Interventions for anaemia in dialysis patients who are resistant to erythropoietin

Many people with chronic kidney disease (CKD) who are on dialysis develop anaemia (too few or poor quality red blood cells). Drugs in the erythropoiesis-stimulating family increase the production of red blood cells to resolve anaemia. Although ESAs have been highly beneficial for many, about 10% of people get either low or no benefit from treatment. Inability to control and stabilise anaemia can lead to poor rates of survival and increased risk of stroke so it is important to find effective treatment to manage anaemia in people who do not respond adequately to ESA therapy.

We searched the literature to find evidence about how best to treat people who do not benefit from ESA treatment. We found two studies: one that assessed intravenous vitamin C and another that looked at high-flux dialyser fluids as possible therapies. These studies were small (total of 90 participants) and were selective: they included haemodialysis, but not peritoneal dialysis, patients. This meant that the results of these studies could not be applied to all people with CKD on dialysis who were receiving ESA therapy. The lack of evidence meant that we could not determine or recommend an alternate treatment for people who do not respond to ESA.

More powerful and rigorous studies are needed to systematically assess all therapies that are aimed to treat people who do not respond to ESA therapy. Until such evidence is available, no therapy can be confidently recommended for this problem.

Authors' conclusions: 

There was inadequate evidence identified to inform recommendation of any intervention to ameliorate ESA hyporesponsiveness. Adequately powered RCTs are required to establish the safety and efficacy of interventions to improve responsiveness to ESA therapy.

Read the full abstract...

People living with end-stage kidney disease (ESKD) often develop anaemia. Erythropoiesis-simulating agents (ESAs) are often given to people living with ESKD to maintain haemoglobin at a level to minimise need for transfusion. However, about 5% to 10% of patients with ESKD exhibit resistance to ESAs, and observational studies have shown that patients requiring high doses of ESA are at increased risk of mortality.


This review aimed to study the effects of interventions for the treatment of ESA-resistant anaemia in people with ESKD.

Search strategy: 

We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE for randomised controlled trials (RCT) that involved participants with ESKD on dialysis or who were pre-dialysis patients with chronic kidney disease (stage 5). Date of last search: April 2013.

Selection criteria: 

ESA resistance was defined as failure to achieve or maintain haemoglobin/haematocrit levels within the desired target range despite appropriate ESA doses (erythropoietin ≥ 450 U/kg/wk intravenously or ≥ 300 U/kg/wk subcutaneously; darbepoetin ≥ 1.5 µg/kg/wk) in people who were not nutritionally deficient, or who had haematological or bleeding disorders. Extended inclusion criteria for ESA hyporesponsive state were: erythropoietin dose ≥ 300 U/kg/wk and ≥ 150 U/kg/wk for intravenous administration; or ≥ 200 U/kg/wk and ≥ 100 U/kg/wk for subcutaneous administration; or darbepoetin dose ≥ 1.0 µg/kg/wk).

Data collection and analysis: 

Two authors independently assessed study quality and extracted data. Statistical analyses were performed using a random effects model and results expressed as risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CI).

Main results: 

Titles and abstracts of 521 records were screened, of which we reviewed 99 from the full text. Only two studies matched our inclusion criteria. One study compared intravenous vitamin C versus no study medication for six months in 42 ESKD patients on haemodialysis who required intravenous erythropoietin (dose ≥ 450 U/kg/wk). The other included study compared high-flux dialyser versus low-flux dialyser for six months in 48 haemodialysis patients who required subcutaneous erythropoietin (dose ≥ 200 U/kg/wk). Because interventions differed, data could not be combined for quantitative meta-analysis.