**6. Clinical outcomes**

Hyporesposiveness to ESA therapy has been found to be associated with higher mortality in several trials [51]. This was shown by one observational study of dialysis patients with Hb levels less than 9.5 gm/dl during larger ESA dose changes over 11 months period. The increased mortality has been in the initial period of therapy as shown by Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) study [52].

Both the underlying cause of ESA hyporesponsiveness and the ESA dose itself contributes to increased mortality, with the former having more importance [53]. ESA hyporesponsiveness has been associated with the development of insulin resistance [54]. Impaired response to ESA therapy can contribute through an unknown mechanism to more rapid progression to end-stage renal disease. This was suggested through a study of 194 consecutive CKD patients on ESA therapy between 2002 and 2006 [55].
