**2.1 Definition**

The definition of haemoglobin variability is not entirely clear and various studies have used different definitions. Intra-individual haemoglobin variability is defined as the fluctuation of haemoglobin above or below (Kalantar-Zadeh & Aronoff 2009) *or* even within the target range over time. Methods to quantify haemoglobin variability are summarised below.

1. Standard deviation of the differences between observed haemoglobin values and haemoglobin slope which represents the mean haemoglobin change over time (Yang et. al., 2007).

Association Between Haemoglobin Variability

Iron supplementation

**Patient-level factors** 

Comorbid conditions

Body mass index

Age Gender

**Factors related to ESA therapy**  Route of administration Long *versus* short acting ESA

Responsiveness to the first dose of ESA Haemoglobin before initiation of ESA

Frequency of the ESA dose adjustments Magnitude of the ESA dose adjustments

Incident *versus* prevalent dialysis

Number and duration of hospitalisation

Proportion of patients prescribed ESAs Frequency of haemoglobin monitoring Frequency of ESA dose monitoring Wider range of target haemoglobin Higher upper target range of haemoglobin Table 1. List of possible factors affecting haemoglobin variability

associated with the length of time-in-target haemoglobin.

Use of catheter as haemodialysis vascular access **Facility-level anaemia management protocols** 

and Clinical Outcomes in Chronic Kidney Disease 31

haemoglobin concentrations outside the target range for more weeks (13.9 ± 4.7 weeks versus 12.5 ± 5 weeks, p=0.04) and (ii) higher standard deviation of haemoglobin (0.84 ± 0.35 versus 0.74 ± 0.27, p=0.01). Interestingly, in one report, the risk of developing haemoglobin variability was greater with long-acting ESAs (Boudville et al., 2009). De Nicola and colleagues did not find any association between long-acting ESAs versus erythropoietin and haemoglobin variability (De Nicola et al., 2007). However, they observed that baseline haemoglobin level, first dose of ESA and initial iron supplementation were directly

Depending on the 6-group classification based on the highest and lowest categories of haemoglobin, Gilbertson and colleagues reported that patients in the low-intermediate group received high doses of erythropoietin and more blood transfusions (Gilbertson et al., 2009). Minutolo and colleagues found that haemoglobin variability was associated with responsiveness to the first dose of erythropoietin (Minutolo et al., 2009). They also observed that a change of erythropoietin dosage occurred less frequently than expected in spite of regular follow up visits. Therefore, they concluded that lack of adjustment of erythropoietin dosage can lead to haemoglobin variability. However, their data on the effect of frequency and magnitude of adjustment of erythropoietin dosage on haemoglobin stabilisation is less clear. In a post hoc analysis of a randomised controlled trial involving 154 ESKD patients on haemodialysis, more frequent adjustments of erythropoietin dosage as well as larger changes of erythropoietin dosage were associated with haemoglobin variability (Lau et al., 2010).

Using data from the Dialysis Outcomes and Practice Patterns Study (DOPPS) involving 26,510 patients, Pisoni and colleagues studied the associations between facility-level


#### **2.2 Prevalence**

Haemoglobin variability is common not only in patients with end-stage kidney disease (ESKD) on dialysis, but also in CKD patients who are not yet on dialysis (non-dialysis CKD). The reported prevalence of haemoglobin variability in non-dialysis CKD patients varies between 61 to 86% (Boudville et. al., 2009; Minutolo et. al., 2009). On the other hand, 82 to 90% of ESKD patients on dialysis exhibit haemoglobin variability (Ebben et al., 2006; Eckardt et. al., 2010; Gilbertson et. al., 2009).
