**4. Etiology**

Causes of anemia of ESA hyporesponsiveness are broadly related to three main categories: namely iron deficiency, inflammatory conditions, and bone marrow suppression. A summary of these causes is shown in **Table 1**.

#### **4.1 Iron deficiency**

It is considered the most common cause of ESA hyporesponsiveness [14]. Iron deficiency may be absolute or functional type, which is more common. The absolute type is characterized by severely deficient or lacking iron storage, mainly due to blood *Hyporesponsiveness to Erythropoietin-Stimulating Agents: Possible Solutions DOI: http://dx.doi.org/10.5772/intechopen.109988*


#### **Table 1.**

*Summary of causes of ESA hyporesponsiveness.*

loss. Usually, transferrin saturation (TSAT)% is less than or equal to 20% with serum ferritin less than 200 ng/mL.

The functional type has normal iron storage with diminished iron availability for erythropoiesis. It is associated with low TSAT % and normal/high ferritin levels. Functional iron deficiency is further divided into two subtypes: the first is related to ESA therapy itself, and the second is attributed to anemia of chronic disease.

Measurement of red blood cells Hb content could be better for the assessment of functional iron deficiency and possible response to iron therapy. This can be achieved through the measurement of hypochromic red blood cell (HRCs) percentage, threshold value more than 6%, and reticulocyte Hb content (CHr); threshold value less than 29 pg., according to NICE guidelines, 2016 [15].

The HRCs % and CHr are more widely used in Europe than in the United States. In cases with ESA-induced iron deficiency, the response can occur to IV iron administration and concurrent increase of ESA dose together with a resulting decrease of ferritin levels. Conversely, in patients with anemia of chronic disease, IV iron administration will not improve erythropoiesis and will be associated with a progressive increase in ferritin levels [16].

#### **4.2 Inflammation**

Chronic inflammatory status is common in hemodialysis patients and is considered a major cause of ESA hyporesponsiveness. Inhibition of production leads to hypoproliferative anemia of chronic disease. Bone marrow and impairment of EPO erythropoiesis renal patient-related specific underlying causes of chronic inflammation include dialysis catheter-related infection, infected or nonfunctioning arteriovenous graft, failed renal allograft, or uremic toxins. Other causes include malignancies, chronic infections, autoimmune disorders, or periodontal disease. Systemic inflammation affecting the immune system function can be a sequence of gut microbiota dysbiosis. IL-6 works in the opposite direction of EPO regarding its effect on bone

marrow proliferation. Serum levels of both IL-6 and TNF-alpha are directly related to ESA dose in hemodialysis patients [17–19].

#### **4.3 Inadequate dialysis**

Uremic toxins can cause ESA hyporesponsiveness through nonselective bone marrow suppression or through selective suppression of erythroid colony-forming units. Accumulation of quinolinic acid in renal failure leads to inhibition of EPO gene expression, possibly mediated by hypoxia-inducible factor (HIF)1 alfa. Other substances like indoxyl sulfate (IS) and indoxyl glucuronide can suppress transcriptional HIF-1 alfa activity leading to inappropriate EPO production. Dialysis dose should be monitored in malfunctioning dialysis catheters and in fistula with lower blood flow rates. The chronic inflammatory state can occur in hemodialysis patients due to lowlevel endotoxin and bacterial contamination of dialysis water. This was confirmed through the beneficial effect of using ultrapure water. Based on large randomized clinical trials, the use of high-flux and online treatments, though supposed better removal of large and middle molecules, was not associated with a significant effect on anemia and ESA requirements.

With high predialysis hematocrit values or slow blood flow of vascular access, red blood cell damage can occur due to shear stress and high pressure in dialyzer capillaries.

It was suggested that the use of mixed pre- and postdilution hemodiafiltration (HDF) might be preferred to postdilution HDF through avoidance of progressive hemoconcentration. However, this hypothesis needs further confirmation. There is no clear evidence supporting the beneficial effect of increasing dialysis frequency per se regarding ESA hyporesponsiveness [20–22].

Efforts to improve dialysis quality have led to the development of a novel class of dialysis membranes; called medium cut-off (MCO) with molecular weight cut-off (MWCO) close to MW of albumin and very high retention onset (HRO) [23]. Recently, these membranes are called HRO membranes. They are made of polyarylethersulfone/polyvinylpyrrolidone with a mean pore radius of 5 nm, in between high-flux and high cut-off (HCO) membranes. They are designed to enhance the clearance of molecules larger than B2-microglobulin with the ability of albumin retention. In addition, the internal diameters of the fibers are reduced to increase blood compartment resistance and enhance dialyzer internal filtration and back-filtration. The resulting convection is comparable to that of classical high flux membranes, with effective removal of middle and large molecules without fluid substitution. Using this novel class of dialyzers, HRO is called expanded hemodialysis (EHDx).

EHDx has improved response to ESA therapy in comparison with the use of a high-flux (HF) dialyzer. That effect was attributed to the superior removal of inflammatory cytokines with better iron metabolism in a hepcidin-independent mechanism. More middle-molecule uremic toxins clearance with more reduction of TNF-alfa was achieved with the use of MCO dialyzers than with HF dialyzers. Additionally, high-flux dialysis did not show superiority to low-flux dialysis in improving ESA hyporesponsiveness [24]. In a comprehensive systematic review and meta-analysis study, it was found that EHDx showed safety regarding albumin loss in dialysate and back-filtration of endotoxins. Moreover, EHDx proved effective clearance of middle and large uremic toxin molecules in comparison with high-flux hemodialysis and online HDF with potential anti-inflammatory activity as well [25, 26].
