**5. Management of haemoglobin variability**

Since the introduction of ESAs, most of the clinical trials with ESA therapy have focused on haemoglobin targets in CKD patients. There is a shortage of clinical trials studying the optimal strategy for haemoglobin monitoring in patients treated with ESAs and interventions to reduce haemoglobin variability.

Association Between Haemoglobin Variability

patients have been very limited.

of comorbid conditions.

insufficiently researched field.

**8. Acknowledgment** 

to declare.

**9. References** 

**7. Summary** 

and Clinical Outcomes in Chronic Kidney Disease 37

Future studies should be designed carefully and conducted prospectively to define the exact magnitude of the effect of haemoglobin variability on mortality. They should also include a greater breadth and depth of the CKD patient populations since dialysis studies have not included patients receiving peritoneal dialysis and studies involving non-dialysis CKD

Most of the current data is merely hypothesis generating. Therefore, well designed and adequately powered randomised controlled trials are needed to determine the optimal frequency of haemoglobin monitoring along with a cost-effective analysis. Further trials are required to define the optimal strategy of frequency and magnitude of ESA and iron dose changes, and study their possible interactions with concurrent acute illness and the presence

Haemoglobin variability is highly prevalent in both non-dialysis and dialysis CKD patients. The factors contributing to haemoglobin variability are not entirely clear. However, the currently available evidence has identified the following factors: younger age, female gender, low body mass index, the presence of comorbid conditions, and the use of ESA and less frequent monitoring of haemoglobin. There is conflicting evidence on the effect of haemoglobin variability on mortality with some studies demonstrating a strong association and others showing no association with mortality. A few small prospective observational studies have found that frequent monitoring of haemoglobin may reduce short-term haemoglobin variability, although the optimal frequency of haemoglobin monitoring is yet to be defined. Evidence-based treatment strategies cannot be currently recommended due to a lack of high quality data. In conclusion, maintaining haemoglobin within a target range continues to pose a challenge to clinicians. Further research is urgently needed in this

Professor David Johnson is a recipient of consultancy fees, research grants, travel sponsorships and speakers' honoraria from Amgen, Roche and Janssen-Cilag. He is a recipient of consultancy fees from Sandoz and is a co-investigator on industry-sponsored research by Amgen, Roche and Janssen-Cilag. He is currently supported by a Queensland Government Health Research Fellowship. Other authors do not have any conflicts of interest

Badve, S. V., Hawley, C. M. , & Johnson, D. W. (2011). Is the problem with the vehicle or the

Besarab, A., Bolton, W. K., Browne, J. K., Egrie, J. C., Nissenson, A. R., Okamoto, D. M.,

in CKD? *Nephrology (Carlton),* Vol.16, No.2, pp. 144-153

destination? Does high-dose ESA or high haemoglobin contribute to poor outcomes

Schwab, S. J. , & Goodkin, D. A. (1998). The effects of normal as compared with low

Ho and colleagues conducted an observational case-control study of unselected ESKD patients on haemodialysis (Ho et. al., 2010). Patients served as their own control. They compared 2x/month laboratory haemoglobin measurements and use of a computerised algorithm to analyse 12x/month monitoring of Crit-line haemoglobin measurements. They found that haemoglobin variability, measured by the mean standard deviation of the residuals, significantly improved during the phase of frequent haemoglobin monitoring. However, this was not a randomised controlled trial. Also, the sample size was small and it was an unblinded study in a single-centre. Nonetheless, the study highlights the importance of frequent monitoring of haemoglobin as it may provide an opportunity to titrate the ESA dose early.

Gaweda and colleagues conducted a case-controlled observational study in which 49 ESKD patients on haemodialysis were included (Gaweda et. al., 2010). The investigators measured haemoglobin using Crit-line at various intervals: twice weekly or 8x/mo, once weekly or 4x/mo, every 2 weeks or 2x/mo and every 4 weeks or 1x/mo. They also calculated the haemoglobin estimation error as a root mean-squared difference between the observed and estimated haemoglobin and compared it with the measurement error. They found that the most accurate haemoglobin estimation was achieved with twice weekly haemoglobin sampling, although it exceeded the accuracy of the measurement device. Twice and once weekly haemoglobin measurements were found to be optimal in 31% and 45% patients, respectively. This was also a single-centre study with a small sample size.

These two studies highlight the paucity of evidence in the area of management of haemoglobin variability. Considering the cost and possible amount of blood loss associated with frequent hemoglobin monitoring, currently available evidence is not sufficient to make any clinical practice recommendations.
