**3. Risk factors**

#### **3.1 ESA therapy**

Requirement of ESA for the treatment of anaemia in CKD is a major risk factor for haemoglobin variability. In a study involving 6,165 non-dialysis CKD patients, only 47% of patients who were not treated with any ESAs demonstrated fluctuations in haemoglobin (Boudville et al., 2009). However, 73% of patients who were already treated with ESAs experienced haemoglobin variability. This prevalence further increased to 77% among individuals who were commenced on ESAs as a new therapy. Patients treated with ESA therapy for a longer duration were less likely to have haemoglobin variability. Each 3-mo increment in the duration of ESA therapy decreased the risk of haemoglobin variability by 6%. In a study involving 5,037 ESKD patients on haemodialysis, the risk of developing haemoglobin variability was more than twice in patients on ESAs, compared to those not on ESAs (Eckardt et al., 2010). These findings suggest that the *need* of ESA rather than ESA therapy *per se* leads to haemoglobin variability (See Table 1).

There is increased interest in studying the effect of various anaemia management protocols on haemoglobin variability. Patel and colleagues studied the effect of route of administration of erythropoietin on haemoglobin variability in a post hoc analysis of a randomised controlled trial involving 157 prevalent ESKD patients on dialysis (Patel et. al., 2009). Over a follow up of 24-weeks, compared to patients treated with intravenous erythropoietin, those treated with subcutaneous erythropoietin were more likely to have (i)

2. Intra-individual standard deviation of 3-month haemoglobin rolling average (Lacson et.

3. Using 3 haemoglobin groups (above/below/within the target) for each of the 6 consecutive monthly haemoglobin values, classification of all patients into 6 groups: (i) consistently low, (ii) consistently high, (iii) consistently within the target range, (iv) low amplitude fluctuation with low haemoglobin values (all-6 mo with low or target-range haemoglobin values), (v) low amplitude fluctuation with high haemoglobin values (all-6 mo with high or target-range haemoglobin values), and (vi) high amplitude fluctuation with high haemoglobin values (low, high and target-range haemoglobin

5. Determining velocity (or deflection) of haemoglobin change by averaging slopes

6. Change in haemoglobin in 6-mo above and below the reference range (based on the

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;

Requirement of ESA for the treatment of anaemia in CKD is a major risk factor for haemoglobin variability. In a study involving 6,165 non-dialysis CKD patients, only 47% of patients who were not treated with any ESAs demonstrated fluctuations in haemoglobin (Boudville et al., 2009). However, 73% of patients who were already treated with ESAs experienced haemoglobin variability. This prevalence further increased to 77% among individuals who were commenced on ESAs as a new therapy. Patients treated with ESA therapy for a longer duration were less likely to have haemoglobin variability. Each 3-mo increment in the duration of ESA therapy decreased the risk of haemoglobin variability by 6%. In a study involving 5,037 ESKD patients on haemodialysis, the risk of developing haemoglobin variability was more than twice in patients on ESAs, compared to those not on ESAs (Eckardt et al., 2010). These findings suggest that the *need* of ESA rather than ESA

There is increased interest in studying the effect of various anaemia management protocols on haemoglobin variability. Patel and colleagues studied the effect of route of administration of erythropoietin on haemoglobin variability in a post hoc analysis of a randomised controlled trial involving 157 prevalent ESKD patients on dialysis (Patel et. al., 2009). Over a follow up of 24-weeks, compared to patients treated with intravenous erythropoietin, those treated with subcutaneous erythropoietin were more likely to have (i)

values within 6-mo period) (Ebben et. al., 2006). 4. Time-in-target haemoglobin range (De Nicola et. al., 2007).

Eckardt et. al., 2010; Gilbertson et. al., 2009).

therapy *per se* leads to haemoglobin variability (See Table 1).

between successive haemoglobin values (Lau et. al., 2010).

median change in haemoglobin in 6-mo) (Regidor et. al., 2006).

al., 2003).

**2.2 Prevalence** 

**3. Risk factors 3.1 ESA therapy** 


Table 1. List of possible factors affecting haemoglobin variability

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

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

Association Between Haemoglobin Variability

haemoglobin (Lau et al., 2010).

**3.3 Facility-level factors** 

generalised to an individual patient.

and Clinical Outcomes in Chronic Kidney Disease 33

catheter use and haemoglobin variability; and a negative association with high baseline

Weinhandl and colleagues studied the risk factors for haemoglobin variability in Medicare haemodialysis patients (Weinhandl et. al., 2011). The study cohort included 3 groups of haemodialysis patients: historical prevalent (prevalent on July 1, 1996; n=78,602), contemporary prevalent (prevalent on July 1, 2006; n= 133,246), and incident (January 1, 2005 - June 30, 2006; n=24,999). In both the prevalent groups, the presence of all comorbid conditions, except hepatic disease, was associated with greater haemoglobin variability. These conditions included atherosclerotic heart disease, congestive heart failure, arrhythmia and other cardiac diseases, cerebrovascular disease, peripheral vascular disease, cancer, chronic obstructive pulmonary disease, diabetes and gastrointestinal bleeding. In the incident group, the presence of cerebrovascular disease, peripheral vascular disease, chronic obstructive pulmonary disease, diabetes and gastrointestinal bleeding were associated with haemoglobin variability. In all 3 groups, cumulative hospital days and number of months with haemoglobin <10 g/dL were positively associated with haemoglobin variability. Similar findings have been reported by Gilbertson and colleagues (Gilbertson et al., 2009).

Pisoni and colleagues studied facility-level risk factors for haemoglobin variability in 26,510 haemoglobin patients from 930 facilities in 12 countries using the DOPPS data (Pisoni et al., 2011). Haemoglobin variability was not associated with the number of haemodialysis patients per facility. However, larger differences in mean facility-level haemoglobin standard deviation were seen between countries. The mean age was nearly 2 years younger in the highest quartile of facility-level haemoglobin standard deviation than the lowest quartile. The investigators found that BMI, neutrophil count, and prevalence of psychiatric disorders and hepatitis C were higher in facilities with higher facility-level haemoglobin standard deviation. They also observed a positive association between haemoglobin variability and increased proportion of patients in a facility with parathyroid hormone level >450 pg/mL. Furthermore, the investigators reported a strong correlation (*r* =0.56) between facility-level haemoglobin standard deviation and within-patient haemoglobin standard deviation. These findings suggest that the results of this facility-level study could be

An emerging body of evidence suggests that haemoglobin variability is associated with increased risk of all-cause death in both non-dialysis CKD and ESKD patients. Boudville and colleagues found an association between haemoglobin variability and death not only in non-dialysis CKD patients treated with ESAs (n=1,823), but also in those who were not on ESAs (n=3,143) (Boudville et al., 2009). For each 1 g/L increase in the residual standard deviation, HR (95%CI) for patients on ESA throughout the study and those who were not receiving ESA were 1.02 (1.01 to 1.04) and 1.03 (1.02 to 1.05), respectively. The analysis of the pooled data from these 2 groups showed similar results. Compared to patients with haemoglobin levels consistently within the target range, those with low amplitude fluctuation with low haemoglobin values (HR 1.62, 95%CI 1.36 to 1.94) and high amplitude fluctuation (HR 1.57, 95%CI 1.24 to 1.98) were at increased risk of all-cause mortality.

**4. Association between haemoglobin variability and mortality** 

anaemia management practices and facility-level haemoglobin standard deviations (Pisoni et. al., 2011). This study identified factors that decreased haemoglobin variability which include reviewing ESA dose at least twice a week and checking haemoglobin levels on a weekly basis. There was also less haemoglobin variability in facilities with a greater percentage of patients prescribed an ESA likely related to better anaemia management with the introduction of an ESA and fewer patients outside the target haemoglobin concentration. The factors that were more likely associated with haemoglobin variability were: facilities with a wider target haemoglobin range, higher upper target haemoglobin, and ESA administration by subcutaneous route (compared to intravenous route).
