Data on anemia were recorded in the database from 2005; analysis of anemia treatment prior to this date was performed on the main module, which was more exhaustive but less detailed and therefore sometimes on slightly different patient populations and centers. A total of 9,467 anemia assessments were performed in 358 patients in 17 centers in mainland France. On the one hand, we report the results of the Anemia module in 568 patients managed with PD during the period 2010-2017, during which time the therapeutic strategies evolved and / or the raw data of the Anemia module have been completed. On the other hand, we analyzed in detail the data of anemia management during the year 2017 where only the last examination was taken into account for each patient and we only retained the files for which we had full confirmation regarding the iron and ESA treatments.

Statistical analysis
Statistical analyzes of the RDPLF Anemia module data included a descriptive analysis of the different variables and the comparison of the different variables over the years by parametric or non-parametric analysis of variance for the quantitative variables.

° Analysis of the demographic data and therapeutic modalities of 568 patients from 2010-2017 in RDPLF Anemia module.
The demographic data are presented in Table I  Biomarker data are presented in Table II as a whole.
These rates do not differ significantly in the Kruskal-Wallis non-parametric variance analysis test (Table III).

Evolution of ferritin and rate of transferrin saturation
Data on ferritin and transferrin saturation are presented globally by year in Figure 2.       (Table III).

Therapeutic modalities
In 194 patients undergoing martial treatment, intravenous iron doses range from 50 mg to 1000 mg / month (64 patients) and oral iron doses from 33 mg to 1056 mg / month (130 patients) depending on the products used.

° Detailed analysis of the management of anemia during the year 2017
The overall hemoglobin distribution of PD patients in 2017 (293 patients in 28 centers) is shown in Figure 3. Patients without and under ESA were included. This figure shows that 16% of patients have a hemoglobin level greater than 13 g / dl.
The distribution of the hemoglobin level of the PD patients only treated with ESA in 2017 is given in Figure  4.
It is noted that 11.9% of patients have a hemoglobin level greater than 13 g / dl.
Treatment data for iron anemia and ESA in 293 patients are listed in Figure 5.
This shows that 33.1% of patients on PD receive neither ESAs nor iron. The rate of administration of ESAs according to the product used is given in Figure 6.   It is observed that in 83.7% of patients on Epoetin-betapegol, the frequency was one injection every 5 weeks.

DISCUSSION
Patients with chronic kidney disease frequently have iron deficiency, which is why an adequate stock is essential for maximum benefit of ESAs. Decreasing iron stores or decreasing iron availability are the most wellknown reasons for resistance to ESAs [12]. However, several authors agree that the consumption of iron is less important in PD than in HD, and this for several reasons [13,14]. It is noted that blood losses differ between PD and HD [15]. Loss of iron in PD is much less important than in HD. By contrast, HD digestive losses are much higher following anticoagulation with heparin or low molecular weight heparins (LMWH) of extracorporeal circuits (Table V).
This contrast between HD and PD partly explains the more frequent use of iron and ESAs in HD, especially since true iron deficiency cannot be compensated by a sufficient absorption of iron in the gastrointestinal tract ( related to iron chelation by various drugs and hyperhepcidinemia observed in terminal IRC) [16]. We also note that the recommendations of good practices (KDIGO 2012, ERBP 2013) [17,18] strongly differ between HD and PD. Indeed, is used almost constantly in first line in HD whereas it is an option in PD and IV iron doses are less important in PD than in HD. Prior to the ESAs era, secondary dialysis hemosiderosis was well known by nephrologists, linked, inter alia, to transfusions. However, studies conducted in the 1980s prior to the discovery of ESAs showed on autopsy data that there was a clear link between tissue iron overload, multiple transfusions, and IV iron infusions [19]. The Canavese study in 2004 [20] in 40 hemodialysis patients analyzed by the susceptometry method (SQUID) showed that 32% of patients had mild overload and 37% had severe overload. Rostoker (7): 531-542) [15] with significant overload in quantitative MRI was, however, within the targets recommended by nephrology societies. There was a correlation between hepatic iron overload and the cumulative dose and the monthly dose of iron administered. However, no study was concerned with the assessment of iron overload on PD. Due to the very different therapeutic modalities between HD and PD, PD represents a true model for martial metabolism study in the terminal renal chronic disease, almost independently of the IV iron administration which is rarely used. The results of a recently published study on the hepatic martial stock, carried out in France in 32 patients treated by PD, show that the martial stock of the body appears most often normal in patients on PD [22]. In fact, quantitative liver MRI revealed in this study a normal iron stock in 81.3% of PD patients, compared to 16% in a first cohort of French patients on HD and 35% in a second cohort of HD patients. The mirror appearance of hepatic iron concentrations thus clearly appears between DP and HD. These data suggest that the ferritin targets proposed by the PD standards are quasi-physiological (ferritin> 100 μg / ml) and supraphysiological in HD (ferritin target between 250 and 500 μg / ml).

CONCLUSION
The data analysis of the Anemia module of the RDPLF registry makes it possible to evaluate the possible differences in practice with respect to the 2013 ERBP reference. Our study shows that the French nephrology teams most often have results within the proposed targets by the European standard for both hemoglobin and martial status. This work also confirms the interest of this module in approaching the reality of the management of anemia as well as its potential for future epidemiological studies for the evaluation of new stabilizing therapies of hypoxia-inducible factor (HIF). -Stabilizers), subject to the completeness of the transmission of information by the teams practicing PD. However, given the number of patients and centers, the figures presented should be interpreted with caution. Nevertheless, they represent the practices of the centers most concerned by this aspect of the management of PD patients.

DISCLOSURE
The authors declare that they have no conflict of interest for this articl