3.3 Effect of erythropoiesis- stimulating agents and iron

3.3.3 Chronic kidney disease

Evidence Statements for Chronic kidney disease (erythropoiesis-stimulating agents)
Evidence Statements – chronic kidney disease (erythropoiesis-stimulating agents)
ES3.19	In anaemic patients with CKD, the effect of ESA therapy to a Hb target of 100 – 110 g/L on mortality is uncertain compared with no ESA therapy.		NA
ES3.20	In anaemic patients with non dialysis- dependent CKD, type 2 diabetes and a history of malignant condition at baseline, ESAs increase the incidence of mortality attributable to cancer.	NA
ES3.21	In anaemic patients with CKD, ESA therapy to a Hb target of 100 – 110 g/L reduces RBC transfusion incidence compared with no ESA therapy.
ES3.22	In anaemic patients with CKD, targeting a Hb concentration above 130 g/L with ESA therapy increases the incidence of stroke and other thromboembolic events. The effect of targeting lower Hb concentrations is uncertain.
ES3.23	In anaemic patients with CKD, ESA therapy to a Hb target of 100 – 110 g/L does not appear to affect the incidence of MI.
ES3.24	In nondiabetic dialysis patients, compared to no treatment, ESA therapy targeted to a Hb 95 g/L may reduce fatigue and improve physical functioning.
ES3.25	In anaemic patients with non dialysis- dependent CKD, ESA therapy to a Hb target of 100 – 110 g/L may reduce fatigue, but has little impact on physical functioning.

Evidence Statements for Chronic kidney disease (iron therapy)
Evidence Statements – chronic kidney disease (iron therapy)
ES3.26	In anaemic patients with CKD receiving ESAs, the effect of IV iron on mortality is uncertain.			NA
ES3.27	In anaemic patients with CKD on dialysis and receiving ESAs, IV iron may reduce the need for an anaemia intervention.^a	X	NA
ES3.28	In anaemic patients with non dialysis- dependent CKD, the effect of IV iron on RBC transfusion requirement is uncertain.	X	NA	X
ES3.29	In anaemic patients with non dialysis- dependent CKD, IV iron therapy may improve functional or performance status compared to oral iron therapy.			X

CKD, chronic kidney disease; ES, evidence statement; ESA, erythropoiesis-stimulating agent; Hb, haemoglobin; IV, intravenous; MI, myocardial infarction; RBC, red blood cell

=A; =B; =C; X=D; NA,not applicable (see Table 2.1)

^a Anaemia intervention was defined as either an increase in ESA dose, non-protocol IV iron or RBC transfusion, resulting in non-completion of study.

Recommendation – chronic kidney disease
R4 Grade B	In anaemic patients with CKD, ESA therapy to a low to intermediate Hb target may be used to avoid RBC transfusion, after consideration of risks and benefits for the individual patient (Grade B). Note: The CARI guidelines recommend a Hb target between 100-115 g/L⁵
R5 Grade C	In anaemic patients with CKD, ESA therapy to a low to intermediate Hb target may be used to relieve fatigue, after consideration of risks and benefits for the individual patient (Grade C). Note: The CARI guidelines recommend a Hb target between 100-115 g/L⁵
R6 Grade B	In anaemic patients with CKD, ESA therapy to a Hb target of over 130 g/L is not recommended because of increased morbidity.
R7 Grade B	In anaemic patients with non dialysis-dependent CKD, type 2 diabetes and a history of malignancy, the routine use of ESAs is not recommended because of the increased risk of cancer-related mortality.

Practice Points – chronic kidney disease
PP13	ESA use is less effective in patients with chronic renal failure who have absolute or functional iron deficiency.
PP14	For comprehensive information about ESA and iron therapy in patients with CKD, refer to CARI iron guidelines.⁵

CARI, Caring for Australasians with Renal Impairment; CKD, chronic kidney disease; ESA, erythropoiesis-stimulating agent; Hb, haemoglobin; PP, practice point; R, recommendation; RBC, red blood cell

Erythropoiesis-stimulating agents – chronic kidney disease

The literature review identified four systematic reviews (Level I) of the use of ESAs for anaemic patients with CKD.^106-109 Only reviews that compared ESAs with no ESA treatment were eligible for inclusion. Therefore, Strippoli et al, which compared Hb targets, rather than treatment with no treatment, was excluded.110 Similarly, when discussing the results from Tonelli et al, only the studies defined by the review as comparing ESA with no ESA, rather than comparing high with intermediate or low target Hb protocols, were eligible for inclusion.¹⁰⁷

A significantly lower incidence of cardiovascular mortality, but not overall mortality, has been identified in patients with CKD treated with ESAs.¹⁰⁷ Increased mortality in ESA-treated CKD patients with a history of malignancy has been reported.¹¹¹ In addition, a significant increase in MI, stroke and other thromboembolic events has been found in diabetic patients with CKD.¹¹²

The incidence of RBC transfusion in patients with non dialysis-dependent CKD¹⁰⁸ and patients on haemodialysis¹⁰⁷ is reduced with ESAs, and the quality of life in dialysed patients is improved with ESAs.^113,114 Although non dialysis-dependent CKD patients with diabetes had an improved score on the FACT-fatigue test, there were no significant differences in energy and functioning scores and severity of cardiac failure in those who received ESAs.^111,112,115

These findings suggest that ESAs can be used to reduce the incidence of RBC transfusion in patients with non dialysis-dependent CKD and in CKD dialysis patients. ESA use can also result in an improved quality of life in dialysed and non dialysis-dependent CKD patients with diabetes. However, in view of the increased risk of MI, stroke and other thromboembolic events in some patients, ESAs should be used with caution in this population. The United States Food and Drug Administration has highlighted an increased risk for patients with a target Hb of >110 g/L. An appropriate target Hb for ESA therapy has not been defined in patients with CKD, but caution is recommended in patients with a Hb >100 g/L.

Intravenous iron – chronic kidney disease

The literature review identified one systematic review (Level I)¹¹⁶ and five RCTs (Level II) of the use of IV iron for anaemic patients with CKD.

The systematic review¹¹⁶ compared the use of IV versus oral iron in anaemic patients with CKD (stages III to V). This review included studies assessing iron therapy in patients with non dialysis-dependent CKD and CKD dialysis patients, with or without ESA treatment.

Two RCTs reported mortality as an outcome, but found no significant difference, including after meta-analysis.^117,118 No studies reported transfusion incidence. Two RCTs reported the proportion of patients requiring an anaemia intervention (i.e. increase in ESA dose, initiation of non-protocol IV iron or RBC transfusion).^119,120 One of these RCTs found no significant difference in the need for an anaemia intervention with IV iron (compared to oral iron);¹¹⁹ however, the other RCT found a significant difference with IV iron compared with no iron.¹²⁰

Meta-analysis of the data from the two studies of patients who required an anaemia intervention did not show a significant difference in the mortality rates of CKD patients treated with IV iron, or with oral or no iron therapy.^119,120

None of the included studies reported the incidence of thromboemoblic events.

Two of the included RCTs^119,121 reported on functional or performance status. One of these studies¹²¹ showed an improvement. Patients treated with IV iron experienced significantly greater improvements in two measures of quality of life (Symptoms and Effects of CKD on Kidney Disease Quality of Life Questionnaire: KDQoL) than patients treated with oral iron.