Frequency of ESA Dose Adjustment: A Novel, Independent Predictor of Survival in HD Patients

Research Article

Austin J Nephrol Hypertens. 2015; 2(5): 1049.

Frequency of ESA Dose Adjustment: A Novel, Independent Predictor of Survival in HD Patients

Amidone M¹*, Dattolo PC¹, Lenti C², Betti G³, Conti P4, Panichi V5, Mannarino A6, Rosati A7 and Pizzarelli F¹

¹Department of Nephrology Units, SM Annunziata Hospital, Italy

²Department of Nephrology Units, Degli Infermi Hospital, Italy

³Department of Nephrology Units, Massa Hospital, Italy

4Department of Nephrology Units, Misericordia Hospital, Italy

5Department of Nephrology Units, Versilia Hospital, Italy

6Department of Nephrology Units, S Giovanni di Dio Hospital, Italy

7Department of Nephrology Units, Campo di Marte Hospital, Italy

*Corresponding author: Marco Amidone, Department of Nephrology Units, SM Annunziata Hospital, 58, Antella Street, Florence, Italy

Received: September 09, 2015; Accepted: November 10, 2015; Published: November 12, 2015


Background: While hazards linked to high dosages of Erythropoietin Stimulating Agents (ESA) are extensively studied, the potential harm of ESA prescription modality is uncertain.

Methods: Dosing patterns of ESA and anemia related parameters were collected monthly during 2008 calendar year and all-cause mortality was assessed in the following year in prevalent in-centre Hemodialysis (HD) patients from 7 Nephrology Units in Tuscany, Italy.

Results: During the observation year, monthly Hemoglobin (Hb) levels and weekly ESA dose were 11.40±0.70 gr/dl and 8425±5128 IU, respectively, in the 366 subjects recruited. The higher the ESA dose the lower the Hb values (r - .38, p <0.0001). During the 1-year follow-up 13% of patients died. In comparison with those who eventually died, survivors had significantly higher ESA changes (p .03) and comparable Hb values and ESA dosages. According to Kaplan- Meier subjects with 6 or more ESA changes had significantly better survival (Log Rank 4.94, p .025) than those with less than 6 ESA changes. In a Cox model adjusted for demography, number of co-morbidities and biochemistry covariates, frequency of ESA dose change was highly and independently associated with better survival [HR for mortality 0,79 (95% CI 0,67 - 0,94), p .01].

Conclusion: Frequency of ESA dose changes is a novel independent predictor of survival among HD patients.

Keywords: Anemia; Erythropoietin; Hemodialysis; Survival


There is evidence that high Hemoglobin (Hb) levels are associated with an increased mortality risk both in CKD as well as in hemodialysis (HD) patients [1-5]. Among the hypotheses for the explanation of increased risk linked to higher Hb targets, the potential role of Erythropoietin Stimulating Agents (ESA) dosages has been suggested [6-9]. Noteworthy, this untoward ESA effect counter stands against the finding that higher Hb concentration naturally occurring by endogenous erythropoietin does not increase mortality among HD patients [10]. Following the early 2000s observations on Hematocrit [11] and Hb [12] serum fluctuations (Hbvar) in HD patients, a number of studies have pointed to Hbvar as additional risk factor for adverse clinical outcomes including mortality [13-17]. However the association has been confuted by others [18] and it has been suggested Hbvar possibly represents just a surrogate of disease severity [19]. Anemia treatment in HD subjects is based on periodic measurements of serum Hb over time with subsequent adjustments of ESA dosages. Very few studies, to the best of our knowledge, have specifically evaluated the clinical relevance of ESA prescription modality [20]. Hence, the independent association between ESA dosing patterns and survival remains to be determined.

With this background, we aimed at evaluating whether dosing patterns of ESA are independent predictors of all-cause mortality among HD patients. Specifically we probed survival prediction of frequency of ESA dose adjustments as possible marker of good clinical practice.

Materials and Methods

Study design

This is a multicentre 2 year retrospective observational cohort study. Time-varying anemia related parameters were collected during 2008 calendar year and all-cause mortality was assessed in the subsequent year.

Following a preceding clinical audit on anemia management [21], seven HD Centers in Tuscany Region of Italy took part in this study. Although no formal protocol was implemented, all Centers shared the practice of monthly control of serum Hb values and, accordingly, promptly adjust ESA dosages with the following targets: serum Hb values 10.5-12 g/dl and amplitude of ESA dose change around 30% of the previous ESA prescription. ESA changes were performed taking into account both punctual Hb values as well as serum Hb trends.


We enrolled prevalent adult (>18y) uremic on in-centre HD treatment alive on 31.12.2008. Subjects had to have at least 9 of the 12 scheduled Hb values and at least 9 documented ESA dosages throughout 2008 calendar year. Moreover, they should have been on HD and ESA treatment at least since June 2007, e.g. 6 months before 2008 observation year, to avoid Hb and ESA variability linked to HD initiation and resulting ESA titration.

Data collection

Demographic, co-morbidities, clinical and biochemical covariates were collected from subject clinical notes and assessed at the study entry. Pre-existent co-morbidities were categorized as cardiovascular (including, cardiac, cerebral and peripheral vascular involvement), pulmonary, hepatic and tumoral (solid and hematopoietic, including myeloma); diabetes, inflammation and/or malnutrition were also recorded. Biochemical covariate data missing at baseline were imputed as the more recent registered for that subject in the following 3 months.

Frequency of ESA dose changes (ESAc) was the count in each subject of every monthly registered ESA dosage different from the previous one. Amplitude of ESA dose adjustment (ESAvar) was defined as intra-patients’ standard deviation of all the values collected in the observation year.

Intra-patient standard deviation of Hb values registered was assumed as a proxy of Hbvar. Time-varying average ESA dosages (ESAx) were expressed in IU administered weekly. ESA molecules were Darbepoetin α (Darbe) or Epoietin α or β (EPO) and no shift among molecules was allowed. To compare Darbe with EPO, the correction factor 1 μg: 200 IU was adopted, as indicated by manufacturer. According to prescription, at the end of HD sessions nurses injected intravenous Darbe 2 or 4 times per month or EPO 1 - 3 times a week.


Data were handled according to the Declaration of Helsinki and the Italian legislation (Guarantee privacy law 6 August 2008, n. 133 and subsequent amendments), and statistically analyzed by SPSS package. Data are reported as mean±Standard Deviation (SD) or median and Interquartile Range [IQR]. Univariate estimates of the associations between time varying anemia related parameters were explored by simple linear regression by calculating the Pearson product moment correlation coefficient. Comparisons between dead and alive subjects at the end of follow up were made by ANOVA. Survival discriminating power of ESAc was assessed by log rank statistics for Kaplan-Meier survival curves. Impact of time-varying Hb and ESA related parameters on all-cause mortality as outcome parameter was evaluated by Cox proportional hazards regression modeling adjusted for a case-mix covariate including baseline demography, co morbidity and biochemistry.


We analyze the 366 subjects fulfilling the selection criteria. Covariate data missing at baseline were less than 4% for each given variable, but CRP 10%. The overwhelming majority of the cohort, e.g. 350 out of 366 subjects, had 100% of longitudinal repeated anemia related parameters with the remaining 16 subjects with 10 or 11 scheduled measures.

Baseline characteristics of the cohort are shown in table 1. This is a typical Italian HD population, elderly, with relevant co-morbidities, fairly well nourished and Fe replenished, with only 25% of subjects with iPTH levels above 330 pg/ml. On average, Hb values were within targets. Fifty-six subjects, e.g. 15%, were on Darbe.