Refractory Anaemia

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Elements of MICS and subsequent cachexia may blunt the responsiveness of anaemia to recombinant human erythropoietin (EPO) in CKD patients. Refractory anaemia appears to be more common in those dialysis patients who suffer from protein-energy malnutrition and/or inflammation [68, 118, 119]. Several previous studies

Table 4.Reverse epidemiology of cardiovascular (CV) risk factors in dialysis patients: the effect of CV risk factors in maintenance dialysis patients is the opposite of the general population. (Data from [123])

Risk factors of cardio- Direction of the associations between risk factors and outcomes vascular disease General population Maintenance dialysis patients

BMI High BMI and obesity are generally High BMI, or weight for height, and moderate deleterious. obesity are protective. Underweight is deleterious

Serum cholesterol

Hypercholesterolemia, high LDL and low HDL are deleterious.

Hypercholesterolemia (and maybe high LDL) is protective. Low serum cholesterol is deleterious

Serum creatinine

Total plasma homocysteine

Serum iron

Hypertension and even borderline high BP are deleterious.

A mild to moderate increase in serum creatinine is an independent risk factor of CVD.

A high level is a risk factor for increased CVD in the general population and likely in dialysis patients

A high serum iron level is associated with haemochromatosis and poor outcome.

Pre-dialysis low BP may indicate a deleterious state

An increased pre-dialysis serum creatinine level is associated with a better survival

Several recent studies have found that a low level is associated with increased risk of cardiovascular disease and mortality

A low iron and transferrin saturation level has been recently found to be associated with higher mortality and hospitalisation in dialysis patients

AGEs

Energy (calorie) and/or protein intake

Patients with higher AGE levels, such as diabetic patients, have a poor outcome.

A high energy and food intake may be associated with risk of obesity and increased mortality.

A recent report indicates a paradoxically reverse association between lower AGE levels and higher mortality in dialysis patients

Increased protein intake is associated with better survival

CVD, cardiovascular disease; MD, maintenance dialysis; LDL, low-density lipoprotein; HDL, high-density lipoprotein; BMI, body mass index; BP, blood pressure; AGEs, advanced glycation end-products report an association between anaemia and inflammation, such as occurs in dialysis patients, which is reflected by a high serum concentration of CRP [118, 120] or of pro-inflammatory cytokines such as IL-6 and TNF-a [121, 122]. We recently reported that serum IL-6 levels had the strongest correlation with administered EPO dose in 339 haemodialysis patients, and that the association remained statistically significant in different statistical analyses and after multivariate adjustments [124]. Both serum CRP and TNF-a showed similar trends and their associations with EPO dose remained significant in some but not all analysis modalities conducted in that study [124].

An inverse association was reported between markers of nutritional status or inflammation, e.g. serum prealbumin, TIBC, and total cholesterol concentration, and blood lymphocyte count, and the EPO dose [124]. Such associations are less well-described than the association between EPO dose and inflammation. Improving nutritional status in CKD patients may improve anaemia and lead to a lower required EPO dose. A cross-sectional study of 59 dialysis patients showed that the required EPO dose was higher in the poorly nourished patients as per SGA scoring [68]. In a meta-analysis by Hurot et al., L-carnitine administration, which is used to improve nutritional state, was associated with improved haemoglobin and a decreased EPO dose and EPO resistance in

J GFR^ J clearance of inflammatory cytokines

Oxidative stress, carbonyl stress

J GFR^ J clearance of inflammatory cytokines

Oxidative stress, carbonyl stress

Fig. 3. The causes and consequences of malnutrition-inflammation complex syndrome (MICS). Modified from [123] BMI,body mass index; DM, diabetes mellitus; GFR, glomerular filtration rate; EPO, erythropoietin

anaemic dialysis patients [125]. Moreover, anabolic steroids have also been used successfully to simultaneously improve both nutritional status and anaemia in dialysis patients [126]. Insulinlike growth factor (IGF)-1 is reported to enhance bone marrow progenitor cell proliferation in uraemic mice [127]. Hence, CKD-associated anaemia may represent both an EPO and a functional IGF-1 deficient state [127].

It is still not completely clear how MICS is related to CKD-associated refractory anaemia pathophysiological^. It has long been known that anaemia is frequently observed in patients suffering from chronic inflammatory disorders even with a normal kidney function [128]. Several mechanisms for cytokine-induced anaemia have been proposed, including impaired iron metabolism, suppression of endogenous EPO production, and reduced erythropoiesis [129,130]. Serum ferritin, a measure of iron stores and a positive acute-phase reactant, has been shown to be paradoxically high in ESRD patients with refractory anaemia [131, 132]. Increased ferritin production may prevent iron delivery to erythrocyte precursors [131]. Moreover, the uptake of iron from the intestine is reduced in inflammatory states [129]. Patients with inflammatory diseases have inappropriately low levels of blood endogenous erythropoietin [133]. IL-1 and TNF-a have been shown to inhibit endogenous erythropoietin production in vitro [134]. Furthermore, increased release or activation of inflammatory cytokines, such as IL-6 or TNF-a, has been shown to have a suppressive effect on ery-thropoiesis [135]. IL-6 and IL-1 have been found to antagonise EPO's ability to stimulate bone marrow proliferation in culture [136]. Finally, patients with inflammation may be more prone to gastrointestinal bleeding [129,130].

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