**2. Definitions**

#### **2.1 Hyporesponsiveness vs. resistance**

The term hyporesponsiveness looks preferable to the term resistance for its more accuracy as a reduced response to ESA therapy is relative in most cases. So, the word hyporesponsiveness describes the use of higher than usual ESA doses without reaching Hb target levels OR the need for incremental ESA doses to keep target Hb levels [9].

According to KDIGO 2012 guidelines, ESA hyporesponsiveness denotes no increase in Hb following 1 month of weight-based dosing (initial type) and/or the need for two increments in ESA dose up to 50% more than the previous dose for achieving stable Hb levels(subsequent type) [10].

According to European Best Practice guidelines (2004), the maximum dose of EPO is 300 units/kg/week and 1.2 mcg/kg/week for darbepoetin alfa [11].

The ideal Hb level for hemodialysis patients is not well-defined. An accepted practice is to have maintenance of Hb target level between 10 and 11.5 gm/dL. This goes in harmony with KDIGO 2012 guidelines.

#### **2.2 ESA resistance index (ERI)**

It is a mathematical representation of the complex relationship between the targeted Hb level and the required ESA dose. It is calculated as the ratio between the average weekly ESA dose/kg body weight and Hb (g/dl) level. Elevated ERI is suggested as a possible clue for modifiable causative factors underlying ESA hyporesponsiveness [12].
