**6. Future research**

There is substantial heterogeneity in the haematological response to ESAs. Although the factors underpinning ESA-hyporesponsiveness are well characterised, those contributing to haemoglobin variability are poorly understood. Future studies should include prospective and systematic data collection to evaluate these factors. Investigations should also be carried out to develop a single and uniformly accepted method to measure haemoglobin variability that is clinically relevant and reproducible, since there is no consensus on a single method for the measurement of haemoglobin variability.

The data on the effect of haemoglobin variability on mortality are conflicting. This could be due to several reasons. Firstly, most of the data originates from retrospective and observational studies. Secondly, the studies are arbitrarily limited to sampling during 6 month periods where monthly haemoglobin values for each month were available. This cross-sectional nature of the study does not reflect long-term fluctuations in haemoglobin values. Thirdly, due to highly selective nature of the study cohorts, sampling bias could be potentially introduced. Most of these studies had a very short follow up period ranging from 6 months to 18 months. Furthermore, different statistical models have demonstrated inconsistent and non-reproducible results due considerable between-study variation in the covariates included in the adjusted models. Therefore, the exact nature and quantification of the effect of haemoglobin variability on mortality is still poorly understood.

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 patients have been very limited.

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 of comorbid conditions.
